GenSight Biologics S.A.

Annual Report (ESEF) • Apr 29, 2022

GENSIGHT URD 2021_ANGLAIS iso4217:EURxbrli:shares iso4217:EUR xbrli:shares 549300NK4AB8OUEX1F54 2021-01-01 2021-12-31 ifrs-full:RetainedEarningsMember 549300NK4AB8OUEX1F54 2021-01-01 2021-12-31 ifrs-full:IssuedCapitalMember 549300NK4AB8OUEX1F54 2020-01-01 2020-12-31 gensight:RetainedEarningsProfiLlossForReportingPeriodMember 549300NK4AB8OUEX1F54 2019-12-31 gensight:RetainedEarningsExcludingProfitLossForReportingPeriodAndReserveOfExchangeDifferencesOnTranslationMember 549300NK4AB8OUEX1F54 2019-12-31 gensight:RetainedEarningsProfiLlossForReportingPeriodMember 549300NK4AB8OUEX1F54 2019-12-31 549300NK4AB8OUEX1F54 2020-01-01 2020-12-31 ifrs-full:IssuedCapitalMember 549300NK4AB8OUEX1F54 2021-12-31 gensight:RetainedEarningsProfiLlossForReportingPeriodMember 549300NK4AB8OUEX1F54 2020-12-31 ifrs-full:IssuedCapitalMember 549300NK4AB8OUEX1F54 2021-01-01 2021-12-31 ifrs-full:SharePremiumMember 549300NK4AB8OUEX1F54 2020-01-01 2020-12-31 gensight:RetainedEarningsExcludingProfitLossForReportingPeriodAndReserveOfExchangeDifferencesOnTranslationMember 549300NK4AB8OUEX1F54 2020-12-31 gensight:RetainedEarningsProfiLlossForReportingPeriodMember 549300NK4AB8OUEX1F54 2021-12-31 549300NK4AB8OUEX1F54 2020-12-31 549300NK4AB8OUEX1F54 2020-01-01 2020-12-31 549300NK4AB8OUEX1F54 2020-12-31 ifrs-full:RetainedEarningsMember 549300NK4AB8OUEX1F54 2019-12-31 ifrs-full:SharePremiumMember 549300NK4AB8OUEX1F54 2021-01-01 2021-12-31 549300NK4AB8OUEX1F54 2020-12-31 gensight:RetainedEarningsExcludingProfitLossForReportingPeriodAndReserveOfExchangeDifferencesOnTranslationMember 549300NK4AB8OUEX1F54 2020-01-01 2020-12-31 ifrs-full:SharePremiumMember 549300NK4AB8OUEX1F54 2021-12-31 ifrs-full:RetainedEarningsMember 549300NK4AB8OUEX1F54 2021-12-31 ifrs-full:SharePremiumMember 549300NK4AB8OUEX1F54 2020-12-31 ifrs-full:SharePremiumMember 549300NK4AB8OUEX1F54 2019-12-31 ifrs-full:IssuedCapitalMember 549300NK4AB8OUEX1F54 2021-12-31 ifrs-full:IssuedCapitalMember 549300NK4AB8OUEX1F54 2021-01-01 2021-12-31 gensight:RetainedEarningsProfiLlossForReportingPeriodMember 1 1. PERSON RESPONSIBLE, THIRD PARTY INFORMATION, EXPERTS’ REPORTS AND COMPETENT AUTHORITY APPROVAL 1.1 Identity of the person responsible 1.2 Declaration of the person responsible 1.3 Experts’ reports 1.4 Third party information 1.5 Competent authority approval 2 2. STATUTORY AUDITORS 2.1 Statutory auditors 2.2 Change in Statutory auditors 3 3. RISK FACTORS 3.1 Financial risks 3.2 Risks related to the discovery and development of and obtaining regulatory approval for our product candidates 3.3 Risks related to manufacturing and commercialization of our product candidates 3.4 Risks related to our business operations 3.5 Legal risks and risks related to our intellectual property 3.6 Insurance and risk management 3.7 Internal control and risk management procedures 4 4. INFORMATION ABOUT THE ISSUER 4.1 Legal and commercial name 4.2 Place of registration, registration number and legal entity identifier (“LEI”) 4.3 Date of incorporation, length of life of the issuer 4.4 Domicile, legal form, legislation, country of incorporation, address, telephone number and website 5 5. BUSINESS OVERVIEW 5.1 Overview 5.2 Our Product Development Pipeline 5.3 Important events in the development of the Company 5.4 Strategy and objectives 5.5 Research and development, patents and licenses 5.6 Competition 5.7 Investments 5.8 Manufacturing 5.9 Sales and marketing 6 6. ORGANIZATIONAL STRUCTURE 7 7. OPERATING AND FINANCIAL REVIEW 7.1 Overview 7.2 Financial Operations Overview 7.3 Results of operations 8 8. CAPITAL RESOURCES 8.1 Overview 8.2 Analysis of Cash Flow 8.3 Funding sources 8.4 Principal uses of cash 8.5 Information regarding the anticipated sources of funds needed 9 9. REGULATORY ENVIRONMENT 10 10. TREND INFORMATION 10.1 Most significant recent trends since the end of the last financial year 10.2 Information on any known trends, uncertainties, demands, commitments or events that are reasonably likely to have a material effect on the company’s prospects 11 11. PROFIT FORECAST OR ESTIMATES 12 12. ADMINISTRATIVE, MANAGEMENT AND SUPERVISORY BODIES AND SENIOR MANAGEMENT 12.1 Composition of management and supervisory bodies 12.2 Conflicts of interest 13 13. COMPENSATION AND BENEFITS 13.1 Compensation and benefits of Senior Executives and Directors 13.2 Directors’ Compensation 13.3 Share Warrants, Share Warrants for founders, stock options and free Shares Granted to Senior Executives and Directors 13.4 History of Allocation of Share Warrants, Share Warrants for Founders and Stock Options 13.5 Share Warrants, Share Warrants for Founders or Stock Options of the Company granted to the Company’s top ten employees 13.6 History of Allocation of Free Shares 13.7 Benefits of Senior Executives 13.8 Equity ratio between the level of compensation of the Chairman and Chief Executive Officer and the compensation average and median of the Company’s employees 13.9 Compliance of Total Executive Director Compensation with the Recommendations of Middlenext Code 13.10 Amount of Provisions Made or Recorded by the Company for the Payment of Pensions, Retirement Plans or Other Benefits 14 14. BOARD PRACTICES 14.1 Terms of Office of Members of the Corporate Bodies and Management Bodies 14.2 Information on Service Contracts between Members of the Administrative and Management Bodies and the Company 14.3 Committees of the Board of Directors 14.4 Statement Relating to Corporate Governance 14.5 Operating Principals of the Board of Directors 15 15. EMPLOYEES 15.1 Human Resources Management 15.2 Shareholdings and stock options 15.3 Employee arrangements 16 16. MAJOR SHAREHOLDERS 16.1 Allocation of share capital 16.2 Shareholders’ Voting Rights 16.3 Control structure 16.4 Agreement likely to a change of control 17 17. RELATED PARTY TRANSACTIONS 17.1 Agreements with the Company’s Major Shareholders 17.2 Transactions with Key Management Persons 17.3 Regulated Agreements 17.4 Statutory Auditors’ Special Report on regulated agreements 18 18. FINANCIAL INFORMATION CONCERNING THE GROUP’S ASSETS AND LIABILITIES, FINANCIAL POSITION AND PROFITS AND LOSSES 18.1 Historical Financial Information 18.2 Interim and Other Financial Information 18.3 Auditing of Historical Annual Financial Information 18.4 Proforma Financial Information 18.5 Dividend Policy 18.6 Legal and Arbitration Proceedings 18.7 Significant Change In Financial Position 19 19. ADDITIONAL INFORMATION 19.1 Share Capital 19.2 Constitutive Documents and Bylaws 20 20. MATERIAL CONTRACTS 20.1 Collaboration, Partnership and Related Agreements 20.2 In-License Agreements 20.3 Manufacturing Agreement 20.4 Customer Agreement 21 21. DOCUMENTS AVAILABLE 22 22. GLOSSARY 23 23. ANNEXES 2021 UNIVERSAL REGISTRATION DOCUMENT GenSight Biologics S.A. Corporation (société anonyme) with a share capital of €1,158,389.78 Registered Office: 74, rue du Faubourg Saint-Antoine 75012 Paris, France 751 164 757 Paris Trade and Companies Register 2021 UNIVERSAL REGISTRATION DOCUMENT This Universal Registration Document (URD) was filed on April 29, 2022 with the AMF (the French Financial Markets Regulator), as the competent authority under Regulation (EU) 2017/1129, without prior approval in accordance with Article 9 of the said Regulation. This Universal Registration Document may be used for the purpose of a public offer of securities or the admission of securities to trading on a regulated market if it supplemented by a securities note and, as the case may be, by a summary and all the amendments to the Universal Registration Document. These documents are together approved by the AMF in accordance with Regulation (EU) 2017/1129. A concordance table is provided in this Universal Registration Document in order to facilitate the retrieval of the information incorporated by reference and that which are updated or amended. Copies of this Universal Registration Document are available free of charge from GenSight (74, rue du Faubourg Saint-Antoine 75012 Paris, France) and on its website (https://www.gensight-biologics.com). CONCORDANCE TABLE The concordance table below makes it possible to identify in this Universal Registration Document: •the information which forms the annual financial report (article L.451-1-2 of the French Monetary and Financial Code and article 222-3 of the General Regulation of the AMF); and •the information which forms the Annual Management report (article L.225-100 et seq. of the French Commercial Code); •the information which forms the Corporate Governance report. Section(s) of the Document 1. CERTIFICATION OF THE PERSON ASSUMING RESPONSIBILITY FOR THE ANNUAL FINANCIAL REPORT Section 1.2 2. COMPANY’S ANNUAL FINANCIAL STATEMENTS – FRENCH STANDARDS (FRENCH-GAAP) Section 18.1.3 3. COMPANY’S ANNUAL CONSOLIDATED FINANCIAL STATEMENTS – INTERNATIONAL FINANCIAL REPORTING STANDARDS (IFRS) Section 18.1.1 4. MANAGEMENT REPORT 4.1. Information on the Company’s business •Presentation of the business (in particular progress achieved and difficulties encountered) and results of the Company Sections 5, 7, 8 and 18 •Analysis of business development, results and financial position and in particular debt of the Company and the Group Sections 18.1, 7 and 8 •Outlook of the Company and the Group Section 10 •Key financial and non-financial indicators of the Company and the Group Sections 18.1, 7 and 8 •Post-closing events of the Company and the Group Section 18.1 •Internal control and risk management procedures relating to the preparation and processing of the accounting and financial information of the Company and the Group Section 3.7 •Information on the use of financial instruments including financial risks and exposure to price, credit, liquidity and cash flow risks of the Company and the Group Section 3.4 •Principal risks and uncertainties incurred by the Company and the Group Section 3 •Financial risks linked to the effects of climate change and presentation of the measures taken to reduce them (low carbon strategy) by the Company and the Group Section 5.7.4 •Information on R&D of the Company and the Group Sections 5.5 and 18.1 •Subsidiaries Section 6 4.2. Legal, financial and tax information on the Company •Shareholder structure and changes thereto Section 16 •Names of company controlled participating in indirect control in the Company and the share of the capital they hold N/A •Material holdings in companies having their registered office in France N/A •Notice of holding more than 10% in the capital of other joint stock companies; transfer of cross-holdings N/A •Purchase and disposal by the Company of own shares (share buybacks) Section 19.1.3 •Employee stock ownership plans Sections 13.3, 13.4, 18.1, 19.1.4 and 19.1.5.2 •Summary of powers in progress granted by the General Meeting for capital increases Section 19.1.6 •Reference to possible adjustments: —for securities giving access to the capital and stock options in the case of share buybacks; Section 19.1.3 —for securities giving access to the share capital in the case of corporate actions. N/A •Disclosure of dividends distributed for the past three financial periods Section 18.5 •Amount of expenses and charges not deductible from taxable income N/A •Aged trial balance information for trade payables and receivables by maturity date Section 18.1 and Annex I •Injunctions or fines for anticompetitive practices N/A •Agreements entered into between a director and/or officer or a shareholder holding more than 10% of the voting rights and a subsidiary of the Company (excluding ordinary agreements) N/A •Amount of inter-company loans N/A •Information on the operation of a SEVESO installation N/A 4.3. Information concerning officers •Summary of dealings in own shares of the Company by executives and related parties Section 12.1.5 4.4. CSR information of the Company N/A 5. STATUTORY AUDITORS’ REPORT ON THE COMPANY’S ANNUAL FINANCIAL STATEMENTS – FRENCH STANDARDS (FRENCH-GAAP) Section 18.1.4 6. STATUTORY AUDITORS’ REPORT ON THE COMPANY’S ANNUAL CONSOLIDATED FINANCIAL STATEMENTS – INTERNATIONAL FINANCIAL REPORTING STANDARDS (IFRS) Section 18.1.2 •Results of the last five financial years Annex I •Aged Trade Payables Annex I 7. BOARD’S REPORT ON CORPORATE GOVERNANCE 7.1. Information relating to remuneration •Principles and criteria for determining, distributing and allocating fixed, variable and exceptional items making up the total remuneration and benefits of any kind attributable to corporate officers as a result of the mandate Section 13.1.1 •Compensation and benefits of any kind paid during the period to each executive officer by the Company, companies that it controls and the company controlling it Section 13.1.2 •Undertakings linked to assuming, terminating or changing functions N/A •In the case of stock option grants, reference to information according to which the Board of Directors took the decision to: —either prohibit executive managers from exercising their options prior to ceasing to exercise their functions; N/A —or to impose lockout obligations to registered holders until they cease to occupy their functions on all or part of the shares resulting from options already exercised (by specifying accordingly the portion that was set). N/A 7.2. Information concerning the composition, operation and powers of the Board •List of offices and responsibilities exercised in any company by each executive officer during the year Sections 12.1.1 and 12.1.2 •Agreements concluded between a corporate officer or a shareholder holding more than 10% of the voting rights and a subsidiary (excluding current agreements) Section 17.3 •Summary of powers in progress granted by the General Meeting for capital increases Section 19.1.6 •Choice made on one of the two methods for exercising executive management in the event of a modification N/A •Composition, conditions of preparation and organization of the Board’s work Section 14 •Diversity Policy Section 15.1.2 •Limitations of the powers of the general management Section 12.1.4 •Reference to a corporate governance code or, failing this, justification and indication of the rules adopted in addition to the legal requirements Section 14.4.1 •Specific terms and conditions of shareholder participation in the general meeting or provisions of the statutes providing for such terms and conditions Section 19.2.5 •Procedure implemented to review the ordinary agreements with related parties Section 14.5.5 7.3. Information related to the items having a potential impact in the event of public offerings: (i)Capital structure of the Company; Section 19.1 (ii)Restrictions under the Articles of association on the exercise of voting rights or the transfer of shares disclosed in accordance with Article L.223-11 of the French Commercial Code; N/A (iii)Direct or indirect holdings in the share capital of the Company of which it is informed under Articles L.233-7 and L.233-12 of the French Commercial Code; Section 16.1.2 (iv)Holders of any securities conferring special rights of control and descriptions thereof; Sections 16.2 – 16.3 (v)Control mechanisms provided for in a potential employee stock ownership system where control rights are not exercised by the latter; N/A (vi)Shareholders’ agreements known to the Company and which may result in share transfer and voting rights restrictions; Section 16.2 (vii)Rules and regulations pertaining to the appointment and replacement of members of the Board of Directors and modifications to the bylaws of the Company; Section 19.2.2 (viii)Powers of the Board of Directors for the issuance and buybacks of shares; Sections 19.1.3 and 19.1.6 (ix)Agreements concluded by the Company that may be modified or terminated in the event of a change in control of the Company, except if such disclosure, excluding the case where legally required, materially adversely affect its interest; N/A (x)Agreements providing for severance payments for members of the Board of Directors or employees in the event of resignation, dismissal without just and sufficient cause or termination of employment resulting from a public offering. Section 17.2.3 The report on Corporate Governance and the information required under this report were prepared and elaborated by the Board of Directors pursuant to Article L.225-37 of the French Commercial Code, with the involvement of the Executive and Management Committees. The report was adopted by the Board of Directors held on April 7, 2022, upon recommendation of the Audit Committee, which met on April 6, 2022 and was sent to the statutory auditors. NOTE In this Universal Registration Document, the terms “Company,” “GenSight Biologics,” “we,” “us” and “our” mean GenSight Biologics S.A. All references herein to “$” are to United States dollars, the currency of the United States of America. This Universal Registration Document describes the Company as of the date hereof. This Universal Registration Document includes our annual financial statements prepared in accordance with French accounting standards for the fiscal year ended December 31, 2021. This Universal Registration Document also includes our consolidated financial statements prepared in accordance with International Financial Reporting Standards, or IFRS, as adopted by the European Union for the fiscal year ended December 31, 2021. The Document may be consulted on the Company’s website (www.gensight-biologics.com). Unless otherwise indicated the selected financial information and comments on the consolidated financial statements presented in this Universal Registration Document have been prepared on the basis of the consolidated financial statements prepared in accordance with IFRS as adopted by the European Union. A glossary defining some of the terms used herein is appended to this Universal Registration Document. Forward-looking Statements This Universal Registration Document contains statements regarding our prospects and growth strategies. These statements are sometimes identified by the use of the future or conditional tense, or by the use of forward-looking terms such as “considers”, “envisages”, “believes”, “aims”, “expects”, “intends,” “should”, “anticipates”, “estimates”, “thinks”, “wishes” and “might”, or, if applicable, the negative form of such terms and similar expressions or similar terminology. Such information is not historical in nature and should not be interpreted as a guarantee of future performance. Such information is based on data, assumptions, and estimates that we consider reasonable. Such information is subject to change or modification based on uncertainties in the economic, financial, competitive or regulatory environments. This information is contained in several sections of this Universal Registration Document and includes statements relating to our intentions, estimates and targets with respect to our markets, strategies, growth, results of operations, financial situation and liquidity. Our forward-looking statements speak only as of the date of this Universal Registration Document. Absent any applicable legal or regulatory requirements, we expressly disclaim any obligation to release any updates to any forward-looking statements contained in this Universal Registration Document to reflect any change in our expectations or any change in events, conditions or circumstances, on which any forward-looking statement contained in this Universal Registration Document is based. We operate in a competitive and rapidly evolving environment; it is therefore unable to anticipate all risks, uncertainties or other factors that may affect our business, their potential impact on our business or the extent to which the occurrence of a risk or combination of risks could have significantly different results from those set out in any forward-looking statements, it being noted that such forward-looking statements do not constitute a guarantee of actual results. Information on the Market and Competitive Environment This Universal Registration Document contains, in particular in Section 5, “Business Overview”, information relating to our markets and to our competitive position. Unless otherwise indicated, the information contained in this Universal Registration Document related to market shares and the size of relevant markets are our estimates and are provided for illustrative purposes only. We believe that the information contained herein in relation to our markets and competitive position is reliable, but the information has not been verified by an independent expert, and we cannot guarantee that a third-party using different methods to collect, analyze or compute market data would arrive at the same results. Risk Factors Investors should carefully consider the risk factors in Section 3, “Risk Factors”. The occurrence of all or any of these risks could have an adverse effect on our business, reputation, results of operation, financial condition or prospects. TABLE OF CONTENT 1 PERSON RESPONSIBLE, THIRD PARTY INFORMATION, EXPERTS’ REPORTS AND COMPETENT AUTHORITY APPROVAL 1.1 Identity of the person responsible 1.2 Declaration of the person responsible 1.3 Experts’ reports 1.4 Third party information 1.5 Competent authority approval 2 STATUTORY AUDITORS 2.1 Statutory auditors 2.2 Change in Statutory auditors 3 RISK FACTORS 3.1 Financial risks 3.2 Risks related to the discovery and development of and obtaining regulatory approval for our product candidates 3.3 Risks related to manufacturing and commercialization of our product candidates 3.4 Risks related to our business operations 3.5 Legal risks and risks related to our intellectual property 3.6 Insurance and risk management 3.7 Internal control and risk management procedures 4 INFORMATION ABOUT THE ISSUER 4.1 Legal and commercial name 4.2 Place of registration, registration number and legal entity identifier (“LEI”) 4.3 Date of incorporation, length of life of the issuer 4.4 Domicile, legal form, legislation, country of incorporation, address, telephone number and website 5 BUSINESS OVERVIEW 5.1 Overview 5.2 Our Product Development Pipeline 5.3 Important events in the development of the Company 5.4 Strategy and objectives 5.5 Research and development, patents and licenses 5.6 Competition 5.7 Investments 5.8 Manufacturing 5.9 Sales and marketing 6 ORGANIZATIONAL STRUCTURE 7 OPERATING AND FINANCIAL REVIEW 7.1 Overview 7.2 Financial Operations Overview 7.3 Results of operations 8 CAPITAL RESOURCES 8.1 Overview 8.2 Analysis of Cash Flow 8.3 Funding sources 8.4 Principal uses of cash 8.5 Information regarding the anticipated sources of funds needed 9 REGULATORY ENVIRONMENT 10 TREND INFORMATION 10.1 Most significant recent trends since the end of the last financial year 10.2 Information on any known trends, uncertainties, demands, commitments or events that are reasonably likely to have a material effect on the company’s prospects 11 PROFIT FORECAST OR ESTIMATES 12 ADMINISTRATIVE, MANAGEMENT AND SUPERVISORY BODIES AND SENIOR MANAGEMENT 12.1 Composition of management and supervisory bodies 12.2 Conflicts of interest 13 COMPENSATION AND BENEFITS 13.1 Compensation and benefits of Senior Executives and Directors 13.2 Directors’ Compensation 13.3 Share Warrants, Share Warrants for founders, stock options and free Shares Granted to Senior Executives and Directors 13.4 History of Allocation of Share Warrants, Share Warrants for Founders and Stock Options 13.5 Share Warrants, Share Warrants for Founders or Stock Options of the Company granted to the Company’s top ten employees 13.6 History of Allocation of Free Shares 13.7 Benefits of Senior Executives 13.8 Equity ratio between the level of compensation of the Chairman and Chief Executive Officer and the compensation average and median of the Company’s employees 13.9 Compliance of Total Executive Director Compensation with the Recommendations of Middlenext Code 13.10 Amount of Provisions Made or Recorded by the Company for the Payment of Pensions, Retirement Plans or Other Benefits 14 BOARD PRACTICES 14.1 Terms of Office of Members of the Corporate Bodies and Management Bodies 14.2 Information on Service Contracts between Members of the Administrative and Management Bodies and the Company 14.3 Committees of the Board of Directors 14.4 Statement Relating to Corporate Governance 14.5 Operating Principals of the Board of Directors 15 EMPLOYEES 15.1 Human Resources Management 15.2 Shareholdings and stock options 15.3 Employee arrangements 16 MAJOR SHAREHOLDERS 16.1 Allocation of share capital 16.2 Shareholders’ Voting Rights 16.3 Control structure 16.4 Agreement likely to a change of control 17 RELATED PARTY TRANSACTIONS 17.1 Agreements with the Company’s Major Shareholders 17.2 Transactions with Key Management Persons 17.3 Regulated Agreements 17.4 Statutory Auditors’ Special Report on regulated agreements 18 FINANCIAL INFORMATION CONCERNING THE GROUP’S ASSETS AND LIABILITIES, FINANCIAL POSITION AND PROFITS AND LOSSES 18.1 Historical Financial Information 18.2 Interim and Other Financial Information 18.3 Auditing of Historical Annual Financial Information 18.4 Proforma Financial Information 18.5 Dividend Policy 18.6 Legal and Arbitration Proceedings 18.7 Significant Change In Financial Position 19 ADDITIONAL INFORMATION 19.1 Share Capital 19.2 Constitutive Documents and Bylaws 20 MATERIAL CONTRACTS 20.1 Collaboration, Partnership and Related Agreements 20.2 In-License Agreements 20.3 Manufacturing Agreement 20.4 Customer Agreement 21 DOCUMENTS AVAILABLE 22 GLOSSARY 23 ANNEXES 1 PERSON RESPONSIBLE, THIRD PARTY INFORMATION, EXPERTS’ REPORTS AND COMPETENT AUTHORITY APPROVAL 1.1Identity of the person responsible Bernard Gilly, Chief Executive Officer of GenSight Biologics S.A. is responsible for the information contained in this Universal Registration Document. 1.2Declaration of the person responsible I hereby declare that, after having taken all reasonable care to that purpose, to the best of my knowledge, the information contained in this Universal Registration Document is in accordance with the facts and contains no omission likely to affect its import. I hereby declare that, to the best of my knowledge, the financial statements have been prepared in accordance with the applicable accounting standards and present a fair view of the assets, liabilities, financial position and results of the Company and all the other companies included in the scope of consolidation, and that the Annual Management Report for which a table of cross-references is presented in this Universal Registration Document, provides a fair presentation of the business developments, results and financial position of the Company and all the other companies included in the scope of consolidation, as well as a description of the main risks and contingencies to which they might be exposed. April 29, 2022 Bernard Gilly, Chief Executive Officer of GenSight Biologics S.A. 1.3Experts’ reports N/A 1.4Third party information N/A 1.5Competent authority approval N/A 2 STATUTORY AUDITORS 2.1Statutory auditors Deloitte & Associés Represented by Stéphane Lemanissier Tour Majunga, 6 place de la Pyramide, 92908 Paris-La Défense Cedex Deloitte & Associés is a member of the Compagnie Régionale des Commissaires aux Comptes de Versailles (the Regional Association of Auditors of Versailles). Becouze Represented by Fabien Brovedani 34, rue de Liège – 75008 Paris, France Becouze is a member of the Compagnie Régionale des Commissaires aux Comptes d’Angers (the Regional Association of Auditors of Angers). Deloitte & Associés’s initial appointment as statutory auditor has been expressed in the bylaws of April 17, 2012, for a six-year term, which has been renewed at the general shareholder’s meeting of the Company on June 11, 2019 for a six-year term and Becouze’s appointment as statutory auditor was approved by the general shareholders’ meeting of the Company on May 19, 2016 for a six-year term, which will end at the close of the Shareholders’ Meeting called to approve the financial statements for the fiscal year ending on December 31, 2021. Guillaume Saby (substitute to Becouze) 1, rue Buffon – 49100 Angers, France Guillaume Saby is a member of the Compagnie Régionale des Commissaires aux Comptes d’Angers (the Regional Association of Auditors of Angers). Guillaume Saby was appointed substitute statutory auditor by our general shareholders’ meeting on May 19, 2016 for a six-year term, which will end at the close of the shareholders’ meeting called to approve the financial statements for the fiscal year ending on December 31, 2021. 2.2Change in Statutory auditors As of the date of this Universal Registration Document, none of the statutory auditors or substitute statutory auditors have resigned or been revoked. 3 RISK FACTORS The Company has opted for a presentation of its risk factors by category of risk, with a hierarchization of these risks within each category from riskier to less risky. Investors should carefully consider all of the information set forth in this Universal Registration Document before making an investment decision, including the risk factors set forth in this Section. Such risks are, as of the date of this Universal Registration Document, the risks that the Company believes, were they to occur, could have a material adverse effect on our business, results of operations, financial condition and prospects. In order to identify and assess the risks likely to have an adverse impact on its business, prospects, financial position, results (or ability to achieve its objectives) and development, the Company has mapped the risks associated with its business since 2012. This enabled the Company first to identify potential risks and assess their probability of impact and, where possible, to assess their potential impact from a financial, legal and reputation point of view, as well as on the achievement of the Company’s objectives. This then made it possible to identify and evaluate ways to control these risks. Risk mapping is a management tool. It is reviewed twice a year by the Management Committee and the Audit Committee. At the time of the periodic risk review, all risks and mitigation measures are reviewed and reassessed. This tool is also supplemented by a detailed analysis of the causes and impacts in the event of the occurrence of any significant risk and takes into account the actions and control measures implemented by the Company. This methodology should provide an overview of the risk environment affecting the Company and should enable the Company to define, if necessary, the action plan for risk management and the areas of internal control and audit for the coming year. The risk mapping exercise enabled the Company to summarize the main risks and group them into the categories indicated below. The Company has grouped these risks into five categories, with no hierarchy between them. The table below summarizes the main risk factors identified by the Company and indicates, for each of them, the criticality level (combination of the probability of their occurrence and their negative impact on the Company) as at the filing date of this Universal Registration Document, taking into account the actions and control measures implemented by the Company as at the filing date of this Universal Registration Document. The probability of occurrence is assessed on three levels (“low”, “moderate” and “high”) and the magnitude of their negative impact is assessed on four levels (“low”, “moderate”, “high” and “critical”). In each of the five categories above, risks have been classified according to this classification, with risks with the highest probability of occurrence and the highest negative impact being placed first. Ref. Risk Factors Criticality level Probability of Occurrence Magnitude of Negative Impact 1. FINANCIAL RISKS 1.1 Liquidity Risk High Critical 1.2 We have never generated revenue from product sales and have incurred significant operating losses since our inception. We expect to continue to incur significant losses for the foreseeable future and may never achieve profitability. Moderate Critical 1.3 We will need to raise additional capital in the future, which may not be available on acceptable terms, or at all, and failure to obtain this necessary capital when needed may force us to delay, limit or terminate our product development efforts or other operations. Moderate Critical 1.4 We may lose access to research tax credits in the event of regulatory or legislative changes or challenges by tax authorities. Low Moderate 1.5 Our current and future shareholders may experience dilution. High Low 1.6 The realization of the security interests attached to our bond financing could have an adverse impact on our capacity to operate our business. Low Moderate 1.7 Risk related to the foreign investment screening procedure. Low Low 2. RISKS RELATED TO THE DISCOVERY AND DEVELOPMENT OF AND OBTAINING REGULATORY APPROVAL FOR OUR PRODUCT CANDIDATES 2.1 The regulatory approval process of the FDA, the EMA and other regulatory authorities and the clinical trials that our product candidates will need to undergo, are time-consuming and expensive, the outcomes of which are unpredictable, and for which there is a high risk of failure. High Critical 2.2 Our product candidates are based on novel technologies, including gene therapy, which may implicate ethical, social and legal concerns about genetic testing and genetic research in general, and such novel technologies make it difficult to predict the timing and costs of development of new and unforeseen regulatory requirements and of subsequently obtaining regulatory approval. Low High 2.3 We may encounter substantial delays in our clinical trials, and we cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. Moderate Moderate 2.4 Our product candidates and the process for administering our product candidates using AAV vectors may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial potential or result in significant negative consequences following any potential marketing approval. Moderate Moderate 2.5 Even if we complete the necessary clinical trials, we cannot predict when, or if, we will obtain regulatory approval to commercialize a product candidate and the approval may be for a narrower indication than we seek. Moderate Moderate 3. RISKS RELATED TO MANUFACTURING AND COMMERCIALIZATION OF OUR PRODUCT CANDIDATES 3.1 Gene therapies are novel, complex and difficult to manufacture. We have limited manufacturing experience and could experience production problems that result in delays in our development or commercialization programs. High Critical 3.2 We rely, and expect to continue to rely, on Brammer Bio, Catalent and other third parties to conduct, supervise and monitor manufacturing for our preclinical studies and clinical trials. If these third parties do not meet our deadlines, successfully carry out their contractual duties or otherwise conduct the manufacturing for these studies and trials as required, we may not be able to obtain regulatory approval for or commercialize our product candidates when expected or at all. High Critical 3.3 We rely on third parties to conduct, supervise and monitor our preclinical studies and clinical trials. If these third parties do not meet our deadlines or otherwise conduct the studies and trials as required, our clinical development programs could be delayed or unsuccessful and we may not be able to obtain regulatory approval for or commercialize our product candidates when expected or at all. Moderate High 3.4 Future insurance coverage and reimbursement status of our product candidates is uncertain. Moderate High 3.5 If we are unable to establish sales, marketing and distribution capabilities for our product candidates, whether it be an internal infrastructure or an arrangement with a commercial partner, we may not be successful in commercializing those product candidates if and when they are approved. Low Moderate 3.6 The commercial success of any of our product candidates will depend upon their degree of market acceptance by physicians, patients, third-party payors and others in the medical community. Low Moderate 4. RISKS RELATED TO OUR BUSINESS OPERATIONS 4.1 Risks related to the impacts of the Covid-19 High Moderate 4.2 Our future success depends on our ability to retain key employees, consultants and advisors and to attract, retain and motivate qualified personnel, and members of our management team may be affected by conflicts of interest to the extent that they serve in management or directorship capacities at our competitors. Moderate Moderate 4.3 We may not be successful in our efforts to identify or discover additional product candidates and may fail to capitalize on programs or product candidates that may be a greater commercial opportunity or for which there is a greater likelihood of success. Moderate Moderate 4.4 We may be subject to product liability lawsuits. Low Moderate 5. LEGAL RISKS AND RISKS RELATED TO OUR INTELLECTUAL PROPERTY 5.1 We do not own any issued patents and our rights to develop and commercialize our product candidates are subject to the terms and conditions of intellectual property licenses granted to us by others. Low Critical 5.2 We or our licensors may be unable to obtain and maintain adequate patent protection for our product candidates and technology. Low Critical 5.3 We may fail to comply with our obligations under the agreements under which we in-license intellectual property and could thereby lose license rights that are important to our business. Low Critical 5.4 We may not be able to protect our intellectual property rights throughout the world. Moderate Moderate 5.5 Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business. Low Moderate 3.1Financial risks 3.1.1LIQUIDITY RISK. As of the date of the filing of this Universal Registration Document, the Company does not have sufficient working capital to meet its obligations fort at least the next 12 months. Since its incorporation, the Company has funded its activities through several equity financings, grants, conditional advances and Research Tax Credit. Since the end of 2019, the Company started to generate revenue from the sale of LUMEVOQ® in France, since the French National Drug Safety Agency (ANSM) granted a named patient Temporary Authorization for Use (ATU nominative) for LUMEVOQ®. As mentioned in note 27 Subsequent events of the Consolidated Financial Statements, following a delay in manufacturing validation batches of LUMEVOQ®, GenSight plan to restart the manufacturing of the validation batches at its Cambridge, US, manufacturing facility during Q3 2022. The Company therefore expects a delay in the commercialization of LUMEVOQ®. Considering the cash position as of December 31, 2021 (amounting to €44.3 million), the reimbursement of the 2021 Research Tax Credit contemplated in 2022 for a consideration of €2.4 million and additional cash related to the ATU sales in France granted during Q1 2022, the Company believes it will be able to fund its operations until early first quarter 2023. In order to meet its obligations beyond this date, the Company will have to find additional funding. Various financing sources are considered among which, the issuance of new debt or equity instruments, in order to complete its working capital needs and to finance its operating expenses. The Company believes it will have the ability to raise additional funds during 2022. However, no assurance can be given at this time as to whether the Company will be able to achieve these financing objectives, therefore there would be substantial doubt regarding its ability to continue as a going concern. However, beyond 2022, if the Company was not able to raise additional funds, the Company would modify its operating plans, in particular by delaying or limiting the scope of its research and development programs and would drastically reduce its sales and marketing expenses. 3.1.2WE HAVE NEVER GENERATED REVENUE FROM PRODUCT SALES AND HAVE INCURRED SIGNIFICANT OPERATING LOSSES SINCE OUR INCEPTION. WE EXPECT TO CONTINUE TO INCUR SIGNIFICANT LOSSES FOR THE FORESEEABLE FUTURE AND MAY NEVER ACHIEVE PROFITABILITY. Since inception, we have devoted substantially all of our efforts to research and development, including preclinical and clinical development of our product candidates, as well as to building our team. We have never generated revenue from product sales, and we have incurred operating losses since inception. We incurred net losses of €34.0 million and €28.6 million for the fiscal years ended December 31, 2020 and 2021, respectively, and these losses have adversely impacted, and will continue to adversely impact, our equity attributable to shareholders and net assets. We anticipate that our operating losses will continue for at least the coming years as we continue with our research and development activities and until we generate substantial revenues from approved product candidates. As of December 31, 2021, we had an accumulated fiscal deficit of approximately €199 million. Our capacity to generate revenues from product sales and to achieve profitability will depend on our ability, alone or with collaborative partners, to successfully complete the development of and to obtain the regulatory approvals necessary to commercialize our product candidates with significant market potential. We do not currently have the required approvals to market our lead product candidate, LUMEVOQ®, and our second most advanced product candidate, GS030 or any other product candidates and we may never obtain such approvals or be able to commercialize any of our current or future product candidates. Our ability to generate future revenues from product sales will depend heavily mainly on our and any of our collaborators’ success in: •continuing our research and development of our second lead product candidate, Phase I/II clinical trial for GS030; •preparing our biologic license application, or BLA, and European Union centralized marketing authorization application, or MAA, for LUMEVOQ® and GS030, and seeking marketing approvals for any of our other product candidates that successfully complete clinical trials; •establishing and maintaining supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical supply and the market demand for our product candidates, if approved; •obtaining market acceptance of our product candidates, if approved, as a viable treatment option and satisfying any post-marketing requirements; •avoiding and defending against third-party interference or infringement claims; and •attracting, hiring and retaining qualified personnel. We may never succeed in any or all of these activities and, even if we do, we may never generate revenues that are significant or large enough to achieve profitability. Even if we do achieve profitability, we may not be able to sustain or increase profitability on an annual basis and may need to obtain additional funding to continue operations. Our failure to become and remain profitable would decrease the value of our Company and could impair our ability to raise capital, maintain our research and development efforts, expand our business, diversify our product pipeline or continue our operations. A decline in the value of our Company could also cause investors to lose all or part of their investment. 3.1.3WE WILL NEED TO RAISE ADDITIONAL CAPITAL IN THE FUTURE, WHICH MAY NOT BE AVAILABLE ON ACCEPTABLE TERMS, OR AT ALL, AND FAILURE TO OBTAIN THIS NECESSARY CAPITAL WHEN NEEDED MAY FORCE US TO DELAY, LIMIT OR TERMINATE OUR PRODUCT DEVELOPMENT EFFORTS OR OTHER OPERATIONS. Our operations have consumed significant cash since inception. To date, we have financed our activities primarily through private placements of our ordinary shares and preferred shares, funding received from Bpifrance Financement, research tax credits (crédit d’impôt recherche), or CIR, and a sale of our ordinary shares in connection with our July 2016 initial public offering on the regulated market of Euronext Paris, or Euronext Paris. We are currently advancing our product candidates through clinical development and towards potential commercialization. Developing product candidates is expensive, lengthy and risky, and we expect our expenses to increase in connection with our ongoing activities, particularly as we continue the research and development of, initiate further clinical trials of and seek marketing approval for, our product candidates. Our expenses could increase beyond our current expectations, mainly depending on: •the scope, progress, results and costs of drug discovery, laboratory testing, preclinical development and clinical trials for our product candidates; •the costs, timing and outcome of regulatory review of our product candidates, including, in particular, if we are required by the U.S. Food and Drug Administration, or FDA, the European Medicines Agency, or EMA, or other regulatory agencies to perform clinical trials and other studies in addition to those that we currently anticipate; •the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending intellectual property-related claims. Until such time that we can generate substantial and recurring revenue from product sales, we expect to finance our operating activities through a combination of our existing liquidity sources and the proceeds of any future financings. If we are unable to generate revenue from product sales, in particular from LUMEVOQ® within our expected timeframes, or if our expenses increase to a level or at a rate beyond our expectations, we will need to raise additional capital. However, we may be unable to raise additional funds or enter into other funding arrangements when needed on favorable terms, or at all. If we are unable to raise capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate certain of our research and development programs. Any additional fundraising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our product candidates. To the extent that additional capital is raised through the sale of equity or equity-linked securities, the issuance of those securities could result in substantial dilution for our current shareholders and the terms may include liquidation or other preferences that adversely affect the holdings or the rights of our current shareholders. To the extent that additional capital is raised through a debt offering, the incurrence of indebtedness would result in increased fixed payment obligations, and we may be required to agree to certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. We could also be required to seek funds through arrangements with collaborative partners or otherwise at an earlier stage than otherwise would be desirable, and we may be required to relinquish rights to some of our technologies or product candidates or otherwise agree to terms unfavorable to us. 3.1.4WE MAY LOSE ACCESS TO RESEARCH TAX CREDITS IN THE EVENT OF REGULATORY OR LEGISLATIVE CHANGES OR CHALLENGES BY TAX AUTHORITIES. Since incorporation, we have received the CIR, which is granted to companies by the French tax authorities in order to encourage them to conduct technical and scientific research. For the year ended December 31, 2020, we recorded CIR in the amount of approximately €2.8 million which was reimbursed in November 2021 For the year ended December 31, 2021, we recorded CIR in the amount of approximately €2.4 million, we expect will be reimbursed before the end of the fiscal year 2022. Companies demonstrating that they have expenditures that meet the required criteria, including research expenditures located in France or, since January 1, 2005, within the European Community or in another State that is a party to the Agreement on the European Economic Area, or the EEA, that has concluded a tax treaty with France that contains an administrative assistance clause, receive a tax credit which can be used against the payment of the corporate tax due the fiscal year in which the expenditures were made and during the next three fiscal years, or, as applicable, can be reimbursed for the excess portion. The expenditures taken into account for the calculation of the CIR only involve research expenses. Legislative or regulatory changes relating to CIR or challenges by the French tax authorities with respect to our research expenditures or our eligibility to receive CIR could have a material adverse effect on our ability to operate our business and our financial condition, results of operations and prospects. 3.1.5OUR CURRENT AND FUTURE SHAREHOLDERS MAY EXPERIENCE DILUTION. Since incorporation, we have issued or allotted share warrants for founders (Bons de souscription de parts de créateur d’entreprise, or BCE), share warrants (Bons de souscription d’actions, or BSA) and free shares (Attributions gratuites d’actions, or AGA). As of December 31, 2021, 502,182 BCE, 735,333 BSA, 1,535,000 AGA and 129,792 SO have been allotted (giving the right to subscribe for or acquire, respectively, 502,182, 735,333, 1,535,000 and 129,792 new shares). See Section 19.1.5.1, “Warrants” of this Universal Registration Document. In the context of the “Kreos Transaction” completed in December 2019 and August 2020, part of the bond issuances was in the form of convertible bonds (Obligations Convertibles en Actions or OCA) (giving the right to subscribe to 1,452,852 new shares) and we had also issued 668,151 share warrants (BSA) subscribed by Kreos, giving the right to subscribe to 668,151 new shares. As of the date of this Universal Registration Document, Kreos Capital has exercised 50% of all the issued convertible bonds and converted the totality of its share warrants. As of December 31, 2021, the exercise of all BCE, all BSA, all SO, all OCA and the definitive acquisition of all AGA allotted and outstanding will thus allow for a subscription or acquisition of 3,628,733 new ordinary shares, generating a dilution of 7.27% based on fully diluted capital. Moreover, the exercise of delegations of authority granted to the Board of Directors by the combined general meeting of April 29, 2021 and by the combined general meeting to be held on May 25, 2022 to carry out one or more capital increases could lead to additional dilution. See Section 19.1.5, “Other Securities Giving Access to Share Capital” of this Universal Registration Document. As part of our policy to provide incentives for our executive officers and employees, and in order to attract additional expertise, we may in the future issue or allot shares or new financial instruments giving access to our share capital, which could result in additional, potentially significant, dilution for our current and future shareholders. 3.1.6THE REALIZATION OF THE SECURITY INTERESTS ATTACHED TO OUR BOND FINANCING COULD HAVE AN ADVERSE IMPACT ON OUR CAPACITY TO OPERATE OUR BUSINESS. The bonds and convertible bonds issued in relation to the Kreos Transaction occurred in December 2019 and August 2020 benefit from pledge agreements on our bank accounts, on our business assets, on the intellectual property rights owned by us (trademarks, patents, software, and domain names) and on our receivables. In the event of default by us in our obligations, including our repayment obligations under the Kreos Transaction, Kreos may be granted ownership of the pledged rights and may proceed against the collateral granted to it to secure repayment of these amounts. In such event, our ability to develop its products could be affected or delayed, which would consequently have a material adverse effect on us, our business, prospects, ability to achieve our objectives, our financial position or operating result. 3.1.7RISK RELATED TO THE FOREIGN INVESTMENT SCREENING PROCEDURE. Any investment (i) by (a) a non-French citizen, (b) a French citizen not residing in France within the meaning of Article 4B of the General Tax Code, (c) a non-French entity or (d) a French entity controlled by one of the aforementioned individuals or entities; (ii) which would have the consequence to (a) acquire the control, within the meaning of Article L.233-3 of the French Commercial Code, of an entity governed by French law (a “French Entity”), (b) acquire all or part of a business line of a French Entity or, (c) for non EU or non-EEA investors, to cross directly or indirectly, alone or in concert, a 25% threshold of voting rights in a French Entity and (iii) such French Entity develops its activities in certain strategic sectors essential to the protection of public health, including research and development in critical technologies including biotechnology, is subject to prior authorization by the Minister of Economy, which authorization may be conditioned on certain undertakings. In the context of the ongoing Covid-19 pandemic, the Decree (décret) n° 2020-892 dated July 22, 2020, as amended on December 22, 2021 by the Decree n° 2021-1758, has supplemented the 25% threshold with an additional temporary 10% threshold of the voting rights for the non-European investments in (i) in an entity with its registered office in France and (ii) whose shares are admitted to trading on a regulated market, applicable, at the date of this Universal Registration Document, until December 31, 2021. A fast-track procedure shall apply for any non-European investor exceeding this 10% threshold who will have to notify the Minister of Economy who will then have 10 days to decide whether or not the transaction should be subject to further examination. If an investment requiring the prior authorization of the Minister of Economy is completed without such authorization having been granted, the Minister of Economy might direct the relevant investor to nonetheless (i) submit a request for authorization, (ii) have the previous situation restored at its own expense or (iii) amend the investment. The relevant investor might also be found criminally liable and might be sanctioned with a fine which cannot exceed the greater of: (i) twice the amount of the relevant investment, (ii) 10% of the annual turnover before tax of the target company and (iii) €5 million (for an entity) or €1 million (for an individual). Failure to comply with such measures could result in significant consequences on the applicable investor. Such measures could also delay or discourage a takeover attempt, and we cannot predict whether these measures will result in a lower or more volatile market price of our ordinary shares. 3.2Risks related to the discovery and development of and obtaining regulatory approval for our product candidates 3.2.1THE REGULATORY APPROVAL PROCESS OF THE FDA, THE EMA AND OTHER REGULATORY AUTHORITIES AND THE CLINICAL TRIALS THAT OUR PRODUCT CANDIDATES WILL NEED TO UNDERGO, ARE TIME-CONSUMING AND EXPENSIVE, THE OUTCOMES OF WHICH ARE UNPREDICTABLE, AND FOR WHICH THERE IS A HIGH RISK OF FAILURE. The regulatory approval process for novel product candidates such as ours can be more expensive and take longer than for other, better known or more extensively studied product candidates. The limited number of gene therapy products approved by regulatory authorities as of the date of the Universal Registration Document makes it difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our product candidates in either the United States or the European Union or how long it will take to commercialize our product candidates. Since the EMA and the FDA have different procedures and evaluation criteria, approvals by the EMA may not be indicative of what the FDA may require for approval, and vice versa. The Company has submitted the Marketing Authorization Application (MAA) for its lead product LUMEVOQ® to the EMA in September 2020. Even if the EMA grants such marketing authorization, it does not mean there will be a similar outcome with the FDA in the United States. In addition, we believe that certain of our product candidates, such as LUMEVOQ® and GS030, and certain of our underlying technology platforms, such as Mitochondrial Targeting Sequence and Optogenetics, may be immediately transferable to the treatment of other diseases, including dry age-related macular degeneration, or dry AMD, and geographic atrophy, or GA, as well as diseases outside of ophthalmology, including central nervous system, or CNS, disorders. These other indications, as well as additional potential product candidates, will require additional, time-consuming and costly development efforts prior to commercial sale, which may be unpredictable and may differ significantly from those of our initial product candidates. 3.2.2OUR PRODUCT CANDIDATES ARE BASED ON NOVEL TECHNOLOGIES, INCLUDING GENE THERAPY, WHICH MAY IMPLICATE ETHICAL, SOCIAL AND LEGAL CONCERNS ABOUT GENETIC TESTING AND GENETIC RESEARCH IN GENERAL, AND SUCH NOVEL TECHNOLOGIES MAKE IT DIFFICULT TO PREDICT THE TIMING AND COSTS OF DEVELOPMENT OF NEW AND UNFORESEEN REGULATORY REQUIREMENTS AND OF SUBSEQUENTLY OBTAINING REGULATORY APPROVAL. We have concentrated our research and development efforts on gene therapy approaches using our core platform technologies, mitochondrial targeting sequence, or MTS, and optogenetics, and our future success depends on our successful development of viable product candidates. We may experience problems or delays in developing LUMEVOQ®, GS030, or any other new product candidates, and such problems or delays may result in unanticipated costs, and there can be no assurance that any such development problems can be solved. We also may experience unanticipated problems or delays in developing a sustainable, reproducible and scalable manufacturing process or transferring that process to commercial partners, which may prevent us from completing our clinical trials, meeting the obligations of our collaborations or commercializing our products on a timely or profitable basis, if at all. For example, we, a collaborator or another group may uncover a previously unknown risk associated with the adeno-associated virus, or AAV, which is the vector currently used in our gene therapy approaches, and this may prolong the period of observation required for obtaining regulatory approval or may necessitate additional clinical testing. Because human gene therapy is a relatively new and expanding area of novel therapeutic interventions, and because we are developing product candidates for the treatment of mitochondrial and neurodegenerative diseases of the eye and central nervous system for which there are no or limited therapies and/or treatments, and for which there is little clinical trial experience, there is an increased risk that the FDA, EMA or other regulatory authorities may not consider the endpoints of our clinical trials to be sufficient for marketing approval. In addition, ethical, social and legal concerns about gene therapy, genetic testing and genetic research could result in additional regulations restricting or prohibiting the processes we may use. The product specifications and the clinical trial requirements of the FDA, EMA and other regulatory authorities and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of such product candidate. The regulatory approval process for novel product candidates such as ours is unclear and may be lengthier and more expensive than the process for other, better-known or more extensively studied product candidates. For example, clinical trial protocols for some gene therapies are potentially subject to review by the Recombinant DNA Advisory Committee, or RAC, a committee of the U.S. National Institutes of Health, or NIH, and the RAC review process can delay the initiation of a clinical trial, even if the FDA has approved the initiation of the trial. In addition, the FDA generally requires multiple well-controlled clinical trials to provide the evidence of effectiveness necessary to support a BLA, although FDA guidance provides that reliance on a single pivotal trial may be appropriate if the trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potential serious outcome, and where confirmation of the result in a second trial would be practically or ethically impossible. Regulatory requirements governing gene and cell therapy products have changed frequently and may continue to change in the future. The FDA has established the Office of Tissues and Advanced Therapies within its Center for Biologics Evaluation and Research, or CBER, to consolidate the review of gene therapy and related products, and has established the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER in its review. CBER and its Advisory Committee, and any new guidelines they promulgate, may lengthen the regulatory review process, require us to perform additional preclinical studies or clinical trials, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of our current or future product candidates or lead to significant post-approval limitations or restrictions. As we advance our product candidates, we will be required to consult with these regulatory and advisory groups and comply with applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of our product candidates. These additional processes may result in a review and approval process that is longer than we otherwise would have expected. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenue, and our business, financial condition, results of operations and prospects would be harmed. Even if our product candidates are approved, we expect that the FDA will require us to submit follow-up data regarding our clinical trial subjects for a number of years after approval. If these follow-up data show negative long-term safety or efficacy outcomes for these patients, the FDA may revoke its approval or change the label of our products in a manner that could have an adverse impact on our business. In addition, adverse developments in clinical trials of gene therapy products conducted by others may cause the FDA or other oversight bodies to change the requirements for approval of our product candidates. Similarly, the EMA may issue new guidelines concerning the development and marketing authorization for gene therapy products and require that we comply with these new guidelines. As a result, it is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for LUMEVOQ®, GS030, or any other new product candidates in either the United States or the European Union or how long it will take to commercialize our other product candidates. Approvals by the EMA may not be indicative of what the FDA may require for approval and vice versa. 3.2.3WE MAY ENCOUNTER SUBSTANTIAL DELAYS IN OUR CLINICAL TRIALS, AND WE CANNOT GUARANTEE THAT ANY CLINICAL TRIALS WILL BE CONDUCTED AS PLANNED OR COMPLETED ON SCHEDULE, IF AT ALL. Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the product candidates. Clinical testing is expensive and time-consuming and the results are uncertain. We cannot guarantee that any clinical trial will be conducted as planned or completed on schedule, if at all. Failure of a clinical trial can occur at any stage of testing. Events that may prevent successful or timely completion of clinical development include: •delays in raising, or inability to raise, sufficient capital to fund the planned or ongoing clinical trials; •delays in reaching a consensus with the FDA, EMA or regulatory authorities on trial design; •delays in reaching agreement on acceptable terms with prospective CROs and clinical trial sites; •delays in opening clinical trial sites or obtaining required independent IRB approval in the United States or approval by an independent ethics committee in the European Union at each clinical trial site; •delays in recruiting suitable patients to participate in our clinical trials; •imposition of a clinical hold by regulatory authorities, including as a result of a serious adverse event or after a negative finding following an inspection of our clinical trial operations or clinical trial sites; •delays in the testing, validation, manufacturing and delivery of our product candidates to the clinical trial sites, including delays by any third parties with whom we have contracted to perform certain of those functions; •selection of clinical endpoints that require prolonged periods of clinical observation or analysis of the resulting data. We do not know whether any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. Any inability to successfully complete preclinical and clinical development could result in additional costs or impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties. In addition, if we make manufacturing or formulation changes to our product candidates, we may need to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business, financial conditions, results of operations and prospects. 3.2.4OUR PRODUCT CANDIDATES AND THE PROCESS FOR ADMINISTERING OUR PRODUCT CANDIDATES USING AAV VECTORS MAY CAUSE UNDESIRABLE SIDE EFFECTS OR HAVE OTHER PROPERTIES THAT COULD DELAY OR PREVENT THEIR REGULATORY APPROVAL, LIMIT THEIR COMMERCIAL POTENTIAL OR RESULT IN SIGNIFICANT NEGATIVE CONSEQUENCES FOLLOWING ANY POTENTIAL MARKETING APPROVAL. During the conduct of clinical trials, patients report changes in their health, including illnesses, injuries and discomforts, to their study doctor. Often, it is not possible to determine whether the product candidate being studied caused these conditions. Various illnesses, injuries and discomforts have been reported from time to time during clinical trials of our product candidates. Regulatory authorities may draw different conclusions or require additional testing to confirm these determinations. In addition, it is possible that as we test our product candidates in larger, longer and more extensive clinical programs, or as use of these product candidates becomes more widespread if they receive regulatory approval, illnesses, injuries, discomforts and other adverse events that were observed in earlier trials, as well as conditions that did not occur or went undetected in previous trials, will be reported by patients. Many times, side effects are only detectable after investigational products are tested in large-scale, Phase III clinical trials or, in some cases, after they are made available to patients on a commercial scale after approval. If additional clinical experience indicates that our product candidates cause serious or life-threatening side effects, the development of our product candidates may fail or be delayed, or, if the product candidate has received regulatory approval, such approval may be revoked, which would harm our business, prospects, operating results and financial condition. Our product candidates may lead to undesirable side effects or adverse reactions. In previous studies involving gene therapy treatments, some subjects experienced significant adverse side effects, including reported cases of leukemia and death seen in other clinical trials using other vectors. While new recombinant vectors have been developed to reduce these side effects, gene therapy is still a relatively new approach to disease treatment and additional adverse side effects could develop. Insertional oncogenesis, where the vector is inserted near a cancer causing gene, or an oncogene, may cause adverse immunologic reactions and we cannot assure that such reactions will not occur in any of our planned or future studies. There also is the potential risk of delayed adverse events following exposure to gene therapy products due to persistent biologic activity of the genetic material or other components of products used to carry the genetic material. Possible adverse side effects that could occur with treatment with gene therapy products include an immunologic reaction shortly after administration which, while not necessarily adverse to the patient’s health, could substantially limit the effectiveness of the treatment. In previous clinical trials involving AAV vectors for gene therapy, some patients experienced the development of a T-cell response, whereby after the vector is within the target cell, the cellular immune response system triggers the removal of transduced cells by activated T-cells. If our products demonstrate a similar effect, we may decide or be required to halt or delay further clinical development of our product candidates. There are also risks inherent in intravitreal injections, including those used to administer LUMEVOQ® and GS030, such as intraocular inflammation, cataract, sterile and culture-positive endophthalmitis, retinal detachment and retinal tear. In addition to any potential side effects caused by our product candidates, the administration process or related procedures also can cause adverse side effects. If any such adverse events occur, our clinical trials could be suspended or terminated. If in the future we are unable to demonstrate that such adverse events were not caused by the product candidate, the FDA, the EMA or other regulatory authorities could deny approval or order us to cease further development of our product candidates for any or all targeted indications. Even if we are able to demonstrate that all future serious adverse events are not product-related, such occurrences could affect patient recruitment or the ability of enrolled patients to complete the clinical trial. Moreover, if we elect or are required to delay, suspend or terminate any clinical trial of any of our product candidates, the commercial prospects of such product candidates may be harmed and our ability to generate product revenues from any of these product candidates may be delayed or eliminated. Any of these occurrences may harm our ability to develop other product candidates and may harm our business, financial condition and prospects significantly. Additionally, if any of our product candidates receives marketing approval, the FDA and the EMA could require us to adopt a Risk Evaluation and Mitigation Strategy, or REMS, or a Risk Management Plan, or RMP, to ensure that its benefits outweigh its risks, which may include, among other things, a medication guide outlining the risks of the product for distribution to patients and a communication plan to healthcare practitioners. Furthermore, if we or others later identify undesirable side effects caused by any of our product candidates, several potentially significant negative consequences could result, including: •regulatory authorities may suspend or withdraw approvals of such product candidate; •regulatory authorities may require additional warnings on the label; •we may be required to change the way a product candidate is administered or conduct additional clinical trials; •we could be sued and held liable for harm caused to patients; and •our reputation may suffer. Any of these events could prevent us from achieving or maintaining market acceptance of our product candidates and could significantly harm our business, prospects, financial condition and results of operations. 3.2.5EVEN IF WE COMPLETE THE NECESSARY CLINICAL TRIALS, WE CANNOT PREDICT WHEN, OR IF, WE WILL OBTAIN REGULATORY APPROVAL TO COMMERCIALIZE A PRODUCT CANDIDATE AND THE APPROVAL MAY BE FOR A NARROWER INDICATION THAN WE SEEK. We cannot commercialize a product candidate until the appropriate regulatory authorities have reviewed and approved the product candidate. Even if our product candidates meet their safety and efficacy endpoints in clinical trials, regulatory authorities may not complete their review processes in a timely manner and may recommend non-approval or may place restrictions on approval. In addition, we may experience delays or rejections as a result of future legislation or administrative action, or changes in regulatory authority policy during the period of product development, clinical trials and the review process. Regulatory authorities also may approve a product candidate for more limited indications than requested, may require precautions or contraindications or they may grant approval subject to the performance of costly post-marketing clinical trials or implementation of REMS. In addition, regulatory authorities may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates. Any of the foregoing events could materially harm the commercial prospects for our product candidates. 3.3Risks related to manufacturing and commercialization of our product candidates 3.3.1GENE THERAPIES ARE NOVEL, COMPLEX AND DIFFICULT TO MANUFACTURE. WE HAVE LIMITED MANUFACTURING EXPERIENCE AND COULD EXPERIENCE PRODUCTION PROBLEMS THAT RESULT IN DELAYS IN OUR DEVELOPMENT OR COMMERCIALIZATION PROGRAMS. We have limited experience manufacturing our product candidates. We may be unable to produce commercial materials or meet demand to support a commercial launch for our product candidates. Any such failure could delay or prevent the development of our product candidates and would have a negative impact on our business, financial condition and results of operations. As of the date of this Universal Registration Document, we have contracts with Brammer Bio and Catalent to manufacture clinical and commercial supplies of our product candidates, and we expect to continue to rely on third parties for our manufacturing needs. This is and will continue to be especially challenging as the manufacturing process to produce our product candidates is complex, novel and has not been validated for commercial use. Several factors could cause production interruptions, including equipment malfunctions, facility contamination, raw material shortages or contamination, natural disasters, disruption in utility services, human error or disruptions in the operations of our current and future suppliers. Our product candidates require processing steps that are more complex than those required for most chemical pharmaceuticals because the physical and chemical properties of a biologic such as ours generally cannot be fully characterized. As a result, assays of the finished product may not be sufficient to ensure that the product will perform in the intended manner. Accordingly, we employ multiple steps to control the manufacturing process to assure that the product candidate is made in strict and consistent compliance with our requirements. Problems with the manufacturing process, including even minor deviations from our requirements, could result in product defects or manufacturing failures that result in lot failures, product recalls, product liability claims or insufficient inventory. In addition, we may encounter problems achieving adequate quantities and quality of clinical-grade materials that meet FDA, EMA or other applicable standards or specifications with consistent and acceptable production yields and costs. The FDA, the EMA and other regulatory authorities may also require submission of samples of any lot of an approved product together with the protocols showing the results of applicable tests. Under some circumstances, the FDA, the EMA or other regulatory authorities may require that a lot not be distributed until the agency authorizes its release. Slight deviations in the manufacturing requirements, including those affecting quality attributes and stability, may result in unacceptable changes in the product that could result in lot failures or product recalls. Lot failures or product recalls could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business, financial condition, results of operations and prospects. We may also encounter problems hiring and retaining the experienced specialist scientific, quality control and manufacturing personnel needed to supervise manufacturing processes carried out by third parties, which could result in delays in our production or difficulties in complying with applicable regulatory requirements. Any problems in the manufacturing process or facilities for our product candidates could make us a less attractive collaborator for potential partners, including larger pharmaceutical companies and academic research institutions, which could limit our access to additional attractive development programs. Problems in our manufacturing process or facilities also could restrict our ability to meet market demand for our products. 3.3.2WE RELY, AND EXPECT TO CONTINUE TO RELY, ON Brammer Bio, CATALENT AND OTHER THIRD PARTIES TO CONDUCT, SUPERVISE AND MONITOR MANUFACTURING FOR OUR PRECLINICAL STUDIES AND CLINICAL TRIALS. IF THESE THIRD PARTIES DO NOT MEET OUR DEADLINES, SUCCESSFULLY CARRY OUT THEIR CONTRACTUAL DUTIES OR OTHERWISE CONDUCT THE MANUFACTURING FOR THESE STUDIES AND TRIALS AS REQUIRED, WE MAY NOT BE ABLE TO OBTAIN REGULATORY APPROVAL FOR OR COMMERCIALIZE OUR PRODUCT CANDIDATES WHEN EXPECTED OR AT ALL. We currently rely and expect to continue to rely to a significant degree, on Brammer Bio, Catalent and other third parties to carry out the production of our preclinical study, clinical trial and commercial materials (see Section 20.3 “Manufacturing Agreement”). We can control only certain aspects of these third-party activities. Under certain circumstances, Brammer Bio and Catalent are entitled to terminate their engagements with us. If we need to enter into alternative arrangements, it could delay our product development activities. Our reliance on Brammer Bio and Catalent for certain manufacturing activities will reduce our control over these activities but will not relieve us of our responsibility to ensure compliance with all required regulations. If Brammer Bio or Catalent does not successfully carry out their contractual duties, meet expected deadlines or manufacture our clinical trial materials in accordance with regulatory requirements, or if there are disagreements between us and Brammer Bio and/or Catalent, we will not be able to complete, or may be delayed in completing, the preclinical studies required to support future IND submissions and the clinical trials required for approval of our product candidates. In such instances, we would need to find an appropriate replacement third-party relationship, which may not be readily available or on acceptable terms, causing additional delay or increased expense prior to the approval of our product candidates. In addition to Brammer Bio and Catalent, we rely on additional third parties to manufacture ingredients of our product candidates and to perform quality testing, and reliance on these third parties rather than manufacturing the product candidates ourselves, exposes us to additional risks, including: •reduced control for certain aspects of manufacturing activities; •termination or non-renewal of such manufacturing agreements in a manner or at a time that is costly or damaging to us; and •disruptions to the operations of our third-party manufacturers caused by conditions unrelated to our business or operations, including the bankruptcy of the manufacturer or service provider. Any of these events could lead to clinical trial delays or failure to obtain regulatory approval, or impact our ability to successfully commercialize future product candidates. Some of these events could be the basis for FDA, EMA or other regulatory authority action, including injunction, recall, seizure or partial or total suspension of product manufacture. 3.3.3WE RELY ON THIRD PARTIES TO CONDUCT, SUPERVISE AND MONITOR OUR PRECLINICAL STUDIES AND CLINICAL TRIALS. IF THESE THIRD PARTIES DO NOT MEET OUR DEADLINES OR OTHERWISE CONDUCT THE STUDIES AND TRIALS AS REQUIRED, OUR CLINICAL DEVELOPMENT PROGRAMS COULD BE DELAYED OR UNSUCCESSFUL AND WE MAY NOT BE ABLE TO OBTAIN REGULATORY APPROVAL FOR OR COMMERCIALIZE OUR PRODUCT CANDIDATES WHEN EXPECTED OR AT ALL. We do not have the ability to conduct all aspects of our preclinical studies or clinical trials ourselves. We rely, and expect to continue to rely, on medical institutions, clinical investigators, CROs, contract laboratories and collaborators to carry out our preclinical studies and clinical trials and to perform data collection and analysis. Such third parties play a significant role in the conduct of these studies and trials and the subsequent collection and analysis of data. While we have agreements governing their activities, we have limited influence over their actual performance and will control only certain aspects of such third parties’ activities. Nevertheless, we are responsible for ensuring that each of our preclinical studies and clinical trials is conducted in accordance with the applicable legal, regulatory, ethical and scientific standards, and our reliance on the third party does not relieve us of our regulatory responsibilities. We and our CROs are required to comply with the FDA’s, the EMA’s and other regulatory authorities’ GCP, cGMP, Good Laboratory Practice, or GLP, and other applicable requirements for conducting, recording and reporting the results of our preclinical studies and clinical trials to assure that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected (See Section 9 “Regulatory Environment”). Regulatory authorities around the world, including the FDA and the EMA, enforce these requirements through periodic inspections of study sponsors, CROs, principal investigators and clinical trial sites. If we, our CROs, our investigators or trial sites fail to comply with applicable GCP, GLP and cGMP requirements, the clinical data generated in our future clinical trials may be deemed unreliable and the FDA, the EMA or other regulatory authorities around the world may require us to perform additional clinical trials before issuing any marketing authorizations for our product candidates. Upon inspection, the FDA or EMA may determine that our clinical trials did not comply with GCP and cGMP requirements, which may render the data generated in those trials unreliable or unusable for the purpose of supporting the marketing authorization applications for our products. In addition, our future clinical trials will require a sufficient number of study subjects to evaluate the safety and efficacy of our product candidates. Accordingly, if, for example, our CROs fail to comply with these regulations or if trial sites fail to recruit a sufficient number of patients, we may be required to repeat such clinical trials or incur delays in the performance of such trials, which would delay the regulatory approval process. Therefore, the timing of the initiation and completion of trials is largely controlled by such third parties and may occur at times substantially different from our estimates. Our development activities, including preclinical studies and clinical trials conducted in reliance on third parties, may be delayed, suspended or terminated if: •we are unable to negotiate agreements with third parties under reasonable terms; •termination or nonrenewal of agreements with third parties occurs in a manner or at a time that is costly or damaging to us; •the third parties do not successfully carry out their contractual duties or fail to meet regulatory obligations or expected deadlines; or •the quality or accuracy of the data obtained by third parties is compromised due to their failure to adhere to clinical protocols, regulatory or ethical requirements, or for other reasons. Third party performance failures in connection with our preclinical studies and clinical trials may increase our costs, delay our ability to obtain regulatory approval, delay or prevent starting or completion of clinical trials and delay or prevent commercialization of our product candidates. In the event of a default, bankruptcy or shutdown of, or a dispute with, a third party, we may be unable to enter into a new agreement with another third party on commercially acceptable terms. In addition, our third-party agreements usually contain a clause limiting such third party’s liability, such that we may not be able to obtain full compensation for any losses we may incur in connection with the third party’s performance failures. While we believe that there are numerous alternative sources to provide these services, in the event that we seek such alternative sources, we may not be able to enter into replacement arrangements without incurring delays or additional costs. 3.3.4FUTURE INSURANCE COVERAGE AND REIMBURSEMENT STATUS OF OUR PRODUCT CANDIDATES IS UNCERTAIN. We expect the cost of a single administration of our products candidates to be substantial, when and if they achieve regulatory approval. We expect that coverage and reimbursement by government and private payors will be essential for most patients to be able to afford these treatments. Accordingly, sales of our product candidates will depend substantially, in the United States and the European Union in particular, on the extent to which the costs of our product candidates will be paid or reimbursed by government authorities, private health coverage insurers and other third-party payors. The marketability of any products for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future. Obtaining coverage and reimbursement for a product from third-party payors is a time-consuming and costly process that could require us to provide to the payor supporting scientific, clinical and cost-effectiveness data. We may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement. If coverage and reimbursement are not available, or are available only at limited levels, we may not be able to successfully commercialize our product candidates. Even if coverage is provided, the approved reimbursement amount may not be adequate to realize a sufficient return on our investment. There is significant uncertainty related to third-party coverage and reimbursement of newly approved products. In many countries outside the United States, product sales generally are subject to extensive government price controls and other market regulations (see Section 9 “Regulatory Environment”). Therefore, it may be difficult to project the impact of these evolving reimbursement metrics on the willingness of payors to cover candidate products that we or our partners are able to commercialize. We expect to experience pricing pressures in connection with the sale of any of our product candidates due to the trend toward managed healthcare, the increasing influence of health maintenance organizations additional legislative changes and downward pressure on healthcare costs in general. As a result, increasingly high barriers are being erected to the entry of new products such as ours. 3.3.5IF WE ARE UNABLE TO ESTABLISH SALES, MARKETING AND DISTRIBUTION CAPABILITIES FOR OUR PRODUCT CANDIDATES, WHETHER IT BE AN INTERNAL INFRASTRUCTURE OR AN ARRANGEMENT WITH A COMMERCIAL PARTNER, WE MAY NOT BE SUCCESSFUL IN COMMERCIALIZING THOSE PRODUCT CANDIDATES IF AND WHEN THEY ARE APPROVED. In addition to the appointment of our Vice President of Marketing in 2017 and of our Senior Vice-President of Commercial Operations in 2022, the country leadership for the five major European markets (Germany, France, the UK, Italy and Spain) were recruited, with additional local positions filled for the first three markets. The teams began identifying and evaluating the potential network of treatment centers when LUMEVOQ® becomes available on the markets. In addition, they have begun assessing the network of Key Opinion Leaders who will drive treatment decisions and potentially support discussions with pricing and reimbursement authorities. To successfully commercialize any of our product candidates, we will need to keep on developing these capabilities, either on our own or with others, which will be expensive and time-consuming and could delay any product launch. Moreover, we cannot be certain that we will be able to successfully develop this capability. We intend to commercialize our products, on our own or with strategic partners, in Europe and the United States and expect to seek partnership agreements in Asia for sales, marketing and distribution. If any current or future collaborators do not commit sufficient resources to commercialize our products, or we are unable to develop the necessary capabilities on our own, we will be unable to generate sufficient product revenue to sustain our business. We will be competing with many companies that have extensive, experienced and well-funded marketing and sales operations to recruit, hire, train and retain marketing and sales personnel. We also face competition in our search for third parties to assist us with the sales and marketing efforts of our product candidates. Without an internal team or the support of a third party to perform marketing, sales and distribution functions, we may be unable to compete successfully against more established companies. 3.3.6THE COMMERCIAL SUCCESS OF ANY OF OUR PRODUCT CANDIDATES WILL DEPEND UPON THEIR DEGREE OF MARKET ACCEPTANCE BY PHYSICIANS, PATIENTS, THIRD-PARTY PAYORS AND OTHERS IN THE MEDICAL COMMUNITY. Our efforts to educate the medical community and third-party payors on the benefits of our product candidates may require significant resources and may never be successful. Such efforts may require more resources than are typically required due to the complexity and uniqueness of our potential products. If LUMEVOQ® or any other product that we commercialize in the future is approved but fails to achieve market acceptance among physicians, patients or third-party payors, we will not be able to generate significant revenues from such product. The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on several factors, including: •the potential and perceived advantages of product candidates over alternative treatments; •the cost of treatment relative to alternative treatments; •patient awareness of genotyping; •the willingness of physicians to prescribe new therapies; •the willingness of the target patient population to try new therapies; •the prevalence and severity of any side effects; •product labeling or product insert requirements of the FDA, the EMA or other regulatory authorities, including any limitations or warnings contained in a product’s approved labeling; •relative convenience and ease of administration; •the strength of marketing and distribution support; •the timing of market introduction of competitive products; •publicity concerning our products or competing products and treatments; and •sufficient third-party payor coverage and adequate reimbursement. Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product will not be fully known until after it is launched. 3.4Risks related to our business operations 3.4.1RISKS RELATED TO THE IMPACTS OF THE COVID-19. The REVERSE and RESCUE Phase III trials of LUMEVOQ® for the treatment of Leber Hereditary Optic Neuropathy (LHON) are completed, and patients have been transferred to long-term follow-up for an additional 3-year period. Given the follow-up nature of these visits and the stability of patients with no safety concern, the Company confirms that the Covid-19 situation has no significant impact on the conduct of the trial. The strategic manufacturing partner (CDMO) for LUMEVOQ®, ThermoFischer Scientific (TFS) in Boston, USA, informed the Company that, as a consequence of the US Defense Production Act (DPA), American suppliers have had to redirect certain consumables towards the manufacture of Covid vaccines in the US. This has resulted in extended timelines for the availability of some items required for manufacturing LUMEVOQ®. Accordingly, the Company anticipated delays in providing data from the planned validation batches to the EMA and, after discussions with the European Agency, agreed upon an extended clock-stop period. The REFLECT Phase III trial of LUMEVOQ® is fully recruited with a primary endpoint at 78 weeks. Although some on-site visits had to be postponed due to Covid-19 travel restrictions, the Company closely partnered with clinical sites and properly documented and reported delays to regulators, as well as pre-specified them in the Statistical Analysis Plan (SAP), in agreement with biostatisticians, before database lock. Consequently, GenSight Biologics was able to collect data from 95 out of 98 patients with no consequence on the primary endpoint, other than a delay in the 78-week read out from Q1 initially to June 2021. In order to protect patients, the Company and investigators together decided to delay recruiting new patients into the 3rd cohort of the PIONEER Phase I/II clinical trial of GS030 until the Covid-19 situation had improved, as RP is a chronic disease and does not require urgent treatment. The use of corticosteroids pre- and post-gene therapy injection, performed as part of the protocol to minimize inflammatory response, was deemed by GenSight and investigators to expose patients to a higher risk of Covid-19 infection. In the interim, the six patients in the first two cohorts were remotely monitored for safety aspects by investigators. Consequently, recruitment took longer than originally planned. PIONEER, combining gene therapy and optogenetics for the treatment of RP, has now fully completed recruitment of the 3rd cohort. Patients continued to benefit from the Temporary Authorization of Use (ATU) granted by the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM). The Company has implemented measures to protect its staff against Covid-19 by encouraging remote working for all employees. 3.4.2OUR FUTURE SUCCESS DEPENDS ON OUR ABILITY TO RETAIN KEY EMPLOYEES, CONSULTANTS AND ADVISORS AND TO ATTRACT, RETAIN AND MOTIVATE QUALIFIED PERSONNEL, AND MEMBERS OF OUR MANAGEMENT TEAM MAY BE AFFECTED BY CONFLICTS OF INTEREST TO THE EXTENT THAT THEY SERVE IN MANAGEMENT OR DIRECTORSHIP CAPACITIES AT OUR COMPETITORS. We are highly dependent on members of our executive team, the loss of whose services may adversely impact the achievement of our objectives. While we have entered into employment agreements with each of our executive officers, any of them could leave our employment at any time, as all of our employees are “at will” employees. We currently do not have “key person” insurance on any of our employees. The loss of the services of one or more of our current employees might impede the achievement of our research, development and commercialization objectives. Recruiting and retaining other qualified employees, consultants and advisors for our business, including scientific and technical personnel, will also be critical to our success. There is a shortage of skilled individuals with substantial gene therapy experience, which is likely to continue. As a result, competition for skilled personnel, including the area of gene therapy research and vector manufacturing, is intense and the turnover rate can be high. We may not be able to attract and retain personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies and academic institutions for individuals with similar skill sets. In addition, failure to succeed in preclinical studies or clinical trials or applications for marketing approval may make it more challenging to recruit and retain qualified personnel. The inability to recruit, or the loss of services of certain executives, key employees, consultants or advisors, may impede the progress of our research, development and commercialization objectives and could have a material adverse effect on our business, financial condition, results of operations and prospects. 3.4.3WE MAY NOT BE SUCCESSFUL IN OUR EFFORTS TO IDENTIFY OR DISCOVER ADDITIONAL PRODUCT CANDIDATES AND MAY FAIL TO CAPITALIZE ON PROGRAMS OR PRODUCT CANDIDATES THAT MAY BE A GREATER COMMERCIAL OPPORTUNITY OR FOR WHICH THERE IS A GREATER LIKELIHOOD OF SUCCESS. Because we have limited resources and access to capital to fund our operations, we must decide which product candidates to pursue and the amount of resources to allocate to each. Our decisions concerning the allocation of research, collaboration, management and financial resources towards particular product candidates may not lead to the development of viable commercial products and may divert resources away from more promising opportunities. Similarly, our potential decisions to delay, terminate or collaborate with third parties with respect to some of our product development programs may also prove not to be optimal and could cause us to miss valuable opportunities. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights. If we make incorrect determinations regarding the market potential of our product candidates or misread trends in the pharmaceutical industry, our business prospects could be harmed. The success of our business currently depends primarily upon our ability to identify, develop and commercialize our lead product candidates, LUMEVOQ® and GS030, as well as to identify other product candidates based on our MTS and optogenetics technology platforms. However, we may be unsuccessful in identifying potential product candidates for development. Alternatively, our potential product candidates may be shown to have harmful side effects or other characteristics that could make the products unmarketable or unlikely to receive marketing approval. If we are forced to abandon our development efforts for a program or programs, this would likely have a material adverse effect on our business and could potentially cause us to cease operations. 3.4.4WE MAY BE SUBJECT TO PRODUCT LIABILITY LAWSUITS. We face an inherent risk of product liability exposure related to the testing of our product candidates in clinical trials and may face an even greater risk if we commercialize any products that we may develop. If we cannot successfully defend ourselves against claims that our product candidates caused injuries, we could incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in: •decreased demand for any product candidates that we may develop; •loss of revenue; •substantial monetary awards to trial participants or patients; •significant time and costs to defend the related litigation; •withdrawal of clinical trial participants; •the inability to commercialize any product candidates that we may develop; and •injury to our reputation and significant negative media attention. 3.5Legal risks and risks related to our intellectual property 3.5.1WE DO NOT OWN ANY ISSUED PATENTS AND OUR RIGHTS TO DEVELOP AND COMMERCIALIZE OUR PRODUCT CANDIDATES ARE SUBJECT TO THE TERMS AND CONDITIONS OF INTELLECTUAL PROPERTY LICENSES GRANTED TO US BY OTHERS. Although since 2016 we have in-licensed at least 10 U.S. and foreign patent applications and at least 22 U.S. and foreign patents, we do not currently own any issued patents, and we are heavily reliant upon licenses to certain patent rights and other third party intellectual property rights that are important or necessary to the development and commercialization of our technology and products, including technology related to our manufacturing process and our gene therapy product candidates. Any of our patent applications may not be granted, and these intellectual property licenses and any patents that issue from these applications may not provide us with rights to use such intellectual property and technology in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and products in the future. In particular, there may be unforeseen areas of technology over which the licensed rights, or any patents that issue from our pending applications, may not extend and for which we may be unable to obtain rights in the future. To the extent our licenses do not cover a relevant field or territory, the third-party licensor of applicable intellectual property rights may block our ability to develop or commercialize our technology and products in such field or territory unless we are able to extend our license to cover such field or territory. Further, our licenses may not provide us with exclusive rights to use such intellectual property in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and products in the future. As a result, we may not be able to prevent competitors from developing and commercializing competing products in fields and/or territories included in our licenses. In some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain or enforce the patents, covering technology licensed to us by third parties. For example, pursuant to our intellectual property license agreement with Adverum Biotechnologies, Inc., or Adverum, Adverum retains control of such activities. Therefore, we cannot be certain that the Adverum patent applications will be prosecuted, maintained and enforced in a manner consistent with the best interests of our business. If our licensors fail to prepare, file, maintain or enforce such patents or patent applications, or lose rights to such patents or patent applications, the rights licensed to us may be reduced or eliminated and our right to develop and commercialize any of our product candidates that are the subject of such licensed rights could be adversely affected. In addition, we face similar risks and uncertainties regarding our pending patent applications and any other patent rights that we may own in the future. In some circumstances, our license agreements provide that we must grant, on a non-exclusive royalty-free basis, a license to the licensor to exploit technological improvements we have made to the licensed technology. Such “grant-back” provisions may limit our exclusive rights in technology we develop in-house, and so may hinder the extent to which we can prevent competitors from developing and commercializing competing products relating to those technologies. We also in-licensed certain patents owned by the Regents of the University of California as Head Licensor through our license agreement with Adverum and we in-license certain patent rights from the Massachusetts Institute of Technology, or M.I.T. Under applicable law, to the extent that the research giving rise to the patents or technology so licensed was funded by the U.S. government, the U.S. government may have certain rights, including (1) a non-exclusive, irrevocable, paid-up license to practice or have practiced such patents or technology on behalf of the United States and (2) “march-in rights” requiring the grant of licenses under such patent rights and technology to one or more third parties. When new technologies are developed with U.S. government funding, the U.S. government generally obtains certain rights in any resulting patents and inventions, including a non-exclusive license to practice or have practiced on behalf of the U.S. government such patents and inventions. These rights may further permit the U.S. government to disclose our confidential information to third parties and to exercise march-in rights to allow third parties to use our licensed technology. The U.S. government can exercise its march-in rights if it determines that action is necessary because we or our licensors fail to achieve practical application of the U.S. government-funded technology, or because action is necessary to alleviate health or safety needs, to meet requirements of federal regulations or to give preference to U.S. industry. In addition, our rights in such inventions may be subject to certain requirements to manufacture products embodying such inventions in the United States. Any exercise by the U.S. government of such rights could harm our business, financial condition, results of operations and prospects. In addition, licenses to additional third-party technology and materials that may be required for our development programs, including additional technology and materials owned by any of our current licensors, may not be available in the future or may not be available on commercially reasonable terms, or at all, which could have an adverse effect on our business and financial condition. 3.5.2WE OR OUR LICENSORS MAY BE UNABLE TO OBTAIN AND MAINTAIN ADEQUATE PATENT PROTECTION FOR OUR PRODUCT CANDIDATES AND TECHNOLOGY. Our success depends, in large part, on our and our licensors’ ability to obtain and maintain patent protection in the United States, the European Union and other countries with respect to our proprietary product candidates and manufacturing technology. We or our licensors have sought and we intend to further seek, to protect our proprietary position by filing patent applications in the United States, the European Union and other jurisdictions related to many of our novel technologies and product candidates that are important to our business. If we or our licensors fail to obtain and maintain patent or other protection for this proprietary intellectual property, we could lose our rights to such intellectual property or our exclusivity with respect to those rights, and our competitors could market competing products using such intellectual property. The patent prosecution process is expensive, time-consuming and complex and we or our licensors may not be able to, or may choose not to, file, prosecute, maintain or enforce in a timely manner, or at all, all issued patents or patent applications that we believe are necessary or desirable for our business. In addition, patents might not be issued or granted with respect to our patent applications that are currently pending, and any issued patents may be challenged, invalidated, circumvented or rendered unenforceable. We cannot assure that either we or our licensors will be successful should such patents be challenged. If our or our licensors’ patent claims are rendered invalid or unenforceable, or narrowed in scope, it could seriously impair our competitive position. Consequently, we would not be able to assert any such patents to prevent others from using our technology for, and developing and marketing competing products to treat, our indications of interest. It is also possible that we will fail to identify patentable aspects of our research and development output in timely manner to obtain patent protection. In some cases, the work of certain academic researchers in the gene therapy field has entered the public domain, which we believe precludes our ability to obtain patent protection for certain inventions relating to such work. Consequently, we will not be able to assert any such patents to prevent others from using our technology for, and developing and marketing competing products to treat, our indications of interest. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection. We may not be aware of all third-party intellectual property rights potentially relating to our current and future product candidates. Because patent applications in the United States and most other countries are confidential for a period of time after filing, and some remain so until issued, and because publication of discoveries in the scientific or patent literature often lags behind actual discoveries and filings of patent applications, we cannot be certain of the priority of inventions covered by any pending patent applications. Accordingly, with respect to our current patent applications and any patent applications that we may file in the future in the European Union or the United States, we may not be the first to file patent applications covering such subject matter, meaning that we may be unable to protect or exploit the invention(s) concerned. Furthermore, for U.S. patent applications in which all claims are entitled to a priority date before March 16, 2013, we may become subject to interference proceedings or derivation proceedings before the United States Patent and Trademark Office, or the USPTO, to determine priority of invention. For U.S. patent applications containing a claim not entitled to priority before March 16, 2013, there is a greater level of uncertainty in the U.S. patent laws in view of the passage of the Leahy-Smith America Invents Act, or the Leahy-Smith Act, signed into law on September 16, 2011, which brought into effect significant changes to these laws, including new procedures for challenging pending patent applications and issued patents. Even if the patent applications that we own or license from third parties or may own in the future do issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors or other third parties from competing with us or otherwise provide us with any competitive advantage. Our competitors or other third parties may be able to design around or otherwise circumvent our or our licensors’ patents by developing similar or alternative technologies or products in a non-infringing manner. The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our licensors’ patents, or any patents that we may independently seek may be challenged in the courts or patent offices in the United States, the European Union or elsewhere. Such challenges may result in loss of exclusivity or in patent claims being narrowed, invalidated or held unenforceable, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and product candidates. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our intellectual property rights may not provide us with sufficient protection to exclude others from commercializing product candidates similar or identical to ours. 3.5.3WE MAY FAIL TO COMPLY WITH OUR OBLIGATIONS UNDER THE AGREEMENTS UNDER WHICH WE IN–LICENSE INTELLECTUAL PROPERTY AND COULD THEREBY LOSE LICENSED RIGHTS THAT ARE IMPORTANT TO OUR BUSINESS. We are a party to a number of intellectual property license agreements, including agreements with Inserm Transfert S.A., Adverum and M.I.T. that are important to our business, and we expect to enter into additional license agreements in the future. Our existing license agreements impose, and we expect that any future license agreements will impose, various diligence, development and commercialization timelines, milestone payments, royalties and other obligations on us. See Section 5.5.5 “Intellectual Property” and Section 20.2 “In-License Agreements” of this Universal Registration Document for a description of our license agreements. If we fail to comply with our obligations under these agreements, or are subject to a bankruptcy or certain other specified events, the licensor may have the right to terminate the license, in which event we would not be able to market products covered by the license. Further, in certain of our license agreements, we have the first right to bring actions against any third party infringers of the patents licensed to us. Certain of our license agreements also require us to meet development thresholds to maintain the license, including establishing a set timeline for developing and commercializing product candidates and minimum yearly diligence obligations in developing and commercializing the product. Disputes may arise regarding intellectual property subject to a licensing agreement, including: •the scope of rights granted under the license agreement and other interpretation-related issues; •the extent to which our technology and processes infringe any intellectual property of the licensor that is not subject to the licensing agreement; •the sublicensing of intellectual property and other rights under our collaborative development, manufacturing and other third-party relationships; •our diligence obligations under the license agreement and what activities satisfy those diligence obligations; •the inventorship or ownership of intellectual property resulting from the joint creation or use of intellectual property by our licensors, consultants, contractors, collaborators or partners and us; and •the priority of invention of patented technology. If disputes over intellectual property that we have in-licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize the affected product candidates. 3.5.4WE MAY NOT BE ABLE TO PROTECT OUR INTELLECTUAL PROPERTY RIGHTS THROUGHOUT THE WORLD. Our patent applications and in-licensed patent rights may not have corresponding patents or patent applications in other countries. In addition, the laws of some other countries do not protect intellectual property rights to the same extent as federal and state laws in the United States or patent laws in Europe. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States and Europe, or from selling or importing products made using our inventions in and into the United States or in Europe or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection or may export otherwise infringing products to territories where we have patent protection, but enforcement is not as strong as in the United States or in Europe. These products may compete with our products, patents or other intellectual property rights that we license from third parties. Proceedings to enforce our intellectual property rights in other jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our in-licensed patents, or patents we may own, at risk of being invalidated or interpreted narrowly and our in-licensed patent applications, or patent applications we own or may own in the future, at risk of not issuing and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or in-license. 3.5.5THIRD PARTIES MAY INITIATE LEGAL PROCEEDINGS ALLEGING THAT WE ARE INFRINGING THEIR INTELLECTUAL PROPERTY RIGHTS, THE OUTCOME OF WHICH WOULD BE UNCERTAIN AND COULD HAVE A MATERIAL ADVERSE EFFECT ON THE SUCCESS OF OUR BUSINESS. Our commercial success depends upon our ability and the ability of our existing or future collaborators and third-party service providers to develop, manufacture, market and sell our product candidates and use our proprietary technologies without infringing the proprietary rights and intellectual property of third parties. The biotechnology and pharmaceutical industries are characterized by extensive and complex litigation regarding patents and other intellectual property rights. We may in the future become party to, or be threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our product candidates and technology, including interference proceedings, post-grant review and inter partes review before the USPTO, the EPO or equivalent measures outside the United States and the European Union. Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future, regardless of their merit. We are aware of certain third-party patents relating to gene delivery to ocular cells and certain vector manufacturing methods that may relate to, and potentially could be asserted to encompass our product candidates. There is a risk that third parties may choose to engage in litigation with us to enforce or to otherwise assert their patent rights against us. A court of competent jurisdiction could hold that these third-party patents are valid, enforceable and infringed by us, which could materially and adversely affect our ability to commercialize our LUMEVOQ® or GS030 product candidates or any other of our product candidates or technologies covered by the asserted third-party patents. In several major territories, including the United States, in order to successfully challenge the validity of any such U.S. patent in federal court, we would need to overcome a presumption of validity. As this is a high burden requiring to present clear and convincing evidence as to the invalidity of such U.S. patent claim, there is no assurance that a court of competent jurisdiction would invalidate the claims of any such U.S. patent. In addition, even if we were to prevail in any such litigation, the cost and diversion of management and employee attention could be significant and could adversely affect our business. Where a patent issued by the EPO, otherwise known as a European Patent, is concerned, it may be necessary to do this on a country-by-country basis, leading to increased litigation costs and diversion of management and employee attention. The risks of such third-party action equally apply outside the United States or the European Union, where it may also be necessary to establish, through a court or other procedure, that a patent is invalid. If we are found to infringe a third party’s valid and enforceable intellectual property rights, we could be forced, including by court order, to cease developing, manufacturing and commercializing the infringing technology or product candidates. In addition, we could be found liable for monetary damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent or other intellectual property right. A finding of infringement could prevent us from manufacturing and commercializing our product candidates or force us to cease some of our business operations. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business, financial condition, results of operations or prospects. We may be able to avoid such an outcome by obtaining a license from such third party to continue developing, manufacturing and marketing our product candidates and technology; however, we may not be able to obtain such a license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us, and it could require us to make substantial licensing and royalty payments. 3.6Insurance and risk management We have implemented a policy to cover the main insurable risks with coverage amounts that we deem compatible with the nature of our operations. The total amount of premiums booked for all of our insurance policies for the fiscal year ended December 31, 2021 amounted to €76 K. As a development-stage business, we are unable to quantify risk to determine a coverage amount, in particular with respect to civil liability. However, we consider that the insurance policies described below adequately cover the risks inherent to our operations and that our insurance policy is consistent with practice in our sector. We do not envisage any particular difficulty in maintaining appropriate levels of insurance in the future subject to market conditions and capacities. Please note that as of the date of this Universal Registration Document, the insurance policies related to RESCUE, REVERSE, REALITY and CLIN01 trials have been terminated, as the trials they covered are finished. Our insurance policies are summarized below: Risks covered Insurer Amount Excess per claim Comprehensive professional insurance GENERALI (N° AT060531) Globally capped at €5,900 K (2021 amounts) Sub-limits for operating direct damages and additional costs combined: •Climate events (excluding natural disasters) €1,000 K •Electrical damages €300 K •Machinary breakdown €900 K •Costs and losses €1,000 K •Liability, including use of third parties €4,500 K •Automatic guarantee €500 K •Error or omissions €500 K •Other damages €2,000 K Sub-limits for direct damages •Theft €100 K •Computer equipment breakdown €700 K •Asset in travel status and/or transport for own account €100 K •Asset in deposit with third parties, limited to fire and assimilated events €2,000 K •Glass breakage €20 K •Research and Development expenses €250 K Directors & Officers civil liability insurance: claims made or pursued worldwide AIG (7.919.283) Capped at €5,000 K except for: (per “insured year”) Reputation damage €100 K Psychological support €50 K Consulting fees in case of extradition €50 K Support expenses in case of property restrictive measures €60 K per insured person with a maximum amount of €200 K per insured year Risk mitigation expenses €500 K per insured year, with a maximum amount of €1,000 K for all insured persons Consulting fees related to a judicial liquidation €50 K Preliminary investigation expenses following a social action ut singuli €250 K Non-separable fault €5,000 K Fund for prevention for financial difficulties €30 K Consulting fees on the WCAM regulation within the framework of a group action related to financial securities €50 K Emergency fees €1,000 K Independent Director €1,000 K Claim related to a pollution €1,000 K Civil Liability CHUBB (N° RC0099500275) Civil operating liability: All damage taken together including bodily harm: €7,500 K per “claim” •Inexcusable fault €1,000 K per victim capped at €3,000 K per “insured year” •All “material” and “non-material” damage including: €1,500 K per “claim” —“non-consecutive non-material damage” €200 K per “claim” €1,500 —“property damage” €50 K per “claim” €1,500 —“any damage resulting from accidental pollution” €300 K per “insured year” €1,500 Criminal defense-Appeal €30 K per dispute €1,500 Civil product liability: All damage taken together including bodily harm: €5,000 K €10 K •“Non-consecutive non-material damage” €200 K except for professional civil liability €1,000 K €10 K Employee Travel Insurance CHUBB (N° FRBBBA22378) Death or total permanent invalidity Up to €500 K depending on the person insured Assistance (for individuals and legal assistance abroad, business assistance, travel incident assistance) Travel incidents: up to €15 K, Legal assistance: up to €20 K Medical insurance and luggage and professional equipment insurance No limitation for medical insurance out of the country of residence and €5 K for luggage and professional equipment Civil responsibility Up to €7,500 K Homeworkers Policy RSA •Employer’s liability Limit of Indemnity any one Event (excluding liability arising directly or indirectly out of Terrorism) £10,000 K Limit of Indemnity any one Event arising directly or indirectly out of Terrorism £5,000 K •Public Liability / Product Liability Limit of Indemnity any one Event £2,000 K Limit of Indemnity any one Period of Insurance in respect of Products £2,000 K Limit if Indemnity any one Period of Insurance in respect of Pollution £2,000 K •Legal Defense Costs Limit of Indemnity in any one Period of Indemnity £250 K •Legal Expenses Insurance Limit any One Claim £100 K Limit in total for all claims in any one Period of Insurance £1,000 K Personal Accident and Travel Policy •Personal Accident Cover AIG £25 K •Travel Up to £5,000 K Research sponsor’s civil liability insurance Study GS-LHON-CLIN-03A in mainland France and its overseas departments and territories: HDI Gerling •Victim €1,000 K €1,500 per victim capped at €16 K per protocol •Research protocol €6,000 K •Claims made during an insurance year by one and the same sponsor for several research protocol €10,000 K Study GS-LHON-CLIN 03A in Italy, U.K. and USA: ALLIANZ •ITALY —Per victim €1,500 K —Per research protocol €5,000 K •UNITED KINGDOM —Per research protocol £5,000 K •UNITED STATES —Per research protocol $5,000 K Study GS-LHON-CLIN-03A in Germany ALLIANZ •Per victim €500 K —if up to 1,000 patients participate in this trial €5,000 K —if more than 1,000 patients and up to 3,000 participate in this trial €10,000 K —if more than 3,000 patients participate in this trial €15,000 K Study GS-LHON-CLIN-03B in France métropolitaine and DOM-TOM: HDI Gerling •Per victim €1,000 K €1,500 per victim capped at €16 K per protocol •Per research protocol €6,000 K •Claims made during an insurance year by one and the same sponsor for several research protocol €10,000 K Study GS-LHON-CLIN-03B in Italy, U.K. and USA ALLIANZ •ITALY —Per victim €1,500 K —Per research protocol €5,000 K •UNITED KINGDOM —Per research protocol £5,000 K •UNITED STATES —Per research protocol $5,000 K Study GS-LHON-CLIN-03B in Germany ALLIANZ •Per victim €500 K —if up to 1,000 patients participate in this trial €5,000 K —if more than 1,000 patients and up to 3,000 participate in this trial €10,000 K —if more than 3,000 patients participate in this trial €15,000 K GS-LHON-CLIN-05 HDI Global SE •FRANCE —Per victim €1,000 K €1,500 per victim capped at €16 K per protocol —Per research protocol €6,000 K —Claims made during an insurance year by one and the same sponsor for several research protocol €10,000 K •ITALY ALLIANZ —Per victim €1,500 K —Per research protocol €5,000 K •UNITED KINGDOM ALLIANZ —Per research protocol £5,000 K •UNITED STATES ALLIANZ —Per research protocol $5,000 K •BELGIUM HDI Global SE —Per victim €650 K —Per research protocol €5,000 K •TAIWAN Allianz GCS —Per victim €500 K —Per research protocol €2,000 K •SPAIN HDI Global SE —Per victim €250 K —Per research protocol €2,500 K Per protocol and annually GS-LHON-CLIN-06 •FRANCE HDI Global SE —Per victim €1,000 K €1,500 per victim capped at €16 K per protocol —Per research protocol €6,000 K —Claims made during an insurance year by one and the same sponsor for several research protocol €10,000 K •ITALY CNA —Per victim €1,000 K —Per research protocol ▪If # subject less than or equal to 50 €5,000 K ▪If # subject more than 50 but less than 200 €7,500 K ▪If # subject more than 200 €10,000 K •UNITED KINGDOM CNA —Per victim £5,000 K —Per research protocol £5,000 K •UNITED STATES CNA —Per victim $5,000 K —Per research protocol $5,000 K •GERMANY HDI Global SE —Per victim (for death) €50 K for patient of 18 up to 64 €37.5 K for patient of 65 up to 69 €25 K for patient of 70 up to 74 —Per victim (for disability) €100 K for patient of 18 up to 64 €75 K for patient of 65 up to 69 €50 K for patient of 70 up to 74 GS030-CLIN-001 HARDY •UNITED STATES —Per claim, per research subject $5,000 K —Per clinical trial $7,500 K —Globally during the period of insurance $7,500 K •FRANCE HDI Global SE —Per victim €1,000 K €1,500 per victim capped at €16 K per protocol —Per research protocol €6,000 K —Claims made during an insurance year by one and the same sponsor for several research protocol €10,000 K •UNITED KINGDOM CAN/HARDY —Per victim £5,000 K —Per research protocol £5,000 K Although we maintain insurance coverage for our clinical trials in the amount of €1 million per victim, €6 million per protocol and €10 million in the aggregate over a one-year period, this insurance may not be adequate to cover all liabilities that we may incur. We anticipate that we will need to increase our insurance coverage each time we commence a clinical trial and if we successfully commercialize any product candidate. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise. 3.7Internal control and risk management procedures As part of its listing on Euronext Paris, the Company has implemented an internal control policy and a certain number of procedures. Over time, the Company seeks to conform to AMF recommendations for small and medium-sized companies with regard to internal control. The internal control procedures implemented by the Company are intended to: •ensure control over operations, employee behavior and optimal resource management, in accordance with the framework defined by management, laws and applicable regulations; •anticipate and control the risks inherent to the Company’s activities, whether operational, industrial or financial. 3.7.1GENERAL INTERNAL CONTROL ORGANIZATION. Internal control within the Company is handled, in fine, by the Board of Directors, assisted by the Audit and Compensation Committees. The Company is managed operationally by two internal committees, the Executive Committee and the Management Committee. Executive Committee Upstream of the Board of Directors, and more operationally, an Executive Committee (ComEx) ensures compliance with current procedures. This Committee meets once a week, and consists of the chief financial officer, chief medical officer, SVP commercial head and chief executive officer, who chairs it. The Executive Committee assists the chief executive officer in the Company’s strategic and operational management. Management Committee The Executive Committee is supported by a Management Committee (CoDir), which is the operational review body for the Company’s projects. The Management Committee meets once a week and consists of the members of the Executive Committee and the Company’s principal managers. It meets to monitor performance and adjust the operational orientation, if needed. The Company’s Management Committee is a true place for exchange and reflection and plays a role in controlling and coordinating all operational teams. The Management Committee is responsible for meeting the Company’s annual corporate objectives. 3.7.2INTERNAL CONTROL AND RISK MANAGEMENT PROCEDURES. The procedures implemented by the Company as part of its internal control are reviewed and evaluated by the statutory auditors during their annual reviews of half-year and annual consolidated financial statements. The findings of these tasks are shared with the Company’s financial management, allowing it to take corrective measures and improve the Company’s internal control. These findings are also shared with the Audit Committee. 3.7.2.1Financial risk management Accounting and financial information The Company’s accounting is operated by both the financial department and an independent accounting firm using a dedicated ERP system. The recording of accounting items, preparation of accounting information, reporting and corporate reports and documentation are provided internally, while the independent firm provides monthly controls, calculation of the research tax credit (CIR) and tax returns. The work is reviewed and analyzed within the Company’s finance department, which prepares quarterly management reports for operations. These reports enable management to assess current expenses, with respect to the budget and various quarterly forecasts, and to take corrective measures if needed. As of the date of this Universal Registration Document, the Company has implemented the following internal control procedures related to accounting and financial information, as well as the preparation of consolidated financial statements: •the Company maintains, internally, a separation between the production and the control of financial operations, accounting procedures and the preparation of consolidated financial statements; •an independent certified public accounting firm provides payroll management, as well as social security and tax returns; •valuation and assessment of specific financial items, either complex or relying on subjective assumptions, are subcontracted to third-party experts. These items include notably the CIR, the provisions for compensation payable to employees on their retirement, the evaluation of derivative financial instruments and their accounting treatment under IFRS and the expense related to share-based payments; •the Company has implemented an integrated system that provides for book keeping and securing the purchase-to-pay workflow, including electronic approvals, as well as automated entries and payments; •the Company has implemented monthly closing procedures and key controls (Cut-off entries, Bank statement reconciliations, Manual journal entries review, Balance sheet substantiation, Payroll reconciliation, etc.) in order to ensure the reliability of the financial information; and •the Company has also implemented expense-control measures, using an electronic purchase order system. Invoice payments are prepared by the “accounting” function, automatically and electronically transmitted to the bank for payment, and validated by the “controlling” function. Payroll management Payroll is also subcontracted in its entirety to an accounting firm. We performed a monthly three-way reconciliation control (reconciliation between the payroll journal, accounting entries and bank statement) over the documentation received by the third-party provider. 3.7.2.2Operational risk management Given its stage of development, the Company’s operations are primarily: •preclinical and toxicity studies of drug candidates; •pharmaceutical and clinical development of drug candidates. 3.7.2.2.1Preclinical research and toxicity studies of drug candidates These activities are subcontracted to top-tier, specialized international providers operating in accordance with Good Laboratory Practices (GLP) and certified by AAALAC International, a private non-profit organization that is an international reference in assessing the humane animal treatment in experimentation. 3.7.2.2.2Pharmaceutical and clinical development of drug candidates These activities are subcontracted to top-tier, specialized international providers operating in accordance with both Good Laboratory Practices (GLP) and Good Clinical Practices (GCP). The manufacturing of clinical supply is subcontracted to Contract Manufacturing Organizations (CMOs). 3.7.2.3Our internal controls, procedures and policies may fail to ensure adherence to applicable regulations Our internal controls, disclosure controls and procedures and corporate governance policies and procedures are periodically reviewed and updated. Any system of controls, however, is based in part on certain assumptions and can provide only reasonable, rather than absolute, assurances that the objectives of the system are met. Any failure or circumvention of our controls and procedures or failure to comply with regulations related to controls and procedures could have a material adverse effect on our business, financial condition, results of operations and prospects. 4 INFORMATION ABOUT THE ISSUER 4.1Legal and commercial name Our corporate name is “GenSight Biologics S.A.” 4.2Place of registration, registration number and legal entity identifier (“LEI”) We are registered with the Paris Trade and Companies Register under number 751 164 757. The Company is identified under the Legal Entity Identifier (LEI) 549300NK4AB8OUEX1F54. 4.3Date of incorporation, length of life of the issuer We were incorporated on April 17, 2012. The Company’s duration is 99 years from the date of its with the Paris Trade and Companies Register except in the event of early dissolution or extension. 4.4Domicile, legal form, legislation, country of incorporation, address, telephone number and website Our registered office is located at 74, rue du Faubourg Saint-Antoine – 75012 Paris, France (Tel.: +33 (0)1 76 21 72 20). We are a French limited liability corporation (société anonyme) with a Board of Directors, governed by French law, including, in particular, Book II of the French Commercial Code. Our website address is www.gensight-biologics.com The information on the website does not form part of this Universal Registration Document unless that information is incorporated by reference into it. 5 BUSINESS OVERVIEW 5.1Overview We are an innovative clinical-stage gene therapy company with an initial focus on discovering, developing and commercializing novel therapies for severe retinal neurodegenerative diseases. We are developing a pipeline of proprietary product candidates to provide patients with a long-lasting cure for severe inherited retinal diseases for which there are no currently approved treatments. Our current product candidates are designed to be administered in a single treatment to each eye by intravitreal, or IVT, injection. We are leveraging our expertise in ophthalmology, gene therapy and drug development to restore vision by combining a gene therapy-based approach with our proprietary technology platforms of mitochondrial targeting sequence, or MTS, and optogenetics. We believe our technology platforms have broad applicability both within and outside of ophthalmology as well as central nervous system, or CNS, disorders. Our lead product candidate, LUMEVOQ®, is a recombinant AAV2-based gene therapy for the treatment of Leber Hereditary Optic Neuropathy, or LHON, and is currently in the registration phase in Europe and in Phase III clinical trials in the United States. We reported 48-week top-line data from our Phase III clinical trials REVERSE (37 patients) in April 2018 and RESCUE (39 patients) in February 2019, Further follow-up demonstrated sustained efficacy and safety 96 weeks after a single injection in one eye, and clear superiority to published natural history. A third Phase III trial with LUMEVOQ®, REFLECT (98 patients), which was designed under a Special Protocol Assessment with the FDA, reported 78-week top-line data in the June 2021 demonstrating the safety of bilateral injections of LUMEVOQ® and a trend towards greater efficacy for bilateral versus unilateral injections. The follow-up at Year 2 of REFLECT, issued in December 2021, showed that the vision improvement was maintained. Our second most advanced product candidate, GS030, for the treatment of Retinitis Pigmentosa, or RP, is currently in an open-label, dose escalation Phase I/II trial. The first subject was treated in October 2018, and after three cohorts treated with different doses, the Data Safety Monitoring Board (DSMB) recommended the use of the highest dose in the extension cohort. Two patient case studies have shown that patients who had long been blinded by RP recovered the ability to detect, locate and count objects in high-contrast settings. LUMEVOQ® for the Treatment of LHON LHON is an orphan mitochondrial disease that causes the sudden and dramatic loss of vision, leading to bilateral blindness in less than a year, most frequently in teens and young adults and for which we believe there is currently no effective treatment option. LHON is estimated to have a prevalence of between one in 31,000 and one in 40,000 in the United States and the European Union, respectively. LHON originates mainly from mutations in three NADH dehydrogenase mitochondrial genes: ND1, ND4 and ND6. NADH dehydrogenase is an enzyme that acts on NADH and is the key enzyme in cellular and mitochondrial metabolism, the complex that supplies energy to cells that promote vision. ND4 and ND1 mutations account for approximately 70% and 15% of the LHON populations, respectively. Our lead product candidate, LUMEVOQ®, was developed using our MTS technology platform and is designed to treat LHON by restoring the function of NADH dehydrogenase resulting from a mutation in the ND4 gene. Our MTS technology platform facilitates efficient expression of a mitochondrial gene by active delivery of messenger ribonucleic acid, or mRNA, to polysomes located at the mitochondrial surface. This enables the synthesis, translocation, internalization and proper localization of the missing mitochondrial protein into the matrix of the mitochondrion. We believe that our MTS technology is the only existing technology that permits missing mitochondrial proteins to be actively shuttled into the mitochondrion, enabling the restoration of mitochondrial function necessary to effectively treat LHON. LUMEVOQ® received orphan drug designation for the treatment of LHON in the United States and the European Union. We conducted a Phase I/II trial for LUMEVOQ® in France in 15 subjects with long-standing vision loss from LHON with the ND4 gene mutation. This trial established the safety of the gene therapy and selected the therapeutic dose used in the three Phase III clinical trials that evaluated the efficacy and safety of the gene therapy in a larger sample of subjects. RESCUE enrolled LHON patients with an onset of vision loss of less than six months in duration, while REVERSE enrolled patients with an onset of vision loss between 6 and 12 months. REFLECT enrolled patients with an onset of vision loss of less than 12 months. We reported top-line data from our first Phase III clinical trial REVERSE in April 2018, highlighting the favorable safety and tolerability profile of LUMEVOQ®, and showing a clinically meaningful improvement of visual acuity of +11 ETDRS letters in treated eyes at 48 weeks as compared to baseline in all 37 patients. A similar improvement was reported in untreated eyes, and caused the trial not to meet its primary endpoint, defined as a difference of improvement in visual acuity in LUMEVOQ®-treated eyes compared to sham-treated eyes at 48 weeks. We reported additional results at 72 and 96 weeks in October 2018 and May 2019, showing a clinically meaningful improvement of visual acuity from baseline of +15 ETDRS letters in treated eyes, and of +13 ETDRS letters in untreated eyes at Week 96, sustained from Week 72. The trial also demonstrated a statistically significant relative preservation of the structure of the retina in treated eyes, specifically the volume of the retinal ganglion cells and the thickness of the nerve fiber layers, while untreated eyes continued to deteriorate. We also reported increasing improvements in quality of life at both 48, 72 and 96 weeks. In addition, we also observed that 68% of REVERSE subjects achieved a Clinically Relevant Recovery (CRR) from baseline compared to 15% in a natural history study conducted by Santhera(1). We reported similar top-line results from our second Phase III trial RESCUE in February 2019, showing visual acuity in LUMEVOQ® -treated eyes and sham-treated eyes evolving with similar trajectories, worsening to a low point, or nadir, before beginning to improve by Week 48. We reported additional results at 72 and 96 weeks in April and September 2019, showing sustained recovery from nadir. By Week 96, LUMEVOQ®-treated eyes improved by +26 ETDRS letters from nadir, sustained from Week 72, compared to the Week 48 improvement of +13 ETDRS letters. This recovery at Week 96 could not yet completely offset deterioration from baseline through the acute phase: LUMEVOQ®-treated eyes were still below baseline by -9 ETDRS letters, compared to ‑19 ETDRS letters at Week 48. The strength of the bilateral recovery shifted the mean BCVA in both sets of eyes from being off-chart at Week 48 to on-chart at Weeks 72 and 96. In addition, 63% of LUMEVOQ®-treated eyes improved by a clinically meaningful difference of +15 ETDRS letters from nadir. Similarly, 71% of subjects treated with LUMEVOQ® improved by a clinically meaningful difference of +10 ETDRS letters from nadir. We also reported that 63% of REVERSE subjects achieved a CRR from nadir compared to 28% in a natural history study conducted by Santhera(1). The RESCUE and REVERSE trials demonstrated that LUMEVOQ® was well-tolerated, with no unexpected treatment-emergent adverse events, no serious adverse events related to the treatment or procedure, and no suspected unexpected serious adverse reactions. Results of REVERSE and RESCUE trials were published in Science Translational Medicine (December 2020) and in Ophthalmology (January 2021), respectively. To further investigate the bilateral effect observed in both REVERSE and RESCUE trials, we conducted a non-clinical study with non-human primates. In this study, we reported evidence that LUMEVOQ® vector DNA reached the non-injected eye after unilateral IVT. LUMEVOQ® vector DNA was detected or quantified in the contralateral non-injected eyes for 5 of the 6 animals in the treatment group. In addition, vector DNA was detected or quantified in the optic chiasm of all 6 animals. The results of the non-human primate study were published in the journal Molecular Therapy – Methods and Clinical Development in December 2021. In September 2020, a new meta-analysis of the natural history of Leber Hereditary Optic Neuropathy (LHON) was published in the Journal of Neuro-Ophthalmology, the official journal of the North American Neuro-Ophthalmology Society (NANOS). The paper, written by leading global authorities on LHON, confirms the low rate of spontaneous visual recovery in patients with a mutated ND4 gene, the most common cause of the disease. For those 15 years or older at onset of visual loss, only an estimated 11.3% experienced some degree of visual recovery. To contrast the results from RESCUE and REVERSE against the observed natural progression of the disease, we also undertook a statistical analysis comparing the trial results to outcomes from published natural history studies and the registry study REALITY, which the Company conducted in 2018-2020. The statistical comparison showed a significant difference in the evolution of visual acuity among patients treated with LUMEVOQ® versus that of those who were not treated. Treated eyes showed progressive and sustained improvement from Month 12 to Month 52, in contrast to the absence of recovery over the same period for untreated eyes. At Month 18, the difference became statistically significant (p = 0.01). By Month 48, the difference between the mean visual acuity in treated patients and that in untreated patients was both statistically significant (p < 0.01) and clinically meaningful (-0.33 LogMAR, or +16.5 ETDRS letters equivalent, in favor of treated eyes). These findings were published in the journal Frontiers in Neurology in May 2021. The complete results at 96 weeks of our Phase III REVERSE trial and RESCUE trial formed the core body of evidence, along with an indirect comparison against natural history, that supported our filing for marketing authorization in the European Union on September 14, 2020. We believe that the benefits of LUMEVOQ® treatment may prevent further vision loss and/or restore vision, leading to increased autonomy and overall quality of life for affected individuals. Review of the MAA for LUMEVOQ® is ongoing. The Company received an initial set of questions from the EMA at the Day 120 clock stop of the procedure. Initially planned to end in May 2021, the D120 clockstop was extended three times by the EMA for a total of 17 months, following operational issues in producing validation batches (PPQ) at the Company's contract manufacturing partner in the US. GenSight Biologics is working with its partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, engineering lots will be used to confirm the robustness of the corrective actions. GenSight targets the restart of the PPQ campaign in Q3 2022 and to submit responses to the Day 120 questions in October 2022, as agreed with the EMA. The responses will incorporate updates based on the trials that were ongoing when the MAA was filed. •One trial was REFLECT, which was a multi-center, randomized, double-masked, placebo-controlled Phase III study to evaluate the safety and efficacy of bilateral injections of LUMEVOQ® in 98 subjects and which was designed under a Special Protocol Assessment with the FDA. The study reported topline results at the time point of its primary efficacy endpoint (1.5 year after treatment) in June 2021 and 2 years results in December 2021. At 1.5 year after injection, mean best-corrected visual acuity (BCVA) in LUMEVOQ®-treated eyes was statistically significantly better than baseline, whereas the improvement from baseline was not statistically significant in placebo eyes. Consistent with REVERSE and RESCUE, unilaterally treated subjects showed a contralateral effect in their placebo-treated eye. The contralateral effect reduced the difference in the outcomes among LUMEVOQ®- and placebo-treated eyes, and consequently, the trial did not meet the pre-defined primary endpoint. Responder analyses showed that most of the subjects responded to treatment and confirmed that bilateral injections provide better efficacy. Comparison against the worst observed visual acuity (the “nadir”) demonstrated the treatment effect even more strongly. Finally, the favorable safety profile of LUMEVOQ® was again confirmed. A subsequent Year 2 readout demonstrated that the visual improvements were maintained. The year 2 analysis showed that the mean BCVA for bilaterally and unilaterally treated subjects reached 1.32 and 1.44 LogMAR respectively, with an absolute difference between treatment arms of +6 ETDRS letters favoring bilaterally treated subjects. This efficacy was demonstrated more clearly in visual acuity improvements from nadir (worst BCVA recorded from baseline to year 2). Subjects treated bilaterally with LUMEVOQ® saw an improvement in BCVA of (-0.39 LogMAR [+20 ETDRS letters equivalent] and ‑0.34 LogMAR [+17 ETDRS letters equivalent]) in the first-affected eye and second-affected/not-yet-affected eye respectively. Subjects treated unilaterally with LUMEVOQ® showed an improvement of (-0.38 LogMar [+19 ETDRS letters equivalent] and -0.27 LogMAR [+14 ETDRS letters equivalent] in the first-affected eye and placebo-treated eye respectively. The results in the placebo-treated eyes confirm the contralateral effect observed in the three previous Phase III clinical trials. •The second trial that will inform the Day 120 responses is RESTORE, the long-term follow-up study to which subjects in RESCUE and REVERSE were invited. Study results at Year 3 showed sustained treatment effect from a unilateral injection of LUMEVOQ® three years after injection in the RESCUE and REVERSE trials; steady improvement of visual acuity meant that the average visual acuity of the subjects was at an on-chart level at Year 3. The improved vision was matched by increased Quality of Life (QoL) self-reported scores from the subjects. The findings were published in the Journal of Neuro-Ophthalmology (JNO) in August 2021. Year 4 results became available in January 2022 and confirm the durability of the Year 3 results. In the United States, the FDA advised in a Type-C meeting in January 2022 that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials. The Company is engaging with the FDA on the design of such a trial and aims to initiate it as soon as product from the PPQ campaign becomes available towards the end of 2022. On September 6, 2021 the Company announced that Lumevoq® had been granted Promising Innovative Medicine (PIM) designation by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of vision loss due to LHON caused by a confirmed m.11778G > A mutation in the ND4 mitochondrial gene. A PIM designation is an early indication that a medicine is a promising candidate for the MHRA’s Early Access to Medicines Scheme (EAMS) for the treatment, diagnosis, or prevention of life-threatening or seriously debilitating conditions with an unmet need. The EAMS is similar to the Cohort ATU (Autorisation Temporaire d’Utilisation de Cohorte [Cohort Temporary Authorization for use]) program in France. For more information on clinical trials protocols, see Section 5.2.2 “Our Lead Product Candidate: LUMEVOQ® for the Treatment of LHON”, of this Universal Registration Document. GS030 for the Treatment of RP We are developing GS030 for the treatment of diseases of photoreceptor degeneration that include RP and dry age-related macular degeneration, or AMD, with and without geographic atrophy, or GA. We initially focused our studies on the treatment of RP, which is an orphan family of diseases caused by multiple mutations in over 100 genes involved in the visual cycle. On average, RP patients begin experiencing vision loss as young adults, eventually becoming blind around the age of 40 to 45. RP is the most widespread hereditary cause of blindness in developed nations, with a prevalence of about 1.5 million people throughout the world. In Europe and the United States, the prevalence of RP is approximately one in 3,500 and one in 4,000 and the incidence of new patients each year is 15,000 and 20,000. There is currently no existing treatment for RP. GS030 utilizes our novel optogenetics technology platform. Optogenetics is a biologic technique that involves the transfer of a gene that is encoding for a light-sensitive protein to cause neuronal cells to respond to light stimulation. Our platform of optogenetics targets retinal ganglion cells, or RGCs, and modifies them into becoming true photoreceptors. This allows us to confer a photoreceptive function to the healthy and preserved RGCs independent of any specific underlying genetic mutation that caused the original degeneration of photoreceptor cells. Light stimulation, which activates the protein, is amplified and enhanced by an external wearable device designed as goggles. We developed these goggles to amplify the light stimulation upon the transduced neuronal cells and expand vision restoration. We believe our technology would be immediately transferable to any disease in which photoreceptors are lost while RGCs remain, such as dry AMD and GA. Approximately 15 million people are affected with AMD in the United States, with a global prevalence of 170 million, and dry AMD accounts for approximately 80% of all cases of late-stage AMD. Given this, we expect to initiate clinical trials of GS030 for the treatment of dry AMD and GA. GS030 received orphan drug designation for the treatment of RP in the United States and the European Union and advanced therapy medicinal product, or ATMP, classification for the treatment of RP in the European Union. Our preclinical proof-of-concept studies have demonstrated that GS030 can restore light sensitivity in the retina of blind mice and non-human primates. In other preclinical studies, we have also restored visual behaviors in vivo in blind rats using GS030 with demonstrable effects upon their visual cortex. We received approval in December 2017 from the UK’s Medicines and Healthcare Products Regulatory Agency, or MHRA, followed by the French Agence nationale de sécurité du médicament et des produits de santé, or ANSM, in May 2018 and the U.S. FDA in August 2018, to conduct a Phase I/II clinical trial in severely affected RP subjects and treated the first subject in October 2018. The Data Safety Monitoring Board (DSMB) completed all safety reviews of the ongoing PIONEER Phase I/II clinical trial of GS030, GenSight’s novel product combining gene therapy and optogenetics for the treatment of Retinitis Pigmentosa (RP). The DSMB found no safety issue in the third cohort of patients, who received an intravitreal injection with the highest dose (5e11 vg) among the three cohorts studied to date, followed by the use of a wearable optronic visual stimulation device. Based on GS030’s safety profile, the DSMB recommended selecting this dose for the extension cohort and using the protocol without any modification in the cohort. Recruitment of this cohort is ongoing. A case report of a patient, who was treated with a low dose (5e10 vg) of the gene therapy and subsequently experienced visual recovery, was published in Nature Medicine in June 2021. In November 2021, the company reported a second case of a patient with late-stage retinitis pigmentosa (RP), who partially recovered her visual function after treatment with GS030 optogenetic therapy. The second patient had been treated with the medium dose (1.5E11 vector genomes) in her worse-seeing eye. The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030 in October 2021. Our Technology Platforms and Other Applications We believe our integrated technology, which combines gene therapy with our core MTS and optogenetics technology platforms, has the potential to replace or restore the function of retinal cells, either RGCs or photoreceptors that have degenerated in order to regain vision for patients, thereby improving the quality of their lives. Beyond our initial product candidate, LUMEVOQ® for the treatment of LHON, we believe that our MTS technology platform can be applied to treatments for LHON caused by other single mutations, including our second LHON product candidate, GS011, to treat LHON due to mutation in the ND1 gene. Similarly, we believe that GS030 using our optogenetics platform can address any disease of photoreceptor degeneration regardless of the etiology and be entirely transferable to dry AMD or GA, offering a meaningful benefit to these diseases that have significant unmet medical needs. In addition, our MTS and optogenetics technologies have potential applicability outside of our initial focus on severe retinal diseases. We believe our MTS technology platform, given its unique ability to actively shuttle mitochondrial proteins into the mitochondrion, enables the development of treatments for the many indications involving defects of the mitochondrion, including such rare diseases as Kearns-Sayre syndrome and Alpers disease, and possibly more common disorders such as Parkinson’s disease and amyotrophic lateral sclerosis, or ALS. Similarly, we believe this gene therapy approach of our optogenetics platform that permits the introduction of proteins sensitive to light stimulation has broad applicability to indications outside ophthalmology that are receptive to light stimulation, such as congenital deafness, pain treatment and vagus nerve stimulation. We own or have exclusively in-licensed all intellectual property rights covering our MTS and optogenetics platform technologies and our current product candidates. In addition, we hold worldwide commercialization rights to our technology platforms, product candidates and development programs. Because of the orphan nature of LHON and RP, we believe a limited and targeted sales and marketing organization would be able to reach specialized ophthalmology centers and their patients. Our Management and Scientific Team We believe that we have a significant competitive advantage as a result of the collective experience of our management and scientific team in the biotechnology industry, specifically in the areas of ophthalmology and gene therapy. Our Chief Executive Officer and co-founder, Bernard Gilly Ph.D., has over 20 years of experience in the pharmaceutical sector and as an entrepreneur. Other members of our executive management team have significant experience in the discovery and development of gene therapy and ophthalmology drug products. Our co-founder, José-Alain Sahel M.D. Ph.D., is Chairman of Departments of Ophthalmology at the Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts and the Rothschild Ophthalmology Foundation in Paris, France. He was the Director of Institut de la Vision until 2021. Since July 2016, Dr. Sahel has also been appointed Chairman of the Department of Ophthalmology at the University of Pittsburgh Medical Center. Such experience plays a critical role in our core MTS and optogenetics technology platforms and reflects substantial cross-disciplinary knowledge. 5.2Our Product Development Pipeline Our pipeline is comprised of two lead product candidates for the treatment of sight-threatening retinal degenerative diseases, together with preclinical development programs targeting ophthalmic and neurodegenerative diseases. Below is a table summarizing our development programs: We filed for regulatory approval of LUMEVOQ® with the EMA in Europe as planned in September 2020. Depending on the progress of our interactions with regulatory authorities, LUMEVOQ® could then potentially be in a position to be approved in Europe in Q3 2023, subject however to a variety of factors, including changes in regulatory requirements, evolutions in guidance from the FDA, the EMA or other European regulatory authorities, and the occurrence of unexpected events in the approval process, preparation for commercialization or otherwise, any of which could impact our anticipated timeline and our ability to obtain regulatory approval and commercialize LUMEVOQ®. For a description of such factors, see Section 3 “Risk Factors” of this Universal Registration Document. 5.2.1GENE THERAPY IN THE EYE: A WELL-VALIDATED APPROACH. The eye is a validated target organ for gene therapy due to its accessibility, small size, compartmentalization and relative immune privileged status. In addition to having a validated manufacturing process, vectors based on adeno-associated virus, or AAV, are believed to be especially well suited for treating severe retinal diseases because AAV is a small, replication-deficient virus that is non-pathogenic and has a well-documented safety profile. The vectors can be directly injected into the diseased tissue and their effects can be non-invasively observed for efficacy and safety. The blood-ocular barrier prevents the widespread dissemination of locally administered vectors throughout the body. Given the small volume of the eye, the amount of vector needed to achieve a therapeutic effect is low, reducing the amount of vector required to be administered to the patient and reducing potential systemic side effects or immune response. In addition, the reduced volume requirement provides us with the advantage of small-scale manufacturing requirements for clinical trials and potential commercialization. Our Gene Therapy Approach Building on our scientific expertise and clinical experience of our team, we have developed two proprietary technology platforms, MTS and optogenetics. These technologies are combined with a gene therapy-based approach and have the potential to reverse vision loss, thereby improving the quality of their lives. •Our MTS technology platform allows for efficient expression of a mitochondrial gene by active delivery of mRNA to polysomes located at the mitochondrial surface. This allows for the synthesis, translocation, internalization and proper localization of the mitochondrial protein into the matrix of the mitochondrion. We believe that our MTS technology is the only existing technology that permits missing mitochondrial proteins to be actively shuttled into the mitochondrion, to enable the restoration of mitochondrial function necessary to potentially treat a variety of diseases involving defects of the mitochondrion. •Our novel optogenetics technology platform permits the introduction of proteins sensitive to light stimulation and may have broad applicability to indications within ophthalmology and others that are receptive to light stimulation, such as congenital deafness, pain treatment and vagus nerve stimulation. 5.2.2OUR LEAD PRODUCT CANDIDATE: LUMEVOQ® FOR THE TREATMENT OF LHON. We are leveraging our MTS technology platform to develop LUMEVOQ® as a treatment for LHON due to a mutation in the ND4 gene, a rare mitochondrial genetic disease that leads to blindness in teens and young adults. We believe that LUMEVOQ® has the potential to be the first therapy approved by the FDA for the treatment of LHON. We have received orphan drug designation for LUMEVOQ® in the United States and the European Union. LHON Overview LHON is a rare maternally inherited disease caused by defects in mitochondrial genes encoding for proteins called NADH dehydrogenase. LHON causes sudden and dramatic loss of vision, leading to bilateral blindness in less than a year, which reduces patients’ autonomy and greatly alters the patient’s ability to perform daily life activities, including recognizing facial features and expressions. In addition, LHON causes patients and their family’s trauma socially, emotionally and financially, and the quality of life of patients with LHON is generally poor. The onset of vision loss due to LHON typically occurs between 15 and 35 years of age. The following images are representative of the early onset of vision loss due to LHON, as described by patients. LHON is caused by defects in mitochondrial genes encoding for proteins called NADH dehydrogenase. These proteins are part of a large enzyme complex known as the respiratory chain complex I, or complex I, which is active in the mitochondrion. Complex I is one of several enzyme complexes necessary for the creation of adenosine triphosphate, or ATP, which is the main energy source within the cell. Three different genes encoding for three NADH dehydrogenases have been linked to LHON and are considered to be the primary mutations for the disease to manifest: ND1, ND4 and ND6. Although the genetic mutation is present throughout the body, LHON symptoms are almost uniquely limited to retinal ganglion cells, or RGCs. RGCs receive visual information from photoreceptors, and collectively transmit visual information from the retina to the brain via the optic nerve. Over the months after onset, LHON is associated with a significant thinning of the RGC layer. Once the RGCs degenerate, signals can no longer be transmitted to the brain. Patients with LHON typically suffer vision loss over a period of weeks and overwhelmingly both eyes are ultimately affected. Commonly, vision loss is sequential, although some patients report simultaneous bilateral onset. Within 6 months after onset, there is atrophy of the optic nerve. Although maintaining some small element of peripheral vision, the majority of patients with the ND4 mutation become legally blind. For most patients with the ND4 mutation, vision is not recovered. For ND4 patients, studies have shown that the delay between the first affected and second affected eye averages 1.8 month and the duration of progression of vision loss averages 3.2 months. The mean Early Treatment Diabetic Retinopathy Study, or ETDRS, score at 12 months is 14.4 letters in patients. The normal visual acuity score is 20/20 or 20/25, equivalent to an ETDRS score of 85 and 80 letters, respectively. For patients with the most severe vision loss, specifically those who cannot count the fingers of the examiner held very close to their face, even small improvements such as going from off-the ETDRS chart to on the-chart or an improvement by five to 10 ETDRS letters can have a positive impact on functionality and quality of life. The following close-up image depicts a cross-section of the human retina: The layers of the retina are visible in the right panel, and the left panel is a cross-section of the eye including unlabeled viral particles. No Effective Existing Therapies for the Treatment of LHON No treatments for LHON have been approved in the United States. In the European Union, the European Medicines Agency, or EMA, granted Marketing Authorization, or MAA, for Raxone/Idebenone under “exceptional circumstances” as a treatment for LHON in September 2015, though no clinically significant effect of this agent has been demonstrated or studied in randomized clinical trials. A MAA under exceptional circumstances is when comprehensive data cannot be provided, and therefore the MAA is reviewed annually to re-assess the risk-benefit balance, in an annual re-assessment procedure. Market Opportunity for LHON LHON is the most common illness caused by mitochondrial DNA mutations. We estimate the incidence of LHON to be approximately 1,400 to 1,500 new patients who lose their sight every year in the United States and Europe. LHON is estimated to have a prevalence of between one in 31,000 and one in 40,000 in Northern Europe. European and North American studies of LHON patients indicate that the ND4 mutation accounts for up to 70% of LHON cases. In Asian countries, the proportion of ND4 mutation is higher, ranging from 80% to 85%. Our Solution: LUMEVOQ® for the Treatment of LHON LUMEVOQ® is developed through our MTS technology platform and is designed to restore the function of NADH dehydrogenase and therefore improves vision. Our LUMEVOQ® product candidate is a recombinant AAV vector, serotype 2, or AAV2, containing the human wild-type mitochondrial ND4 gene combined with our proprietary MTS technology. We are developing LUMEVOQ® for the treatment of LHON due to the ND4 gene mutation with visual loss of less than one year. Our novel, proprietary MTS platform technology has enabled us to develop LUMEVOQ® with potential advantages, including: •IVT administration, a straightforward and common approach well-accepted by ophthalmologists, in contrast to subretinal injections; •use of the AAV2 vector, which is the most studied of all AAVs, with a demonstrated safety profile and validated manufacturing process; in addition, there are currently no IP rights attached to AAV2 and thus no royalty payments associated with its use; •small viral load administered, decreasing the risk of systemic immunologic response; •injection of small volumes, reducing the likelihood of ophthalmic complications; and •small required volumes, resulting in ease of manufacturing. The following image depicts the schematic design of LUMEVOQ®, which includes the steps listed below the image. LUMEVOQ® allows an efficient expression in the cell nucleus of a mitochondrial wild-type ND4 gene, encoding for a protein which is normally produced in the mitochondrion. ITR: Inverted Terminal Region; PCMV: Promoter cytomegalovirus; cDNA: complementary DNA; ND4: NADH Dehydrogenase Subunit 4. •The ND4 transgene is flanked by two oligonucleotide sequences, referred as MTS1 and MTS2 in the above diagram. •MTS2 allows the ND4 mRNA to be addressed to polysomes that are attached to the outer mitochondrial membrane, where it is translated into ND4 protein. •MTS1, in turn, allows the ND4 protein to be transported through the mitochondrion membrane into the matrix where it integrates the complex I of the respiratory chain in order to restore normal function. Our construction of LUMEVOQ®, that includes the two MTSs and the functional transgene, is what actively drives this into the mitochondrial matrix, and characterizes the unique nature of our MTS platform, as depicted in the following image. Clinical Development Program for LUMEVOQ® We have completed REVEAL, a Phase I/II clinical trial for LUMEVOQ® and our two most advanced Phase III clinical trials, RESCUE and REVERSE, reported top-line results in 2018 and 2019. Both of these Phase III trials are designed as randomized, double-masked, sham-controlled, multi-center clinical trials in Europe and the United States, of LHON subjects with the ND4 mutation with vision loss. RESCUE has enrolled 39 subjects with an onset of vision loss of less than 6 months in duration and REVERSE has enrolled 37 subjects with an onset of vision loss between 6 and 12 months. Based on our regulatory interactions, subjects as young as 15 are included in our Phase III clinical trials. Time since onset of vision loss is considered a major factor in the ability to intervene therapeutically due to the neuro-degenerative nature of LHON and the cell death of the RGCs. We have therefore chosen to evaluate two subject groups in these two Phase III clinical trials based on the onset of vision loss of less than one year. This will allow us to define the efficacy of LUMEVOQ® in early affected populations of subjects at different stages of the disease and to compare an otherwise homogeneous patient population. Our Phase III clinical trials are intended to determine if LUMEVOQ® is an effective treatment in halting or reversing vision loss associated with LHON due to the ND4 mutation. A dose level of 9E10 vg/eye was administered once by IVT injection in both trials to a randomly chosen single eye of each subject. The dose level of LUMEVOQ® in our Phase III clinical trials was determined based on outcomes of the safety and tolerability in our Phase I/II clinical trial. The primary endpoint of the RESCUE and REVERSE clinical trials is based on Best Corrected Visual Acuity, or BCVA, as measured with the ETDRS at 48 weeks post-injection relative to baseline. The patients’ log of the Minimal Angle of Resolution, or logMAR, scores, which are derived from the number of letters they read on the ETDRS chart, will be used for statistical analysis. Both trials have been adequately powered to evaluate a clinically relevant difference of at least 15 ETDRS letters between treated and untreated eyes adjusted to baseline. The secondary efficacy endpoints compare the best seeing eyes that received LUMEVOQ® to those that received sham, and compare worse seeing eyes that received LUMEVOQ® to those that received sham. We will evaluate the proportion of subjects who maintain vision (< ETDRS 15L loss), the proportion of subjects who gain 15 ETDRS letters from baseline, and the proportion of subjects with Snellen acuity of > 20/200. Complementary vision metrics will include automated visual fields, optical coherence tomography, or OCT, and color and contrast sensitivity, in addition to quality of life scales, bio-dissemination and the time course of immune response. Full results of REVEAL were published in BioDrugs in February 2021. REVERSE: Results at 48, 72 and 96 weeks In April 2018, we reported top-line results from REVERSE, our first Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of LUMEVOQ® (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment. Top-line results highlight the favorable safety and tolerability profile of LUMEVOQ®, and demonstrate a clinically meaningful improvement of +11 ETDRS letters (-0.218 LogMAR) in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters (-0.211 LogMAR). Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in LUMEVOQ®-treated eyes compared to sham-treated eyes at 48 weeks. We reported additional results at 72 weeks in October 2018 and 96 weeks in May 2019, showing a continued clinically meaningful improvement of visual acuity of +15 ETDRS letters (-0.308 LogMAR) in treated eyes, and of +13 ETDRS letters (-0.259 LogMAR)(2) in untreated eyes. This improvement, which extends the positive trend that had been reported at Weeks 48 and 72, points to a sustained functional outcome for the trial subjects. The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which limited partial spontaneous recovery is reported in only 8 to 22% of patients with the G11778 ND4 mutation (Lam et al. 2014, Riordan-Eva et al. 1995). The graph below shows the mean change from baseline in visual acuity, in both treated (LUMEVOQ®) and untreated (sham) eyes, over time in LogMAR: Continued bilateral improvement was also observed in contrast sensitivity as determined by Pelli-Robson low-contrast testing. At 96 weeks, LUMEVOQ®-treated eyes and sham-treated eyes gained on average +0.22 LogCS and +0.12 LogCS versus baseline, respectively. In a natural history study conducted by Santhera(3), 15% of subjects who had the 11778A mutation achieved the following definition of spontaneous “clinically relevant recovery” (CRR) from baseline in at least one eye: •Improved by at least 10 ETDRS letters from on-chart visual acuity, or •Improved from off-chart visual acuity to being able to read at least 5 ETDRS letters. By comparison, 68% of REVERSE subjects achieved this definition of CRR in at least one eye at Week 96, with LUMEVOQ®-treated eyes significantly more likely to achieve this than sham-treated eyes (62% vs. 43%, p = 0.0348). The objectively measured endpoints were the effects of LUMEVOQ® on parameters measured with high resolution Spectral-Domain Optical Coherence Tomography (SD-OCT). The trial demonstrated relative preservation of the structure of the retina in both treated and untreated eyes, specifically the volume of the retinal ganglion cells and the thickness of the nerve fiber layers. The critical secondary endpoint of the change in retinal ganglion cell macular volume measured from baseline to Week 96 demonstrated a reduced loss of volume of –0.018 mm3 for LUMEVOQ® eyes and -0.031 mm3 for sham eyes. The secondary endpoint of change in thickness of the papillo-macular bundle of the retinal nerve fiber layer from baseline to Week 96 demonstrated preservation of retinal nerve fibers LUMEVOQ®-treated eyes showing a change in thickness of +1.3 µm and sham eyes showing change in thickness equal to +0.6 µm. The change in thickness of the temporal quadrant of the retinal nerve fiber layer from baseline to Week 96 demonstrated reduced loss of retinal never fibers, with LUMEVOQ® eyes showing a change in thickness of -1.5 µm and sham eyes –2.4 µm. In May 2019, we reported continued quality of life improvements at 96 weeks. All 37 patients in REVERSE were asked to complete the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), a reliable and valid vision-specific quality-of-life instrument that measures patients’ perception of their ability to perform daily activities requiring high-acuity vision and their general sense of well-being. The test defines sub-scales for functions such as near-distance vision and vision-related dependency as well as measures of well-being such as ocular pain and vision-related mental health. These sub-scale scores are aggregated into a composite score, excluding the general health rating question. Well-accepted as a source of patient-reported measures of vision-related function, the questionnaire has been used in many clinical trials. A study in neovascular AMD – which, like LHON, leads to loss of central vision – showed that a clinically meaningful 15-letter change in BCVA was associated with a 4- to 6-point change in the NEI VFQ-25 composite score and in sub-scores in three pre-specified areas (near activities, distance activities, and vision-specific dependency). At Week 96, REVERSE patients reported mean improvement from baseline for NEI VFQ-25 scores in domains important to patients with loss of central vision: near activities, distance activities, vision-specific dependency and composite score. An improvement had already been observed at Week 48, confirming sustained enhancement of ability to perform activities of daily living. In addition, large improvements were also noted in other domains relevant to LHON patients: role difficulties, general vision, and overall mental health. Again, the improvements observed at Week 48 were sustained at Weeks 72 and 96. The relevant comparison in REVERSE is against patients’ own baseline, because the NEI VFQ-25 is assessed by patient; by design, all REVERSE patients received an injection in one eye. NEI VFQ-25 Results from REVERSE Mean change from baseline (absolute score and percent) Composite Score Near Activities Distance Activities Dependency Role Difficulties General Vision Mental Health Week 48 +7.2 +10.4 +9.6 +12.4 +14.5 +10.3 +11.2 23.2% 65.1% 49.8% 100.6% 65.0% 50.9% 81.9% Week 72 +8.1 +9.5 +8.2 +18.9 +15.2 +11.9 +15.2 25.2% 58.1% 42.5% 130.2% 70.9% 54.1% 105.6% Week 96 +9.5 +13.3 +10.7 +18.5 +15.9 +6.5 +16.1 28.8% 78.1% 47.4% 130.2% 78.9% 32.4% 108.2% Clinically relevant difference* +3.90 to +4.34 +4.67 to +6.06 +5.15 to +5.38 +4.72 to +4.98 +3.31 to +4.70 +4.38 to +4.82 +4.70 to +4.88 * Suñer et al. (2009): clinically relevant score differences based on a clinically significant 15-letter BCVA improvement at 12 months. ** The composite score is an average of the vision-targeted sub-scale scores, excluding the general health rating question. Full results of REVERSE were published in Science Translational Medicine in December 2020. RESCUE: Results at 48, 72 and 96 weeks In February 2019, we reported top-line results from RESCUE, our second Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of LUMEVOQ® (rAAV2/2-ND4) in 39 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced up to 6 months prior to study treatment. Visual loss in LHON usually progresses such that vision reaches a nadir in 3 to 5 months, before stabilizing; the duration and severity of this progression to nadir varies from patient to patient. In RESCUE, mean best-corrected visual acuity (BCVA) of LUMEVOQ®-treated eyes and sham-treated eyes evolved with similar trajectories, worsening to a low point before showing an improvement at Week 48. At Week 48, change from baseline for LUMEVOQ®-treated eyes was +0.380 LogMAR (–19 ETDRS letters), while that for sham-treated eyes was +0.392 LogMAR (-20 ETDRS letters). These figures incorporate a recovery from the nadir of vision loss for drug- and sham-treated eyes: mean improvement from nadir was +13 ETDRS letters equivalent in LUMEVOQ®-treated eyes and +12 ETDRS letters equivalent in sham-treated eyes. Due to this bilateral improvement, the primary efficacy endpoint, defined as a +15‑letter difference in visual acuity improvement for LUMEVOQ®-treated eyes compared to sham-treated eyes at 48 weeks, was not met. Planned analysis of other visual functions and anatomic measures showed results broadly consistent with the direction of BCVA evolution: similar trajectories for LUMEVOQ®-treated and sham-treated eyes with the difference in change from baseline not being statistically significant at Week 48. We reported follow-up results at 72 weeks in April and 96 weeks in September 2019, showing sustained recovery from the lowest point, or nadir, experienced in the acute phase of the disease. By Week 96, LUMEVOQ®-treated eyes improved by -0.526 LogMAR (+26 ETDRS letters) from nadir, compared to the Week 48 improvement of -0.257 LogMAR (+13 ETDRS letters) and the Week 72 improvement of -0.413 LogMAR (+21 ETDRS letters). This sustained at Week 96 could not yet completely offset deterioration from baseline through the acute phase: LUMEVOQ®-treated eyes were still below baseline by 0.178 LogMAR (-9 ETDRS letters), compared to 0.380 LogMAR (-19 ETDRS letters) at Week 48. The U-shaped curve thus closely matched that of LUMEVOQ®-treated eyes, so a statistically significant difference in visual acuity between LUMEVOQ®- and sham-treated eyes could not be shown. Time Course of Best-Corrected Visual Acuity (BCVA) in LogMAR The strength of the bilateral recovery shifted the mean BCVA in both sets of eyes from off-chart values at Week 48 to on-chart values at Weeks 72 and 96. In addition, 61% of LUMEVOQ®-treated eyes improved by a clinically meaningful difference of at least -0.3 LogMAR (+15 ETDRS letters) from nadir. Similarly, 71% of LUMEVOQ®-treated eyes improved by a clinically meaningful difference of -0.2 LogMAR (+10 ETDRS letters) from nadir. Contrast sensitivity (CS), a second visual function, evolved in a manner similar to BCVA: while values for LUMEVOQ®-treated eyes and sham-treated eyes remained below baseline, CS also recovered so that the gap to baseline diminished at Weeks 72 and 96 compared to Week 48. The two sets of eyes closely matched each other, so that the difference between their CS values was not statistically significant. Full results of RESCUE were published in Ophthalmology, the journal of the NANOS, in January 2021. In a natural history study conducted by Santhera, 28% of subjects who had the 11778A mutation achieved the following definition of spontaneous “clinically relevant recovery” (CRR) from nadir in at least one eye: •Improved by at least 10 ETDRS letters from on-chart visual acuity, or •Improved from off-chart visual acuity to being able to read at least 5 ETDRS letters. By comparison, 68% of REVERSE subjects achieved this definition of CRR in at least one eye at Week 96, with LUMEVOQ®-treated eyes as likely to achieve this as sham-treated eyes (58% vs. 45%, p = 0.0956). Change from in Best-Corrected Visual Acuity (LogMAR and ETDRS Letter Equivalents) Change from BASELINE Week 48 Week 72 Week 96 LS Mean (SE) (a) n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent GS010 Eyes 37 -0.218 (0.055) +11 37 -0.294 (0.063) +15 37 -0.308 (0.068) +15 Sham Eyes 37 -0.211 (0.055) +11 37 -0.246 (0.063) +12 37 -0.259 (0.068) +13 Change from BASELINE Week 48 Week 72 Week 96 LS Mean (SE) (a) n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent GS010 Eyes 34 +0.380 (0.129) -19 34 +0.192 (0.104) -10 34 +0.168 (0.132) -8 Sham Eyes 34 +0.392 (0.129) -20 33 +0.216 (0.104) -11 34 +0.238 (0.132) -12 (a) Efficacy Endpoint was assessed using a mixed model of analysis of covariance (ANCOVA), with change from baseline at week of interest as the response, and subject, eyes of the subject as random factor, treatment and the baseline LogMAR value as covariates. Change from NADIR(a) Week 48 Week 72 Week 96 Mean (SD) (b) n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent GS010 Eyes 37 -0.487 (0.426) +24 37 -0.553 (0.444) +28 37 -0.566 (0.450) +28 Sham Eyes 37 -0.432 (0.462) +22 37 -0.478 (0.498) +24 37 -0.490 (0.480) +24 Change from NADIR(a) Week 48 Week 72 Week 96 Mean (SD) (b) n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent n LogMAR ETDRS Letters Equivalent GS010 Eyes 34 -0.287 (0.377) +14 34 -0.509 (0.496) +25 34 -0.526 (0.479) +26 Sham Eyes 34 -0.238 (0.325) +12 33 -0.452 (0.495) +23 34 -0.457 (0.485) +23 (a) Nadir was defined as the lowest Visual Acuity value from baseline up to Week of interest. LP/NLP vision was not included in the analysis. (b) Mean change from nadir was calculated using observed values (no data were imputed). REVERSE and RESCUE Safety REVERSE and RESCUE studies demonstrated a consistent safety read-out: LUMEVOQ® was well-tolerated over 96 weeks. There were no serious adverse events in LUMEVOQ®-treated eyes, and no discontinuations due to ocular events. Most frequently seen ocular adverse events in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation, likely related to LUMEVOQ®, and responsive to conventional treatment and without sequelae. There were neither systemic serious adverse events nor discontinuations that were related to study treatment or study procedure. Non-Human Primate Study We conducted a non-clinical study in non-human primates to further investigate the bilateral effect observed in both REVERSE and RESCUE trials. In this study, we reported positive proof of LUMEVOQ® DNA transfer from one eye to the other eye following unilateral intravitreal injection of primates.Tissue samples from the non-injected eye of monkeys that had been unilaterally injected with LUMEVOQ® were found to contain LUMEVOQ® DNA three months after injection, indicating the expression of the therapeutic gene in the contralateral eye. LUMEVOQ® is currently being investigated in an additional ongoing Phase III trial, REFLECT, while patients in REVERSE and RESCUE continue to be followed for a total period of 5 years. REFLECT REFLECT is a multi-center, randomized, double-masked, placebo-controlled Phase III study to evaluate the safety and efficacy of bilateral injections of LUMEVOQ® in subjects with LHON due to the NADH dehydrogenase 4 (ND4) mutation. REFLECT is conducted under a Special Protocol Assessment with the FDA on request of the Agency. The trial enrolled 98 patients with vision loss up to 1 year in duration and will be conducted in multiple centers in Europe and in the U.S. In the active arm, LUMEVOQ® will be administered as a single intravitreal injection to both eyes of each subject. In the placebo arm, LUMEVOQ® will be administered as a single intravitreal injection to the first affected eye, while the fellow eye will receive a placebo injection. The primary endpoint for the REFLECT trial is the BCVA reported in LogMAR at 1.5-Year post-treatment in the second-affected/not-yet-affected eye. The change from baseline in second-affected/not-yet-affected eyes receiving LUMEVOQ® and placebo will be the primary response of interest. The secondary efficacy endpoints include: BCVA reported in LogMAR at 2-Years post-treatment in the second-affected/not-yet-affected eye compared to both placebo and the first-affected eye receiving LUMEVOQ®, OCT and contrast sensitivity and quality of life scales. The first subject was treated in March 2018, and enrollment was completed in July 2019, ahead of schedule. On June 30, 2021, the company reported the topline results from the REFLECT phase III clinical trial, confirming LUMEVOQ® efficacy including better efficacy with bilateral treatment. On December 14, 2021, the company reported topline efficacy and safety results at 2 years post-treatment administration in the REFLECT Phase III clinical trial with LUMEVOQ®. The results show sustained efficacy and safety for bilateral intravitreal injection of the gene therapy, including better efficacy compared to unilateral injection. Significant visual acuity improvement over baseline, with better results for bilaterally injected patients At the primary time point of the analysis, 1.5 years after injection, mean best-corrected visual acuity (BCVA) in LUMEVOQ®-treated eyes was statistically significantly better than baseline, whereas the improvement from baseline was not statistically significant in placebo eyes. Table 1: Change in Best-Corrected Visual Acuity (BCVA versus Baselin, 1.5 Year after Injection 1st-affected eye 2nd-affected eye Bilaterally injected subjects LUMEVOQ 0.23 LogMAR (+12 ETDRS letters equivalent; p = 0.001) LUMEVOQ 0.15 LogMAR (+8 ETDRS letters equivalent; p < 0.05) Unilaterally injected subjects LUMEVOQ 0.15 LogMAR (+8 ETDRS letters equivalent; p < 0.05) PLACEBO 0.08 LogMAR (+4 ETDRS letters equivalent; p = NS) Consistent with REVERSE and RESCUE, unilaterally treated subjects showed a contralateral effect in their placebo-treated eye (Figure 1). The contralateral effect reduced the difference in the outcomes among LUMEVOQ®- and placebo-treated eyes, and consequently, the trial did not meet the pre-defined primary endpoint. The difference of the change from baseline in BCVA between the second affected LUMEVOQ® and placebo-treated eyes was -0.05 LogMAR (+3 ETDRS letters equivalent; p = 0.6080). Figure 1: Best-Corrected Visual Acuity (BCVA) Change fom Baseline (LogMAR) – Eye Groups Note: Differene from baseline LogMAR. LS mean are estimated by mixed models at the eye level, adjusted on baseline, with repeated values for each patient. A dose effect, seen between bilaterally and unilaterally treated subjects, provides new evidence on LUMEVOQ® efficacy. In each group, the BCVAs of both eyes improved from baseline in tandem, but with a higher treatment effect for bilaterally treated subjects (Figure 2). The mean BCVA at 1.5 years for bilaterally and unilaterally treated subjects reached 1.35 and 1.45 LogMAR, respectively, with an absolute difference between arms of +5 letters in favor of bilaterally treated subjects. Figure 2: Mean BCVA over time (LogMAR) – Eye Groups Note: Mean LogMAR at each timepont. Responder analyses show that most of the subjects responded to treatment and confirm that bilateral injections provide better efficacy. Most of the subjects had on-chart BCVAs at 1.5 year (able to read letters on a screen): 85% of bilaterally treated subjects and 72% of unilaterally treated subjects. The REFLECT trial confirmed the favorable safety profile of LUMEVOQ®, with no study discontinuation related to systemic or ocular adverse events. The main ocular adverse event was intraocular inflammation which was mostly mild and responded to conventional treatment. The safety and efficacy profile of LUMEVOQ® from the three phase III trials, RESCUE, REVERSE, and REFLECT is highly consistent across studies. Based on the data from our Phase III trials, we plan to initiate preclinical studies of GS011, our product candidate for the treatment of LHON subjects with the ND1 mutation with vision loss. Phase I/II Dose-Escalation Safety Trial for LUMEVOQ® In 2014, we initiated a 15 subject Phase I/II safety trial of LUMEVOQ® (CLIN-01), which was designed to test the safety and tolerability profile of LUMEVOQ® with ascending doses in subjects with LHON due to the ND4 mutation. Each subject received a single IVT injection of LUMEVOQ® in the more severely affected eye. Subjects enrolled were required to have severe vision loss, with acuities of less than 20/200. The trial included four ascending dose cohorts each comprised of three subjects: 9E9 vector genome per eye, or vg/eye in cohort 1, 3E10 vg/eye in cohort 2, 9E10 vg/eye in cohort 3 and 1.8 E11 vg/eye in cohort 4. Once the maximum tolerated dose was established, according to the protocol, we included three additional subjects in the trial. Overall, LUMEVOQ® was well tolerated with no unexpected treatment-emergent adverse events, no serious adverse events related to the treatment or procedure, and no suspected unexpected serious adverse reactions. The most common ocular side effects were elevated intraocular pressure, or IOP, and ocular inflammation. These side effects were mostly mild, transient and, when required, treatment responsive to standard therapies, without vision loss. The secondary endpoints included immuno-monitoring and vector bio-dissemination, visual acuity, color and contrast vision as well as structural tests such as OCT and electrophysiological tests related to the functioning of the RGCs and the optic nerve. The results of our Phase I/II clinical trial, which were released in June 2016, demonstrated that: •all 15 subjects completed 48 weeks of follow-up; •consistent with the protocol requiring treatment of the worst functioning eye, baseline mean logMAR, visual acuity was worse in the treated eyes than non-treated fellow eyes; •the magnitude of the treatment effect was impacted by disease duration and baseline vision status at the time of treatment; •a greater magnitude of treatment effect was observed when disease duration was less than two years compared to greater than two years; and •the magnitude of treatment effect was greater when the baseline vision status was relatively better. After talks with consultants, we designed our ongoing Phase III trials to target a more homogeneous patient population, with more recently diagnosed (less than 12 months) vision loss, to maximize the benefits and efficacy of treatment. Visual Function Evolution: Trends of Improved Acuity at 2.5 Years of Follow-up In December 2017, we reported results in 14 subjects after 2.5 years of follow-up (one subject withdrew its consent after 48 weeks of follow-up). As described in the following table, we continued to observe a greater magnitude of treatment effect when the disease duration was less than two years as compared to a disease duration that was greater than two years. ETDRS letters (LogMAR) Visual Acuity change from baseline ∆ Treated Eye vs. Untreated Eye 1.0 year 1.5 year 2.0 years 2.5 years All subjects (n = 14) +3 letters (-0.06) +8 letters (-0.16) +0 letters (-0.00) +7 letters (-0.14) Subjects with ≤ 2y disease duration (n = 5) +17 letters (-0.34) +20 letters (-0.40) +14 letters (-0.28) +15 letters (-0.30) Note () Excludes “hand motion” subjects, in accordance with the Phase III protocol. In the following chart, five letters correspond to one line on the ETDRS chart. Therefore, a difference of 15 letters is equivalent to three lines on the ETDRS chart, the widely recognized standard of clinically significant improvement. Evolution of visual acuity in the treated eye vs. untreated eye at 2.5 years of follow-up in subjects with vision loss duration ≤ 2 years and Baseline LogMAR ≤ 2.79 (n = 5) (i.e., excludes “hand motion” subjects, in accordance with the Phase III protocol). Long-term Safety at 5 Years of Follow-Up In February 2021, we published in the journal BioDrugs full results of the REVEAL trial, demonstrating favorable safety and tolerability of LUMEVOQ® over a 5-year follow-up period. Additional Studies REALITY REALITY is a retrospective and cross-sectional observational study of subjects with LHON, conducted in centers across Spain, Italy, France, United Kingdom, and the United States. The objective is to generate insights about the natural history of the disease based on an approach that would facilitate comparisons with REVERSE and RESCUE. The study seeks to enroll 50 subjects by the second quarter of 2020. Interim analysis of REALITY reported in December 2019, based on the fifteen subjects with the ND4 mutation who were at least 15 years old at onset and who had enrolled in the study as of September 2019, shows the dramatic and usually irreversible decline in visual acuity that is the typical outcome for ND4 LHON patients. Unlike in subjects enrolled in REVERSE and RESCUE, who all received a unilateral injection of LUMEVOQ®, mean visual acuity in REALITY subjects did not recover after the initial decline. The results confirm LHON experts’ observations from their clinical practice. Figure 1. LHON Natural History from Interim Analysis of REALITY vs. Time Course of Visual Acuity from REVERSE and RESCUE Note: BCVA = best-corrected visual acuity. The LOWESS line for REALITY (n = 15 subjects) is based on a series of polynomial regressions around each data point. The regressions use a limited look back and look forward and give distant points less weight. The time course of BCVA for REVERSE and RESCUE uses the least-squares mean based on a mixed model ANCOVA analysis. The starting points of the curves are set to the average time from onset to time of treatment (16 weeks for RESCUE, 39 weeks for REVERSE). A second set of results, derived from a pooled dataset of baseline readings from the REVERSE and RESCUE patient populations, shows that eyes farther along the progression of the disease, as measured by time since onset, had worse visual acuity. Figure 2. Best-Corrected Visual Acuity (BCVA) Prior to Injection Among REVERSE and RESCUE Patients, by Time Since Onset Note: Eyes of REVERSE and RESCUE patients were categorized according to the time between onset of vision loss and baseline reading (one day before injection). The n’s represent the number of eyes in each time grouping. By design, the maximum value for onset in the pooled data is 12 months. The average for each group represents the least-squares mean of BCVA values in LogMAR. The y-axis shows an inverted LogMAR scale to represent worse vision with lower vertical positions. The picture of visual decline is based on cross-sectional data, yet remains consistent with the pattern revealed by the interim analysis for REALITY. Statistical analysis of the visual acuity in 23 REALITY subjects aged 15 or older with a mutated ND4 gene shows that on average, vision failed to recover from an initial sudden decline, even several years after vision loss. The sharp deterioration followed by an extended period of low visual acuity stands in sharp contrast with the improvements observed in the LUMEVOQ® RESCUE and REVERSE trials. The study aimed to enroll 50 subjects, but enrollment was curtailed due to measures taken to protect patients in the Covid-19 pandemic. Of the 44 subjects who were enrolled before the Covid-19 measures took effect, 23 were 15 years old or older at the time of vision loss due to their mutated ND4 gene. Of these 23 ND4 subjects, 15 had been treated with idebenone, the majority within 12 months of their vision loss. The RESCUE and REVERSE pivotal trials evaluated the efficacy and safety of a single intravitreal injection of LUMEVOQ® in LHON subjects who were at 0-6 months and 6-12 months, respectively, from onset of vision loss due to carrying a mutated ND4 mitochondrial gene. 61 of the RESCUE and REVERSE subjects accepted the invitation for long-term follow-up in the CLIN06 trial, which recently reported initial results. Indirect comparison to Natural History In order to address the bilateral effect observed in RESCUE and REVERSE, the Company performed a statistical analysis of pooled data from LUMEVOQ® trials and natural history studies demonstrating a statistically significant and clinically meaningful difference between the visual outcomes in LUMEVOQ®-treated patients and untreated patients. Treated patients showed progressive and sustained improvement from Month 12 to Month 52, in contrast to the absence of recovery over the same period for untreated patients. At Month 18, the difference became statistically significant (p = 0.01). By Month 48, the difference between the mean visual acuity in treated patients and that in untreated patients was both statistically significant (p < 0.01) and clinically meaningful (–0.33 LogMAR, or +16.5 ETDRS letters equivalent, in favor of treated eyes). Figure 1. Evolution of Visual Acuity in LUMEVOQ®-treated Patients (N = 76) versus Untreated Patients (N = 208) Note: All patients had a confirmed G11778A mutation in the ND4 mitochondrial gene and were at least 15 years old. The diagram shows the Locally Estimated Scatterplot Smoothing (LOESS) curves for visual acuity in LUMEVOQ®-treated patients and untreated patients. The shaded areas represent the 95% confidence interval for the mean BCVA. “Treated” eyes refer to all eyes (LUMEVOQ® and sham) from the RESCUE, REVERSE and CLIN06 trials (N = 76 patients / 152 eyes). Untreated eyes refer to patient-level data from the REALITY study and a matched data set from two prospective and eight retrospective natural history studies (N = 208 patients / 408 eyes). LOESS curves were estimated using a non-parametric, local regression model that treated each eye as independent of the other. LOESS curves are shown from Month 12 to depict post-treatment progression among treated patients (93% of LUMEVOQ® patients had already been treated within 12 months from onset). Statistically significant difference between mean visual acuity of treated and untreated eyes at M18, M24, M36 and M48, as illustrated by the non-overlapping confidence intervals. The analysis compared data from the completed Phase III trials RESCUE and REVERSE studies and interim results from the long-term follow-up CLIN06 study to a matched sample created from the REALITY registry study and 10 other natural history studies. The natural history studies were identified from an extensive review of the scientific literature and selected based on specific inclusion criteria for their patient-level data. In all, the visual outcomes in 76 treated patients could be compared to the visual outcomes of 208 untreated patients. Separate analysis of patients enrolled in RESCUE and REVERSE demonstrated similarly favorable results compared to untreated patients. Full findings from the indirect comparison were included in the European Marketing Authorization Application (MAA) for LUMEVOQ® and are being prepared for publication in a peer-reviewed journal. In addition, a new meta-analysis of the natural history of Leber Hereditary Optic Neuropathy (LHON) was published in September 2020 in the Journal of Neuro-Ophthalmology, the official journal of the North American Neuro-Ophthalmology Society (NANOS). The paper, written by leading global authorities on LHON, confirms the low rate of spontaneous visual recovery in patients with a mutated ND4 gene, the most common cause of the disease. For those 15 years or older at onset of visual loss, only an estimated 11.3% experienced some degree of visual recovery. The Journal of Neuro-Ophthalmology paper, entitled “Visual Outcomes in Leber Hereditary Optic Neuropathy Patients with the m.11778G>A (MTND4) Mitochondrial DNA Mutation”, overcame the challenge of small patient numbers by conducting a meta-analysis of 12 retrospective and 3 prospective studies, which were identified after an extensive review of the scientific and medical literature. Treatment with idebenone did not exclude patients from the sample. This approach enabled the authors to analyze the evolution of visual function in 695 patients with a mutated ND4 gene. The estimate of the rate of spontaneous recovery in the paper provides important context for the bilateral improvement observed in the pivotal trials RESCUE and REVERSE for GenSight Biologics’ lead product, LUMEVOQ®, a gene therapy for patients with LHON caused by a mutated ND4 gene. In the trials, the rate of clinically meaningful improvement from nadir of at least 0.3LogMAR, or at least 3 lines on the Snellen chart, was 76% in REVERSE and 71% in RESCUE. Non-clinical mechanistic study in primates In 2019, we conducted a non-clinical study to investigate the local biodistribution of LUMEVOQ®. Tissue samples from the non-injected eye of monkeys that had been unilaterally injected with LUMEVOQ® were found to contain LUMEVOQ® DNA three months after injection, indicating the expression of the therapeutic gene in the contralateral eye. Performed by CiToxLAB France, a leading CRO for preclinical research, the study was initiated by GenSight to investigate potential mechanisms behind the unexpected contralateral effect seen in two of LUMEVOQ®’s Phase III trials, REVERSE and RESCUE. Both trials documented sustained bilateral improvements in LogMAR mean visual acuity. The contralateral effect did not conform to expectations for gene therapies administered to only one eye. The CiToxLAB study used a purpose-bred species of monkeys, which is favored by scientists and accepted by regulatory bodies due to physiological similarities with humans. For testing at three months, a control monkey was given an intravitreal injection of saline solution in its right eye and was not injected in its left eye. Three test monkeys were given an intravitreal injection of LUMEVOQ® in their right eyes and not injected in their left eyes. The dosage of LUMEVOQ® was calibrated to be the allometric equivalent of that used in the LUMEVOQ® Phase III trials. Three months after the injection, tissues from the right and left eyes were sampled and tested using a qPCR test which had been validated in a dedicated prior study. The highly sensitive and accurate test contains a protocol that specifically targets a portion of the LUMEVOQ® DNA and can detect the LUMEVOQ® DNA matrix. As expected, the qPCR test did not detect the LUMEVOQ® DNA in any of the tissue samples from the control monkey unilaterally injected with saline solution. Also as expected, the test was able to detect, and in many cases, quantify the presence of LUMEVOQ® DNA in tissue samples from LUMEVOQ®-injected right eye. Remarkably the qPCR test was also able to detect, and even quantify, viral DNA vector in the contralateral eye, which had received no injection. Presence of LUMEVOQ® DNA in the visual and cerebral systems of test monkeys Note: qPCR test used to detect LUMEVOQ® DNA was validated in a dedicated study conducted prior to the monkey study. The graph depicts the number of monkeys whose tissues contained DNA that were within the sensitivity of the test to detect. In some cases, the levels were above the quantifiable threshold. DNA was detected and quantified in the anterior segment, the retina, as well as the optic nerve of the non-injected contralateral eye. In addition, DNA was detected and quantified in the optic chiasm, suggesting that the anatomic route taken by the viral vector DNA from the treated eye to the non-treated eye could be via the optic nerves and chiasm. RESTORE The company reported in January 2022 the results of the RESTORE study, four years after injection. RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials. When RESTORE subjects enrolled in the study, 2 years after the one-time injection, they had already experienced clinically meaningful improvements relative to the lowest point (the “nadir”) of their bestcorrected visual acuity (BCVA): +18.8 ETDRS letters equivalent in their LUMEVOQ®-treated eyes and +17.3 letters equivalent in their sham-treated eyes. Four years after treatment, the bilateral improvement from nadir was sustained, with LUMEVOQ®-treated eyes achieving a mean improvement against nadir of +22.5 letters equivalent and sham-treated eyes demonstrating a mean improvement of +20.5 letters equivalent. The impact of such results on patients is demonstrated by increases in the self-reported quality of life (QoL) scores at Year 4 vs. baseline. Mean overall QoL increased by a clinically meaningful magnitude relative to baseline, driven by clinically meaningful increases in the sub-scores corresponding to mental health and the ability to carry out activities autonomously (e.g., role difficulties, dependency, near and far activities, general vision). RESTORE is one of the largest long-term follow-up studies for a rare disease treatment, with 62 subjects accepting the invitation to enroll. All subjects, who were affected by LHON caused by a mutated ND4 mitochondrial gene, were treated with an intravitreal injection of LUMEVOQ® in one eye and with sham injection in the other. Table 1: BCVA Mean Improvement vs. Nadir in LUMEVOQ® long-term follow-up (RESTORE) 2 Years post-injection 3 Years post-injection 4 Years post-injection LOGMAR (Std Error) Letters Equivalent LOGMAR (Std Error) Letters Equivalent LOGMAR (Std Error) Letters Equivalent LUMEVOQ®-treated eyes -0.375 (0.306) +18.8 -0.410 (0.365) +20.5 -0.453 (0.440) +22.5 Sham-treated eyes -0.346 (0.291) +17.3 -0.367 (0.369) +19.4 -0.406 (0.361) +20.5 Note: The RESTORE sample consists of the RESCUE and REVERSE participants who accepted to be followed in the long-term follow-up study. Year 4 values were the LogMAR readings nearest to 461 days post-treatment recorded between 1461+/- 273 days post-treatment. Missing values were imputed using the Last Observation Carried Forwad (LOCF) method. * Nadir = worst best-corrected visual aculty recorded from baseline to Year4. ** Assessments of best-corrected visual aculty (BCVA) were recorded in LogMAR was converted to “letters equivalent” improvement by multiplying the LogMAR by -50 (ref. J.T. Holladay, J. Refrac Surgery, 1997; 13, 388-391). Responder analyses at Year 4 indicate that improved BCVA was a benefit for a substantial proportion of the study participants. 71.0% of RESTORE subjects achieved Clinically Relevant Recovery (CRR)4 against nadir four years after treatment, and 80.7% of them had on-chart vision (BCVA ≤ 1.6 LogMAR) in one or both eyes. Viewed against the trend in vision typically seen in untreated patients5, the findings represent a significant departure from the natural progression of LHON. Figure 1: Evolution of BCVA in LUMEVOQ®-treated Patients (RESCUE/REVERSE/RESTORE) vs. Untreated Patients Note: The Locally Estimated Scatterplot Smooting (LOESS) curves show the evolution, from 12 months to 52 months after onset of vision loss, of the mean BCVA in all eyes (LUMEVOQ®- and sham-treated) from REVERSE/RESCUE/RESTORE studies and all eyes from a matched cohort of patients not treated with LUMEVOQ®. The shaded areas represent the 95% confidence interval for the mean BCVA. The values < 52 months were set to 52 months. The curve starts at 12 months after onset when 92.7% of eyes in RESCUE and REVERSE had received treatment, either with LUMEVOQ® or a sham injection. The untreated cohort consisted of 208 ND4-LHON patients that wre followed in the REALITY registry and from two prospective and eight retrospective natural history studies Safety findings at 4 years post-injection were consistent with previous readouts, which concluded that LUMEVOQ® is well-tolerated: no serious adverse events were recorded among LUMEVOQ®-treated eyes, and no discontinuations occurred due to ocular events. There were no systemic serious adverse events or discontinuations related to study treatment or study procedure. Regulatory Interaction for LUMEVOQ® In October 2014, we initiated our first discussions with the FDA regarding the prerequisites for future initiation of clinical trials in the United States. In June 2015, we submitted an application in the United States, which was cleared by the FDA on August 19, 2015. Following our meetings with the FDA in April and December 2016, the FDA made recommendations with respect to our RESCUE and REVERSE studies, as well as the bilateral treatment of LHON subjects. Based on these recommendations, a special protocol assessment, or SPA, of a bilateral clinical protocol was submitted to the FDA in July 2017 for subjects with vision loss due to the ND4 mutation. The design and planned analysis of the REFLECT protocol (GS-LHON-CLIN-05) testing the efficacy and safety of bilateral injections of LUMEVOQ® has been agreed to with FDA. In December 2019, the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM), granted a named patient Temporary Authorization for Use (“ATU nominative”) for LUMEVOQ® to the CHNO of the Quinze-Vingts. Dr. Catherine Vignal, who as the prescribing physician originated the request, will be able to use LUMEVOQ® to treat a patient recently affected by Leber Hereditary Optic Neuropathy (LHON). GenSight Biologics committed to provide the drug for a bilateral injection. The temporary authorization is the outcome of a close partnership between physicians and pharmacists from the CHNO of the Quinze-Vingts, the “Ouvrir les yeux” (Open the eyes) patient advocacy group and GenSight Biologics, to the benefit of patients affected by LHON. In France, use of pharmaceutical products not yet approved with a Marketing Authorization (AMM) and not recruiting for a clinical trial requires first obtaining an ATU from the ANSM. Named patient ATUs are granted by the ANSM under the following conditions: •The product is meant to treat, prevent or diagnose a severe or rare disease, •No other appropriate treatment is available in France, •The product’s efficacy and safety are presumed in the state of scientific knowledge, •The ATU is requested by and remains under the responsibility of the prescribing physician when the drug has the potential to benefit the patient. On September 6, 2021 the company announced that LUMEVOQ® had been granted Promising Innovative Medicine (PIM) designation by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of vision loss due to LHON caused by a confirmed m.11778G > A mutation in the ND4 mitochondrial gene. A PIM designation is an early indication that a medicine is a promising candidate for the MHRA’s Early Access to Medicines Scheme (EAMS) for the treatment, diagnosis, or prevention of life-threatening or seriously debilitating conditions with an unmet need. The EAMS is similar to the Cohort ATU (Autorisation Temporaire d’Utilisation de Cohorte [Cohort Temporary Authorization for use]) program in France. In the United States, the FDA advised in a Type-C meeting in January 2022 that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials. The Company is engaging with the FDA on the design of such a trial and aims to initiate it as soon as product from the PPQ campaign becomes available towards the end of 2022. LUMEVOQ® submission for Marketing Authorization On September 14, 2020, the Company has submitted LUMEVOQ® to the EMA for marketing authorization. The Company received an initial set of questions from the EMA at the Day 120 clock stop of the procedure. Initially planned to end in May 2021, the D120 clockstop was extended three times by the EMA for a total of 17 months, following operational issues in producing validation batches (PPQ) at the Company's contract manufacturing partner in the US. GenSight Biologics is working with its partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, engineering lots will be used to confirm the robustness of the corrective actions. GenSight targets the restart of the PPQ campaign in Q3 2022 and to submit responses to the Day 120 questions in October 2022, as agreed with the EMA. Approval is now expected in Q3 2023. 5.2.3OUR SECOND PRODUCT CANDIDATE: GS030 FOR THE TREATMENT OF PHOTORECEPTOR DEGENERATION. We are leveraging our optogenetics technology platform to develop GS030 for the treatment of diseases of photoreceptor degeneration that include RP, dry AMD and GA. Our most advanced clinical program using our optogenetics platform is for the treatment of RP, which is an orphan family of diseases caused by multiple mutations in over 100 genes involved in the visual cycle. There is currently no existing treatment for RP. GS030 has received orphan drug designation for the treatment of RP in the United States and the European Union and advanced therapy medicinal product, or ATMP, classification for the treatment of RP in the European Union. We are currently conducting a Phase I/II clinical trial in end stage, non-syndromic RP subjects. The first subject was treated in October 2018, and we completed the recruitment of the first three cohort in Q3 2020. We anticipate receiving interim data in H2 2022. The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030 in October 2021. Upon evidence of clinical proof of concept in RP and demonstration of our approach, we believe this technology would be immediately transferable to any disease in which photoreceptors are lost while RGCs remain, such as dry AMD and GA. Given this, we expect to initiate clinical trials of GS030 for the treatment of dry AMD and GA. RP Overview RP is the leading cause of hereditary blindness in developed countries. RP represents a group of related genetic eye disorders that clinically manifest in visual disability. The mutations that cause RP are heterogeneous and include recessive, dominant and X-linked forms of more than 100 genes. RP causes progressive vision loss due to degeneration of rod photoreceptors resulting in the loss of peripheral vision followed by degeneration of cone photoreceptors resulting in loss of central vision. The first symptom of RP is usually difficulty with night vision, which may occur as early as childhood. The disease progresses over a period of years or decades and often ultimately leads to complete loss of vision. Some patients become blind as early as age 30, and the majority of patients become legally blind before the age of 60. RP reduces patients’ autonomy and greatly alters the patients’ ability to perform daily life activities. The following images illustrate a representation of the deterioration of normal vision to blindness in RP. No Existing Therapies for the Treatment of RP No treatments for RP have been approved in the United States or the European Union. Other gene therapy approaches under development to treat vision loss due to RP are focused on specific mutations and these therapies, if approved, would be limited to specific patient subpopulations. Another alternative to treat vision loss from RP involves medical devices in the form of retinal implants, certain of which products have received marketing approval in Europe and the United States. Retinal implants have proven to restore some visual perception in patients and are intended for patients with advanced RP who have lost their photoreceptors. Therefore, treatment of RP is considered a significant unmet medical need. Market Opportunity in RP RP is the leading cause of hereditary blindness in developed countries, with a prevalence of about 1.5 million people throughout the world. In Europe and the United States, about 265,000 to 350,000 patients suffer from RP, and every year an estimated 10,000 to 15,000 patients with RP lose their sight. Some studies of prevalence rates of RP may underestimate the number of severely visually impaired patients with RP because they are based on patients with active follow-up care in ophthalmology clinics. We believe that many patients stop seeing ophthalmologists within a few years after reaching blindness because of a perceived lack of treatment and difficulty in traveling to medical centers. Our Solution: GS030 for the Treatment of Photoreceptor Degeneration GS030 is developed through our optogenetics platform and is designed to confer light sensitivity to normally light insensitive retinal neurons, specifically RGCs, in order to restore vision. While there is significant loss of photoreceptor cells in these diseases, RGCs are preserved. Our novel, proprietary optogenetics platform technology has enabled us to develop GS030 with potential advantages over other therapies currently in development, including: •potential to address any photoreceptor degenerative disease independent of genotype; •IVT administration, a straightforward and common approach well-accepted by ophthalmologists, in contrast to subretinal injections; •small viral load administered, decreasing the risk of systemic immunologic response; •injection of small volumes, reducing the likelihood of ophthalmic complications; and •small required volumes, resulting in ease of manufacturing. Our primary optogenetics strategy consists of introducing ChrimsonR, a light-sensitive protein belonging to the channel rhodopsin family into normally light insensitive cells present in the inner retinal layer, particularly RGCs, via a gene therapy product injected into the vitreous of an affected eye. Upon light stimulation, the ChrimsonR protein is activated leading to an electrical response of the cell, which in turn carries electrical signals encoding visual information through the optic nerve into the visual cortex of the brain. This process mimics the natural function of the retina without the need for the initial step of the transduction cascade, which normally occurs in the outer segments of the cone. By stimulating RGCs, partial restoration of retina performance allowing daily life tasks is expected. The figure below illustrates our optogenetics strategy aimed at restoring vision in retinal degenerative diseases, which includes the following steps: The photoswitch gene (gene encoding for ChrimsonR protein) is packaged into an AAV2 7m8 vector. The AAV2 7m8 carries the transgene into RGCs, resulting in synthesis of ChrimsonR protein within the membrane of the RGCs. When appropriate light (590nm wavelength) is shed onto the RGCs expressing ChrimsonR, it results in a depolarization of the cells, creating an action potential which is then transmitted to the visual cortex by the optic nerve. The visual cortex will then assemble the signals to form a useful image. Because cells expressing optogenetic protein are less light sensitive than normal photoreceptors, vision under regular daylight conditions is unlikely to be possible. However, amplifying the light source and mimicking the normal retinal activity of capturing visual information will then amplify the light signal at the appropriate wavelength to enable vision restoration. Product Structure for GS030 GS030 consists of two components: •a gene therapy product comprising a gene encoding a photoactivatable channelrhodopsin protein, ChrimsonR, delivered via a modified AAV2 known as AAV2 7m8; and •an external wearable device in the form of biomimetic goggles that stimulate the engineered retinal cells. The images are projected by a light source that uses a specific wavelength onto the retina. Development Program of GS030 for the Treatment of RP We have conducted numerous preclinical studies including a local tolerance study in mice and a long-term toxicity and biodistribution study in monkeys. GS030 for the treatment of RP is currently in an ongoing Phase I/II trial. The first subject was treated in October 2018, and we are currently recruiting the extension cohort. Preclinical Studies of GS030 in Non-Human Primates GS030 was injected intravitreally in both eyes of monkeys. After two months, the retinas were dissected and connected to a multi-electrode array system to record the electrical activity of RGCs. At regular intervals the firing activity of the transduced RGCs was measured upon light activation at the appropriate wavelength and at varying intensities. The results demonstrate that two months post-injection, the RGCs of non-human primates are active, and have the ability to transmit visual information as normal RGCs would. We conducted a confirmatory study in monkeys to assess the activity of GS030 at various doses and at six months post-injection. GS030 proof-of-concept in non-human primates at six months post-injection In healthy retinas, RGCs fire electric spikes to the visual cortex at frequencies that are proportional to light intensity, which is referred to as irradiance. In this experiment, monkeys are treated with GS030 and their retina is sampled after either 2 or 6 months. Retina are put on a multielectrode array and 590nm light is then shed onto the retina at increasing intensity. As irradiance increases, the electrodes are measuring the increase of the firing frequency of each transduced RGC. As shown in the chart above, the firing frequency of the RGCs increases almost proportionally to the light intensity, which is what one would expect in a normal eye. These photographs above show microscopic views of monkey retinas after receiving treatment with GS030. (A) and (C) show that GS030 achieves efficient transfection of the central part of the retina (fovea and peri-fovea region). (B) shows a magnification of one RGC showing that the protein is in the cytoplasm and in the membrane of the cell, as confirmed in (D) with the view of the RGCs and their axons. This study confirmed the initial data and supports the expression of ChrimsonR in the retina of monkeys. Results of this study were published in Communications Biology in February 2021. GLP Toxicity Studies to Assess Phototoxicity This study assessed the phototoxicity of three levels of light intensities following GS030 injection of rd1 mice, a relevant model of RP. One dose level of GS030, which was the highest dose, was combined to a single two-hour exposure to 600nm light at three levels of intensity in order to cover the intended use in our Phase I/II clinical setting. The purpose of the study was to determine the local tolerability of light exposure on transduced RP retinas based on the following endpoints: histopathology of the retina, outer layer thickness, number of RGCs, cell viability and/or apoptosis. GLP Toxicity Study to Evaluate Toxicity and Biodistribution This study evaluated the toxicity, biodistribution and shedding of viral particles as well as immunogenicity of GS030 vector and ChrimsonR protein after IVT injection in non-human primates. Two dose levels of GS030 were injected bilaterally. The study allowed us to evaluate and confirm at three and six months the safety and local tolerability of the vector and protein, the biodistribution and shedding of the vector in tissues and fluids, as well as systemic and local ocular immunogenicity. Proof-of-Concept Study Showing Restoration of Retinal Electrical Activity in a Mouse Model of RP An rd1 mouse is affected by the degeneration of rods followed by the degeneration of cones, leading to the loss of vision five to six weeks after birth. When the retinas of such mice are dissected post-mortem and connected to a multi-electrode array, an electrical response to light is not detected. Using the same method with the retinas from rd1 mice that have received an IVT injection of GS030, an electrical response to light is produced and detected with the multi-electrode array and this response is a function of light intensity. A New Generation of Channelrhodopsin-Based Gene Therapy An Optimized Optogenetic Protein We have conducted proof-of-concept studies with channelrhodopsin-2, or ChR2, which when introduced into RGCs, has proven to restore vision in a murine model of RP. However, activation of ChR2 requires high-intensity blue light at 470nm wavelength which has been shown to be toxic for the retina and is not practical for clinical use. We have therefore developed a novel channelrhodopsin protein, known as ChrimsonR, which responds to light at near-red wavelength, where light scattering decreases and absorption by endogenous chromophores is reduced, meaning that long-term safety should be significantly improved compared to other channelrhodopsins. A Powerful Gene Delivery Vector Since RGCs are the cells closest to the vitreo-retinal surface, they are amenable to AAV infection with IVT injection, a major advantage from a surgical standpoint given the relative ease of administration. Our AAV is an AAV2 modified in its capsid with an inserted 7m8 sequence. Experiments have demonstrated that AAV2 7m8 has markedly improved expression in RGCs and other retinal cells compared to AAV2 in both rodents and non-human primates. Optoelectronic External Wearable Medical Device: The Biomimetic Goggles The natural range of light sensitivity of human photoreceptor cells is broader than that of channelrhodopsins. To achieve adequate stimulation of transduced RGCs, we combine our gene therapy-based treatment with an external wearable medical device, which allows the amplification of the image at specific optimal wavelength of the selected opsin. We are developing an external wearable medical device composed of: •a visual interface integrating an asynchronous time-based image sensor (also called a neuromorphic video camera), and a digital micromirror array, or DMD, driven by a microprocessor, that convey the visual information signal and light to the macula; and •a pocket processor connected to an optoelectronic stimulation device that processes the visual information and controls a light source in order to encode and amplify corresponding light signals at a specific narrowband wavelength of 580-610nm. Software is provided to medical centers that allows the tuning and definition of parameters to optimize the patient response. The figure set forth below presents the components of the external wearable medical device: External Wearable Medical Device Components We determined the necessary specifications for the external wearable medical device to optimize the specific light wavelength for activation of the ChrimsonR proteins while considering the particular anatomy of the eye. Our team is developing the algorithms necessary to operate the device in close collaboration with the Laboratory of Mathematics Applied to Vision of the Université Pierre et Marie Curie, or UPMC, in Paris, France. We have designed a prototype that will be further developed in advance of Phase III clinical trials and commercialization. Preclinical Development of GS030 for RP We have also conducted several studies in order to support the clinical Phase I/II CTA submission. Preliminary Toxicity Study Showing Safety of GS030 in Non-Human Primates We conducted an exploratory ocular histopathology study in non-human primates to investigate potential ocular toxicity following single bilateral IVT administration of GS030. No ophthalmological signs of intolerance or toxicity, structural modifications or inflammation of the retina were observed up to six months post-injection. A slight and transient increase in the serum anti-AAV2 immunogenicity, or neutralizing antibodies, was observed. GS030 was thus locally and systemically well tolerated up to six months. We submitted a request for a non-clinical scientific advice recommendation from the EMA in April 2016, as well as a request for a Type C meeting with the FDA in December 2016, to validate the non-clinical program and future requirements for the device. Both the EMA and the FDA have agreed with our strategy in principle to evaluate toxicity in a rodent disease model and in non-human primates, and we therefore initiated the studies during the fourth quarter of 2016. Clinical Development Program of GS030 for RP We have initiated a Phase I/II, open-label, multi-center trial to evaluate the safety and tolerability of GS030 and the external wearable medical device in RP subjects. Our CTA was authorized in the United Kingdom in December 2017, in France in May 2018 and our IND was released in August 2018 in the United States. The trial includes secondary endpoints that could serve to demonstrate proof-of-concept of the efficacy of our optogenetics approach in RP patients. Restoration of visual perception would serve as a proof-of-concept for the combination of GS030 treatment with the use of biomimetic goggles. We plan to enroll up to 18 subjects across up to four cohorts. The first subject was treated in October 2018 at the Moorfields Eye Hospital in London, United Kingdom, and the recruitment of the third cohort was completed in Q3 2020. The initial three cohorts has undergone dose escalation to determine the maximum tolerated or feasible dose of GS030. In the fourth cohort, the maximum tolerated will be administered for safety analysis and proof-of-concept data collection based on the fourth DSMB recommendation in September 2021. We anticipate receiving interim data in H2 2022. The trial is planned to include adult subjects with documented diagnosis of RP. The initial cohorts will enroll RP subjects with virtually no light perception or limited to light perception. Pending safety outcomes, RP subjects with higher levels of visual acuity may be considered for inclusion in the fourth cohort. As RP is a disease of photoreceptor degeneration, the restoration of vision sense will require some level of intactness of the downstream components of the visual apparatus, including the neuronal elements of the retina, RGCs, optic nerve and primary visual cortex. We believe that subjects with higher degree of visual acuity would derive greater benefit from treatment with our GS030 product candidate by virtue of their visual apparatus being better preserved. The trial is planned to encompass the testing of traditional ophthalmic parameters, such as visual acuity tests and also functional vision tests, such as avoiding obstacles or moving in unfamiliar or changing environments. We plan to carry out subject evaluation prior to GS030 administration with and without the biomimetic goggles to establish baseline parameters. Subsequent to IVT injection of GS030, a visual rehabilitation program will ensue, comprising a training period for learning to use the biomimetic goggles in a controlled laboratory environment, including in fixed and mobile simulations and subsequently in common indoor and outdoor environmental conditions. Baseline ophthalmological testing will be completed before and after IVT injection of GS030 with and without biomimetic goggles. Given the varied levels of disease state, it is not expected that all subjects will show improvement in all secondary outcome measures. Furthermore, use of the biomimetic goggles will require training and, therefore, we expect that the learning period will vary among subjects. As a result, the time point of demonstrating efficacy may vary among subjects. Improvement will be assessed by whether a subject can perform a visual task with “goggles on” when light-induced activation of the optogenetic protein is expected to occur compared to baseline and also compared to “goggles off” when no or insufficient photo-activation of the optogenetic protein should take place. The Data Safety Monitoring Board (DSMB) completed its second planned safety review of the ongoing PIONEER Phase I/II clinical trial of GS030, GenSight’s novel product combining gene therapy and optogenetics for the treatment of Retinitis Pigmentosa (RP). The DSMB confirmed the absence of any safety issues for the second cohort of three subjects, who each received a single intravitreal injection of 1.5e11 vg (viral genomes) and used a wearable optronic visual stimulation device after the injection. The DSMB recommended moving forward as planned without any modification in the protocol and recruiting the third cohort of three subjects who are to receive the maximal dose of 5e11 vg. The independent Data Safety Monitoring Board (DSMB) completed its third safety review of the ongoing PIONEER Phase I/II clinical trial of GS030 combining AAV2-based gene therapy with optogenetics for the treatment of Retinitis Pigmentosa (RP) in September 2021. The DSMB found no safety issue in the third cohort of patients, who received an intravitreal injection with the highest dose (5e11 vg) among the three cohorts studied to date, followed by the use of a wearable optronic visual stimulation device. Based on GS030’s safety profile, the DSMB recommended selecting this dose for the extension cohort and using the protocol without any modification. Recruitment of this cohort has begun. On May 25, 2021 the Company announced that the top-notch scientific journal Nature Medicine published the first case report of the partial recovery of visual function in a blind subject with late stage RP. The subject had been diagnosed with RP 40 years prior to enrollment in the PIONEER phase I/II clinical trial. Prior to receiving GS030 the patients visual acuity was so low he could only perceive light. Four and a half months after injection of GS030, the subject was trained on the use of the GS030-MD device (proprietary light-stimulating goggles that project the right wavelength and intensity of light onto the treated retina). Seven months after the start of his training, the subject began to report signs of visual improvement. Visual function tests showed he acquired the ability to perceive, locate, count and touch objects when the treated eye was stimulated with theGS030-MD goggles. The subject could not perform the tasks without the goggles. Electroencephalographic (EEG) recordings were taken while the subject performed vision-oriented tasks and the corresponding signals demonstrated neurophysiological activity in the visual cortex. A second patient case was reported by the Company on November 17, 2021 showing significant visual recovery after GS030 optogenetic treatment. Twelve months following injection of GS030 the subject could detect and correctly locate objects of different sizes and contrasts placed on a white table, with a 57% success rate when wearing the GS030-MD goggles compared to only 24% without the device. The optogenetic therapy has been well-tolerated up to 3 years after a single injection administered to 9 subjects treated. There have been no systemic issues related to the gene therapy and no adverse events leading to study discontinuation and no participants have withdrawn. Regulatory Interaction for GS030 In April 2016, we requested the EMA’s Committee for Advanced Therapies, or CAT, to issue a recommendation on the classification of our GS030 product, which is constituted of the biological product, in the form of gene therapy, and an external wearable medical device, in the form of biomimetic goggles. Based on the above considerations, EMA/CAT considers that the Product GS030 falls within the definition of a Gene Therapy Medicinal Product of an Advanced Therapy Medicinal Product as provided in Article 2(1) of Regulation (EC) No 1394/2007. We sought the same advice at the FDA’s Office of Combination Products. GS030 has been classified as a combination product whose primary mode of action is provided by the gene therapy part of GS030-DP, and the Center for Biologics Evaluation and Research, or CBER, is the jurisdiction in charge of evaluation. The regulatory pathway is based on the following classification: an IND will be necessary for clinical trial initiation, and a BLA will be required at the time of marketing authorization. In order to validate the adequacy of our non-clinical toxicology and safety program designed to support the first-in-man study, we submitted a request for non-clinical scientific advice from the EMA in April 2016 and an early Type C meeting with the FDA. Both the EMA and FDA have agreed with our strategy in principle to evaluate toxicity in a rodent disease model and in non-human primates, and we completed these toxicology studies in 2017. In order to obtain agreement on the adequacy of the data presented to support initiation of an IND in the United States, a formal Type B Pre-IND meeting was held with the FDA in December 2017. During this meeting, the FDA agreed in principle with our Phase I/II clinical trial design, as well as CMC and medical device aspects to support an IND. The U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030 in October 2021. Fast Track is a process intended to facilitate the development and expedite the review of drugs for the treatment of serious conditions where there is an unmet medical need. The purpose is to get important new drugs to the patient earlier. Drugs that receive Fast Track designation may be eligible for more frequent communications and meetings with FDA to discuss the drug's development plan, including the design of the proposed clinical trials, and ensure collection of appropriate data needed to support drug approval. Drugs with Fast Track designation may also qualify for Accelerated Approval, Priority Review or Rolling Review of New Drug Applications (NDA) or Biologic License Applications (BLA) if relevant criteria are met. Market Opportunity for GS030 in Dry AMD and GA AMD is a degenerative disorder characterized by loss of the photoreceptors and preservation of the RGCs, and is driven by genetic and environmental factors. Central vision, which is essential to read, perform precise tasks and recognize faces, is lost. Peripheral visual field is usually preserved. Macular degeneration typically occurs in patients over the age of 55. The early form of AMD is called dry AMD and can evolve over time to late AMD. Late AMD can take two forms, either wet AMD or GA. Dry AMD is six times more prevalent than wet AMD. Approximately 15 million people are affected with AMD in the United States, with a global prevalence of 170 million, and dry AMD accounts for approximately 80% of all cases of late-stage AMD. The prevalence of AMD increases significantly in those older than 75, reaching 22% in the population over 90. The following image illustrates the deterioration of normal vision to blindness in AMD: GS030: Our Planned Strategy for the Treatment of Dry AMD and GA We believe that our optogenetics technology platform could be used for the treatment of dry AMD or GA. Because GS030 uses optogenetics and can address diseases of photoreceptor degeneration regardless of the type of mutation, we believe that GS030, if successful in the treatment of RP, would be entirely transferable to the dry form of AMD and would offer enormous benefit to a common disease currently unamenable to therapy. Although RP and GA have very different origins, both diseases are characterized by the degeneration of the photoreceptor cells in the patient’s retina. Upon evidence of clinical proof-of-concept in RP, we may initiate clinical trials of GS030 for the treatment of dry AMD and GA. 5.2.4LEVERAGING OUR PLATFORMS TO ADDRESS CENTRAL NERVOUS SYSTEM DISORDERS. We have established an integrated development platform to replace or restore the function of retinal cells that have degenerated in order to regain quality of sight for patients, thereby transforming their lives. We intend to pursue the application of our integrated development platform to other indications beyond ophthalmology, in particular, for degenerative diseases of the central nervous system. 5.2.5PHARMACO-ECONOMICS OF BLINDNESS AND VISUAL IMPAIRMENT. Blindness and visual impairment impact not only the individual but also the family, caregivers, and the community, leading to significant societal costs. The total annual cost of vision disorders and blindness in the United States was estimated to be $139 billion in 2013, and the total cost of blindness alone in the European Union was estimated at €32 billion, or up to €60,000 per patient per year. These figures include direct costs such as medical treatment, medical visual prostheses, adaptations and assistance devices, and special training and assistance programs, as well as indirect costs resulting from impaired vision, the loss of productivity and the need for supportive care, long-term care and the costs of social programs. These conditions also can have significant, multidimensional effects on patients’ quality of life, including their physical and emotional well-being. 5.3Important events in the development of the Company April 2012 Incorporation of the Company on the basis of a collaborative effort involving renowned academic institutions. March 2013 Series A private round raising €19.7 million through Novartis Venture Fund, Abingworth, Versant Ventures, Vitavest S.à r.l. and Bpifrance (FBIMR). February 2014 Initiation of a Phase I/II clinical trial to assess safety and tolerability of LUMEVOQ® in Leber’s Hereditary Optic Neuropathy, or LHON. June 2015 Positive interim safety report of the Phase I/II clinical trial confirming safety and tolerability of LUMEVOQ® in LHON. July 2015 Series B private round raising €32.1 million (or €30.8 million net proceeds) through our Series A investors joined by Fidelity Management & Research Company, Perceptive Advisors, Jennison Associates, HealthCap and Sphera Global HealthCare Fund. December 2015 Initiation of two Phase III clinical trials to demonstrate efficacy of LUMEVOQ® in LHON. July 2016 Listing of our shares on Euronext Paris which allowed the Company to raise approximately €45.2 million (or €41.4 million net proceeds). January 2017 U.S. Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to the Company’s product candidate GS030 for the treatment of Retinitis Pigmentosa. April 2017 Creation of the first subsidiary, GenSightBiologics Inc., registered and located in the Unites States of America. June 2017 Capital Increase which allowed to raise €22.5 million (or €20.7 million net proceeds), by means of a private placement reserved to a category of persons, U.S. and European institutional investors specialized in healthcare and biotechnology. December 2017 Positive long-term visual acuity gains and safety results from Phase I/II Study of LUMEVOQ® for the treatment of Leber Hereditary Optic Neuropathy. December 2017 GenSight Biologics received MHRA approval to initiate Phase I/II PIONEER clinical trial of GS030 gene therapy in Retinitis Pigmentosa. April 2018 Top-line data at 48 weeks of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON. October 2018 Top-line data at 72 weeks of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON. October 2018 Treatment of first subject in first-in-man PIONEER Phase I/II clinical trial of GS030 combining gene therapy and Optogenetics for the treatment of Retinitis Pigmentosa. December 2018 Additional data reporting sustained quality of life improvements at Week 72 of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON. February 2019 Top-line data at 48 weeks of the RESCUE Phase III clinical trial with LUMEVOQ® in LHON. February 2019 Completion of an €8 million capital increase without discount subscribed entirely by Sofinnova. April 2019 Top-line data at 72 weeks of the RESCUE Phase III clinical trial with LUMEVOQ® in LHON. May 2019 Top-line data at 96 weeks of the REVERSE Phase III clinical trial with LUMEVOQ® in LHON. July 2019 GenSight Biologics completes enrollment of LUMEVOQ® REFLECT Phase III trial in the treatment of LHON ahead of schedule. September 2019 Top-line data at 96 weeks of the RESCUE Phase III clinical trial with LUMEVOQ® in LHON. October 2019 Reporting of evidence of LUMEVOQ® DNA transfer to contralateral eye of primates unilaterally injected with LUMEVOQ® Gene Therapy. December 2019 First Temporary Authorization for Use (ATU nominative) granted to the National Eye Hospital of the Quinze-Vingts in Paris by the French National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM). December 2019 Interim analysis of 15 patients in REALITY natural history study supporting REVERSE and RESCUE efficacy results. December 2019 GenSight Biologics obtains €15 million in financing through a bond issuance from Kreos Capital and a reserved capital increase from Sofinnova and 3SBio. April 2020 Positive Data Safety Monitoring Board Review of PIONEER Phase I/II Trial of GS030. July 2020 Sustained efficacy and safety among LHON patients 3 years after LUMEVOQ® treatment. July 2020 GenSight Biologics obtains €7million non-dilutive loan and renegotiate bond agreement with Kreos Capital. July 2020 Final REALITY natural history study supporting REVERSE and RESCUE efficacy results. July 2020 GenSight Biologics draws down €4 million through Tranche B from Kreos Capital. September 2020 GenSight Biologics submits EU Marketing Authorization Application for LUMEVOQ®. September 2020 GenSight Biologics reports new analysis demonstrating statistically significant and clinically meaningful difference between visual outcomes in LUMEVOQ®-treated patients and natural history of Leber Hereditary Optic Neuropathy (LHON). October 2020 GenSight Biologics successfully raises €25 million in an oversubscribed private placement with U.S. and European institutional investors. November 2020 GenSight Biologics reports validation of LUMEVOQ® Marketing Authorization Application (MAA) by European Medicines Agency. December 2020 GenSight Biologics Announces Publication of Results from LUMEVOQ® REVERSE Pivotal Phase III Trial and Non-Human Primate Study in Science Translational Medicine. December 2020 GenSight Biologics announces the partial conversion of convertible bonds and full exercise of share warrants by Kreos Capital. January 2021 GenSight Biologics Announces Publication of Results from LUMEVOQ® RESCUE Pivotal Phase III Trial in AAO journal Ophthalmology®. February 2021 GenSight Biologics Announces the Publication in Communications Biology of the Proof-of-Concept for GS030-Drug Product in Non-Human Primates. February 2021 GenSight Biologics Announces Publication of Results from LUMEVOQ® Phase I/IIa Clinical Trial REVEAL in BioDrugs. March 2021 GenSight Biologics successfully raises €30 million in an oversubscribed private placement with European and U.S. institutional investors. May 2021 GenSight Biologics Announces Publication of Results from the REALITY LHON Natural History Study in the Journal Eye. May 2021 GenSight Biologics Provides 2021 Operations Update in the Context of Covid-19. May 2021 GenSight Biologics Appoints Country Leads for France, Germany and the UK in Preparations for LUMEVOQ® Commercial Launch. May 2021 GenSight Biologics Announces Nature Medicine Case Report Showing Visual Recovery after GS030 Optogenetic Treatment. June 2021 GenSight Biologics Announces Publication of Indirect Comparison Showing Treatment Effect of LUMEVOQ® versus Natural History in Frontiers in Neurology. June 2021 GenSight Biologics Reports Topline Results from REFLECT Phase III Clinical Trial, Confirming LUMEVOQ® Efficacy Including Better Efficacy with Bilateral Treatment. July 2021 GenSight Biologics Announces Approval of the LUMEVOQ® Cohort Temporary Authorization for Use (ATUc) in France. August 2021 GenSight Biologics Announces Publication of RESTORE Study Data Demonstrating Sustained Efficacy 3 Years After Unilateral Injection of LUMEVOQ®. September 2021 Clinical Data on GenSight Biologics’ LUMEVOQ® and GS030 Gene Therapies to be Presented at 2021 ISGEDR and Several Investor and Industry Meetings in September. September 2021 UK MHRA grants GenSight Biologics’ LUMEVOQ® ophthalmic gene therapy Promising Innovative Medicine designation. September 2021 GenSight Biologics Announces Publication Analyzing Visual Parameters of ND4-LHON Subjects before LUMEVOQ® treatment in Phase III Trials. September 2021 GenSight Biologics Announces Positive Data Safety Monitoring Board Review of PIONEER Phase I/II Clinical Trial of GS030 as Optogenetic Treatment for Retinitis Pigmentosa. October 2021 GenSight Biologics Announces the Publication of a Review of Gene Therapy Trials for LHON in International Ophthalmology Clinics. October 2021 GenSight Biologics Announces FDA Grant of Fast Track Designation for Optogenetic Therapy GS030 as Treatment for Retinitis Pigmentosa. November 2021 GenSight Biologics Provides Update on Manufacturing Timeline Needed for LUMEVOQ® Regulatory Filing. November 2021 GenSight Biologics Announces Extension of Day 120 Clock Stop of LUMEVOQ® EMA Regulatory Filing. November 2021 GenSight Biologics Reports Second Patient Case Showing Significant Visual Recovery after GS030 Optogenetic Treatment. December 2021 GenSight Biologics Announces Publication of Non-Human Primate Study Reporting Presence of LUMEVOQ® Vector DNA in Contralateral Eyes After Unilateral Injection. December 2021 GenSight Biologics Confirms Sustained Efficacy and Safety of Bilateral LUMEVOQ® Injections at 2-Year Follow-Up of REFLECT Phase III Trial. December 2021 GenSight Biologics Company has incorporated a second subsidiary, GenSight Biologics France SAS registered and located in France. January 2022 GenSight Biologics reports clinically meaningful vision improvement is maintained 4 years after one-time treatment with LUMEVOQ® gene therapy. April 2022 GenSight Biologics provides update on LUMEVOQ® manufacturing timeline April 2022 GenSight Biologics Granted Six-Month Extension in LUMEVOQ® European Regulatory Review 5.4Strategy and objectives Our goal is to transform the lives of patients suffering from severe degenerative diseases of the eye and central nervous system through the development and commercialization of novel therapies by combining gene therapy-based approaches with our proprietary MTS and optogenetics technology platforms. The key elements of our strategy are the following: •Complete clinical development and obtain regulatory approval for our lead product candidate, LUMEVOQ®, for the treatment of LHON. We reported top-line results of our two most advanced ongoing Phase III clinical trials of LUMEVOQ® for the treatment of LHON, RESCUE and REVERSE, in 2018 and 2019. We reported topline of our third Phase III clinical trial REFLECT in June and December 2021. We expect that the complete results at 96 weeks of our Phase III REVERSE and RESCUE trials will be sufficient to support filing for marketing authorization in the European Union. LUMEVOQ® has received orphan drug designation for the treatment of LHON in the United States and the European Union. We believe that LUMEVOQ® has the potential to be the first FDA-approved therapy for LHON. •Advance clinical development of our second most advanced product candidate, GS030, using our optogenetics technology for the treatment of RP. GS030 has demonstrated that it can restore light sensitivity in the retina in animal models. In late 2017, we received MHRA approval to conduct a Phase I/II clinical trial of GS030 in blind RP subjects. We treated the first subject in October 2018 and expect to complete recruitment of the extension cohort in the second half of 2022. We anticipate receiving interim data within one year after the last subject is treated. GS030 has received orphan drug designation for the treatment of RP in the United States and the European Union. The FDA has granted Fast Track Designation to GS030 in October 2021. We believe that due to its ability to introduce a gene encoding for light-sensitive protein into target cells, GS030 has the potential to be the first therapy that partially or fully restores sight to RP patients. •Expand our pipeline by leveraging our proprietary MTS technology platform. Mitochondrial defects are associated with several severe degenerative diseases of the optic nerve as well as diseases of the central nervous systems. We believe our discovery capabilities and clinical experience will allow us to pursue the preclinical and clinical development of treatments using our MTS technology platform to more broadly target degenerative diseases such as other forms of LHON or diseases of the central nervous system. For example, while our later stage Phase III LHON trials are designed to treat subjects with the mutation in the ND4 gene, we plan to initiate preclinical development for GS011 using our MTS technology to treat LHON due to mutation in the ND1 gene. In addition, our MTS technology platform has the potential to address neurodegenerative diseases of the central nervous system caused by mitochondrial defects, such as Kearns-Sayre syndrome, Alpers disease, Parkinson’s disease and ALS. •Pursue preclinical development of other indications using our optogenetics technology platform. The initial focus of our optogenetics technology platform using GS030 is for disorders of the photoreceptor cells, in particular RP. However, because GS030 can address diseases of photoreceptor degeneration regardless of the type of mutation, we believe that GS030 may be extended to address patients suffering from dry AMD and GA, both areas of significant unmet medical need. We plan to explore other indications outside of ophthalmology where we are able to use light to stimulate the neurons, such as congenital deafness, pain treatment and vagus nerve stimulation. •Directly commercialize our lead product candidate, LUMEVOQ®, in key geographies and retain the option to commercialize GS030 by ourselves. We hold worldwide commercialization rights to our platform technologies, product candidates and development programs. If approved, we intend to commercialize LUMEVOQ®, initially in the United States and the European Union, ourselves. Due to the orphan nature of LHON, we believe a targeted sales and marketing organization would be able to reach specialized ophthalmology centers and their patients. We have built, and continue to expand upon, key relationships with ophthalmic experts and patients of severe retinal neurodegenerative diseases around the globe, since we anticipate that a large majority of patients suffering from this disease will be referred to a limited number of large, well-equipped centers with neuro-ophthalmologists and retina specialists in each country. We have initiated early dialogue meetings with relevant payers and HTA bodies in the key markets to prepare for timely local reimbursement submissions. Due to the broad patient populations that GS030 may address, we may enter into strategic partnerships to maximize commercial value of our product candidate. •Acquire or in-license complementary technologies and product candidates. In addition to our current product candidates, we will evaluate acquisition or in-licensing opportunities with the potential to expand and diversify our pipeline in ophthalmology and other neurodegenerative disorders. We believe that our management team’s expertise in the gene therapy field and the broad applicability of our proprietary technology platforms provide us with a competitive advantage in evaluating product opportunities. 5.5Research and development, patents and licenses 5.5.1OVERVIEW. We engage in substantial research and development efforts to develop innovative product candidates. Research and development expenses consist primarily of: •sub-contracting, collaboration and consultant expenses, that primarily include the cost of third-party contractors such as CROs, who conduct our non-clinical studies and clinical trials; •personnel costs, including salaries, related benefits and share-based compensation, for our employees engaged in scientific research and development functions; •licensing and intellectual property costs, including upfront payment for exclusive licensing; •purchases, real-estate leasing costs and rental income received from sublease agreements, as well as conferences and travel costs; and •depreciation and amortization. Our research and development expenses in the periods presented, and for the current period to date, mainly relate to the following activities: •LUMEVOQ®: Our Phase I/II dose-escalation safety study REVEAL for LUMEVOQ® was initiated in 2014, recruitment was completed in April 2015 and a follow-up study is currently ongoing. LUMEVOQ® entered into two parallel Phase III trials, RESCUE and REVERSE, in the fourth quarter of 2015, following the release of our IND application by the FDA. The trials are designed as a double-masked, sham-controlled, multi-center, multi-country clinical trial in Europe and the United States. We completed enrollment of all 37 patients for REVERSE in February 2017, and completed the enrollment of 39 patients for RESCUE in July 2017. A third Phase III trial was initiated in the fourth quarter of 2017, REFLECT. This trial is designed as a randomized, double masked, placebo-controlled, multi-center clinical trial. The recruitment of 98 patients was completed in July 2019. Topline data were issued during the second quarter of 2021. •GS030: In 2015, we conducted preclinical, proof-of-concept studies with different molecules that led to the definition of GS030. We initiated GLP, toxicology studies on non-human primates. We obtained the approval to initiate Phase I/II PIONEER clinical trials from MHRA in December 2017. The first patient was treated in October 2018 in the United Kingdom. The recruitment of the third cohort was completed in Q3 2020. Our direct research and development expenses consist principally of external costs, such as manufacturing expenses, non-clinical studies, startup fees paid to investigators, consultants, central laboratories and CROs in connection with our clinical studies, acquiring and manufacturing clinical study materials and costs related to collaborations, which we allocate to our specific research programs. In addition, we allocate personnel-related costs, depreciation and other indirect costs to specific programs. Research and development activities are central to our business. Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We expect that our research and development expenses will continue to increase in the foreseeable future as we initiate clinical trials for certain product candidates and pursue later stages of clinical development of other product candidates. A change in the outcome of any of these variables with respect to the development of LUMEVOQ®, GS030 or any other product candidate that we are developing could mean a significant change in the costs and timing associated with the development of such product candidates. For example, if the FDA, the EMA or other regulatory authority were to require us to conduct non-clinical and clinical studies beyond those which we currently anticipate will be required for the completion of clinical development, or if we experience significant delays in enrollment in any clinical trials, we could be required to spend significant additional financial resources and time on the completion of clinical development. For a discussion on the risks associated with completing the development projects on schedule, see Section 3.2, “Risks Related to the Discovery and Development of and Obtaining Regulatory Approval for Our Product Candidates” of this Universal Registration Document. 5.5.2RESEARCH AND DEVELOPMENT EXPENDITURES. From 2020 to 2021, the total amount spent by us for research and development activities slightly increased from €22.4 million to €22.9 million, respectively. Our research and development expenses for the periods presented, and for the current period to date, mainly relate to LUMEVOQ® and GS030, see Section 7.3, “Results of Operations – Comparisons for the Twelve Months Ended December 31, 2020 and 2021 – Research and Development Expenditures” of this Universal Registration Document. Our research and development expenses consist principally of external costs, such as manufacturing expenses, non-clinical studies, startup fees paid to investigators, consultants, central laboratories and CROs in connection with our clinical studies, costs related to acquiring and manufacturing clinical study materials and costs related to collaborations, which we allocate to our specific research programs. In addition, we allocate personnel-related costs and other indirect costs to specific programs. The following table sets forth the cost for our research and development for the fiscal years ending December 31, 2020 and 2021: In thousands of euros As of December 31, 2020 2021 Personnel expenses (1) 3,903 4,844 Sub-contracting, collaborations and consultants 15,359 15,626 Licensing and intellectual property 2,168 1,318 Office costs 28 22 Travel and entertainment expenses 245 323 Depreciation and amortization expenses 397 366 Others 286 421 Total research and development expenses 22,386 22,920 (1) Includes €749 K and €1,404 K related to share-based compensation expense as of December 31, 2020 and 2021 respectively. 5.5.3MEDICAL AND SCIENTIFIC COMMITTEE. In addition to our own research and development teams, we have a Scientific Advisory Board comprised of seven renowned scientists from different countries who are opinion leaders in their Specialties and key assets to our business. The function of the Scientific Advisory Board is to identify new technological advances that may be of interest for our business. Since our inception, our Scientific Advisory Board has been comprised of the following members: •Dr. Botond Roska (Chairman of our Scientific Advisory Board) is Director of the Institute of Molecular and Clinical Ophthalmology Basel, Switzerland. He was educated at University of California Berkeley, Harvard University and Harvard Medical School as well as at Semmelweis Medical School. He studies the structure and function of the retina, thalamus and cortex. His group pioneered cell type specific optogenetic vision restoration. •Professor José-Alain Sahel (Vice-Chairman of our Scientific Advisory Board) chairs the Institut de la Vision, a center of excellence in ophthalmology assembling scientific teams (UPMC, INSERM and CNRS) as well as the French National Eye Hospital, featuring access to cohorts of well-diagnosed patients and a state-of-the-art Clinical Investigation Center. He chaired the Institut de la Vision, a center of excellence in ophthalmology assembling scientific teams (UPMC, INSERM and CNRS) until 2021. •Professor Jean Bennett (Vice-Chairman of our Scientific Advisory Board) is Professor of Ophthalmology and Cell and Developmental Biology and a Senior Investigator in the F. M. Kirby Center for Molecular Ophthalmology at the University Of Pennsylvania School Of Medicine. Professor Bennett also has an appointment as a Senior Investigator at the Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia. •Luk H. Vandenberghe, Ph.D., is Assistant Professor at Harvard Medical School and runs an active research laboratory at the Massachusetts Eye and Ear Infirmary and the Schepens Eye Research Institute. He directs the Grousbeck Gene Therapy Center which is focused on the biology of somatic gene transfer, the development of enabling technologies in gene therapy and the translation of clinical programs with a particular emphasis on vision and hearing restoration. •Professor Ernst Bamberg is Professor of Biophysical Chemistry at University of Frankfurt, and Director of the Department of Biophysical Chemistry of the Max Planck Institute für Biophysik in Frankfurt. Pr. Bamberg is the inventor of the optogenetics approach and has been at the fore front of this technology since its discovery. •Professor Connie Cepko is Professor at Harvard Medical School. Professor Cepko works on the mechanisms that direct development of the central nervous system of vertebrates and, in particular, on the vertebrate retina. Professor Cepko has produced seminal works in the mechanisms that lead to the death of photoreceptors in the many inherited forms of human blindness. •Dr. Serge Picaud, Ph.D., chairs the Institut de la Vision, a center of excellence in ophthalmology assembling scientific teams (UPMC, INSERM and CNRS). Over the last 15 years, Dr. Picaud has developed many cellular and animal models of different retinal diseases for assessing the efficacy of neuroprotection or other therapeutic strategies. Dr. Picaud thus developed the culture of post-mortem human retinal tissue, which provides the means to test AAV vectors efficacy on human retinal neurones. To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between the position of Dr. Botond Roska and Professor José-Alain Sahel in the Company and their position in FMI and Institut de la Vision, respectively. 5.5.4COLLABORATION, PARTNERSHIP AND RELATED AGREEMENTS. To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between the duties of our directors and officers and their personal interests, as they have no interest of any kind in the companies that are parties to the collaboration, partnership and related agreements mentioned below. Our main collaboration, partnership and related agreements include the following as of this Universal Registration Document: Agreements Relating to LUMEVOQ® Genethon Partnership Agreement Relating to the Research, Development and Commercialization of LUMEVOQ® •Object: In February 2013, we entered into a partnership agreement with Genethon. Under the terms of this agreement, Genethon is free to exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to the processes, materials and assays used to manufacture biological products for any purpose without further obligation or payment to us. We may exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to a product being developed by the parties pursuant to a given research and development project for any purpose at our own discretion, subject to the payment to Genethon of any milestone payments and royalties negotiated and agreed in a product addendum. •Obligations of GenSight: Under the terms of the partnership agreement, we are primarily responsible for (i) the performance of all in vitro and in vivo preclinical studies and for all clinical activities and, as sponsor, for the initiation, conduct and management of all clinical trials to be conducted in the context of the research and development project, and (ii) all regulatory affairs matters related to the development of the product(s) (other than matters specific to product manufacturing) with support from Genethon. •Obligations of Genethon: Genethon is primarily responsible for (i) the development of the processes to manufacture product(s) and for the manufacture of product(s) required for preclinical and clinical studies; and (ii) all regulatory affairs matters related to the manufacture of the product(s), including the elements of clinical trial and marketing authorization submissions that relate to the manufacture of the product(s). •Financial obligations: Costs are shared between us and Genethon in accordance with certain principles set forth in the partnership agreement. Each party bears its own internal costs incurred in the performance of preclinical activities. We are responsible for all external costs incurred by the parties in the performance of preclinical activities. Genethon is responsible for all internal and external costs incurred to manufacture research quality grade batches of the products in the context of preclinical activities. Genethon also assumes the internal and external costs incurred to manufacture all batches, whether GMP or not, of products used for regulatory preclinical toxicology studies, and one GMP batch for the initial Phase I clinical studies. We are responsible for all internal and external costs incurred by the parties in the performance of clinical activities. In addition, we bear all internal and external costs for the manufacture of all GMP batches of products other than any GMP preclinical toxicology batches, and the initial GMP both for Phase I clinical studies, the costs of which are borne by Genethon. Genethon bears all internal costs associated with activities of regulatory support in connection with manufacturing a product, while all such external costs are borne by us. •Proprietary rights: Under the terms of the partnership agreement, Genethon is free to exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to the processes, materials and assays used to manufacture biological products for any purpose without further obligation or payment to us. We may exploit the data, know-how, materials and inventions, whether patentable or not, developed or generated in the course of performing a given research and development project that relate to a product being developed by the parties pursuant to a given research and development project for any purpose at our own discretion, subject to the payment to Genethon of any milestone payments and royalties negotiated and agreed in a product addendum. •Term and termination: The partnership agreement will continue in full force and effect for the longer of (i) a period of 10 years; or (ii) until the expiration/termination of the last project addendum duly executed between us and Genethon, unless otherwise terminated under the terms of the partnership agreement. Agreements Relating to GS030 Sight Again Program Consortium Agreement Relating to the Research and Development of Complimentary Therapeutic Remedies for GS030 •Object: In July 2014, we entered into a consortium agreement with Pixium Vision S.A., a company based in France that develops vision restoration systems and Fondation Voir et Entendre, or FVE, a scientific foundation that funds scientific programs in the field of ophthalmic diseases. This consortium agreement, known as “Sight Again,” or the Program, aims to further unlock technology hurdles in the development of new therapeutic approaches to restore sight to legally blind patients suffering from differing stages of RP. Sight Again is part of Programme d’Investissement d’Avenir, a major investment initiative launched and organized by the French Government. Under the agreement, we, in conjunction with Pixium Vision and FVE, are focusing on two complementary therapeutic remedies: an optogenetic gene therapy developed by us, GS030, and a vision restoration system comprising a sub-retinal implant developed by Pixium Vision, PRIMA, designed to deliver improved visual perception. Both therapeutic remedies require a visual stimulation device, comprising a visual interface, a mobile processor and software. During the collaboration period, the Program is governed by a joint steering committee, or JSC, consisting of representatives of the parties to the collaboration agreement. The JSC is responsible for, among other things, monitoring and assessing the progress of collaboration activities, validating the results and information provided by working groups, modifying or suspending the program in whole or in part and approving amendments to the agreement. •Obligations of GenSight: Under the terms of this agreement we are responsible for conducting all research and development activities in relation to our product candidates, from proof of concept to request for marketing authorizations. •Proprietary rights: Under the terms of the agreement, results obtained become the property of the party responsible for carrying out the research. In the case of joint research, results become the property of the parties involved with the research on a prorata basis in accordance with their respective contributions. We may freely use our own and joint results, except for research benefiting third-parties. We may be granted an operating license should we need specific knowledge of results of another party, and a free use of rights of products developed by FVE under the Program as well as a right of first review on any of the results of FVE. We and Pixium Vision have been granted a joint-exclusive operating license, each in our respective fields, on joint results obtained within the program. •Financial obligations: In consideration for this joint exclusivity, we and Pixium Vision pay royalties to FVE, calculated as a percentage of net sales generated by the joint results and joint patents. Such royalties may not exceed 0.6 percent of revenues generated by the commercial use of the patent, and an annual threshold of €50 K per Company, and shall expire when the cumulated amount of royalties paid reaches a total of €500 K. •Term and termination: The term of the agreement is five years and six months, subject to prior termination. Master Agreement Relating to the Sight Again Program In December 2014, we entered into a master agreement relating to the Program with Bpifrance Financement, Pixium Vision and FVE setting forth the characteristics of the Program, to fix the amount and conditions for awarding funding granted by Bpifrance Financement as well as to clarify the principles and arrangements for monitoring the implementation of the Program by Bpifrance Financement. Financial Aid Agreement Relating to the Sight Again Program In December 2014, we entered into a financial aid agreement relating to the Program with Bpifrance Financement setting forth the amounts and conditions upon which Bpifrance Financement shall grant financial aid to the Program. We will benefit from approximately €6.8 million, of which €1.1 million is available as subsidies and approximately €5.7 million as repayable advances. The approximately €5.7 million repayable advances and any interest thereon will only be repayable if and when the product hits the market. Should we, within two years following the termination of this financial aid agreement, reach cumulated revenues of €80.0 million (excluding taxes) for a period of 15 years from the first year of repayment we shall be required to make an additional payment to Bpifrance Financement of a maximum aggregate amount of approximately €2.7 million. The financial aid from Bpifrance Financement is intended to cover both industrial research and experimental development. On June 3, 2020, the PSPC Steering Committee made the following decisions: For all the partners of the SIGHT AGAIN Project consortium: expenses will be taken into account until key step 4. For GenSight Biologics, •removal of the specific regulatory condition in key step 3, •postponement of repayment deadlines by 2 years for Gensight Biologics, •implementation of a minimum lump sum reimbursement of €819,185, i.e. 20% of the overall recoverable advance paid. The terms of the financial aid agreement have been modified accordingly. Amendments Relating to GS030 The terms of the consortium agreement, master agreement and financial aid agreement originally applied to the development of the optogenetics product candidate targeting RP known as GS020, a precursor to GS030. The parties have supplemented the agreements to include provisions relating to the development of GS030. Agreements Relating to LUMEVOQ® and GS030 Specific Research Agreements Under the Framework Agreement Relating to Research and Development in Ophthalmic Diseases (LUMEVOQ® and GS030) In October 2014, as a part of the framework agreement, we entered into a specific agreement with UPMC, Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique for the development and evaluation of the visual stimulation goggles, for a duration of 24 months. This agreement terminated on October 2016. In November 2014, as a part of the framework agreement, we entered into a specific research agreement with UPMC, Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique for a program aiming to restore high acuity vision with optogenetic therapy, and defining the technical means required and the milestones to be achieved. In June 2015, as a part of the framework agreement, we entered into a specific research agreement with UPMC, Institut National de la Santé et de la Recherche Médicale and Centre National de la Recherche Scientifique for a program aiming to develop and approve clinical prototypes of glasses for the stimulation of an optogenetically transfected retina. 5.5.5INTELLECTUAL PROPERTY. To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between the duties of our directors and officers and their personal interests as they have no interest of any kind in the companies that are parties to the in-license agreements mentioned below. We rely on licenses granted by third-parties to develop our product candidates. We have rights to use and exploit certain issued patents and pending patent applications under license from certain third-parties. Our main in-license agreements include the following: Agreements Relating to LUMEVOQ® Inserm Transfert License Agreement for Patents Relating to LUMEVOQ® •Object: On October 12, 2012, we entered into a license agreement with Inserm Transfert S.A. (acting as delegatee of Inserm). Under the license agreement, Inserm Transfert and Inserm granted us (i) an exclusive, royalty-bearing worldwide license under certain patent rights and biological material in the treatment of ocular diseases in humans (including mitochondrial diseases of the ocular area), (ii) a non-exclusive, royalty-bearing worldwide license under certain patent rights and biological material in the treatment of mitochondrial diseases in humans together with (iii) a non-exclusive, royalty-bearing worldwide license under certain know-how, to develop, make, have made, use, and sell or otherwise distribute certain products, in the treatment of mitochondrial diseases and ocular diseases in humans, with a limited right to grant sublicenses. •Proprietary rights: Inserm Transfert and Inserm reserved the right on their behalf and that of all other non-profit academic research institutions to practice and use the patent rights and biological material in the treatment of ocular diseases in humans (including mitochondrial diseases of the ocular area) (i) for any academic purposes as well as (ii) for the performance of research programs performed in the frame of industrial partnerships and (iii) with our prior written approval on the clinical protocol, for certain non-profit clinical research. Inserm Transfert reserved (a) the right to practice and use the know-how for any purposes and (b) the right to practice and use as the patent rights and biological material for any purposes outside the treatment of ocular diseases in humans. Under the agreement, we have the first right of negotiation for exploitation rights of any results that may issue from such non-profit clinical research in the treatment of ocular diseases in humans (including mitochondrial diseases of the ocular area) and under certain conditions. •Obligations of GenSight: We are required to use our best efforts to develop the products in compliance with a certain development plan and to use our reasonable efforts to introduce the product into the commercial market, in each case, as soon as practicable, consistent with reasonable business practices. Under the agreement, we manage the prosecution, defense and maintenance of the licensed patent rights, at our own cost and in consultation with Inserm Transfert. •Financial obligations: Upon entering into the license agreement we paid an upfront license fee and reimbursed Inserm Transfert for all expenses incurred by it prior to entry into the license agreement in connection with the filing, prosecution, defense and maintenance of the patent rights. We are responsible for the payment of all future fees and costs relating to the prosecution, defense and maintenance of the patent rights during the term of the license agreement. In addition, we are required to make certain milestone payments to Inserm Transfert upon the achievement of certain development, regulatory and commercial milestone events. Under the terms of the license agreement, we also are required to pay Inserm Transfert low-to mid-single-digit royalties on incremental annual worldwide net sales of the product. •Term and termination: The license agreement will continue in full force and effect until the later of (i) the expiration of the last to expire patent right covering the manufacture, use or sale of the licensed product in any country of the world and (ii) ten years after the first commercial sale of the licensed product in a country in which a royalty is paid, unless otherwise earlier terminated under the terms of the license agreement. Inserm Transfert may at its sole discretion convert the license in the treatment of ocular diseases in humans into a non-exclusive license or terminate the agreement if (a) we have not timely met any of the development milestones in the development plan and fail to cure within 60 days of written notice from Inserm; (b) we interrupt certain development activities in respect of any licensed product for more than nine months; (c) we interrupt commercialization of a licensed product for more than 12 months after a first commercialization of such product in a country; (d) there is no commercialization of a licensed product within two years following the obtaining of its commercialization approval in a country; (e) we have not put the licensed product into commercial use and are not keeping the products reasonably available to the public within ten years of the effective date of the agreement; or (f) if we cease business operations or become the subject of a petition in bankruptcy. Association Française contre les Myopathies License Agreement for Scientific Data Relating to LUMEVOQ® •Object: On December 2, 2013, we entered into a license agreement for use of scientific data with the Association Française contre les Myopathies, or AFM, the French Muscular Dystrophy Association, Genethon and Inserm Transfert, acting as a delegate of Inserm and on behalf of the UPMC, or UPMC collectively, the licensors. Under the agreement, the licensors granted us a worldwide, exclusive, royalty-bearing license, with a limited right to grant sublicenses, for the use of certain scientific data and information developed, owned or controlled by the licensors, to develop, make, have made, use, and sell or otherwise distribute certain products, including to obtain authorization to develop and commercialize products for the treatment of mitochondrial diseases and ocular diseases in humans as described in our license agreement with Inserm Transfert. The scientific data are defined as data needed to obtain agencies authorizations. •Obligations of GenSight: We are required to use all commercially reasonable efforts to develop the products in compliance with the development plan set forth in our license agreement with Inserm Transfert and to use our reasonable efforts to introduce the product into the commercial market, in each case, as soon as practical, consistent with our reasonable business practices. Under the license agreement, we have committed to achieving certain milestones relating to the development, manufacture and commercialization of the licensed products, including certain regulatory, clinical and commercial objectives. Under certain circumstances, such as the imposition of government regulation restricting the implementation of the development program or requiring changes thereto, unforeseen results in preclinical experiments or clinical trials or technical constraints, we and Inserm Transfert may reasonably extend the development plan. •Financial obligations: We paid the licensors a one-time license fee of €10 K. We also are obliged to make milestone payments ranging from €13 K to €375 K upon the achievement of certain development, regulatory and commercial milestone events. Under the terms of the license agreement, we are required to pay to the licensors low single-digit royalty payments on annual worldwide net sales. •Term and termination: The license agreement will continue in full force and effect until the later of (i) the expiration of the patent rights licensed to us under our license agreement with Inserm Transfert and (ii) ten years after the first commercial sale of the product in a country in which a royalty is paid, unless otherwise earlier terminated under the terms of the license agreement. Inserm Transfert may at its sole discretion convert the exclusive license under the agreement into a non-exclusive license or terminate the agreement if (a) we have not timely met any of the development milestones in the development plan; (b) we interrupt certain development activities in respect of any product for more than nine months; (c) we have not put the product into commercial use and are not keeping the products reasonably available to the public within ten years of the effective date of the agreement; or (d) if we cease business operations to become the subject of a petition in bankruptcy. President and Fellows of Harvard College License Agreement for the use of Harvard Master Cell Bank relating to LUMEVOQ® •Object: On June 18, 2019, we entered into a license agreement with President and Fellows of Harvard College (“Harvard”). Under the license agreement, Harvard granted us a non-exclusive, worldwide, royalty-bearing license, non-transferable without its prior consent, with right to grant sublicenses, for the use of biological material (an Harvard proprietary Master Cell Bank) to develop, have developed, make, have made, market, offer for sale, sell, have sold, promote, have promoted, import and/or export any licensed products (including LUMEVOQ®), for the prevention and/or the treatment of ocular diseases. •Obligations of Harvard: Harvard is required to deliver us a reasonable supply of the biological material as soon as practicable and to the extent reasonably request by ourselves. •Obligations of GenSight: We are required to use commercially reasonable efforts to develop, market and commercialize the licensed products and we are subject to reporting obligations. •Financial obligations: We paid Harvard a non-refundable license issuance fee of $25 K. In addition, we agreed to pay an annual license maintenance fee as from the first commercial sale of a licensed product ranging from $25 K to $75 K (creditable against running royalties), a milestone payment of $25 K upon achievement of marketing authorization for the first licensed product in any country, and a running royalty of less than 1% on net sales for a period of 15 years from the date of the first commercial sale (on a licensed product by licensed product basis). •Term and termination: The license agreement will continue in full force and effect until the expiration of the payment obligations, unless earlier terminated. We also have the right to terminate the agreement at any time and for any reason upon 90 days’ prior written notice. Upon termination, we will have a perpetual, fully paid-up, non-exclusive, worldwide, non-transferable license to use Harvard’s Master Cell Bank to make, have made, market, offer for sale, sell, have sold, import and/or export any licensed products, including LUMEVOQ® for the prevention and/or the treatment of ocular diseases. Agreements Relating to GS030 Adverum Biotechnologies (formerly Avalanche Biotechnologies) License Agreement for Patents Relating to GS030 •Object: On February 23, 2014, we entered into a non-exclusive license agreement with Adverum. Under the license agreement, Adverum granted us a worldwide non-exclusive royalty-bearing sublicense, with a limited right to grant further sublicenses, under certain patents and patent applications to which Adverum has obtained certain rights from the Regents of the University of California, or the Regents, to use, make, have made, import, sell, and offer for sale products and services that comprise a recombinant adeno-associated virus serotype 2 7m8 vector, or AAV2 7m8, to deliver any of three genes (channelrhodopsin, halorhodospin or rod-derived cone viability factor) for the treatment of ocular diseases in humans. •Obligations of GenSight: Under our license agreement with Adverum, we are obliged to use commercially reasonable efforts to develop, manufacture and commercialize the licensed products at our own cost and expense in accordance with a specific development plan under the Adverum agreement and are obligated to achieve certain specified milestones, including regulatory approvals, by certain target dates. If we fail to achieve any of these milestones by its target date, we have the option to extend the target date by 12 months upon the payment of $50 K to Adverum for each such extension. •Financial obligations: We paid Adverum a one-time license fee of $30 K in addition to $145 K as reimbursement for past costs for preparing, filing, prosecuting and maintaining the licensed patent rights. Under the terms of the license agreement, we also are required to reimburse Adverum for all such present and future costs up to a maximum of $30 K per year, together with an annual license maintenance fee of $30 K (minus the patent expenses paid in the prior year). Further milestone payments on a product-by-product basis will be due, upon the achievement of certain milestone events. Further, upon the sale of any products or services licensed under the Adverum agreement, we are required to pay to Adverum low-to mid-single-digit royalties on annual worldwide net sales of such licensed products and services. Our royalty payment obligations to Adverum endure on a country-by-country and product/service-by-product/service basis for so long as at least one valid claim of any patent sublicensed from Adverum covers the manufacture, use or sale of a given product/service in a given country. •Obligations of Adverum: Adverum is responsible for and retains sole control over the prosecution, filing, maintenance and enforcement of all patents licensed to us under the agreement. •Term and termination: The license agreement will continue in full force and effect on a country-by-country basis until there are no remaining royalty obligations in any country, at which time the agreement shall expire in such country, unless otherwise terminated by the parties in accordance with the terms of the license agreement. We may terminate the agreement at any time upon 90 days’ prior written notice to Adverum, and Adverum may terminate the agreement in part or its entirety upon written notice to us if we assign the agreement in violation of its terms or fail to timely meet any of our specified development or milestones achievement obligations. Upon the termination of the license agreement between Adverum and Regents, our license agreement with Adverum will survive, provided that, among other things, we will be required to make any monetary payments that Adverum would have been required to make under its agreement with Regents had it not been terminated. Massachusetts Institute of Technology License Agreement for Patents Relating to GS030 •Object: On January 6, 2016, we entered into a license agreement with the Massachusetts Institute of Technology, or M.I.T., upon exercising an option right granted under the patent option agreement between M.I.T. and us, dated January 9, 2015. Under this license agreement, M.I.T. granted to us a royalty-bearing, license to certain patent rights jointly owned by M.I.T. and the University of Alberta, for use of the ChrimsonR or photoactivatable halorhodopsin protein (known as Jaws) gene expression sequences, in the retina for the prevention and treatment of blindness in humans. The license is exclusive but subject to the rights of M.I.T., the University of Alberta and any other non-profit research institute to practice under the patent for research, teaching and educational purposes, the U.S. government’s royalty-free, non-exclusive, non-transferable license to practice the patent, and certain mandatory third-party sublicensing requirements. •Financial obligations: Under the terms of this license agreement, we agreed to pay a license issue fee of $45 K, license maintenance fees up to $100 K per year and variable payments up to $7.3 million depending on the achievement of milestone events. We also agreed to pay running mid-single-digit royalties on future net sales. This license agreement has been amended in April 2017, under which we will provide the M.I.T. with a written research and development plan no later than July 1, 2018. This license agreement has been amended a second time in May 2018, under which we will provide the M.I.T. with a written research and development plan no later than July 1, 2019. This license agreement shall remain in effect until the expiration or abandonment of all issued patents and patent applications under this license agreement, unless earlier terminated. We have the right to terminate this license agreement, for any reason, upon at least six months prior written notice to M.I.T., and upon payment of all amounts due to M.I.T. under the agreement. M.I.T. has the right to terminate this license agreement (i) immediately upon written notice if we cease to carry on our business related to the agreement, or (ii) if we fail to pay any amounts due and payable within 30 days. Sorbonne Université, CNRS, Inserm and SATT Lutech License Agreements for Patents relating to GS030 •Object: On May 6, 2019, we entered into a license agreement with Sorbonne Université, CNRS, Inserm and SATT Lutech. Under this license agreement, we are granted an exclusive, worldwide, royalty-bearing license, non-transferable without the licensors’ prior consent and with right to grant sublicenses, to certain patents to develop, have developed, manufacture, have manufactured, own, supply, use, register, have registered, promote, distribute, have distributed, import, have imported, export, have exported, market and have marketed the product, a light stimulating device of photosensitive cells, part of GS030, for the treatment of vision disorders by optogenetic therapy. •Proprietary rights: Sorbonne Université, CNRS and Inserm reserved the right (i) to use the patent rights for any academic purposes and research programs performed by themselves or in the frame of partnerships with third parties, including in the field of treatment of vision disorders by optogenetic therapy, (ii) to grant any rights in the patents to third parties for any purposes outside the treatment of vision disorders by optogenetic therapy. •Obligations of GenSight: We are required to use commercially reasonable efforts to develop, market, promote and commercialize the product in the field of the treatment of vision disorders by optogenetic therapy. If we fail, without cause, to use such efforts to obtain at least a marketing authorization (MA) or biological license application (BLA) for a product by certain target dates or to develop product sales thereafter, SATT Lutech, on behalf of Sorbonne Université, CNRS and Inserm, will have the right to convert the exclusive license into a non-exclusive license. •Financial obligations: We paid the licensors a one-time license upfront payment of €30 K. We are also obliged to pay milestone payments upon achievement of certain development and regulatory milestone events. After the grant of a MA or BLA for the product, we are required to pay a fixed royalty fee for each first use of a product on a patient who has received the associated gene therapy treatment. In addition, we are required to pay an annual license maintenance fee creditable against the total paid amount of fixed royalty fee due on the same year. We are responsible for the payment of all future fees and costs relating to the prosecution, defense and maintenance of the patent rights during the term of the license agreement unless i) we expressly refused the generating step and industrial property costs associated during the consultation phase with the licensors, in which case the patent right in question will automatically be excluded from the patents covered by the license, ii) SATT Lutech has granted a license on the patents to one or more third party outside the field of the treatment of vision disorders by optogenetic therapy in which case the costs will be shared equally, iii) the license has been converted into a non-exclusive license, in which case we will pay at most 50% of the industrial property costs due after the conversion (weighted, if relevant, by application of ii)). If we decide to cease bearing the industrial property costs, in full or part, the corresponding patent(s) will automatically be excluded from the scope of the license and the licensors will have the right to license said patent rights to third parties including in the field of treatment of vision disorders by optogenetic therapy. •Obligation of the Satt Lutech Satt Lutech, on behalf of Sorbonne Université, CNRS and Inserm, is responsible for and retains sole control over the management of the licensed patents, in consultation with us and, if relevant, with the third party licensed outside the field of the treatment of vision disorders by optogenetic therapy. •Term and termination: The license agreement will remain in force until the expiration of the last valid claim of the patent rights, on a country-by-country and product-by-product basis. We also have the right to terminate the agreement at any time and for any reason upon six months’ prior written notice. 5.5.5.1Our Intellectual Property Estate Patents We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to the development of our business, including seeking, maintaining and defending certain patent rights licensed from third-parties. We also rely on trade secrets and know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position in the fields of allogeneic transfer, optogenetics, gene therapy and specific optics and algorithms that may be important for the development of our business. We additionally may rely on regulatory protection afforded through data exclusivity, market exclusivity and patent term extensions where available. See Section 9, “Regulatory environment” of this Universal Registration Document. Our future commercial success may depend, in part, on our ability to obtain and maintain patent and other proprietary protection for commercially important technologies, inventions and know-how related to our business; defend and enforce our in-licensed patents and any patents that we may own in the future; preserve the confidentiality of our trade secrets and proprietary know-how; and operate without infringing the patents and proprietary rights of third-parties. Our ability to stop third-parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights, either owned or in-licensed, under valid and enforceable patents, trade secrets or other know-how that cover these activities. In some cases, these rights may need to be enforced by third-party licensors. Our rights to intellectual property, whether in-licensed, owned or co-owned are generally directed to methods of treatment or prevention of clinical indications important for our development programs, allotopic expression, mitochondrial trafficking, optogenetics, AAV vectors, transferring genetic material into cells, processes to manufacture and purify our product candidates, optics and other proprietary technologies and processes related to our product candidates. We also possess significant know-how and trade secrets relating to our product candidates. In-licensed Patent Rights As of the date of this Document, we in-licensed at least 3 U.S. and foreign patent applications and at least 39 U.S. and foreign patents, that have been filed by or on behalf of our licensors. Product candidate Owner Title Patent Term Countries Current status LHON (LUMEVOQ®) Inserm Expression of mitochondrial protein by an enhanced allotopic approach 2026 United States European Union European Union: granted, no opposition filed United States: two divisional pending RP (GS030) University of California (Adverum) Adeno-associated virus virions with variant capsid and methods of use thereof 2032 Australia, Canada Singapore, Israel, China (3x), European Union (2x), Korea, Japan, United States (4x), Russia, Mexico, South Africa Granted in US, EP, JP, CN, MX, RU, ZA and AU RP (GS030) M.I.T. Channelrhodopsins for optical control of cells 2032 Korea, United States, European Union, Hong Kong United States: three patents granted and one application pending Granted in Europe and Korea RP (GS030) Sorbonne Univ. CNRS INSERM Method and device for controlling a device for aiding vision 2032 Australia, Canada, Hong Kong, China, European Union, Korea, Japan, United States Granted in US, EP, JP, CN, KR, AU, HK, CA RP (GS030) Sorbonne Univ. CNRS INSERM Display control precedent and device for implementing the method European Union, United States Granted in EP and US RP (GS030) Sorbonne Univ. CNRS INSERM Method for downsampling a signal outputted by anasynchronous sensor European Union, United States Granted in Europe and US With regard to the LUMEVOQ® product candidate, as discussed above, we have in-licensed a patent family from Inserm Transfert that relates to an expression vector for the delivery of a protein into the mitochondrion of a mammalian cell and the uses thereof. This patent family contains two pending U.S. application and one granted European patent. The granted European patent and the pending U.S. applications, if issued, are expected to expire in 2026, subject to possible patent term extensions. With regard to the GS030 product candidate, as discussed above, we have exclusively in-licensed from M.I.T. patent applications pending in the United States, Hong Kong and South Korea and a granted European patent directed to ChrimsonR. The granted European patent and pending applications, if issued, are expected to expire in 2032, subject to possible patent term extensions. In addition, as discussed above, we have non-exclusively in-licensed from Adverum a patent family that relates to the AAV2 7m8 vector, with patents granted in the U.S., Europe, China, Australia, Mexico, Russia, South Africa and Japan, and patent applications pending in China, United States, Europe, Canada, Israel, South Korea, Singapore and Brazil, where the granted patents and pending applications, if issued, are expected to expire in 2032, subject to possible patent term extensions. Product candidate Owner Title Patent Application Number Filing date Countries Currents status RP (GS030) GenSight Biologics UPMC CNRS INSERM Optogenetic visual restoration using ChrimsonR US62/329692 29/04/2016 United States, European Union, China, Japan, Korea, Canada, Australia, Hong Kong Granted in Japan and pending elsewhere RP (GS030) GenSight Biologics UPMC CNRS INSERM Device for illuminating an object with a controlled light intensity and associated method EP16305741.7 17/06/2016 United States, European Union, China, Japan, Korea, Canada, Australia Pending RP (GS030) GenSight Biologics UPMC CNRS INSERM Medical device intended to be worn in front of the eyes EP16306005.6 02/08/2016 United States, European Union Granted in the U.S. and Europe RP (GS030) GenSight Biologics UPMC CNRS INSERM Objective, camera and system adapted for optogenetics EP17305805.8 28/06/2017 United States, European Union, China, Japan, Korea, Canada, Australia Granted in China and pending elsewhere RP (GS030) GenSight Biologics Method and device for processing asynchronous signals generated by an event-based light sensor EP 18305020.2 11/01/2018 United States, European Union, China, Japan, Korea Pending LHON (LUMEVOQ®) GenSight Biologics Recombinant AAV2 vectors and methods of using the same US62/683,501 11/06/2018 United States, European Union, China, Japan, Korea, Canada, Australia Pending RP (GS030) GenSight Biologics Method for controlling an optogenetic device using a command law for the radiant power of a light source and associated devices EP19305135.6 05/02/2019 United States, European Union, China, Japan, Korea, Canada, Australia Pending RP (GS030) GenSight Biologics Method for controlling an optogenetic device using filtering and associated devices EP19305136.4 05/02/2019 United States, European Union, China, Japan, Korea, Canada, Australia Pending RP (GS030) GenSight Biologics Viewing apparatus and method for projecting a light signal EP19305561.3 03/05/2019 United States, European Union, China, Japan, Korea, Canada, Australia Pending Trademarks GenSight is a registered Community Trademark covering 26 member States of the European Union (including UK). The brand name chosen for GS010, as approved by the EMA for use in the MAA, is LUMEVOQ® (lenadogene nolparvovec). LUMEVOQ® is a registered Community Trademark (including UK), and is also registered in the U.S, Australia, Israel, New Zealand, Singapore, and Taiwan. Upon regulatory approval, GenSight intends to commercialize GS010 under LUMEVOQ® trademark. The brand name chosen for GS030 is LUMOVI®. LUMOVI® is a registered Community Trademark (including UK), and is also registered in the U.S. Upon regulatory approval, GenSight intends to commercialize GS030 under LUMOVI® trademark. We may, in the future, file additional applications to register GenSight, LUMEVOQ® and/or LUMOVI® in other territories and/or file applications for new trademarks covering current or future products and/or services in certain markets of interest. See Section 3.5, “Legal Risks and Risks Related to our Intellectual Property — Our trademarks and trade names may not be adequately protected and we may not be able to build name recognition in our markets of interest” and Section 18.6, “Legal and Arbitration Proceedings” of this Universal Registration Document. 5.6Competition The biopharmaceutical industry, including the gene therapy field, is characterized by rapid scientific technological changes and significant competition. Any product candidates that we successfully develop and commercialize will have to compete with therapies that may become available in the future. We face competition from pharmaceutical and biotechnology companies, as well as from academic institutions, governmental agencies and public and private research institutions. We are aware of a number of companies focused on developing gene therapies in various indications, including Adverum Biotechnologies, Inc., Ultragenyx Pharmaceutical, Inc., Applied Genetic Technologies Corporation, Asklepios BioPharmaceutical, Inc., Audentes Therapeutics, Inc., bluebird bio, Inc., GlaxoSmithKline, Biogen, Inc., Spark Therapeutics, Inc., uniQure N.V. and Voyager Therapeutics, Inc., as well as several companies addressing other methods for modifying genes and regulating gene expression. Any advances in gene therapy technology made by a competitor may be used to develop therapies that could compete against any of our product candidates. For our specific retinal gene therapy products, the main competitors include: LUMEVOQ® for the Treatment of LHON: The Huazhong University in China, which completed Phase I/II studies in 2013 using gene therapy, recently published data with nine months follow-up and the evaluation of both safety and some visual acuity outcomes. The purpose of these studies is exclusively academic. We are aware of a Chinese company, Neurophth, whose gene therapy NR082, which uses recombinant adeno-associated viral serotype 2 vector (rAAV2) containing a codon-optimized of NADH-dehydrogenase subunit 4 (ND4) gene, that was granted an orphan designation in the U.S. in September 2020 and received IND clearance in January 2022 to proceed to clinical trials in the U.S.. The data on safety and efficacy were generated from three investigator-initiated trials. Their gene therapy was also granted orphan designation by the EMA in January 2022. We are aware of other companies and institutions focused on developing therapies in the LHON space that do not involve gene therapy, including: Santhera Pharmaceuticals Holding AG using a chemical entity, Idebenone, approved under exceptional circumstances in Europe; and Mitotech, whose mitochondria-targeting cardiopolin peroxidation inhibitor Visomitin had been originally developed for the treatment of Dry Eye. GS030 for the Treatment of RP: To our knowledge, we are the only Company in the Clinic with a technology that utilizes light at near-red wavelength with goggles. RetroSense Therapeutics, LLC, or RetroSense, is developing a ChR2-based optogenetic product that is in Phase I studies that will have to utilize blue light to stimulate the ChR2 without goggles. Retrosense was acquired by Allergan plc in September 2016. Applied Genetic Technologies Corporation, or AGTC, is partnering with Bionic Sight to develop an optogenetic therapy combining a ChR-based gene therapy and a neuro-prosthetic device using an algorithm for retinal coding. This program is still in preclinical development. In addition, the only approved non-therapeutic treatment for RP is retinal implants. Nanoscope Therapeutics is developing optogenetic gene therapies using Multi-Characteristic Opsin (MCO) to re-sensitize the retina to detect low light levels. Their lead product, MCO-010, is in clinical development for retinitis pigmentosa (RP) and Stargardt disease. GS030 for the Treatment of GA: No approved therapy currently exists for GA. Most major clinical-stage therapeutic treatments for GA are in the field of cell therapy, including lampalizumab, an anti-Factor D, the development of which F. Hoffmann-La Roche Ltd. terminated post unsuccessful Phase III data. GlaxoSmithKline plc’s anti-amyloid beta monoclonal for patients with GA is in Phase II clinical trials. Novartis’ LFG-316 C5 monoclonal antibody for patients with GA is in Phase II clinical trials. Apellis Pharmaceuticals, Inc. is currently developing a C3 inhibitor, which has completed Phase II and initiated Phase III clinical trials. Gyroscope Therapeutics, Ltd, started in 2019 a Phase I/II FOCUS study of a gene therapy (GT005) coding for an inhibitor of the Complement System, in patients with geographic atrophy due to dry AMD. GS030 for the Treatment of Dry AMD: No approved therapy currently exists for dry AMD. Ophthotech Corporation’s Zimura, a complement C5 inhibitor, is currently in a Phase IIb clinical trial. Johnson and Johnson are developing Palucorcel, which utilizes human embryonic stem cells that recently completed a Phase I/II trial. Similarly, Astellas Pharma Inc. is developing a stem cell treatment currently in Phase II. BioTime, Inc. is developing OpRegen, a dry AMD-targeted therapy that replaces missing retinal pigment epithelium cells with OpRegen cells and is currently in a Phase I/IIa dose escalation study. Regenerative Patch Technologies requires a subretinal implant of stem cells and is in a Phase I/II trial. Many of our potential competitors, alone or with their strategic partners, have substantially greater financial, technical and other resources than we do, such as larger research and development, clinical, marketing and manufacturing organizations. Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of competitors. Our commercial opportunity could be reduced or eliminated if competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. Additionally, technologies developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors. 5.7Investments 5.7.1HISTORICAL INVESTMENTS. Our historical investments since 2015 involve mainly the acquisition of property, plant and equipment, and intangible assets. The following table sets forth our net cash used in investing activities as of December 31, 2020 and 2021: In thousands of euros As of December 31, 2020 2021 Cash flows from investment activities Acquisitions of property, plant and equipment (6) (32) Acquisitions of intangible assets — — Acquisitions / reimbursement of non-current financial assets (370) — Acquisitions / reimbursement of current financial assets — 16 Net cash flows from investment activities (376) (16) 5.7.2FUTURE PLANNED INVESTMENTS. As of the date of this Universal Registration Document, we do not have any material commitments to make investments in the future. 5.7.3JOINT VENTURE. N/A 5.7.4ENVIRONMENTAL ISSUES. •The Company has not identified any significant environmental risks related to its business that could require it to set a provision for such risks or to provide specific training for its employees. To date, the Company has not identified any opportunity to join an initiative to protection of biodiversity and adaptation to the consequences of climate change. The actions of the fight against food waste are not an issue given the activity of the Company. •The Company regularly raises awareness among its employees on ways to reduce its environmental impact. Despite an environmental impact deemed low, the Company and its employees are involved in sustainable development initiatives. The Company applies environmentally responsible paper management practices such as the use of an electronic document management system, setting all printers to default to double-sided printing, and purchasing only reams of paper of “ecological quality” (EU Ecolabel or PEFC). All of these practices thus constitute a virtuous cycle that makes it possible to avoid cutting down trees as much as possible. 5.8Manufacturing We have chosen to outsource manufacturing to specialized contract manufacturing organizations, or CMOs. As part of this strategy, we have hired experienced chemistry, manufacturing and controls, or CMC, and quality assurance personnel in order to (i) assess potential CMO partners, (ii) conduct the necessary audits and due diligence in connection with partner CMOs, (iii) oversee, review and audit the CMC process to be used for all regulatory submissions and (iv) oversee, review and control all the methods and protocols used to ensure that the final product meets our quality specifications. We partner with leading CMOs in gene therapy manufacturing, including Brammer Bio and Catalent to produce non-clinical and clinical drug products for clinical development and future commercialization. We have made significant efforts to scale up and optimize the manufacturing process with a view to the delivery of commercial batches. Our AAV-based gene therapy products are produced using transient triple transfection process for LUMEVOQ® and the baculovirus process for GS030. Production is carried out in compliance with current good manufacturing practices, or cGMP, by CMOs that have been certified by national regulatory authorities. Manufacturing Process Using Transient Triple Transfection for LUMEVOQ® The transient triple transfection-based production process uses adherent HEK293 cells amplified in multi-tray cell-culture systems. Cells are co-transfected with three independent plasmids. Transfected cells are harvested and cell lysate is then clarified in order to eliminate cellular debris. Purification of the AAV vector is then achieved by immunoaffinity and filtration in the final formulation buffer, leading to drug substance. The concentration of the drug substance is adjusted to a defined concentration, before being sterile filtered and filled into individual vials, to eventually become the drug product. Drug product is stored at <-60°C. Batches for the Phase III trials were produced at the Henogen S.A., which was acquired by Groupe Novasep, facility in Belgium in compliance with cGMPs. In anticipation of our commercial needs and process validation, we implemented the transfer of the manufacturing process to the Brammer Bio facility in Cambridge, Massachusetts in October 2017, to ensure commercial supply for the European Union and the United States. The batches used for the ongoing Temporary Authorization for Use have been produced at Brammer Bio facility. For each batch production, a series of quality control tests are performed during the process and at release to assess product strength, quality, purity and safety under controlled and validated standard operating procedures in accordance with cGMP. In November 2021, the Company announced that its planned PPQ campaign at Brammer Bio had failed due to an equipment issue in the filtration steps. A new campaign was initiated in December 2021 generating drug substance whose viral genome titer fell below the acceptance threshold. Resulting investigations led by external experts have traced the outcome to operational difficulties in specific stages of the downstream process. To prevent the repeat of these issues, the Company is working with its manufacturing partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, the Company has decided to manufacture engineering lots to confirm the robustness of the corrective actions. GenSight Biologics has appointed Scott Jeffers in April 2022 as Chief Technical Officer, based in the Boston area in the US where Brammer Bio is located, to lead all pharmaceutical development and manufacturing activities. The Company now targets the restart of the PPQ campaign in Q3 2022. Manufacturing Process Using Baculovirus Production for GS030 The AAV is produced in SF9 insect cells using two recombinant baculovirus vectors. One vector carries the viral genome, and the other carries elements for the expression of functions required for replication of the AAV genome and assembly of the viral capsids. The SF9 cells are cultivated in suspension in a serum-free medium in single-use bioreactors. Production of AAV by the SF9 insect cells/baculovirus method has proven to be an efficient and scalable means of recombinant AAV production. During the manufacturing process, the AAV vector is isolated from lysed, harvested cells by affinity chromatography. The vector is further purified by ion-exchange chromatography to create the bulk drug substance, or BDS. To produce the drug product, the BDS is adjusted to a defined concentration with formulation buffer, then sterile filtered before being filled into individual vials. Drug product is stored at <-60°C. Manufacturing Process for the GS030 Medical Device The goggles will be manufactured and tested at an established ISO13485-certified site in France, under the control of our Quality Assurance team. The devices will be certified to initially meet European and U.S. requirements, and will be extended to other countries via the international MDSAP program. 5.9Sales and marketing We hold worldwide commercialization rights to our platform technologies, product candidates and development programs. If approved, we intend to commercialize LUMEVOQ®, initially in the European Union and the United States, ourselves. We will be opportunistic in pursuing partnerships that can broaden the geographic footprint of LUMEVOQ® outside our initial focus markets, once the core regulatory files are finalized. Because LHON is a rare disease, we believe a targeted sales and marketing organization would be able to reach specialized ophthalmology centers and their patients while effectively engaging with reimbursement authorities to secure access for these patients. We have built, and continue to expand upon, key relationships with ophthalmic experts and patients of severe retinal neurodegenerative diseases around the globe, since we anticipate that a large majority of patients suffering from this disease will be referred to a limited number of large, well-equipped centers with top neuro-ophthalmologists and retina specialists in each country. Due to the broad patient populations that GS030 may address, we may enter into strategic partnerships to maximize commercial value of our product candidate. The Company has appointed Sissel Rodhal in February 2022 as Senior Vice President of Commercial Operations to build a strong and adaptable commercial organization to secure the successful launch of LUMEVOQ® in Europe in Q4 2023. 6 ORGANIZATIONAL STRUCTURE On April 28, 2017, the Company incorporated its first subsidiary, GenSight Biologics Inc., a Delaware corporation, registered and located in the United States of America. On December 30, 2021, the Company incorporated a second subsidiary, GenSight Biologics France SAS registered and located in France. Both subsidiaries are wholly owned by GenSight Biologics S.A. 7 OPERATING AND FINANCIAL REVIEW The following information concerning our financial condition and results of operations is derived from our consolidated financial statements prepared in accordance with IFRS as adopted by the European Union as of and for the fiscal year ended December 31, 2021 and should be read in conjunction with our consolidated financial statements prepared in accordance with IFRS as adopted by the European Union as of and for the fiscal year ended December 31, 2021 included in Section 18.1.1, “Company’s Annual Consolidated Financial Statements (IFRS) for the Fiscal Year Ending December 31, 2021” to this Universal Registration Document. Our consolidated financial statements were prepared in accordance with IFRS as adopted by the European Union for the fiscal years in question. Deloitte & Associés and Becouze have audited our consolidated financial statements as of and for the fiscal year ended December 31, 2021. The report of our Statutory Auditors for the consolidated financial statements included in this Universal Registration Document is included in Section 18.1.2. The main differences between IFRS as adopted by the European Union and French GAAP affecting the financial position and results of operations of the Company are broken down as follows for the year ended December 31, 2021: In thousands of euros As of December 31, 2021 Statutory net loss under French GAAP (25,172) GenSight Inc. result (loss) 13 GenSight Biologics SAS France result (loss) (1) Share-based payments (4,834) Net impact of IFRS 16 (36) Financial provisions 296 Impact of the valuation of convertible Bonds and Bank loan based on the effective interest rate (1,071) Impact of the Change in Derivative Financial Instrument Fair Value 1,309 Employee benefits (18) Net (gain) / loss from the sale of Treasury Stocks 9 Discounting effect 878 Other 10 Net loss under IFRS (28,617) Share-based payments Under French GAAP, share-based compensation related to the grant of equity instruments is not recognized in the income statement. Under IFRS, the cost of the transactions paid with equity instruments is recognized as an expense in exchange for an increase in the shareholders’ equity. Financial provisions Under French Gaap, a provision related to the current account with the subsidiary has been booked for a total amount of €251 K, as well as a provision related to our Treasury Stock for €45 K. Impact of the valuation of Convertible Bonds under IFRS Under IFRS, the issuing company must separately identify the liability and derivatives components of convertible bonds and treat them accordingly in the financial statements. Initially, the financial debt component is calculated by discounting the future cash flows of the bonds (interest and principle) at the rate of a similar debt instrument without the conversion option. Subsequently, Interest is charged to the income statement based on the effective interest rate, which is usually higher than the nominal rate, to reflect the true opportunity cost of the financial liability. Intangible assets Under IFRS, an intangible asset was recognized and amortized in the context of a license agreement. The acquisition of this license has resulted in the issuance of ordinary shares as consideration paid for the license. Impact of the change in Derivative Financial Instrument Fair Value The convertible bonds in which the Group is already engaged are a financial instrument that will or may be settled in the entity’s own equity instrument and is a derivative that will or may be settled other than by the exchange of a fixed amount of cash or another financial asset for a fixed number of the entity’s own equity instruments (IAS 32.11), and is therefore a financial liability. The convertible option is a (derivative) financial liability initially measured at fair-value according to IFRS 9 and subsequently measured at fair-value through profit and loss. Derivatives are recorded in the statement of financial position at their fair value. Changes in fair value are recognized in profit or loss. Leases IFRS 16 – Leases has become effective as of January 1, 2019. This standard replaced existing standards for leases, including IAS 17 – Leases, IFRIC 4 “Determining whether a agreement contains a lease agreement, “SIC-15” Advantages in Operating Leases “and SIC-27” Assessment of the Substance of Transactions Taking the Legal Form of a Lease”. The objective of IFRS 16 is to report information that (a) faithfully represents lease transactions and (b) provides a basis for users of financial statements to assess the amount, timing and uncertainty of cash flows arising from leases. To meet that objective, a lessee should recognize assets and liabilities arising from a lease. IFRS 16 introduces a single lessee accounting model and requires a lessee to recognize assets and liabilities for all leases with a term of more than 12 months, unless the underlying asset is of low value. A lessee is required to recognize a right-of-use asset representing its right to use the underlying leased asset and a lease liability representing its obligation to make lease payments. Employee benefits Under French GAAP, the Company has chosen not to recognize liabilities in relation to long-term employee benefits. Under IFRS, a liability has to be recognized for employee benefits for the defined benefit obligation and is measured as the present value of benefits that have accrued to employees through services rendered up to that date, based on actuarial methods of calculation. Net (gain) / loss from the sale of Treasury Stocks Under IFRS, the Net (gain) / loss from the sale of treasury stocks is not recognized in the income statement, but as part of equity, in Consolidation Adjustments. Discounting Effect The discounting effect reflects the difference between the "future value" of a payment and the "present value" of the same payment. It is the gain implied by the payment delay of an obligation. In thousands of euros As of December 31, 2020 2021 Operating income Revenues 4,394 5,276 Other income 3,046 2,433 Total operating income 7,440 7,709 Operating expenses Research and development 22,386 22,920 General and administrative 8,006 7,411 Sales and marketing 1,982 5,505 Total operating expenses 32,374 35,835 Operating profit (loss) (24,934) (28,126) Financial income 631 2,013 Financial expenses (9,711) (2,502) Financial income (loss) (9,079) (489) Income tax (2) (2) Net income (loss) (34,015) (28,617) Basic and diluted earnings (loss) per share(1) (0.97) (0.63) Number of shares used for computing basic and diluted earnings (loss) per share 35,126,688 45,150,592 (1) See Note 24 to our consolidated financial statements as of and for the fiscal year ended December 31, 2021 for further details on the calculation of basic and diluted earnings (loss) per share. 7.1Overview We are an innovative clinical-stage gene therapy Company with an initial focus on discovering, developing and commercializing novel therapies for severe retinal neurodegenerative diseases. We are developing a pipeline of proprietary product candidates to provide patients with a long-lasting cure for severe inherited retinal diseases for which there are no currently approved treatments. Our current product candidates are designed to be administered in a single treatment to each eye by intravitreal, or IVT, injection. We are leveraging our expertise in ophthalmology, gene therapy and drug development to restore vision by combining a gene therapy-based approach with our proprietary technology platforms of mitochondrial targeting sequence, or MTS, and optogenetics. We believe our technology platforms have broad applicability both within and outside of ophthalmology as well as central nervous system, or CNS, disorders. Our lead product candidate, LUMEVOQ®, is a recombinant AAV2-based gene therapy for the treatment of Leber Hereditary Optic Neuropathy, or LHON, and has finished three Phase III clinical trials. We reported top-line results for REVERSE at 48, 72 and 96 weeks in April, October 2018, and May 2019, respectively. Top-line results for RESCUE at 48, 72 and 96 weeks were reported in February, April and September 2019, respectively. Top-line results for REFLECT at 78 weeks and 2 years were reported in June and December 2021, respectively. Our second most advanced product candidate, GS030, for the treatment of Retinitis Pigmentosa, or RP, is currently in an ongoing Phase I/II trial. The recruitment of the first 3 cohorts was completed in Q3 2020. The DSMB recommended moving forward as planned without any modification in the protocol and recruiting the third cohort of three subjects who are to receive the maximal dose of 5e11 vg. We have never generated any revenues from marketed product sales. We do not expect to generate material revenue from product sales unless and until we successfully complete development of, and obtain marketing approval for, one or more of our product candidates, which is subject to significant uncertainty. To date, we have financed our operations primarily through private placements of ordinary shares and preferred shares, through conditional advances and non-refundable subsidies received from Bpifrance Financement, part of Bpifrance, a French public investment bank, sales of our ordinary shares in connection with the initial public offering of our ordinary shares on Euronext Paris in July 2016, through Bond Financing with Kreos and the State-guaranteed loan (Prêt Garanti par l’État or PGE). All of our operating losses resulted from costs incurred in connection with our development programs and from general and administrative expenses associated with our operations. See Section 3.1, “Financial Risks”. We expect to incur substantial losses from operations in the foreseeable future as we will continue the deployment of the commercial strategy towards the commercialization of LUMEVOQ®, if approve by regulatory authorities and our research and development efforts for GS030 and other product candidates through preclinical and clinical development, seek regulatory approval. Specifically, we have incurred and we expect to continue to incur substantial expenses in connection with any Phase III clinical trials, as well as Chemistry Manufacturing and Controls, or CMC, activities and investing in our commercial structure that we may conduct for LUMEVOQ® and our planned clinical studies for GS030. We anticipate that our expenses will increase substantially in connection with our ongoing activities, as we: •continue the development of our product candidates, including planned and future clinical trials; •seek regulatory approvals for our product candidates; •prepare for the potential launch and commercialization of our product candidates, if approved; •establish a sales and marketing infrastructure for the commercialization of our product candidates, if approved; and •add operational, financial and management information systems and personnel, including personnel to support our product development and commercialization efforts and operations as a French public company. Until such time that we can generate substantial revenue from product sales, we expect to finance these expenses and our operating activities through a combination of our existing liquidity and proceeds from any additional future financing. If we are unable to generate revenue from product sales, in particular from LUMEVOQ®, in accordance with our desired timeframes, we will need to raise additional capital. However, we may be unable to raise additional funds or enter into other funding arrangements when needed on favorable terms, or at all, which would have a negative impact on our financial condition and could force us to delay, limit, reduce or terminate our development programs or commercialization efforts or grant other rights to develop or market product candidates that we would otherwise prefer to develop and market ourselves. Failure to receive additional funding could cause us to cease operations, in part or in full. As indicated in Note 2 of our consolidated financial statements for the period ended December 31, 2021, such consolidated financial statements have been prepared in accordance with International Financial Reporting Standards, or IFRS, issued by the International Accounting Standards Board, or IASB, as adopted by the European Union. IFRS includes the International Accounting Standards, or IASs, approved by the IASB and the accounting interpretations issued by the International Financial Reporting Interpretations Committee, the former Standing Interpretations Committee. 7.2Financial Operations Overview 7.2.1OPERATING INCOME. Our operating income consists of revenues and other income. 7.2.2REVENUES The Company started the sale of LUMEVOQ® through the named patient Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts. Total income solely comes from those named patient ATU. The Company will be paid a preliminary price by the hospitals, ultimately fully covered by the health insurance. Upon obtaining full marketing authorization and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price Estimated rebates are considered to be variable consideration and include significant estimates. •Management determined that the agreement with the CHNO of the Quinze Vingts includes a variable amount. At contract inception, the variable consideration is estimated based on the expected value amount of consideration expected from the transaction and constrained to the extent it is highly probable that a significant revenue reversal in the amount of cumulative revenue recognized will not occur when the associated uncertainty with respect the variable consideration is subsequently resolved. •The methodology and assumptions used to estimate rebates are monitored and adjusted regularly in the light of contractual and legal obligations, historical trends, past experience and projected market conditions. In 2021, in the light of changes in legal obligations, and projected market conditions, the Company adjusted the variable considerations for which it’s highly probable that a significant reversal in the amount of cumulative revenue recognized will not occur. Net revenue is recorded, net of variable consideration related to certain allowances and accruals, at the time the customer obtains control of the product. Our ability to keep generating product revenue and become profitable depends upon our ability to successfully develop and commercialize our product candidates. Because of the numerous risks and uncertainties associated with product development, we are unable to predict the amount or timing of product revenue. 7.2.3OTHER INCOME. Our other income consists of subsidies and conditional advances and research tax credits. Subsidies and Conditional Advances Due to the innovative nature of our product candidate development programs, we have benefited from subsidies and conditional advances from Bpifrance Financement. Bpifrance Financement’s mission is to provide assistance and support to emerging French companies to facilitate the development and commercialization of innovative technologies. The funds we have received are intended to finance our research and development efforts and the recruitment of specific personnel. Such funding is in the form of non-refundable subsidies and conditional advances. We account for non-refundable subsidies as other income ratably over the duration of the funded project. Funds are recognized in other income in our statement of income (loss) for the fiscal year in which the financed expenses or expenditures were recorded. Since inception, we have received a grant from Bpifrance Financement of a non-refundable subsidy of €1,147 K in connection with our development of product candidates using our optogenetics technology platform. The received non-refundable subsidy was fully amortized over 2014, 2015 and 2020, and we do not expect to receive any additional subsidies. Funds received from Bpifrance Financement in the form of conditional advances have been recognized as financial liabilities, as we are obligated to reimburse Bpifrance Financement for such conditional advances in cash based on a repayment schedule and are not included in other income. For more information with respect to the subsidies and conditional advances, see Section 8.3, “Funding Sources” of this Universal Registration Document. Research Tax Credits The research tax credit (crédit d’impôt recherche), or CIR is granted to companies by the French tax authorities in order to encourage them to conduct technical and scientific research and included as other income. Companies demonstrating that they have expenditures that meet the required criteria, including research expenditures located in France or, since January 1, 2005, within the European Community or in another State that is a party to the Agreement on the European Economic Area that has concluded a tax treaty with France that contains an administrative assistance clause, receive a tax credit that can be used against the payment of the corporate tax due the fiscal year in which the expenditures were made and during the next three fiscal years, or, as applicable, can be reimbursed for the excess portion. The expenditures taken into account for the calculation of the CIR only involve research expenses. The main characteristics of the CIR are the following: •the CIR results in a source of cash inflow for us from the tax authorities, since it is used to offset the payment of corporate tax or is paid directly to us for the portion that remains unused for corporate tax; •a company’s corporate tax liability does not limit the amount of the CIR – a company that does not pay any corporate tax can request direct cash payment of the research tax credit; and •the CIR is not included in the determination of the corporate tax. As a result, we have concluded that the CIR meets the definition of a government grant as defined in IAS 20 Accounting for Government Grants and Disclosure of Government Assistance and, as a result, it has been classified as other income within operating income in our statement of income (loss). We have requested the reimbursement of the 2019 CIR in the amount of €4.2 million, which was received in May 2020. We have requested the reimbursement of the 2020 CIR in the amount of €2.8 million, which was received in November 2021. We have requested the reimbursement of the 2021 CIR in the amount of €2.4 million, which has not been received as of the date of this Universal Registration Document. Legislative or regulatory changes relating to CIR or challenges by the French tax authorities with respect to our research expenditures or our eligibility to receive CIR could have a material adverse effect on our ability to operate our business and our financial condition, results of operations and prospects. 7.2.4OPERATING EXPENSES. Since inception, our operating expenses have consisted primarily of research and development activities and general and administrative costs and since 2017, marketing and sales expenses, which have significantly increased in 2021 towards the expected commercial launch of LUMEVOQ® targeted for Q4 2023 in Europe. 7.2.4.1Research and Development We engage in substantial research and development efforts to develop innovative pharmaceutical product candidates. Research and development expenses consist primarily of: •sub-contracting, collaboration and consultant expenses, that primarily include the cost of third-party contractors such as contract research organizations, or CROs, who conduct non-clinical studies and clinical trials; •personnel costs, including salaries, related benefits and share-based compensation, for our employees engaged in scientific research and development functions, and which includes contributions required by French law related to certain share-based compensation, which we refer to as social contributions; •licensing and intellectual property costs, including upfront payment for exclusive licensing; •purchases, real-estate leasing costs and rental income received from sublease agreements, as well as conferences and travel costs; and •depreciation and amortization. Our research and development expenses in the periods presented, and for the current period to date, mainly relate to the following activities: •LUMEVOQ®: Our Phase I/II dose-escalation safety study for LUMEVOQ® was completed in 2016. In 2017, we reported additional clinical trial results with the product candidate after two and two and a half years of follow-up in our Phase I/II study. LUMEVOQ® entered into Phase III trials, RESCUE and REVERSE, in the fourth quarter of 2015, following the release of our investigational new drug, IND, application by the U.S. Food and Drug Administration, or the FDA. The trials are designed as a double-masked, sham-controlled, multi-center, multi-country clinical trial in Europe and the United States. We completed enrollment of all 37 subjects for REVERSE and 39 subjects for RESCUE in February and August 2017, respectively. Top-line results for REVERSE at 48, 72 and 96 weeks were reported in April and October 2018 and in May 2019, respectively. Top-line results for RESCUE at 48, 72 and 96 weeks were reported in February, April and September 2019, respectively. Patients from RESCUE and REVERSE trials have been enrolled in a follow-up study, RESTORE. We have reported results from RESTORE 4 years after the first injection in January 2022. REFLECT, a bilateral Phase III clinical trial conducted pursuant to a special protocol assessment with the FDA, was initiated in 2018. The recruitment of 98 patients was completed in July 2019. 78 weeks topline data were published in June 2021 and 2 years topline data in December 2021. We have submitted an EU Marketing Authorization Application for LUMEVOQ® in September 2020. Approval is now expected in Q3 2023. •GS030: From 2014 to 2016, we conducted preclinical proof-of-concept studies with different molecules that led to the discovery of GS030. In 2017, we have initiated good laboratory practice, toxicology studies on non-human primates. We received the approval to initiate Phase I/II clinical trials in December 2017. The first subject was treated in the United Kingdom in October 2018. The recruitment of the first 3 cohorts was completed in Q3 2020. The DSMB reviewed the safety data of all treated subjects in each cohort and made recommendations before a new cohort receives the next dose. The DSMB recommended selecting the highest dose (5e 11 vg/eye) for the extension cohort currently recruiting. The primary outcome analyses will be on the safety and tolerability at one year post-injection. We announced in October 2021 that the U.S. Food & Drug Administration (FDA) has granted Fast Track Designation to GS030. Our direct research and development expenses consist primarily of external costs, such as manufacturing expenses, non-clinical studies, startup fees paid to investigators, consultants, central laboratories and CROs in connection with our clinical trials, acquiring and manufacturing clinical trial materials and costs related to collaborations, which we allocate to our specific research programs. In addition, we allocate personnel-related costs, depreciation and other indirect costs to specific programs. Research and development activities are central to our business. Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of preclinical and clinical development, primarily due to the increased size and duration of later-stage clinical trials, as well as the ramp-up of CMC and manufacturing activities in preparation for regulatory submission, and ultimately commercialization. We expect that our research and development expenses will continue to increase in the foreseeable future as we initiate clinical trials for our product candidates, and complete clinical development and prepare for commercialization of other product candidates. We cannot determine with certainty the duration or costs of the current or future clinical trials of our product candidates or if, when, or to what extent we will generate revenue from the commercialization and sale of any of our product candidates that obtain regulatory approval. We may never succeed in achieving regulatory approval for any of our product candidates. The duration, costs and timing of clinical trials and development of our product candidates will depend on a variety of factors, including: •the scope, rate of progress and expense of our ongoing, as well as any additional, non-clinical studies, clinical trials and other research and development activities; •clinical trial and early-stage results; •the terms and timing of regulatory approvals; •the expense of filing, prosecuting, defending and enforcing patent claims and other intellectual property rights; and •the ability to market, commercialize and achieve market acceptance for LUMEVOQ®, GS030 or any other product candidate that we may develop in the future. A change in the outcome of any of these variables with respect to the development of LUMEVOQ®, GS030 or any other product candidate that we are developing could mean a significant change in the costs and timing associated with the development of such product candidates. For example, if the FDA, the EMA or other regulatory authority were to require us to conduct non-clinical and clinical studies beyond those which we currently anticipate will be required for the completion of clinical development, or if we experience significant delays in enrollment in any clinical trials, we could be required to spend significant additional financial resources and time on the completion of clinical development. For a discussion on the risks associated with completing the development projects on schedule, see Section 3.2, “Risks Related to the Discovery and Development of and Obtaining Regulatory Approval for Our Product Candidates”. 7.2.4.2General and Administrative General and administrative expenses consist primarily of personnel costs and share-based compensation for personnel other than research and development or sales and marketing staff. General and administrative expenses also consist of fees for professional services, mainly related to audit, IT, accounting, recruitment and legal services, communication and travel costs, real-estate leasing costs, office furniture and equipment costs, allowance for amortization and depreciation, directors’ attendance fees, insurance costs and overhead costs, such as telecommunications expenses. We anticipate that our general and administrative expenses will increase in the future as we grow our support functions for the expected increase in our research and development activities and the potential commercialization of our product candidates. We also anticipate increased expenses associated with being a public company in France, including costs related to audit, legal, regulatory and tax-related services associated with maintaining compliance with Euronext Paris listing and AMF requirements, director and officer insurance premiums, as well as communication and investor relations costs. 7.2.4.3Sales and Marketing Sales and marketing expenses consist primarily of personal costs, professional fees, communication and branding fees. There has been an significant increase in personnel costs and related expenses as well as external expenses as we approach the expected commercial launch of LUMEVOQ® in Europe, expected in Q4 2023. 7.2.4.4Finance Income (Expense) Our financial expenses relate to the impact of the change in the derivative financial instruments fair value, to interest expenses related to our convertible bond loan, state-guaranteed loan and our conditional advances, to the interest expenses related to the application of the standard IFRS 16 on Lease expenses as well as to foreign currency losses related to the purchase of services denominated in U.S. dollars. Our cash and cash equivalents have been deposited only in a non-interest-bearing current account. We expect to follow an investment philosophy whereby our cash and cash equivalents are deposited primarily in savings and money market and time deposit accounts with original maturities of three months or less. We expect our savings and deposit accounts and marketable securities to generate a modest amount of interest income. 7.2.5CRITICAL ACCOUNTING POLICIES AND ESTIMATES. Our consolidated financial statements are prepared in accordance with IFRS. Some of the accounting methods and policies used in preparing our financial statements under IFRS are based on complex and subjective assessments by our management or on estimates based on past experience and assumptions deemed realistic and reasonable based on the circumstances concerned. The actual value of our assets, liabilities and shareholders’ equity and of our earnings could differ from the value derived from these estimates if conditions change and these changes had an impact on the assumptions adopted. We believe that the most significant management judgments and assumptions in the preparation of our financial statements are described below. See Note 3 to our consolidated financial statements for the period ended December 31, 2021 for a description of our other significant accounting policies. Licenses Recognized as Intangible Assets As of December 31, 2013, we recorded an intangible asset relating to exclusive in-licenses for two patent families from Novartis Pharma AG. We issued 670,588 ordinary shares as consideration paid for the exclusive licenses. Given that the fair value of the licenses cannot be reliably estimated, in accordance with IFRS 2 Share-based Payment, or IFRS 2, the amount of the intangible asset being recognized was determined by reference to the fair value of the ordinary shares that we issued based on an independent valuation. The licenses are being amortized over 15 years from February 2013, the date the licenses were entered into, which corresponds to the expected useful life of the licenses. Conditional Advances In 2014, we received a grant from Bpifrance Financement of both subsidies and conditional advances in relation to the development of our optogenetics technology platform. The program would be funded according to a specified schedule set forth in the contract, subject to completion of milestones. As the program advances, we will provide Bpifrance Financement with interim progress reports and a final report when the funded project ends. Based on these reports, we are entitled to conditional advances from Bpifrance Financement. Each award of an advance is made to help fund a specific development milestone. The total amount of the conditional advances initially granted was €5.7 million. The total amount received as of the date of the Universal Registration Document is €4.1 million, of which €678 K was received in December 2014, €2.3 million was received in July 2016 and €1.1 million was received in July 2020 and recognized as non-current liabilities in our statement of financial position, as this conditional advance is repayable by us according to a repayment schedule. Last amendment of our contract with Bpifrance Financement sets forth a repayment schedule that totals a maximum amount of €6.6 million. Following the repayment of the conditional advances, we may be required to make additional payments over a period of two years of approximately €2.0 million, depending on whether we reach cumulative revenues, excluding taxes, of €80.0 million by 2039. Our obligation to repay these amounts is based on the technical and commercial success of the funded program, as determined by the revenue forecasts or revenues deriving from direct or indirect exploitation of the products and results of our optogenetics technology platform. In the event Bpifrance Financement determines that the program is not successful, the Company guarantees the payment of a minimum amount of €0.8 million, corresponding to 20% of the total of the conditional advances received by the Company. The current and non-current portions of the financial liability recognized in our consolidated financial statements associated with these conditional advances are determined based on the applicable reimbursement schedules at the end of each reporting period and measured using the effective rate method. The portion of the conditional advances for terms longer than one year are classified as non-current liabilities while the portion for terms of less than one year are classified as current liabilities. Fair value of the convertible bond The measurement of the fair value of the liability component of the convertible bond, calculated on the basis of the contractually agreed interest and amortization payments discounted at market interest rates. Fair Value of the derivatives The measurement of the fair value of the derivatives directly linked with the convertible bonds and warrants is calculated on the basis of financial mathematic models. Revenue The Company started the sale of LUMEVOQ® through the named patient Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts on December 2019. Variable consideration under IFRS 15 are required to be estimated at contract inception. The Group assessed individual contracts to determine the estimated variable consideration and related constraints. The total revenue presented in our financial statements as of December 2020 and 2021 is therefore net from those variable considerations. Share-Based Compensation We have granted share-based warrants in the form of share warrants for founders (Bons de Souscription de Parts de Créateur d’Entreprise, or BCE) and share warrants (Bons de Souscription d’Actions, or BSA), stock options (Options de souscription ou d’achat d’actions, or SO) and free shares (Attributions gratuites d’actions, or AGA), since January 1, 2016 with the following exercise prices for each of the grant dates reflected below: Grant date Number of warrants granted Exercise price per share Ordinary share fair market value per share at grant date Per share fair value of warrants granted July 8, 2013 (1) 892,000 €0.025 €1.025 €0.44 July 8, 2013 (1) 328,000 €0.025 €1.025 €0.36 April 9, 2014 (1) 193,800 €0.025 €1.025 €0.44 April 9, 2014 (1) 33,000 €0.025 €1.025 €0.36 December 3, 2014 (1) 60,000 €0.025 €2.150 €2.15 July 8, 2015 (1) 733,298 €3.275 €7.800 €5.56 July 8, 2015 (1) 121,000 €3.275 €7.800 €5.31 July 26, 2016 205,000 €8.080 €8.000 €2.94 July 27, 2017 165,000 €5.040 €5.15 €1.64 September 18, 2018 20,000 €2.22 €3.74 €2.02 July 23, 2019 105,000 €1.45 €2.65 €1.83 January 28,2020 40,000 €3.48 €3.19 €1.84 November 2, 2020 80,000 €3.99 €7.28 €5.09 February 25, 2021 40,000 €7.19 €8.58 €5.61 October 21, 2021 30,000 €6.80 €5.56 €3.46 December 14, 2021 65,000 €5.47 €2.12 €1.03 (1) The figures have been adjusted in order to reflect the 5 for 2 reverse stock split which took place on August 17, 2015. Grant date Number of stock options granted Exercise price per share Ordinary share fair market value per share at grant date Per share fair value of stock options granted July 27, 2017 220,000 €5.04 €5.12 €2.09 December 19, 2017 300,000 €5.55 €5.55 €2.20 March 14, 2018 175,000 €6.98 €6.98 €2.63 September 18, 2018 30,000 €2.19 €2.10 €0.91 September 22, 2020 155,000 €2.82 €3.00 €1.91 February 25, 2021 20,000 €7.51 €8.87 €5.77 Grant date Number of free shares granted Ordinary share fair market value per share at grant date July 26, 2016 766,000 €8.00 July 27, 2017 593,500 €5.12 December 19, 2017 72,500 €5.55 September 18, 2018 380,000 €2.10 December 19, 2018 135,000 €4.04 July 23, 2019 610,000 €1.88 January 28, 2020 1,007,500 €3.72 September 22, 2020 85,000 €3.00 February 25, 2021 880,000 €8.87 October 21, 2021 380,000 €7.16 We account for share-based compensation in accordance with IFRS 2. Under the fair value recognition provisions of this guidance, share-based compensation is measured at the grant date based on the fair value of the award and is recognized as expense, net of estimated forfeitures, over the requisite service period, which is generally the vesting period of the respective award. Our determination of the fair value of the warrants and ordinary shares is described below. Fair Value of Our Warrants We use the Black-Scholes option-pricing model to determine the fair value of warrants. Use of this valuation method requires management to apply judgment and make estimates, including: •the expected term of our share-based warrants; •the volatility of our ordinary shares; •the risk-free rate for a period that approximates the expected term of our share-based warrants; •the expected dividend yield; and •the fair value of our ordinary shares on date of grant. To determine the grant date fair value of share-based warrants, these complex and subjective variables are estimated as follows: Expected Term. The expected term represents the period that our share-based awards are expected to be outstanding. As we do not have sufficient historical experience for determining the expected term of the warrant awards granted, we have based our expected term on the simplified method, which represents the average period from vesting to the expiration of the award. Expected Volatility. As we do not have a sufficient amount of trading history for our ordinary shares to make reliable volatility estimates, the expected share price volatility for our ordinary shares was estimated by taking the average historic price volatility for industry peers based on daily price observations over a period equivalent to the expected term of the warrant grants. We did not rely on implied volatilities of traded warrants and options in our industry peers’ shares because the volume of activity was relatively low. We intend to continue to consistently apply this process using the same or similar public companies until a sufficient amount of historical information regarding the volatility of our own ordinary share price becomes available. Risk-Free Interest Rate. The risk-free interest rate is based on the yields of France Treasury securities with maturities similar to the expected term of the warrant for each warrant group. Dividend Yield. We have never declared or paid any cash dividends and do not presently plan to pay cash dividends in the foreseeable future. Consequently, we used an expected dividend yield of zero. If any of the assumptions used in the Black-Scholes model changes significantly, share-based compensation for future awards may differ materially compared with the awards granted previously. The following table presents the weighted-average assumptions used to estimate the fair value of warrants and stock options granted during the periods presented: BCE / BSA As of December 31, 2020 2021 Volatility 83.61% / 85.70% 83.70% / 92.40% Risk-free interest rate -0.45% / -0.48% -0.37% / -0.38% Expected life (in years) 5 years 5 years Dividend yield — % — % Stock Options As of December 31, 2020 2021 Volatility 83.8% 83.7% Risk-free interest rate -0.58% -0.48% Expected life (in years) 5 years 5 years Dividend yield — % — % Fair Value of Our Ordinary Shares Since being listed on Euronext Paris in July 2016, the fair value of our ordinary shares generally has been determined by reference to the closing price of a share on the grant date. 7.3Results of operations Comparisons for the Twelve Months Ended December 31, 2020 and 2021 Operating Income We generated operating income of €7.7 million in 2021 and €7.4 million in 2020, an increase of 3.6%. The revenue reported as of December 31, 2021 and 2020 solely comes from the named patient Temporary Authorizations for Use (“ATU nominative”) for LUMEVOQ® granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts. The CIR has slightly decreased, from €2.8 million in 2020 to €2.4 million in 2021. This evolution directly derives from the end of the clinical development of LUMEVOQ® towards its commercialization. The Company received in July 2020 an additional non-refundable subsidy of €0.3 million from Bpifrance Financement. In thousands of euros As of December 31, 2020 2021 Revenues 4,394 5,276 Other income 3,046 2,433 Research Tax Credit 2,764 2,433 Subsidies 282 – Total operating income 7,440 7,709 As no research and development expenditure is capitalized before obtaining a marketing authorization, the CIR related to a research program is entirely recorded as operating income. For 2020, we recorded other income related to CIR of €2.8 million, which was reimbursed in cash in November 2021. We requested the reimbursement of the 2021 CIR in the amount of €2.4 million, which has not been received at the date of this Universal Registration Document. Research and Development Expenditures In thousands of euros As of December 31, 2020 2021 Personnel expenses(1) 3,903 4,844 Sub-contracting, collaboration and consultants 15,359 15,626 Licensing and intellectual property 2,168 1,318 Offices costs 28 22 Travel and entertainment expenses 245 323 Allowance for amortization 397 366 Others 286 421 Total research and development expenses 22,386 22,920 (1) Includes €0.7 million and €1.4 million related to share-based compensation expense for 2020 and 2021, respectively. From 2020 to 2021, the total amount spent by the Group for research and development activity slightly increased from €22,386 K to €22,920 K, or an increase of 2.4%. The rise has been primarily driven by: •24% or €0.9 million increase in personnel costs, mainly explained by additional recruitments in research and development staff during 2021, from 18 employees at the end of 2020 to 25 employees at the end of 2021, leading to an increase of €0.3 million in wages and salaries and social contributions; as well as an increase of €0.7 million in share-based compensation expenses. •A €1.9 million increase in CMC activities, mostly related to the restart of the manufacturing of the PPQ-campaign in December 2021. •The increases described above have been partially offset by a decrease of €0.9 million in licensing costs as a major contractual milestone related to the submission of our MAA with the EMA for LUMEVOQ® have been paid in 2020, a decrease of €0.8 million in Regulatory expenses deriving from the drop of the consulting costs involved in the preparation of the filing with the EMA submitted in September 2020, as well as a decrease of €0.3 million in device engineering, as the team focused mainly on the development of a new design of the goggles during 2021. The table below summarizes our research and development expenses incurred by program: In thousands of euros As of December 31, 2020 2021 Direct research and development expense by program: LUMEVOQ® 15,168 15,706 GS030 1,623 1,659 Total direct research and development expense 16,791 17,366 Personnel related (including share-based compensation) 3,903 4,844 Indirect research and development expense 1,692 710 Total research and development expenses 22,386 22,920 General and Administrative Expenses During the period presented, our general and administrative expenses decreased from €8.0 million in 2020 to €7.4 million in 2021. Our general and administrative expenses are broken down as follows: In thousands of euros As of December 31, 2020 2021 Personnel expenses(1) 5,839 5,135 Fees 1,421 1,633 Communication and travel expenses 97 46 Real estate property rental — — Office furniture and small equipment 84 92 Postal and telecommunication expenses 11 7 Allowance for amortization and depreciation 142 16 Directors attendance fees and expenses 222 255 Insurance and banking fees 53 52 Others 138 175 Total G&A expenses 8,006 7,411 (1) Includes €2.6 million and €3.0 million related to share-based compensation expense as of December 31, 2020 and 2021, respectively. The decrease in our general and administrative expenses (7.4% or €0.6 million) from year to year mainly results from the decrease of €0.7 million in personnel expenses, primarily related to the reversal of the social contribution provision on 2020 AGA plan, as well as the 2021 bonus provision, which was based on an achievement of 50% of the Corporate Objectives, versus a 110% achievement in 2020. Those decreases have been partially offset by the increase in share-based compensation expenses. We have observed as well an increase of €0.2 million in Professional fees, as we have invested more efforts in our communication and investor relations as in the improvement of our internal structure as we are continuing our development. Sales and Marketing Expenses During the period presented, our sales and marketing expenses significantly increased from €2.0 million in 2020 to €5.5 million in 2021 (+€3.5 million or +178%). In thousands of euros As of December 31, 2020 2021 Personnel expenses(1) 412 1,750 Fees 1,230 3,389 Communication and travel expenses 1 31 Office costs 17 2 Depreciation and amortization expenses 112 119 Others 210 212 Total S&M expenses 1,982 5,505 (1) Includes €0.1 million and €0.4 million related to share-based compensation expense as of December 31, 2020 and 2021, respectively. The increase primarily derives from the professional fees, as well as the personnel expenses. The Group has initiated the deployment of its pre-launch roadmap activities for LUMEVOQ®, mainly focused on our commercial model as well as payer landscape analysis. We have recruited the Country Leads for France, Germany and the UK, and they have started to build their local teams in preparations for LUMEVOQ® commercial launch. Operating Loss Our operating loss decreased from €(24.9) million in 2020 to €(28.1) million in 2021. As described above, this increase of €3.2 million was driven by the ramp up of sales and marketing expenses over the period in preparation for the expected commercial launch of LUMEVOQ® in Europe in Q4 2023. Financial Loss Our net financial loss significantly decreased with a loss of €(489) K in 2021 versus €(9,079) K in 2020. This strong decrease is directly explained by the change in derivative financial instrument fair value booked for an financial gain of €1,309 K in 2021 versus a loss of €(7,359) K in 2020. These financial income and expenses, respectively, are non-cash expenses and represent the change In Fair Value of the convertible option and share warrants attached to our Bond Financing with Kreos. The fair value is calculated based on financial mathematic models using observable market data as of December 31, 2021and 2020, respectively. The Company has booked interest expenses attached to our bond financing and our state-guaranteed loan for €(1,781) K based on the effective interest rate, versus €(1,565) K in 2020. Our interest expenses corresponding to accrued interests of conditional advances amount to €(260) K. We also booked interest expenses deriving from the application of the standard IFRS 16 for €(125) K versus €(152) K in 2020. The financial income mainly arose from the foreign exchange gains coming from the purchase of services denominated in U.S. dollars. We generated a net foreign exchange gain of €367 K in 2021, versus a net foreign exchange loss of €(93) K in 2020. They relate to the purchase of services denominated in foreign currencies, primarily in U.S. dollars. 8 CAPITAL RESOURCES 8.1Overview We have financed our operations since inception primarily through private placements of equity securities and sale of ordinary shares, raising a total of €179.8 million net of transaction-related costs as of the date of this Universal Registration Document including, inter alia, the sale of Series B preferred shares for which we received net proceeds of €30.8 million in a private placement which occurred in July 2015, the sale of ordinary shares in our initial public offering on Euronext Paris in July 2016 for which we received net proceeds of €41.4 million, the capital increase in June 2017 whose net proceeds amounted to €20.7 million, the capital increase in February 2019, entirely subscribed by Sofinnova, whose net proceeds amounted to €7.9 million, the capital increase in December 2019, subscribed by both Sofinnova and 3Sbio, whose net proceeds amounted to €8.3 million, as well as the capital increase in October 2020, for the benefit of a category of persons, whose net proceeds amounted to €23.1 million and finally the capital increase in March 2021, for the benefit of a category of persons, whose net proceeds amounted to €28.1 million. 8.2Analysis of Cash Flow The table below summarizes our sources and uses of cash for the years ended December 31, 2020 and 2021: In thousands of euros As of December 31, 2020 2021 Net cash flows from operating activities (15,044) (17,139) Net cash flows from investment activities (376) (16) Net cash flows from financing activities 33,859 23,739 Net (decrease)/increase in cash and cash equivalents 18,439 6,584 Our net cash flows from operating activities were €(15.0) million and €(17.1) million for 2020 and 2021, respectively. During 2021, the Group has mainly focused on the preparation of the commercial readiness as well as the final pharmaceutical development steps for LUMEVOQ® in preparation for the European marketing authorization. These were mainly preparatory activities to ensure manufacturing readiness to commercialize under Good Manufacturing Practices (GMP). We also strongly accelerated our investments in Sales and Marketing operations towards the future commercial launch notably with the recruitment of the country leads in Germany, France and in the UK as well as additional local positions. The Company also recorded revenues from the sale of LUMEVOQ® under a Temporary Authorization for Use (ATU) in France amounting to a total of €5.3 million in 2021 compared to €4.4 million in 2020, despite the COVID situation. Our net cash from operating activities in 2021 consisted primarily of a net loss of €(28.6) million adjusted of non-cash items, including the change in derivative financial instrument fair value of €(1.3) million, share-based payments of €4.8 million, amortization and depreciation of €928 K, other financials items of €2.2 million. Changes in working capital amounted to €5,567 K and €4,841 K for 2020 and 2021, respectively. The significant items in the change in working capital in 2021 include an increase of the other current and non-current liabilities of €4.4 million, mainly coming from the refund liability related to the potential rebates obligations resulting from the current regulatory framework of the Temporary Authorization for Use (ATU) as well as an increase of the net Trade Payables of €2.4 million, partially offset by an increase of €0.9m of the prepaid expenses, as well as an increase of €0.7m of our Trade receivables. Our net cash flows from investment activities were €(376) K and €(16) K in 2020 and 2021, respectively. The negative cash flows are due to the acquisition of computer equipment mostly, as well as the additional deposits paid to some vendors, partly offset by the sale of own shares as part of the liquidity contract. Our net cash flows from financing activities decreased from €33.9 million in 2020 to €23.7 million in 2021. The positive cash flows from financing activities are mainly due to the net proceeds from the €28.1 million private placement in March 2021 by means of an accelerated bookbuilding process, as well as €0.4 million obtained through the subscription and exercise of equity instruments. The Company has also reimbursed a total of €3.9 million, including interests, to Kreos and our banks, related to our Bond financing and the state-guaranteed loan. 8.3Funding sources During 2016 and 2017, we obtained new financings by both issuance of securities and receipt of conditional advances from Bpifrance Financement. We did not get any new financing in the course of 2018, we completed two capital increases for a total net proceeds of €16.2 million in 2019, as well as a bond financing of €6.0 million. In 2020, we obtained a stateguaranteed loan from banks (Prêt Garanti par l’État or PGE) of €6.8 million, a bond financing of €4.0 million, additional conditional advance and subsidy by Bpifrance Financement for a total amount of €1.4 million as well as a capital increase for a total net proceeds of €23.1 million. Finally, in 2021, as of the date of this Universal Registration Document, we received a total net proceeds of €28.1 million from a capital increase completed on March, 26. In thousands of euros Equity capital Bond financing Borrowings from Banks Conditional advances Subsidies Total 2014 (including financing and advances received prior to 2014) 19,436 — — 678 865 20,979 2015 30,837 — — — — 30,837 2016 41,439 — — 2,279 — 43,718 2017 20,724 — — — — 20,724 2019 16,182 5,742 — — — 21,924 2020 23,133 3,921 6,750 1,139 282 35,225 2021 28,058 — — — — 28,058 Total 179,809 9,663 6,750 4,096 1,147 201,465 On July 7, 2015, we sold 4,624,871 Series B preferred shares for which we received net proceeds of €30.9 million in a private placement. On July 8, 2015, we issued 1,833,247 warrants for which we received proceeds of €30 K. On July 13, 2016, we issued 5,000,000 ordinary shares for which we received net proceeds of €36.4 million in our initial public offering on Euronext Paris. On August 10, 2016, we issued 655,859 ordinary shares for which we received net proceeds of €5.0 million after exercising the overallotment option in connection with our initial public offering on Euronext Paris. On September 3, 2016, we issued 112,000 ordinary shares for which we received net proceeds of €3 K in connection with the exercise of share warrants. On October 6, 2016, we issued 32,720 ordinary shares for which we received net proceeds of €4 K in connection with the exercise of share warrants. On October 31, 2016, we issued 205,000 warrants for which we received proceeds of €133 K. On June 27, 2017, we issued 3,750,000 ordinary shares for which we received net proceeds of €20.7 million. On February 25, 2019, we issued 3,921,568 ordinary shares for which we received net proceeds of €7.9 million. On December 19, 2019, we issued 3,799,701 ordinary shares for which we received net proceeds of €8.3 million. On October 22, 2020, we issued 5,954,650 new ordinary shares with a nominal value of €0.025 each for total net proceeds of €23.1 million. On March 26, 2021, we issued 4,477,612 new ordinary shares with a nominal value of €0.025 each for total net proceeds of €28.1 million. Bond Financing In December 2019, GenSight Biologics obtained a committed financing in the form of a bond financing of up to €12 million from Kreos Capital VI (UK) Limited (the “Kreos Transaction”). The main characteristics are the following: Tranche A Tranche B Straight Bonds A Straight Bonds B Issuance date December 19, 2019 July 31, 2020 Amount €4,200,000 €2,500,000 Number 420,000,000 Straight Bonds with a nominal value of €0.01 250,000,000 Straight Bonds B with a nominal value of €0.01 Drawdown conditions Completion of the 3SBio-Sofinnova Transaction Satisfaction of certain conditions precedent, including completion of a Qualifying Financing Maturity date 45 months as from the issuance date 42 months as from the issuance date Fixed interest rate 9.25% per annum (interest-only period extended until January 2021) 9.25% per annum (interest-only period until February 2021) Principal reimbursement schedule Monthly installments from January 2021 Monthly installments from February 2021 Repayment schedule Monthly Monthly Convertible Bonds A Original Convertible Bonds B Additional Convertible Bonds B Issuance date Simultaneously with the Straight Bonds Simultaneously with the Straight Bonds Simultaneously with Tranche B Amount €1,800,000 €1,200,000 €300,000 Number 1,800,000 Convertible Bonds with a nominal value of €1 1,200,000 Convertible Bonds with a nominal value of €1 300,000 Additional Convertible Bonds B with a nominal value of €1 Conversion conditions At Kreos' option At Kreos' option At Kreos' option Maturity date and conversion deadline 42 months as from the issuance date 42 months as from the issuance date 42 months as from the issuance date Interest rate Identical to the Straight Bonds A Identical to the Straight Bonds B Identical to Straight Bonds B Redemption Terms Identical to the Straight Bonds A Identical to the Straight Bonds B Identical to Straight Bonds B Conversion ratio (CR) 1 / ( (0.9 * P) – D ) P: €2.494 (3-day VWAP prior to the board pricing meeting i.e. December 16, 17 and 18, 2019) D: dividend per share paid by the Company between the issuance date and the conversion date 1 / ( (0.9 * P) – D ) P: €2.494 (3-day VWAP prior to the board pricing meeting i.e. December 16, 17 and 18, 2019) D: dividend per share paid by the Company between the issuance date and the conversion date 1 / ((0.85 * P) – D ) P: €3.028 (5-day VWAP prior to the pricing i.e. July 24, 27, 28, 29 and 30, 2020) D: dividend per share paid by the Company between the issuance date and the conversion date Conversion price €2.245 €2.245 €2.574 Discount to the 3-days VWAP 10% 10% 15% Maximum number of shares issued upon conversion 801,781 534,521 116,550 Tranche A Tranche B Warrants A Warrants B Issuance date Simultaneously with the Straight Bonds Simultaneously with the Straight Bonds Amount €1,200,000 €300,000 Number 534,521 133,630 Drawdown conditions Drawdown of the Straight Bonds Drawdown of the Straight Bonds Maturity date and exercise deadline The earlier of the following events: (i) the tenth anniversary of the Warrants A Issuance Date or (ii) the acceptance by the shareholders of the Company of a third-party bona fide offer to purchase all outstanding shares of the Company The earlier of the following events: (i) the tenth anniversary of the Warrants B Issuance Date or (ii) the acceptance by the shareholders of the Company of a third-party bona fide offer to purchase all outstanding shares of the Company Exercise price €2.245 (3-day VWAP prior to the board pricing meeting i.e. December 16, 17 and 18, 2019) discounted by 10% €2.245 (3-day VWAP prior to the board pricing meeting i.e. December 16, 17 and 18, 2019) discounted by 10% Discount to the 3-day VWAP 10% 10% Maximum number of shares issued upon exercise of the warrants 534,521 133,630 As of the date of this Universal Registration Document, Kreos Capital has converted 50% of the convertible bonds of tranches A and B (at a price of €2.245 per share), as well as 50% of the additional convertible bonds of tranche B (at a price of €2.574 per share). They have also exercised all share warrants of tranches A and B (at a price of €2.245 per share), representing a total issuance of 1,182,953 new ordinary shares. Bpifrance Financement Conditional advances and non-refundable subsidy In 2014, we received a grant from Bpifrance Financement of both non-refundable subsidies and conditional advances in relation to the development of our optogenetics technology platform. The program would be funded according to a specified schedule set forth in the contract, subject to completion of milestones. As the program advances, we provided Bpifrance Financement with interim progress reports and a final report when the funded project would end. Based on these reports, we were entitled to conditional advances from Bpifrance Financement. Each award of an advance was made to help fund a specific development milestone. The total intended amount of the conditional advances initially granted was €5.7 million, of which €0.7 million were received in December 2014 and €2.3 million in July 2016. On June 3, 2020, the following was decided by the Steering Committee: •Payment of a last conditional advance of €1.1 million and a subsidy of €0.3 million to cover for the expenses related to the key-steps 3 and 4; •removal of the specific regulatory condition in key-step 3; •postponement by 2 years of the repayment schedule, i.e. a first repayment deadline on June 30, 2024 instead of June 30, 2022; •establishment of a minimum lump sum reimbursement of €0.8 million, or 20% of the overall received conditional advance. Bpifrance Financement conditional advance The repayment schedule of the conditional advances has been updated accordingly for a total amount of €4,687 K (€4,096 K of cash received + €591 K of capitalized interests) and is as follows: •€550 K from June 30, 2024; •€1,000 K from June 30, 2025; •€1,500 K from June 30, 2026; and •€1,637 K from June 30, 2027; Following the repayment of all of the conditional advances, the Company may be required to make additional payments over a period of two years, depending on whether the Company reaches cumulative revenues, excluding taxes, of €80.0 million. These additional repayments should correspond to the difference between 140% of the conditional advance, considering an interest rate of 1.44% and the amount already reimbursed as per the repayment schedule; and should be done within 15 years following the first year of reimbursement, i.e. 2039. Bpifrance Financement non-refundable subsidy We have been granted a total of €1.1 million in non-refundable subsidies as follows: •€865 K received in December 2014; •€282 K received in July 2020. The table below summarizes the aggregate amounts of subsidies and conditional advances we have received as of the date of this Universal Registration Document: In thousands of euros Entitled Granted Repayed To be granted Conditional advances 5,686 4,096 — — Subsidies 1,147 1,147 — — Total 6,833 5,243 — — State-guaranteed loan The Company obtained a €6.75 million loan from a bank syndicate formed with Crédit Industriel et Commercial (CIC), BNP Paribas and Bpifrance, in the form of a state-guaranteed loan (Prêt Garanti par l’État) (the “PGE“). Initiated by the French Government to support companies during the Covid-19 crisis, the PGE is a bank loan with a fixed interest rate ranging from 0.25% and 1.75% for the first 12 months. After an initial interest-only term of one year, the loan can be amortized over up to five years at the option of the Company. The French Government guarantees 90% of the borrowed amount. The Group has signed in June 2021 amendments to the initial agreements, including an amortization period of three years; until mid-2024, as well as effective interest rates ranging from 1,01% to 2,25%. 8.4Principal uses of cash 8.4.1CONTRACTUAL OBLIGATIONS AND COMMITMENTS. The following table discloses aggregate information about our material contractual obligations and the periods in which payments are due as of December 31, 2021. Future events could cause actual payments and timing of payments to differ from the amounts set forth below. In thousands of Euros Total Less than one year One to three years Four to five years More than five years Conditional advances 4,939 — 356 1,797 2,787 Pension and employee benefits 41 — — — 41 G&A operations related services 1,329 443 886 — — Corporate bonds 5,051 2,465 2,586 — — Borrowings from Banks 5,268 2,210 3,058 — — Total 16,628 5,118 6,888 1,797 2,828 The amounts of contractual obligations set forth in the table above are associated with contracts that are enforceable and legally binding and that specify all significant terms, fixed or minimum services to be used, fixed, minimum or variable price provisions, and the approximate timing of the actions under the contracts. The table does not include obligations under agreements that we can cancel without a significant penalty. 8.4.2OPERATING CAPITAL REQUIREMENTS. Since its incorporation, the Company has funded its activities through several equity financings, grants, conditional advances and Research Tax Credit. To date, the Company has limited revenue deriving from the sale of LUMEVOQ® under a Temporary Authorization for Use (ATU) in France, and management expects operating losses to continue for the foreseeable future until, where appropriate, generate revenue from sale of its development drug candidates. The Company continues to actively prepare for the launch of its LUMEVOQ® product in Europe in 2023, if approved by regulatory authorities. The Company has also continued the current development of its GS030 product and has resumed the activities in 2021, which notably the recruitment of our Chief Technical Officer to lead the GS030 Device Engineering. The Company expects to seek additional funds, most likely from equity or structured debt financings. Our present and future funding requirements will depend on many factors, including, among other things: •the size, progress, timing and completion of our clinical trials for any current or future product candidates, including our lead product candidates, LUMEVOQ® and GS030; •the number of potential new product candidates we identify and decide to develop; •the costs involved in filing patent applications and maintaining and enforcing patents or defending against claims of infringement raised by third-parties; •the time and costs involved in obtaining regulatory approval for our product candidates and any delays we may encounter as a result of evolving regulatory requirements or adverse results with respect to any of these product candidates; •selling and marketing activities undertaken in connection with the anticipated commercialization of the LUMEVOQ® product candidate and any other current or future product candidates, including GS030 and other product candidates in preclinical development, together with the costs involved in the creation of an effective sales and marketing organization; and •the amount of revenues, if any, we may derive either directly, or in the form of royalty payments from any future potential partnership agreements, on the LUMEVOQ® platform or relating to our other product candidates. For more information as to the risks associated with our future funding needs, see the section of this Universal Registration Document entitled Section 3 “Risk Factors”. 8.4.3CAPITAL EXPENDITURES. Our main capital expenditures in 2020 and 2021 were primarily related to leasehold improvements and office and IT equipment for our headquarters. Clinical research and development costs are not capitalized until marketing authorizations are obtained. In thousands of euros As of December 31, 2020 2021 Licenses, software — — Property, plant and equipment 6 32 Non-current financial assets — — Total 6 32 As of December 31, 2021, we had no material contractual commitments to acquire property, plant or equipment. 8.5Information regarding the anticipated sources of funds needed Not applicable. 9 REGULATORY ENVIRONMENT We are subject to a variety of laws and regulations in France, the United States and the European Union (or EU). Our product candidates use biological products and medical devices that are subject to laws and regulations regarding testing, manufacturing, safety, efficacy, labeling, packaging, storage, record keeping, distribution, export and import, reporting, approval, advertising and other promotional practices. Clinical Trials on Human Subjects Before testing any biological product candidate, including a gene therapy product, in humans, the product candidate enters the preclinical testing stage. Preclinical tests, also referred to as non-clinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies to assess the potential safety and activity of the product candidate. Preclinical tests must comply with the laws and regulations and other requirements, including Good Laboratory Practices (GLP), in each jurisdiction in which they are conducted. Clinical trials involving human beings are typically conducted in three sequential phases that may overlap or be combined: •Phase I. The biological product is initially introduced into healthy human subjects and tested for safety, dose tolerance, absorption, metabolism, distribution and excretion. In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients. •Phase II. The biological product is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule. •Phase III. Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies are intended to provide an adequate basis for marketing approval. Studies in Phase III may also further explore the dose-response relationship, or explore the drug’s use in wider populations, in different stages of disease, or in combination with another drug. Clinical trials may, at times, be necessary after marketing in order to explain certain side effects, explore a specific pharmacological effect, or obtain additional data that is more precise. A regulatory authorization is required for the conduct of clinical trials. The regulatory authorities may block the protocols for clinical trials suggested by the companies that apply to test products, suspend them, or require significant modifications in them. Moreover, the patient must be kept informed of the objective, the methodology, and the time period of the research, as well as of the anticipated benefits, constraints, and foreseeable risks resulting from the administration of the products that are the object of the clinical trials. The information communicated is summarized in a written document delivered to the patient prior to any administration of products, and the latter must confirm his or her agreement to participate in the clinical trial by signing an informed consent form. Government Regulation in the European Union Regulatory Authorization/Approval Required for the Conduct of a Clinical Trial in the EU In the EU, since its implementation in 2004, requirements for the conduct of clinical trials on medicinal products have been provided for in the European Directive No. 2001/20/EC of the European Parliament and of the Council of April 4, 2001 relating to the implementation of good clinical practices (or GCP) in the conduct of clinical trials on medicinal products for human use, or Clinical Trials Directive. Each country of the European Union had to implement this Directive into national law by eventually adapting it to its own regulatory framework. Although the European Directive No. 2001/20/EC has sought to harmonize the EU clinical trials regulatory framework, setting out common rules for the control and authorization of clinical trials in the EU, the EU Member States have transposed and applied the provisions of the Directive differently. This has led to significant variations in the Member State regimes. To improve the current system, the Clinical Trials Directive will be replaced by Regulation (EU) No. 536/2014 of the European Parliament and of the Council of April 16, 2014 on clinical trials on medicinal products for human use, adopted on April 16, 2014 and published in the Official Journal of the EU on May 27, 2014 (the “Clinical Trials Regulation”). The Clinical Trials Regulation entered into force on June 16, 2014 and on January 31, 2022 it repealed the Clinical Trials Directive. There is now a transition period until January 30, 2023, during which sponsors may choose to run a clinical trial under either the Clinical Trials Directive or Clinical Trials Regulation; from January 31, 2023, sponsors must run clinical trials under the Clinical Trials Regulation; and from January 31, 2025, any trials approved under the Clinical Trials Directive that continue running will need to comply with the Clinical Trials Regulation. Under either regime, before a clinical trial can be initiated it must be approved in each of the EU Member States where the trial is to be conducted by two distinct bodies: the National Competent Authority, or NCA, and/or one or more Ethics Committees (or ECs). The authorization and oversight of clinical trials remains the responsibility of each Member State. Regulatory Authorization/Approval Required for the Conduct of a Clinical Trial in France General framework. In France, the Clinical Trials Directive has been notably implemented by Act No. 2004-806 of August 9, 2004 relative to the public health policy, as amended, and by Decree No. 2006-477 of April 26, 2006, modifying the title of the French Public Health Code, or PHC, on research involving human beings, this for all categories of products concerned: medicinal products, medical devices, biological products, ATMP, etc. French Order No. 2016-800 of June 16, 2016 on research involving human beings and Act No. 2012-300 of March 5, 2012 (or “Loi Jardé”) related to biomedical research involving human beings have recently adapted French law to the new provisions of Clinical Trials Regulation. France adopted several changes to the laws and regulations on clinical trials since then. Applicable provisions. The main French provisions applicable to the conduct of clinical trials are the following: •Decree No. 2017-884 of May 9, 2017 modifying some regulatory provisions on research involving human beings; •Order of May 3, 2017 establishing the list of researches referred to in Article L.1121-1, 2°, of the French Public Health Code; •Decree No. 2016-1538 of November 16, 2016 on the unique agreement for the implementation of commercial clinical trials involving human beings in health care institutions; •Decree No. 2016-1537 of November 16, 2016 on research involving human beings; •Order No. 2016-800 of June 16, 2016 on research involving human beings; •Act No. 2016-41 of January 26, 2016 for the modernization of our health system; •Decision of December 29, 2015 establishing the rules for good clinical practice; •Act No. 2012-300 of March 5, 2012 (or “Loi Jardé”) related to biomedical research involving human beings; •Act No. 2011-2012 of December 29, 2011 aiming to strengthen health safety of medicinal and health products; •Decree No. 2007-454 of March 25, 2007 on agreements and relationships between companies and members of some healthcare professions, amending the PHC; •Decision of December 11, 2006 establishing the rules of good manufacturing practice; •Decision of November 24, 2006 establishing the rules for good clinical practice for research involving human subjects; •Decree No. 2006-477 of April 26, 2006 amending Chapter I of Title II of Book I of the first part of the PHC on biomedical research; •Act No. 2004-806 of August 9, 2004 on public health policy; •Decision of January 5, 2006 concerning the approval of a methodology for the reference to the processing of personal data carried out within the context of biomedical research; •Act No. 2002-3003 of March 4, 2002 on rights of patients and on the quality of the healthcare system and its implementing decrees; •European Directive No. 2001/20/EC of the European Parliament and of the Council of April 4, 2001 relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use; •Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/CE (General Data Protection Regulation), and the Act No. 78-17 of January 6, 1978 on Information Technology, Data Files and Civil Liberties, as last amended in 2018, and its implementing decrees; •Decision No. 2018-154 of May 3, 2018 concerning the approval of a standard methodology for processing personal data in the context of research in the field of health, which does not require the express consent of the person involved (methodology MR-003); and •Decision No. 2018-153 of May 3, 2018 concerning the approval of a standard methodology for processing personal data in the context of research in the field of health, which requires the express consent of the person involved (standard methodology MR-001). Ethics Committee assessment. Under French law, a favorable opinion of a competent research and Ethics Committee (Comité de Protection des Personnes or “CPP”) of the jurisdiction in which the investigator exercises its activity is always required for the conduct of clinical trials. Under Article L.1123-7 of the PHC, the competent Ethics Committee – selected randomly by drawing lots under Article L.1123-6 of the PHC – shall notably assess whether the conditions in which the trial will be conducted are valid. This assessment should be based on whether: adequate protection is offered to individuals, in particular to participants; adequate information is provided to the participants and appropriate procedure is in place to obtain their informed consent; the project is relevant; the benefits/risks assessment is satisfactory; the objectives of the trial are adequate to the means implemented; the qualification of the investigator(s) is satisfactory; the conditions and amount of patients’ remuneration is compliant; and the method for recruiting participants is adequate. ANSM authorization. A prior authorization issued by the ANSM is required for some types of clinical trials (interventional clinical trials implying an intervention on a natural person that is not justified by his/her usual medical care). In practice, the applicant must submit to the ANSM a request for authorization of a clinical trial along with a file, which shall, in particular, contain information on the clinical protocol and specific product data and its quality control, as well as results of preclinical studies. After submission of the complete file, the ANSM may inform the sponsor that it objects to the implementation of the research. The sponsor can then modify the contents of its research project and submit an amended or supplemented request to the ANSM; this procedure may not, however, be applied more than once. If the sponsor does not alter the content of its request, the request is considered rejected. Under French law, the time limit for the examination of a request for authorization of a clinical trial cannot exceed 60 days from the date of receipt of the complete file by ANSM (Article R.1123-38 PHC) and 45 days for the CPP (Article R.1123-23 PHC). In the case of trials involving medicinal products for gene therapy or somatic cell therapy or medicinal products containing genetically modified organisms the time limit for the examination by ANSM and CPP is a 90-day period may which can be extended by a further 90 days in the event of consultation of a group (Articles R.1125-8, R.1125-10, R.1125-11 PHC). In the event of a risk to public health or if the ANSM considers that the conditions in which the research is implemented no longer correspond to the conditions indicated in the request for authorization or does not comply with the provisions of the PHC, the ANSM may at any time request changes to procedures for the realization of research, and suspend or ban this research (Article L.1123-11 PHC). Under Article L.1123-7 PHC, the CPP shall deliver its opinion on the conditions of validity of the research, particularly with respect to the protection of participants, their information and how they collect informed consent, as well as the project’s general relevance, the satisfactory nature of the assessment of benefits and risks and the adequacy between the objectives pursued and the means implemented. The decision of November 24, 2006 sets forth the rules for good clinical practice (“GCP”), for biomedical research on medicines for human use provided for in Article L.1121-3 PHC. The purpose of the rules for GCP is to ensure both the reliability of data arising from clinical trials and the protection of persons participating in these clinical trials. GCPs shall apply to all clinical trials, including pharmacokinetics, bioavailability and bioequivalence studies in healthy volunteers and Phase II to IV clinical trials. Under French law, a specific authorization issued by the Director General of ANSM is required before commencing clinical trials involving some advanced therapy medicinal products, including in particular medicinal products for gene therapy and somatic cell therapy including xenogenic (see Article L.4211-9-1 PHC). Protection of Clinical Trial Subjects. Under French law (Article L.1121-2 PHC), a clinical trial may be undertaken only if (i) it is based on the latest stage of scientific knowledge and on sufficient preclinical testing, (ii) the foreseeable risk incurred by the subjects is outweighed by the benefit expected for these persons or the interest of the research, (iii) it aims at expanding scientific knowledge and the means possible to improve the human condition and (iv) the research was designed to reduce the pain, inconveniences, fear and other predictable inconvenience connected to the disease or to the research, by taking into account in particular the degree of maturity of minors and the capacity of understanding of adults unable to express an informed consent. All these conditions must be fulfilled in order to start a clinical trial. A clinical trial (Article L.1121-3 PHC) may be undertaken under the following technical conditions: (a) under the direction and the supervision of a qualified physician and (b) under adapted material and technical conditions, compatible with the rigorous imperatives of science and the safety of the clinical trial subjects. Two documents must be provided to clinical trial subjects before the conduct of the trial. First, the patient must receive a patient information sheet which must contain in particular a description of the objective, the methodology and the time period of the research, as well as a description of the alternative treatments, the number of subjects expected to take part in the study, the anticipated benefits, the constraints and the foreseeable risks resulting from the administration of the products that are the object of the clinical trials but also the favorable opinion of the Ethics Committee and the authorization of the ANSM, and information on processing of personal data. The information communicated must be summarized in a written document delivered to the patient prior to any administration of products by the investigator or a physician (Article L.1122-1 PHC). Second, the patient must confirm his or her agreement to participate in the clinical study by signing an informed consent form (Article L.1122-1-1 PHC). For each study, patient information must include a right to refuse to participate and to withdraw consent at any time and by any means without further consequences or prejudice. A clinical trial on a minor may be undertaken only if, in particular, the informed consent of the parents or legal representative has been obtained. Furthermore, a clinical trial on adults under guardianship requires the informed consent of the adult’s legal representative. Responsibility of the sponsor and insurance obligation of the sponsor. The sponsor shall indemnify the subject of the trial in case of damage arising as a consequence of the research, unless he proves that the damage does not result from his fault or the fault of any other person intervening in the trial (Article L.1121-10 PHC). The sponsor must have an insurance covering its civil liability and the liability of any person intervening in the research, for any damage arising from the trial for a minimum of 10 years as of the end of the trial (Article L.1121-10 PHC). Market protection in the European Union To obtain regulatory approval of an investigational biological product under European Union regulatory systems, we must submit a Marketing Authorization Application (MAA). The application format used to file the MAA, i.e. the Common Technical Document (CTD), is harmonized between Europe, USA and Japan, with the exception of, among other things, country-specific document requirements. The European Union also provides data protection. In the European Union, upon receiving marketing authorization (or MA), new chemical entities receive eight years of data exclusivity and an additional two years of market protection. Data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic application. During the additional two-year period of market exclusivity, a generic marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic product can be marketed until the expiration of the 10 years. This market protection period may be extended by one year in case of new indication. Orphan Medicinal Products The European Union provides opportunities for market exclusivity. Pursuant to abovementioned Regulation (EC) No. 141/2000, products receiving orphan designation in the EU can receive ten years of market exclusivity following the marketing approval, during which time no similar medicinal product may be placed on the market for the same therapeutic indication. Under Article 37 of the Regulation (EC) No 1901/2006, an orphan product can also obtain an additional two years of market exclusivity in the EU for pediatric studies (in this case for orphan drugs no extension to any supplementary protection certificate can be granted, see further detail below). Under Article 3 of the Regulation (EC) No 141/2000, a medicinal product may be designated as orphan if: (1) (a) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the EU when the application is made, or (b) it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the necessary investment; and (2) that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the EU or, if such method exists, that the drug will be of significant benefit to those affected by that condition, as defined in Regulation (EC) 847/2000. Pursuant to Regulation (EC) No. 847/2000 of April 27, 2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts “similar medicinal product” and “clinical superiority,” a sponsor applying for designation of a medicinal product as an orphan medicinal product shall apply for designation at any stage of the development of the medicinal product. Where a marketing authorization in respect of an orphan medicinal product is granted pursuant to Regulation (EC) No. 726/2004 or where all the Member States have granted marketing authorizations for this product, in accordance with the procedures for mutual recognition, the Community and the Member States shall not, for a period of 10 years, accept another application for a marketing authorization, or grant a marketing authorization or accept an application to extend an existing marketing authorization, for the same therapeutic indication, in respect of a similar medicinal product. The 10-year market exclusivity may however be reduced to six years if, at the end of the fifth year, it is established, in respect of the medicinal product concerned, that the above-mentioned criteria no longer met, inter alia, where it is shown on the basis of available evidence that the product is sufficiently profitable not to justify maintenance of market exclusivity (Article 8). Pursuant to Regulation No. 1901/2006 on medicinal products for pediatric use, for orphan medicinal products, instead of an extension of the supplementary protection certificate, the 10-year period of orphan market exclusivity should be extended to 12 years if the requirement for data on use in the pediatric population is fully met (i.e. when the request contains the results of all studies carried out under the approved Pediatric Investigation Plan (“PIP”) and when the declaration attesting the conformity of the request to this PIP is included in the marketing authorization). However, by way of derogation, a marketing authorization may be granted, for the same therapeutic indication, to a similar medicinal product if: •the holder of the marketing authorization for the original orphan medicinal product has given his consent to the second applicant; or •the holder of the marketing authorization for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product; or •the second applicant can establish in the application that the second medicinal product, although similar to the orphan medicinal product already authorized, is safer, more effective or otherwise clinically superior. The abovementioned Regulation (EC) No. 141/2000 provides for other incentives regarding orphan medicinal products. Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and scientific assistance for study proposals (Articles 6 and 9). The application for orphan drug designation must be submitted before the application for marketing authorization (Article 5). The applicant will receive a fee reduction for the marketing authorization application if the orphan drug designation has been granted, but not if the designation is still pending at the time the marketing authorization is submitted. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. Regulation (EC) No. 141/2000 also provides that medicinal products designated as orphan medicinal products under the provisions of this Regulation shall be eligible for incentives made available by the Community and by the Member States to support research into, and the development and availability of, orphan medicinal products and in particular aid for research for small- and medium-sized undertakings provided for in framework programs for research and technological development. Protection of Personal Data The Regulation 2016/679, known as the General Data Protection Regulation, or GDPR, as well as EU Member State implementing legislations, apply to the collection and processing of personal data, including health-related information, by companies located in the EU, or in certain circumstances, by companies located outside of the EU and processing personal information of individuals located in the EU. These laws impose strict obligations on the ability to process personal data, including health-related information, in particular in relation to their collection, use, disclosure and transfer. Also, in certain countries, in particular France, the conduct of clinical trials is subject to compliance with specific provisions of the Act No.78-17 of January 6, 1978 on Information Technology, Data Files and Civil Liberties, as amended, and in particular Chapter IX relating to the processing of personal data in the health sector. These provisions require, among others, the filing of compliance undertakings with “standard methodologies” adopted by the French Data Protection Authority (the CNIL), or, if not complying, obtaining a specific authorization from the CNIL. The most common standard methodologies are the following: •Decision No. 20186-263154 of July 21, May 3, 2018 concerning the approval of a standard methodology for processing personal data in the context of research in the field of health, which does not require the express consent of the person involved (methodology MR-003); •Decision No. 20186-153262 of July 21, May 3, 2018 concerning the approval of a standard methodology for the processing of personal data carried out within the context of research in the field of health clinical trials, which requires the express consent of the person involved (standard methodology MR-001). In certain specific cases, entities processing health personal data may have to comply with article L1111-8 of the French Public Health Code which imposes certain certifications for the hosting service providers. Expedited Programs at the EMA, Expedited Development and Review Programs EMA is authorized to expedite the review of MAAs in several ways. Accelerated assessment, which shortens the CHMP review timeline to 150 days. In order to qualify, the sponsor must justify in their application that the drug is “of major public health interest”. Typically, this requires evidence that the drug in question addresses an unmet medical need “to a significant extent”. Conditional marketing authorization pathway, which allows the CHMP to grant a conditional, annually renewable approval for drugs that meet certain criteria. In order to qualify, a drug must be aimed at treating, preventing, or diagnosing a serious or life-threatening disease; intended for emergency use; or designated as an orphan drug. Additionally, the CHMP must determine that the drug meets four key criteria: 1) based on the existing evidence, the drug’s benefits outweigh the risks, 2) the sponsor will be able to collect comprehensive post-market data, 3) the drug fulfills an unmet medical need, and 4) the benefits of its immediate availability outweigh the risks associated with approving it with more limited data. The sponsor must continue to collect post-market data on the drug to confirm its benefit. The authorization may be converted to a standard approval once sufficient data is available, or revoked if it is determined that the drug’s benefits do not outweigh its risks. In certain exceptional circumstances, EMA may also grant conditional authorization for a therapy that does not have comprehensive data on safety and efficacy (referred to as “authorization under exceptional circumstances”). This may occur when the condition or disease to be treated is very rare, or collection of full information is either not possible or would be considered unethical. PRIME scheme fosters frequent and early interaction between sponsors and regulators, and is aimed at improving trial design and streamlining the development process. Sponsors whose product has been approved under the PRIME pathway benefit from a designated CHMP liaison, early feedback on development and regulatory strategy, and scientific advice when certain development milestones have been met. While large pharmaceutical companies are eligible for PRIME following proof-of-concept trials, smaller companies and academic groups – which would particularly benefit from earlier scientific consultation and advice – can apply at an earlier stage, on the basis of compelling non-clinical and tolerability data from initial clinical trials. European Union Marketing Authorizations In the EEA, medicinal products can only be commercialized after obtaining a marketing authorization or MA, from the competent regulatory authorities. There are different types of marketing authorizations including: Centralized Procedure Regulation (EC) No. 726/2004 of the European Parliament and of the Council of March 31, 2014 provides for the Centralized authorization procedure. It results in a single marketing authorization, or MA, granted by the European Commission that is valid across the European Economic Area, or the EEA (i.e., the EU as well as Iceland, Liechtenstein and Norway). Under the annex to this Regulation, the centralized procedure is compulsory for the following medicinal products: (1) medicinal products developed by means of one of the following biotechnological processes: recombinant DNA technology, controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells, hybridoma and monoclonal antibody methods; (2) advanced therapy medicinal products as defined in Article 2 of Regulation (EC) No 1394/2007; (3) medicinal products containing a new active substance which, on the date of entry into force of this Regulation, was not authorized in the Community, for which the therapeutic indication is the treatment of any of the following diseases: HIV/AIDS, cancer, neurodegenerative disorder, diabetes, auto-immune diseases and other immune dysfunctions and viral diseases; and (4) medicinal products that are designated as orphan medicinal products pursuant to Regulation (EC) No 141/2000. Under Article 3 of this Regulation, the Centralized procedure is optional for any medicinal product not appearing in the Annex if: (1) the medicinal product contains a new active substance which, on the date of entry into force of this Regulation, was not authorized in the Community; or (2) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorization in accordance with this Regulation is in the interests of patients or animal health at Community level. The European Medicines Agency, or EMA, shall ensure in the scope of the Centralized procedure that the opinion of the Committee for Medicinal Products for Human Use, or CHMP, is given within 210 days after receipt of a valid application (Article 6.3). This excludes so-called clock stops, during which additional written or oral information is to be provided by the applicant in response to questions asked by the Committee for Medicinal Products for Human Use, or CHMP (Article 7). At the end of the review period, the CHMP provides an opinion to the European Commission. If this opinion is favorable, the Commission may then adopt a decision to grant a MA. When an application is submitted for a MA in respect of medicinal products for human use which are of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation, the applicant may request an accelerated assessment procedure. The request shall be duly substantiated. If the CHMP accepts the request, the time-limit laid down in Article 6(3), first subparagraph, shall be reduced to 150 days (Article 14(9)). National authorization procedure National MAs issued by the competent authorities of the Member States of the EEA, through the Mutual Recognition Procedure or Decentralized Procedure, only cover their respective territory. These procedures are not applicable to gene therapy product as they are available only for products not falling within the mandatory scope of the centralized procedure. Regulatory Approval of Medical Devices in the European Union CE Marking Requirements Manufacturers of medical devices, in the EU are required under the EU Medical Devices Directive (Council Directive 93/42/EEC, the “MDD”) to affix a CE marking of conformity (a “CE mark”) to their products in order to sell these products in Member States of the EU. The CE mark is a symbol that demonstrates conformity to certain essential principles of safety and performance mandated in the MDD, which are referred to as the “Essential Requirements”. Subject to national restrictions, CE marked products may be sold within the European Economic Area (the “EEA”), which is composed of the 27 Member States of the EU plus Norway, Iceland and Liechtenstein, as well as in other countries that recognize the validity of the CE mark. Devices in the EU are classified in four different classes (I, IIa, IIb and III) depending on a number of factors that are defined in the MDD. Typically, the highest class (Class III) groups those devices that are deemed to present the highest risk and are therefore subject to more stringent requirements. Conformity Assessment Procedures Premarket approval of medical devices does not exist in the European Union; however, the European Union has adopted numerous directives and standards regulating, among other things, the design, manufacture, clinical trials, labeling, approval and adverse event reporting for medical devices. The conformity assessment of medical devices with the essential requirements varies depending on the classification of the device and the directive that is applicable. The lowest-risk devices require only a self-declaration of conformity by the manufacturer. Higher-risk devices require the involvement of third-party bodies called “notified bodies,” which are certification organizations designated by the competent authorities of Member States to carry out the conformity assessment procedures described in the Medical Devices Directives. The notified body’s tasks will vary depending on the classification of the products concerned and the conformity assessment route a manufacturer has chosen. Under the conformity assessment procedure, Notified Body will audit and examine the technical file and the quality system applied to the manufacture, design and final inspection of the products. Following successful completion of the applicable procedure, the Notified Body will issue an EC Certificate of Conformity. This certificate entitles a manufacturer to affix the CE mark to its medical devices after having prepared and signed a “EC Declaration of Conformity” indicating that the product meets the Essential Requirements. Such certificate is valid for a maximum of five years, and may be extended on application for a further period of five years. Medical devices which comply with the essential requirements of the Medical Devices Directives must bear the conformity CE-marking when marketed in EU Member States. The CE-marking has to be placed visibly and legibly on the product or, if not possible due to the nature of the product, be affixed to the packaging and the accompanying documentation. If a notified body has been involved in the conformity assessment procedure, its identification number must also be displayed. Compliance with these requirements is a prerequisite to be able to affix the CE Mark of Conformity to medical devices, without which they cannot be marketed or sold in the EEA. Actual implementation of these directives, however, may vary on a country-by-country basis. If the devices are substantively modified, one may need to broaden, or re-perform, the certification underlying the CE marking of the modified product. The CE marking can be suspended or withdrawn. The same may be true for any new products that we may develop in the future. The Medical Devices Regulation New rules have recently been adopted in the EU on medical devices which will have a direct impact on our business in the near future. Specifically, on May 25, 2017, the new Medical Devices Regulation (Regulation (EU) 2017/745, the “MDR”) entered into force, with a three-year transition period. The MDR will progressively replace the MDD and introduce substantial changes to the current regulatory regime applicable to medical devices. Under the transitional provisions of the MDR, until May 26, 2020, the certification procedures underlying the CE marking of medical devices can be carried out, at the manufacturer’s choice, either in accordance with the MDR or in accordance with the MDD. Should a manufacturer elect to perform certification under the MDD, the related certificates will remain valid until the earlier of: a) the end of the period indicated on the certificate (typically five years, but it could be less); and b) May 27, 2024. The medical devices to which these certificates apply may only be sold in the EEA if they continue to comply with the MDD and provided that no significant changes are brought to these devices’ design or intended purpose. Moreover, the manufacturers of those devices that are certified under the MDD will have to comply with a number of requirements of the MDR, e.g., those relating to post-market surveillance and vigilance, and they will be able to sell such devices only up until May 27, 2025 at the latest. After that date, all devices sold in the EEA will have to be fully compliant with the MDR. Under the MDR, all devices incorporating or consisting of nanomaterials will be classified as Class III if they present a high or medium potential for internal exposure. The MDR introduces higher clinical data requirements for such Class III devices. In particular, manufacturers will be required to conduct new clinical investigations in case they do not have “sufficient” clinical data to support the safety, performance and clinical benefit claims of their devices. The MDR also introduces increased scrutiny of conformity assessments by Notified Bodies for implantable Class III devices. For such devices, the MDR requires that relevant European Commission expert panels scrutinize, as part of the conformity assessment procedure, the clinical assessment of the concerned Notified Body. Such devices will be further subject to a mechanism allowing competent authorities of the EEA and the European Commission Medical Device Coordination Group to scrutinize the documentation submitted by the manufacturer as well as the documentation produced by the Notified Body and the relevant expert panels, in the context of the applicable conformity assessment procedure. In addition, under the MDR, manufacturers of Class III devices will be subject to a new annual safety reporting requirement called the Periodic Safety Update Report, aimed at capturing the analyses of the post-market surveillance data gathered, including data from their Post-Market Clinical Follow-Up. The amount of guidance available on these new requirements is currently very limited and the European Commission is set to adopt a number of delegated and implementing acts to further specify applicable requirements and obligations under the MDR. EU France: Coverage and Reimbursement In certain countries, the proposed pricing for a drug must be approved before it may be lawfully marketed. The requirements governing drug pricing vary widely from country to country. In some countries, pricing and reimbursement coverage also depend on assessments performed by national Health Technology Assessment (HTA) bodies. These assessments may be completed before or after a product is available in the market and may affect the invoiced and/or net price of an approved drug. The European Union provides options for its Member States of the EEA to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. For example, in France, effective access to the reimbursed market assumes that our future products will be supported by the hospital (through an agreement for local communities) and reimbursed by social security. Once Health Technologic Assessment is done for a drug or device, the price of reimbursed medications in France is negotiated with the Economic Committee for Health Products, or CEPS. It exists in France an exceptional procedures which is designed to ensure for specific situations (severe disease without appropriate therapeutic alternative) early of access and the greatest possible security for the use of medicines outside the common reimbursement fields: The Early Access (AP) allows patients to benefit from pharmaceutical specialities whereas they do not have any marketing authorization yet, provided that they are intended for the treatment of serious or orphan diseases and in the absence of appropriate treatment. Drugs benefiting from an AP are 100% covered by the health insurance during the AP period. They are supplied to the health establishment by the laboratory holding the exploitation rights, free of charge or in return for an indemnity the amount of which is freely determined by the laboratory. However, if appropriate, the laboratory would have to reimburse the difference between the price invoiced to the hospital during the AP period and the eventually net commercial price agreed with the CEPS. The EU has legislation that provides for some harmonization of access to drugs that treat rare diseases. For example, Cross Border Healthcare Directive requires Member States to reimburse, possibly with restrictions, a treatment approved in the EU but currently unavailable locally. But the pricing and market access is dynamic, as the EU is evaluating multiple initiatives to provide access to rare disease therapies, particularly regenerative treatments like gene therapy, and national bodies are assessing their reimbursement pathways and valuation methodologies in light of the curative promise from these therapies. Early Access Compassionate use is a treatment option that allows the use of an unauthorized medication. The legal framework for the provision of compassionate use in the EU is introduced under Article 83 of Regulation (EC) No. 726/2004. Under strict conditions, products under development may be made available to groups of patients who have a disease without satisfactory therapy and who cannot participate in clinical trials. The European Medicines Agency (EMA) makes recommendations through the Committee for Medicinal Products for Human Use (CHMP), but these do not constitute a legal framework. Compassionate use programs are coordinated and implemented by the Member States who set their own rules and procedures. At European level: PRIME is a scheme launched by the European Medicines Agency (EMA) to enhance support the development of medicines that target an unmet medical need. This voluntary scheme is based on enhanced interaction and early dialogue with developers of promising medicines, to optimize development plans and speed up evaluation so these medicines can reach patients earlier. PRIME is limited to medicinal products under development that are not authorized in the EU and for which the applicant intends to submit an initial marketing authorization application through the centralized procedure. Eligibility is based on the level of innovation of the medicinal product and its response to an unmet medical need. The eligibility criteria for PRIME are identical to those required for the EMA accelerated assessment, and target medicinal products of major public health interest, in particular from the point of view of therapeutic innovation. In France, the exceptional use of pharmaceutical specialties that do not benefit yet from a marketing authorization and are not the subject of a clinical trial is subject to the prior obtaining of an Early Access article 78 of Law n° 2020-1576 of December 14, 2020 concerning social security financing (LFSS) for 2021 has completely redesigned the current system for the exceptional use of pharmaceutical specialties that do not benefit from a marketing authorization and are not the subject of a clinical trial.Two new paths have been put in place in July 2021: •The early access (“Accès précoce”) for medicinal products with strongly assumed efficacy and safety, that meet an unmet medical need, for a rare, severe or debilitating disease, likely to be innovative and for which the laboratory commits to submitting a Marketing Authorization Application (MAA) within 2 years or an application for reimbursement under common law. In practice, request for authorization of early access (AAP) are submitted by the laboratory to the HAS (French National Authority for Health), to the French Ministry of Health, and to the ANSM. •The compassionate access (“Accès compassionnel”) for medicinal products which are not necessarily innovative, which are not initially intended to obtain a Marketing Authorization but which satisfactorily meet an unmet medical need. —Nominative Compassionate access: request submitted by a HCP for medicinal product not authorized and available in France, for a named patient. —Compassionate prescribing framework: ANSM takes the initiative to secure the off-label use of a medicinal product authorized in France in a different indication, when this off-label use prescription is well established in France. Provision is made for the ANSM to be able to grant an authorization for compassionate access, at the request of a physician, for medicinal products which are the subject of clinical research in an indication considered at a very early stage. It’s called very early compassionate access. The granting by the ANSM of this access is subject to several eligibility conditions: •The treatment cannot be deferred; •The patient cannot participate in the clinical studies; •The laboratory must commit to filing an early access request within a specified period following the first very early compassionate access authorization. Drugs benefiting from an early access or compassionate access are 100% covered by the health insurance. They are supplied to the health establishment by the laboratory holding the exploitation rights, free of charge or in return for an indemnity the amount of which is freely determined by the laboratory. However, if appropriate, the laboratory would have to reimburse the difference between the price set for the sale of the early access and the commercial price to the health insurance. Early access authorization is subject to compliance, by the laboratory, with a protocol for therapeutic use and data collection (PUT-RD), defined by HAS, in conjunction with ANSM where applicable, and appended to the authorization decision. This PUT-RD collects observational/real-life data from patients benefiting from an early access authorization drug. This is a collection of data in real conditions of care and not a collection of data for clinical research. The data collected under the authorization of early access is not intended to replace the clinical trials and do not modify the expectations of the Transparency Committee (CT) in terms of clinical development specified in the CT doctrine for inclusion on the list of reimbursable medicines (common law). On the other hand, these data are complementary and therefore contribute to the evaluation of the medicinal product by the HAS for the renewal of the authorization for early access and ultimately for assessment of reimbursement. The collection of information under the authorization of early access must be the subject of a declaration of compliance to the CNIL reference system specific to this data processing in the context of early access. Early access authorizations should not replace clinical trials: patients eligible for an ongoing clinical trial in the indication under consideration must be included in this clinical trial as a priority. France: Post-marketing requirements Any pharmaceutical product or medical device distributed in France will be subject to pervasive and continuing regulation by the ANSM and HAS, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing updated safety and efficacy information, distribution requirements, complying with promotion and advertising requirements. France: Advertising French law strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market and imposes requirements and restrictions on drug manufacturers, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities. Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each EU Member State and can differ from one country to another. French Pharmaceutical Company Status To commercialize a product in France, it is mandatory to have the pharmaceutical establishment license directly, either as distributor “exploitant” or as manufacturer. This license can be obtained after the submission of a request file specific to each of the two qualifications with the ANSM, and only granted after review and evaluation by the ANSM, usually after verification that the company has adequate premises, the necessary personnel and an adapted structure with satisfactory procedures for carrying out the proposed pharmaceutical activities, in particular pharmaceutical supply and pharmacovigilance. France: Declarations of Financial Interests “Transparency” or “French Sunshine Act” The French Public Health Code (PHC) contains certain provisions regarding transparency of fees and rewards received by some healthcare professionals from industries, i.e. companies manufacturing or marketing health products, resulting from Act No. 2011-2012 of December 29, 2011 aiming at strengthening health safety of medicinal and health products, amended by an Act No. 2016-41 of January 26, 2016, and corresponding implementing decrees. It results from these provisions (Articles L.1453-1 and D.1453-1 et seq. PHC) that companies manufacturing or marketing healthcare products (medicinal products, medical devices, etc.) in France shall publicly disclose (on a specific public website available at: https://www.entreprises-transparence.sante.gouv.fr) the advantages and fees paid to healthcare professionals amounting to €10 or above, as well as the agreements concluded with the latter, along with detailed information about each agreement (the precise subject matter of the agreement, the date of signature of the agreement, its end date, the total amount paid to the healthcare professional, etc.). “Anti-gift”requirements The French Public Health Code also contains “anti-gift” provisions, which, subject to limited exceptions, prohibit payments and rewards from industries, i.e. companies manufacturing or marketing health products, to healthcare professionals and strictly defines the conditions under which such payments or rewards are lawful. The provisions enacted under Act No. 2011-2012 were amended by Order No. 2017-49 of January 19, 2017, which notably extended their application to a broader range of legal and physical persons, specified the scope of the operations excluded from the prohibition and those authorized under some conditions, and provided for a new authorization process. The amendments to the “anti-gift” rules in Articles L.1453-3 to L.1453-12 PHC entered into force on July 1, 2018, without new implementing provisions. Failure to comply with the above applicable regulatory requirements may result in reputational risk, public reprimands, restrictions on the marketing of a product or withdrawal of the product from the market as well as possible administrative or criminal sanctions or fines. Foreign investment screening procedure Any investment (i) by : (a)a natural person of foreign nationality, (b)any individual of French nationality not domiciled in France within the meaning of Article 4B of the French General Tax Code, (c)any entity governed by foreign law, and (d)any entity governed by French law controlled by one or more of the entities mentioned in (a) to (c); (ii) which would result in (a) the acquisition of control within the meaning of Article L.233-3 of the French Commercial Code of a French company, (b) the acquisition of all or part of a branch of activity of a French company, or (c) for individuals or legal entities that are not nationals of a Member State of the European Union or of a State party to the Agreement on the European Economic Area, the crossing of the threshold of 25% of the voting rights of a French company; and (iii) which develops its activities in certain strategic sectors essential to the protection of public health, including research and development in critical technologies including biotechnology, is subject to prior authorization by the Minister of the Economy. If an investment in the Company requiring the prior authorization of the Minister of the Economy is made without such authorization having been granted, the Minister of the Economy may order the investor concerned (i) to submit an application for authorization, (ii) to have the previous situation restored at its own expense or (iii) to modify the investment. The investor concerned could also be declared criminally liable and be sanctioned by a fine that may not exceed the higher of the two following fines: (i) twice the amount of the investment concerned, (ii) 10% of the Company’s annual pre-tax revenues, and (iii) €5 million (for a company) or €1 million (for an individual). Regulatory Framework in the United States In the United States, biological products, including gene therapy products and medical devices are subject to regulation under the Federal Food, Drug, and Cosmetic Act, or FD&C Act, and the Public Health Service Act, or PHS Act, and other federal, state, local and other national statutes and regulations. Both the FD&C Act and the PHS Act and their corresponding regulations govern, among other things, the testing, manufacturing, safety, efficacy, labeling, packaging, storage, record keeping, distribution, export and import, reporting, approval, advertising and other promotional practices involving biological and medical device products. Food and Drug Administration (FDA) approval must be obtained before marketing of biological products. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and national statutes and regulations require the expenditure of substantial time and financial resources, and regulatory approval is not guaranteed. The FDA works closely with the National Institute of Health (NIH) and its Recombinant DNA Advisory Committee (RAC), which makes recommendations to the NIH on gene therapy issues and engages in a public discussion of scientific, safety, ethical and societal issues related to proposed and ongoing gene therapy protocols. The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols. U.S. Biological Products Development Process The process required by the FDA before a biological product may be marketed in the United States generally involves the following: •completion of non-clinical laboratory tests and animal studies according to GLP, and applicable requirements for the humane use of laboratory animals or other applicable regulations; •submission to the FDA of an application for an Investigational New Drug (IND), which must become effective before human clinical trials may begin; •performance of adequate and well-controlled human clinical trials according to the FDA’s regulations, commonly referred to as GCPs, and any additional requirements for the protection of human research subjects and their health information, to establish the safety and efficacy of the proposed biological product for its intended use; •submission to the FDA of a Biological License Application BLA for marketing approval that includes substantive evidence of safety, purity and potency from results of non-clinical testing and clinical trials; •satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological product is produced to assess compliance with Good Manufacturing Practice (GMP), to assure that the facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and purity and, if applicable, the FDA’s current good tissue practices, or GTPs, for the use of human cellular and tissue products; •potential FDA audit of the non-clinical and clinical trial sites that generated the data in support of the (BLA); and •FDA review and approval, or licensure, of the BLA. Where a gene therapy study is conducted at, or sponsored by, institutions receiving NIH funding for recombinant DNA research, prior to the submission of an IND application to the FDA, a protocol and related documentation is submitted to and the study is registered with the NIH Office of Biotechnology Activities, or OBA, pursuant to the NIH Guidelines for Research Involving Recombinant DNA Molecules, or NIH Guidelines. Compliance with the NIH Guidelines is mandatory for investigators at institutions receiving NIH funds for research involving recombinant DNA; however, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them. Institutions that receive NIH funding also are potentially subject to review by the NIH Office of Biotechnology Activities’ RAC; the RAC will only publicly review clinical trials if the trials cannot be evaluated by standard oversight bodies and pose unusual risks. The clinical trial sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. Some preclinical testing may continue even after the IND is submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA places the clinical trial on a clinical hold within that 30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. The FDA may impose clinical holds on a biological product candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA imposes a clinical hold, studies may not recommence without FDA authorization and then only under terms authorized by the FDA. Clinical trials involve the administration of the biological product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the study sponsor’s control. Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety, including stopping rules that assure a clinical trial will be stopped if certain adverse events should occur. Each protocol and amendments to the protocol must be submitted to the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP requirements, including the requirement that all research subjects provide informed consent. Further, each clinical trial must be reviewed and approved by an Institutional Review Board (IRB) at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of study participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the form and content of the informed consent that must be signed by each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed. Clinical trials also must be reviewed by an institutional biosafety committee, or IBC, a local institutional committee that reviews and oversees basic and clinical research conducted at that institution. The IBC assesses the safety of the research and identifies any potential risk to public health or the environment. In some cases, the FDA may condition approval of a BLA for a product candidate on the sponsor’s agreement to conduct additional clinical trials after the product’s approval. In other cases, a sponsor may voluntarily conduct additional clinical trials post-approval to gain more information about the product. Post-approval clinical trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval. These clinical trials are used to gain additional information from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up. The FDA recommends that sponsors observe subjects for potential gene therapy-related delayed adverse events for a 15-year period, including a minimum of five years of annual examinations followed by ten years of annual queries, either in person or by questionnaire, of study subjects. During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA, the NIH and the investigators for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Phase I, Phase II and Phase III clinical trials may not be completed successfully within any specified period, if at all. The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the biological product has been associated with unexpected serious harm to patients. Sponsors of clinical trials of investigational products are required to register on clinicaltrials.gov, a National Institute of Health website registry database, and disclose certain clinical trial information. Information related to the product, patient population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part of the registration. Sponsors are also obligated to discuss the results of their clinical trials after completion. Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved. Competitors may use this publicly-available information to gain knowledge regarding the progress of development programs. The NIH and the FDA have a publicly accessible database, the Genetic Modification Clinical Research Information System which includes information on gene transfer studies and serves as an electronic tool to facilitate the reporting and analysis of adverse events on these studies. Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the physical characteristics of the biological product as well as finalize a process for manufacturing the product in commercial quantities in accordance with GMP requirements. To help reduce the risk of the introduction of adventitious agents (unwanted viruses or bacteria), with use of biological products, the PHS Act emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the sponsor must develop methods for testing the identity, strength, quality, potency and purity of the final biological product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the biological product candidate does not undergo unacceptable deterioration over its shelf life. U.S. Biological Product Review and Approval Processes After the completion of clinical trials of a biological product, FDA approval of a BLA must be obtained before commercial marketing of the biological product. The BLA must include results of product development, laboratory and animal studies, human studies, information on the manufacture and composition of the product, proposed labeling and other relevant information. In addition, under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA must contain data to assess the safety and effectiveness of the biological product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of data or full or partial waivers. Unless otherwise required by regulation, PREA does not apply to any biological product for an indication for which orphan designation has been granted. The testing and approval processes require substantial time and effort and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all. Under the Prescription Drug User Fee Act, or PDUFA, as amended, each BLA must be accompanied by a user fee. The FDA adjusts the PDUFA user fees on an annual basis. PDUFA also imposes an annual program fee on prescription biologics. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business. Additionally, no user fees are assessed on BLAs for products designated as orphan drugs, unless the product also includes a non-orphan indication. Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the agency accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA. The FDA reviews the BLA to determine, among other things, whether the proposed product is safe and potent, or effective, for its intended use, and has an acceptable purity profile, and whether the product is being manufactured in accordance with GMP to assure and preserve the product’s identity, safety, strength, quality, potency and purity. The FDA may refer applications for novel biological products or biological products that present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an Advisory Committee, but it considers such recommendations carefully when making decisions. During the biological product approval process, the FDA also will determine whether a Risk Evaluation and Mitigation Strategies (REMS) is necessary to assure the safe use of the biological product. If the FDA concludes REMS is needed, the sponsor of the BLA must submit proposed REMS; the FDA will not approve the BLA without REMS, if required. Before approving a BLA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with GMP requirements and adequate to assure consistent production of the product within required specifications. For a gene therapy product, the FDA also will not approve the product if the manufacturer is not in compliance with the Good Tissue Practices (GTPs). The GTPs are FDA regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues, and cellular and tissue based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, infusion, or transfer into a human recipient. The primary intent of the GTP requirements is to ensure that cell and tissue based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable disease. FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, when applicable, to evaluate donors through screening and testing. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study requirements and GCP requirements. To assure cGMP, GTP and GCP compliance, an applicant must incur significant expenditure of time, money and effort in the areas of training, record keeping, production and quality control. Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the BLA does not satisfy its regulatory criteria for approval and deny approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data. If the agency decides not to approve the BLA in its present form, the FDA will issue a complete response letter that usually describes all of the specific deficiencies in the BLA identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example, requiring additional clinical trials. Additionally, the complete response letter may include recommended actions that the applicant might take to place the application in a condition for approval. If a complete response letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application. If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling. The FDA may impose restrictions and conditions on product distribution, prescribing, or dispensing in the form of a risk management plan, or otherwise limit the scope of any approval. In addition, the FDA may require post marketing clinical trials, sometimes referred to as Phase IV clinical trials, designed to further assess a biological product’s safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been commercialized. One of the performance goals agreed to by the FDA under the PDUFA is to review 90% of standard BLAs in 12 months of receipt and 90% of priority BLAs in eight months of receipt, whereupon a review decision is to be made. The FDA does not always meet its PDUFA goal dates for standard and priority BLAs, and its review goals are subject to change from time to time. The review process and the PDUFA goal date may be extended by three months if the FDA requests or the BLA sponsor otherwise provides additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date. Orphan Drug Designation Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug or biological product available in the United States for this type of disease or condition will be recovered from sales of the product. Orphan drug designation must be requested before submitting a BLA. After the FDA grants orphan drug designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan drug designation does not shorten the duration of the regulatory review and approval process. If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug or biological product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity. Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity. Orphan product exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same biological product as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication. If a drug or biological product designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan product exclusivity. Orphan drug status in the European Union has similar, but not identical, benefits. Expedited Development and Review Programs The FDA is authorized to expedite the review of BLAs in several ways. For example, the Fast Track program is intended to expedite or facilitate the process for reviewing new drugs and biological products that meet certain criteria. Specifically, new drugs and biological products and products designated as RMAT (regenerative medicines advanced therapy) are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition. Fast Track designation applies to the product and the specific indication for which it is being studied. The sponsor of a new drug or biologic may request the FDA to designate the drug or biologic as a Fast Track product at any time during the clinical development of the product. Following designation as a Fast Track product, the FDA may consider for review sections of the marketing application on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application. Any product submitted to the FDA for marketing, including under a Fast Track program, may be eligible for other types of FDA programs intended to expedite development and review, such as breakthrough therapy designation, priority review and accelerated approval. Priority review. Any product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease compared to marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for a new drug or biological product designated for priority review in an effort to facilitate the review. Accelerated approval. A product may be eligible for accelerated approval. Drug or biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means that they may be approved on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity that is likely to reasonably predict a clinical benefit. As a condition of approval, the FDA may require that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post marketing clinical trials. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product. Breakthrough therapy designation. To qualify for the breakthrough therapy program, product candidates must be intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence must indicate that such product candidates may demonstrate substantial improvement on one or more clinically significant endpoints over existing therapies. The FDA will seek to ensure the sponsor of a breakthrough therapy product candidate receives intensive guidance on an efficient development program, intensive involvement of senior managers and experienced staff on a proactive, collaborative and cross-disciplinary review, and rolling review. Fast Track designation, breakthrough designation, priority review and accelerated approval do not change the standards for approval, but may expedite the development or approval process. Biological product manufacturers and other entities involved in the manufacture and distribution of approved biological products are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with GMPs and other laws. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain GMP compliance. Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved BLA, including withdrawal of the product from the market. In addition, changes to the manufacturing process or facility generally require prior FDA approval before being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further FDA review and approval. U.S. Patent Term Restoration and Marketing Exclusivity Depending upon the timing, duration and specifics of the FDA approval of the use of our product candidates, some of the U.S. patents that we in-license may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of a BLA plus the time between the submission date of a BLA and the approval of that application. Only one patent applicable to an approved biological product is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we may apply for restoration of patent term for one of our currently owned or in-licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA. A biological product can obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study. This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot accept or approve a biosimilar application. The Biologics Price Competition and Innovation Act, or BPCIA, created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference biological product. A reference biologic is granted twelve years of exclusivity from the time of first licensure of the reference product. Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or trials. Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic. However, complexities associated with the larger and often more complex structure of biological products, as well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being worked out by the FDA. Review and Approval of Medical Devices in the United States Medical devices in the United States are strictly regulated by the FDA. Under the FD&C Act, a medical device is defined as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is, among other things: intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes. This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended purpose of the product is achieved through chemical action or by being metabolized by the body, the product is regulated as a drug or biological product. Unless an exemption applies, a new or modified medical device may not be marketed in the United States unless and until it has been cleared through filing of a 510(k) premarket notification, or 510(k), or approved by the FDA pursuant to a Premarket Approval, or PMA, application. The information that must be submitted to the FDA in order to obtain clearance or approval to market a new or modified medical device varies depending on how the medical device is classified by the FDA. Medical devices are classified into one of three classes on the basis of the controls deemed by the FDA to be necessary to reasonably ensure their safety and effectiveness. Class I devices are low risk devices for which reasonable assurance of safety and effectiveness can be provided by adherence to the FDA’s general controls for medical devices, which include applicable portions of the FDA’s Quality System Regulation, or QSR, facility registration and product listing, reporting of adverse medical events and malfunctions and truthful and non-misleading labeling. Many Class I devices are exempt from premarket regulation; however, some Class I devices require premarket clearance by the FDA through the 510(k) premarket notification process. Class II devices are moderate risk devices and are subject to the FDA’s general controls, and any other special controls, such as performance standards, post-market surveillance and FDA guidelines, deemed necessary by the FDA to provide reasonable assurance of the devices’ safety and effectiveness. Premarket review and clearance by the FDA for Class II devices are accomplished through the 510(k) premarket notification procedure, although some Class II devices are exempt from the 510(k) requirements. Premarket notifications are subject to user fees, unless a specific exemption applies. Class III devices are deemed by the FDA to pose the greatest risk, such as those for which reasonable assurance of the device’s safety and effectiveness cannot be assured solely by the general controls and special controls described above and that are life-sustaining or life-supporting. A PMA application must provide valid scientific evidence, typically extensive preclinical and clinical trial data and information about the device and its components regarding, among other things, device design, manufacturing and labeling. PMA applications (and supplemental PMA applications) are subject to significantly higher user fees than are 510(k) premarket notifications. 510(k) Premarket Notification To obtain 510(k) clearance, a manufacturer must submit a premarket notification demonstrating that the proposed device is “substantially equivalent” to a predicate device, which is a previously cleared 510(k) device or a pre-amendment device that was in commercial distribution before May 28, 1976, for which the FDA has not yet called for the submission of a PMA application. The FDA’s 510(k) clearance pathway usually takes from three to 12 months from the date the application is submitted and filed with the FDA, but it can take significantly longer and clearance is never assured. The FDA has issued guidance documents meant to expedite review of a 510(k) and facilitate interactions between applicants and the agency. To demonstrate substantial equivalence, a manufacturer must show that the device has the same intended use as a predicate device and the same technological characteristics, or the same intended use and different technological characteristics and is as safe and as effective as the predicate device and does not raise new questions of safety and effectiveness than the predicate device. Most 510(k)s do not require clinical data for clearance, but the FDA may request such data. The FDA seeks to review and act on a 510(k) within 90 days of submission, but it may take longer if the agency finds that it requires more information to review the 510(k). If the FDA determines that the device is substantially equivalent to a predicate device, the subject device may be marketed. However, if the FDA concludes that a new or modified device is not substantially equivalent to a predicate device, the new or modified device will be classified in Class III and the manufacturer will be required to submit a PMA application to market the product. Devices of a new type that the FDA has not previously classified based on risk are automatically classified into Class III by operation of the FD&C Act, regardless of the level of risk they pose. To avoid requiring PMA review of low- to moderate-risk devices classified in Class III by operation of law, the FD&C Act allows the FDA to classify a low- to moderate-risk device not previously classified into Class I or II, a process known as the de novo process. A company may apply directly to the FDA for classification of its device as de novo or may submit a de novo petition within 30 days of receiving a not substantially equivalent determination. Modifications to a 510(k)-cleared device may require the submission of a traditional 510(k), but modifications meeting certain conditions may be candidates for FDA review under a Special 510(k). A new 510(k) is required when the modification constitutes a major change in the device’s intended use or would significantly affect the safety or effectiveness of the device. A Special 510(k) allows a manufacturer to declare conformance to design controls without providing new data. When the modification involves a change in material, the nature of the “new” material will determine whether a traditional or Special 510(k) is necessary. A modification to a 510(k)-cleared product that would constitute a major change in its intended use or any change that would significantly affect the safety or effectiveness of the device may, in some circumstances, even cause the product to be a new, Class III device. In that case, the significant changes would require the submission of a PMA application, if the change raises complex or novel scientific issues or the product has a new intended use. A manufacturer may be required to submit extensive preclinical and clinical data depending on the nature of the changes. The FDA requires every manufacturer to make the determination regarding the need for a new 510(k) submission in the first instance, but the FDA may review any manufacturer’s decision. If the FDA disagrees with the manufacturer’s determination and requires a new 510(k) clearance, or even PMA application approval, for modifications to previously cleared products for which the manufacturer concluded that new a clearance or approval is unnecessary, the manufacturer may be required to cease marketing or distribution of the products or to recall the modified product until it obtains clearance or approval, and the manufacturer may be subject to significant regulatory fines or penalties. In addition, the FDA may make substantial changes to industry requirements regarding the 510(k) process. Premarket Approval Application The PMA application process for approval to market a medical device is more complex, costly and time-consuming than the 510(k) clearance procedure. A PMA application must be supported by extensive data, including technical information regarding device design and development, preclinical studies, clinical trials, manufacturing and controls information and labeling information that demonstrate the safety and effectiveness of the device for its intended use. After a PMA application is submitted, the FDA has 45 days to determine whether it is sufficiently complete to permit a substantive review. If the PMA application is complete, the FDA will file the PMA application. If the FDA accepts the application for filing, the agency will begin an in-depth substantive review of the application. By statute, the FDA has 180 days to review the application although, generally, review of the application often takes between one to three years, and may take significantly longer. If the FDA has questions, it will likely issue a first major deficiency letter within 150 days of filing. It may also refer the PMA application to an FDA advisory panel for additional review, and will conduct a preapproval inspection of the manufacturing facility to ensure compliance with the Medical Device Quality System Regulation, or QSR, either of which could extend the 180-day response target. In addition, the FDA may request additional information or request the performance of additional clinical trials in which case the PMA application approval may be delayed while the trials are conducted and the data acquired are submitted in an amendment to the PMA. Even with additional trials, the FDA may not approve the PMA application. If the FDA’s evaluations of both the PMA application and the manufacturing facilities are favorable, the FDA will either issue an approval letter authorizing commercial marketing or an approvable letter that usually contains a number of conditions that must be met in order to secure final approval. If the FDA’s evaluations are not favorable, the FDA will deny approval of the PMA application or issue a not approvable letter. The PMA application process, including the gathering of clinical and non-clinical data and the submission to and review by the FDA, can take several years, and the process can be expensive and uncertain. Moreover, even if the FDA approves a PMA application, the FDA may approve the device with an indication that is narrower or more limited than originally sought. The FDA can impose post-approval conditions that it believes necessary to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution. After approval of a PMA application, a new PMA application or PMA application supplement may be required for a modification to the device, its labeling, or its manufacturing process. PMA application supplements often require submission of the same type of information as an initial PMA application, except that the supplement is limited to information needed to support any changes from the device covered by the approved PMA application and may or may not require as extensive technical or clinical data or the convening of an advisory panel. The time for review of a PMA application supplement may vary depending on the type of change, but it can be lengthy. In addition, in some cases the FDA might require additional clinical data. Investigational Device Exemption A clinical trial is typically required for a PMA application and, in a small percentage of cases, the FDA may require a clinical trial in support of a 510(k) submission. A manufacturer that wishes to conduct a clinical study trial involving the device is subject to the FDA’s IDE regulation. The IDE regulation distinguishes between significant and nonsignificant risk device studies and the procedures for obtaining approval to begin the study differ accordingly. A significant risk device presents a potential for serious risk to the health, safety, or welfare of a subject. Significant risk devices are devices that are substantially important in diagnosing, curing, mitigating, or treating disease or in preventing impairment to human health. Studies of devices that pose a significant risk require both FDA and an IRB approval prior to initiation of a clinical trial. Nonsignificant risk devices are devices that do not pose a significant risk to the human subjects. A nonsignificant risk device study requires IRB approval prior to initiation of a clinical trial, and FDA approval of the study is deemed to be in effect if certain conditions are met. An IDE application must be supported by appropriate data, such as animal and laboratory testing results, showing that it is safe to test the device in humans and that the testing protocol is scientifically sound. An IDE application is considered approved 30 days after it has been received by the FDA, unless the FDA otherwise informs the sponsor prior to 30 calendar days from the date of receipt, that the IDE is approved, approved with conditions, or disapproved. IDE approval permits a specified number of subjects to be enrolled at specified study centers. The clinical trial must be conducted in accordance, and FDA approval of the study is deemed to be in effect if certain conditions are met, with applicable regulations, including, but not limited to, the FDA’s IDE regulations and GCP. The investigators must obtain subject informed consent, rigorously follow the investigational plan and study protocol, control the disposition of investigational devices, and comply with all reporting and record keeping requirements. A clinical trial may be suspended or terminated by the FDA, the IRB or the sponsor at any time for various reasons, including a determination that the risks to the study participants outweigh the benefits of participation in the trial. Approval of an IDE does not bind the FDA to accept the results of the trial as sufficient to prove the product’s safety and efficacy, even if the trial meets its intended success criteria. Post-Approval Regulation of Biological Products and Medical Devices in the United States After a biological product or device is placed on the market, numerous regulatory requirements apply including, but not limited to: •submitting and updating establishment registration and device listings with the FDA; •compliance with the manufacturing regulations and standards, including cGMP, for biological products, and the QSR, which require device manufacturers to follow stringent design, testing, control, documentation, record maintenance, including maintenance of complaint and related investigation files, and other quality assurance controls during the manufacturing process; •unannounced routine or for-cause inspections by the FDA, which may include suppliers’ facilities; •advertising and promotion regulations, which prohibit the promotion of products for uncleared or unapproved or “off-label” uses and impose other restrictions on advertising and labeling; •post-approval restrictions or conditions, including requirements to conduct post-market surveillance studies to establish continued safety data or tracking products through the chain of distribution to the patient level; and •compliance with the regulations requiring the reporting of adverse events and certain device malfunctions to the FDA. The failure to comply with applicable regulatory requirements can result in enforcement action by the FDA, which may include any of the following sanctions: •untitled letters, warning letters, fines, injunctions or civil penalties; •recalls, detentions or seizures of products; •operating restrictions; •delays in the introduction of products into the market; •total or partial suspension of production; •delay or refusal of the FDA or other regulators to grant 510(k) clearance or PMA application approvals of new products; •withdrawals of 510(k) clearance or PMA application approvals; or •criminal prosecution. Review and Approval of Combination Products in the United States Certain products may be comprised of components that would normally be regulated under different types of regulatory authorities, and frequently by different Centers at the FDA. These products are known as combination products. Specifically, under regulations issued by the FDA, a combination product may be: •a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity; •two or more separate products packaged together in a single package or as a unit and comprised of drug and device products; •a drug or device packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug or device where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or •any investigational drug or device packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. Under the FD&C Act, the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product. That determination is based on the “primary mode of action” of the combination product. Thus, if the primary mode of action of a device-drug combination product is attributable to the drug product, the FDA Center responsible for premarket review of the drug product would have primary jurisdiction for the combination product, but the other relevant FDA Centers would consult on the review. The FDA has also established an Office of Combination Products to address issues surrounding combination products and provide more certainty to the regulatory review process. That office serves as a focal point for combination product issues for agency reviewers and industry. It is also responsible for developing guidance and regulations to clarify the regulation of combination products, and for assignment of the FDA Center that has primary jurisdiction for review of combination products where the jurisdiction is unclear or in dispute. Other Healthcare Laws and Regulations Healthcare providers, physicians and third-party payors in the United States and elsewhere will play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval. Our current and future arrangements with healthcare professionals, principal investigators, consultants, customers and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws, including, without limitation, the federal Anti-Kickback Statute and the federal civil False Claims Act, that may constrain the business or financial arrangements and relationships through which we sell, market and distribute any product candidates for which we obtain marketing approval. In addition, we may be subject to physician payment transparency laws and patient privacy and security regulation by the federal government and by the states and foreign jurisdictions in which we conduct our business. The applicable federal, state and foreign healthcare laws that may affect our ability to operate include the following: •the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order or recommendation of, any good, facility, item or service, for which payment may be made, in whole or in part, under federal and state healthcare programs such as Medicare and Medicaid; •federal civil and criminal false claims laws, including, without limitations, the federal civil False Claims Act, which impose criminal and civil penalties, including through civil whistleblower or qui tam actions, against individuals or entities for, among other things, knowingly presenting, or causing to be presented, to the federal government, including federal health care programs, such as, the Medicare and Medicaid programs, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government; •the civil monetary penalties statute, which imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim to a federal health program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent; •HIPAA, which created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of whether the payor is public or private, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters; •HIPAA, as amended by HITECH, and their respective implementing regulations, which impose obligations on “covered entities,” including healthcare providers, health plans, and healthcare clearinghouses, as well as their respective “business associates” that create, receive, maintain or transmit individually identifiable health information for or on behalf of a covered entity, with respect to safeguarding the privacy, security and transmission of individually identifiable health information; •the Physician Payments Sunshine Act, created under Section 6002 of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the ACA, imposed annual reporting requirements for certain manufacturers of drugs, devices, biologics and medical supplies for certain payments and “transfers of value” provided to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members; and •analogous state and foreign laws, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers; state and foreign laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or to adopt compliance programs as prescribed by state laws and regulations, or that otherwise restrict payments that may be made to healthcare providers; state and foreign laws that require manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures; and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts. Further, the ACA, among other things, amended the intent requirement of the federal Anti-Kickback Statute and the healthcare fraud statute. A person or entity no longer needs to have actual knowledge of these statutes or specific intent to violate them. In addition, the ACA provided that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. Efforts to ensure that our future business arrangements with third parties will comply with applicable healthcare laws and regulations may involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we or our directors, officers, employees, principal investigators or consultant partners may be subject to significant civil, criminal and administrative penalties, including, without limitation, damages, fines, imprisonment, disgorgement, exclusion from participation in government healthcare programs, such as Medicare and Medicaid, additional reporting requirements and/or oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, as well as reputational harm, which could significantly harm our business. Defending against any such actions may be costly, time-consuming and may require significant financial and personnel resources. Even if we are successful in defending against any such actions that may be brought against us, our business may be impaired. If the physicians or other providers or entities with whom we expect to do business are found not to be in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusion from government funded healthcare programs. Coverage and Reimbursement Our ability to commercialize any product candidates successfully will depend, in part, on the extent to which coverage and adequate reimbursement for our product candidates will be available from government payor programs at the federal and state levels, including Medicare and Medicaid, private health insurers, managed care plans and other third-party payors. Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which medical products they will pay for and establish reimbursement levels. A number of gene therapy products have been approved over the past year by the FDA. Although the Center for Medicare and Medicaid Services, or CMS, subsequently approved its first method of coverage and reimbursement for one such product, the methodology has been subject to challenge by members of Congress. CMS’s decision as to coverage and reimbursement for one product does not mean that all similar products will be eligible for analogous coverage and reimbursement. As there is no uniform policy for coverage and reimbursement amongst third-party payors in the United States, even if CMS approves coverage and reimbursement for any of our product candidates, it is unclear what affect, if any, such a decision will have on our ability to obtain and maintain coverage and adequate reimbursement from other private payors. In addition, third-party payors are increasingly requiring that manufacturers provide them with predetermined discounts from list prices and are challenging the prices charged for products. Coverage and reimbursement may not be available for any product that we commercialize and, even if these are available, the level of reimbursement may not be adequate, which may adversely affect the demand for, or the price of, any product candidate for which we obtain marketing approval. Obtaining and maintaining adequate reimbursement may be difficult. Third-party payors are also increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. We may be required to conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level of reimbursement compared to other therapies. If coverage and adequate reimbursement are not available or reimbursement is available only to limited levels, we may not be able to successfully commercialize any product candidates for which marketing approval is obtained. Further, the United States government, state legislatures and other governments have shown significant interest in implementing cost containment programs to limit the growth of government-paid health care costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs. There has been heightened governmental scrutiny recently over the manner in which manufacturers set prices for their marketed products, which have resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, reduce the cost of products under Medicare, and reform government program reimbursement methodologies for products. At the federal level, the Trump administration’s budget proposal for fiscal year 2019 contains further price control measures that could be enacted during the 2019 budget process or in other future legislation, including, for example, measures to permit Medicare Part D plans to negotiate the price of certain products under Medicare Part B, to allow some states to negotiate product prices under Medicaid, and to eliminate cost sharing for generics for low-income patients. While any proposed measures will require authorization through additional legislation to become effective, Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control pharmaceutical costs. At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our products or additional pricing pressure. Healthcare Reform Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. In March 2010, then-President President Obama signed into law the ACA, a sweeping law intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for the healthcare and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms. The ACA established an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations, and provided incentives to programs that increase the federal government’s comparative effectiveness research. In addition, the ACA implemented payment system reforms including a national pilot program on payment bundling to encourage hospitals, physicians and other providers to improve the coordination, quality and efficiency of certain healthcare services through bundled payment models. There have been judicial and Congressional challenges to certain aspects of the ACA, as well as recent efforts by the Trump administration to repeal or replace certain aspects of the ACA. Since January 2017, President Trump has signed two Executive Orders and other directives designed to delay the implementation of certain provisions of the ACA or otherwise circumvent some of the requirements for health insurance mandated by the ACA. Concurrently, Congress has considered legislation that would repeal or repeal and replace all or part of the ACA. While Congress has not passed comprehensive repeal legislation, two bills affecting the implementation of certain taxes under the ACA have been signed into law. The Tax Cuts and Jobs Act includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” Additionally, on January 22, 2018, President Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the implementation of certain ACA-mandated fees, including the so-called “Cadillac” tax on certain high cost employer-sponsored insurance plans, the annual fee imposed on certain health insurance providers based on market share, and the medical device excise tax on non-exempt medical devices. Further, the Bipartisan Budget Act of 2018, or the BBA, among other things, amends the ACA, effective January 1, 2019, to increase from 50 percent to 70 percent the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole.” Congress could consider additional legislation to repeal or repeal and replace certain elements of the ACA. In addition, other legislative changes have been proposed and adopted since the ACA was enacted. On August 2, 2011, then-President President Obama signed into law the Budget Control Act of 2011, which, among other things, created the Joint Select Committee on Deficit Reduction to recommend to Congress proposals in spending reductions. The Joint Select Committee did not achieve a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, triggering the legislation’s automatic reduction to several government programs. This includes reductions to Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and, due to subsequent legislation, including the BBA, will remain in effect through 2027 unless additional Congressional action is taken. On January 2, 2013, then-President President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. There are several proposals being tabled in Congress, with industry participants providing input, to allow the use of value-based contracts and other innovative payment models for regenerative therapies while remaining consistent with rebate and price reporting requirements such as Medicaid Best Price. Additional new laws may result in additional reductions in funding to Medicare and other federal health care programs. Further, new laws may, among other things, increase drug rebates or discounts owed under federal health care programs, impose additional reporting or compliance obligations, and/or otherwise put additional downward pressure on drug prices or increase the burden of compliance on pharmaceutical manufacturers. Government Regulation Outside of the European Union and the United States In addition to regulations in the European Union and the United States, we will be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials, commercial sales and distribution of our products, and pricing and reimbursement. The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country. If we fail to comply with applicable national regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution. 10 TREND INFORMATION 10.1Most significant recent trends since the end of the last financial year Please refer to Section 18.7, “Significant Change in Financial position” of the Document. 10.2Information on any known trends, uncertainties, demands, commitments or events that are reasonably likely to have a material effect on the company’s prospects None. 11 PROFIT FORECAST OR ESTIMATES We have elected not to include a profit forecast or a profit estimate in this Universal Registration Document. 12 ADMINISTRATIVE, MANAGEMENT AND SUPERVISORY BODIES AND SENIOR MANAGEMENT 12.1Composition of management and supervisory bodies We are a French corporation with limited liability (société anonyme) with a Board of Directors. A description of the main provisions of our bylaws relating to the functioning and powers of the Board of Directors as well as a summary of the main provisions of the internal regulations of the Board of Directors and of the special Board Committees that we have implemented, are included in Section 14, “Board Practices” and in Section 19, “Additional Information” of this Universal Registration Document. 12.1.1DIRECTORS AND OFFICERS. We currently have eight directors and one non-voting member. The table below gives the identity of our directors and officers as of the date of this Universal Registration Document and the main positions and offices held by them outside of the Company during the last five years. Unless otherwise stated, the business address for our directors and officers is c/o GENSIGHT BIOLOGICS S.A., 74, rue du Faubourg Saint-Antoine, 75012 Paris, France. Name Expiration date of term of office() Main position within the Company() Main positions and offices held outside the Company during the last 5 years Bernard Gilly 2024 Chief Executive Officer Director Co-Founder Position and offices held as of the date of this Universal Registration Document: •Chairman of the Boards of Directors of Pixium Vision S.A., BrainEver SAS, Prophesee S.A., Eye TechCare S.A., Chronolife SAS, IBionext SAS and GrAI Matter Labs, Director of Tilak SAS Position and offices held during the last 5 years that are no longer held: •Chairman of the Board of Directors of the Tilak SAS Michael Wyzga 2024 Chairman of the Board of Directors Independent Director Position and offices held as of the date of this Universal Registration Document: •President of MSW Consulting Inc., a strategic consulting group focused in the life science area •Member of the Board of Directors and Chair of the Audit Committee of Adagio Therapeutics and LogicBio •Chairman of the Board of Directors of X4 Pharmaceuticals, Inc. •Chairman of the Board of Directors of Mereo Pharmaceuticals Position and offices held during the last 5 years that are no longer held: •Member of the Board of Directors, member of the compensation committee and chair of the audit committee of Akebia Therapeutics, Inc. •Member of the Board of Directors of Altus Pharmaceuticals, Inc. •Member of the Board of Directors of Idenix Pharmaceuticals, Inc. •Served as a member of the supervisory board of Prosensa Holding B.V. •Member of the Board of Directors and Audit Chair of Exact Sciences •Member of the Board of Directors and Audit Chair of OncoMed Pharmaceuticls Thomas Gidoin – Chief Financial Officer Position and offices held as of the date of this Universal Registration Document: •None Position and offices held during the last 5 years that are no longer held: •None Magali Taiël – Chief Medical Officer Position and offices held as of the date of this Universal Registration Document: •None Position and offices held during the last 5 years that are no longer held: •VP clinical Development at ProQR Therapeutics Sissel Rodahl – Senior Vice-President Commercial Head Position and offices held as of the date of this Universal Registration Document: •None Position and offices held during the last 5 years that are no longer held: •VP & General Manager European Mid-Sized Countries at Novartis Gene Therapis Marie-Claude Holtz 2022 Deputy Chief Executive Officer Quality Vice-President Chief Pharmacist Position and offices held as of the date of this Universal Registration Document: •None Position and offices held during the last 5 years that are no longer held: •Pharmaceuticals Affairs Director, Chief Executive officer and Responsible pharmacist at Exeltis Santé S.A.S •Pharmacist Quality Assurance at Hospira France, A Pfizer Company Peter Goodfellow 2023 Independent Director Position and offices held as of the date of this Universal Registration Document: •Science advisor and consultant for Abingworth LLP and the Bill and Melinda Gates Foundation •Chairman of the Board of Directors of GammaDelta Therapeutics Ltd. •Chairman of the Board of Directors of Adaptate Biotherapeutics Position and offices held during the last 5 years that are no longer held: •Director of Virion Health Simone Seiter 2022 Independent Director Position and offices held as of the date of this Universal Registration Document: •Senior partner at Simon-Kucher •Head of the Clinical and Commercial Advisory Board at Priothera Position and offices held during the last 5 years that are no longer held: •Vice President at IQVIA Françoise de Craecker 2023 Independent Director Position and offices held as of the date of this Universal Registration Document: •Independant director at X4 Paharmaceuticals Position and offices held during the last 5 years that are no longer held: •General Manager Europe Middle East & Africa at Avexis •Group Vice President & General Manager Europe Middle East & Africa at Chiesi Orphan B.V •Group Vice President and General Manager Europe Middle East and Africa at Horizon •General Manager Europe at Shire Maritza McIntyre 2022 Independent Director Position and offices held as of the date of this Universal Registration Document: •President/Owner Advanced Therapies Partners LLC •Board of Directors, American Society of Gene and Cell Therapies Position and offices held during the last 5 years that are no longer held: •Chief Development Officer, StrideBio Inc •Board Member, Standards Coordinating Body •Executive Director, Gene Therapy Product Lead-Pfizer Inc. •Executive Vice President Regulatory Affairs and Product Development-Bamboo Therapeutics •Vice President Regulatory Affairs-NanoCor Therapeutics Sofinnova Partners SAS (as represented by Cédric Moreau) 2022 Director Position and offices held as of the date of this Universal Registration Document: •Partner at Sofinnova Partners •Serves as a board member on the board of Sensorion SA (as the representant of Sofinnova Partners) •Serves as a board member on the board of Mainstay Medical plc (as the representant of Sofinnova Partners) •Member of the board of Association France Biotech •Member of the board of Association Life Sciences Acceleration Alliance (LSAA) •Member of the Endowment fund Health Tech For care (HTFC) Position and offices held during the last 5 years that are no longer held: •Managing Director – Corporate Finance – Head of Healthcare at ODDO-BHF •Director – Corporate Finance – Healthcare at Bryan Garnier & Co Elsy Boglioli 2022 Independent Director Position and offices held as of the date of this Universal Registration Document: •Founder and CEO of Bio-Up •Chairman of the Board of ThreeFrog Therapeutics •Serves as a Board Member of OSE Immunotherapeutics, Metafora Biosystems, Inova and Womed Position and offices held during the last 5 years that are no longer held: •Executive Vice President, Chief Operating Officer at Cellectis •Partner and Managing Director at the Boston Consulting Group (BCG) (*) According to our bylaws, the duration of the term of office of the members of our Board of Directors is 3 years. The Expiration date is only provided for directors’ current terms. The term expires at the end of the Ordinary General Meeting convened to approve the accounts for the previous financial year during the year in which their term office expires. () Please note that, except for the Chief Executive Officer and the Deputy Chief Executive Officer, none of the officers is a representative (dirigeant mandataire social) of the Company. Mr. Collier has resigned from the Board of Directors and has been replaced by Ms. Seiter on April 19, 2017. Ms. Mount joined the Board of Directors on May 31, 2017. Mr. Lloyd-Harris has resigned from the Board of Directors on March 16, 2018. Mr. Magni has resigned from the Board of Directors on April 24, 2019. In consideration for the subscription by Sofinnova Crossover I SLP for the capital increase of €8 million implemented in February 2019, Sofinnova Partners and one independant member proposed by Sofinnova, Maritza McIntyre have been appointed as Directors by the Shareholders’ Meeting held on June 11, 2019. Mrs. Holtz has been appointed Deputy Chief Executive Director and Chief Pharmacist by the Board of Directors on April 29, 2020. Mr. Higueret has resigned from the Board of Directors on July 22, 2020 and has been replaced by Elsy Boglioli on September 22, 2020. Ms. Mount has resigned from the Board of Directors on April 29, 2021 and has been replaced by Françoise de Craecker on the same day during the board meeting held after the annual general meeting. As of the date of this Universal Registration Document, the Company has two executive directors, Mr. Gilly (CEO) and Mrs. Holtz (DCEO). The table below gives the identity of our non-voting observers are also attending board meetings as of the date of this Universal Registration Document: Name Expiration date of term of office José-Alain Sahel 2024 Audrey Cacaly has resigned on July 22, 2020. Thibaut Roulon has resigned on January 7, 2021. Kreos Capital (UK) Limited (as represented by Maurizio Petitbon) has resigned on December 11, 2020. Separation of the Offices of Chairman of the Board and Chief Executive Officers On March 2, 2016, our Board of Directors decided to separate the offices of the Chairman of the Board of Directors and of the Chief Executive Officer. As of the date of this Universal Registration Document, Bernard Gilly is Co-Founder, Director and Chief Executive Officer and Michael Wyzga is the Chairman of our Board of Directors. Director Independence We consider that, under the recommendations of the MiddleNext Code, six current directors are “independent directors”. The MiddleNext Code sets out the five following criteria justifying the independence of directors, characterized by the absence of any significant financial, contractual or family relationship likely to affect their independence of judgment: •they must not be a salaried employee or corporate officer of us or our Group and must not have held such a position within the last five years; •they must not be in a significant business relationship with us or our Group (e.g., client, supplier, competitor, provider, creditor, banker, etc.) within the last two years; •they must not be a reference shareholder or hold a significant number of voting rights; •they must not have close relationships or family ties with any of our corporate officer or reference shareholder; and •they must not have been our auditor within the last six years. Based on these criteria, our Board of Directors determined that Mr. Wyzga, Dr. Seiter, Ms. de Craecker, Dr. Goodfellow, Dr. McIntyre and Ms. Boglioli are “independent directors” under the independence criteria of the MiddleNext Code. In making such determination, the Board of Directors considered the relationships that each non-employee director has with us and all other facts and circumstances, the Board of Directors deemed relevant in determining the director’s independence, including the number of ordinary shares beneficially owned by the director and his or her affiliated entities, if any. 12.1.2BIOGRAPHICAL INFORMATION ABOUT THE MEMBERS OF THE BOARD OF DIRECTORS AND OFFICERS OF THE COMPANY. Officers Bernard Gilly, Ph.D., one of our founders, has served as our Chief Executive Officer since our creation. From our creation through 2016, Dr. Gilly served as Chairman of our Board of Directors. From 2011 through 2014, Dr. Gilly served as Chief Executive Officer at Pixium Vision and from which date he has served as non-executive Chairman of the Board of Directors. Additionally, Mr. Gilly currently serves on the boards of Prophesee S.A. (formerly Chronocam) and EyeTechCare S.A. From 2005 to 2009, he founded and was Chairman and Chief Executive Officer of Fovea Pharmaceuticals S.A., a privately funded biotech company, which was acquired by Sanofi S.A., or Sanofi. He then became Senior Vice-President of the Ophthalmology Division of Sanofi and served in that role until March 2012. Prior to Fovea, Dr. Gilly was a partner at Sofinnova Partners S.A.S. from December 2000 to November 2005. From January 1992 to October 2000, he was Chief Executive Officer of Transgene S.A., a company listed on the NASDAQ stock exchange and the Nouveau Marché of Euronext Paris, France. Dr. Gilly received an engineering degree from École Nationale d’Agronomie and a Ph.D. from Université de Rennes. Thomas Gidoin has been our Chief Financial Officer since June 2015. From 2012 to mid-2015, Mr. Gidoin was Vice President Finance at DBV Technologies S.A., where he led the Corporate Finance team and participated in public offerings and private placements, including the dual listing of DBV Technologies S.A. on the NASDAQ Global Select Market in 2014. From 2008 to 2011, Mr. Gidoin served in various positions at Ipsen S.A., including UK Operations Controller in London and Senior Financial Analyst in the Global Operations division in Paris. He started his career in audit at Ernst & Young. Mr. Gidoin received a Master’s degree in International Finance from ESGF Paris and a Master’s degree in International Management from Neoma Business School in France. Magali Taiël, M.D. completed her doctorate in Medicine with a specialization in Ophthalmology from the University of Paris in 1993, and her Associate Professor Degree in 1998. Dr. Magali Taiël was an Associate Professor of Ophthalmology, standing in for the Ophthalmology Department Head for 3 years at Academic Hospital, France. After 13 years of ophthalmology public and private practice, she moved to the Pharma Industry: firstly worked as a R&D International Project Manager in Servier Company (2 years), then as Medical Advisor in Ophthalmology area (Glaucoma and AMD) in Pfizer (3 years), and then held international and management positions in various therapeutic areas, including both technical and supervision duties, at Eli Lilly Company (13 years). Since 2016, as VP Clinical Development, she leads Clinical Development and Operations, to develop drugs and gene therapy in Inherited Retinal and Neuro-Ophthalmology diseases, at ProQR Therapeutics and now at GenSight Biologics. She made several critical contributions to the clinical development plan and launch of products, and authored numerous protocols and publications. Sissel Rodahl has been our Senior Vice-President Commercial Head since February 1, 2022. Sissel Rodahl joins GenSight after more than 25 years in rare diseases and gene therapies, in a range of commercial leadership roles that brought her expanding responsibilities during her tenure at Serono, Merck KGaA, Shire, Raptor, Horizon and AveXis. She joined AveXis as one of the first people to build from scratch the multi-functional team that successfully launched Zolgensma, the first one-time gene therapy for the treatment of Spinal Muscular Atrophy (SMA). She had a key role in developing and executing the go-to-market strategy and in building the AveXis organization in Europe, the Middle East and Africa (EMEA), which was later acquired by Novartis. Most recently Sissel Rodahl served as Vice President for Novartis Gene Therapies where she successfully led the launch of Zolgensma for a cluster of 15 countries in Western Europe. Sissel Rodahl holds a Master’s in Science in Biochemistry from the University of Oslo, Norway and a BSc in Biotechnology from Oslo University College of Engineering. Marie-Claude Holtz has been our Quality Vice-President and Chief Pharmacist (Responsible Pharmacist) since June 1, 2020. Marie-Claude joined the Company after more than 25 years in the pharmaceutical industry, where she held senior positions in the areas of quality (quality control, quality assurance), regulatory affairs and pharmacovigilance at a number of pharmaceutical groups and companies, including ratiopharm GmbH / Teva Group, Galderma Group, Abbvie, Hospira. In her past role as Chief Pharmacist or deputy Chief Pharmacist, she supported the research, development, manufacture, and marketing of drugs and medical devices. As the Responsible Pharmacist at GenSight Biologics, she is leading the activities to register the Company as a pharmaceutical establishment, a designation that is required for marketing gene therapies in France. Marie-Claude holds a Doctor of Pharmacy degree and a Specialized Higher Studies degree (DESS) in Industrial Pharmacy from the University of Pharmacy of Strasbourg, and a university degree (Diplôme d’université, or DU) in Pharmacovigilance and Drug Safety from the University of Pharmacy of Paris V. Directors Michael Wyzga has served as a director since October 2013 and as our Chairman since March 2016. Mr. Wyzga is currently the President of MSW Consulting Inc., a strategic consulting group focused in the lifesciences area. From December 2011 until November 2013, Mr. Wyzga served as President and Chief Executive Officer and a member of the Board of Directors of Radius Health, Inc., a publicly traded biopharmaceutical company. Prior to that, Mr. Wyzga served in various senior management positions at Genzyme Corporation, a publicly traded global biotechnology company. Mr. Wyzga joined Genzyme in February 1998 and most recently served as Executive Vice President, Finance from May 2003 until November 2011 and as chief financial officer from July 1999 until November 2011. From February 2014 to December 2018. Since July 2018, Mr. Wyzga has also served as Chairman of the Board of Directors of X4 Pharmaceuticals. He also serves on the Board of Directors of LogicBio and Adagio Therapeutics. Mr. Wyzga is also the Chairman of the Board of Directors of Mereo Pharmaceuticals. Until 2018, Mr. Wyzga served as a member of the Board of Directors of Akebia Therapeutics, Inc., a publicly traded biopharmaceutical company, where he was also a member of the compensation committee and chair of the audit committee. From February 2015 to June,2021 Mr. Wyzga has also served as a member of the Board of Directors of Exact Sciences Corporation, a publicly traded medical technology company, where he is also Chair of the audit committee and member of the compensation committee. From October 2013 to October 2019, Mr. Wyzga has also served as a member of the Board of Directors of Oncomed Pharmaceuticals, Inc., where he was also a member of the audit committee. Mr. Wyzga also previously served as a member of the Board of Directors of Idenix Pharmaceuticals, Inc., a publicly traded biotechnology company that was acquired by Merck in August 2014, where he also served as the chair of the audit committee and a member of the compensation committee, and as a member of the Supervisory Board of Prosensa Holding B.V., a publicly traded biopharmaceutical company, from June 2014 until the Prosensa acquisition by BioMarin Falcon B.V. in December 2014. He received an MBA from Providence College and a B.S. from Suffolk University. Peter Goodfellow, Ph.D. has served as a director since June 2014. Dr. Goodfellow is a scientific consultant for Abingworth, Sanofi and the Bill and Melinda Gates Foundation. Dr. Goodfellow was previously the Balfour Professor of Genetics at Cambridge University before working for SmithKline Beecham (later GlaxoSmithKline) as head of research. He has founded several biotechnology companies and has sat on the boards of Prosensa deCode and several medical charities. Dr. Goodfellow currently serves as the chairman of the Board of Directors of GammaDelta Therapeutics and Adaptate Biotherapeutics. Dr. Goodfellow holds doctorates from Oxford and Bristol Universities. Simone Seiter, M.D., Ph.D. has served as a director since April 2017. Dr. Seiter has worked as Senior Partner with Simon-Kucher & Partners since 2020 leading the global Life Sciences commercial strategy consulting practice. In 2020 she co-founded Priothera a oncology focused pre-commercial biotech company based in Ireland where she now serves as the head of the clinical and commercial advisory board. Prior to joining Simon-Kucher & Partners she worked as a Vice President with IQVIA (formerly QuintilesIMS) based in Frankfurt, Germany from 2006 to 2019. Prior to joining IQVIA she worked at Capgemini as a consultant for six years and served as a postdoctoral Fellow at the National Institutes of Health (United States) for two years. Previously, Dr. Seiter worked at the Universities of Heidelberg and Homburg, Germany as board certified dermatologist. Dr. Seiter holds an M.D. Ph.D. degree from the University of Heidelberg and an MBA from the University of Applied Sciences in Neu-Ulm, Germany. Françoise de Craecker, M.D. led the EMEA (Europe, Middle East & Africa) region at AveXis, further acquired by Novartis. She built from scratch the multifunctional team launching Zolgensma, the first one-shot Gene Therapy for the treatment of Spinal Muscular Atrophy, in the EMEA region. She paved the way for the approval, distribution, market access and commercialization, working with authorities on innovative funding pathways and early access. She also established a wide presence in the main European markets and a network of distributors in the Middle East and other European countries. Prior to joining AveXis, Mrs. de Craecker was leading EMEA operations for Raptor Pharmaceuticals (later acquired by Horizon and Chiesi) at the critical phase of a shift from R&D to commercialization of their lead product in Cystinosis, followed by the launch of their acquired product in Cystic Fibrosis. Before that, she was at Shire Human Genetics for 14 years. Originally, she was part of the team launching the first Orphan Drug approved in Europe. She then took different positions of increasing responsibilities and led various strategic and operational teams, locally and globally based in different European counties and USA. Mrs. de Craecker holds a Master’s in Science from the Faculty of Medicine of the University of Leuven (Belgium). Maritza C. McIntyre, Ph.D. is the President of Advanced Therapies Partners, LLC. Dr. McIntyre has 20 years of experience in the development, evaluation and regulation of biological and small molecule products within startup biotech firms, the Food and Drug Administration (FDA), and as a consultant. Dr. McIntyre was a product reviewer and ultimately Branch Chief in the Division of Cellular and Gene Therapies at FDA/CBER, where she was actively involved in policy development and liaison activities to stakeholder groups. She has since worked in regulatory affairs and product development at Bavarian Nordic, REGENXBIO, Inc. and NanoCor Therapeutics (acquired by Bayer). She served as Executive Vice President of Regulatory Affairs and Product Development at Bamboo Therapeutics where, as part of the senior management team, she participated in portfolio selection, product development and fundraising that resulted in an initial $50 million finance round and ultimate the sale of the company to Pfizer. Most recently she served as the Chief Development Officer at StrideBio, Inc. where she oversaw the development of neurological gene therapy programs partnered with Takeda and Sarepta as well as internal cardiac gene therapy programs. As president of Advanced Therapies Partners LLC, Dr. McIntyre provided strategic regulatory and product development advice to biotech companies, academics, and venture capital firms. Through her participation in industry associations, including ASGCT and the Standards Coordinating Body she has continued to contribute to gene therapy regulatory policy development. Dr. McIntyre received a Ph.D. in virology from the University of Chicago and graduated magna cum laude with an Honors B.S. in biology from Wayne State University. Cédric Moreau has served as the representative of Sofinnova Partners since June 2019. Cédric joined Sofinnova Partners in June 2018 and brought 18 years of experience in life sciences investment banking. He brings to the Sofinnova Crossover team his transactional expertise in the biopharma industry, with an extensive network of Key Opinion Leaders (KOLs), bankers and lawyers. Cedric joined from Oddo BHF where he was Managing Director and Head of Healthcare at the Corporate Finance department. In 2017, Oddo BHF was top ranked in the European biotech equity capital market deals league tables. Prior to this, he was Director at Bryan Garnier & Co where he completed several sizeable cross border transactions. In total, he has managed transactions (IPO/ FOn/ PIPEs) in European healthcare companies totaling around €2bn in value. He is well known to the Sofinnova team having executed several mandates for portfolio companies. Before his corporate finance career, he spent 10 years as a Healthcare Equity Analyst and was several times EXTEL top ranked (awarded for both individual and team performances) at Natixis and Fortis. He was in charge of both listed biotech and pharma companies coverage. He brings to the Crossover team his transactional expertise in the biopharma industry, with an extensive network of Key Opinion Leaders (KOLs), bankers and lawyers. Cedric holds a Master’s in Economics and post-graduate diploma in Finance and Taxation (Sorbonne) and Diploma from the Société Française des Analystes Financiers (SFAF). Elsy Boglioli is the founder and CEO of Bio-Up, a healthcare advisory firm supporting companies in strong scale up or transformation phases, mainly in the field of cell and gene therapy. She has far-reaching expertise and a broad network within the pharma and medtech industries. Before she created Bio-Up, Elsy was Executive Vice President, Chief Operating Officer at Cellectis, a French biotechnology company focused on gene editing and its applications in oncology. At Cellectis she led various strategic and operational functions: strategy, business development, clinical trials program management, as well as manufacturing, with the objective of building in-house capacity. Prior to joining Cellectis, Elsy worked at the Boston Consulting Group (BCG) for 12 years. She served as Partner and Managing Director in the Paris Office, was the leader of BCG’s biotech-focused business in Europe. She worked closely with Biotech and Pharma companies on topics such as specialty product launch optimization, partnering and M&A. Elsy graduated from the Ecole Polytechnique in Paris, France and holds a master’s degree in economy and management from the Pompeu Fabra University in Barcelona, Spain. She also completed a College degree in Immuno-oncology at Institut Gustave Roussy. 12.1.3BALANCE IN THE COMPOSITION OF THE BOARD OF DIRECTORS. Further to the nomination by the Shareholders’ Meeting held on May 31, 2017 of Simone Seiter and Natalie Mount as members of the Board of Directors, the Board of Directors held on May 31, 2017 stated that since this date the Company complies with the balanced representation of men and women required by Article L 225-18-1 of the French Commercial Code, which provides that the proportion of directors of each gender shall be no less than 40% or no more than a difference of two. To date, our Board of Directors is composed of 4 women and 4 men. Therefore, the Board of Directors held on May 31, 2017 has decided to release the payment of attendance fees, which was suspended insofar as such requirement was not met on January 1, 2017, including any arrears. 12.1.4LIMITATION OF AUTHORITY OF THE CHIEF EXECUTIVE OFFICER. Limitation of authority of the Chief Executive Officer The rules of procedure of the Board of Directors provide that decisions deemed “important” as mentioned below are subject to prior approval of the Board ruling by simple majority: “Any decision to make a transfer of any substantial asset or any substantial intellectual/industrial property belonging to the Company; Any decision to make an acquisition of strategic assets, in particular an industrial property element for the benefit of the Company; Any investment or divestment decision of any kind (whether in the form of CAPEX or OPEX), commitments or decommitments, acquisition or disposal of assets not provided for in the annual budget and for a unit amount in excess of €500,000 or a cumulative amount in excess of €1,000,000; Any acquisition or sale, taking or disposal of stakes in other entities or joint ventures, exchanges concerning property, shares or securities within the scope of acquisition or sale transactions, for a unit amount in excess of €1,000,000 or a cumulative amount in excess of €2,000,000; Any entry into financing (including credit facilities and leasing arrangements) not provided for in the annual budget, for a unit amount in excess of €1,000,000 or a cumulative amount in excess of €2,000,000; Any decision to set up a structure outside French territory, in particular through offices, branches or establishments, including with regard to R&D activities, or withdrawal from any such structures, it being specified that the transfer of the Company’s registered office or its management team outside France will require the express prior authorization of the director appointed upon the proposal of Bpifrance Participations, which may not be refused without reasonable cause duly substantiated to the Board; Any decision to proceed with the creation of a subsidiary or any trading in the securities of any subsidiary of the Company; Any significant transaction that could affect the Company’s strategy or change its financial structure or its scope of business. Furthermore, the Chief Executive Officer shall submit for the Board’s approval the Company’s annual budget and any revision of such budget and shall act within the limits set by the budget approved by the Board. The Board carries out the controls and verifications it deems appropriate and may ask for the documents that it considers useful for the accomplishment of its tasks to be provided to it.” 12.1.5STATEMENT REGARDING THE MEMBERS OF THE ADMINISTRATIVE MANAGEMENT OR SUPERVISORY BODIES. As of the date of this Universal Registration Document, to our knowledge, there are no family relationships among any of our executive officers or directors. To our knowledge, over the course of the past five years: (i) none of the above persons has been subject of any conviction in relation to fraudulent offences; (ii) none of the above persons has been associated with any bankruptcy, receivership, liquidation or companies put into administration ; (iii) no official public incrimination and/or sanctions involving any of the above persons have been brought by statutory or regulatory authorities (including designated professional bodies); and (iv) none of the above persons has been disqualified by a court from acting as a member of the administrative, management or supervisory body of any company, or from acting in the management or conduct of the affairs of any issuer. 12.1.6SUMMARY STATEMENT REGARDING TRANSACTIONS BY EXECUTIVE OFFICERS AND DIRECTORS INVOLVING SHARES OF THE COMPANY DURING THE FISCAL YEAR ENDED DECEMBER 31, 2021. During the fiscal year ended December 31, 2021, the following transactions were carried outby the executive officers and directors on the Company's shares: Directors concerned Type of transaction Number of shares Average Price (EUR) Bernard Gilly Acquisition of free shares 270,000 — Sale of shares 250,000 7.5043 12.2Conflicts of interest To our knowledge, and subject to the relationships described in Section 17, “Related Party Transactions” and Section 3.4, “Risk Related to Our Business Operations,” as of the date of this Universal Registration Document there are no potential conflicts of interest between the duties of the members of the administrative, management or supervisory bodies and their private interests (including Bernard Gilly’s interests as non-executive Chairman of the Board of Directors of Pixium Vision, given the difference of technologies developed by Pixium Vision and the Company). To our knowledge, as of the date of this Universal Registration Document, there are no conflicts of interest between Bernard Gilly’s position in the Company and his positions as Chairman of the Boards of Directors of Brain Ever SAS, Pixium Vision S.A., Prophesee S.A., Eye TechCare S.A., Chronolife SAS, IBionext SAS, Tilak Healthcare SAS and GrAI Matter Labs. In addition, and as of the date of this Universal Registration Document, Bernard Gilly is not a shareholder of Passage de l’Innovation anymore. To our knowledge, as of the date of this Universal Registration Document, there are no arrangement or undertakings of any kind with shareholders, customers, suppliers or others pursuant to which any member of our administrative, management or supervisory bodies was selected to such position. As of the date of this Universal Registration Document, the members of the administrative, management or supervisory bodies have not agreed to any restriction on the disposal within a certain period of time of their holdings in the issuer’s securities, with the exception of rules relating to the prevention of insider trading and the recommendations of the MiddleNext Code, as amended in September 2016, with respect to obligation to retain shares. As of the filing date of this Universal Registration Document and subject to certain customary lockup agreements entered into with the underwriters in connection with our capital increase on June 27, 2017 (a description of which has to be included in the prospectus for that transaction), the members of our Board of Directors and officers have not agreed to any restrictions relating to the sale of their holdings in our share capital except for the rules relating to the prevention of insider trading. Management of conflicts of interest within the Board of Directors Concerning the prevention and management of conflicts of interest, the Board’s rules of procedure provide: “2.5 Conflict of interest – non-competition obligation – obligation of loyalty Each director has the duty and obligation to inform the Board spontaneously of any conflict of interest situation, even a potential or future conflict, with the Company, or one of its subsidiaries, in which he/she is to be found or may find him/herself. He/she must refrain from participating in the discussions and the voting on the corresponding deliberation(s), and furthermore undertakes, in such event, to exit the Board meeting during the discussions and voting on such deliberation(s). Any agreement of which the signature is planned, to be entered into between a director and the Company, directly or indirectly or via an intermediary, or between the Company and a company or an undertaking of which he/she is the owner, partner with unlimited liability, managing director, director, member of the Supervisory Board or, in general, a senior manager, except, in accordance with the provisions of Article L.225-39 of the French Commercial Code, (i) those concerning day-to-day transactions and entered into under arm’s length conditions, and (ii) those entered into between two companies, one of which holds, directly or indirectly, the entire share capital of the other (where applicable, after deduction of the minimum number of shares required to satisfy the requirements of Article 1832 of the French Civil Code or Articles L.225-1 and L.226-1 of the French Commercial Code), must be communicated by the interested director to the Chairman of the Board. At the time of the Board’s deliberation having the effect of authorizing the signature of that agreement, the director will refrain from taking part in the voting. In general, the Board of Directors takes preventive action with regard to conflicts of interest by raising the awareness of directors and asking them to update their declarations regularly. Finally, the Board of Directors reviews known conflicts of interest at least once a year. For regulated related-party agreements, the Board may have an independent expert appraisal carried out when it considers this relevant. A director or the permanent representative if the director is a legal entity cannot engage, on a personal basis, in companies or businesses that compete with the Company, without having previously informed the Board and without having received its authorization. The director is bound by a duty of loyalty. A director who no longer believes he/she is in a position to fulfill his/her duties on the Board or the Committees of which he/she is a member, must resign.” 13 COMPENSATION AND BENEFITS 13.1Compensation and benefits of Senior Executives and Directors 13.1.1COMPENSATION POLICY. This part constitutes the report of the Board of Directors drawn up by application of Articles L. 22-10-8 and R. 22-10-14 of the French Commercial Code, that shall be submitted to the vote of the shareholders at the Annual Combined Shareholders’ Meeting to be held on May 25, 2022 in its 12th, 13th and 14th resolutions. On the recommendation of the Remuneration Committee and taking into account the recommendations of the MiddleNext Code, the Board of Directors has established a remuneration policy for each of the corporate officers of the Company in compliance to its social interest, contributing to its sustainability and forming part of its commercial strategy as described in Chapter 5 of the Universal Registration Document. To do this, the Board set the remuneration policy for the Chief Executive Officer, Chairman of the Board and the members of the Board of Directors in connection with these elements, in particular by setting criteria for our Chief Executive Officer variable remuneration and the allocation of free shares linked to the implementation of this commercial strategy while respecting the social interest. No other remuneration, of any kind whatsoever, may be determined, awarded or paid by the Company, nor any commitment made by the Company if it does not comply with the approved remuneration policy or, in its absence, to the remuneration or practices existing within the Company. However, in exceptional circumstances, the Board of Directors may derogate from the application of the remuneration policy if this derogation is temporary, in accordance with social interest and necessary to guarantee sustainability or viability of the Society. In the event of changes in governance, the remuneration policy will be applied to the new corporate officers of the Company, if necessary with the necessary modifications. General principles regarding the compensation of executive corporate officers Within the context of the determination of the global remuneration of the directors who are Company representatives, the Board of Directors, at the proposal of the Remuneration Committee, has taken into consideration the following principles, pursuant to the recommendations of R16 of the MiddleNext corporate governance code of September 2021: •Exhaustiveness: the determination of the remuneration of directors who are Company representatives shall be exhaustive: fixed part, variable part (bonus), stock options, bonus shares, attendance fees, retirement conditions and specific benefits shall be considered in the global assessment of remuneration. •Equilibrium between the elements of the remuneration: each element of the remuneration shall be grounded and shall correspond to the general interest of the Company. •Benchmark: this remuneration shall be assessed, as far as possible, in the context of a business and of the reference market and proportional to the situation of the Company, while paying attention to its inflationary effect. •Consistency: the remuneration of the director who is a Company representative shall be determined in accordance with that of the other directors and of the Company’s employees. •Comprehensibility of the rules: the rules shall be simple and transparent; the performance criteria used to establish the variable part of the remuneration or, as appropriate, for the attribution of options or bonus shares, shall be linked to the performance of the Company, correspond to its objectives, be demanding, explainable and, as far as possible, sustainable. These shall be detailed, albeit without calling into question the confidentiality which may be justified for certain elements. •Measurement: the determination of the remuneration and attributions of options or of bonus shares must strike a fair balance and take account of the general interest of the Company, of market practices and of the performances of the directors. •Transparency: the annual information annual of “shareholders” on all of the remuneration and benefits received by the directors shall be carried out pursuant to the applicable regulations. Long-term compensation policy We believe that our ability to grant incentive awards is a valuable and necessary compensation tool that allows us to attract and retain the best available personnel for positions of substantial responsibility, provides additional incentives to employees and promotes the success of our business. Due to French corporate law and tax considerations, historically, we have granted several different equity incentive instruments to our directors, executive officers, employees and other service providers. These are: •share warrants for founders, otherwise known as bons de souscription de parts de créateurs d’entreprise, or BCE, granted to our officers and employees; •share warrants, otherwise known as bons de souscription d’actions, or BSA, typically granted only to non-employee directors not eligible for share warrants for founders; •stock options, otherwise known as options de souscription ou d’achat d’actions, or SO, granted to our officers and employees; and •free shares, otherwise known as attributions gratuites d’actions, or AGA, granted to our officers and employees. The Board of Directors’ authority to grant these equity incentive instruments and the aggregate amount authorized to be granted must be approved by a two-thirds majority of the votes held by our shareholders present, represented or voting by authorized means at the relevant extraordinary shareholders’ meeting. Once approved by the shareholders, the Board of Directors can continue to grant equity awards for 18 months for share warrants for founders and share warrants and for 38 months for stock options and free shares authorized by the shareholders. As a result, we typically request that our shareholders authorize new pools of equity incentive instruments at every annual general shareholders’ meeting. In general, share warrants for founders and share warrants no longer continue to vest following termination of the employment, office or service of the holder and all vested shares must be exercised within post-termination exercise periods set forth in the grant documents. In the event of certain changes in our share capital structure, such as a consolidation or share split or dividend, French law and applicable grant documentation provides for appropriate adjustments of the numbers of shares issuable and/or the exercise price of the outstanding warrants or share options. 13.1.1.1Compensation policy of the Chairman of the Board of Directors This compensation policy set by the Board, at the recommendation of the Remuneration Committee, is as follows : Fixed remuneration The Chairman of the Board of Directors shall receive fixed remuneration, payable in 12 monthly instalments. This amount shall be revised each year on the basis of market practices observed in comparable companies, through recommendations of the specialist external consulting firm. It is determined upon the following criteria: •responsibilities and assignments attached to this mandate, aiming in particular to ensure a proper governance and the correct functioning of the Company’s corporate bodies (Board of Directors and its Committees, General Meeting of Shareholders); •skills, experience, expertise and background required for assuming this function; •market analyzes and studies on the remuneration of similar positions in comparable companies. Since 2016, our Chairman’s fixed compensation was set at €145,154. It has been revised downwards since January 1, 2020 and set at €120,000. Attribution of Equity Warrants (BSA) The Chairman of the Board of Directors shall be eligible for attribution of equity warrants. These unlisted equity warrants may be exercised for 10 years for the plans approved before 2016 and 7 years for 2016 to 2021 plans after their issue for a price set by the Board equal to at least 8% of the market value of an ordinary share on the date of attribution. The exercise price shall be equal to the weighted average of the price of the last 20 trading sessions preceding the attribution date. Other Compensation The Chairman of the Board of Directors does not benefit from any other compensation (including attendance fees) linked to his participation in meetings of the Board of Directors or specialized committees, nor from severance pay in the event of termination of his duty. 13.1.1.2Compensation policy of the Chief Executive Officer This compensation policy, set by the Board, at the recommendation of the Compensation Committee, is as follows. Fixed remuneration The Chief Executive Officer shall receive fixed remuneration, payable in 12 monthly instalments. This amount shall be revised each year on. The fixed compensation is determined upon the following criteria: •level and complexity of the missions and responsibilities attached to this function, the Chief Executive Officer having the broadest powers to act in all circumstances on behalf of the Company and to represent it in its dealings with third parties; •skills, experience, expertise and background; •market analyzes and studies on the remuneration of similar positions in comparable companies. The fixed remuneration of our Chief Executive Officer has been increased for the first time since 2017 and set at €505,000 from January 1, 2022 Annual variable remuneration The annual variable remuneration is capped at a maximum of 60% of the fixed annual remuneration. In view of the profile of the Company, the criteria for determining the annual variable remuneration are for all or for some qualitative. The qualitative criteria have been pre-established by the Board of Directors, at the proposal of the Remuneration Committee, but are not made public on grounds of confidentiality. They principally represent operational milestones linked to the development of research and development projects, funding options to ensure the viability of the Company and the conduct of operations and the development of the Company in general. In respect of the 2021 financial year, for the purpose of the determination of the annual variable remuneration, the performance criteria and respective weigh were the following: 75% Manufacturing Strategy Objective 5% Clinical Objective 20% Corporate and Financial Objective Based on the work and review performed by the Compensation Committee, the Board of Directors met on December 14, 2021 and reviewed the level of achievement of the objectives. It was decided, upon recommendation of the Compensation Committee and subject to the favorable vote of the General Meeting, that the achievement of the performance criteria would be set at 50%. It was therefore decided that our Chief Executive Officer would receive, during the financial year 2022, for the financial year 2021, 50% of its annual variable portion, the latter thus amounting to €91,250 gross, or 25% of his annual fixed compensation. In respect of the 2022 Financial year, for the purpose of the determination of the annual variable remuneration, the performance criteria are composed of a manufacturing and regulatory objective, a commercial launch preparation objective as well as Corporate and Financial objective. Attribution of Free Shares (AGA) The Board of Directors considers that the grant of performance shares, which also benefits to other key corporate functions, is particularly suited to the role of Chief Executive Officer given the expected level of its direct contribution to the long-term performance of the Company. This mechanism, which is based on performance criteria in line with the objectives communicated to the market, as well as on the development of the value of the Company, strengthens the motivation and loyalty of the Chief Executive Officer while facilitating the alignment of his interests with those of the shareholders as well as with the social interest of the Company. The amount of attributions of free shares is set on the basis of market practices observed in comparable companies, through recommendations of the specialist external consulting firm. Performance conditions The shares are subject to an acquisition period of two years, and achievement of performance criteria. The acquisition of shares varies according to the achievement of internal performance conditions, the measurement of which will be carried out over two years and the level of achievement of which will be communicated by criteria once the performance assessment has been established by the Board of Directors. The criteria used are intended to measure overall performance and are directly linked to the Company’s main strategical development objectives. For more details regarding the performance criteria attached to the free shares, see Section 19.1.4 of this Universal Registration Document. Condition of presence The acquisition of performance shares by the Chief Executive Officer is also subject to his presence in the Group on the date of acquisition of the shares. Benefits in kind The Chief Executive Officer shall benefit from a Company flat. Exceptional remuneration The Board of Directors may decide, at the proposal of the Remuneration Committee, to grant exceptional remuneration to the Chief Executive Officer in view of very special circumstances. The payment of this type of remuneration must be justifiable by an event, such as the execution of a major transaction for the Company, or an operational outperformance measure. The payment of the elements of variable remuneration and, as appropriate, exceptional remuneration attributed for a financial year, is conditional on approval by the Ordinary General Meeting of the elements of remuneration of the Chief Executive Officer, paid or attributed by way of the said financial year (ex post vote). In case the Board of Directors decides to combine the functions of Chairman and Chief Executive Officer, the compensation policy applicable to the Chief Executive Officer would be applicable to the Chairman and Chief Executive Officer, if necessary, with the necessary modifications (he could in particular collect attendance fees). Compensation policy of the Deputy Chief Executive Officer The compensation policy applicable to the Chief Executive Officer would be applicable to the Deputy Chief Executive Officers, if necessary, with the necessary modifications. The Company has entered into a compensation agreement with Mrs. Holtz on June 1, 2020, relating to her VP, Quality position. Her annual fixed remuneration is set at €130,000. Her annual variable compensation represents a maximum of 30% of her annual fixed compensation. She does not receive any remuneration related to her Deputy Chief Executive Officer position. 13.1.1.3Commitments with regard to the Chief Executive Officer Departure indemnities The amount of the sudden termination indemnity shall be equal to twelve (12) months’ remuneration calculated on the basis of the last annual remuneration (fixed and variable) in the event of cessation by Mr. Bernard Gilly of his duties as Chief Executive Officer (or of Chairman and Chief Executive Officer, in the event that the Board of Directors subsequently decides to combine the functions of Chairman of the Board of Directors and those of Chief Executive Officer) for whatever reason. As an exception to the above, this Termination Indemnity shall not be due: (i)in the event of dismissal of Mr. Bernard Gilly from his duties as Chief Executive Officer (or of Chairman and Chief Executive Officer, in the event that the Board of Directors subsequently decides to combine the functions of Chairman of the Board of Directors and those of Chief Executive Officer) for serious misconduct or gross negligence, as these notions are defined by the case law applicable to Labor law; or (ii)in the event of resignation by Mr. Bernard Gilly from his mandate as Chief Executive Officer (or of Chairman Chief Executive Officer, in the event that the Board of Directors subsequently decides to combine the functions of Chairman of the Board of Directors and those of Chief Executive Officer), unless this resignation is due to illness or for family reasons, it being specified that in these latter two cases, the Termination Indemnity shall then be due to Mr. Bernard Gilly. The Termination Indemnity shall not be due if Mr. Bernard Gilly changes position within the Group or leaves the Company at his own initiative in order to take up new positions. The payment of the Termination Indemnity shall be contingent on meeting the following conditions: Achievement of at least 50% of the annual objectives for the past year. These objectives both of quantitative and qualitative nature, are established annually by the Board of Directors, at the proposal of the Remuneration Committee, but are not made public for reasons of confidentiality. They principally represent operational milestones linked to the development of research and development projects, funding options to ensure the viability of the Company, the conduct of operations and the development of the Company in general. The reference annual compensation will be his last annual gross compensation, including his last gross variable compensation paid to him for the last financial year. The termination indemnity will not be definitively acquired until verification by the Board of Directors that the above criteria are met. Non-competition commitment The monthly non-competition commitment to the benefit of Mr. Bernard Gilly, Chief Executive Officer, authorized by the Board Meeting of March 9, 2017 for a period of one (1) year starting from his departure from the Company, equal to 40% of his last net monthly remuneration, excluding any bonus (after deduction of any other amount received in any capacity by way of a non-competition obligation) as consideration for the commitment made by this latter party for the same duration of one year starting from his departure: •not to hold in Europe, Canada, the United States or any country in which the Company exercises its Activity, a position of manager, director, employee or consultant in a company conducting the Activity; or •not to hold shares in the share capital of a company carrying out the Activity, with the exception of a holding in any listed company representing at most 1% of the share capital held exclusively for financial reasons. 13.1.1.4Compensation policy of the Board members Our shareholders at the mixed General Shareholders’ Meeting held on May 19, 2016 set the total annual attendance fees to be distributed among non-employee directors except those who are affiliated with one of our significant shareholders at €300,000 as a maximum for the 2016 fiscal year and for the following fiscal years. Please note that considering the appointment of a new independent director and on the recommendation of the Compensation Committee, it is proposed to the 2021 Shareholders' Meeting in its ninth resolution to increase the annual fixed sum to be allocated to directors from 300,000 euros to 360,000 euros for the current financial year and until further decision. The criteria for distributing the annual fixed sum allocated by the General Meeting to the members of the Board were set by the Board, upon recommendation of the Compensation Committee and are as follows: •only the independent directors receive a compensation; •the annual attendance fee for an independent director at €45,000 for each director, irrespective of the number of Board meeting held during the year and their actual presence; •an additional €15,000 as a chair of a committee, regardless of the number of meetings held. Our Chairman of the Board of Directors and our Chief Executive Officer and Co-Founder, are directors but do not receive any additional compensation for their services as directors. For information related to the composition of our Board of Directors, the term of their office, and their main positions and offices held outside the Company, see section 12.1.1 of this Universal Registration Document. 13.1.2SUMMARY TABLE OF COMPENSATION, OPTIONS AND SHARES GRANTED TO SENIOR EXECUTIVES FOR THE FISCAL YEARS 2020 AND 2021. The tables below summarize the compensation and benefits of any kind paid to our Chief Executive Officer and to our directors, in accordance with the tables on executive compensation of the AMF recommendation No. 2014-14. The aggregate compensation paid and benefits in kind granted by the Company to our current executive officers and directors, including share-based compensation, for the year ended December 31, 2021, was €3,021,775. For the year ended December 31, 2021, no amounts have been set aside or accrued to provide pension, retirement or similar benefits to our employees was attributable to our executive officers. The payment of the elements of variable remuneration and, as appropriate, exceptional remuneration attributed for a financial year to Chairman of the Board and the Chief Executive Officer is conditional on approval by the next Ordinary General Meeting of their elements of remuneration, paid or attributed during the said financial year (individual ex post vote). Our Shareholders’ Meeting will be held on May 25, 2022, and will be asked in its 16th and 17th resolutions, to vote accordingly on the elements of remuneration granted and paid to Michael Wyzga and Bernard Gilly during the financial year 2021, that will be described in the report of the Board of Directors included in the notice of General Meeting. Our Shareholders’ Meeting will be held on May 25, 2022, and will be asked in its 15th resolution, to vote accordingly on the elements below that constitute the information given accordingly to the Article L. 22-10-9 of the French Commercial Code and comply with AMF recommendation 2021-02. Table 1 (AMF definition) (in euros) Fiscal year ending December 31, 2020 Fiscal year ending December 31, 2021 Michael Wyzga Chairman Compensation granted for the fiscal year(as detailed in Section 13.1.3 of this Universal Registration Document) 120,000 120,000 Valuation of multi-year variable compensation granted in the course of the fiscal year — — Valuation of share warrants granted during the fiscal year(as detailed in Section 13.3.1 of this Universal Registration Document) 101,800 20,662 Valuation of share warrants for founders granted during the fiscal year(as detailed in Section 13.3.1 of this Universal Registration Document) — — Valuation of shares warrants granted during the fiscal year(as detailed in Section 13.3.3 of this Universal Registration Document) — — TOTAL 221,800 140,662 (in euros) Fiscal year ending December 31, 2020 Fiscal year ending December 31, 2021 Bernard Gilly Chief Executive Officer Compensation granted for the fiscal year(as detailed in Section 13.1.3 of this Universal Registration Document) 615,833 508,092 Valuation of multi-year variable compensation granted in the course of the fiscal year — — Valuation of share warrants granted during the fiscal year(as detailed in Section 13.3.1 of this Universal Registration Document) — — Valuation of share warrants for founders granted during the fiscal year (as detailed in Section 13.3.1 of this Universal Registration Document) — — Valuation of free shares granted during the fiscal year(as detailed in Section 13.3.3 of this Universal Registration Document) 1,004,400 (1) 1,774,000 (2) TOTAL 1,620,233 2,282,092 (1) The original amount of the free shares granted during the fiscal year 2020, and included in the 2020 Universal Registration Document was 1,822,800. As detailed in the paragraph 13.3.3, the performance share plan 2020 as been fully cancelled as of the date of the 2021 Universal Registration Document, therefore, only remains the amount representing the 270,000 free shares whitout performance conditions granted to Mr Gilly in 2020. (2) This amount represents half of the valuation of the free shares granted during the fiscal year 2021, considering that half of the 2021 plan has been cancelled following the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022. (in euros) Fiscal year ending December 31, 2020 Fiscal year ending December 31, 2021 Marie-Claude Holtz Deputy Chief Executive Officer Compensation granted for the fiscal year(as detailed in Section 13.1.3 of this Universal Registration Document) 90,823 149,380 Valuation of multi-year variable compensation granted in the course of the fiscal year — — Valuation of share warrants granted during the fiscal year(as detailed in Section 13.3.1 of this Universal Registration Document) — — Valuation of share warrants for founders granted during the fiscal year(as detailed in Section 13.3.1 of this Universal Registration Document) — — Valuation of free shares granted during the fiscal year(as detailed in Section 13.3.1 of this Universal Registration Document) — (1) 44,350 (2) TOTAL 90,823 193,730 (1) The original amount of the free shares granted during the fiscal year 2020, and included in the 2020 Universal Registration Document was 255,000. As detailed in the paragraph 13.3.3, the performance share plan 2020 as been fully cancelled as of the date of the 2021 Universal Registration Document. (2) This amount represents half of the valuation of the free shares granted during the fiscal year 2021, considering that half of the 2021 plan has been cancelled following the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022. 13.1.3COMPENSATION OF SENIOR EXECUTIVES. Table 2 (AMF definition) (in euros) Fiscal year ending December 31, 2020 Fiscal year ending December 31, 2021 Granted Paid Granted Paid Michael Wyzga Chairman Fixed Compensation (1) 120,000 120,000 120,000 120,000 Variable Compensation — — — — Valuation of multi-year variable compensation granted in the course of the fiscal year — — — — Exceptional Compensation — — — — Directors’ Fees — — — — Benefits in kind — — — — TOTAL 120,000 120,000 120,000 120,000 (in euros) Fiscal year ending December 31, 2020 Fiscal year ending December 31, 2021 Granted Paid Granted Paid Bernard Gilly Chief Executive Officer Fixed Compensation 365,000 365,000 365,000 365,000 Variable Compensation (2) 182,500 109,500 91,250 182,500 Valuation of multi-year variable compensation granted in the course of the fiscal year — — — — Exceptional Compensation 18,250 — — 18,250 Directors’ Fees — — — — Benefits in kind (3) 50,083 50,083 51,842 51,842 TOTAL 615,833 524,583 508,092 617,592 (in euros) Fiscal year ending December 31, 2020 Fiscal year ending December 31, 2021 Granted Paid Granted Paid Marie-Claude Holtz Deputy Chief Executive Officer Fixed Compensation (4) 68,753 68,753 125,004 125,004 Variable Compensation (5) 22,070 — 24,376 22,070 Valuation of multi-year variable compensation granted in the course of the fiscal year — — — — Exceptional Compensation — — — — Directors’ Fees — — — — Benefits in kind (3) — — — — TOTAL 90,823 68,753 149,380 147,074 (1) Mr. Wyzga was appointed Chairman of the Board of Directors on March 2, 2016. On March 9, 2017, the Board of Directors set Mr. Wyzga’s fixed compensation at €120,000 gross for the fiscal year ended December 31, 2021. (2) On December 14, 2020, the Board of Directors of the Company awarded Mr. Gilly a variable compensation of €182,500 as a bonus for achieving qualitative and quantitative objectives regarding the fiscal year ended December 31, 2020 as well as an exceptional remuneration of €18,250. On December 14, 2021, the Board of Directors of the Company awarded Mr. Gilly a variable compensation of €91,250 as a bonus for achieving qualitative and quantitative objectives regarding the fiscal year ended December 31, 2021. It should be remembered that the payments of this variable and this exceptional remuneration are subject to a favorable vote of the 17th resolution the Ordinary General Meeting which will be held on May 25, 2022, pursuant to the “say-on-pay” regulation introduced by the Sapin 2 Law. (3) Consisting of a housing allowance. (4) Mrs. Holtz was appointed Deputy Chief Executive Officer and Chief Pharmacist on April, 22, 2020. The Company has entered into a compensation agreement with Mrs. Holtz on June 1, 2020, relating to her VP, Quality position. Her annual fixed remuneration was set at €125,000 gross for the fiscal year ended December 31, 2021. She does not receive any remuneration related to her Deputy Chief Executive Officer position. (5) On December 14, 2021, the Board of Directors of the Company awarded Ms. Holtz a variable compensation of €24,376 as a bonus for achieving qualitative and quantitative objectives regarding the fiscal year ended December 31, 2021. 13.2Directors’ Compensation The table below summarize the compensation and benefits of any kind paid to our directors during the period covered: Table 3 (AMF definition) (in euros) Granted / Paid 2020 Granted / Paid 2021 Peter Goodfellow Directors’ fee 60,000 60,000 Other Compensation — — Bpifrance Participations (as represented by Mr. Laurent Higueret)(1) Directors’ fee — — Other Compensation — — Natalie Mount(2) Directors’ fee 45,000 14,750 Other Compensation — — Simone Seiter Directors’ fee 60,000 60,000 Other Compensation(5) 76,350 15,497 Sofinnova Partners SAS (as represented by Mr. Cédric Moreau) Directors’ fee — — Other Compensation — — Maritza McIntyre Directors’ fee 45,000 45,000 Other Compensation(6) 76,350 15,497 Elsy Boglioli(3) Directors’ fee 12,363 45,000 Other Compensation(7) 152,700 15,497 Françoise de Craecker(4) Directors’ fee — 30,250 Other Compensation(8) — 103,800 TOTAL 527,763 405,291 (1) Mr. Laurent Higueret resigned from the Board of Directors on July 22, 2020. (2) Ms. Mount resigned from the Board of Directors on April, 29, 2021. (3) Ms. Boglioli joined the Board of Directors on September 22, 2020. (4) Ms. de Craecker joined the Board of Directors on April 29, 2021 (5) Consisting of 15,000 share warrants (BSA) granted in 2020 at an exercise price of €3.99 and 15,000 share warrants (BSA) granted in 2021 at an exercise price of €5.47. (6) Consisting of 15,000 share warrants (BSA) granted in 2020 at an exercise price of €3.99 and 15,000 share warrants (BSA) granted in 2021 at an exercise price of €5.47. (7) Consisting of 30,000 share warrants (BSA) granted in 2020 at an exercise price of €3.99 and 15,000 share warrants (BSA) granted in 2021 at an exercise price of €5.47. (8) Consisting of 30,000 share warrants (BSA) granted in 2021 at an exercise price of €6.80. Director’s fees are paid quarterly. Our directors are reimbursed for reasonable expenses incurred in connection with attending Board and Committee meetings. Except as described in the Section 17.2 “Transactions with Key Management Persons” of this Universal Registration Document with respect to Mr. Gilly, there are no arrangements or understandings between us and any of our directors providing for benefits upon termination of their service as our directors. 13.3Share Warrants, Share Warrants for founders, stock options and free Shares Granted to Senior Executives and Directors As of December 31, 2021, BCE warrants and BSA warrants held by our directors could be exercised for the purchase of an aggregate of 524,000 ordinary shares at a weighted average exercise price of €3.658 per share. In addition, BCE warrants and BSA warrants could be exercised for the purchase of an aggregate of 1,237,515 ordinary shares at a weighted average exercise price of €3.999 per share. As of December 31, 2021, 562,500 AGA granted to our directors are outstanding and could be acquired subject to performance criteria. 13.3.1SHARE WARRANTS OR SHARE WARRANTS FOR FOUNDERS GRANTED TO SENIOR EXECUTIVES AND DIRECTORS IN 2020, 2021 AND AS OF THE DATE OF THIS DOCUMENT. Table 4 (AMF definition) Name Grant Date Type of Grant Number of Ordinary Shares Underlying Awards (#) Exercise Price (€) Expiration Date Michael Wyzga 11/22/2020 BSA (1) 20,000 3.99 11/21/2027 12/14/2021 BSA (1) 20,000 5.47 12/13/2028 Simone Seiter 11/22/2020 BSA (1) 15,000 3.99 11/21/2027 12/14/2021 BSA (1) 15,000 5.47 12/13/2028 Maritza McIntyre 11/22/2020 BSA (1) 15,000 3.99 11/21/2027 12/14/2021 BSA (1) 15,000 5.47 12/13/2028 Elsy Boglioli 11/22/2020 BSA (1) 30,000 3.99 11/21/2027 12/14/2021 BSA (1) 15,000 5.47 12/13/2028 Françoise de Craecker 10/21/2021 BSA (1) 30,000 6.80 10/20/2028 (1) BCE refers to share warrants for founders. BSA refers to share warrants. AGA refers to free shares. BSA are subscribed by directors at a price of 8% of the exercise price, therefore, representing an investment risk and aligning directors and shareholders interest. The exercise price of share warrants is determined as the weighted average of the share price of the last 20 trading sessions preceding the attribution date. Amounts reported as Other Compensation in the above table represent the net fair value of granted share warrants (BSA), including the payment of the subscription price, as determined by an independent expert using a Black-Scholes model. See section 7.2.5, “Critical accounting policies and estimates” of this Universal Registration Document for more information on the valuation method. 13.3.2SHARE WARRANTS OR SHARE WARRANTS FOR FOUNDERS EXERCISED BY SENIOR EXECUTIVES AND DIRECTORS IN 2020, 2021 AND AS OF THE DATE OF THIS DOCUMENT. Table 5 (AMF definition) Name Grant Date Number of Share Warrants and Share Warrants for Founders Exercised Exercise Price (€) Bernard Gilly — — — Marie-Claude Holtz — — — Peter Goodfellow — — — Michael Wyzga — — — Simone Seiter — — — Natalie Mount 07/27/2017 30,000 5.04 09/18/2018 4,479 2.22 Maritza McIntyre — — — Elsy Boglioli — — — Françoise de Craecker — — — 13.3.3FREE SHARES TO SENIOR EXECUTIVES AND DIRECTORS GRANTED IN 2020, 2021 AND AS OF THE DATE OF THIS DOCUMENT. Table 6 (AMF definition) Name Grant Date Number of Shares Granted Value of Shares according to IFRS 2 at Grant Date Number of shares Vested / Vesting as of the date of the Document Value of Shares according to IFRS 2 as of the date of the Document Beginning of Acquisition Period End of Lock-up Period Performance Criteria Bernard Gilly 01/28/2020 220,000 €818,400 — — 01/28/2020 (2) (3) 01/28/2020 270,000 €1,004,400 270,000 €1,004,400 01/28/2020 (2) — 02/25/2021 400,000 €3,548,000 200,000 €1,774,000 02/25/2021(1) (2) (5) Marie-Claude Holtz 09/22/2020 85,000 €255,000 — — 09/22/2020 (2) (4) 02/25/2021 10,000 €88,700 5,000 €44,350 02/25/2021(1) (2) (5) (1) If the performance criteria are not fulfilled by February 24, 2023 at the latest, the free shares granted will be canceled. (2) The lock-up period will end one (1) year after the end of the actual acquisition date. (3) In January 2020, the Company issued 1,007,500 free shares (AGA 2020) to employees of the Company of which: •567,500 were subject to the achievement of the following performance criteria at the latest originally on January 27, 2022: —50% will be acquired upon the approval with the European Medicines Agency (EMA) of the application for market authorization (MA) at the European level of the LUMEVOQ®, and —50% will be acquired upon the filing with the Food and Drug Agency (FDA) of the application for Biologics License Application (BLA) for the LUMEVOQ®, and —in the event of a public tender offer or public exchange offer on the Company's shares, the Performance Conditions 1 and 2 will be deemed not applicable from the Date of the Public Offer, and •452,500 are not subject to performance conditions, but subject to a one-year vesting period. In this context, Mr. Bernard Gilly received 220,000 free shares with performance conditions and, in addition to his fixed and variable compensation, 270,000 free shares without performance conditions (as permitted by the legal and regulatory provisions applicable on that date). Those 270,000 free shares without performance conditions are subject to a one-year vesting period as well as a lock-up period of one year (until 01/27/2022). (4) In September 2020, the Company issued 85,000 free shares (AGA 2020) to Ms. Holtz. They were subject to the achievement of the following performance criteria at the latest originally on January 27, 2022: •50% will be acquired upon the approval with the European Medicines Agency (EMA) of the application for market authorization (MA) at the European level of the LUMEVOQ®; •50% will be acquired upon the filing with the Food and Drug Agency (FDA) of the application for Biologics License Application (BLA) for the LUMEVOQ®; and •in the event of a public tender offer or public exchange offer on the Company's shares, the Performance Conditions 1 and 2 will be deemed not applicable from the Date of the Public Offer. The Board of Directors has decided on September 21, 2021, to amend both Performance Bonus Shares Plans 2020 in order to postpone the deadline for the completion of Performance Conditions 1 and 2, by one year, which will now be set on January 28, 2023, has further decided that the Vesting Period of each of Tranches 1 and 2 shall end, in consequence thereof, on the date of fulfillment of the Performance Conditions affecting each tranche, without however it being able to end before September 21, 2022, even if the Performance Conditions are fulfilled before this date. Please see the paragraphe below for further information. (5) In February 2021, the Company issued 880,000 free shares (AGA 2020) to employees of the Company of which: •845,000 are subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below at the latest on February 24, 2023: —50% could have been acquired acquired upon the first commercial sale of the LUMEVOQ®, and —50% will be acquired upon at the completion of the recruitment of the extension cohort of the Phase I/II clinical trial with GS030 in retinisis pigmentosa. —in the event of a public tender offer or public exchange offer on the Company's shares, the Performance Conditions 1 and 2 will be deemed not applicable from the Date of the Public Offer, and •35,000 were not subject to performance conditions, but subject to a one-year vesting period and were therefore fully acquired on February 25, 2022. Following the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022, the Group assessed that it will not be in a position to achieve the first Performance Condition before the given deadline and has therefore decided to cancel 50% of the Performance Bonus Share Plan on the same date. Modification of the Performance Bonus plans granted on January 28, 2020 and on September 22, 2020 Having regard to the consequences of the Covid-19 pandemic on the Company’s business and, more specifically, of the impact on the Company’s partners directly involved in the process of obtaining the marketing authorization for LUMEVOQ®, having led the legislator of a foreign country to adopt exceptional and binding regulations of national interest that were completely unpredictable when determining the Performance Conditions and their completion schedule; the Board of Directors has decided on September 21, 2021, to amend the Performance Bonus Shares Plans in order to postpone the deadline for the completion of Performance Conditions 1 and 2, by one year, which will now be set on January 28, 2023, has further decided that the Vesting Period of each of Tranches 1 and 2 shall end, in consequence thereof, on the date of fulfillment of the Performance Conditions affecting each tranche, without however it being able to end before September 21, 2022, even if the Performance Conditions are fulfilled before this date. Following the feedback provided by the FDA recommending that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials, the Group has considered that the second Performance Condition could not be achieved before the new deadline of Completion, i.e. January 28, 2023 and therefore has decided to cancel 50% of both Performance Bonus Share Plans on December 31, 2021. In addition, the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022 will not allow the Group to timely achieve the first Performance Condition, and has therefore led to the cancellation of the remaining 50% of both Performance Bonus Share Plans on the same date. 13.3.4FREE SHARES AVAILABLE IN 2020, 2021 AND AS OF THE DATE OF THIS DOCUMENT. The following free shares became available in 2020, 2021 and as of the date of this Document. Name Grant Date Number of Shares Granted Number of Shares which became available during the exercise Performance Criteria Bernard Gilly 09/18/2018 45,000 45,000 (1) (2) 07/23/2019 220,000 220,000 (1) (3) 01/28/2020 270,000 270,000 — (1) 50% of AGA 2018 and 50% of AGA 2019 were acquired upon completion of the enrollment of the patients of the Phase I/II clinical trials with GS030 in retinitis pigmentosa, on July 29, 2020. (2) 50% of AGA 2018 were acquired upon completion of the production of the first PPQ batch of LUMEVOQ® on September 1, 2020. (3) 50% of AGA 2019 were acquired upon the filing with the European Medicine Agency of the application for Market Authorization (MA) at the European level of LUMEVOQ® on September 14, 2020. 13.4History of Allocation of Share Warrants, Share Warrants for Founders and Stock Options 13.4.1HISTORY OF SHARE WARRANTS FOR FOUNDERS (BCE). Table 8 (AMF definition) BCE Issued July 2013(1) BCE Issued April 2014 BCE Issued December 2014 BCE Issued July 2015(1) Date of shareholders’ meeting 02/05/2013 02/05/2013 06/25/2014 06/29/2015 Date of allocation by the Board of Directors 07/08/2013 04/09/2014 12/03/2014 07/08/2015 Total number of BCE authorized 2,334,959 2,334,959 2,334,959 856,000 Total number of BCE granted 892,000 193,800 60,000 733,298 Including those granted to Mr. Gilly 300,000 — — 161,000 Including those granted to Mr. Wyzga — — — — Start date for the exercise of the BCE 07/08/2013 04/08/2014 12/03/2014 07/08/2015 BCE expiry date 07/07/2023 04/07/2024 12/02/2024 07/07/2025 BCE exercise price €0.025 €0.025 €0.025 €3.275 Number of shares subscribed as of April 30, 2022 844,400 193,800 60,000 99,765 Total number of BCE canceled or obsolete as of April 30, 2022 — — — 178,952 Total number of BCE outstanding as of April 30, 2022 47,600 — — 454,582 Total number of shares available for subscription as of April 30, 2022 47,600 — — 454,582 (1) The figures have been adjusted in order to reflect the 5 for 2 reverse stock split which took place on August 17, 2015. 13.4.2HISTORY OF SHARE WARRANTS (BSA). BSA Issued July 2013(1) BSA Issued April 2014(1) BSA Issued July 2015(1) BSA Issued July 2016 BSA Issued July 2017 BSA Issued September 2018 BSA Issued July 2019 BSA Issued January 2020 BSA Issued November 2020 BSA Issued February 2021 Date of shareholders’ meeting 02/05/2013 02/05/2013 06/29/2015 05/19/2016 05/19/2016 04/12/2018 06/11/2019 06/11/2019 04/29/2020 04/29/2020 Date of allocation by the Board of Directors 07/08/2013 04/09/2014 07/08/2015 07/26/2016 07/27/2017 09/18/2018 07/23/2019 01/28/2020 11/02/2020 02/25/2021 Total number of BSA authorized 2,334,959 2,334,959 856,000 680,456 1,211,711 1,436,227 1,436,227 656,847 656,847 Total number of BSA subscribed 328,000 33,000 121,000 205,000 165,000 20,000 105,000 40,000 80,000 40,000 Including those granted to Mr. Gilly — — — — — — — — — — Including those granted to Mr. Wyzga — — 40,000 31,000 15,000 10,000 20,000 — 20,000 — Start date for the exercise of the BSA 07/08/2013 04/09/2014 07/08/2015 07/26/2016 07/27/2017 09/18/2018 07/23/2019 01/28/2020 11/02/2020 02/25/2022 BSA expiry date 07/07/2023 04/08/2024 07/07/2025 07/25/2023 07/26/2024 09/17/2025 07/22/2026 01/27/2027 11/01/2027 02/24/2028 BSA exercise price €0.025 €0.025 €3.275 €8.08 €5.04 €2.22 €1.45 €3.48 €3.99 €7.19 BSA subscription price €0.002 €0.002 €0.25 €0.65 €0.40 €0.18 €0.13 €0.30 €0.35 €0.63 Number of shares subscribed as of April 30, 2022 328,000 — — — 30,000 4,479 21,667 — — — Total number of BSA canceled or obsolete as of April 30, 2022 — — — 47,000 — 521 — — — — Total number of BSA outstanding as of April 30, 2022 — 33,000 121,000 158,000 135,000 15,000 83,333 40,000 80,000 40,000 Total number of shares available for subscription as of April 30, 2022 — 33,000 121,000 158,000 135,000 15,000 83,333 40,000 80,000 40,000 (1) The figures have been adjusted in order to reflect the 5 for 2 reverse stock split which took place on August 17, 2015. BSA Issued October 2021 BSA Issued December 2021 Date of shareholders’ meeting 04/29/2021 04/29/2021 Date of allocation by the Board of Directors 10/21/2021 12/14/2021 Total number of BSA authorized 919,546 919,546 Total number of BSA subscribed 30,000 65,000 Including those granted to Mr. Gilly — — Including those granted to Mr. Wyzga — 20,000 Start date for the exercise of the BSA 10/21/2022 12/14/2022 BSA expiry date 10/29/2028 12/13/2028 BSA exercise price €6.80 €5.47 BSA subscription price €0.63 €0.48 Number of shares subscribed as of April 30, 2022 — — Total number of BSA canceled or obsolete as of April 30, 2022 — — Total number of BSA outstanding as of April 30, 2022 30,000 65,000 Total number of shares available for subscription as of April 30, 2022 30,000 50,000 BSA are subscribed by directors at a price of 8% of the exercise price, therefore, representing an investment risk and aligning directors and shareholders interest. The exercise price of share warrants is determined as the weighted average of the share price of the last 20 trading sessions preceding the attribution date. The net fair value of granted share warrants (BSA) has been determined by an independent expert using a Black-Scholes model. 13.4.3HISTORY OF STOCK OPTIONS (SO). SO Issued July 2017 SO Issued December 2017 SO Issued March 2018 SO Issued September 2018 SO Issued September 2020 SO Issued February 2021 Date of shareholders’ meeting 05/31/2017 05/31/2017 05/31/2017 04/12/2018 04/12/2018 04/12/2018 Date of allocation by the Board of Directors 07/27/2017 12/19/2017 03/14/2018 09/18/2018 09/22/2020 02/25/2021 Total number of SO authorized 977,022 1,211,711 Total number of SO granted 220,000 300,000 175,000 30,000 155,000 20,000 Including those granted to Mr. Gilly — — — — — — Including those granted to Mr. Wyzga — — — — — — Including those granted to Mrs. Holtz — — — — — — Start date for the exercise of the SO (1) (2) (2) (2) (2) (3) SO expiry date 07/26/2024 12/18/2024 03/13/2025 09/17/2025 09/21/2027 02/24/2028 SO exercise price €5.040 €5.55 €6.98 €2.19 €2.82 €7.51 Number of shares subscribed as of April 30, 2022 — — — — 45,208 — Total number of SO canceled or obsolete as of April 30, 2022 220,000 300,000 175,000 30,000 109,792 20,000 Total number of SO outstanding as of April 30, 2022 — — — — — — Total number of shares available for subscription as of April 30, 2022 — — — — — — (1) 25% of the stock options are exercisable at the grant date; the remaining 75% will become exercisable at a rate of 1/36 per month during the 3 following years. (2) 25% of the stock options are exercisable at the first anniversary of the grant date; the remaining 75% will become exercisable at a rate of 1/36 per month during the 3 following years. (3) 1/3 of the stock options are exercisable at the first anniversary of the grant date; 1/3 will become exercisable on the second anniversary and the remaining 1/3 will become exercisable on the third anniversary of the date of grant. 13.5Share Warrants, Share Warrants for Founders or Stock Options of the Company granted to the Company’s top ten employees Table 9 (AMF definition) Total number of options awarded / shares subscribed or purchased Weighted average price Free shares granted during the fiscal year ended December 31, 2021 by the Company to the ten employees of the Company who received the highest number of such free shares (overall figure) 780,000 8.04 Free shares on the Company definitively acquired during the fiscal year ended December 31, 2021 by the ten employees of the Company (overall figure) 167,500 3.72 Options granted during the fiscal year ended December 31, 2021 by the Company to the ten employees of the Company who received the highest number of such options (overall figure) 20,000 7.51 Options on the Company exercised during the fiscal year ended December 31, 2021 by the ten employees of the Company who purchased or subscribed for the greatest number of options (overall figure) 45,208 2,82 13.6History of Allocation of Free Shares Table 10 (AMF definition) AGA Issued July 2016 AGA Issued July 2017 AGA Issued December 2017 AGA Issued September 2018 AGA Issued December 2018 AGA Issued July 2019 AGA Issued January 2020 AGA Issued September 2020 AGA Issued February 2021 AGA Issued October 2021 Date of shareholders’ meeting 05/19/2016 05/19/2016 05/19/2016 04/12/2018 04/12/2018 04/12/2018 04/12/2018 04/29/2020 04/29/2020 04/29/2021 Date of allocation by the Board of Directors 07/26/2016 07/27/2017 12/19/2017 09/18/2018 12/19/2018 07/23/2019 01/28/2020 09/22/2020 02/25/2021 10/21/2021 Total number of AGA authorized 10% share capital at the grant date 10% share capital at the grant date 10% share capital at the grant date 10% share capital as of the date of the General Meeting 10% share capital as of the date of the General Meeting 10% share capital as of the date of the General Meeting 10% share capital as of the date of the General Meeting 5% share capital as of the date of the General Meeting 5% share capital as of the date of the General Meeting 5% share capital as of the date of the General Meeting Total number of AGA granted 766,000 593,500 72,500 380,000 135,000 610,000 1,007,500 85,000 880,000 380,000 Including those granted to Mr. Gilly 250,000 200,000 — 45,000 — 220,000 490,000 — 400,000 — Including those granted to Mr. Wyzga — — — — — — — — — — Including those granted to Mrs. Holtz — — — — — — — 85,000 10,000 — Date of definitive acquisition of AGA 07/26/2017 07/27/2018 12/19/2018 09/18/2019 12/19/2019 07/23/2020 01/27/2023(2) 02/25/2023(3) 10/20/2023(4) End of lock-up period (1) (1) (1) (1) (1) (1) (1) (1) (1) Number of shares definitively acquired as of April 30, 2022 602,000 505,000 72,500 225,000 135,000 575,000 437,500 — 35,000 — Total number of AGA canceled or obsolete as of April 30, 2022 164,000 88,500 — 155,000 — 35,000 570,000 85,000 447,500 190,000 Total number of AGA outstanding as of April 30, 2022 — — — — — — — — 397,500 190,000 (1) The lock-up period will end one (1) year after the end of the actual acquisition date. (2) If the performance terms are not fulfilled by January 27, 2023 at the latest, the free shares granted will be canceled. (3) If the performance terms are not fulfilled by February 24, 2023 at the latest, the free shares granted will be canceled. (4) If the performance terms are not fulfilled by October 20, 2023 at the latest, the free shares granted will be canceled 13.7Benefits of Senior Executives Table 11 (AMF definition) Employment Agreement Supplemental Pension Plan Benefits or advantages due or likely to be due as a result of termination or change of office Benefits relating to a non-compete clause Yes No Yes No Yes No Yes No Bernard Gilly Chief Executive Officer Beginning of term: 2018 End of term: General Meeting which will be held on 2024 X X X(1) X(2) Michael Wyzga Chairman of the Board of Directors Beginning of term: 2018 End of term: 2024 X X X X Marie-Claude Holtz Deputy Chief Executive Officer Responsible Pharmacist Beginning of term: 2020 End of term: 2024 X X X X(3) (1) On February 14, 2013, our Board of Directors resolved that the Company may pay Mr. Gilly a termination payment equal to the last 12 months of his fixed and variable compensation and not capped except in the event of (1) dismissal by us for gross negligence or (2) resignation, other than resignation for health or family reasons. •Subject to the satisfaction of certain performance criteria, the Company may pay Mr. Gilly a termination payment equal to the last 12 months of his fixed and variable compensation, except in the event of (1) dismissal by us for gross negligence or (2) resignation, other than resignation for health or family reasons. The Board resolved that such termination payment shall not be paid in the case of a change in the duties performed by Mr. Gilly or in the event that he decides on his own initiative to leave the Company to perform new duties. (2) On March 9, 2017, our Board of Directors resolved that the Company may pay Mr. Bernard Gilly for a period of one year from the termination of his duties with the Company, a monthly payment of 40% of his total net monthly compensation excluding any bonuses in consideration of his undertaking not to engage in certain competitive activities for a period of one year from the termination of his duties. •The principle of the benefits of the senior executives during 2021 and the compensation policy for our senior executives for 2022 will be subject to a report that will be submitted to the Shareholders’ Meeting called to approve the consolidated financial statements for the fiscal year ended December 31, 2021. (3) The Employment Agreement of Ms. Holtz includes, for a period of one year from the termination of her duties with the Company, a monthly payment of 60% of her total net average monthly compensation during the last twelve months of duties in consideration of her undertaking not to engage in certain competitive activities for a period of one year from the termination of her duties. 13.8Equity ratio between the level of compensation of the Chairman and Chief Executive Officer and the compensation average and median of the Company’s employees This presentation was made in accordance with article L.22-10-9 I 6° and 7° C.com. It mentions the level of remuneration of the Chairman and CEO of the Company on the one hand, and on the other hand the average compensation and the median compensation of the employees (excluding the directors), as well that the evolution of these two ratios over the five most recent years. It is to be noted that Ms. Holtz does not receive any remuneration related to her Deputy Chief Executive Officer position. Therefore, the salary she receives related to her VP Quality position is taken into account in the calculation of the average and median compensation of the employees. 2016 2017 2018 2019 2020 2021 Bernard Gilly CEO Ratio with average compensation 10.5 9.8 5 8.1 9.6 9.9 Ratio with median compensation 16.4 18.4 8.3 12.4 19.8 23.6 Michaël Wyzga (1) Chairman of the Board Ratio with average compensation 1.2 1.1 1.3 1.5 1.3 0.6 Ratio with median compensation 1.9 2.0 2.2 2.4 2.7 1.5 (1) Mike Wyzga has been appointed Chairman of the Board on March 2016. Annual evolution of the remuneration of Chairman of the Board of Directors (N/N-1) Annual evolution of the remuneration of Chief Executive Officer (N/N-1) Annual evolution of the average compensation of the Company’s employees Annual evolution of the Company’s performance Annual evolution of equity ratios with CEO’s compensation Annual evolution of equity ratios with Chairman’s compensation / average compensation of the Company’s employees / median compensation of the Company’s employees / average compensation of the Company’s employees / median compensation of the Company’s employees 2016 N/A 85.90% -1.50% N/A 88.80% 36.10% N/a N/a 2017 -40.70% -35.50% -31.30% N/A -6.10% 12.30% -13.60% 3.30% 2018 -2.20% -59.70% -20.20% N/A -49.50% -54.90% 22.50% 9.40% 2019 9.90% 50.80% -7.50% N/A 63.00% 48.90% 18.80% 8.50% 2020 22.1% 71.0% 44.1% N/A 18.6% 60.0% -15.3% 14.2% 2021 -36.6% 40.8% 36.5% N/A 3.2% 19.4% -53.5% -46.2% The ratios have been calculated on the basis of fixed and variable compensation paid during the years mentioned, as well as free shares and warrants granted during the same periods and valued at their fair value at the date of grant. The figures include the information regarding the employees of GenSight Biologics S.A. only. The significant variations of both Chief Executive Officer’s compensation and average compensation of the Company’s employees year-on-year is mainly explained by the allocation of free shares, performance shares and share warrants during the fiscal year, and especially the share price on the date of attribution which is used for the calculation of the valuation of the free shares and the share warrants, whose fluctuations since our IPO have therefore had a significant impact on the total remuneration level. As mentioned in section 13.1.1.2, the performance shares are subject to an acquisition period, conditional on the presence and achievement of performance criteria linked to the strategy and development objectives of the Company. Main explanation regarding the evolution of the ratio: •2016: The Company completed our Initial Public Offering (IPO) on Euronext Paris. GenSight granted its first AGA plan in July when the stock price was €8. Mr. Gilly has been granted with 250,000 AGA. •2017: Mr. Gilly was granted with 200,000 AGA at a grant price of €5.12. In addition, his annual compensation increased from €250 K in 2016 to €365 K in 2017. •2018: Mr. Gilly was granted with 45,000 AGA at a grant price of €2.10. •2019: Mr. Gilly was granted with 220,000 AGA at a grant price of €1.80. •2020: Mr. Gilly was granted with 490,000 AGA at a grant price of €3.72. As of the Date of this Universal Registration Document, 220,000 AGA have been fully cancelled. The calculation of the 2020 ratios have been updated to reflect the cancellation of the 2020 free share plans. •2021: Mr. Gilly was granted with 400,000 AGA at a grant price of €8.87. We have considered in the calculation of the ratios only 50% of the valuation of the free shares granted in 2021 for the CEO as well as for the employees as 50% of the plans have been cancelled as of the Date of the Universal Registration Document. 13.9Compliance of Total Executive Director Compensation with the Recommendations of Middlenext Code Since the listing of our shares on Euronext Paris, we comply with the MiddleNext Code, as amended on September 2016, (See Section 14.4, “Statement relating to Corporate governance” of this Universal Registration Document for more information). The MiddleNext Code may be consulted on the Internet. We keep copies of such code available to the members of our governing bodies at all times. 13.10Amount of Provisions Made or Recorded by the Company for the Payment of Pensions, Retirement Plans or Other Benefits We have not provisioned any amounts for payments of pensions, retirements or other similar benefits to our directors. 14 BOARD PRACTICES 14.1Terms of Office of Members of the Corporate Bodies and Management Bodies The terms of office of the members of our Board of Directors and senior management can be found in Section 12.1, “Composition of Management and Supervisory Bodies” of this Universal Registration Document. 14.2Information on Service Contracts between Members of the Administrative and Management Bodies and the Company As of the date of this Universal Registration Document and to our knowledge, there are no service contracts between the members of the administrative, management or supervisory bodies and the issuer or any of its subsidiaries providing for benefits upon termination of employment. 14.3Committees of the Board of Directors Pursuant to the internal rules (règlement intérieur) of our Board of Directors, our Board of Directors may create committees charged with examining questions submitted to it by the Board or its Chairman. Since the listing of our shares on Euronext Paris, three such Board Committees have been created: an Audit Committee, a Compensation Committee and a Nominations Committee. The composition and duties of these Committees are described below. The composition and functioning of all of our Committees comply with all applicable requirements of the French Commercial Code. In accordance with French law, Committees of our Board of Directors only have an advisory role and can only make recommendations to our Board of Directors. As a result, decisions will be made by our Board of Directors taking into account the non-binding recommendations of the relevant Board Committee. In accordance with the MiddleNext Code, below is a table of the current composition of our Board of Directors and our Committees. Name and title of Board members Independent Board member Year of first nomination Audit Committee Compensation Committee Nominations Committee Michael Wyzga, Chairman of the Board of Directors Yes 2013 Chairman — Member Peter Goodfellow Yes 2014 — Member Chairman Simone Seiter Yes 2017 Member Chairman — Maritza McIntyre Yes 2019 — — — Sofinnova Partners (as represented by Cédric Moreau) No 2019 — Member — Elsy Boglioli Yes 2020 — — — Françoise de Craecker Yes 2021 — — Member Mr. Magni has resigned from the Board of Directors on April 24, 2019. On consideration for the subscription by Sofinnova Crossover I SLP for the capital increase of €8 million implemented in February 2019, Sofinnova Partners and one independant member proposed by Sofinnova, Maritza McIntyre have been appointed as directors by the Shareholders’ Meeting held on June 11, 2019. Bpifrance Participations has resigned from the Board of Directors on July 22, 2020 and has been replaced by Ms. Elsy Boglioli on September 22, 2020. Natalie Mount has resigned from the Board of Directors on April 29, 2021 and has been replaced by Ms. Françoise de Craecker on the same day. 14.3.1AUDIT COMMITTEE. Our Audit Committee reviews our internal accounting procedures, consults with and reviews the services provided by our Statutory Auditors and assists the Board of Directors in its oversight of our corporate accounting and financial reporting. 14.3.1.1Composition The Board of Directors has amended its internal rules on July 27, 2020 to provide that the Audit Committee is composed of at least two members. The Audit Committee is composed of at least two members including at least one who is particularly knowledgeable in finance and accounting and one who is independent, nominated by our Board of Directors further to an opinion from the Compensation Committee. The term of office of the Audit Committee members is renewable. The length of the term of members of the Audit Committee coincides with the length of their term as a member of the Board of Directors. The Chairman of the Audit Committee is appointed by the members of the Audit Committee for the length of his term of office as a committee member, from among the independent directors. Our Audit Committee is composed of Mr. Wyzga and Ms. Seiter. Mr. Wyzga is the Chairman of the Audit Committee. Mr. Wyzga and Ms. Seiter are independent members of the Board of Directors. 14.3.1.2Duties Under French law, the Audit Committee oversees matters related to the preparation and control of accounting and financial information. Our Board of Directors has specifically assigned the following duties to the Audit Committee: •monitoring the process for preparing financial information and making recommendations to guarantee its integrity; •ensuring the effectiveness of the internal control and risk management systems as well as of internal audit, with regard to the procedures relating to the preparation and processing of accounting and financial information, without infringing on its independence; •making recommendations to the Board of Directors on the Statutory Auditors proposed for nomination to general meetings for appointment as well as renewal; •monitoring the performance by the Statutory Auditors of their engagement; •ensuring the independence of the Statutory Auditors and take appropriate enforcement action, if necessary; •regularly reviewing the status of major disputes; •approving the provision of non-audit services; •reporting on a regular basis to the Board of Directors on the performance of its duties; and •in general, providing advice and making appropriate recommendations in connection with the above matters. The Audit Committee regularly reports to the Board of Directors on the performance of its tasks and the results of the statutory audit engagement, its contribution to the integrity of the financial information and the role that it played in this process. The Audit Committee must inform the Board of Directors without delay of any difficulty it encounters. The Board of Directors or the Chairman of the Board of Directors may also submit any other issue to the Audit Committee for its opinion. In addition, the Audit Committee may decide to consider any issue and give its opinion thereon. 14.3.1.3Activities of the Committee during the last fiscal year The Audit Committee met three times in 2021. The main topics discussed by the Committee, and on which it made recommendations to the Board of Directors, were the review and approval of 2020 full year financial statements, 2021 half year consolidated financial statements, and 2022 budget. 14.3.2COMPENSATION COMMITTEE. Our Compensation Committee assists the Board of Directors in reviewing and making recommendations to the Board of Directors with respect to the compensation of our executive officers and directors. 14.3.2.1Composition The Compensation Committee is composed of at least three members, nominated by our Board of Directors, among which at least one will be chosen from the independent members of the Board of Directors. The Compensation Committee may not include any senior executive or officer of the Company. The term of office of the Compensation Committee members is renewable. The length of the term of members of the Compensation Committee coincides with the length of their term as a member of the Board of Directors. Our Compensation Committee is composed of Dr. Seiter, Dr. Goodfellow and Sofinnova Partners SAS represented by Mr. Moreau. Dr. Seiter is the chairman of the Compensation Committee. None of the members of the Compensation Committee has at any time during the prior three years been one of our officers or employees. None of our executive officers currently serves, or in the past fiscal year has served, as a member of the Board of Directors or Compensation Committee of any entity that has one or more executive officers serving on our Board or Compensation Committee. For a description of any transactions between us and members of the Compensation Committee and affiliates of such members, please see Section 17, “Related Party Transactions” of this Universal Registration Document. 14.3.2.2Duties The principal duties and responsibilities of our Compensation Committee include: •reviewing the main objectives proposed by executive management with respect to compensation of our managers who are not corporate officers, including free share plans and share subscription or purchase options; •reviewing the compensation of our managers who are not corporate officers, including free share plans and share subscription or purchase options, retirement and insurance plans and benefits in kind; •submitting recommendations and proposals to the Board of Directors concerning: —compensation, retirement, insurance and benefit plans, non-cash benefits, and other financial rights, including severance pay, of executive officers (mandataires sociaux). The Committee proposes compensation amounts and structures, in particular the rules for calculating the variable component of compensation, taking into account our strategies, objectives and performance, as well as market practices; and —free share plans, share subscription or stock options, and any other similar incentive plan, in particular benefits granted to specific corporate officers who are eligible for such plans; •reviewing the total amount of directors’ fees and the method for distributing them among the directors, as well as the requirements for obtaining reimbursement of expenses that directors of the Board may incur; •preparing and submitting to the Board of Directors any reports that may be required by the internal rules; •making any other recommendation concerning compensation that may be requested of it by the Board of Directors; and •in general, the Compensation Committee provides advice and makes appropriate recommendations in connection with the above matters. The Board of Directors or the Chairman of the Board of Directors may also submit any other issue to the Compensation Committee for its opinion. In addition, the Compensation Committee may decide to consider any issue and give its opinion thereon. 14.3.2.3Activities of the Committee during the last fiscal year The Compensation Committee met five times in 2021. The main topics discussed by the Committee, and on which it made recommendations to the Board of Directors, were the grant of share options (BSA) to independent directors and consultants, free shares (AGA) and stock options (SO) to employees and senior executives, review of corporate objectives achievement for 2021 and the related variable compensation for officers. 14.3.3NOMINATIONS COMMITTEE. Our Nominations Committee makes proposals to the Board of Directors relating to the appointment or renewal of the offices of directors submitted to the general meeting or relating to the cooptation of directors. 14.3.3.1Composition The Nominations Committee is composed of at least three members, nominated by our Board of Directors, among which at least one is chosen from the independent members of the Board of Directors. The length of the term of members of the Nominations Committee coincides with the length of their term as member of the Board of Directors. The term of office of the Nominations Committee members is renewable. As of the date of this Universal Registration Document, we have a Nominations Committee composed of Dr. Goodfellow, Mr. Wyzga and Ms. de Craecker. Dr. Goodfellow is the chairman of the Nominations Committee. 14.3.3.2Duties The principal duties and responsibilities of our Nominations Committee include: •making all proposals to the Board of Directors related to the identification of candidates for the post of director, in particular both within the scope of the Company’s obligation to comply with the provisions of Article L.225-18-1 of the French Commercial Code and in connection with the identification of independent directors and more generally in connection with the changes in the composition of the Board; •assisting the Board of Directors in connection with the assessment of the independence criteria making it possible to classify a director as an independent director in the light of the code of corporate governance chosen by the Company; •assisting the Board of Directors in setting up a succession plan for the executive officers, in particular, in the event of an unanticipated vacancy; •assisting the Board of Directors in a review of the insurance coverage of the corporate officers’ civil liabilities; and •in general, making any proposal to the Board of Directors concerning the appointment or renewal of the offices of directors submitted to the general meeting of shareholders or concerning the cooptation of directors. The Board of Directors or the Chairman of the Board of Directors may also decide to submit to it for its opinion any issue in relation with the appointment of directors and, more generally, the composition of the Board of Directors. Likewise, the Nominations Committee may decide to look at any issue and express any opinions. 14.3.3.3Activities of the Committee during the last fiscal year The Nominations Committee met twice in 2021, as part of the nomination of Ms. Françoise de Craecker as a new Board member and as part of the examination of the status of the independent directors. 14.4Statement Relating to Corporate Governance 14.4.1CORPORATE GOVERNANCE. Regarding the Code of Corporate Governance, our Company refers to the MiddleNext Code of Corporate Governance for Small and Medium-Sized Companies as amended in September 2021, available on the MiddleNext website (www.middlenext.com), hereinafter the Code of Practice. The Board of Directors acknowledges that it is familiar with the information presented under the “due diligence points” (Points de vigilance) section of this Code of Practice. The Board of Directors considers that its organization and the procedures it has implemented allow it to satisfactorily address these due diligence points and all the Code of Practice’s recommendations. Pursuant to the MiddleNext Code, three powers are involved in the governance of a company: •“sovereign power”, expressed in particular at the general meeting of shareholders; •“supervisory, advisory and control power”: the directors; and •“executive power”: the managers. For the fiscal year ended December 31, 2021, in addition to the information provided in this section, the status of application of the guidelines in the MiddleNext Code is as follows: Recommendations of the MiddleNext Code Adopted Will be adopted I. The sovereign body This Code does not provide any recommendation intended for the shareholders. II. The supervisory body R 1: Ethics for the members of the Board of Directors X R 2: Conflicts of interest X R 3: Composition of the Board – Presence of independent members of the Board X R 4: Information to the members of the Board X R 5 : Education of the members of the Board X R 6: Organization of the meetings of the Board and Committees X R 7: Creation of Committees X R 8: Implementation of a CSR Committee X R 9: Implementation of an internal regulation of the Board X R 10: Election of each director X R 11: Term of office of the members of the Board X R 12: Compensation of directors X R 13: Implementation of an assessment of the work of the Board X R 14: Relationship with the “shareholders” X III. The executive body R 15: Equity and Diversity Policy within the Company X R 16: Definition and transparency of the compensation of senior executives X R 17: Succession plan of senior executives X R 18: Combined employment / corporate office contracts X R 19: Severance compensation X R 20: Supplementary pension schemes X R 21: Stock options and allocation of bonus shares X R 22: Review of points of vigilance X 14.4.2CODE OF ETHICS (CODE DE DÉONTOLOGIE). Each director shall refrain from engaging in any transaction involving our shares when such director, by virtue of his or her position within the Company, is in possession of material non-public information. Sale and purchase transactions involving our securities or derivatives carried out by our corporate executives and directors whether on the open market or in off-market block trading, be it directly or indirectly, are forbidden during the period of: •thirty (30) calendar days preceding the day of publication of our half-yearly and annual financial statements; and •fifteen (15) calendar days preceding the day of publication of our quarterly information if applicable. Persons subject to these black-out periods are not permitted to trade in our securities until the day after the information has been released. In any case, the Board of Directors can decide, in the event of a material fact that could significantly affects the market price of our securities, to set a period during which sale and purchase transactions involving our securities or derivatives carried out by our corporate executives and directors whether on or off-market, be it directly or indirectly, will be forbidden. 14.5Operating Principals of the Board of Directors 14.5.1CONDITIONS OF PREPARATION FOR BOARD’S ACTIVITIES. To allow the Board members to usefully prepare meetings, the Chairman seeks to provide all necessary information or documents in advance. Thus, the draft of the annual consolidated financial statements was sent to the directors several days before the Board meeting to approve them was held. Whenever a Board member so requests, the Chairman shall send all possible additional information and documents requested. 14.5.2CONTENT OF BOARD MEETINGS. Meetings are convened in writing at least five business days in advance. Meetings are held at the corporate headquarters. The Board of Directors met 8 times in 2021. During this period, members’ attendance at Board meetings was as follows: •63% of directors at the meeting on February 15, 2021; •75% of directors at the meeting on February 25, 2021; •100% of directors at the meeting on March 9, 2021; •100% of directors at the meeting on April 29, 2021; •100% of directors at the meeting on July 28, 2021; •63% of directors at the meeting on September 21, 2021; •75% of directors at the meeting on October 21, 2021; •100% of directors at the meeting on December 14, 2021. Average attendance was thus 84% during the period. The Statutory Auditors were convened to Audit Committee meetings in preparation for meetings of the Board of Directors convened to approve the half year and annual consolidated financial statements. They effectively attended them. 14.5.3RULES OF PROCEDURE OF THE BOARD OF DIRECTORS. Internal rules of the Board of Directors may be consulted on our website (www.gensight-biologics.com). In accordance with the MiddleNext Code, our internal rules of the Board of Directors with at least the following 8 headings: •role of the Board of Directors and, where applicable, transactions subject to prior authorization of the Board of Directors; •composition of the Board of Directors/criteria of independence of its members; •definition of the role of specialized committees, if any; •duties of the members of the Board of Directors (professional responsibility: loyalty, non-competition, disclosure of conflicts of interest and duty of abstention, ethics, confidentiality, etc.); •operation of the Board of Directors (frequency, convening, information to members, self-assessment, use of videoconferencing and telecommunications facilities, etc.) and, when there are committees, specify their missions; •terms and conditions of protection for corporate officers: civil liability insurance for corporate officers; •rules for determining directors’ compensation; •the question of the succession plan for the “manager” and key persons. 14.5.4TOPICS DISCUSSED DURING BOARD MEETINGS AND ACTIVITY REPORT. During fiscal year 2021, the Board of Directors specifically discussed the following subjects: Financial: Preparation of the annual financial statements and half-year consolidated financial statements, examination of draft management documents, and review and approval of the 2022 budget and long-term strategic plan; review and analysis of the financing strategy, completion of a private placement. Compensation: Examination and modification of the compensation of the chairman and chief executive officer, grant of free shares to all employees, grant of share purchase warrants to independent directors, and certain consultants, grant of stock options to one employee, review of corporate objectives and grant of 2021 performance bonuses, modification of the 2020 and 2020-4 Performance Share Award Plans implementation and review of 2021 corporate objectives, review of compensation for independent directors and officers; Strategy: Business updates related to the Covid situation and the U.S. Defense Production Act, Review of the medium- and long-term strategic plan; update on Business Development initiatives; preparation of the commercialization, authorization of a regulated agreement. Governance: Decision to maintain the Board’s current operating method, renewal of the term of Chairman of the Board of Directors, review of the status of independent Board members, appointment of a new board member, Board of Directors’ self assessment. 14.5.5Procedure implemented to review the ordinary agreements signed with related parties. Background and scope Following the enactment of French Law 2019-486 of May 22, 2019, known as Loi PACTE the Company’s Supervisory Board created a procedure to regularly assess whether the agreements with related parties which relate to ordinary transactions and have been entered into upon customary terms & conditions (Ordinary Agreements) meet the legal requirements to qualify as such. This procedure applies to all members of the Legal and Finance Departments within the Group, as well as to the members of the Management Board and Supervisory Board. Description and implementation of the procedure Any member of the Legal or Finance Departments who is aware of an agreement, or a draft agreement, that may fall within the scope of Articles L.225-86 et seq. of the French Commercial Code shall report thereon to the General Counsel without delay. The General Counsel, or any qualified person designated by the General Counsel, determines, in accordance with the applicable legal criteria, whether the agreement in question falls within the regime of regulated agreements or constitutes an Ordinary Agreement. If the General Counsel or his designee determines that the agreement falls within the scope of the Ordinary Agreements, he/she shall record the reasons accurately and in writing. The explanatory memorandum will be kept in the archives of the Legal Department. It may be provided to the Statutory Auditors upon request. At least once per calendar year, the Management Board will provide the Audit and Corporate Governance Committee and the Supervisory Board with a summary of the Ordinary Agreements entered into or performed during the previous fiscal year, together with the reasons justifying their categorization as Ordinary Agreements. This will be followed by a discussion of the Supervisory Board, during which the Board will check that the agreements so reported do indeed meet the criteria required by law to qualify as Ordinary Agreements. 14.5.6SELF-EVALUATION OF THE Board of Directors. In accordance with the recommendation of the Code of Practice, at its meeting of March 9, 2022, the Board of Directors undertook a review, followed by an evaluation, of its work and activities, and that of its special committees, as described in Section 14.3 of this Universal Registration Document. This review, articulated around an open discussion, highlighted positive findings for the Board of Directors as to its operations, information and the quality of its discussions. 15 EMPLOYEES 15.1Human Resources Management 15.1.1NUMBER AND BREAKDOWN OF EMPLOYEES. As of December 31, 2021, we had 38 employees, all were full-time, 11 of whom hold Ph.D., Pharm.D. or M.D. degrees, 25 of whom are engaged in preclinical development and regulatory affairs, clinical development, research, engineering and production, 5 of whom are engaged in management and administration and 8 of whom are engaged in sales and marketing. As of December 31, 2021, 33 of our employees were located in France, 3 were located in the United Kingdom, 1 was located in Germany and 1 in the United States. The table below shows the changes in the number of our employees over the last two years. 2020 2021 As of January 1 25 25 New hires 8 17 Departures(1) 6 4 Dismissals(2) 2 - As of December 31 25 38 (1) This category includes both voluntary and involuntary departures. (2) Individual dismissals (for cause). 15.1.2HUMAN RESOURCES POLICY. Our human resources management is organized around the following principles: We apply the “Convention collective nationale des ingénieurs et cadres de la métallurgie”. There are no company-wide agreements, other than our internal rules and regulations. Standard employment contracts contain clauses that deal with inventions and copyright. As from the end of their employment contracts, our management employees are bound by a one-year covenant not to compete and a two-year obligation not to solicit our customers. With respect to remuneration policy, all employees hired pursuant to permanent employment contracts receive a variable remuneration in addition to their fixed remuneration, which is a percentage ranging between 10% and 40% of their fixed salary. 15.1.3CORPORATE SOCIAL RESPONSIBILITY. Employment As at December 31, 2021, GenSight Biologics personnel totaled 38, distributed by contract type, sex and age range as follows: 2020 2021 Headcount as at December 31 25 38 of which permanent 25 38 of which fixed-term – – of which women 16 22 of which men 9 16 < 35 years old 6 11 > 35 years old 19 27 Employee movements during the fiscal year ended December 31, 2021 (hirings and departures) may be broken down as follows: 2020 2021 Number of hirings (1) 8 17 of which permanent 8 17 of which fixed-term _ _ Number of departures (2) 8 4 (1) These hirings are related to the activity growth of the Society as well as replacements. (2) These departures correspond to both voluntary departures and dismissals. Compensation The payroll expense for the fiscal year ended December 31, 2021 was the following: in thousands of euros 2020 2021 Payroll expense 6,664 6,878 Employees under a permanent employment contract are entitled to fixed salary and a variable compensation in the form of a bonus scheme based on both corporate and individual objectives and ranging from 10% to 40% of the fixed amount. They are eligible to receive employee share warrants (bons de souscription de parts de créateur d’entreprise or “BCEs”) or free shares (attributions gratuites d’actions, or AGA). Organization of work As at December 31, 2021, out of 38 employees, 9 were senior managers (“cadre dirigeant”), 29 were managers (“cadre”). Managers worked 37 hours weekly and were compensated by 12 days of additional holiday (“Réduction du Temps de Travail”). As at December 31, 2021, 100% of employees were full-time. The table below presents the absenteeism rate for the years 2020 and 2021: 2020 2021 Absenteeism rate 1.01% 0.78% Corporate dialogue Given the size of the Company and the number of employees, corporate dialogue is a natural component of the working environment at GenSight Biologics. Personnel representatives elections took place on May 13, 2019. The Company acknowledged the absence of a candidate. Health & Safety In compliance with regulations, GenSight Biologics has carried out in its “Document Unique d’Entreprise” a risk analysis of its activities and proposed an action plan to mitigate these risks. No case of work-related disease was declared in 2021. No accident at work was declared in 2021. GenSight Biologics considers that it does not expose its employees to any specific risk. Training The Company aims to provide its employees with training opportunities, to develop general skills (management and languages, etc.) as well as technical skills specific to each position. 2020 2021 Number of training hours taken 81 210 Diversity GenSight Biologics gives special attention to the diversity of its teams. The distribution by sex, as presented in the table below, is a meaningful measure of this commitment: 2020 2021 Percentage of female employees 64% 58% The proportion of women within the Management Committee was 58% in 2021, stable versus 2020. GenSight Biologics does not employ any disabled persons, and will pay an annual financial contribution of €15,342 to the Agefiph, the French public agency that promotes integration into the workplace of disabled people. 87% of employees GenSight Biologics are based in France, 7% are based in United Kingdom, 3% in Germany and 3% in the United States. The Company complies with all applicable regulations. Furthermore, France has ratified the eight fundamental conventions of the ILO. The ILO has qualified as “fundamental agreements” the conventions concerning the following principles and fundamental labor rights: freedom to unionize and effective recognition of the right of collective bargaining, elimination of forced or compulsory work, effective abolition of child labor and elimination of discrimination in the area of employment and profession. GenSight Biologics shares these principles, which are implemented in the Company’s social relations, its policy regarding recruitment and equality of opportunity. 15.2Shareholdings and stock options See Section 13, “Compensation and Benefits” of this Universal Registration Document. 15.3Employee arrangements See Section 13, “Compensation and Benefits” of this Universal Registration Document. 16 MAJOR SHAREHOLDERS 16.1Allocation of share capital 16.1.1SHAREHOLDERS. As of the date of this Universal Registration Document, we are not controlled by any majority shareholder and our share capital is equal to €1,158,389.78 divided into 46,335,591 fully authorized, subscribed and paid-up ordinary shares with a nominal value of €0.025. The table below sets forth the non-diluted share capital structure, based on available information as of the date of this Universal Registration Document. Shareholders Number of shares/voting rights % of share capital/voting rights (non-diluted) 5% Shareholders: Sofinnova 7,129,233 15.39% Amiral Gestion 3,219,500 6.95% BPIFrance Investissement SAS 2,399,681 5.18% Directors and Executive Officers 1,692,600 3.65% Employee Shareholding 192,700 0.42% Other Shareholders (total) 31,701,877 68.42% TOTAL 46,335,591 100.00% The table below sets forth our fully-diluted share capital structure, based on available information as of the date of this Universal Registration Document. Shareholders Number of shares/voting rights % of share capital/voting rights (fully diluted) 5% Shareholders: Sofinnova 7,129,233 14.56% Amiral Gestion 3,219,500 6.58% BPIFrance Investissement SAS 2,399,681 4.90% Directors and Executive Officers 2,806,600 5.73% Employee Shareholding 423,200 0.86% Other Shareholders (total) 32,973,818 67.37% TOTAL 48,952,032 100.00% 16.1.2HISTORY OF ALLOCATION OF SHARE CAPITAL. Shareholders As of December 31 2017 As of December 31 2018 As of December 31 2019 As of December 31 2020 As of December 31 2021 Number of shares/voting rights post-reverse stock split % of share capital/voting rights Number of shares/voting rights post-reverse stock split % of share capital/voting rights Number of shares/voting rights post-reverse stock split % of share capital/voting rights Number of shares/voting rights post-reverse stock split % of share capital/voting rights Number of shares/voting rights post-reverse stock split % of share capital/voting rights Founders 2,095,086 8.65% 2,320,086 9.35% 2,420,086 7.37% 2,416,443 5.91% 2,678,087 5.78% Sofinnova Partners – – – – 5,610,044 17.09% 6,681,472 16.35% 7,129,233 15.40% Amiral Gestion 25,000 <5% 25,000 <5% 25,000 <5% 25,000 <5% 3,219,500 6.95% BPIFrance Investissement SAS 2,975,666 12.28% 2,975,666 12.00% 2,975,666 9.06% 3,137,016 7.67% 2,399,681 5.18% 3SBio – – – – 2,110,595 6.43% 2,110,595 5.16% 2,110,595 <5% Tangible Investment Management – – – – – – – – 1,854,856 <5% Arix – – – – – – 601,816 <5% 1,350,770 <5% Abingworth Bioventures VI LP 3,139,973 12.96% 3,139,973 12.66% 1,402,588 <5% 1,402,588 <5% 1,308,521 <5% Fidelity 1,628,865 6.72% 1,060,344 <5% 1,060,344 <5% 1,060,344 <5% 65,284 <5% Novartis Pharma AG 3,521,774 14.53% 3,521,774 14.20% 1,390,487 <5% 1,390,487 <5% – – Versant 3,280,381 13.54% 3,280,381 13.23% 3,280,381 9.99% 1,576,428 <5% – – Vitavest S.à.r.l 1,339,706 5.53% 1,339,706 5.40% 1,339,706 <5% – – – – Other investors 6,227,772 25.70% 7,140,043 28.79% 11,212,465 34.16% 20,473,776 50.09% 24,184,064 52.23% Total 24,234,223 100.00% 24,802,973 100.00% 32,827,362 100.00% 40,875,965 100.00% 46,300,591 100.00% During the last four years, the following events have changed the number and classes of the issued and our outstanding shares: •In 2016: —On July 13, 2016, we completed our Initial Public Offering (IPO) on Euronext Paris, raising €40.0 million, and issued 5,000,000 ordinary shares. —On August 10, 2016, we partly exercised the overallotment option as part of our IPO on Euronext Paris, raising an additional €5.2 million, and issued 655,859 ordinary shares. —These figures give effect to the 5-for-2 reverse split of our outstanding shares approved by the general shareholders’ meeting on August 17, 2015, which became effective on September 3, 2015, 15 days after publication of the notice of the split in the French Bulletin des Annonces Légales Obligatoires, or BALO, pursuant to French law. •In 2017: —On June 27, 2017, we issued 3,750,000 ordinary shares in a private placement on Euronext Paris for which we received net proceeds of €20,724 K. •In 2019: —On February 25, 2019, we issued 3,921,568 ordinary shares in a private placement subscribed entirely by Sofinnova Crossover I SLP for which we received net proceeds of €7,906 K. —On December 19, 2019, we issued 3,799,071 new shares with a nominal value of €0.025 each in a private placement subscribed entirely by Sofinnova Crossover I SLP and 3SBio for which we received net proceeds of €8,276 K. •In 2020: —On October 22, 2020, the Company has issued 5,954,650 new ordinary shares with a nominal value of €0.025 each, for total gross proceeds of approximately €25 million by means of an accelerated bookbuilding process to the benefit of categories of persons. —On December 10, 2020, GenSight received the notification by Kreos of the conversion of 50% of the convertible bonds of tranches A and B (at a price of €2.245 per share), the conversion of 50% of the additional convertible bonds of tranche B (at a price of €2.574 per share) and the exercise of all share warrants of tranches A and B (at a price of €2.245 per share), representing a total issuance of 1,182,953 new ordinary shares. •In 2021: —On March 26, 2021, GenSight has issued 4,477,612 new ordinary shares with a nominal value of €0.025 each, for total gross proceeds of approximately €30 million by means of an accelerated bookbuilding process to the benefit of categories of persons. 16.2Shareholders’ Voting Rights Each of our share, either ordinary or preferred, entitles the holder to one vote. Our bylaws, by express derogation to Article L.225-123 paragraph 3 of the French Commercial Code, do not grant double voting rights to our shares. 16.3Control structure As of the date of this Universal Registration Document, no shareholder has exclusive control over the Company. 16.4Agreement likely to a change of control To our knowledge, there are no provisions either in the Company’s bylaws or in any internal charter or internal rules that could have the effect of delaying, postponing or preventing a change of control of the Company. 17 RELATED PARTY TRANSACTIONS We comply with French law regarding approval of transactions with related parties. Since January 1, 2015, we have engaged in the following transactions with our directors, executive officers and holders of more than 5% of our outstanding voting securities and our affiliates, which we refer to as our related parties. 17.1Agreements with the Company’s Major Shareholders 17.1.1SHAREHOLDERS’ AGREEMENT. In connection with our initial public offering on Euronext Paris, Bpifrance Participations, Mr. José Sahel, Mr. Bernard Gilly, Novartis Pharma AG, Abingworth Bioventures VI L.P., Versant Venture Capital IV, L.P., Versant Side Fund IV, L.P., Vitavest S.à.r.l. and Fonds Biothérapies Innovantes et Maladies Rares, several of our major shareholders, have entered into a shareholders’ agreement to organize their relationship as shareholders of our Company. Under this shareholders’ agreement, the parties have also agreed to vote in a certain way with respect to (i) the election of a director and an observer proposed by Bpifrance Large Venture and (ii) the modification of the internal rules in order to grant the Board of Directors the power to approve strategic investments and to increase its information rights. 17.1.2LICENSE AGREEMENT WITH NOVARTIS PHARMA AG. On February 5, 2013, we entered into a license agreement with Novartis Pharma AG, or Novartis, pursuant to which we have an exclusive in-license to research, develop, make, use, sell, offer for sale or otherwise distribute, import and export any products within the scope of the patents and patent applications under two patent families for all ophthalmologic uses. This license agreement relates to our GS020 product candidate, which is not currently part of our product and development pipeline. As the licensee, we may grant and authorize sublicenses within the scope of the license granted by Novartis, as the licensor, provided that we notify Novartis for prior approval, which shall only be withheld by Novartis for duly justified ethical reasons. In consideration for the rights granted by Novartis to us, we paid Novartis an upfront license fee through the issuance of 670,588 (corresponding to 268,235 after taking into account the reverse share split on September 3, 2015) new ordinary shares, corresponding to 15% of our share capital. The subscription of such shares was made by offsetting the upfront license fee claim against Novartis. In compliance with IAS 38, the rights acquired have been recorded as intangible assets at the fair value of the ordinary shares issued in payment. The fair value of the 670,588 ordinary shares is €0.41 per ordinary share. For more information, please see Note 22 to our consolidated financial statements as of December 31, 2021 and Section 5.2.3, “Our Second Product Candidate: GS030 for the Treatment of Photoreceptor Degeneration” of this Universal Registration Document. 17.2Transactions with Key Management Persons 17.2.1FOUNDER NON-COMPETE UNDERTAKING. In March 2017, the Board of Directors authorized our entry into an agreement with Mr. Gilly pursuant to which Mr. Gilly would agree not to engage in certain competitive activities for a period of one year from his departure from the Company in the event that he terminates his duties with us. For a period of one year from the termination of this undertaking, and unless we elect to waive these restrictions, we will be required to make a monthly payment of 40% of Mr. Gilly’s last total net monthly compensation excluding any bonuses for a period of one year following his termination. 17.2.2LEASE AGREEMENT WITH PASSAGE DE L’INNOVATION. On January 1, 2015, we entered into a sublease agreement for our new premises with Passage de l’Innovation, amended on October 1, 2015, January 1, 2016, April 25, 2017, July 1, 2018, October 1, 2018, November 1, 2019, October 1, 2021 and January 1, 2022. Pursuant to this last amendment, we will have to pay €822 K excluding taxes, on an annual basis, comprised of €489 K for rent, €29 K for rental charges and up to €304 K for other services provided by the lessor. The main space’s lease ends in December 2023, however, our engagement with smaller surfaces ends in 2027. In 2021 we paid an amount of €495 K, comprised of €293 K for rent, €16 K for rental charges and €186 K for other services (including reception desk, maintenance, cleaning services, IT management and services, access to shared areas such as equipped meeting rooms and a lunch area). The President of the Passage de l’Innovation and one of its shareholders was Bernard Gilly, our Chief Executive Officer, until he resigned from this position in Passage de l’Innovation on June 30, 2016. Mr. Gilly has retained a shareholding interest in this company until June 26, 2021. The amounts the Passage de l’Innovation has charged, and currently charges us are at fair market value. 17.2.3SERVICES AGREEMENT WITH PASSAGE DE L’INNOVATION. The Group entered into a services contract with Passage de l’Innovation in connection with human resources, legal and intellectual property services on May 1, 2017, which was amended on December 15, 2017, January 31, 2018, December 18, 2018 and January 1, 2021. According to the last amendment terms and conditions, the annual cost is fixed at €244 K and each party can terminate the contract after a six-month notice period. In 2021 we paid an amount of €247K for services related to general administration, human resources, legal and intellectual property, Corporate and Business Development services. The increase of the annual expenses included in the last amendment is particularly related to the Intellectual Property costs. 17.2.4EMPLOYMENT ARRANGEMENTS. Bernard Gilly Mr. Gilly, our Chief Executive Officer, does not have an employment agreement with us. Mr. Gilly’s compensation is determined by our Board of Directors upon recommendation of the Compensation Committee. On February 14, 2013, our Board of Directors resolved that we may pay Dr. Gilly a termination payment equal to the last 12 months of his fixed and variable compensation not capped except in the event of (1) dismissal by us for gross negligence or (2) resignation, other than resignation for health or family reasons. On March 9, 2017, our Board of Directors resolved to replace this termination payment by a termination payment satisfying the requirements under Article L.225-42-1 of the French Commercial Code. Consequently, subject to the satisfaction of certain performance criteria, the Company may pay Mr. Gilly a termination payment equal to the last 12 months of his fixed and variable compensation, except in the event of (1) dismissal by us for gross negligence or (2) resignation, other than resignation for health or family reasons. The Board of Directors resolved that such termination payment shall not be paid in the case of a change in the duties performed by Mr. Gilly or in the event that he decides on his own initiative to leave the Company to perform new duties. On March 9, 2017, our Board of Directors resolved that we may pay to Mr. Gilly for a period of one year from the termination of his duties, a monthly payment of 40% of his total net monthly compensation excluding any bonuses in consideration of his undertaking not to engage in certain competitive activities for a period of one year from the termination of his duties. Pursuant to the Sapin 2 Law, the terms of Bernard Gilly’s employment arrangement must be approved by the Shareholders’ Meeting which will be held on May 25, 2022. Marie-Claude Holtz Marie-Claude Holtz has been our Deputy Chief Executive Officer and our Responsible Pharmacist since April 29, 2020; and our VP Quality since June 1, 2020. The Company has entered into an employment agreement with Mrs. Holtz which covers her VP Quality duties. This agreement has standard terms relating to base salary, bonuses, equity grants, termination and restrictions on competitive activities. This agreement has not been approved by the Board of Directors before its conclusion. Mrs. Holtz does not receive any remuneration related to her Deputy Chief Executive Officer position. Employment Agreements with Key Management Persons We have entered into employment agreements with Thomas Gidoin, Magali Taiël and Sissel Rodahl. These agreements have standard terms relating to base salary, bonuses, equity grants, termination and restrictions on competitive activities. 17.3Regulated Agreements Agreements entered into between a corporate officer or a shareholder holding more than 10% of the Company’s voting rights, and another corporation controlled by the Company within the meaning of Article L.233-3 of the French Commercial Code (excluding agreements which relate to ordinary transactions and have been entered into upon customary terms & conditions). Agreement concluded between the Company and BrainEver On October 1, 2021, the Company concluded an Agreement with BrainEver, of which Mr. Bernard Gilly, director of the Company and Chief Executive Officer, is Chairman. The Company and BrainEver entered into a handover agreement concerning Ms. Caroline Denot, an employee of BrainEver, for a period of 9 months, from October 1, 2021, at 80% of her time — with the latter continuing to work for the company BrainEver at a rate of 20% of its time — at a total cost over the relevant period of €87,489 including social security charges for the Company. He indicated that this provision will enable the Company to have additional competence in carrying out an assessment of the appropriateness and preparation of pre-clinical work concerning the use of MTS technology in a new program. This regulated agreement was authorized by the Board of Directors on September 21, 2021. Mr. Bernard Gilly did not take part in the deliberations or the vote in accordance with the provisions of Article L.225-40 of the French Commercial Code. 17.4Statutory Auditors’ Special Report on regulated agreements Shareholders’ Meeting held to approve the financial statements for the year ended December 31, 2021 This is a free translation into English of the Statutory Auditors’ report on regulated agreements with third parties that is issued in the French language and is provided solely for the convenience of English speaking readers. This report on regulated agreements should be read in conjunction, and construed in accordance with, French law and professional auditing standards applicable in France. It should be understood that the agreements reported on are only those provided by the French Commercial Code (Code de commerce) and that the report does not apply to those related party transactions described in IAS 24 or other equivalent accounting standards. To the GENSIGHT BIOLOGICS S.A. Shareholders’ Meeting, In our capacity as Statutory Auditors of your Company, we hereby report on regulated agreements. We are required to inform you, based on information provided to us, of the characteristics and principal terms and conditions as well as the reasons justifying the interest for your Company of those agreements of which we have been informed or which we discovered at the time of our engagement, without expressing an opinion on their usefulness and appropriateness or identifying such other agreements, if any. It is your responsibility, pursuant to article R. 225-31 of the French commercial Code (Code de commerce), to assess the interest involved in respect of the conclusion of these agreements prior to their approval. Furthermore, we are required, where applicable, to inform you in accordance with article R. 225-31 of the French Commercial Code (Code de commerce) relating to the performance, during the past fiscal year, of the agreements already approved by the Annual Shareholders’ Meeting. We performed the procedures that we considered necessary with regard to the professional guidelines of the French National Institute of Statutory Auditors (Compagnie Nationale des Commissaires aux Comptes) applicable to this engagement. 1 AGREEMENTS SUBMITTED TO THE APPROVAL OF THE ANNUAL SHAREHOLDERS’ MEETING 1.1 Agreements authorized and concluded during the year In accordance with article L. 225-40 of the French commercial code (Code de commerce), we have been informed of the following agreements previously authorized by the Board of Directors. Nature and purpose: On October 1st, 2021, the Company concluded an Agreement concerning an employee of BrainEver, of which Mr. Bernard GILLY, Director of the Company and Chief Executive Officer, is the Chairman. With: the company BrainEver S.A.S, of which Mr. Bernard GILLY is the Chairman. Person concerned: Mr. Bernard GILLY, Director and Chief Executive Officer of the Company, and Chairman of BrainEver S.A.S. which entered into a handover agreement concerning an employee of BrainEver. Terms: The handover agreement relates to Ms. Caroline DENOT, an employee of BrainEver, for a period of 9 months, from October 1st, 2021, at 80% of her time at a total cost over the relevant period of €87,489 including social security charges for the Company. The total cost of the employee’ handover for the year ended December 31st, 2021 amounts to €29,166. Reasons justifying the interest of this agreement for the Company: The handover agreement will enable the Company to have additional competence in carrying out an assessment of the appropriateness and preparation of pre-clinical work concerning the use of MTS technology in a new program, without having to go through a recruitment process, involving a delay in its realization and additional costs. This agreement was previously authorized by the Board of Directors on September 21st, 2021. 2 AGREEMENTS PREVIOUSLY APPROVED BY THE SHAREHOLDERS’ MEETING 2.1 Agreements previously authorized remained in effect during the fiscal year under review In accordance with Article R. 225‑30 of the French Commercial Code (Code de commerce), we have been notified that the implementation of the following agreements, which were approved at a Shareholders’ Meeting in a prior fiscal year, remained in effect during the fiscal year under review. Nature and purpose: The Company has entered into a compensation agreement with Mrs. HOLTZ on June 1st, 2020, relating to her Vice-President, Quality position. The agreement initially reached was 80% part-time and was increased to 100% from August 1st, 2020. Person concerned: Mrs. Marie-Claude HOLTZ, appointed Deputy Chief Executive Director and Chief Pharmacist by the Board of Directors on April 29, 2020, and Quality Vice-President on June 1st, 2020. Terms: Ms. HOLTZ, as Quality Vice-President, would receive a gross annual fixed compensation (full-time) of €125,000, plus a bonus of up to 30% of its gross annual fixed compensation depending on the achievement of individual performance objectives set by the Chief Executive Officer (30%) and corporate objectives (70%) set by the Board of Directors, on the proposal of the Remuneration Committee. Compensation granted for the fiscal year ending December 31st, 2021 amount to €147,074. Terms Reasons justifying the interest of this agreement for the Company: Ms. HOLTZ does not receive any remuneration related to her Deputy Chief Executive Officer position. By entering into a compensation agreement relating to her position of Quality Vice-President, the Company will benefit from her skills in Quality Assurance and will offer Ms. HOLTZ social security coverage that she did not receive in the context of her duties as a corporate officer, granted in application of the Public Health Code. Paris and Bordeaux, April 29, 2022 The Statutory Auditors French original signed by Becouze Fabien BROVEDANI Partner Deloitte & Associés Stéphane LEMANISSIER Partner 18 FINANCIAL INFORMATION CONCERNING THE GROUP’S ASSETS AND LIABILITIES, FINANCIAL POSITION AND PROFITS AND LOSSES 18.1Historical Financial Information The tables below present selected financial information and the income statement and other data of the Company, as of and for the periods ended on the dates indicated below. This Universal Registration Document includes our annual consolidated financial statements prepared in accordance with IFRS as adopted by the European Union as of and for the fiscal year ended December 31, 2021 presented in this Universal Registration Document in Section 18.1.1, “Company’s Annual Consolidated Financial Statements (IFRS) for the Fiscal Year Ending December 31, 2021.” This Universal Registration Document also includes the financial statements of the parent company, prepared in accordance with French accounting standards for the fiscal year ended December 31, 2021. These financial statements are presented in Section 18.1.3, “Company’s Annual Financial Statements (French GAAP) for the Fiscal Year Ending December 31, 2021” of this Universal Registration Document. Unless otherwise indicated, the selected financial information as of and for the fiscal year ended December 31, 2021 has been derived from our consolidated financial statements prepared in accordance with IFRS as adopted by the European Union as of and for the fiscal year ended December 31, 2021. These consolidated financial statements for the fiscal year ended December 31, 2021 have been audited by Deloitte & Associés and Becouze, Statutory Auditors. The Statutory Auditors’ report on the consolidated financial statements as of and for the fiscal year ended December 31, 2021 is included in Section 18.1.2, “Statutory Auditors’ Report on the Company’s Annual Consolidated Financial Statements (IFRS) for the Fiscal Year Ending December 31, 2021” of this Universal Registration Document. The information in this section should be read together with (i) our consolidated financial statements contained in Section 18.1.1, “Company’s Annual Consolidated Financial Statements (IFRS) for the Fiscal Year Ending December 31, 2021” of this Universal Registration Document, (ii) our analysis of our results presented in Section 7, “Operating and Financial Review,” and (iii) our analysis of our liquidity and capital resources presented in Section 8, “Capital Resources.” 18.1.1COMPANY’S ANNUAL CONSOLIDATED FINANCIAL STATEMENTS (IFRS) FOR THE FISCAL YEAR ENDING DECEMBER 31, 2021. CONSOLIDATED STATEMENTS OF FINANCIAL POSITION In thousands of Euros Notes As of December 31, 2021 2020 ASSETS Non-current assets Intangible assets 4 112 133 Property, plant and equipment 5&6 2,549 3,154 Other non-current financial assets 7 624 315 Total non-current assets 3,285 3,602 Current assets Trade accounts receivable 8 754 52 Other current assets 8 8,321 5,764 Cash and cash equivalents 9 44,288 37,943 Total current assets 53,363 43,759 TOTAL ASSETS 56,648 47,361 In thousands of Euros Notes As of December 31, 2021 2020 LIABILITIES Shareholders’ equity 10 Share capital 1,158 1,022 Premiums related to the share capital 181,175 152,776 Reserves (137,726) (108,034) of which cumulative translation adjustment 25 207 Net income (loss) (28,617) (34,015) Total shareholders’ equity 15,989 11,749 Non-current liabilities Corporate bonds—non-current portion 11 2,586 3,715 Derivative liabilities – non-current portion 11 — — Borrowings from Banks—non-current portion 11 3,058 5,725 Conditional advances—non-current portion 11 4,939 4,679 Lease liability—non-current portion 11 1,512 2,045 Other liability – non-current portion 13 6,281 2,294 Non-current provisions 12 41 31 Total non-current liabilities 18,417 18,489 Current liabilities Corporate bonds—current portion 11 2,465 2,405 Derivative liabilities – Current portion 11 2,536 3,845 Borrowings from Banks—current portion 11 2,210 — Lease liability—current portion 11 735 560 Trade accounts payable 14 11,561 7,588 Current provisions 61 22 Other current liabilities 14 2,675 2,703 Total current liabilities 22,242 17,123 TOTAL LIABILITIES AND SHAREHOLDERS’ EQUITY 56,648 47,361 * The financial statements as of December 31, 2020 have been modified in order to take into account the IFRC interpretation of the norm IAS 19, published in 2021, which modifies the way of calculating the commitments relating to certain defined benefit plans. CONSOLIDATED STATEMENTS OF INCOME (LOSS) In thousands of Euros Notes As of December 31, 2021 2020 Operating income Revenues 16 5,276 4,394 Other income 17 2,433 3,046 Total operating income 7,709 7,440 Operating expenses Research and development 18 22,920 22,386 General and administrative 18 7,411 8,006 Sales and marketing 18 5,505 1,982 Total operating expenses 35,835 32,374 Operating profit (loss) (28,126) (24,934) Financial income 20 2,013 631 Financial expenses 20 (2,502) (9,711) Financial income (loss) (489) (9,079) Income tax 21 (2) (2) Net income (loss ) (28,617) (34,015) Basic and diluted earnings (loss) per share 24 (0.63) (0.97) CONSOLIDATED STATEMENTS OF COMPREHENSIVE INCOME (LOSS) In thousands of Euros As of December 31, 2021 2020 Net income (loss) (28,617) (34,015) Actuarial gains and losses on employee benefits, net of income tax 8 108 Foreign currency translation differences, net of income tax (215) 223 Total comprehensive income (loss) (28,824) (33,684) CONSOLIDATED STATEMENTS OF CASH FLOWS In thousands of Euros Notes As of December 31, 2021 2020 Cash flows from operating activities Net income (loss) (28,617) (34,015) Operating activities Amortization and depreciation 4&5 928 926 Retirement pension obligations 12 18 36 Expenses related to share-based payments 19.5 4,834 3,455 Other financial items 20 858 8,924 Other non-monetary items - 63 Operating cash flows before change in working capital (21,981) (20,611) Accounts receivable (698) 791 Accounts payable, net of prepayments 2,398 344 Other receivables (1,287) 2,381 Other current and non-current liabilities 4,428 2,051 Change in working capital 4,841 5,567 Net cash flows from operating activities (17,139) (15,044) Cash flows from investment activities Acquisitions of property, plant and equipment 5 (32) (6) Acquisitions of intangible assets 4 — — Acquisitions / reimbursement of non-current financial assets — (370) Acquisitions / reimbursement of current financial assets 16 — Net cash flows from investment activities (16) (376) Cash flows from financing activities New borrowings obtained 11 — 11,711 Interests expenses (835) (708) Repayment of obligation under bond and bank financings (3,069) — Repayment of obligation under finance leases 6 (584) (710) Treasury shares (305) 369 Subscription and exercise of share warrants 10&19 439 64 Capital increases, net of transaction costs 10 28,094 23,134 Net cash flows from financing activities 23,739 33,859 Increase/(decrease) in cash and cash equivalents 6,584 18,439 Cash and cash equivalents at the beginning of the period 37,943 19,250 Effect of changes in exchange rates on Cash and cash equivalent (238) 254 Cash and cash equivalents at the close of the period 44,288 37,943 CONSOLIDATED STATEMENTS OF CHANGES IN SHAREHOLDERS’ EQUITY In thousands of Euros, except for number of shares Share capital Premiums related to the share capital Reserves Net income (loss) Total shareholders’ equity Number of shares Amount At January 1, 2020 32,827,362 821 128,130 (87,565) (30,868) 10,518 Net income (loss) — — — — (34,015) (34,015) Cumulative translation adjustment — — — 223 — 223 Other comprehensive income — — — 108 — 108 Total comprehensive income (loss) — — — 331 (34,015) (33,684) Allocation of prior period net income (loss) — — — (30,868) 30,868 — Allocation to reserves — — — — — — Capital increase by issuance of ordinary shares 5,954,650 149 24,861 — — 25,010 Capital increase transaction costs — — (1,876) — — (1,876) Exercise and subscription of equity instruments 2,093,953 52 1,661 6,244 — 7,957 Treasury shares — — — 369 — 369 Share-based payments — — — 3,455 — 3,455 At December 31, 2020 40,875,965 1,022 152,776 (108,034) (34,015) 11,749 At January 1, 2021 40,875,965 1,022 152,776 (108,034) (34,015) 11,749 Net income (loss) — — — — (28,617) (28,617) Cumulative translation adjustment — — — (215) — (215) Other comprehensive income — — — 8 — 8 Total comprehensive income (loss) — — — (207) (28,617) (28,824) Allocation of prior period net income (loss) — — — (34,015) 34,015 — Allocation to reserves — — — — — — Capital increase by issuance of ordinary shares 4,915,112 123 29,877 — — 30,000 Capital increase transaction costs — — (1,906) — — (1,906) Exercise and subscription of equity instruments 509,514 13 427 — — 440 Treasury shares — — — (305) — (305) Share-based payments — — — 4,834 — 4,834 At December 31, 2021 46,300,591 1,158 181,175 (137,726) (28,617) 15,989 * The financial statements as of December 31, 2020 have been modified in order to take into account the IFRIC interpretation of the norm IAS 19, published in 2021, which modifies the way of calculating the commitments relating to certain defined benefit plans. NOTES TO THE CONSOLIDATED FINANCIAL STATEMENTS Note 1:General information about the Company Founded in 2012, GenSight Biologics S.A. (hereinafter referred to as “GenSight Biologics” or the “Company” and together with its subsidiaries as the “Group”) is a clinical-stage biotechnology group discovering and developing novel therapies for neurodegenerative retinal diseases and diseases of the central nervous system. GenSight Biologics’ pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from severe degenerative retinal diseases. The Group focus is in ophthalmology where it develops product candidates to restore eyesight to patients suffering from retinal diseases that would otherwise lead to blindness. The Company has incurred losses and negative cash flows from operations since its inception and shareholders’ equity amounts to €15,989 K as of December 31, 2021 as a result of several financing rounds (see Note 11). The Group anticipates incurring additional losses until such time, if ever, that it can generate significant revenue from its product candidates in development. Substantial additional financing will be needed by the Company to fund its operations and to commercially develop its product candidates. The Group’s future operations are highly dependent on a combination of factors, including: (i) the success of its research and development; (ii) regulatory approval and market acceptance of the Group’s proposed future products; (iii) the timely and successful completion of additional financing; and (iv) the development of competitive therapies by other biotechnology and pharmaceutical companies. The presented consolidated Financial Statements are expressed in thousands of euros, unless stated otherwise. For ease of presentation, numbers have been rounded. Calculations, however, are based on exact figures. Therefore, the sum of the numbers in a column of a table may not conform to the total figure displayed in the column. The reporting date for the consolidated financial statements is December 31 and covers a twelve-month period. The individual statements of the consolidated subsidiary GenSight Biologics Inc. is prepared at the same reporting date, i.e., December 31, and cover a one-year period. On December 30, 2021, GenSight Biologics S.A. created a second subsidiary, GenSight Biologics France SAS registered and located in France, which is fully owned and consolidated. The financial statements of the second subsidiary hence cover a one day-period. The consolidated financial statements as of December 31, 2021 have been prepared under the responsibility of management of the Group and were approved on April 7, 2022 by the Board of Directors. MAIN EVENTS OF THE FISCAL YEAR On March 26, 2021, GenSight Biologics announced the success of a capital increase. The Company has issued 4,477,612 new ordinary shares with a nominal value of €0.025 each (the “New Shares“), for total gross proceeds of approximately €30 million by means of an accelerated bookbuilding process to the benefit of categories of persons (the “Reserved Offering“). The book was largely oversubscribed, based on demand from new investors. The issue price of the New Shares is €6.70 per share, representing a 9.0% discount to the last closing share price and a 12.7% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., March 19, 22, 23, 24 and 25, 2021), in accordance with the 19th resolution of the combined annual general meeting of shareholders of the Company held on April 29, 2020. On December 30, 2021, GenSight Biologics incorporated a second subsidiary, GenSight Biologics France SAS, registered and located in France. It is wholly owned by GenSight Biologics S.A. and therefore fully consolidated. MAIN EVENTS OF THE PREVIOUS FISCAL YEAR On October 22, 2020, GenSight announced that it had raised €25 million in an oversubscribed private placement with Us and European institutional investors. The transaction was led by Arix Bioscience plc (LON: ARIX), Invus and Sofinnova Partners.The Company has issued 5,954,650 new ordinary shares with a nominal value of €0.025 each (the “New Shares”), for total gross proceeds of approximately €25 million by means of an accelerated bookbuilding process to the benefit of categories of persons (the “Reserved Offering”). The book was oversubscribed, based on demand from new and existing investors. The issue price of the New Shares is €4.20 per share, representing a 12.5% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., October 15, 16, 19, 20 and 21, 2020), in accordance with the 19th resolution of the combined annual general meeting of shareholders of the Company held on April 29, 2020. On December 10, 2020, GenSight Biologics announced that it has received, in connection with its bond agreement entered with Kreos Capital VI (Expert Fund) LP (“Kreos“), the notification by Kreos of the conversion of 50% of the convertible bonds of tranches A and B (at a price of €2.245 per share), the conversion of 50% of the additional convertible bonds of tranche B (at a price of €2.574 per share) and the exercise of all share warrants of tranches A and B (at a price of €2.245 per share), representing a total issuance of 1,182,953 new ordinary shares. Note 2:Statement of compliance and transition to IFRS 2.1Statement of compliance The consolidated financial statements have been prepared in accordance with International Financial Reporting Standards (IFRS) as issued by the International Accounting Standards Board (IASB). As the shares of the Company are listed on Euronext Paris, in compliance with European regulation n° 1606 / 2002 adopted on July 19, 2002 by the European Parliament and the European Council, the Group's consolidated financial statements for the year ended December 31, 2021 were prepared in accordance with IFRS, as endorsed by the European Union on the date of preparation. The IFRS as adopted by the European Union differ in certain aspects with the IFRS published by the IASB. Nevertheless, the Group ensured that the financial information for the periods presented is not substantially different between IFRS published by the IASB and IFRS as adopted by the European Union. International accounting standards include IFRS, International Accounting Standards (IAS), as well as the interpretations issued by the Standing Interpretations Committee (SIC), and the International Financial Reporting Interpretations Committee (IFRIC). New standards, amendments and interpretations that became applicable to the Group from January 1, 2021 In the current year, the Group has applied a number of amendments to IFRS Standards and Interpretations issued by the IASB that are effective for an annual period that begins on or after January 1, 2021. Their adoption has not had any material impact on the disclosures or on the amounts reported in these financial statements. Amendments to IFRS 4 Postponement of application of IFRS 9 for insurance transactions to 01/01/2023 Reform regarding the interest rates benchmark (IBOR) Amendments to IFRS 9, IAS 39, IFRS 7, IFRS 4 and IFRS 16 Amendments to IFRS 16 Covid-19 related rent concessions over June 2021 (lessees only) IFRIC interpretation of IAS 19 IFRIC interpretation of the norm IAS 19, published in 2021, modifies the way of calculating the commitments relating to certain defined benefit plans New and revised IFRS Standards in issue but not yet effective IFRS 17 (including the June 2020 amendments to IFRS 17) Insurance Contracts Amendments to IFRS 10 and IAS 28 Sale or Contribution of Assets between an Investor and its Associate or Joint Venture Amendments to IAS 1 Classification of Liabilities as Current or Non-Current Amendments to IFRS 3 Reference to the Conceptual Framework Reference to the Conceptual Framework Amendments to IAS 16 Property, Plant and Equipment—Proceeds before Intended Use Amendments to IAS 37 Onerous Contracts Onerous Contracts—Cost of Fulfilling a Contract Annual Improvements to IFRS Standards 2018-2020 Cycle Amendments to IFRS 1 First-time Adoption of International Financial Reporting Standards, IFRS 9 Financial Instruments, IFRS 16 Leases, and IAS 41 Agriculture Amendments to IAS 1 and IFRS Practice Statement 2 Disclosure of Accounting Policies Amendments to IAS 8 Definition of Accounting Estimates Definition of Accounting Estimates Amendments to IAS 12 Deferred Tax related to Assets and Liabilities arising from a Single Transaction The Group does not expect that the adoption of the Standards listed above will have a material impact on the financial statements of the Group in future periods. 2.2Going concern Since its incorporation, the Company has funded its activities through several equity financings, grants, conditional advances and Research Tax Credit. Since the end of 2019, the Company started to generate revenue from the sale of LUMEVOQ® in France, since the French National Drug Safety Agency (ANSM) granted a named patient Temporary Authorization for Use (ATU nominative) for LUMEVOQ®. As mentioned in note 27 Subsequent events, following a delay in manufacturing validation batches of LUMEVOQ®, GenSight plan to restart the manufacturing of the validation batches at its Cambridge, US, manufacturing facility during Q3 2022. The Company therefore expects a delay in the commercialization of LUMEVOQ®. Considering the cash position as of December 31, 2021 (amounting to €44.3 million), the reimbursement of the 2021 Research Tax Credit contemplated in 2022 for a consideration of €2.4 million and additional cash related to the ATU sales in France granted during Q1 2022, the Company believes it will be able to fund its operations until early first quarter 2023. By that date, the Company will have to find additional funding. Various financing sources are considered among the issuance of new debt or equity instruments. The Company believes it will have the ability to raise additional funds during 2022. On this basis, the financial statements have been prepared on a going concern basis. Note 3:Accounting principles 3.1Consolidation scope and methods On April 28, 2017 the Group incorporated GenSight Biologics Inc. in the United States. On December 30, 2021, the Company created a second subsidiary, GenSight Biologics France SAS registered and located in France. As 100% of the voting rights and ownership interests are held by the Group, both subsidiaries are fully consolidated. 3.2Functional currency and translation of financial statements in foreign currency The Financial Statements are presented in thousands of euros (“KEuros”), which is also the functional currency of the parent Company GenSight Biologics S.A. The statements of financial position of GenSight Biologics Inc. having a functional currency different from the euro are translated into euros at the closing exchange rate (spot exchange rate at the statement of financial position date), and the statements of income, statements of comprehensive income and statement of cash flow of GenSight Biologics Inc. are translated at the average period to date exchange rate. The resulting translation adjustments are included in equity under the caption “Cumulative translation adjustment” in the Consolidated Statement of Changes in Shareholders’ Equity. 3.3Intangible assets Pursuant to IAS 38 Intangible Assets (“IAS 38”), intangible assets acquired are recognized as assets on the Consolidated Statement of Financial Position at their acquisition cost. Research and development Research costs are recorded in the Financial Statements as expenses. In accordance with IAS 38, development costs are recognized in the Financial Statements as intangible assets only if all of the following criteria are met: (a)it is technically feasible to complete the development of the project; (b)intention on the part of the Company to complete the project and to utilize it; (c)capacity to utilize the intangible asset; (d)proof of the probability of future economic benefits associated with the asset; (e)availability of the technical, financial and other resources for completing the project; and (f)reliable evaluation of the development expenses. Because of the risks and uncertainties related to regulatory authorizations and to the research and development process, the Company believes that the six criteria stipulated by IAS 38 have not been fulfilled to date and the application of this principle has resulted in all development costs to be expensed as incurred in all periods presented. Software The costs related to the acquisition of licenses for software are recognized as assets on the basis of the costs incurred to acquire and to implement the software. They are amortized using the straight-line method over a period of one to three years depending on the anticipated period of use. License In February 2013, the Company entered into a partnership agreement with Novartis Pharma AG (“Novartis”) which provides for exclusive in-licenses for two patent families. The Company issued 670,588 ordinary shares as consideration paid for the exclusive licenses. Given that the fair value of the licenses cannot be reliably estimated, in accordance with IFRS 2, the amount of the intangible asset being recognized has been determined by reference to the fair value of the ordinary shares that were granted by the Company, based on an independent valuation. The licenses are amortized over 15 years from the date the agreement was signed, which corresponds to the expected useful life of the licenses. 3.4Property, plant and equipment Property, plant and equipment are recorded at their acquisition cost or, if applicable, at their production cost. Property, plant and equipment are depreciated using the straight-line method over the estimated useful period of the property. Rented fixtures are depreciated over the term of their lifetime or over the term of the rental agreement, whichever is shorter. The depreciation periods used are the following: Property, plant and equipment item Depreciation period Fixtures and improvements in structures 9 years Research and development / production tools 5 to 10 years Computer equipment 3 years Office equipment and furniture 5 years 3.5Financial assets Financial assets are initially measured at fair value plus directly attributable transaction costs in the case of instruments not measured at fair value through profit or loss. Directly attributable transaction costs of financial assets measured at fair value through profit or loss are recorded in the consolidated statement of income (loss). Under IFRS 9, financial assets are classified in the following three categories: •Financial assets at amortized cost; •Financial assets at fair value through other comprehensive income (“FVOCI”); and •Financial assets at fair value through profit or loss. The classification of financial assets depends on: •The characteristics of the contractual cash flows of the financial assets; and •The business model that the entity follows for the management of the financial asset. Financial assets at amortized cost Financial assets are measured at amortized cost when (i) they are not designated as financial assets at fair value through profit or loss, (ii) they are held within a business model whose objective is to hold assets in order to collect contractual cash flows and (iii) they give rise to cash flows that are solely payments of principal and interest on the principal amount outstanding (“SPPI” criterion). They are subsequently measured at amortized cost, determined using the effective interest method (“EIR”), less any expected impairment losses in relation to the credit risk. Interest income, exchange gains and losses, impairment losses and gains and losses arising on derecognition are all recorded in the consolidated statement of income (loss). This category primarily includes trade receivables, as well as other loans and receivables. Long-term loans and receivables that are not interest-bearing or that bear interest at a below-market rate are discounted when the amounts involved are material. Financial assets at fair value through other comprehensive income Financial assets at fair value through other comprehensive income is mainly comprised is composed of debt instruments whose contractual cash flows represent payments of interest or repayments of principal, and which are managed with a view to collecting cash flows and selling the asset. Gains and losses arising from changes in fair value are recognized in equity within the statement of comprehensive income in the period in which they occur. When such assets are derecognized, the cumulative gains and losses previously recognized in equity are reclassified to profit or loss for the period within the line items Financial income or Financial expenses. The Company did not hold this type of instrument during the periods presented in these financial statements. Financial assets at fair value through profit or loss Financial assets at fair value through profit or loss is comprised of: •instruments whose contractual cash flows represent payments of interest or repayments of principal, but which are managed other than with a view to collecting cash flows and/or selling the asset; and •instruments that management has designated as “fair value through profit or loss” on initial recognition. Gains and losses arising from changes in fair value are recognized in profit or loss within the line items financial income or financial expenses. Impairment of financial assets measured at amortized cost The main assets involved are trade receivables and others. Trade receivables are recognized when the Company has an unconditional right to payment by the customer. Impairment losses on trade receivables and others are estimated using the expected loss method, in order to take account of the risk of payment default throughout the lifetime of the receivables. The expected credit loss is estimated collectively for all accounts receivable at each reporting date using an average expected loss rate, determined primarily on the basis of historical credit loss rates. However, that average expected loss rate may be adjusted if there are indications of a likely significant increase in credit risk. If a receivable is subject to a known credit risk, a specific impairment loss is recognized for that receivable. The amount of expected losses is recognized in the balance sheet as a reduction in the gross amount of accounts receivable. Impairment losses on accounts receivable are recognized within Operating expenses in the consolidated statement of income (loss). 3.6Recoverable amount of the intangible assets and property, plant and equipment The property, plant and equipment and intangible assets that have an established lifetime are subject to an impairment test when the recoverability of their book value is called into question by the existence of indications of impairment. An impairment is recognized in the Financial Statements up to the amount of the excess of the book value over the recoverable value of the asset. The recoverable value of an asset corresponds to its fair value minus the costs of sale or its use value, whichever is higher. 3.7Cash and cash equivalents Cash equivalents are short-term, highly liquid investments, that are readily convertible to known amounts of cash and which are subject to an insignificant risk of changes in value. Cash and cash equivalents comprise the cash that is held at the bank and petty cash as well as the short-term fixed deposits for which the maturity is less than three months. For the purpose of establishing the statement of cash flows, cash and cash equivalents include cash in hand, demand deposits and short fixed-term deposits with banks and short-term highly liquid investments with original maturities of three months or less, net of bank overdrafts. Cash and cash equivalents are initially recognized at their purchase costs on the transaction date, and are subsequently measured at fair value. Changes in fair value are recognized in profit or loss. 3.8Share capital Ordinary shares are classified under shareholders’ equity. The costs of share capital transactions that are directly attributable to the issue of new shares or options are recognized in shareholders’ equity as a deduction from the revenue from the issue, net of tax. The Company’s own shares bought in the context of a brokering/liquidity agreement are presented as a reduction in shareholders’ equity until their cancellation, their reissuance or their disposal. 3.9Convertible Bonds - Derivatives The convertible bonds in which the Group is already engaged are financial instruments that will or may be settled in the entity’s own equity instrument and are derivatives that will or may be settled other than by the exchange of a fixed amount of cash or another financial asset for a fixed number of the entity’s own equity instruments (IAS 32.11), and are therefore financial liabilities. The convertible option is a (derivative) financial liability initially measured at fair-value according to IFRS 9 and subsequently measured at fair-value through profit and loss. Derivatives are recorded in the statement of financial position at their fair value. Changes in fair value are recognized in profit or loss. Transaction costs that relate to the issue of the convertible loan are included in the carrying amount of the liability component and are amortized over the lives of the convertible loan notes using the effective interest method. 3.10Share-based payment Free shares (Attributions Gratuites d’Actions, or “AGA”), stock-options (Options de souscription et/ou d’achat d’actions, or “SO”) and employee warrants (Bons de souscription de parts de créateur d’entreprise, or “BCE”) are awarded to employees or executives. Non-employee warrants (Bons de souscription d’actions, or “BSA”) are primarily awarded to directors and scientific consultants. Pursuant to IFRS 2, these awards are measured at their fair value on the date of grant. The fair value is calculated with the most relevant formula regarding the settlement and the conditions of each plan. The fair value is recorded in personnel expenses (allocated by function in the Consolidated Statement of Income) on a straight-line basis over each milestone composing the vesting period with a corresponding increase in shareholders’ equity. At each closing date, we re-examine the number of options likely to become exercisable. If applicable, the impact of the review of the estimate is recognized in the Consolidated Statement of Income with a corresponding adjustment in equity. 3.11Financial liabilities Borrowings and other financial liabilities, excepted for derivative financial liabilities (see upon), are measured initially at their fair value and then at amortized cost, calculated on the basis of the EIR method. The transaction expenses that are directly attributable to the acquisition or to the issue of a financial liability reduce that financial liability. These expenses are then amortized actuarially over the lifetime of the liability, on the basis of the EIR. The EIR is the rate that equalizes the anticipated flow of future cash outflows with the current net book value of the financial liability in order to deduct its amortized cost therefrom. The amount resulting from the benefit of financial liabilities that do not bear interest at market rates is considered a subsidy. This benefit is determined by applying a discount rate equal to the rate the Company would have to pay for a bank borrowing over a similar maturity. The implicit interest rate resulting from taking into account the whole repayments is used to determine the amount recognized annually as a finance cost. The subsidy is presented as a differed income which is amortized in the P&L over the same period. Other financial liabilities include trade accounts payable, which are measured at fair value (which in most cases equates to face value) on initial recognition, and subsequently at amortized cost. 3.12Research tax credit, subsidies and conditional advances Research tax credit The research tax credit (Crédit d’Impôt Recherche, or “CIR”) (the “Research Tax Credit”) is granted to companies by the French tax authorities in order to encourage them to conduct technical and scientific research. Companies that prove that they have expenditures that meet the required criteria (research expenditures located in France or, since January 1, 2005, within the European Community or in another State that is a party to the Agreement on the European Economic Area that has concluded a tax treaty with France that contains an administrative assistance clause) receive a tax credit that can be used for the payment of the corporate tax due for the fiscal year in which the expenditures were made and the next three fiscal years, or, as applicable, can be reimbursed in cash. The expenditures taken into account for the calculation of the Research Tax Credit involve only research expenses. The Company has received the Research Tax Credit since its inception. The Company received the reimbursement of the Research Tax Credit for the year 2020 in November 2021 for an amount of €2,764 K. It will request the reimbursement of the 2021 Research Tax Credit in 2022 under the Community tax rules for small and medium firms in compliance with the regulatory texts in effect for the amount of €2,433 K. The CIR is presented under other income in the Consolidated Statement of Income (Loss) as it meets the definition of government grant as defined in IAS 20 Accounting for Government Grants and Disclosure of Government Assistance. Subsidies and conditional advances Due to the innovative nature of its product candidate development programs, the Company has benefited from certain sources of financial assistance from Bpifrance Financement whose mission is to provide financial assistance and support to emerging French enterprises to facilitate the development and commercialization of innovative technologies. The funds received by the Company are intended to finance its research and development efforts and the recruitment of specific personnel. The Company has received such funding in the form of non-refundable subsidies and conditional advances. Subsidies Subsidies received are grants that are not repayable by the Company and are recognized in the Financial Statements where there exists reasonable assurance that the Company will comply with the conditions attached to the subsidies and the subsidies will be received. Subsidies that are upfront payments are presented as deferred revenue and recognized ratably through income over the duration of the research program to which the subsidy relates. A public subsidy that is to be received either as compensation for expenses or for losses already incurred, or for immediate financial support of the Company without associated future costs, is recognized in the Financial Statements as other income for the period in which the grant is classified as a receivable. The amount resulting from the benefit of financial liabilities that do not bear interest at market rates is considered a subsidy. This benefit is determined by applying a discount rate equal to the rate the Company would have to pay for a bank borrowing over a similar maturity. The implicit interest rate resulting from taking into account the whole repayments is used to determine the amount recognized annually as a finance cost. This finance cost is netted with the the impact of the amortization of the subsidy in the P&L. Conditional advances Funds received from Bpifrance Financement in the form of conditional advances are recognized as financial liabilities, as the Company has a contractual obligation to reimburse Bpifrance Financement based on a repayment schedule. Each advance is made to fund a specific development milestone. Details concerning conditional advances are provided in Note 11. Receipts and reimbursements of conditional advances are reflected as cash flows from financing activities in the Consolidated Statement of Cash Flows. The rate used to determine the amount recognized annually as a finance cost, the EIR takes into account the estimated future cash flows. In the event of a change in payment schedule of the stipulated repayments of the conditional advances, the Company recalculates the net book value of the debt resulting from the discounting of the anticipated new future cash flows at the initial EIR. The adjustment that results therefrom is recognized in the Consolidated Statement of Income (Loss) for the period during which the modification is recognized. The conditional advance that can be subject to this type of modification is the advance received from Bpifrance Financement, presented in Note 11.2. 3.13Retirement pension obligations The employees of the Company receive the retirement benefits stipulated by law in France: •compensation paid by the Company to employees upon their retirement (defined-benefit plan) and; •a payment of retirement pensions by the Social Security agencies, which are financed by the contributions made by companies and employees (defined-contribution plans). For the defined-benefit plans, the costs of the retirement benefits are estimated by using the projected credit unit method. According to this method, the cost of the retirement benefit is recognized in the Consolidated Statement of Income (Loss) so that it is distributed uniformly over the term of the services of the employees. The retirement benefit commitments are valued at the current value of the future payments estimated using, for discounting, the market rate for high quality corporate bonds with a term that corresponds to that estimated for the payment of the benefits. The difference between the amount of the provision at the beginning of a period and at the close of that period is recognized through profit or loss for the portion representing the costs of services rendered and the net interest costs, and through other comprehensive income for the portion representing the actuarial gains and losses. The Company’s payments for the defined-contribution plans are recognized as expenses on the Consolidated Statement of Income (Loss) of the period during which they become payable. In April 2021, the IFRIC (“IFRS Interpretations Committee”) or addressed to the IAS Board (International Accounting Standards Board), for decision (approval or refusal or intermediate position), a “ TAD” (“Tentative Agenda Decision” or “Provisional Decision”) by which it proposes to modify the way of calculating the commitments relating to certain defined benefit plans. The IAS Board validated this position in early June 2021, while specifying that there was no need to modify anything in IAS 19 which already allows this interpretation. By its new position, the IFRIC considers that, from the moment when, on the one hand, no right is acquired in the event of departure before retirement age and, on the other hand, the rights are capped after a certain number of years of seniority (N), it would be the last N years of the employee's career in the company that confer rights upon departure. In addition, according to the consensus, it is also mandatory to modify the valuation method for Companies using collective agreements whose rights are defined by age bracket. Indeed, they consider that, given the fact that the rights are defined in stages, a certain number of years of service performed by a given employee does not give rise to the allocation of rights. It is then necessary, for the evaluation, to linearize the rights over the last N years, N representing the number of years which gives rise to the allocation of rights and therefore the last level that the employee will reach at the time of his departure in retirement. GenSight Biologics is particularly impacted, considering that it is applying the Metallurgy collective agreement which provides for rights defined by levels of seniority, whether or not there is an absolute seniority ceiling. This new method has the following consequences: •Decrease in commitments. The impact of the decrease in commitments is recognized in equity, •Proportional reduction of the financial cost which is recognized in the P&L, •Potential increase in the cost of services: The consequence of the decrease in commitments is potentially the increase in the costs of future services booked in the P&L. Depending on the demographic structure of society and the fee structure, the increase in service costs may not be immediate. We have implemented the changes of interpretation in the 2021 financial statements. As it required a retrospective application, the impact has been carried forward in the 2020 financial statements: •The provision for retirement obligation has been reduced from €113 K to €31 K; and •The total equity has been increased accordingly, from €11,667K to €11,749 K. 3.14Provisions for risks and expenses The provisions for risks and lawsuits correspond to the commitments resulting from lawsuits and various risks whose due dates and amounts are uncertain. A provision is recognized in the Financial Statements when the Group has a legal or implicit obligation to a third party resulting from a past event, which is likely or certain to cause an outflow of resources to that third party, and provided that the future outflows of liquid assets can be estimated reliably. The amount recognized in the Financial Statements as a provision is the best estimate of the expenses necessary to extinguish the obligation. 3.15Leases The Group applies the definition of a lease and related guidance set out in IFRS 16 to all contracts entered into or changed on or after January 1, 2019. Applying IFRS 16, for all leases (except as noted below), the Group: (a)Recognizes right-of-use assets and lease liabilities in the consolidated statement of financial position, initially measured at the present value of the future lease payments; (b)Recognizes depreciation of right-of-use assets and interest on lease liabilities in profit or loss; (c)Separates the total amount of cash paid into a principal portion (presented within financing activities) and interest (presented within financing activities) in the consolidated statement of cash flows. Lease incentives (e.g. rent-free period) are recognized as part of the measurement of the right-of-use assets and lease liabilities whereas under IAS 17 they resulted in the recognition of a lease incentive, amortized as a reduction of rental expenses generally on a straight-line basis. Under IFRS 16, right-of-use assets are tested for impairment in accordance with IAS 36. For short-term leases (lease term of 12 months or less) and leases of low-value assets (such as tablet and personal computers, small items of office furniture and telephones), the Group has opted to recognize a lease expense on a straight-line basis as permitted by IFRS 16. This expense is presented within ‘other expenses’ in profit or loss. 3.16Revenue The core principle of this revenue standard is that a company should recognize revenue to depict the transfer of promised goods or services to customers in an amount that reflects the consideration to which the company expects to be entitled in exchange for those goods or services. The following five steps are applied to achieve that core principle: •Step 1: Identify the contract with the customer, •Step 2: Identify the performance obligations in the contract, •Step 3: Determine the transaction price, •Step 4: Allocate the transaction price to the performance obligations in the contract, •Step 5: Recognize revenue when the company satisfies a performance obligation. In order to identify the performance obligations in a contract with a customer, a company must assess the promised goods or services in the contract and identify each promised good or service that is distinct. A performance obligation meets IFRS15’s definition of a “distinct” good or service (or bundle of goods or services) if both of the following criteria are met: •a good or service (or bundle of goods or services) that is distinct; or •a series of distinct goods or services that are substantially the same and that have the same pattern of transfer to the customer. In accordance with IFRS 15, variable considerations cannot be included in the estimated transaction price as long as it not highly probable that the related revenue will not reversed in the future. According to the level of uncertainty relating to the results of preclinical and clinical trials and the decisions relating to the regulatory approvals, variable considerations depending on these events are excluded from the transaction price as long as the trigger event is not highly probable. When the trigger event occurs, the corresponding milestone is added to the transaction price. Such adjustments are recorded on a cumulative catch-up basis, which would affect revenues and net income (loss) in the period of adjustment. The Company started the sale of LUMEVOQ® through the named patient Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts. Total income solely comes from those named patient ATU. The Company will be paid a preliminary price by the hospitals, ultimately fully covered by the health insurance. Upon obtaining full marketing authorization and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price Estimated rebates are considered to be variable consideration and include significant estimates. •Management determined that the agreement with the CHNO of the Quinze Vingts includes a variable amount. At contract inception, the variable consideration is estimated based on the expected value amount of consideration expected from the transaction and constrained to the extent it is highly probable that a significant revenue reversal in the amount of cumulative revenue recognized will not occur when the associated uncertainty with respect the variable consideration is subsequently resolved. •The methodology and assumptions used to estimate rebates are monitored and adjusted regularly in the light of contractual and legal obligations, historical trends, past experience and projected market conditions. In 2021, in the light of changes in legal obligations, and projected market conditions, the Company adjusted the variable considerations for which it’s highly probable that a significant reversal in the amount of cumulative revenue recognized will not occur. •Net revenue is recorded, net of variable consideration related to certain allowances and accruals, at the time the customer obtains control of the product. We record a related liability, for components related to product sold during the reporting period. The discounted value of this liability is booked in the Financial Statements. 3.17Income tax Deferred taxes are recognized for all the temporary differences arising from the difference between the tax basis and the accounting basis of the assets and liabilities that appear in the Financial Statements. The primary temporary differences are related to the tax losses that can be carried forward or backward. The legal tax rates as of the closing date are utilized to determine the deferred taxes. The deferred tax assets are recognized in the Financial Statements only to the extent that it is likely that the future profits will be sufficient to absorb the losses that can be carried forward or backward. Considering its stage of development, which precludes the income projections from being sufficiently reliable to be made, the Group has not recognized deferred tax assets in relation to tax loss carryforward in the Consolidated Statement of Financial Position. 3.18Segment information The Company operates in a single operating segment: the conducting of research and development of novel therapies for mitochondrial and neurodegenerative diseases of the eye and central nervous system in order to market them in the future. The assets, liabilities and operating loss realized are located mainly in France. In 2020 and 2021, revenues were entirely generated by one customer. 3.19Presentation of financial assets and financial liabilities measured at fair value In accordance with IFRS 7 Financial Statements: Disclosures, financial instruments are presented in three categories based on a hierarchical method used to determine their fair value: •level 1: fair value calculated using quoted prices in an active market for identical assets and liabilities; •level 2: fair value calculated using valuation techniques based on observable market data such as prices of similar assets and liabilities or parameters quoted in an active market; and •level 3: fair value calculated using valuation techniques based wholly or partly on unobservable inputs such as prices in an inactive market or a valuation based on multiples for unlisted securities. 3.20Use of estimates The Financial Statements are prepared in accordance with IFRS. The preparation of the Financial Statements requires management to make estimates, assumptions and judgments that affect the reported amounts of assets, liabilities, income and expenses during the reporting period. The Group bases estimates and assumptions on historical experience when available and on various factors that it believes to be reasonable under the circumstances. The Group’s actual results may differ from these estimates under different assumptions or conditions. The full extent to which the Covid-19 pandemic will directly or indirectly impact our business, results of operations and financial condition, including sales, expenses, reserves and allowances, the supply of our products and product candidates, clinical trials and research and development costs, will depend on future developments that are highly uncertain, including as a result of new information that may emerge concerning Covid-19 and variants thereof, and the actions taken to contain or treat it or vaccinate against it, as well as the economic impact on local, regional, national and international customers and markets. We have made estimates of the impact of Covid-19 within our financial statements and there may be changes to those estimates in future periods. Actual results may differ from these estimates. These estimates and judgments involve mainly: •the estimate of the amount of the intangible asset recognized in the context of a license agreement. The acquisition of this license in 2013 resulted in the issuance of ordinary shares as consideration paid for the license. The amount of the intangible asset recognized was determined based on the fair value of the ordinary shares, €0.41 per share, issued as consideration for the license (see Note 4); •the estimate of the repayments of the conditional advances obtained by the Company from public institutions, such as Bpifrance Financement. The anticipated repayments of the conditional advances are analyzed at each reporting period (see Note 11), and the measurement of the conditional advances classified as financial liabilities based on the effective rate method; •the measurement of the fair value of the various equity instruments granted to employees, executives or non-employee members of the Board of Directors as well as scientific consultants and service providers, such as AGA, SO, BCE or BSA, which is performed on the basis of actuarial models; these models require the use by the Company of certain calculation assumptions such as the expected volatility of the underlying security (see Note 19); •research and development expenses include estimates of the amount recognized over the year for subcontracts. At year-end closing, an analysis of the services already performed but not invoiced and / or already invoiced but not performed is carried out by the project managers and validated by the company's management (see Note 18); •the measurement of the fair value of the liability component of the convertible bond, calculated on the basis of the contractually agreed interest and amortization payments discounted at market interest rates (see Note 11); •the measurement of the fair value of the derivatives directly linked with the convertible bonds and warrants, calculated on the basis of financial mathematic models (see Note 11); •the estimate of the selling price for LUMEVOQ® to the CHNO of the Quinze-Vingts. The National Drug Safety Agency, granted to GenSight Biologics several Temporary Authorizations for Use (“ATU nominative”). Variable consideration under IFRS 15 are required to be estimated at contract inception. The Group assessed individual contracts to determine the estimated variable consideration and related constraints. In 2021, in the light of changes in legal obligations, and projected market conditions, the Company adjusted the variable considerations for which it is highly probable that a significant reversal in the amount of cumulative revenue recognized will not occur. The total revenue presented in our financial statements as of December 31, 2021 is therefore net from those variable considerations. The total revenue presented in our financial statements as of December 2020 and 2021 is therefore net from those variable considerations (see Note 16). Note 4:Intangible assets The intangible assets are broken down as follows: In thousands of Euros As of December 31, 2021 2020 Patents, licenses, trademarks 275 275 Software 18 18 Total historical cost 293 293 Accumulated amort. of patents, licenses and trademarks (163) (145) Accumulated depreciation of software packages (18) (15) Accumulated amortization and depreciation (181) (160) Net total 112 133 An intangible asset was recognized at December 31, 2013 as a result of the license agreement signed with Novartis. The initial recognition cost amounted to €275 K and was determined by reference to the fair value of the 670,588 ordinary shares, €0.41 per ordinary share, issued as consideration for the license. There has been no recognition of impairment losses in application of IAS 36 Impairment of Assets over the periods presented. Note 5:Property, plant and equipment Changes in property, plant and equipment gross book values and accumulated depreciation are presented in the following table: In thousands of Euros As of December 31, 2020 Increase Decrease Currency translation adjustment As of December 31, 2021 Technical equipment and installations 610 3 — 6 620 IFRS 16 – Right of use - Building 3,501 96 — 177 3,774 Leasehold improvement 959 — — 23 982 Office and Computer equipment 206 28 — 1 236 IFRS 16 – Right of use - Other 19 — — — 19 Furniture 492 1 — 14 505 Total gross property, plant and equipment 5,786 128 — 222 6,136 Accumulated depreciation of technical equipment and installations (417) (71) — (2) (491) IFRS 16 – Right of use - Building (1,164) (616) — (67) (1,847) Accumulated depreciation of leasehold improvement (461) (108) — (8) (576) Accumulated depreciation of office and computer equipment (188) (18) — (1) (207) IFRS 16 – Right of use - Other (15) (4) — — (19) Accumulated depreciation of furniture (387) (50) — (9) (447) Total accumulated depreciation (2,632) (868) — (87) (3,587) Total net property, plant and equipment 3,154 (740) — 135 2,549 Note 6:IFRS 16 - Leases The main impacts on the balance sheet resulting from the application of the IFRS 16 on the financial year ending December 31, 2021 are the following: Balance sheet Right-of-use (in thousands of Euros) As of December 31, 2020 New contracts / Modifications Amortization Currency translation adjutments As of December 31, 2021 Right-of-use - Buildings 2,337 96 (616) 110 1,927 Right-of-use - Others 4 — (4) — — Net value of the righ-of-use 2,342 96 (620) 110 1,927 Lease liability (in thousands of Euros) As of December 31, 2020 New contracts /Modifications Repayments Currency translation adjutments Reclassification non-current / current As of December 31, 2021 Lease liability - Buildings 2,045 — — 100 (633) 1,512 Lease liability - Others — — — — — — Total non-current 2,045 — — 100 (633) 1,512 Lease liability - Buildings 557 96 (580) 30 633 735 Lease liability - Others 4 — (4) — — — Total current 561 96 (584) 30 633 735 Total 2,605 96 (584) 130 — 2,247 Commitments under the scope of IFRS 16 Agreement with Passage de l’Innovation On January 1, 2015, we entered into a lease agreement for our headquarters premises in Paris, France with Passage de l’Innovation, which was amended on October 1, 2015, January 1, 2016, May 1, 2017, January 8, 2018, July 1, 2018, October 1, 2018, November 1, 2019 and October 1, 2021. As the company pursued its development, additional spaces were included in the contract. The main space’s lease ends in December 2024, however, our engagement with smaller surfaces ends in 2027. The agreement includes expenses for rent, rental charges and other services provided by the lessor. The amendment signed on October 1, 2021, consisted especially in an increased rent as the Group is using more office space. The associated services (e.g., reception, printers and information technology and access to meeting rooms) have increased accordingly. U.S.- based subsidiary The Group entered into a binding office lease agreement in New York for its U.S.-based subsidiary on September 6, 2017. The lease commencement was based upon substantial completion of the landlord’s work and delivery of possession of the premises and occurred on April 18, 2018. The lease term is 7 years and 5 months. Note 7:Other non-current financial assets The non-current financial assets correspond to the deposits paid to the lessors for the registered offices of the Group in Paris and New York for €387 K. The remaining corresponds to deposits paid to the CRO’s in charge of the management of the long term follow up of several of our clinical trials. In thousands of Euros As of December 31, 2021 2020 Guarantee deposits 624 315 Total non-current financial assets 624 315 Note 8:Accounts receivable and other current assets 8.1Accounts receivable and related receivables All accounts receivable have payment terms of less than one year. No valuation allowance was recognized on accounts receivable as there is no past due receivable. As of December 31, 2020 and 2021, the Company has receivables mainly resulting from the sale of LUMEVOQ®. 8.2Other current assets The other current assets are broken down as follows: As of December 31, 2021 As of December 31, 2020 Prepayments 1,816 243 Research tax credit 2,433 2,764 Other tax receivables 1,108 448 Liquidity contract 337 642 Prepaid expenses 2,552 1,667 Other current assets 74 — Total 8,321 5,764 Prepayments are made of advances to suppliers. The significant increase from year to year is explained mainly by the advances paid to suppliers related to the future commercial batches of LUMEVOQ®. Other tax receivables essentially refers to VAT receivables. As of December 31, 2021, prepaid expenses were primarily manufacturing costs, rental and scientific and marketing collaborations. Research Tax Credit The Company benefits from the provisions in Articles 244 quater B and 49 septies F of the French Tax Code related to the Research Tax Credit. In compliance with the principles described in Note 3.11, the Research Tax Credit is recognized in the Consolidated Statement of Income (Loss) in “other income” during the year in which the eligible research expenditures are incurred. Changes in the Research Tax Credit over the last two periods are presented as follows: Amounts in K€ Opening balance sheet receivable as of January 1, 2020 4,242 Other operating income 2,764 Payment received (4,242) Closing balance sheet receivable as of December 31, 2020 2,764 Amounts in K€ Opening balance sheet receivable as of January 1, 2021 2,764 Other operating income 2,433 Payment received (2,764) Closing balance sheet receivable as of December 31, 2021 2,433 Note 9:Cash and cash equivalents Cash and cash equivalents items are broken down as follows: In thousands of Euros As of December 31, 2021 2020 Cash 44,288 37,943 Cash equivalents — — Total cash and cash equivalent as reported in the statements of financial position 44,288 37,943 Bank overdrafts — — Total net cash and cash equivalents as reported in the statements of cash flows 44,288 37,943 The Group does not hold any short-term investment and all of its cash balances are cash at hand deposits with high-credit quality financial institutions. Note 10:Capital The share capital as of December 31, 2021, amounts to €1,157,514.78. It is divided into 46,300,591 fully authorized, subscribed and paid-up ordinary shares with a nominal value of €0.025. On July 13, 2016, the Company completed its Initial Public Offering (IPO) on Euronext Paris, raising €40 million in gross proceeds, and the Company issued 5,000,000 ordinary shares with a nominal value of €0.025 and a share premium of €7.975 per share. On August 10, 2016, the Company partly exercised its overallotment option as part of its IPO on Euronext Paris, raising an additional €5.2 million in gross proceeds, and the Company issued 655,859 ordinary shares with a nominal value of €0.025 and a share premium of €7.975 per share. On June 27, 2017, the Company operated a capital increase whose gross proceeds amounted to €22.5 million, by means of a private placement reserved to a category of persons, U.S. and European institutional investors specialized in healthcare and biotechnology. The majority of the new shares were allocated to U.S. investors. This increase corresponds to 3,750,000 new shares, par value €0.025 each. On February 25, 2019, GenSight Biologics announced the completion of a capital increase of €8 million subscribed entirely by Sofinnova Crossover I SLP (“Sofinnova“). The purpose of this capital increase is to pursue the final stages of clinical development of LUMEVOQ®, and file for marketing authorization in Europe. This increase corresponds to 3,921,568 new shares, par value €0.025 each. On December 20, 2019 GenSight Biologics announced that it had completed a capital increase of €9 million subscribed for by one of its main shareholders Sofinnova Crossover I SLP ("Sofinnova") and by a new strategic Chinese investor Strategic International Group Limited, a wholly owned subsidiary of 3SBio Inc. ("3SBio"). This increase corresponds to 3,799,071 new shares, par value €0.025 each. On October 22, 2020, GenSight completed a capital increase of €25 million. The Company has issued 5,954,650 new ordinary shares with a nominal value of €0.025 each, for total gross proceeds of approximately €25 million by means of an accelerated bookbuilding process to the benefit of categories of persons. The issue price of the New Shares is €4.20 per share, representing a 12.5% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., October 15, 16, 19, 20 and 21, 2020), in accordance with the 19th resolution of the combined annual General Meeting of Shareholders of the Company held on April 29, 2020. On December 10, 2020, GenSight received the notification by Kreos of the conversion of 50% of the convertible bonds of tranches A and B (at a price of €2.245 per share), the conversion of 50% of the additional convertible bonds of tranche B (at a price of €2.574 per share) and the exercise of all share warrants of tranches A and B (at a price of €2.245 per share), representing a total issuance of 1,182,953 new ordinary shares. On March 26, 2021, GenSight completed a capital increase of €30 million. The Company has issued 4,477,612 new ordinary shares with a nominal value of €0.025 each, for total gross proceeds of approximately €30 million by means of an accelerated bookbuilding process to the benefit of categories of persons. The book was largely oversubscribed, based on demand from new investors. The issue price of the New Shares is €6.70 per share, representing a 9.0% discount to the last closing share price and a 12.7% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., March 19, 22, 23, 24 and 25, 2021), in accordance with the 19th resolution of the combined annual General Meeting of Sshareholders of the Company held on April 29, 2020. The 46,300,591 outstanding shares does not include BSA, BCE and AGA. BSA are granted to investors and other individual non-employees, BCE are granted to employees only, AGA are granted to employees and / or executives. The table below shows the changes occurred in the share capital during the last two periods: In thousands of Euros, except for number of shares Share Capital Share premium Number of shares Balance as of January 1, 2020 821 128,130 32,827,362 Capital increase by issuance of ordinary shares 149 24,861 5,954,650 Less cost of issuance of shares — (1,876) — Issue of shares upon exercise of equity instruments(1) 52 1,661 2,093,953 Total as of December 31, 2020 1,022 152,776 40,875,965 Share Capital Share premium Number of shares Balance as of January 1, 2021 1,022 152,776 40,875,965 Capital increase by issuance of ordinary shares 123 29,877 4,915,112 Less cost of issuance of shares — (1,906) — Issue of shares upon exercise of equity instruments(1) 13 427 509,514 Total as of December 31, 2021 1,158 181,175 46,300,591 (1) The share premium includes the subscription price of non-employee warrants and the exercise price in excess of the share nominal value for employee and non-employee warrants. All the changes relating to employee warrants, non-employee warrants and free shares, as well as their impact on the profit and loss for the period are detailed in Note 19. Note 11:Financial liabilities 11.1Bond financing In 2019, GenSight Biologics obtained committed financing in the form of a bond financing of up to €12 million from Kreos Capital VI (UK) Limited and which included two main tranches. The first tranche of €6 million, including a €4.2 million straight bond issuance and a €1.8 million convertible bond issuance was drawn in December 2019 (“Tranche A”). The second tranche of €4 million in straight and convertible bonds was available to be drawn through September 2020, conditioned on GenSight obtaining a qualifying financing (“Tranche B”). Following the grant of the PGE and the amount of revenues anticipated to be generated from Autorisations Temporaires d’Utilisation payantes (“ATUs”), the parties have agreed that Tranche B may be drawn under more flexible conditions and no longer conditioned to the initial qualifying financing. Although the total amount of €4 million for Tranche B remains unchanged, the proportion between straight bonds and convertible bonds has been amended to include €0.3 million of additional convertible bonds B and proportionally fewer straight bonds B. Ultimately, Tranche B included a €2.5 million of straight bond issuance and €1.5 million of convertible bond issuance. Kreos also agreed to extend the interest-only period to December 2020. The €1.2 million of original convertible loan notes were issued on August 3, 2020 at an issue price of €2.245 per note. The €0.3 million of additional convertible loan notes were issued on August 3, 2020 at an issue price of €2.574 per note. The notes are convertible into ordinary shares of the Company at any time between the date of issue of the notes and their settlement date. Interest of 9.25% per cent will be paid annually up until that settlement date. On December 8, 2020, Kreos Capital VI (“Kreos”) decided to convert half of the convertible bonds (the “OC”) of tranches A and B and of the additional OC of tranche B. On the same date, Kreos exercised all of the share warrants (the “BSA”) of tranches A and B. The financing obtained from Kreos is qualified as a hybrid instrument in the Group’s financial statements. The two derivative instruments are, in accordance with IFRS 9, measured at fair value, with a change in fair value recognized in profit or loss. The amount remaining in debt is recognized at amortized cost using the effective interest rate. 11.2Conditional advances In 2014, we received a grant from Bpifrance Financement of both non-refundable subsidies and conditional advances in relation to the development of our optogenetics technology platform. The program would be funded according to a specified schedule set forth in the contract, subject to completion of milestones. As the program advances, we provided Bpifrance Financement with interim progress reports and a final report when the funded project would end. Based on these reports, we were entitled to conditional advances from Bpifrance Financement. Each award of an advance was made to help fund a specific development milestone. The total intended amount of the conditional advances initially granted was €5.7 million, of which €0.7 million were received in December 2014 and €2.3 million in July 2016. The advances were initially planned to be paid according to the following schedule, subject to completion of milestones: •€678 K received in December 2014; •€2,279 K received in July 2016(4); •€494 K initially expected to be received in the first half of 2018(5); •€853 K initially expected to be received in November 2018; and •€986 K initially expected to be received in November 2019. On June 3, 2020, the following was decided by the steering committee: •payment of a last conditional advance of €1.1 million and a subsidy of €0.3 million to cover for the expenses related to the key-steps 3 and 4; •removal of the specific regulatory condition in key step 3; •postponement by 2 years of the repayment schedule, i.e. a first repayment deadline on June 30, 2024 instead of June 30, 2022; •establishment of a minimum lump sum reimbursement of €819 K, or 20% of the overall received conditional advance. The repayment schedule of the conditional advances has been updated accordingly for a total amount of €4,687 K (€4,096 K of cash received + €591 K of capitalized interests) and is as follows: •€550 K from June 30, 2024; •€1,000 K from June 30, 2025; •€1,500 K from June 30, 2026; and •€1,637 K from June 30, 2027. Following the repayment of all of the conditional advances, the Company may be required to make additional payments over a period of two years, depending on whether the Company reaches cumulative revenues, excluding taxes, of €80.0 million. These additional repayments should correspond to the difference between 140% of the conditional advance, considering an interest rate of 1.44% and the amount already reimbursed as per the repayment schedule; and should be done within 15 years following the first year of reimbursement, i.e. 2039. The obligation to repay these amounts is based on the technical and commercial success of the funded program, as determined by the revenues forecast or revenues deriving from direct or indirect exploitation of those products and results of its optogenetics technology platform. In the event Bpifrance Financement determines that the program is not successful, Bpifrance Financement will meet with the Company to assess the impact on the repayments and the repayment schedule. The Company has decided to include the future cash flows resulting from the additional payments in the calculation of the EIR, based on the first sales projections of its second product. The current and non-current portions of the financial liability recognized in our financial statements associated with these conditional advances are determined based on the applicable reimbursement schedules at the end of each reporting period. The portion of the conditional advances for terms longer than one year are classified as non-current liabilities while the portion for terms of less than one year are classified as current liabilities. The table below presents the details of the financial liabilities recorded on the statements of financial position: In thousands of Euros Balance as of January 1, 2021 4,679 Receipts — Repayments — Accrued interest 260 Other — Balance as of December 31, 2021 4,939 Non-current portion 4,939 Current portion — 11.3State-guaranteed loan The Company obtained a €6.75 million loan from a bank syndicate formed with Crédit Industriel et Commercial (CIC), BNP Paribas and Bpifrance, in the form of a state-guaranteed loan (Prêt Garanti par l’État) (the “PGE“). Initiated by the French Government to support companies during the Covid-19 crisis, the PGE is a bank loan with a fixed interest rate ranging from 0.25% and 1.75% for the first 12 months. After an initial interest-only term of one year, the loan can be amortized over up to five years at the option of the Company. The French Government guarantees 90% of the borrowed amount. The Group has signed in June 2021 amendments to the initial agreements, including an amortization period of three years; until mid-2024, as well as effective interest rates ranging from 1.01% to 2.25%. This benefit, resulting from the low interest is determined by applying a discount rate equal to the rate the Company would have to pay for a bank borrowing over a similar maturity. The implicit interest rate resulting from taking into account the whole repayments is used to determine the amount recognized annually as a finance cost. 11.4Maturity dates Maturity dates of non-derivative financial liabilities as of December 31, 2020, are as follows: In thousands of Euros Gross amount Less than one year One to five years More than five years Conditional advances 4,679 — 1,026 3,653 Corporate bonds 6,120 2,405 3,715 — Borrowings from Banks 5,725 — 5,725 — Lease Liability 2,605 560 2,037 8 Total financial liabilities 19,129 2,965 12,503 3,661 Maturity dates of financial liabilities as of December 31, 2021, are as follows: In thousands of Euros Gross amount Less than one year One to five years More than five years Conditional advances 4,939 — 2,152 2,787 Corporate bonds 5,051 2,465 2,586 — Borrowings from Banks 5,268 2,210 3,058 — Lease Liability 2,247 735 1,512 — Total financial liabilities 17,505 5,410 9,308 2,787 Note 12:Non-current provisions Non-current provisions are exclusively composed of employee benefits relating to a compensation payable to French employees upon their retirement - Indemnités de Fin de Carrière ("IFC"). The following tables show the changes in the provision during the last two periods: In thousands of Euros As of January 1, 2020 103 Cost of services rendered (operating expense) 36 Interest expense — Benefits paid — Actuarial gain (loss) (108) As of December 31, 2020 K€ 31 As of January 1, 2021 31 Cost of services rendered (operating expense) 18 Interest expense — Benefits paid — Actuarial gain (loss) (8) As of December 31, 2021 K€ 41 The main assumptions used for the purposes of actuarial valuations are listed below: •Social security contribution: 45% in 2020 and 2021; •Salary increase: 3% in 2020 and 2021; •Discount rate: iBoxx Corporates AA+ index, 0.33% and 0.98% in 2020 and 2021, respectively: •Retirement age: 67; •Terms of retirement: voluntary retirement; •Life table: TGHF 2005; •Collective agreement: Convention Collective Nationale des Ingénieurs et des Cadres de la Métallurgie (National Collective Agreement for Engineers and Executives in the Metalworking Industry); and •Personnel turn-over: 10% (20-49), 0% above 50. Note 13:Other non-current liabilities 13.1Refund liability GenSight Biologics recorded a refund liability, related to the potential rebates obligations resulting from the current regulatory framework of the Temporary Authorization for Use (ATU) with the Social Security and Family Allowance Contribution Collection Offices (URSSAF). In France, use of pharmaceutical products not yet approved with a Marketing Authorization (AMM) and not recruiting for a clinical trial requires first obtaining an ATU from the ANSM. The Company will be paid a preliminary price by the hospitals. Upon obtaining full marketing authorization and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price. A discounting effect has been recognized. 13.2Subsidy The benefit resulting from the low interest of the State-guaranteed loan (PGE) is treated as a subsidy. This amount is recognized as financial income over the applicable repayment period. This benefit is determined by applying a discount rate equal to the rate the Company would have to pay for a bank borrowing over a similar maturity. The implicit interest rate resulting from taking into account the whole repayments is used to determine the amount recognized annually as a finance cost. 13.3Maturity dates Maturity dates of other current liabilities as of December 31, 2021 are as follows: In thousands of Euros Gross amount Less than one year One to five years More than five years Refund Liability 5,517 — 5,517 — Subsidy 581 161 420 — Other 345 1 345 — Total Other non-current liabilities 6,443 162 6,281 — Note 14:Accounts payable and other current liabilities 14.1Accounts payable and related payables With respect to accounts payable and related payables, no discounting effect has been recognized to the extent that amounts did not represent payables on terms longer than one year at the end of each period presented. Maturity dates of accounts payables as of December 31, 2021, are as follows: In thousands of Euros Gross amount Less than one year One to five years More than five years Trade accounts payable 11,561 11,561 — — 14.2Other current liabilities The following table provides the detail of other current liabilities for the presented periods: In thousands of Euros As of December 31, 2021 2020 Employee-related payable 2,452 2,641 Other taxes liabilities 24 18 Subsidy 161 - Deferred Revenue 37 41 Other current liabilities 1 3 Total 2,675 2,703 Note 15:Financial instruments recognized in the consolidated statements of financial position and related effect on the consolidated statement of income (loss) As of December 31, 2020 Book value on the statement of financial position Fair value through profit and loss(1) At amortized cost(2) Fair Value Financial assets Non-current financial assets 315 — 315 315 Current financial assets 642 642 — 642 Accounts receivable and related receivables 52 — 52 52 Cash and cash equivalents 37,943 — 37,943 37,943 Total financial assets 38,952 642 38,310 38,952 Financial liabilities Bond financing 6,120 — 6,120 6,120 Derivative liabilities 3,845 3,845 — 3,845 Borrowings from Banks 5,725 — 5,725 5,725 Conditional advances (non-current portion) 4,679 — 4,679 4,679 Lease liability - Buildings 2,601 — 2,601 2,601 Lease liability - Others 4 — 4 4 Accounts payable and related payables 7,588 — 7,588 7,588 Total financial liabilities 30,562 3,845 26,717 30,562 As of December 31, 2021 Book value on the statement of financial position Fair value through profit and loss(1) At amortized cost(2) Fair Value Financial assets Non-current financial assets 624 — 624 624 Current financial assets 337 337 — 337 Accounts receivable and related receivables 754 — 754 754 Cash and cash equivalents 44,288 — 44,288 44,288 Total financial assets 46,003 337 45,666 46,003 Financial liabilities Bond financing 5,051 — 5,051 5,051 Derivative liabilities 2,536 2,536 — 2,536 Borrowings from Banks 5,268 — 5,268 5,268 Conditional advances (non-current portion) 4,939 — 4,939 4,939 Lease liability - Buildings 2,247 — 2,247 2,247 Lease liability - Others — — — — Accounts payable and related payables 11,561 — 11,561 11,561 Total financial liabilities 31,602 2,536 29,066 31,602 (1) The fair value of financial assets classified as fair value through profit and loss corresponds to the market value of the assets. (2) The book amount of financial liabilities measured at amortized cost was deemed to be a reasonable estimation of fair value. Note 16:Income The Company started the sale of LUMEVOQ® through the named patient Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts on December 2019. Total income as of December 31, 2020 and 2021 solely comes from those named patient ATU. Our net product revenues are recognized, net of variable consideration related to certain allowances and accruals, at the time the customer obtains control of our product, i.e. after acceptance of the delivery by the customer. The sole component of variable consideration related to product revenues is related to the potential obligations resulting from the current regulatory framework of the Temporary Authorization for Use (ATU) with the Social Security and Family Allowance Contribution Collection Offices (URSSAF). In France, use of pharmaceutical products not yet approved with a Marketing Authorization (AMM) and not recruiting for a clinical trial requires first obtaining an ATU from the ANSM. The Company will be paid a preliminary price by the hospitals. Upon obtaining full marketing authorization and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price. Note 17:Other income Other income is detailed in the table below: In thousands of Euros As of December 31, 2021 2020 Research tax credit (see Note 8) 2,433 2,764 Subsidies — 282 Total 2,433 3,046 Note 18:Operating expenses 18.1Research and development expenses The table below shows the breakdown of general and administrative expenses by cost nature for the periods presented: In thousands of Euros As of December 31, 2021 2020 Personnel expenses(1) 4,844 3,903 Sub-contracting, collaboration and consultants 15,626 15,359 Licensing and intellectual property 1,318 2,168 Offices cost 22 28 Travel and entertainment expenses 323 245 Depreciation and amortization expense 366 397 Other 421 286 Total R&D expenses 22,920 22,386 (1) Includes €749 K and €1,404 K related to share-based compensation expense as of December 31, 2020 and 2021 respectively. 18.2General and administrative expenses The table below shows the breakdown of research and development expenses by cost nature for the periods presented: In thousands of Euros As of December 31, 2021 2020 Personnel expenses(1) 5,135 5,839 Professional Fees 1,633 1,421 Communication and travel expenses 46 97 Offices cost — — Equipment rental — — Office furniture and small equipment 92 84 Postal and telecommunication expenses 7 11 Depreciation and amortization expense 16 142 Attendance fees 255 222 Insurance 52 53 Others 175 138 Total G&A expenses 7,411 8,006 (1) Includes €2,630 K and 2 ,986 K related to share-based compensation expense as of December 31, 2020 and 2021 respectively. 18.3Sales and Marketing expenses The table below shows the breakdown of sales and marketing expenses by cost nature for the periods presented: In thousands of Euros As of December 31, 2021 2020 Personnel expenses(1) 1,750 412 Professional Fees 3,389 1,230 Communication and travel expenses 31 1 Offices cost 2 17 Depreciation and amortization expense 119 112 Others 212 210 Total S&M expenses 5,505 1,982 (1) Includes €76 K and €444 K related to share-based compensation expense as of December 31, 2020 and 2021, respectively. 18.4Personnel expenses The Group was employing 38 people on permanent contract as of December 31, 2021, compared to 25 as of December 2021. The following table shows the nature of costs included in personnel expenses: In thousands of Euros As of December 31, 2021 As of December 31, 2020 R&D G&A S&M TOTAL R&D G&A S&M TOTAL Wages and salaries 2,342 1,346 951 4,640 1,951 1,468 206 3,625 Social contributions 1,088 797 353 2,238 1,179 1,733 126 3,038 Service cost (employee benefit) 10 6 2 18 24 8 4 36 Share-based payments 1,404 2,986 444 4,834 749 2,630 76 3,455 Total 4,844 5,135 1,750 11,730 3,903 5,839 412 10,154 Note 19:Share-based payments The Board of Directors has been authorized by the general meeting of the shareholders to grant to employees BCE, BSA, AGA and SO and to implement share options plans as follows: •with the authorization of the General Meeting of Shareholders on February 5, 2013, the Board of Directors issued: —892,000 employee warrants (BCE 2013-02) on July 8, 2013. —328,000 non-employee warrants (BSA 2013-02) on July 8, 2013. —193,800 employee warrants (BCE 2013-02) on April 9, 2014. —33,000 non-employee warrants (BSA 2013-02) on April 9, 2014. •with the authorization of the General Meeting of Shareholders on June 25, 2014, the Board of Directors issued 60,000 employee warrants (BCE 2014-06) on December 3, 2014. •with the authorization of the General Meeting of Shareholders on June 29, 2015, the Board of Directors issued: —121,000 non-employee warrants (BSA 2015-06) on July 7, 2015. —733,298 employee warrants (BCE 2015-06) on July 7, 2015. •with the authorization of the General Meeting of Shareholders on May 19, 2016, the Board of Directors issued: —205,000 non-employee warrants (BSA 2016) on July 26, 2016. —766,000 free shares (AGA 2016) on July 26, 2016. —593,500 free shares (AGA 2016) on July 27, 2017. —72,500 free shares (AGA 2016) on December 19, 2017. —165,000 non-employee warrants (BSA 2016) on July 27, 2017. —220,000 stock options (SO 2017) on July 27, 2017. —300,000 stock options (SO 2017) on December 19, 2017. —175,000 stock options (SO 2018) on March 14, 2018. •with the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors issued: —380,000 free shares (AGA 2018) on September 18, 2018. —20,000 non-employee warrants (BSA 2018) on September 18, 2018. —30,000 stock options (SO 2018-1) on September 18, 2018. —135,000 free shares (AGA 2018) on December 19, 2018. —610,000 free shares (AGA 2018) on July 23, 2019. —1,007,500 free shares (AGA 2020) on January 28, 2020. —155,000 stock options (SO 2018-2) on September 22, 2020. —20,000 stock options (SO 2018-3) on February 25, 2021. •with the authorization of the General Meeting of Shareholders on June 11, 2019, the Board of Directors issued: —105,000 non-employee warrants (BSA 2019) on July 23, 2019. —40,000 non-employee warrants (BSA 2019) on January 28, 2020. •with the authorization of the General Meeting of Shareholders on April 29, 2020, the Board of Directors issued: —85,000 free shares (AGA 2020) on September 22, 2020. —80,000 non-employee warrants (BSA 2020) on November 2, 2020. —40,000 non-employee warrants (BSA 2021) on February 25, 2021. —880,000 free shares (AGA 2021) on February 25, 2021. •with the authorization of the General Meeting of Shareholders on April 29, 2021, the Board of Directors issued: —30,000 non-employee warrants (BSA 2021-2) on October 21, 2021. —380,000 free shares (AGA 2021) on October 21, 2021 —80,000 non-employee warrants (BSA 2021-3) on December 14, 2021. These warrants have not yet been subscribed by the beneficiaries as of December 31, 2021. 19.1Employee warrants (BCE) Vesting schedule All BCE granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 10 years from the date of grant. Details and main characteristics of the BCE granted to date BCE 2013-02 BCE 2013-02 BCE 2014-06 BCE 2015-06 Date of grant July 8, 2013 April 9, 2014 December 3, 2014 July 8, 2015 Plan expiration date July 7, 2023 April 8, 2024 December 2, 2024 July 7, 2025 Number of warrants initially granted 892,000 193,800 60,000 733,298 Share entitlement per warrant 1 1 1 1 Exercise price €0.025 €0.025 €0.025 €3.275 Valuation method Black - Scholes Expected volatility 42.50% 42.50% 75.21% 76.49% Expected dividend 0.00% 0.00% 0.00% 0.00% Fair value per warrant €0.44 €0.44 €2.15 €5.56 Changes in the balances of BCE BCE 2013-02 BCE 2014-06 BCE 2015-06 Total Balance outstanding at January 1, 2021 123,720 60,000 466,582 650,302 Granted during the period — — — — Exercised during the period (76,120) (60,000) (12,000) (148,120) Forfeited during the period — — — — Balance outstanding at December 31, 2021 47,600 — 454,582 502,182 Of which exercisable 47,600 — 454,582 502,182 19.2Non-employee warrants (BSA) Vesting schedule BSA 2013-02 and BSA 2015-06 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 10 years from the date of grant. BSA 2016 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 100% on the first anniversary of the date of grant; and •at the latest within 10 years from the date of grant. BSA 2017 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 on the date of the grant; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within 7 years from the date of grant. BSA 2018 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 on the date of the grant; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within 7 years from the date of grant. BSA 2019 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 on the date of the grant; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within 7 years from the date of grant. BSA 2020 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 on the date of the grant; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within 7 years from the date of grant. BSA 2021 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •1/3 as from the first anniversary of the allotment date; •1/3 as from the second anniversary of the allotment date; and •1/3 as from the third anniversary of the allotment date. BSA 2013-02 BSA 2013-02 BSA 2015-06 BSA 2016 BSA 2017 BSA 2018 BSA 2019 BSA 2019 BSA 2020 BSA 2021 BSA 2021 Date of grant July 8, 2013 April 9, 2014 July 8, 2015 July 26, 2016 July 27, 2017 September 18, 2018 July 23, 2019 January 28, 2020 November 2, 2020 February 25, 2021 October 21, 2021 Plan expiration date July 7, 2023 April 8, 2024 July 7, 2025 July 25, 2023 July 26, 2024 September 17, 2025 July 22, 2026 January 27, 2027 November 1, 2027 February 24, 2028 October 20, 2028 Number of warrants initially granted 328,000 33,000 121,000 205,000 165,000 20,000 105,000 40,000 80,000 40,000 30,000 Exercise price €0.025 €0.025 €3.275 €8.08 €5.04 €2.22 €1.45 €3.48 €3.99 €7.19 €6.80 Share entitlement per warrant 1 1 1 1 1 1 1 1 1 1 1 Valuation method Black & Scholes Expected volatility 42.50% 42.50% 76.49% 62.46% 49,37% 58.02% 78.5% 85.7% 83.6% 83.7% 92.4% Expected dividend 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% Subscription price per warrant €0.08 €0.08 €0.25 €0.65 €0.40 €0.18 €0.13 €0.30 €0.13 €0.63 €0.59 Fair value per warrant (subscription price deducted) €0.36 €0.36 €5.31 €2.94 €1.64 €2.02 €1.83 €1.84 €5.09 €5.61 €3.46 Changes in the balances of BSA BSA 2013-02 BSA 2015-06 BSA 2016 BSA 2017 BSA 2018 BSA 2019 BSA 2019 BSA 2020 BSA 2021 BSA 2021 Total Balance outstanding at January 1, 2021 293,040 121,000 158,000 165,000 20,000 105,000 40,000 — — — 902,040 Granted during the period — — — — — — — 80,000 40,000 30,000 150,000 Exercised during the period (260,040) — - (30,000) (4,479) (21,667) — — — — (316,186) Forfeited during the period — — — — (521) — — — — — (521) Balance outstanding at December 31, 2021 33,000 121,000 158,000 135,000 15,000 83,333 40,000 80,000 40,000 30,000 735,333 Of which exercisable 33,000 121,000 158,000 135,000 14,583 68,021 29,167 41,667 — — 600,437 19.3Free shares (AGA) Vesting schedule In July 2016, the Company’s Board of Directors granted an aggregate of 766,000 free shares (AGA 2016) as follows: •546,000 AGA 2016 were fully acquired by key managers, including Mr. Bernard Gilly, the Chief Executive Officer of the Company, subject to the achievement of the following performance criteria no later than July 2018: —291,000 of these free shares were acquired at the completion of enrollment in RESCUE and REVERSE clinical trials in July 2017; and —255,000 free shares were acquired at the enrollment of the first patient in a Phase I/II clinical trial of GS030 in RP in July 2018. •56,000 AGA 2016 were fully acquired in July 2017 (one year after their grant date). The AGA 2016 were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. In July 2017 and in December 2017, the Company’s Board of Directors granted an aggregate of 666,000 additional AGA 2016 as follows: •544,500 AGA 2016 were acquired by key managers, including Mr. Bernard Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below no later than July 2019: —281,250 of these free shares were acquired upon receipt of the definitive results of the GS010 REVERSE clinical trial; and —the remaining 263,250 free shares were acquired upon completion of the enrollment of 50% of the patients of a Phase I/II clinical trial of GS030 in RP, on May 17, 2019. •32,500 AGA 2016 (43,500 initially granted, of which 11,000 were canceled in 2018) were fully acquired on July 2018 (one year after their grant date). The AGA 2016 were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. In September 2018 and December 2018, the Company’s Board of Directors granted an aggregate of 515,000 additional AGA 2018 as follows: •320,000 AGA 2018 (140,000 were canceled), were fully acquired by key managers, including Mr. Bernard Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below no later than September 2020: —160,000 of these free shares were acquired upon completion of the enrollment of the patients of a Phase I/II clinical trial of GS030 in RP on July 29, 2020; and —the remaining 160,000 free shares were acquired upon of the production of the first PPQ Batch of GS010 on September 1, 2020. •40,000 AGA 2018 (15,000 AGA were canceled) were fully acquired on September 18, 2019 (one year after their grant date). The AGA 2018 were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. In July 2019, the Company’s Board of Directors granted an aggregate of 610,000 additional AGA 2018 as follows: •547,500 AGA 2018 (25,000 were canceled) were fully acquired by key managers, including Mr. Bernard Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below no later than July 2021: —273,750 of these free shares were acquired upon the filing with the European Medicines Agency (EMA) of the application for Market Authorization (MA) at the European level of LUMEVOQ®, on September 14, 2020; —the remaining 273,750 of these free shares were acquired upon completion of the enrollment of the patients of a Phase I/II clinical trial of GS030 in RP on July 29, 2020; and •27,500 (10,000 were canceled) AGA 2018 were fully acquired in July 2020 (one year after their grant date). The AGA 2018 were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. With the authorization of the General Meeting of Shareholders on April 12, 2018 and of the General Meeting of Shareholders on April 29, 2020, the Board of Directors granted 1,007,500 free shares (AGA 2020) on January 28, 2020 and 85,000 (AGA 2020) on September 22, 2020, respectively, among which: •437,500 AGA 2020 were fully acquired on January 28, 2021 (one year after their grant date). The new shares were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. •As per the original plan, 652,500 (of which 347,500 were cancelled) AGA 2020 might have been fully acquired by key managers, including Mr. Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below no later than January 28, 2022: —326,250 of these free shares could have been acquired upon the approval with the European Medicines Agency (EMA) of the application for market authorization (MA) at the European level of the LUMEVOQ®; —326,250 of these free shares could have been acquired upon the filing with the Food and Drug Administration (FDA) of the application for Biologics License Application (BLA) for the LUMEVOQ®. Having regard to the consequences of the Covid-19 pandemic on the Company’s business and, more specifically, of the impact on the Company’s partners directly involved in the process of obtaining the marketing authorization for LUMEVOQ®, having led the legislator of a foreign country to adopt exceptional and binding regulations of national interest that were completely unpredictable when determining the Performance Conditions and their completion schedule; the Board of Directors has decided on September 21, 2021, to amend the Performance Bonus Shares Plans in order to postpone the deadline for the completion of Performance Conditions 1 and 2, by one year, which will now be set on January 28, 2023, has further decided that the Vesting Period of each of Tranches 1 and 2 shall end, in consequence thereof, on the date of fulfillment of the Performance Conditions affecting each tranche, without however it being able to end before September 21, 2022, even if the Performance Conditions are fulfilled before this date. Moreover, following the feedback provided by the FDA recommending that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials, the Group has considered that the second Performance Condition could not be achieved before the new deadline of Completion, ie. January 28, 2023 and therefore has decided to cancel 50% of both Performance Bonus Share Plans on December 31, 2021. With the authorization of the General Meeting of Shareholders on April 29, 2020, the Board of Directors granted 880,000 (of which 30,000 were canceled) free shares (AGA 2021) on February 25, 2021, to employees of the Company, of which: •845,000 may be fully acquired by key managers, including Mr. Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below at the latest on February 24, 2023: —50% will be acquired upon the first commercial sale of the LUMEVOQ®; and —50% will be acquired upon at the completion of the recruitment of the extension cohort of the Phase I/II clinical trial with GS030 in retinisis pigmentosa; •35,000 are not subject to performance conditions, but subject to a one-year vesting period. With the authorization of the General Meeting of Shareholders on April 29, 2021, the Board of Directors granted 380,000 free shares (AGA 2021) to employees of the Company. They are subject to (i) a two years acquisition period from the date of grant and (ii) achievement of the performance criteria described below at the latest on October 20, 2023: •50% will be acquired upon the first commercial sale of the LUMEVOQ®; and •50% will be acquired upon at the completion of the recruitment of the extension cohort of the Phase I/II clinical trial with GS030 in retinisis pigmentosa. Details and main characteristics of the AGA granted to date AGA 2016 AGA 2016 AGA 2016 AGA 2018 AGA 2018 AGA 2018 AGA 2020 AGA 2020 AGA 2021 AGA 2021 Date of grant July 26, 2016 July 27, 2017 December 19, 2017 September 18, 2018 December 19, 2018 July 23, 2019 January 28, 2020 September 22, 2020 February 25, 2021 October 21, 2021 Number of Share Awards initially granted 766,000 593,500 72,500 380,000 135,000 610,000 1,007,500 85,000 880,000 380,000 Vesting period (in Years) 1 1 1 1 1 1 1 1 1 1 Grant date Fair-value €8.08 €5.12 €5.55 €2.10 €4.04 €1.80 €3.72 €3.00 €8.87 €7.16 Performance conditions (1) Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes (1) Performance conditions concern only grants to key managers, other employees are only subject to a service condition. Changes in the balances of AGA AGA 2020 AGA 2021 TOTAL Balance outstanding at January 1, 2021 1,077,500 — 1,077,500 Granted during the period — 1,260,000 1,260,000 Vested during the period (437,500) — (437,500) Forfeited during the period (335,000) (30,000) (365,000) Balance outstanding at December 31, 2021 305,000 1,230,000 1,535,000 19.4Stock options (SO) Vesting schedule The SO 2017 granted on December 19, 2017, may be exercised by the beneficiary on the basis of the following vesting schedule: •Up to 1/4 on the date of the grant; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within seven years from the date of grant. The SO 2017 granted on March 14, 2018, may be exercised by the beneficiary on the basis of the following vesting schedule: •25% of the Options shall vest on the first anniversary of the Vesting Commencement Date; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within seven years from the date of grant. The SO 2018 granted on December 19, 2018, may be exercised by the beneficiary on the basis of the following vesting schedule: •25% of the Options shall vest on the first anniversary of the Vesting Commencement Date; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within seven years from the date of grant. The SO 2018 granted on September 22, 2020, may be exercised by the beneficiary on the basis of the following vesting schedule: •25% of the Options shall vest on the first anniversary of the Vesting Commencement Date; •the remaining 75% becoming exercisable up to 1/36 per month from the date of grant; and •at the latest within seven years from the date of grant. The SO 2018 granted on February 25, 2021, may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/3 of the SO 2021 on the first anniversary of the date of grant; •1/3 of the SO 2021 will become exercisable on the second anniversary of the date of grant and the remaining 1/3 will become exercisable on the third anniversary of the date of grant; and •at the latest within 7 years from the date of grant. Details and main characteristics of the SO granted to date SO 2017 SO 2017 SO 2017 SO 2018 SO 2018 SO 2018 Date of grant July 27, 2017 December 19, 2017 March 14, 2018 September 18, 2018 September 22, 2020 February 25, 2021 Plan expiration date July 26, 2024 December 18, 2024 March 13, 2025 September 17, 2025 September 21 2027 February 24, 2028 Number of warrants initially granted 220,000 300,000 175,000 30,000 155,000 20,000 Exercise price €5.04 €5.55 €6.98 €2.19 €2.82 €7.51 Share entitlement per stock option 1 1 1 1 1 1 Valuation method Black - Scholes Expected volatility 51.09% 50.36% 48.75% 58.02% 83.82% 83.70% Expected dividend 0.00% 0.00% 0.00% 0.00% 0.00% 0.00% Fair value per option €2.09 €2.20 €2.63 €0.91 €1.91 €5.77 Changes in the balances of SO SO 2018 TOTAL Balance outstanding at January 1, 2021 155,000 155,000 Granted during the period 20,000 20,000 Exercised during the period (45,208) (45,208) Forfeited during the period — — Balance outstanding at December 31, 2021 129,792 129,792 Of which exercisable 3,229 3,229 19.5Reconciliation with P&L share-based expenses In thousands of Euros As of December 31, 2021 As of December 31, 2020 R&D G&A S&M TOTAL R&D G&A S&M TOTAL Non-Employee Warrants (BSA) 128 335 — 463 87 62 — 149 Employee Warrants (BCE) — — — — — — — — Performance Shares (AGA) 1,064 2,651 444 4,159 614 2,568 76 3,258 Stock Options (SO) 212 — — 212 48 — — 48 Share-based payments expense 1,404 3,044 444 4,834 749 2,630 76 3,455 Note 20:Financial income and expenses The financial income and expenses are broken down as follows: In thousands of Euros As of December 31, 2021 2020 Foreign exchange gains 703 542 Net change in Derivative Financial Instrument Fair Value 1,309 — Other — 89 Financial income 2,013 631 Foreign exchange losses (336) (635) Interest expenses from Borrowings (260) — Interest expenses from Lease (125) (152) Amortized cost (Effective Interest Method) (1,781) (1,565) Net change in Derivative Financial Instrument Fair Value — (7,359) Financial expenses (2,502) (9,711) Total (489) (9,079) Foreign exchange gains and losses primarily arise from the purchase of services labeled in U.S. dollars. Derivative Financial Instruments are measured at fair-value through profit. The fair value is calculated based on financial mathematic models using observable market data as of December 31, 2020 and 2021. Interest expenses from Lease reflect interest on the lease liability deriving from the application of IFRS 16 standard. Amortized cost (Effective Interest Method) represents the calculated interests expenses of the bond Financing with Kreos as well as the interest expenses calculated on the state-guaranteed loan. Note 21:Income tax expense As mentioned in Note 3.12—Accounting Principles—Research Tax Credit, subsidies and conditional advances, the French Research Tax Credit is not included in the line item income taxes but included in the line item other income. As the Group is generating tax losses, no income tax expense has been recognized. Moreover, in accordance with the principles described in Note 3.17, and with respect to the stage of development of the Company, no deferred tax assets have been recognized in the Financial Statements. As of December 31, 2021, accumulated tax loss carryforwards since inception amounted to €199,291 K. This tax loss can be carried forward indefinitely and charged against future profits, in accordance with current French tax laws (CGI art. 209, I-al. 3 et BIC-XIV-2000s). Reconciliation between the effective and nominal income tax expense. The following table shows the reconciliation between the effective and nominal tax expense at the statutory French rate of 25.00% as of December 31, 2020 and 2021, excluding additional contributions: In thousands of Euros As of December 31, 2021 2020 Income before taxes (28,617) (34,015) Statutory tax rate 25.00% 25.00% Nominal tax expense 7,154 8,504 Increase/decrease in tax expense arising from: — — •Research tax credit (46) (414) •Share-based compensation 432 601 •Non-recognition of deferred tax assets related to tax losses and temporary differences (7,538) (8,689) •Other differences — — Income tax expense (2) (2) •Effective tax rate 0% 0% Note 22:Commitments and contingencies 22.1Commitments given Agreement with Passage de l’Innovation Services included in the lease agreement On January 1, 2015, we entered into a lease agreement for our headquarters premises in Paris, France with Passage de l’Innovation, which was amended on October 1, 2015, January 1, 2016, May 1, 2017, January 8, 2018, July 1, 2018, October 1, 2018, November 1, 2019 and October 1, 2021. The agreement includes other services provided by the lessor, among which the general management of the building, office cleaning, maintenance, electricity, reception, access to meeting rooms. The amendment signed on October 1, 2021 includes a fixed amount of €199 K to cover for the related services expenses. Commitments under service agreement – G&A operations The Group entered into a services contract with Passage de l’Innovation in connection with human resources, legal and intellectual property services on May 1, 2017, which was amended on December 15, 2017, January 31, 2018, December 18, 2018, January 1, 2020 and January 1, 2021. According to the last amendment terms and conditions, the annual cost is fixed at €244 K and each party can terminate the contract after a six-month notice period. The following table discloses information about the period in which payments are due as of December 31, 2021: In thousands of Euros Total Less than one year One to three years Four to five years More than five years Agreements with Passage de l’Innovation 1,329 443 886 — — Commitments related to R&D operations The Company has signed various licensing and collaboration agreements: •In October 2012, the Group entered into a license agreement with Inserm Transfert S.A. (“Inserm”), a French public scientific and technological institute. The Group paid a license fee of €40 K in 2013 upon the execution of the agreement, which has been recognized as research and development expenses in the statement of income. Upon completion of development milestones, the Group has to pay non-refundable fees up to €2,750 K in the aggregate. Upon commercialization of any product covered by the licensed patents, the Group will be obligated to pay a percentage of net sales as a royalty. The royalty rate varies depending on the amount of net sales. •In December 2013, the Group entered into a license agreement for use of scientific data with the Association Française contre les Myopathies, (“AFM”), a non-profit association, the French Muscular Dystrophy Association, Genethon and Inserm Transfert, acting as a delegate of Inserm, a French public scientific and technological institute and the Université Pierre et Marie Curie, (“UPMC”), a French university. The Group paid a license fee of €10 K upon the execution of the agreement, which has been recognized as research and development expenses in the Consolidated Statement of Income. Upon completion of development milestones, the Group has to pay non-refundable fees up to €688 K. Upon commercialization of any product covered by the license patents, the Group will be obligated to pay an annual royalty of 1% of net sales. •In February 2013, the Group entered into a license agreement with Novartis. The Company issued 670,588 ordinary shares as consideration paid for the licenses. The amount of the intangible asset recognized was €275 K (see Note 4) and determined by reference to the fair value of the ordinary shares that were granted by the Company in exchange for the licenses. Upon commercialization of any product covered by the licenses, the Company will be obligated to pay a royalty of 5% of net sales. •In February 2014, the Company entered into a non-exclusive license, development and commercialization agreement with Avalanche Technologies (“Avalanche” renamed “Adverum Biotechnologies”), a biotechnology company. The annual license fee payable by the Group is $30 K, which was a €26 K payment each year from 2014 to 2018 recognized as research and development expenses in the statement of income. Upon completion of development milestones, the Group has to pay specified non-refundable fees of up to $5,900 K. As of December 31, 2021, the residual commitments amount to $5,500 K. Upon commercialization of any product covered by the license patents, the Group will be obligated to pay a percentage of net sales as a royalty. The royalty rate varies depending on the amount of net sales. •In January 2016, the Group entered into a license agreement with M.I.T., upon exercising an option right granted under the patent option agreement between M.I.T. and the Group, dated January 9, 2015. Under the terms of this license agreement, the Group recognized as a research and development expense and agreed to pay a license issue fee of $45 K, license maintenance fees up to $100 K per year and variable payments up to $7,300 K depending on the achievement of milestone events. As of December 31, 2021, the residual commitments amount to $6,700 K. The Group will also pay running mid-single-digit royalties on future net sales. •In 2019, the Company entered into a non-exclusive license agreement with President and Fellows of Harvard College. Under the terms of this license agreement, we agreed to pay a non-refundable license issuance fee of $25 K. In addition, we agreed to pay an annual license maintenance fee as from the first commercial sale of a licensed product ranging from $25 K to $75 K (creditable against running royalties), a milestone payment of $25 K upon achievement of marketing authorization for the first licensed product in any country, and a running royalty of less than 1% on net sales for a period of 15 years from the date of the first commercial sale (on a licensed product by licensed product basis). •In 2019, GenSight Biologics entered into an exclusive license agreement with Sorbonne University, Centre National de la Recherche Scientifique (“CNSR”), Institut National de la Santé et de la Recherche Médicale and Satt Lutech. Under this license agreement, we paid the licensors a one-time license upfront payment of €30 K. We are also obliged to pay milestone payments upon achievement of certain development and regulatory milestone events. After the grant of a MA or BLA for the product, we are required to pay a fixed royalty fee for each first use of a product on a patient who has received the associated gene therapy treatment. In addition, we are required to pay an annual license maintenance fee creditable against the total paid amount of fixed royalty fee due on the same year. For each of these licensing and collaboration agreements, based on the significant uncertainties in the development of the product candidates as well as the Group having sole discretion to decide whether it would like to proceed with the research and development activities, the Group has concluded, based on the stage of development of its product candidates, that it is remote that a payment will be made by the Group to the parties under these licensing and collaboration agreements. Security interests attached to our bond financing The bonds and convertible bonds issued in relation to the Kreos Transaction occurred in December 2019 and August 2020 benefit from pledge agreements on our bank accounts, on our business assets, on the intellectual property rights owned by us (trademarks, patents, software, and domain names) and on our receivables. 22.2Commitments received The Group entered into a sublease agreement in New York for its U.S.-based subsidiary offices on February 13, 2020, amended on April 17, 2020. The sublease term is 2 years and will end on March 31, 2022. Sublessee delivered to the Group, an unconditional, irrevocable, self-renewing and transferable letter of credit for a total Amount of $364 K. Note 23:Relationships with related parties The Group did not conclude any new significant transactions with related parties during the period. Key management personnel compensation The compensation amounts presented below, which were awarded to key management personnel which are members of the Board of Directors of the Group, were recognized as expenses during the period presented: In thousands of Euros As of December 31, 2021 2020 Short-term employee benefits 993 867 Share-based payments benefits 2,050 1,651 Total 3,043 2,518 The methods and assumptions used for the measurement of share-based payments are described in Note 18. Liabilities to key management personnel as of December 31, 2020 and 2021 are set forth below: In thousands of Euros As of December 31, 2021 2020 Variable compensation 91 201 Total 91 201 Transactions with related parties: Mr. Bernard Gilly, CEO of GenSight Biologics, was a shareholder of Passage de l’Innovation until June 26, 2021. Therefore, Passage de l’Innovation is not a related party as of December 31, 2021. In January 2015, the Company entered into an agreement with Passage de l’Innovation for the rental of its new premises. Several amendments were signed on October 2015, January 2016, May 2017, January, July and October 2018, November 2019 and October 2021. In May 2017, the Company has entered into a service agreement (notably related to human resources, legal and intellectual property) with Passage de l’Innovation, amended consecutively in December 2017, January 2018, December 2019, January 2020 and January 2021. The related amounts presented below were recognized as expenses in 2020: In thousands of Euros As of December 31, 2020 Rent and services 730 Total 730 No liabilities are due to related parties as of December 31, 2020 and December 31, 2021, respectively. Note 24:Earnings per share The basic earnings per share is calculated by dividing the net income for the period attributable to the shareholders of the Group by the weighted average number of ordinary shares outstanding during the period. Preferred shares had the same rights and dividends as ordinary shares for purposes of calculating earnings per share. All preferred shares were converted on a one-for-one basis into ordinary shares upon completion of the IPO on Euronext Paris in July 2016. All outstanding ordinary shares have been taken into consideration for purposes of calculating basic earnings per share. The weighted average number of ordinary shares was 35,126,688 and 45,150,592 for the years ended December 31, 2020 and 2021, respectively. The diluted earnings per share is calculated by dividing the net income for the period attributable to shareholders of the Group by the weighted average number of shares outstanding plus any potentially dilutive shares not yet issued from share-based compensation plans (see Note 18). Dilution is defined as a reduction of earnings per share or an increase of loss per share. When the exercise of outstanding share options and warrants decreases loss per share, they are considered to be anti-dilutive and excluded from the calculation of loss per share. Thus, basic and diluted earnings (loss) per share are equal as all equity instruments issued, representing 3,511,268 and 3,628,733 potential additional ordinary shares, for the years ended December 31, 2020 and 2021, respectively, have been considered anti-dilutive. In thousands of Euros, except for earning (loss) per share As of December 31, 2021 2020 Net income (loss) of the reporting period (28,617) (34,015) Adjusted weighted average number of outstanding shares 45,150,592 35,126,688 Basic and diluted earnings (loss) per share €(0.63) €(0.97) Note 25:Management of financial risks The principal financial instruments held by the Group are cash and cash equivalents. The purpose of holding these instruments is to finance the ongoing business activities of the Group. It is not the Group’s policy to invest in financial instruments for speculative purposes. The Group does not utilize derivatives. The principal risks to which the Group is exposed are liquidity risk, foreign currency exchange risk, interest rate risk and credit risk. Liquidity risk Ultimate responsibility for liquidity risk management rests with the Board of Directors, which has established an appropriate liquidity risk management framework for management of the Group’s short, medium and long-term funding and liquidity management requirements. The Group manages liquidity risk by maintaining adequate reserves, banking facilities and reserve borrowing facilities, by continuously monitoring forecast and actual cash flows, and by matching the maturity profiles of financial assets and liabilities. The note 11.3 details the Group’s remaining contractual maturity for its non-derivative financial liabilities with agreed repayment periods. As of December 31, 2021, the Group has sufficient net working capital to meet its obligations during the next 12 months. See Note 2.2 Going Concern. Foreign currency exchange risk The Group is exposed to foreign exchange risk inherent in certain services provided in the United States, which have been invoiced in U.S. dollars. The Group does not currently have revenues in dollars nor in any other currency. Due to the relatively low level of these expenditures, the exposure to foreign exchange risk is unlikely to have a material adverse impact on the results of operations or financial position of the Group. The Group’s exposure to currencies other than the U.S. dollar is negligible. For the years ended December 31, 2020 and 2021, approximately 32% and 35%, respectively, of its purchases and other external expenses were made in U.S. dollars, generating a net foreign exchange loss of €92 K and gain of €367 K, respectively. In light of these insignificant amounts, the Group has not adopted, at this stage, a hedging mechanism in order to protect its business activity against fluctuations in exchange rates. As the Group further increases its business, particularly in the United States, the Group expects to face greater exposure to exchange rate risk and would then consider adopting an appropriate policy for hedging against these risks. Interest rate risk The Company has low exposure to interest rate risk. The Group borrow funds at fixed interest rates. The repayment flows of the advances from Banque Publique d’Investissement (“BPI France”) and the borrowings are not subject to interest rate risk. Credit risk In order to minimize credit risk, the Group has adopted a policy of only dealing with creditworthy counterparties and obtaining sufficient collateral, where appropriate, as a means of mitigating the risk of financial loss from defaults. The Group’s exposure and the credit ratings of its counterparties are continuously monitored and the aggregate value of transactions concluded is spread amongst approved counterparties. The credit risk related to the Group’s cash and cash equivalents is not significant in light of the quality of the co-contracting financial institutions. The Group does not have significant credit risk exposure to any single customer or any group of counterparties having similar characteristics. Fair value The fair value of financial instruments traded on an active market is based on the market rate as of December 31, 2021. The market prices used for the financial assets owned by the Company are the bid prices in effect on the market as of the valuation date. The nominal value, less the provisions for depreciation, of the accounts receivable and current debts, is presumed to approximate the fair value of those items. Capital risk management The Group manages its capital to ensure that entities in the Group will be able to continue as going concerns while maximizing the return to shareholders through the optimization of the debt and equity balance. The Group’s overall strategy remains unchanged from 2020. The capital structure of the Group consists of net debt (borrowings disclosed in notes 10 after deducting cash and bank balances) and equity of the Group (comprising issued capital, reserves and retained earnings and non-controlling interests as disclosed in Note 10). The Group is not subject to any externally imposed capital requirements. Note 26:Auditor’s fees The auditors’ fees paid by the Group in 2021 amounted to €331 K. In thousands of Euros 2021 Becouze Deloite & Associés Amount % Amount % Audit certification 146 57% 160 59% Reports and diligences related to Financing Operations 2 35% 12 35% Other reports for French legal purposes 11 8% — 6% Total 159 100% 172 100% Note 27:Subsequent events On April 7, 2022, the Company announced a delay in the completion of the validation (PPQ) batches for LUMEVOQ®. The latest campaign, which was initiated after the company addressed an equipment issue that caused the 2021 campaign to fail, generated drug substance whose viral genome titer fell below the acceptance threshold. Resulting investigations led by external experts have traced the outcome to operational difficulties in specific stages of the downstream process. To prevent the repeat of these issues, the Company is working with its manufacturing partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, the Company has decided to manufacture smaller engineering lots to confirm the robustness of the corrective actions. The supply of LUMEVOQ® vials available for compassionate use has been used up, so treatments can only resume in early 2023 when test results confirm the quality of the product from the new PPQ campaign. Since the issues described above occurred in 2022, the company considers the developments after the reporting date as a non-adjusting subsequent event. 18.1.2Statutory Auditors’ report on the consolidated financial statements for the year ended December 31, 2021 This is a translation into English of the statutory auditors’ report on the financial statements of the Company issued in French and it is provided solely for the convenience of English speaking users. This statutory auditors’ report includes information required by French law, such as information about the appointment of the statutory auditors or verification of the Management report and other documents provided to shareholders. This report should be read in conjunction with, and construed in accordance with, French law and professional auditing standards applicable in France. To the GENSIGHT BIOLOGICS S.A. Shareholder’s Meeting, Opinion In compliance with the engagement entrusted to us by your bylaws and your Shareholders’ Meeting, we have audited the accompanying consolidated financial statements of GENSIGHT BIOLOGICS S.A. for the year ended December 31st, 2021. In our opinion, the consolidated financial statements give a true and fair view of the assets and liabilities and of the financial position of the Group as of December 31st, 2021 and of the results of its operations for the year then ended in accordance with International Financial Reporting Standards as adopted by the European Union. The audit opinion expressed above is consistent with our report to the Audit Committee. Basis for Opinion Audit Framework We conducted our audit in accordance with professional standards applicable in France. We believe that the audit evidence we have obtained is sufficient and appropriate to provide a basis for our opinion. Our responsibilities under those standards are further described in the Statutory Auditors' Responsibilities for the Audit of the Consolidated Financial Statements section of our report. Independence We conducted our audit engagement in compliance with independence requirements of the French Commercial Code (Code de commerce) and the French Code of Ethics (Code de déontologie) for statutory auditors, for the period from January 1st, 2021 to the date of our report, and specifically we did not provide any prohibited non-audit services referred to in Article 5(1) of Regulation (EU) No 537/2014. Justification of Assessments – Key Audit Matters Due to the global crisis related to the Covid-19 pandemic, the financial statements of this period have been prepared and audited under specific conditions. Indeed, this crisis and the exceptional measures taken in the context of the state of sanitary emergency have had numerous consequences for companies, particularly on their operations and their financing, and have led to greater uncertainties on their future prospects. Those measures, such as travel restrictions and remote working, have also had an impact on the companies' internal organization and the performance of the audits. It is in this complex and evolving context that, in accordance with the requirements of Articles L. 823-9 and R. 823-7 of the French Commercial Code (Code de commerce) relating to the justification of our assessments, we inform you of the key audit matters relating to risks of material misstatement that, in our professional judgment, were of most significance in our audit of the consolidated financial statements of the current period, as well as how we addressed those risks. These matters were addressed in the context of our audit of the consolidated financial statements as a whole, approved in the conditions mentioned above, and in forming our opinion thereon, and we do not provide a separate opinion on specific items of the consolidated financial statements. Key Audit Matter 1: Recording of research and development costs (Refer to note "3.20 Use of estimates" and note "18.1 Research and development expenses" to the notes to the consolidated financial statements as of December 31st, 2021) Description of the risk Research and development costs represent a significant component of the Company’ financial statements, considering Company’s activity and its current development phase, as they account for almost 64 % of total operating expenses. These expenses mainly include external subcontracting costs or product manufacturing as well as personnel costs. There may be discrepancies between the achievement of subcontracting or manufacturing services and their related invoicing. The need of estimating the amount of services already achieved but not invoiced, or at the opposite, services already invoiced but not realized, leads to a risk of misevaluation of the invoices to be received or prepaid expenses regarding these external costs at year end. The estimate of the amount of services already performed to be recognized at year end thus requires significant judgments from the Management. We therefore considered that the accounting of research and development expenses is a key audit matter. Audit procedures implemented to deal with identified risks As part of our audit, we reviewed the internal control procedures related to the accounting of subcontracting and manufacturing expenses in order to identify control activities implemented by Management and evaluate their design. Our work was supplemented by procedures, on a sampling basis, of account payable confirmation requests and an analysis of subcontracting invoices received before and after year end, in order to identify which exercise they related to and evaluate the correct linkage with fiscal year. Key Audit Matter 2: Determination of LUMEVOQ®’s price (Refer to notes “3.16 Revenue”, “3.20 Use of estimates”, “13.1 Refund liability” and “16: Income” to the notes to the consolidated financial statements as of December 31st, 2021) Description of the risk The Company started in 2019 the sale of LUMEVOQ® through the named patient program Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts. Revenues generated by LUMEVOQ® through ATU nominative amount to €5.3 million as of December 31st, 2021 compared to €4.4 million as of December 31st, 2020. The Company receives a preliminary price by the hospitals. Upon obtaining full marketing authorization (ANM) and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price, difference that is considered as a variable consideration according to IFRS 15. The methodology and assumptions used by the Company to estimate the amount that may be required to reimburse to URSSAF are monitored and adjusted regularly by Management in the light of contractual and legal obligations development, past experience, trends and projected market conditions. Thus, in 2021, the Company adjusted the variable consideration for which it’s highly probable that a significant reversal in the amount of cumulative revenue recognized will not occur. The Company records a refund liability for the discounted value of the consideration received for which the Company expects to refund the URSSAF. The discounted liability for this reimbursement amounts to €5.5 million as of December 31st, 2021 compared to €1.2 million as of December 31st, 2020. The assessment of the variable consideration included in the transaction price is a key audit matter, given the amounts involved and the high level of estimation and judgment required from Management. Audit procedures implemented to deal with identified risks We obtained an understanding of the process and analyzed the design of controls relating to Management’s assessment of the variable consideration to be included in the transaction price. Our audit procedures also included, among others, evaluating the appropriateness of the significant assumptions used by Management. Evaluating Management’s assumptions involved evaluating whether the assumptions used by Management were reasonable by considering the consistency of assumptions with (i) external market and industry data, such as than the selling price of comparable products and (ii) with evidence obtained in other areas of the audit such as internal company communications and presentations, external communications and analyst reports. Key Audit Matter 3: Going concern (Refer to note “2.2 Going concern” and note“25: Management of financial risks” to the notes to the consolidated financial statements as of December 31st, 2021) Description of the risk At the approval date of the financial statements, the Company assessed the going concern, taken into consideration the Company believes it will be able to fund its operations until early first quarter 2023, considering: •Cash and cash equivalents held by the Company amounting to €44.3 million as of December 31st, 2021; •The cash consumption forecasted for the year 2022; •The 2022 revenue forecast generated by LUMEVOQ®; •The expected reimbursement in 2022 of research tax credits receivable. We identified the assessment of the Company's ability to continue as a going concern as a key audit matter because the assessment of going concern is dependent upon certain Management assumptions and judgments and due to the inherent uncertainty involved in forecasting future cash flows. Audit procedures implemented to deal with identified risks We have in particular: •gained an understanding of the process implemented to prepare the cash flow forecasts and estimated expenditures; •assessed the key assumptions used by Management in the cash flow forecasts, based on our understanding of the Company’s business and future plans approved by the Board of Directors; •assessed the appropriateness of the related disclosures in the notes to the consolidated financial statements; •enquired of Management whether there are circumstances or events which occurred since December 31st, 2021, that might put into question the going concern assessment. Specific Verifications We have also performed, in accordance with professional standards applicable in France, the specific verifications required by laws and regulations of the information pertaining to the Group presented in the Management report of the Board of Directors. We have no matters to report as to its fair presentation and its consistency with the consolidated financial statements. Other Legal and Regulatory Verifications or Information Format of presentation of the consolidated financial statements intended to be included in the annual financial report We have also verified, in accordance with the professional standard applicable in France relating to the procedures performed by the statutory auditor relating to the annual and consolidated financial statements presented in the European single electronic format, that the presentation of the consolidated financial statements intended to be included in the annual financial report mentioned in Article L. 451-1-2, I of the French Monetary and Financial Code (Code monétaire et financier), prepared under the responsibility of Management, complies with the single electronic format defined in the European Delegated Regulation No 2019/815 of December 17, 2018. As it relates to consolidated financial statements, our work includes verifying that the tagging of these consolidated financial statements complies with the format defined in the above delegated regulation. Based on the work we have performed, we conclude that the presentation of the consolidated financial statements intended to be included in the annual financial report complies, in all material respects, with the European single electronic format. We have no responsibility to verify that the consolidated financial statements that will ultimately be included by your Company in the annual financial report filed with the AMF are in agreement with those on which we have performed our work. Appointment of the Statutory Auditors We were appointed as statutory auditors of GENSIGHT BIOLOGICS S.A. by the bylaws of April 17, 2012 for Deloitte & Associés and by the Shareholders’ Meeting of May 19, 2016 for Becouze. As at December 31st, 2021, Deloitte & Associés was in the 9th year of total uninterrupted engagement and Becouze was in the 6th year of total uninterrupted engagement, including six years of joint work since securities of the Company were admitted to trading on a regulated market. Responsibilities of Management and Those Charged with Governance for the Consolidated Financial Statements Management is responsible for the preparation and fair presentation of the consolidated financial statements in accordance with International Financial Reporting Standards as adopted by the European Union, and for such internal control as Management determines is necessary to enable the preparation of consolidated financial statements that are free from material misstatement, whether due to fraud or error. In preparing the consolidated financial statements, Management is responsible for assessing the Company’s ability to continue as a going concern, disclosing, as applicable, matters related to going concern and using the going concern basis of accounting unless it is expected to liquidate the Company or to cease operations. The Audit Committee is responsible for monitoring the financial reporting process and the effectiveness of internal control and risks management systems and where applicable, its internal audit, regarding the accounting and financial reporting procedures. The consolidated financial statements were approved by the Board of Directors. Statutory Auditors’ Responsibilities for the Audit of the Consolidated Financial Statements Objectives and audit approach Our role is to issue a report on the consolidated financial statements. Our objective is to obtain reasonable assurance about whether the consolidated financial statements as a whole are free from material misstatement. Reasonable assurance is a high level of assurance but is not a guarantee that an audit conducted in accordance with professional standards will always detect a material misstatement when it exists. Misstatements can arise from fraud or error and are considered material if, individually or in the aggregate, they could reasonably be expected to influence the economic decisions of users taken on the basis of these consolidated financial statements. As specified in Article L. 823-10-1 of the French Commercial Code (Code de commerce), our statutory audit does not include assurance on the viability of the Company or the quality of management of the affairs of the Company. As part of an audit conducted in accordance with professional standards applicable in France, the statutory auditor exercises professional judgment throughout the audit and furthermore: •Identifies and assesses the risks of material misstatement of the consolidated financial statements, whether due to fraud or error, designs and performs audit procedures responsive to those risks, and obtains audit evidence considered to be sufficient and appropriate to provide a basis for his opinion. The risk of not detecting a material misstatement resulting from fraud is higher than for one resulting from error, as fraud may involve collusion, forgery, intentional omissions, misrepresentations, or the override of internal control. •Obtains an understanding of internal control relevant to the audit in order to design audit procedures that are appropriate in the circumstances, but not for the purpose of expressing an opinion on the effectiveness of the internal control. •Evaluates the appropriateness of accounting policies used and the reasonableness of accounting estimates and related disclosures made by Management in the consolidated financial statements. •Assesses the appropriateness of Management’s use of the going concern basis of accounting and, based on the audit evidence obtained, whether a material uncertainty exists related to events or conditions that may cast significant doubt on the Company’s ability to continue as a going concern. This assessment is based on the audit evidence obtained up to the date of his audit report. However, future events or conditions may cause the Company to cease to continue as a going concern. If the statutory auditor concludes that a material uncertainty exists, there is a requirement to draw attention in the audit report to the related disclosures in the consolidated financial statements or, if such disclosures are not provided or inadequate, to modify the opinion expressed therein. •Evaluates the overall presentation of the consolidated financial statements and assesses whether these statements represent the underlying transactions and events in a manner that achieves fair presentation. •Obtains sufficient appropriate audit evidence regarding the financial information of the entities or business activities within the Group to express an opinion on the consolidated financial statements. The statutory auditor is responsible for the direction, supervision and performance of the audit of the consolidated financial statements and for the opinion expressed on these consolidated financial statements. Report to the Audit Committee We submit a report to the Audit Committee which includes in particular a description of the scope of the audit and the audit program implemented, as well as the results of our audit. We also report, if any, significant deficiencies in internal control regarding the accounting and financial reporting procedures that we have identified. Our report to the Audit Committee includes the risks of material misstatement that, in our professional judgment, were of most significance in the audit of the consolidated financial statements of the current period and which are therefore the key audit matters, that we are required to describe in this report. We also provide the Audit Committee with the declaration provided for in Article 6 of Regulation (EU) N° 537/2014, confirming our independence within the meaning of the rules applicable in France such as they are set in particular by Articles L.822-10 to L.822-14 of the French Commercial Code (Code de commerce) and in the French Code of Ethics (Code de déontologie) for statutory auditors. Where appropriate, we discuss with the Audit Committee the risks that may reasonably be thought to bear on our independence, and the related safeguards. Paris and Bordeaux, April 29, 2022 The Statutory Auditors French original signed by Becouze Fabien BROVEDANI Partner Deloitte & Associés Stéphane LEMANISSIER Partner 18.1.3COMPANY’S ANNUAL FINANCIAL STATEMENTS (FRENCH GAAP) FOR THE FISCAL YEAR ENDING DECEMBER 31, 2021 1.BALANCE SHEET ASSETS In thousands of Euros Note 12/31/2021 12/31/2020 Gross Deprec. Prov. Net Net Non-current assets Intangible assets 1 Software 18 18 1 3 Tangible assets 2 Property, plant and equipment 1,213 910 303 437 Other tangible assets 546 507 38 45 Financial assets 3 Other financial assets 1,611 45 1,566 1,231 Total non-current assets 3,387 1,479 1,908 1,716 Current assets Receivables 4 Down payments 1,866 — 1,866 293 Accounts receivable 1,914 — 1,914 1,094 Other receivables 3,615 — 3,615 3,212 Loans and receivables 6,095 3,327 2,768 2,200 Cash 5 Cash and cash equivalents 43,924 — 43,924 37,758 Prepaid expenses 2,514 — 2,514 1,667 Total current assets 59,929 3,327 56,602 46,224 Regularization accounts: Foreign exchange differences - assets 6 — 6 240 TOTAL ASSETS 63,323 4,807 58,516 48,180 The attached note forms an integral part of the financial statements. LIABILITIES AND SHAREHOLDERS’ EQUITY In thousands of Euros Note 12/31/2021 12/31/2020 Shareholders' equity 6 Share capital 1,158 1,022 Premiums related to the share capital 181,175 152,776 Legal reserve - - Restricted reserves 174 174 Retained earnings (141,004) (119,092) Net loss (25,172) (21,911) Total Shareholders' equity 16,331 12,969 Provisions for liabilities and charges: Provisions for liabilities 67 261 Total provisions for liabilities and charges 67 261 Liabilities: 7 Straight bonds 4,567 6,700 Convertible bonds 1,650 1,650 Borrowings from Banks 5,829 6,768 Refundable advances 4,939 4,679 Trade payables 15,511 10,846 Tax and social liabilities 2,446 2,659 Other liabilities 7,064 1,564 Total liabilities 42,005 34,866 Regularization accounts: Foreign exchange differences - liabilities 112 84 TOTAL LIABILITIES AND SHAREHOLDERS' EQUITY 58,516 48,180 The attached note forms an integral part of the financial statements. 2.STATEMENTS OF INCOME (LOSS) In thousands of Euros 12/31/2021 12/31/2020 Sales of products or services 10 4,470 4,070 Income 4,470 4,070 Operating revenues: Grants - 282 Transferred expenses 5 - Other revenues 160 570 Total operating revenues (I) 4,635 4,923 Operating expenses: Purchases of raw material 43 427 Other purchases and external expenses 22,985 18,992 Tax expenses 121 77 Payroll expenses 4,431 3,680 Social charges 2,130 2,877 Depreciation, amortization and provision 212 212 Provision for Risks and Expenses — — Other expenses 1,472 2,225 Total operating expenses (II) 31,394 28,490 OPERATING LOSS (I-II) (26,760) (23,567) Financial income Foreign exchange gains 335 — Other financial income 246 520 Total financial income (III) 581 520 Financial expenses Foreign exchange losses 138 51 Depreciation and amortization 302 940 Interest expenses on borrowings and financial debt 969 637 Other financial expenses 9 - Total Financial expenses (IV) 1,418 1,628 FINANCIAL INCOME (EXPENSES) (III-IV) 11 (838) (1,108) EARNING BEFORE TAX (I-II+III-IV) (27,597) (24,675) EXTRAORDINARY INCOME (EXPENSES) (V-VI) 12 (8) — Income taxes 15 2,433 2,764 NET INCOME (LOSS) (25,172) (21,911) The attached note forms an integral part of the financial statements. For ease of presentation, numbers have been rounded. Calculations, however, are based on exact figures. Therefore, the sum of the numbers in a column of a table may not conform to the total figure displayed in the column. 3.NOTES TO THE FINANCIAL STATEMENTS GOING CONCERN Since its incorporation, the Company has funded its activities through several equity financings, grants, conditional advances and Research Tax Credit. Since the end of 2019, the Company started to generate revenue from the sale of LUMEVOQ® in France, since the French National Drug Safety Agency (ANSM) granted a named patient Temporary Authorization for Use (ATU nominative) for LUMEVOQ®. As mentioned in the paragraph Events after the close of the fiscal year, following a delay in manufacturing validation batches of LUMEVOQ®, GenSight plan to restart the manufacturing of the validation batches at its Cambridge, US, manufacturing facility during Q3 2022. The Company therefore expects a delay in the commercialization of LUMEVOQ®. Considering the cash position as of December 31, 2021 (amounting to €43.9 million), the reimbursement of the 2021 Research Tax Credit contemplated in 2022 for a consideration of €2.4 million and additional cash related to the ATU sales in France granted during Q1 2022, the Company believes it will be able to fund its operations until early first quarter 2023. By that date, the Company will have to find additional funding. Various financing sources are considered among the issuance of new debt or equity instruments. The Company believes it will have the ability to raise additional funds during 2022. On this basis, the financial statements have been prepared on a going concern basis. MAIN EVENTS OF THE FISCAL YEAR On March 26, 2021, GenSight Biologics announced the success of a capital increase. The Company has issued 4,477,612 new ordinary shares with a nominal value of €0.025 each (the “New Shares“), for total gross proceeds of approximately €30 million by means of an accelerated bookbuilding process to the benefit of categories of persons (the “Reserved Offering“). The book was largely oversubscribed, based on demand from new investors. The issue price of the New Shares is €6.70 per share, representing a 9.0% discount to the last closing share price and a 12.7% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., March 19, 22, 23, 24 and 25, 2021), in accordance with the 19th resolution of the combined annual general meeting of shareholders of the Company held on April 29, 2020. On December 30, 2021, GenSight Biologics incorporated a second subsidiary, GenSight Biologics France SAS, registered and located in France. It is wholly owned by GenSight Biologics S.A. and therefore fully consolidated. MAIN EVENTS OF THE PREVIOUS FISCAL YEAR On October 22, 2020, GenSight announced that it had raised €25 million in an oversubscribed private placement with Us and European institutional investors. The transaction was led by Arix Bioscience plc (LON: ARIX), Invus and Sofinnova Partners.The Company has issued 5,954,650 new ordinary shares with a nominal value of €0.025 each (the “New Shares”), for total gross proceeds of approximately €25 million by means of an accelerated bookbuilding process to the benefit of categories of persons (the “Reserved Offering”). The book was oversubscribed, based on demand from new and existing investors. The issue price of the New Shares is €4.20 per share, representing a 12.5% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., October 15, 16, 19, 20 and 21, 2020), in accordance with the 19th resolution of the combined annual general meeting of shareholders of the Company held on April 29, 2020. On December 10, 2020, GenSight Biologics announced that it has received, in connection with its bond agreement entered with Kreos Capital VI (Expert Fund) LP (“Kreos“), the notification by Kreos of the conversion of 50% of the convertible bonds of tranches A and B (at a price of €2.245 per share), the conversion of 50% of the additional convertible bonds of tranche B (at a price of €2.574 per share) and the exercise of all share warrants of tranches A and B (at a price of €2.245 per share), representing a total issuance of 1,182,953 new ordinary shares. EVENTS AFTER THE CLOSE OF THE FISCAL YEAR On April 7, 2022, the Company announced a delay in the completion of the validation (PPQ) batches for LUMEVOQ®. The latest campaign, which was initiated after the company addressed an equipment issue that caused the 2021 campaign to fail, generated drug substance whose viral genome titer fell below the acceptance threshold. Resulting investigations led by external experts have traced the outcome to operational difficulties in specific stages of the downstream process. To prevent the repeat of these issues, the Company is working with its manufacturing partner to implement targeted corrections around enhanced process control and more rigorous supervision inside the manufacturing suites. In addition, the Company has decided to manufacture smaller engineering lots to confirm the robustness of the corrective actions. The supply of LUMEVOQ® vials available for compassionate use has been used up, so treatments can only resume in early 2023 when test results confirm the quality of the product from the new PPQ campaign. Since the issues described above occurred in 2022, the company considers the developments after the reporting date as a non-adjusting subsequent event. ACCOUNTING PRINCIPLES The annual financial statements for the financial year ended December 31, 2021 have been prepared and presented in accordance with French accounting rules in compliance with the principle of prudence and independence of financial years. The annual financial statements have been prepared in accordance with the provisions of the French Commercial Code and ANC regulation 2014-03 of June 5, 2014 relating to the general chart of accounts and the ANC regulations modifying it. In accordance with Article L.222-3 of the AMF General Regulations, the Company has opted to postpone for one year the obligation to draw up its annual financial report in a single electronic information format such as as defined by European Delegated Regulation no. 2019/815 of December 17, 2018. Non-current assets Tangible and intangible assets are recorded at the contribution value or at their original purchase price. Depreciation of tangible assets is calculated using the straight-line method to take into account the economic depreciation of fixed assets. At the closing of the accounts, whenever events or market developments suggest the need for impairment of intangible and tangible assets, expected future revenues of the activity are compared to the net value of its assets. If applicable, the corresponding assets are written down to bring them to their fair value. Intangible assets Research costs are recorded in the financial statements as expenses. Development costs are recognized in the financial statements as intangible assets only if all the following criteria are met: •It is technically feasible to complete the development of the project; •Intention of the Company to complete the project and to utilize it; •Capacity to utilize the intangible asset; •Proof of the probability of future economic benefits associated with the asset; •Availability of the technical, financial and other resources for completing the project; and •Reliable evaluation of the development expenses. Because of the risks and uncertainties related to regulatory authorizations and to the research and development process, the Company considers that the six criteria would be deemed fulfilled as from the grant of market authorization. Intangible assets consist of patents, costs related to the acquisition of software licenses. They are depreciated using the straight-line method over their expected period of use. Items Depreciation period Patents 20 years Software 3 years Tangible assets Tangible assets are recorded at their acquisition cost or, if applicable, at their production cost. Tangible assets are depreciated using the straight-line method over the estimated useful period of the property. Rented fixtures are depreciated over the term of their lifetime or over the term of the rental agreement, whichever is shorter. The depreciation periods used are the following: Items Depreciation period Fixtures and improvementin structures 9 years Research and development equipments 5 to 10 years Computer equipment 3 years Office equipment and furniture 5 years Financial assets Investments These items are recognized in the balance sheet at purchase cost excluding incidental expenses. Their value is assessed annually by reference to their value in use which is mainly based on the current and forecast profitability of the subsidiary concerned and the share of equity owned. If the value in use falls below the net book value, a depreciation is recognized. Security deposit They are recorded at their original value. Short-term investments Marketable securities are held in order to meet short-term cash commitments rather than an investment objective or for other purposes. They are immediately convertible into a known amount of cash and subject to insignificant risk of changes in value. Short-term investments are stated at acquisition cost and consist of immediately mobilized term investments without penalty. Receivables and payables Receivables and payables are measured at their nominal. Receivables are depreciated as a provision in order to take into account potential losses due to recovery difficulties. Receivables and payables in foreign currencies are converted into euros based on exchange rate at the closing of year-end, the gap being carried over in an adjustment account for the asset or a liability depending on whether a loss or profit potential. In the case of a potential loss, a provision for foreign exchange loss is recognized. Loans Loans are booked at their nominal value. Related transaction costs are immediately expensed. Accrued interests are recognized as a liability at the interest rate provided in the contract. Provisions for risks and expenses The Company establishes provisions for risks and expenses in accordance with the definition given in the notice CRC 00-06 on liabilities, namely: •A provision for risk and expenses corresponds to the commitments whose due dates and amounts are uncertain. •A provision is recognized in the financial statement when the Company has a legal or implicit obligation to a third party resulting from a past event, which is likely or certain to cause an outflow of resources to that third party, and provided that the future outflows of liquid assets can be estimated reliably. Conditional advances The Company has benefited from a financial assistance in the form of non-refundable subsidies and conditional advances. Subsidies are recognized in the financial statements where there exists reasonable assurance that: •The Company will comply with the conditions attached to the subsidies; and •The subsidies will be received. A public subsidy that is to be received either as a compensation for expenses or for losses already incurred or for immediate financial support of the company without associated future costs, is recognized in the financial statements as other income for the period in which the grant is classified as a receivable. Funds received in the form of conditional advances are recognized as financial liabilities, including capitalized interests. The obligation to repay totally or partially the advance is based on the technical and commercial success of the funded program. Details related to the conditional advances are provided in Note 7. Revenue recognition A product is recognized in the operating income of the current period if it is incurred, that is to say that it is certain both in principle at the end of the year and in its amount on the date of closing of the financial statements. When the amount estimate includes a significant uncertainty and if an estimate in the form of a range is possible, the lowest assumption must be applied, so that only the certain part of the income is recognised. Our net product revenues are recognized, net of variable consideration related to certain allowances and accruals, at the time the customer obtains control of our product, i.e. after acceptance of the delivery by the customer. The sole component of variable consideration related to product revenues is related to the potential obligations resulting from the current regulatory framework of the Temporary Authorization for Use (ATU) with the Social Security and Family Allowance Contribution Collection Offices (URSSAF). In France, use of pharmaceutical products not yet approved with a Marketing Authorization (AMM) and not recruiting for a clinical trial requires first obtaining an ATU from the ANSM. The Company will be paid a preliminary price by the hospitals. Upon obtaining full marketing authorization and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price. As a result, the Company estimated these amounts and deducted them from its gross product revenues at the time the revenue is recognized. Use of estimates The preparation of the Financial Statements requires management to make estimates, assumptions and judgments that affect the reported amounts of assets, liabilities, income and expenses during the reporting period. The Group bases estimates and assumptions on historical experience when available and on various factors that it believes to be reasonable under the circumstances. The Company’s actual results may differ from these estimates under different assumptions or conditions. These estimates and judgments involve mainly: •the estimate of the repayments of the conditional advances obtained by the Company from public institutions, such as Bpifrance Financement. The anticipated repayments of the conditional advances are analyzed at each reporting period (see Note 11), and the measurement of the conditional advances classified as financial liabilities based on the effective rate method; •research and development expenses include estimates of the amount recognized over the year for subcontracts. At year-end closing, an analysis of the services already performed but not invoiced and / or already invoiced but not performed is carried out by the project managers and validated by the Company's management; and •the estimate of the selling price for LUMEVOQ® to the CHNO of the Quinze-Vingts. The National Drug Safety Agency, granted to GenSight Biologics sevaral Temporary Authorizations for Use (“ATU nominative”). Variable consideration are required to be estimated at contract inception. The Group assessed individual contracts to determine the estimated variable consideration and related constraints. In 2021, in the light of changes in legal obligations, and projected market conditions, the Company adjusted the variable considerations for which it’s highly probable that a significant reversal in the amount of cumulative revenue recognized will not occur. The total revenue presented in our financial statements as of December 31, 2021 is therefore net from those variable considerations. NOTE 1 —INTANGIBLE ASSETS Other Intangible assets break down as follows: In thousands of Euros 01/01/2021 Increase Decrease 12/31/2021 Gross 18 — — 18 Software 18 — — 18 Depreciation (15) (3) — (18) Software (15) (3) — (18) NET 3 (3) — 1 NOTE 2 —TANGIBLE ASSETS Tangibles assets break down as follows: In thousands of Euros 01/01/2021 Increase Decrease 12/31/2021 Gross 1,729 29 — 1,758 Technical equipment and installations 528 3 — 531 Leasehold improvement 681 — — 681 1,209 3 — 1,213 Office and computer equipment 194 26 — 220 Furniture 325 — — 325 520 26 — 546 Depreciation (1,247) (170) — (1,417) Technical equipment and installations (393) (62) — (455) Leasehold improvement (379) (76) — (455) (772) (138) — (910) Office and computer equipment (177) (17) — (194) Furniture (298) (16) — (313) (475) (32) — (507) NET 482 (141) — 341 NOTE 3 —FINANCIAL ASSETS Financial assets break down as follows: In thousands of Euros 01/01/2021 Increase Decrease 12/31/2021 Gross 1,231 685 (305) 1,611 Investments — 100 — 100 Security deposits 296 289 — 585 Long-term deposits 642 — (305) 337 Own shares 293 296 — 589 Depreciation — (45) — (45) Security deposits — — — — Long-term deposits — — — — Own shares — (45) — (45) TOTAL 1,231 640 (305) 1,566 On December 30, 2021, the Company created a second subsidiary, GenSight Biologics France SAS registered and located in France. The list of subsidiaries and affiliates is presented at the end of the present notes. In the context of its initial public offering, GenSight Biologics implemented a liquidity agreement. As of December 31, 2021: •Long-term deposits consisted of free cash available within this liquidity agreement; •Own shares amount to €589 K and are composed of 97,793 shares valued at the year-end rate (€5.56), adjusted by unrealized losses of €45 K. During the year, the number of shares purchased amounts to 867,377 at an average purchase price of €7.50 and the number of shares sold amounts to 814,583 at an average selling price of €7.61. NOTE 4 —RECEIVABLES Breakdown of receivables is summarized in the following table: In thousands of Euros Less than one year More than one year Total Downpayments 1,866 — 1,866 Accounts receivable and related receivables 1,914 — 1,914 Other receivables 3,469 146 3,615 Research tax credit 2,433 — 2,433 VAT 971 137 1,108 Others 65 9 74 Loans and receivables 2,768 — 2,768 Prepaid expenses 2,514 — 2,514 NET 12,532 146 12,678 Prepayments are made of advances to suppliers. As of December 31, 2021, the Company has receivables mainly resulting from the service agreement contracted with its U.S.-based subsidiary, amounting to €1,197 K, as well as resulting from the sale of LUMEVOQ®. The Company has a research tax credit amounting to €2,433 K. In the context of the inception of its U.S.-based subsidiary, the parent company granted cash advances of approximately $350 K (€300 K) on a quarterly basis. The gross balance amounts to €6,095 K as of December 31, 2021. Due to the uncertainty of the recoverability of this loan, the Company has deemed reasonable to book a depreciation of €3,327 K, representing the net amount due by the GenSight Biologics Inc., taking into account the management fees and recharges between the two entities. Prepaid expenses correspond mainly to advances on manufacturing contracts, rents, research contracts. NOTE 5 —CASH As of December 31, 2021, the Cash and cash equivalent amount to €43,924 K (€37,758 K as of December 31, 2020). NOTE 6 —SHAREHOLDERS’ EQUITY 6.1 —Share capital As of December 31, 2021, share capital amounts to €1,158 K and consists of 46,300,591 ordinary shares with a nominal value of €0.025. Each ordinary share shall carry to holders a proportional part to the benefits and the net assets of the Company. Share class and number of shares 01/01/2021 Capital Increase Exercise of employee warrants and Acquisition of free shares Conversion of convertible Bonds Exercise of Kreos’ Warrants 12/31/2021 Share capital in €K Ordinary shares 40,875,965 4,477,612 947,014 — — 46,300,591 1,158 TOTAL 40,875,965 4,477,612 947,014 — — 46,300,591 1,158 Capital increases in favor of categories of persons On March 26, 2021, GenSight completed a capital increase of €30 million. The Company has issued 4,477,612 new ordinary shares with a nominal value of €0.025 each, for total gross proceeds of approximately €30 million by means of an accelerated bookbuilding process to the benefit of categories of persons. The book was largely oversubscribed, based on demand from new investors. The issue price of the New Shares is €6.70 per share, representing a 9.0% discount to the last closing share price and a 12.7% discount to the volume weighted average of the share prices on Euronext Paris for the last five trading sessions preceding the date on which the issuance price is set (i.e., March 19, 22, 23, 24 and 25, 2021), in accordance with the 19th resolution of the combined annual General Meeting of Shareholders of the Company held on April 29, 2020. Capital increases resulting from the exercise of Employee share Warrants (BCE) On January 19, 2021, 150,000 BCE 2014 were exercised by one holder and resulted in the issuance of 60,000 new ordinary shares. On January 22, 2021, 30,000 BCE 2015 were exercised by one holder and resulted in the issuance of 12,000 new ordinary shares. On February 12, 2021, 190,300 BCE 2013 were exercised by one holder and resulted in the issuance of 76,120 new ordinary shares. Capital increases resulting from the definitive acquisition of warrants (BSA) On March 8, 2021, 95,200 BSA 2013 were exercised and resulted in the issuance of 38,080 new ordinary shares. On June 28, 2021, 30,000 BSA 2017 were exercised and resulted in the issuance of 30,000 new ordinary shares. On June 28, 2021, 4,479 BSA 2018 were exercised and resulted in the issuance of 4,479 new ordinary shares. On November 17, 2021, 554,900 BSA 2013 were exercised and resulted in the issuance of 221,960 new ordinary shares. On November 17, 2021, 21,667 BSA 2019 were exercised and resulted in the issuance of 21,667 new ordinary shares. Capital increases resulting from the definitive acquisition of free shares (AGA) On January 28, 2021, 27,500 AGA 2020 were fully acquired by holders. On January 28, 2021, 410,000 AGA 2020 were fully acquired by holders. Capital increases resulting from the definitive acquisition of stock option (SO) On November 29, 2021, 25,208 SO 2020 were fully acquired by holders. On December 14, 2021, 20,000 SO 2020 were fully acquired by holders. 6.2 —Non-employee share warrants (BSA) The following table relates to warrants (BSA) to purchase ordinary shares as of December 31, 2021: Type of warrants BSA 2013-02 BSA 2015-06 BSA 2016 BSA 2017 BSA 2018 BSA 2019 BSA 2020 BSA 2020 BSA 2021 BSA 2021 Number of warrants issued 33,000(1) 121,000(1) 158,000 135,000 15,000 83,333 40,000 80,000 40,000 30,000 Subscription price per warrant (euros) 0.0008 0.10 0.65 0.40 0.18 0.13 0.30 0.13 0.63 0.59 Number of shares to be issued 33,000 121,000 158,000 135,000 15,000 83,333 40,000 80,000 40,000 30.000 Exercise price per share (euros) 0.025 0.025 8.080 5.040 2.22 1.45 3.48 3.99 7.19 6.80 Expiration date 04/09/24 07/07/25 07/25/23 07/27/24 09/18/25 07/22/26 01/28/27 11/01/27 02/24/28 10/20/28 (1) The figures have been adjusted in order to reflect the 5 for 2 reverse stock split which took place on August 17, 2015. 6.3 —Employee share warrants (BCE) The following table relates to warrants (BCE) to purchase ordinary shares as of December 31, 2021: Type of warrants BCE 2013-02 BCE 2015-06 Number of warrants issued 47,600(1) 454,582(1) Subscription price per warrant (euros) — — Number of shares to be issued 47,600 454,582 Exercise price per share (euros) 0.025 3.275 Expiration date 07/07/2023 07/07/2025 (1) The figures have been adjusted in order to reflect the 5 for 2 reverse stock split which took place on August 17, 2015. 6.4 —Free shares (AGA) The following table relates to free shares (AGA) as of December 31, 2021: Free shares 2020 AGA 2020-04 AGA 2021 AGA 2021-02 AGA Number of granted shares 262,500 42,500 850,000 380,000 Share value at grant (euros) 3.72 3.00 8.87 7.16 Acquisition date 01/28/2023(1) 01/28/2023(1) 02/24/2022 10/20/2023 (1) The Board of Directors decided, during its meeting dated September 21, 2021, to amend the 2020 and 2020-4 Performance Bonus Shares Plans in order to postpone the deadline for the completion of Performance Conditions 1 and 2, by one year, which will now be set on January 28, 2023. 6.5 —Stock Option (SO) The following table relates to stock option (SO) as of December 31, 2021: Stock options SO 2020 SO 2021 Number of Stock Options issued 109,792 20,000 Exercise price per share (euros) 2.82 7.51 Number of shares to be issued 109,792 20,000 Expiration date 09/21/2027 02/24/2028 6.6 —Statement of changes in shareholders’ equity In thousands of Euros Share capital Premiums related to the share capital Restricted reserves Reserves Net income (loss) Total Shareholders' equity As of 01/01/2021 1,022 152,776 174 (119,092) (21,911) 12,969 Capital increase 112 29,888 — — — 30,000 Capital increase related costs — (1,906) — — — (1,906) Exercise of employee warrants and Acquisition of free shares 16 154 — — — 170 Exercise of convertible bonds — — — — — — Allocation of prior period income (loss) — — — (21,911) 21,911 — Subscription and Exercise of share warrants 8 262 — — — 270 Net income (loss) — — — — (25,172) (25,172) As of 12/31/21 1,158 181,175 174 (141,004) (25,172) 16,331 NOTE 7 —LIABILITIES The breakdown of liabilities is provided by the following table: In thousands of Euros Less than one year Between one and five years More than five years Total Straight Bonds 2,348 2,219 — 4,567 Convertible Bonds — 1,650 — 1,650 Borrowing from Banks 2,260 3,569 — 5,829 Refundable advances — 2,152 2,787 4,939 Trade payables 15,511 — — 15,511 Tax and social liabilities 2,446 — — 2,446 Due to employees 842 — — 842 Social security and payroll contribution 1,520 — — 1,520 VAT — — — — Other taxes 84 — — 84 Other debts 1 7,063 — 7,064 TOTAL 22,565 16,653 2,787 42,005 With respect to accounts payable and related payables, no discounting effect has been recognized to the extent that amounts did not represent payables on terms longer than one year at the end of each period presented. State-guaranteed loan The Company obtained in 2020 a €6.75 million loan from a bank syndicate formed with Crédit Industriel et Commercial (CIC), BNP Paribas and Bpifrance, in the form of a state-guaranteed loan (Prêt Garanti par l’État) (the “PGE“). Initiated by the French Government to support companies during the Covid-19 crisis, the PGE is a bank loan with a fixed interest rate ranging from 0.25% and 1.75% for the first 12 months. After an initial interest-only term of one year, the loan can be amortized over up to five years at the option of the Company. The French government guarantees 90% of the borrowed amount. The Group has signed in June 2021 amendments to the initial agreements, including an amortization period of three years; until mid-2024, as well as effective interest rates ranging from 1.01% to 2.25%. Bond financing with Kreos Capital In 2019, GenSight Biologics obtained committed financing in the form of a bond financing of up to €12 million from Kreos Capital VI (UK) Limited and which included two main tranches. The first tranche of €6 million, including a €4.2 million straight bond issuance and a €1.8 million convertible bond issuance was drawn in December 2019 (“Tranche A”). The second tranche of €4 million in straight and convertible bonds was available to be drawn through September 2020, conditioned on GenSight obtaining a qualifying financing (“Tranche B”). Following the grant of the PGE and the amount of revenues anticipated to be generated from Autorisations Temporaires d’Utilisation payantes (“ATUs”), the parties have agreed that Tranche B may be drawn under more flexible conditions and no longer conditioned to the initial qualifying financing. Although the total amount of €4 million for Tranche B remains unchanged, the proportion between straight bonds and convertible bonds has been amended to include additional convertible bonds B and fewer straight bonds B. Ultimately, Tranche B included a €2.5 million of straight bond issuance and €1.5 million of convertible bond issuance. Kreos also agreed to extend the interest-only period to December 2020. In December 2020, Kreos Capital has converted 50% of the convertible bonds of tranches A and B (at a price of €2.245 per share), as well as 50% of the additional convertible bonds of tranche B (at a price of €2.574 per share). They have also exercised all share warrants of tranches A and B (at a price of €2.245 per share), representing a total issuance of 1,182,953 new ordinary shares. Kreos Capital did not exercise any bond in 2021. Bpifrance Financement refundable advance In 2014, we received a grant from Bpifrance Financement of both non-refundable subsidies and conditional advances in relation to the development of our optogenetics technology platform. The program would be funded according to a specified schedule set forth in the contract, subject to completion of milestones. As the program advances, we provided Bpifrance Financement with interim progress reports and a final report when the funded project would end. Based on these reports, we were entitled to conditional advances from Bpifrance Financement. Each award of an advance was made to help fund a specific development milestone. The total intended amount of the conditional advances initially granted was €5.7 million, of which €0.7 million were received in December 2014 and €2.3 million in July 2016. On June 3, 2020, the following was decided by the Steering Committee: •Payment of a last conditional advance of €1.1 million and a subsidy of €0.3 million to cover for the expenses related to the key-steps 3 and 4; •removal of the specific regulatory condition in key step 3; •postponement by 2 years of the repayment schedule, i.e. a first repayment deadline on June 30, 2024 instead of June 30, 2022; •establishment of a minimum lump sum reimbursement of €819 K, or 20% of the overall received conditional advance. The repayment schedule of the conditional advances has been updated accordingly for a total amount of €4,687 K (€4,096 K of cash received + €591 K of capitalized interests) and is as follows: •€550 K from June 30, 2024; •€1,000 K from June 30, 2025; •€1,500 K from June 30, 2026; and •€1,637 K from June 30, 2027; Following the repayment of all of the conditional advances, the Company may be required to make additional payments over a period of two years, depending on whether the Company reaches cumulative revenues, excluding taxes, of €80.0 million. These additional repayments should correspond to the difference between 140% of the conditional advance, considering an interest rate of 1.44% and the amount already reimbursed as per the repayment schedule; and should be done within 15 years following the first year of reimbursement, i.e. 2039. Refund liability The company recognizes a liability related to the amount received for which it expects a full or partial reimbursement obligation to the URSSAF. The refund liability amounts to 6.6 million euros as of December 31, 2021 compared to 1.6 million euros as of December 31, 2020. NOTE 8 —RESEARCH AND DEVELOPMENT EXPENSES As indicated in the accounting policies, R&D expenses are not capitalized but recorded as operating expenses. For fiscal year 2021, R&D expenses amounted to €21,530 K. NOTE 9 —ACCRUED EXPENSES The amount of accrued expenses is as follows: In thousands of Euros Less than one year More than one year Total Accounts payable, accrued expenses 9,637 — 9,637 Employees, accrued expenses 601 — 601 Employees, paid vacation 224 — 224 Social organizations, accrued expenses 487 — 487 Social organizations, paid vacation 107 — 107 Social organizations, other accrued expenses 925 — 925 Other, accrued expenses 1 7,063 7,064 TOTAL 11,981 7,063 19,045 NOTE 10 —INCOME The Company started the sale of LUMEVOQ® through the named patient Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts on December 2019. Total income as of December 31, 2020 and 2021 solely comes from those named patient ATU. Our net product revenues are recognized, net of variable consideration related to certain allowances and accruals, at the time the customer obtains control of our product, i.e. after acceptance of the delivery by the customer. The sole component of variable consideration related to product revenues is related to the potential obligations resulting from the current regulatory framework of the Temporary Authorization for Use (ATU) with the Social Security and Family Allowance Contribution Collection Offices (URSSAF). In France, use of pharmaceutical products not yet approved with a Marketing Authorization (AMM) and not recruiting for a clinical trial requires first obtaining an ATU from the ANSM. The Company will be paid a preliminary price by the hospitals. Upon obtaining full marketing authorization and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price. NOTE 11 —FINANCIAL INCOME (LOSS) Financial income (loss) as of December 31, 2021 is as follows: In thousands of Euros 12/31/2021 12/31/2020 Financial revenues 581 520 Foreign exchange gains 335 — Other financial income 246 520 Financial expenses (1,418) (1,628) Foreign exchange losses (138) (51) Financial depreciation and amortization (302) (940) Interest expenses on borrowings and financial debt (969) (637) Other financial expenses (9) — Financial Income (loss) (838) (1,108) The financial depreciation and amortization mainly correspond to the additional depreciation booked on the cash advances granted by the Company to its U.S.-based subsidiary for €251 K. Due to the uncertainty of the recoverability of this loan, the Company has deemed reasonable to book a total depreciation of €3,327 K, representing the net amount due by the GenSight Biologics Inc., taking into account the management fees and recharges between the two entities. NOTE 12 —EXTRAORDINARY INCOME (LOSS) The extraordinary income amounts to a loss of €(8) K as of December 31, 2021. NOTE 13 —HEADCOUNT As of 12/31/2021 12/31/2020 Managers 37 25 NET 37 25 NOTE 14 —INCREASE AND REDUCTIONS NOT RECOGNIZED IN FUTURE TAX DEBT (IN BASE) At the close of fiscal year 2021, the amount of deficit being indefinitely carried forward is as follows: In thousands of euros Basis Potential corporate tax savings Net operating losses 199,291 49,823 NOTE 15 —RESEARCH TAX CREDIT The Company benefits from the provisions in Articles 244 quater B and 49 septies F of the French Tax Code related to the Research Tax Credit. Changes in the Research Tax Credit over the last two periods are presented as follows: •2020: €2,764 K, reimbursed in 2021. •2021: €2,433K. NOTE 16 —Transactions with related parties The compensation granted to the Directors of the Company amounted to €993 K for fiscal year 2021. Until June 2021, the CEO of GenSight Biologics was shareholder of the Company with which GenSight Biologics has a lease contract and a service agreement (in connection with Human Resources, legal and Intellectual Property services). Therefore, Passage de l’Innovation is not a related party as of December 31, 2021. In January 2015, the Company entered into an agreement with Passage de l’Innovation for the rental of its new premises. Several amendments were signed on October 2015, January 2016, May 2017, January, July and October 2018, November 2019 and October 2021. In May 2017, the Company has entered into a service agreement (notably related to human resources, legal and intellectual property) with Passage de l’Innovation, amended consecutively in December 2017, January 2018, December 2019, January 2020 and January 2021. The related amounts presented below were recognized as expenses in 2020: In thousands of Euros As of December 31, 2020 Rent and services 730 Total 730 NOTE 17 —COMMITMENTS 17.1 —Commitments under operating leases Commitments existing as of December 31, 2021 have not changed significantly at the end of the reporting period. The table below shows the minimum contractual future payments relating to those contracts as of December 31, 2021: In thousands of Euros As of December 31, 2021 2022 528 2023 528 2024 258 2025 49 2026 49 2027 11 Total 1,422 17.2 —Commitments under service agreement – G&A operations The Company signed an addendum to the services contract in connection with human resources, legal and intellectual property services on January 1, 2021. According to this last addendum terms and conditions, the annual cost is fixed at €244 K and each party can still terminate the contract after a six-month notice period. 17.3 —Commitments related to R&D operations The Company has signed various licensing and collaboration agreements: •In 2012, the Company entered into a license agreement with a French public scientific and technological institute. The Company paid a license fee of €40 K in 2013 upon the execution of the agreement. Upon completion of development milestones, the Company has to pay non-refundable fees up to €2,750 K in the aggregate. Upon commercialization of any product covered by the licensed patents, the Company will be obligated to pay a percentage of net sales as a royalty. The royalty rate varies depending on the amount of net sales. •In 2013, the Company entered into a license agreement with a non-profit association. The Company paid a license fee of €10 K upon the execution of the agreement. Upon completion of development milestones, the Company has to pay non-refundable fees up to €688 K. Upon commercialization of any product covered by the license patents, the Company will be obligated to pay an annual royalty of 1% of net sales. •In 2013, the Company entered into a license agreement with Novartis. Upon commercialization of any product covered by the licenses, the Company will be obligated to pay a royalty of 5% of net sales. •In 2014, the Company entered into a non-exclusive license, development and commercialization agreement with a biotechnology company. The annual license fee payable by the Company is U.S.$30 K. Upon completion of development milestones, the Company has to pay specified non-refundable fees of up to U.S.$5,900 K. As of December 31, 2021, the residual commitments amount to U.S.$5,500 K. Upon commercialization of any product covered by the license patents, the Company will be obligated to pay a percentage of net sales as a royalty. The royalty rate varies depending on the amount of net sales. •In 2016, the Company entered into a license agreement with a U.S. academic research institute. Under the terms of this license agreement, the Company agreed to pay a license issue fee of $45 K, license maintenance fees up to $100 K per year and variable payments up to $7,300 K depending on the achievement of milestone events. As of December 31, 2021, the residual commitments amount to $6,700 K. The Company will also pay running mid-single-digit royalties on future net sales. •In 2019, the Company entered into a non-exclusive license agreement with a U.S. educational and charitable corporation. Under the terms of this license agreement, we agreed to pay a non-refundable license issuance fee of $25 K. In addition, we agreed to pay an annual license maintenance fee as from the first commercial sale of a licensed product ranging from $25 K to $75 K (creditable against running royalties), a milestone payment of $25 K upon achievement of marketing authorization for the first licensed product in any country, and a running royalty of less than 1% on net sales for a period of 15 years from the date of the first commercial sale (on a licensed product by licensed product basis). •In 2019, GenSight Biologics entered into an exclusive license agreement with 3 Scientific and Technological Public Institutes (EPST) and a private technology transfer company. Under this license agreement, we paid the licensors a one-time license upfront payment of €30 K. We are also obliged to pay milestone payments upon achievement of certain development and regulatory milestone events. After the grant of a MA or BLA for the product, we are required to pay a fixed royalty fee for each first use of a product on a patient who has received the associated gene therapy treatment. In addition, we are required to pay an annual license maintenance fee creditable against the total paid amount of fixed royalty fee due on the same year. 17.4 —Retirement commitments The employee retirement commitment is not recorded in the accounts in accordance with the option offered by the French accounting regulations. This commitment amounted to €41 K as of December 31, 2021. As part of the estimate of the retirement commitments, the following assumptions were used for all categories of employees: •Social security contribution: 45% in 2020 and 2021; •Salary increase: 3% in 2020 and 2021; •Discount rate: iBoxx Corporates AA+ index, 0.33% and 0.98% in 2020 and 2021, respectively; •Retirement age: 67; •Terms of retirement: voluntary retirement; •Life table: TGHF 2005; •Collective agreement: Convention Collective Nationale des Ingénieurs et des Cadres de la Métallurgie (National Collective Agreement for Engineers and Executives in the Metalworking Industry); and •Personnel turn-over: 10% (20-49), 0% above 50. NOTE 18 —TABLE OF SUBSIDIARIES AND HOLDINGS On April 28, 2017, GenSight Biologics created its first subsidiary, GenSight Biologics Inc., registered and located in the United States of America (State of Delaware). On December 30, 2021, the Company created a second subsidiary, GenSight Biologics France SAS registered and located in France. Capital (in Euros) Reserves and retained earnings brought forward (in thousands of Euros) % interest Book value of shares held (in Euros) Loans and advances granted not yet refunded (in thousands of Euros) Guarantees and security granted Turnover excluding tax Net income in last year (in thousands of Euros) Dividends booked during the year Gross Net GenSight Biologics Inc. 0.44 (2,541) 100% 0.44 0.44 6,095 — — (13.2) — Gensight Biologics France SAS 100,000 — 100% 100,000 100,000 — — — (0.5) — The capital reserves and retained earnings of the U.S. subsidiary have been translated into thousands of euros on the basis of year-end exchanges rates, while profits and losses have been translated at average rate. A provision of €3,327 K has been booked on the loans and advances granted in GenSight Biologics SA’s financial statements as of 2021. GenSight Biologics SA draws up consolidated accounts in which its subsidiaries GenSight Biologics Inc. and GenSight Biologics France SAS are fully consolidated. 18.1.4Statutory auditors’ report on the financial statements for the year ended December 31, 2021 This is a translation into English of the statutory auditors’ report on the financial statements of the Company issued in French and it is provided solely for the convenience of English speaking users. This statutory auditors’ report includes information required by French law, such as information about the appointment of the statutory auditors or verification of the Management report and other documents provided to shareholders. This report should be read in conjunction with, and construed in accordance with, French law and professional auditing standards applicable in France. To the GENSIGHT BIOLOGICS S.A. Shareholder’s Meeting, Opinion In compliance with the engagement entrusted to us by your bylaws and your Shareholders’ Meeting, we have audited the accompanying financial statements of GENSIGHT BIOLOGICS S.A. for the year ended December 31st, 2021. In our opinion, the financial statements give a true and fair view of the assets and liabilities and of the financial position of the Company, as of December 31st, 2021 and of the results of its operations for the year then ended in accordance with French accounting principles. The audit opinion expressed above is consistent with our report to the Audit Committee. Basis for Opinion Audit Framework We conducted our audit in accordance with professional standards applicable in France. We believe that the audit evidence we have obtained is sufficient and appropriate to provide a basis for our opinion. Our responsibilities under those standards are further described in the "Statutory Auditors' Responsibilities for the Audit of the Financial Statements" section of our report. Independence We conducted our audit engagement in compliance with independence requirements of the French Commercial Code (Code de commerce) and the French Code of Ethics (Code de déontologie) for statutory auditors, for the period from January 1st 2021 to the date of our report, and specifically we did not provide any prohibited non-audit services referred to in Article 5(1) of Regulation (EU) No 537/2014. Justification of Assessments – Key Audit Matters Due to the global crisis related to the Covid-19 pandemic, the financial statements of this period have been prepared and audited under specific conditions. Indeed, this crisis and the exceptional measures taken in the context of the state of sanitary emergency have had numerous consequences for companies, particularly on their operations and their financing, and have led to greater uncertainties on their future prospects. Those measures, such as travel restrictions and remote working, have also had an impact on the companies' internal organization and the performance of the audits. It is in this complex and evolving context that, in accordance with the requirements of Articles L. 823-9 and R. 823-7 of the French Commercial Code (Code de commerce) relating to the justification of our assessments, we inform you of the key audit matters relating to risks of material misstatement that, in our professional judgment, were of most significance in our audit of the financial statements of the current period, as well as how we addressed those risks. These matters were addressed in the context of our audit of the financial statements as a whole, approved in the conditions mentioned above, and in forming our opinion thereon, and we do not provide a separate opinion on specific items of the financial statements. Key Audit Matter 1: Recording of research and development costs (Refer to note "Use of estimates" and "Note 8 - Research and development expenses" to the notes to the financial statements as of December 31st, 2021) Description of the risk Research and development costs represent a significant component of the Company’ financial statements, considering Company’s activity and its current development phase, as they account for more than 69% of total operating expenses. These expenses mainly include external subcontracting costs or product manufacturing as well as personnel costs. There may be discrepancies between the achievement of subcontracting or manufacturing services and their related invoicing. The need of estimating the amount of services already achieved but not invoiced, or at the opposite, services already invoiced but not realized, leads to a risk of misevaluation of the invoices to be received or prepaid expenses regarding these external costs at year end. The estimate of the amount of services already performed to be recognized at year end thus requires significant judgments from the Management. We therefore considered that the accounting of research and development expenses is a key audit matter. Audit procedures implemented to deal with identified risks As part of our audit, we reviewed the internal control procedures related to the accounting of subcontracting and manufacturing expenses in order to identify control activities implemented by Management and evaluate their design. Our work was supplemented by procedures, on a sampling basis, of account payable confirmation requests and an analysis of subcontracting invoices received before and after year end, in order to identify which exercise they related to and evaluate the correct linkage with fiscal year. Key Audit Matter 2: Determination of LUMEVOQ®’s price (Refer to note "Use of estimates" and "Note 10 - Income" to the notes to the financial statements as of December 31st, 2021) Description of the risk The Company started in 2019 the sale of LUMEVOQ® through the patient program Temporary Authorization for Use (“ATU nominative”) granted by the National Drug Safety Agency (Agence Nationale de Sécurité du Médicament or ANSM) to the CHNO of the Quinze-Vingts. Revenues generated by LUMEVOQ® through ATU nominative amount to €4.4 million as of December 31st, 2021 compared to €4.1 million as of December 31st, 2020. The Company receives a preliminary price by the hospitals. Upon obtaining full marketing authorization (ANM) and completing pricing negotiations, it may be required to rebate to the URSSAF the difference between the preliminary price and the final price. Revenue is recognized in the statement of income only to the extent it is certain, both in its principle and in its amount at the end of the year. When the estimate of the amount of revenue involves significant uncertainty and if an estimate of a range of amounts is possible, the lowest amount must be considered, so that only certain income is recognized. The Company estimated the amount of revenue recorded so that it includes only the portion of revenue considered as certain. The methodology and assumptions used to estimate the amount that may be required to reimburse to the URSSAF are monitored and adjusted regularly in the light of contractual and legal obligations, trends, past experience and projected market conditions. In 2021, in light of changes in legal obligations, and projected market conditions, the Company adjusted the amount of revenue recognized. The Company records a refund liability for the consideration received for which the Company expects to refund the URSSAF. The liability for this reimbursement amounts to €6.6 million as of December 31st, 2021 compared to €1.6 million as of December 31st, 2020. The Company is required to exercise judgment in determining the final price of LUMEVOQ®, as the estimation requires significant estimates from the Company. We therefore considered this subject as a key audit matter. The assessment of the amount of revenue recognized is a key audit matter, given the amounts involved and the high level of estimation and judgment required from Management. Audit procedures implemented to deal with identified risks We obtained an understanding of the process and analyzed the design of controls relating to Management’s assessment of the variable consideration to be included in the transaction price. Our audit procedures also included, among others, evaluating the appropriateness of the significant assumptions used by Management. Evaluating Management’s assumptions involved evaluating whether the assumptions used by Management were reasonable by considering the consistency of assumptions with (i) external market and industry data, such as than the selling price of comparable products and (ii) with evidence obtained in other areas of the audit such as internal company communications and presentations, external communications and analyst reports. Key Audit Matter 3: Going concern (Refer to note “3 - Going concern” to the notes to the financial statements as of December 31st, 2021) Description of the risk At the approval date of the financial statements, the Company assessed the going concern, taken into consideration the Company believes it will be able to fund its operations until early first quarter 2023, considering: •Cash and cash equivalents held by the Company amounting to €43.9 million as of December 31st, 2021; •The cash consumption forecasted for the year 2022; •The 2022 revenue forecast generated by LUMEVOQ®; •The expected reimbursement in 2022 of research tax credits receivable. We identified the assessment of the Company's ability to continue as a going concern as a key audit matter because the assessment of going concern is dependent upon certain Management assumptions and judgments and due to the inherent uncertainty involved in forecasting future cash flows. Audit procedures implemented to deal with identified risks We have in particular: •gained an understanding of the process implemented to prepare the cash flow forecasts and estimated expenditures; •assessed the key assumptions used by Management in the cash flow forecasts, based on our understanding of the Company’s business and future plans approved by the Board of Directors; •assessed the appropriateness of the related disclosures in the financial statements; •enquired of Management whether there are circumstances or events which occurred since December 31st, 2021, that might put into question the going concern assessment. Specific Verifications We have also performed, in accordance with professional standards applicable in France, the specific verifications required by laws and regulations. Information given in the Management report and in the other documents on the financial position and the financial statements accounts to the shareholders We have no matters to report as to the fair presentation and the consistency with the financial statements of the information given in the Management report of the Board of Directors and in the other documents with respect to the financial position and the financial statements provided to shareholders. We attest the fair presentation and the consistency with the financial statements of the information relating to payment deadlines mentioned in Article D.441-6 of the French Commercial Code (Code de commerce). Report on corporate governance We attest that the Board of Directors’ report on corporate governance sets out the information required by Article L. 225-37-4, L. 22-10-10 and L. 22-10-9 the French Commercial Code (Code de commerce). Concerning the information given in accordance with the requirements of Article L. 22-10-9 of the French Commercial Code (Code de commerce) relating to remunerations and benefits received by or awarded to the directors and any other commitments made in their favour, we have verified its consistency with the financial statements, or with the underlying information used to prepare these financial statements and, where applicable, with the information obtained by your Company from controlled enterprises included in the scope of consolidation. Based on these procedures, we attest the accuracy and fair presentation of this information. With respect to the information relating to items that your company considered likely to have an impact in the event of a takeover bid or exchange offer, provided pursuant to Article L. 22-10-11 of the French Commercial Code (Code de commerce), we have agreed this information to the source documents communicated to us. Based on these procedures, we have no observations to make on this information. Other Information In accordance with French law, we have verified that the required information concerning the purchase of investments and controlling interests and the identity of the shareholders and holders of the voting rights has been properly disclosed in the Management report. Other Legal and Regulatory Verifications or Information Format of presentation of the financial statements intended to be included in the annual financial report We have also verified, in accordance with the professional standard applicable in France relating to the procedures performed by the statutory auditor relating to the annual and consolidated financial statements presented in the European single electronic format, that the presentation of the financial statements intended to be included in the annual financial report mentioned in Article L. 451-1-2, I of the French Monetary and Financial Code (Code monétaire et financier), prepared under the responsibility of Management, complies with the single electronic format defined in the European Delegated Regulation No 2019/815 of December 17, 2018. Based on the work we have performed, we conclude that the presentation of the financial statements intended to be included in the annual financial report complies, in all material respects, with the European single electronic format. We have no responsibility to verify that the financial statements that will ultimately be included by your Company in the annual financial report filed with the AMF are in agreement with those on which we have performed our work. Appointment of the Statutory Auditors We were appointed as statutory auditors of GENSIGHT BIOLOGICS S.A. by the bylaws of April 17, 2012 for Deloitte & Associés and by the Shareholders’ Meeting of May 19, 2016 for Becouze. As at December 31st, 2021, Deloitte & Associés was in the 9th year of total uninterrupted engagement and Becouze was in the 6th year of total uninterrupted engagement, including six years of joint work since securities of the Company were admitted to trading on a regulated market. Responsibilities of Management and Those Charged with Governance for the Financial Statements Management is responsible for the preparation and fair presentation of the financial statements in accordance with French accounting principles, and for such internal control as Management determines is necessary to enable the preparation of financial statements that are free from material misstatement, whether due to fraud or error. In preparing the financial statements, Management is responsible for assessing the Company’s ability to continue as a going concern, disclosing, as applicable, matters related to going concern and using the going concern basis of accounting unless it is expected to liquidate the Company or to cease operations. The Audit Committee is responsible for monitoring the financial reporting process and the effectiveness of internal control and risks management systems and where applicable, its internal audit, regarding the accounting and financial reporting procedures. The financial statements were approved by the Board of Directors. Statutory Auditors’ Responsibilities for the Audit of the Financial Statements Objectives and audit approach Our role is to issue a report on the financial statements. Our objective is to obtain reasonable assurance about whether the financial statements as a whole are free from material misstatement. Reasonable assurance is a high level of assurance but is not a guarantee that an audit conducted in accordance with professional standards will always detect a material misstatement when it exists. Misstatements can arise from fraud or error and are considered material if, individually or in the aggregate, they could reasonably be expected to influence the economic decisions of users taken on the basis of these financial statements. As specified in Article L. 823-10-1 of the French Commercial Code (Code de commerce), our statutory audit does not include assurance on the viability of the Company or the quality of management of the affairs of the Company. As part of an audit conducted in accordance with professional standards applicable in France, the statutory auditor exercises professional judgment throughout the audit and furthermore: •Identifies and assesses the risks of material misstatement of the financial statements, whether due to fraud or error, designs and performs audit procedures responsive to those risks, and obtains audit evidence considered to be sufficient and appropriate to provide a basis for his opinion. The risk of not detecting a material misstatement resulting from fraud is higher than for one resulting from error, as fraud may involve collusion, forgery, intentional omissions, misrepresentations, or the override of internal control. •Obtains an understanding of internal control relevant to the audit in order to design audit procedures that are appropriate in the circumstances, but not for the purpose of expressing an opinion on the effectiveness of the internal control. •Evaluates the appropriateness of accounting policies used and the reasonableness of accounting estimates and related disclosures made by management in the financial statements. •Assesses the appropriateness of Management’s use of the going concern basis of accounting and, based on the audit evidence obtained, whether a material uncertainty exists related to events or conditions that may cast significant doubt on the Company’s ability to continue as a going concern. This assessment is based on the audit evidence obtained up to the date of his audit report. However, future events or conditions may cause the Company to cease to continue as a going concern. If the statutory auditor concludes that a material uncertainty exists, there is a requirement to draw attention in the audit report to the related disclosures in the financial statements or, if such disclosures are not provided or inadequate, to modify the opinion expressed therein. •Evaluates the overall presentation of the financial statements and assesses whether these statements represent the underlying transactions and events in a manner that achieves fair presentation Report to the Audit Committee We submit a report to the Audit Committee which includes in particular a description of the scope of the audit and the audit program implemented, as well as the results of our audit. We also report, if any, significant deficiencies in internal control regarding the accounting and financial reporting procedures that we have identified. Our report to the Audit Committee includes the risks of material misstatement that, in our professional judgment, were of most significance in the audit of the financial statements of the current period and which are therefore the key audit matters that we are required to describe in this report. We also provide the Audit Committee with the declaration provided for in Article 6 of Regulation (EU) N° 537/2014, confirming our independence within the meaning of the rules applicable in France such as they are set in particular by Articles L. 822-10 to L. 822-14 of the French Commercial Code (Code de commerce) and in the French Code of Ethics (Code de déontologie) for statutory auditors. Where appropriate, we discuss with the Audit Committee the risks that may reasonably be thought to bear on our independence, and the related safeguards. Paris and Bordeaux, April 29, 2022 The Statutory Auditors French original signed by Becouze Fabien BROVEDANI Partner Deloitte & Associés Stéphane LEMANISSIER Partner 18.1.5DATE OF LATEST FINANCIAL INFORMATION Our latest financial information is the half-year financial statements (French GAAP and IFRS) for the fiscal year ended December 31, 2021. 18.2Interim and Other Financial Information Not applicable. 18.3Auditing of Historical Annual Financial Information In accordance with provisions of Article 19 of the Prospectus Regulation (EU) 2017/1129, the Company’s annual consolidated financial statements (IFRS) for the fiscal year ended December 31, 2019, the Company’s annual consolidated financial statements (IFRS) for the fiscal year ended December 31, 2020 and the Statutory Auditor’s report on the Company’s annual consolidated financial statements (IFRS) for the fiscal year ending December 31, 2019, the Statutory Auditor’s report on the Company’s annual consolidated financial statements (IFRS) for the fiscal year ending December 31, 2020 are incorporated by reference in this Universal Registration Document. These informations are included in the Documents registered with the AMF on April 8, 2020 under number D.20-0271 and on April 8, 2021 under number D-21-0276. These Registration Documents may be consulted on the Company’s (http://www.gensight-biologics.com) and on the AMF’s website. 18.4Proforma Financial Information Not applicable. 18.5Dividend Policy We have never declared or paid any cash dividends on our ordinary shares. We currently intend to retain all future earnings for use in the operation and expansion of our business and do not anticipate paying cash dividends in the foreseeable future. Subject to the requirements of French law and our bylaws, dividends may only be distributed from our distributable profits, plus any amounts held in our available reserves, which are those reserves other than the legal and statutory reserves and the revaluation surplus. The declaration and payment of any dividends in the future will be determined by the Board of Directors, in our discretion, and will depend on a number of factors, including our earnings, capital requirements, overall financial condition, and contractual restrictions, including restrictions contained in any agreements governing any indebtedness the Company may incur. 18.6Legal and Arbitration Proceedings From time to time, we may become involved in legal proceedings or be subject to claims arising in the ordinary course of our business. As of the date of this Universal Registration Document, to our knowledge, there are no governmental, legal or arbitral proceedings (including any proceedings of which we are aware, that are pending or with which we are threatened), likely to have, or having had in the course of the last twelve months, a material adverse effect on our operations, financial position or results. Regardless of the outcome, litigation can have an adverse impact on us because of defense and settlement costs, diversion of management resources and other factors. 18.7Significant Change In Financial Position To our knowledge, there has been no material change in our financial position since December 31, 2021, other than those described in this Universal Registration Document. 19 ADDITIONAL INFORMATION 19.1Share Capital 19.1.1AMOUNT OF ISSUED CAPITAL. As of the date of this Universal Registration Document, our share capital is equal to €1,158,389.78, divided into 46,335,591 shares, with nominal value of €0.025 per share, fully authorized, subscribed and paid-up. 19.1.2SECURITIES NOT REPRESENTING SHARE CAPITAL. As of the date of this Universal Registration Document, we have not issued any securities not representing the share capital. 19.1.3SHARES CONTROLLED BY THE COMPANY, TREASURY SHARES AND PURCHASE BY THE COMPANY OF ITS OWN SHARES. Our Combined General Shareholders’ Meeting of April 29, 2021 authorized our Board of Directors to implement a buyback program of our shares, according to the provisions of Article L.225-209 of the French Commercial Code. The maximum number of shares that can be purchased is 5% of the share capital of the Company (at any time whatsoever, such percentage applying to a capital, which shall be adjusted based on the transactions subsequently affecting it). Objectives of the buybacks: •to ensure the buoyancy of the secondary market or the liquidity of the Company shares through the intermediary of an investment service provider by way of a liquidity agreement in compliance with the Code of Ethics of the AMAFI (French Financial Markets’ Association) admitted by the regulations, it being specified that in this context, the number of shares taken into account for the calculation of the limitation referred to hereabove corresponds to the number of shares purchased, following the deduction of the number of shares, which have been re-sold; •to keep the purchased shares and to subsequently put them up for exchange or as payment in the context of any external growth transactions; •to ensure the coverage of share purchase option schemes and/or share schemes allocated on a free of charge basis (or similar schemes) in favor of the salaried employees and/or the corporate officers of the Group as well as any share allocations pursuant to a company or group savings scheme (or similar scheme) in respect of a company profit sharing scheme and/or any other forms of allocation of shares to the salaried employees and/or to the corporate officers of the Group; •to ensure the coverage of securities giving right to the allocation of shares of the Company in the context of the regulations in force; •to carry out the possible cancellation of the acquired shares, in accordance with the authorization granted or to be granted by the Extraordinary General Meeting. The maximum purchase price is €25 per share. In case of a transaction affecting the share capital, and notably of a share consolidation or split, or allocation of bonus shares to the shareholders, the above-mentioned price will be adjusted to the same proportion (a coefficient of the ratio between the number of shares comprising the share capital before the transaction and the number of shares after the transaction). The maximum amount of the funds intended for the program of the repurchase of the shares shall amount to € 51,874,575. During the fiscal year ended December 31, 2021, this buyback program was used exclusively within the scope of a liquidity agreement with the objective of stimulating trading or liquidity of the Company’s shares, stipulated with Oddo & Cie as investment services provider. Number of shares purchased 867,377 Average purchase price 7.4984 Number of shares sold 814,583 Average selling price 7.6103 Total amount of negotiation costs 25,000 Number of shares used in 2021 — Number of shares owned as of December 31, 2021 97,793 Value at average purchase price 733,291 Nominal value 1,944.83 19.1.4FREE SHARES. (a) Free shares granted by the Company We have granted free shares (Attributions Gratuites d’Actions, or AGA) since July 26, 2016. As of the date of this Universal Registration Document, 2,587,000 of the granted shares have been definitively acquired, including 1,958,500 performance shares and 628,500 non-performance shares. AGA 2016 granted on July 26, 2016 With the authorization of the General Meeting of Shareholders on May 19, 2016, the Board of Directors granted 766,000 free shares (AGA 2016) on July 26, 2016, as follows: •546,000 AGA 2016 were fully acquired by key managers, including Mr. Gilly, and were subject to the achievement of the following performance criteria: —291,000 of these free shares were acquired at the completion of enrollment in RESCUE and REVERSE clinical trials; and —the remaining 255,000 free shares were acquired at the enrollment of the first patient in a Phase I/II clinical trial of GS030 in RP, on July 24, 2018. •56,000 AGA 2016 were fully acquired in July 26, 2017 (one year after their grant date). The AGA 2016 were issued at their nominal value and will be subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on July 27, 2017 acknowledged the definitive acquisition of 347,000 free shares and decided accordingly to increase the capital increase of €8,675. The Board of Directors held on July 24, 2018 acknowledged the definitive acquisition of 255,000 free shares and decided accordingly to increase the capital increase of €6,375. AGA 2016 granted on July 27, 2017 With the authorization of the General Meeting of Shareholders on May 19, 2016, the Board of Directors granted 593,500 free shares (AGA 2016) on July 27, 2017, including: •505,000 AGA 2016 were fully acquired by key managers, including Mr. Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below: —245,000 of these free shares were acquired upon receipt of the definitive results of LUMEVOQ® REVERSE clinical trial on July 27, 2018; and, —the remaining 227,500 free shares have been acquired upon completion of the enrollment of 50% of the patients of a Phase I/II clinical trial of GS030 in RP on May 17, 2019. •32,500 AGA 2016 were fully acquired on July 27, 2018 (one year after their grant date). The AGA 2016 were issued at their nominal value and will be subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on July 24, 2018 acknowledged the definitive acquisition of 245,000 free shares and decided accordingly to increase the capital increase of €6,937.5. The Board of Directors held on June 11, 2019 acknowledged the definitive acquisition of 227,500 free shares and decided accordingly to increase the capital increase of €5,687.5. AGA 2016 granted on December 19, 2017 With the authorization of the General Meeting of Shareholders on May 19, 2016, the Board of Directors granted 72,500 free shares (AGA 2016) on December 19, 2017. The AGA 2016 were fully acquired by one key manager, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below: •36,250 of these free shares were acquired after the one year acquisition period and upon receipt of the definitive results of the LUMEVOQ® REVERSE clinical trial on December 19, 2018; and •the remaining 36,250 free shares were acquired upon completion of the enrollment of 50% of the patients of a Phase I/II clinical trial of GS030 in RP on May 17, 2019. The AGA 2016 were issued at their nominal value and will be subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on December 19, 2018 acknowledged the definitive acquisition of 36,250 free shares and decided accordingly to increase the capital increase of €906.25. The Board of Directors held on June 11, 2019 acknowledged the definitive acquisition of 36,250 free shares and decided accordingly to increase the capital increase of €906.25. AGA 2018 granted on September 18, 2018 With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors granted 380,000 free shares (AGA 2018) on September 18, 2018, including: •185,000 AGA 2018 were fully acquired by key managers, including Mr. Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below: —92,500 of these free shares were acquired upon completion of the enrollment of the patients of a Phase I/II clinical trial of GS030 in RP on July 29, 2020; and —the remaining 92,500 free shares were acquired upon completion of the production of the first PPQ Batch of LUMEVOQ® on September 1, 2020. •40,000 AGA 2018 were fully acquired on September 18, 2019 (one year after their grant date). The AGA 2018 were issued at their nominal value and are subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on September 25, 2019 acknowledged the definitive acquisition of 40,000 free shares and decided accordingly to increase the capital increase of €1,000. The Board of Directors held on July 29, 2020 acknowledged the definitive acquisition of 92,500 free shares and decided accordingly to increase the capital increase of €2,312.5. The Board of Directors held on September 22, 2020 acknowledged the definitive acquisition of 92,500 free shares and decided accordingly to increase the capital increase of €2,312.5. AGA 2018 granted on December 19, 2018 With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors granted 135,000 free shares (AGA 2018) on December 19, 2018. The AGA 2018 were fully acquired by one key manager, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below: •67,500 of these free shares were acquired upon completion of the enrollment of the patients of a Phase I/II clinical trial of GS030 in RP on July 29, 2020; •the remaining 67,500 free shares were acquired upon completion of the production of the first PPQ Batch of LUMEVOQ® on September 1, 2020. The AGA 2018 were issued at their nominal value and will be subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on July 29, 2020 acknowledged the definitive acquisition of 67,500 free shares and decided accordingly to increase the capital increase of €1,687.5. The Board of Directors held on September 22, 2020 acknowledged the definitive acquisition of 67,500 free shares and decided accordingly to increase the capital increase of €1,687.5. AGA 2018 granted on July 23, 2019 With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors granted 610,000 free shares (AGA 2018) on July 23, 2019: •547,500 AGA 2018 were fully acquired by key managers, including Mr. Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below: —273,750 of these free shares were acquired upon the filing with the European Medicines Agency (EMA) the application for market authorization (MA) at the European level of the LUMEVOQ® on September 14,2020; —273,750 of these free shares were acquired upon completion of the enrollment of the patients of a Phase I/II clinical trial of GS030 in RP on July 29,2020. •27,500 AGA 2018 were fully acquired on July 23, 2020 (one year after their grant date). The AGA 2018 were issued at their nominal value and will be subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on July 29, 2020 acknowledged the definitive acquisition of 273,500 free shares and decided accordingly to increase the capital increase of €6,843.75. The Board of Directors held on September 22, 2020 acknowledged the definitive acquisition of 273,750 free shares and decided accordingly to increase the capital increase of €6,843.75. AGA 2020 granted on January 28, 2020 and on September 22, 2020 With the authorization of the General Meeting of Shareholders on April 12, 2018 and of the General Meeting of Shareholders on April 29, 2020, the Board of Directors granted 1,007,500 free shares (AGA 2020) on January 28, 2020 and 85,000 (AGA 2020) on September 22, 2020, respectively, among which: •437,500 AGA 2020 were fully acquired on January 28, 2021 (one year after their grant date). The new shares were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. The AGA 2020 were issued at their nominal value and will be subject to a lock-up period of one year after their actual acquisition date. The Board of Directors held on February 15, 2021 acknowledged the definitive acquisition of 437,500 free shares and decided accordingly to increase the capital of €10,937. •As per the original plan, which has been fully forfeited as of the date of this Universal Registration Document, 652,500 AGA 2020 might have been fully acquired by key managers, including Mr. Gilly, subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below no later than January 28, 2022: —326,250 of these free shares could have been acquired upon the approval with the European Medicines Agency (EMA) of the application for market authorization (MA) at the European level of the GS010; —326,250 of these free shares could have been acquired upon the filing with the Food and Drug Administration (FDA) of the application for Biologics License Application (BLA) for the GS010; —in the event of a public tender offer or public exchange offer on the Company’s shares, the Performance Conditions 1 and 2 would have been deemed not applicable from the Date of the Public Offer. Having regard to the consequences of the Covid-19 pandemic on the Company’s business and, more specifically, of the impact on the Company’s partners directly involved in the process of obtaining the marketing authorization for LUMEVOQ®, having led the legislator of a foreign country to adopt exceptional and binding regulations of national interest that were completely unpredictable when determining the Performance Conditions and their completion schedule; the Board of Directors has decided on September 21, 2021, to amend the Performance Bonus Shares Plans in order to postpone the deadline for the completion of Performance Conditions 1 and 2, by one year, which will now be set on January 28, 2023, has further decided that the Vesting Period of each of Tranches 1 and 2 shall end, in consequence thereof, on the date of fulfillment of the Performance Conditions affecting each tranche, without however it being able to end before September 21, 2022, even if the Performance Conditions are fulfilled before this date. Moreover, following the feedback provided by the FDA recommending that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials, the Group has considered that the second Performance Condition could not be achieved before the new deadline of Completion, i.e. January 28, 2023 and therefore has decided to cancel 50% of both Performance Bonus Share Plans on December 31, 2021. In addition, the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022 will not allow the Group to timely achieve the first Performance Condition, and has therefore led to the cancellation of the remaining 50% of both Performance Bonus Share Plans on the same date. AGA 2021 granted on February 25,2021 With the authorization of the General Meeting of Shareholders on April 29, 2020, the Board of Directors granted 880,000 free shares (AGA 2021) to employees of the Company, of which: •845,000 (of which 447,500 were cancelled) are subject subject to (i) a one year acquisition period from the date of grant and (ii) achievement of the performance criteria described below at the latest on February 24, 2023: —50% could have been acquired upon the first commercial sale of the LUMEVOQ®; and —50% will be acquired upon at the completion of the recruitment of the extension cohort of the Phase I/II clinical trial with GS030 in retinisis pigmentosa; —in the event of a public tender offer or public exchange offer on the Company's shares, the Performance Conditions 1 and 2 will be deemed not applicable from the date of the Public Offer. •35,000 AGA 2021 were fully acquired in February 2022 (one year after their grant date). The AGA 2021 were issued at their nominal value and are subject to a lock-up period of one year after their acquisition date. Following the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022, the Group assessed that it will not be in a position to achieve the first Performance Condition before the given deadline and has therefore decided to cancel 50% of the Performance Bonus Share Plans on the same date. AGA 2021 granted on October 21,2021 With the authorization of the General Meeting of Shareholders on April 29, 2021, the Board of Directors granted 380,000 free shares (AGA 2021) (of which 190,000 were cancelled) to employees of the Company. The free shares are subject to (i) a two years acquisition period from the date of grant and (ii) achievement of the performance criteria described below at the latest on October 20, 2023: •50% could have been acquired upon the first commercial sale of the LUMEVOQ®, and •50% will be acquired upon at the completion of the recruitment of the extension cohort of the Phase I/II clinical trial with GS030 in retinisis pigmentosa; •in the event of a public tender offer or public exchange offer on the Company's shares, the Performance Conditions 1 and 2 will be deemed not applicable from the date of the Public Offer. Following the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022, the Group assessed that it will not be in a position to achieve the first Performance Condition before the given deadline and has therefore decided to cancel 50% of the Performance Bonus Share Plans on the same date. (b) Conditions governing the free shares granted by the Company Free shares are granted to employees only. The beneficiary will definitively acquire the shares for free after an “acquisition period,” given that he/she is still within the Company at this time. Then a “retain period” is applied before shares can be disposed. (c) Free shares holders The table below sets forth the free shares granted by us to our executive officers and directors as of the date of this Universal Registration Document: Name Grant Date Number of free shares Performance condition Bernard Gilly 07/26/2016 250,000 Yes 07/27/2017 200,000 Yes 09/18/2018 45,000 Yes 07/23/2019 220,000 Yes 01/28/2020 220,000 Yes (1) 01/28/2020 270,000 No (1) 02/25/2021 400,000 Yes (2) Thomas Gidoin 07/26/2016 150,000 Yes 07/27/2017 90,000 Yes 09/18/2018 45,000 Yes 07/23/2019 150,000 Yes 01/28/2020 150,000 Yes (1) 01/28/2020 100,000 No 02/25/2021 200,000 Yes (2) Magali Taiël 12/19/2018 135,000 Yes 07/23/2019 65,000 Yes 01/28/2020 100,000 Yes (1) 01/28/2020 40,000 No 02/25/2021 120,000 Yes (2 Marie-Claude Holtz 09/22/2020 85,000 Yes (1) 02/25/2021 10,000 Yes (2) Total 3,045,000 (1) In January and September 2020, the Company issued 1,092,500 free shares (AGA 2020) to employees of the Company, of which: •652,500 are subject to the achievement of the following performance criteria as per the original plan at the latest on January 27, 2022: —50% will be acquired upon the filing with the European Medicines Agency (EMA) of the application for market authorization (MA) at the European level of the LUMEVOQ®, and —50% will be acquired upon the filing with the Food and Drug Agency (FDA) of the application for Biologics License Application (BLA) for the LUMEVOQ®, and —in the event of a public tender offer or public exchange offer on the Company's shares, the Performance Conditions 1 and 2 will be deemed not applicable from the date of the Public Offer. •440,000 are not subject to performance conditions, but subject to a one-year vesting period. In this context, Mr. Bernard Gilly received 220,000 free shares with performance conditions and, in addition to his fixed and variable compensation, 270,000 free shares without performance conditions (as permitted by the legal and regulatory provisions applicable on that date). Those 270,000 free shares without performance conditions were fully acquired on January 28, 2021 and are subject to a lock-up period of one year (until 01/27/2022). Marie-Claude Holtz received 85,000 free shares with performance conditions. Having regard to the consequences of the Covid-19 pandemic on the Company’s business; the Board of Directors has decided on September 21, 2021, to amend the Performance Bonus Shares Plans granted on January 28, 2020 and September 22, 2020 in order to postpone the deadline for the completion of Performance Conditions 1 and 2, by one year, which will now be set on January 28, 2023, has further decided that the Vesting Period of each of Tranches 1 and 2 shall end, in consequence thereof, on the date of fulfillment of the Performance Conditions affecting each tranche, without however it being able to end before September 21, 2022, even if the Performance Conditions are fulfilled before this date. Moreover, following the feedback provided by the FDA recommending that the Company conduct an additional placebo-controlled trial to bolster the demonstration of LUMEVOQ® efficacy in view of the unexpected bilateral effect observed in unilaterally treated patients in the RESCUE, REVERSE and REFLECT trials, the Group has considered that the second Performance Condition could not be achieved before the new deadline of Completion, i.e. January 28, 2023 and therefore has decided to cancel 50% of both Performance Bonus Share Plans on December 31, 2021. In addition, the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022 will not allow the Group to timely achieve the first Performance Condition, and has therefore led to the cancellation of the remaining 50% of both Performance Bonus Share Plans on the same date. (2) Following the delay in the completion of the validation (PPQ) batches for LUMEVOQ® announced on April 7, 2022, the Group assessed that it will not be in a position to achieve the first Performance Condition before the given deadline and has therefore decided to cancel 50% of the 2021 Performance Bonus Share Plans on the same date. 19.1.5OTHER SECURITIES GIVING ACCESS TO SHARE CAPITAL. As of the date of this Universal Registration Document, the total number of ordinary shares that can be issued by full exercise of all of the securities giving access to the capital and instruments issued to date amounts to 2,601,441, or a maximum dilution of 5.61% on the basis of the capital and voting rights existing to date and 5.32% on the basis of the capital and the fully diluted voting rights. The following table summarizes the instruments giving access to share capital as of the date of this Universal Registration Document: Number of share warrants for founders, share warrants or free shares Exercise Price range in euro BCE 502,182 0.025 – 3.275 BSA 800,333 0.025 – 8.080 AGA 587,500 — SO — — OCA 726,426 — Total outstanding instruments giving access to capital as of the date of this Universal Registration Document 2,616,441 19.1.5.1Warrants (a) Warrants granted by the Company We have granted share-based warrants in the form of share warrants for founders (Bons de Souscription de Parts de Créateur d’Entreprise, or BCE) and share warrants (Bons de Souscription d’Actions, or BSA). As of the date of this Universal Registration Document, 502,182 share warrants for founder (BCE) will give right to 502,182 ordinary shares with nominal value of €0.025 at an average exercise price of €2.967 per share. As of the date of this Universal Registration Document, 800,333 share warrants (BSA) will give right to 800,333 ordinary shares with nominal value of €0.025 at an average exercise price of €4.7653 per share. BCE 2013-02 warrants and BSA 2013-02 warrants With the authorization of the General Meeting of Shareholders on February 5, 2013, the Board of Directors issued 892,000 BCE 2013-02 warrants with an exercise price of €0.025 per share, and 328,000 BSA 2013-02 warrants with an exercise price of €0.025 per share on July 8, 2013. With the authorization of the General Meeting of Shareholders on February 5, 2013, the Board of Directors issued 193,800 BCE 2013-02 warrants, with an exercise price of €0.025 per share and 33,000 BSA 2013-02 warrants, with an exercise price of €0.025 per share on April 9, 2014. The BCE 2013-02 and BSA 2013-02 warrants are exercisable on the basis of the following vesting schedule: •up to 1/4 of the BCE 2013-02 and BSA 2013-02 warrants on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 10 years from the date of grant. BCE 2014-06 warrants With the authorization of the General Meeting of Shareholders on June 25, 2014, the Board of Directors issued 60,000 BCE 2014-06 warrants on December 3, 2014, with an exercise price of €0.025 per share. The BCE 2014-06 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 of the BCE 2014-06 warrants on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 10 years from the date of grant. BCE 2015-06 warrants and BSA 2015-06 warrants With the authorization of the General Meeting of Shareholders on June 29, 2015, the Board of Directors issued 733,298 BCE 2015-06 warrants, with an exercise price of €3.275 per share, and 121,000 BSA 2015-06 warrants, with an exercise price of €3.275 per share on July 8, 2015. The BCE 2015-06 and BSA 2015-06 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 of the BCE 2015-06 and BSA 2015-06 warrants on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 10 years from the date of grant. BSA 2016 warrants With the authorization of the General Meeting of Shareholders on May 19, 2016, the Board of Directors issued 205,000 BSA 2016 warrants, with an exercise price of €8.08 per share on July 26, 2016. The BSA 2016 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •100% of the BSA 2016 warrants on the first anniversary of the date of grant; and •at the latest within 7 years from the date of grant. With the authorization of the General Meeting of Shareholders on May 19, 2016, the Board of Directors issued 165,000 BSA 2016 warrants, with an exercise price of €5.04 per share on July 27, 2017. The BSA 2016 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 of the BSA 2016 warrants on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 7 years from the date of grant. BSA 2018 warrants With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors issued 20,000 BSA 2018 warrants, with an exercise price of €2.22 per share on September 18, 2018. The BSA 2018 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 as from the date of grant; •the remaining 75% on the basis of 1/36th per month as from the Date of Grant (i.e. as from September 18, 2018), at the end of each month; and •at the latest within 7 years from the date of grant. BSA 2019 warrants With the authorization of the General Meeting of Shareholders on June 11, 2019, the Board of Directors issued 105,000 BSA 2019 warrants, with an exercise price of €1.45 per share on July 23, 2019. The BSA 2019 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 as from the date of grant; •the remaining 75% on the basis of 1/36th per month as from the Date of Grant (i.e. as from July 23, 2019), at the end of each month; and •at the latest within 7 years from the date of grant. BSA 2019 KREOS-A With the authorization of the General Meeting of Shareholders on June 11, 2019, the Board of Directors issued 534,521 BSA 2019 KREOS-A warrants, with an exercise price of €2.245 per share on December 19, 2019. The period of validity of the BSA 2019-KREOS-A warrants shall start upon their issuance and shall expire on the occurrence of the earlier of the following two events: (i) the tenth anniversary of the grant date, or (ii) the acceptance by the shareholders of the Borrower of a third-party bona fide offer for all outstanding shares in the Issuer. BSA 2019-2 warrants With the authorization of the General Meeting of Shareholders on June 11, 2019, the Board of Directors issued 40,000 BSA 2019-2 warrants, with an exercise price of €3.48 per share on January 28, 2020. The BSA 2019 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 as from the date of grant; •the remaining 75% on the basis of 1/36th per month as from the Date of Grant (i.e. as from January 28, 2020), at the end of each month; and •at the latest within 7 years from the date of grant. BSA 2019 KREOS-B With the authorization of the General Meeting of Shareholders on June 11, 2019, the Board of Directors issued 133,630 BSA 2019 KREOS-B warrants, with an exercise price of €2.245 per share on July 31, 2020. The period of validity of the BSA 2019-KREOS-B warrants shall start upon their issuance and shall expire on the occurrence of the earlier of the following two events: (i) the tenth anniversary of the grant date, or (ii) the acceptance by the shareholders of the Borrower of a third-party bona fide offer for all outstanding shares in the Issuer. As of the date of this Universal Registration Document, Kreos Capital has converted all the issued BSA 2019 KREOS-A and BSA KREOS-B. See section 5.3 “Funding Sources” for further details on the Bond Financing with Kreos Capital. BSA 2020 warrants With the authorization of the General Meeting of Shareholders on April 29, 2020, the Board of Directors issued 80,000 BSA 2020 warrants, with an exercise price of €3.99 per share on November 2, 2020. The BSA 2020 warrants may be exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 as from the date of grant; •the remaining 75% on the basis of 1/36th per month as from the Date of Grant (i.e. as from November 2, 2020), at the end of each month; and •at the latest within 7 years from the date of grant. BSA 2021 warrants With the authorization of the General Meeting of Shareholders on April 29, 2020, the Board of Directors issued 40,000 BSA 2021-1 warrants, with an exercise price of €7.19 per share on February 25, 2021. With the authorization of the General Meeting of Shareholders on April 29, 2021, the Board of Directors issued 30,000 BSA 2021-2 warrants, with an exercise price of €6.80 per share on October 21, 2021 With the authorization of the General Meeting of Shareholders on April 29, 2021, the Board of Directors issued 65,000 BSA 2021-3 warrants, with an exercise price of €5.47 per share on December 14, 2021. BSA 2021 granted may be exercised by the beneficiary on the basis of the following vesting schedule: •1/3 as from the first anniversary of the allotment date; •1/3 as from the second anniversary of the allotment date; and •1/3 as from the third anniversary of the allotment date. See also Section 13.4.1, “History of Share Warrants for Founders (BCE)”, and Section 13.4.2, “History of Share Warrants (BSA)” of this Universal Registration Document. (b) Conditions governing the warrants granted by the Company Share warrants for founders (BCE) Share warrants for founders entitle a holder to exercise the warrant for the underlying vested shares at an exercise price per share determined by our Board of Directors and at least equal to the fair market value of an ordinary share on the date of grant. Share warrants for founders may only be issued by companies meeting certain criteria, which we will not meet following the listing of our shares on Euronext Paris. Share warrants for founders are not transferable and may not be sold, pledged, assigned, hypothecated, transferred or disposed of in any manner other than by will or by laws of descent or distribution and may be exercised, during the lifetime of the beneficiary, only by the beneficiary. Share warrants (BSA) Share warrants need to be subscribed for a price which is determined by the Board on the date of grant, in addition to any exercise price payable by a holder upon the exercise of any share warrant. Share warrants may not be transferred to any person subject to certain exceptions detailed in our BSA plan. (c) Warrants holders The table below sets forth the warrants granted by us to our executive officers and directors as of the date of this Universal Registration Document: Name Grant Date Type of Grant Number of Ordinary Shares Underlying Awards (#)(1) Exercise Price (€) Expiration Date Bernard Gilly 07/08/2013 BCE 300,000 0.025 07/07/2023 07/08/2015 BCE(2) 161,000 3.275 07/07/2025 José-Alain Sahel 07/08/2013 BSA 280,000 0.025 07/07/2023 07/08/2015 BSA 48,000 3.275 07/07/2025 07/26/2016 BSA 120,000 8.08 07/25/2023 07/27/2017 BSA 80,000 5.04 07/26/2024 07/23/2019 BSA 40,000 1.45 07/22/2026 01/28/2020 BSA 40,000 3.45 01/27/2027 02/25/2021 BSA 40,000 7.19 02/24/2028 Peter Goodfellow 04/09/2014 BSA 33,000 0.025 04/08/2024 07/08/2015 BSA 7,000 3.275 07/07/2025 07/26/2016 BSA 7,000 8.08 07/25/2023 07/27/2017 BSA 10,000 5.04 07/26/2024 Thomas Gidoin 07/08/2015 BCE(2) 160,000 3.275 07/07/2025 Michael Wyzga 07/08/2015 BSA 40,000 3.275 07/07/2025 07/26/2016 BSA 31,000 8.08 07/25/2023 07/27/2017 BSA 15,000 5.04 07/26/2024 09/18/2018 BSA 10,000 2.22 09/17/2025 07/23/2019 BSA 20,000 1.45 07/22/2026 11/02/2020 BSA 20,000 3.99 11/01/2027 12/14/2021 BSA 20,000 5.47 12/13/2028 Simone Seiter 07/27/2017 BSA 30,000 5.04 07/26/2024 09/18/2018 BSA 5,000 2.22 09/17/2025 07/23/2019 BSA 15,000 1.45 07/22/2026 11/02/2020 BSA 15,000 3.99 11/01/2027 12/14/2021 BSA 15,000 5.47 12/13/2028 Maritza McIntyre 07/23/2019 BSA 30,000 1.45 07/22/2026 11/02/2020 BSA 15,000 3.99 11/01/2027 12/14/2021 BSA 15,000 5.47 12/13/2028 Elsy Boglioli 11/02/2020 BSA 30,000 3.99 11/01/2027 12/14/2021 BSA 15,000 5.47 12/13/2028 Françoise de Craecker 10/21/2021 BSA 30,000 6.80 10/20/2028 Total 1,697,000 (1) Each BCE and BSA warrant entitles its holder to subscribe to one ordinary share, with a nominal value of €0.025 each, at an exercise price of €0.025, €3.275, €8.08, €1.45, €2.245, €3.45, €3.99, €7.19, €6.80 and €5.47. (2) The figures have been adjusted in order to reflect the 5 for 2 reverse stock split which took place on August 17, 2015. 19.1.5.2Stock Options With the authorization of the General Meeting of Shareholders on May 31, 2017, the Board of Directors issued 220,000 SO 2017, with an exercise price of €5.040 per share on July 27, 2017. These have been fully forfeited as of the date of this Universal Registration Document. With the authorization of the General Meeting of Shareholders on May 31, 2017, the Board of Directors issued 300,000 SO 2017, with an exercise price of €5.55 per share on December 19, 2017. These have been fully forfeited as of the date of this Universal Registration Document. With the authorization of the General Meeting of Shareholders on May 31, 2017, the Board of Directors issued 175,000 SO 2017, with an exercise price of €6.98 per share on March 14, 2018. These have been fully forfeited as of the date of this Universal Registration Document. With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors issued 30,000 SO 2018, with an exercise price of €2.19 per share on September 18, 2018. These have been fully forfeited as of the date of this Document. With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors issued 155,000 SO 2018, with an exercise price of €2.82 per share on September 22, 2020; of which 45,208 have been exercised and 109,792 have been fully forfeited as of the date of this Universal Registration Document. The SO 2018 might have been exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/4 of the SO 2018 on the first anniversary of the date of grant; •the remaining 75% becoming exercisable up to 1/36 per month from the first anniversary of the date of grant; and •at the latest within 7 years from the date of grant. With the authorization of the General Meeting of Shareholders on April 12, 2018, the Board of Directors issued 20,000 SO 2018, with an exercise price of €7.51 per share on February 25, 2021. Those SO 2018 have been fully forfeited as of the Date of this Universal Registration Document. The SO 2018 might have been exercised by the beneficiary on the basis of the following vesting schedule: •up to 1/3 of the SO 2018 on the first anniversary of the date of grant; •1/3 of the SO 2018 would have become exercisable on the second anniversary of the date of grant and the remaining 1/3 will become exercisable on the third anniversary of the date of grant; and •at the latest within 7 years from the date of grant. The beneficiaries would be the salaried employees or some of them, or certain categories of the personnel, of the Company and, as appropriate, companies or economic interest groups which are bound to it under the conditions of Article L.225-180 of the Commercial Code and the corporate officers that meet the conditions provided by Article L.225-185 of the Commercial Code. 19.1.5.3Convertible Bonds On December 20, 2019 and July 30, 2020, the Company issued, with the authorization of the General Meeting of Shareholders on June 11, 2019, drawdown notices thereunder for the first tranche of €6 million and second tranche of €4 million of the bond financing with Kreos Capital, including €1.8 million in the form of convertible bonds for the first tranche and €1.5 million for the second tranche. The convertible bonds (nominal value of €1) bear an annual interest of 9.25%. Each convertible bond will arrive to maturity 42 months after their issuance. The convertible bonds might be converted into ordinary shares at any time from their issuance date to their maturity date at a price of €2.245 reflecting a 10% discount to the volume weighted average price of the Company’s shares on the regulated market of Euronext Paris over the three last trading days before pricing, i.e., December 16, 17 and 18, 2019. Following a renegotiation with Kreos Capital, the Company issued, with the authorization of the Ordinary and Extraordinary Shareholders’ Meeting of April 29, 2020, 300,000 additional convertible bonds which are included in the €1.5 million in the form of convertible bonds for the second tranche. These convertible bonds might be converted into ordinary shares at any time from their issuance date to their maturity date at a price of €2.754 reflecting a 15% discount to the volume weighted average price of the Company’s shares on the regulated market of Euronext Paris over the five last trading days before pricing, i.e., July 24, 27, 28, 29 and 30, 2020. As of the date of this Universal Registration Document, Kreos Capital has exercised 50% of the total issued convertible bonds. See section 5.3 “Funding Sources” for further details on the Bond Financing with Kreos Capital. 19.1.6TERMS GOVERNING ANY RIGHT OF ACQUISITION AND/OR ANY OBLIGATION ATTACHED TO SUBSCRIBED BUT NOT PAID-UP CAPITAL. The table below sets forth the resolutions regarding issuance of shares currently in force: Purpose Maximum amount Period of validity Global maximum amount in euros Use of the delegations Residual maximum amount in euros Delegation of authority to be given to the Board of Directors to increase the capital by incorporation of reserves, profits and/or premiums in accordance with the provisions of Articles L.225-129-2, L.225-130 and L.22-10-50 of the French Commercial Code (18th resolution of the 2021 Shareholders' Meeting) 100% of the hare capital at the date of the 2021 Shareholders' Maeeting, i.e. €1,149,431.93 26 months i.e. until June 28, 2023 100% of the hare capital at the date of the 2021 Shareholders' Maeeting, i.e. €1,149,431.93 — Capital increase: €1,149,431.93 Delegation of authority to be given to the Board of Directors to issue ordinary shares giving access, where applicable, to ordinary shares or to the issuance of debt securities (in the company or in a group company), and/or securities giving access to ordinary shares (in the company or in a group company), with maintenance of the preferential subscription right in accordance with the provisions of Articles L.225-129-2, L.225-132 and L.228-92 of the Commercial Code (19th resolution of the 2021 shareholders' meeting) Capital increase: Maximum 50% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €574,715.97 Debt instruments giving access to equity securities: €50,000,000 26 months i.e. until June 28, 2023 Capital increase: Maximum 50% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €574,715.97 Debt instruments giving access to equity securities: €50,000,000 — Capital increase: €574,715.97 Debt instruments giving access to equity securities: €50,000,000 Delegation of authority to be given to the Board of Directors in order to issue common shares (2) giving, where applicable, access to common shares or the award of debt securities (for the company or a company in the group) and/or securities entitling to common shares (in the company or a company in the group) with the elimination of the preemptive right to the benefit of categories of persons fulfilling certain characteristics, duration of the delegation of authority, maximum par value of the capital increase(4), issue bonus, option of limiting the amount of subscriptions or distributing unsubscribed shares (20th resolution of the 2021 Shareholders' Meeting). Capital increase: Maximum 60% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €689,659.16 Debt instruments giving access to equity securities: €50,000,000 18 months i.e. until October 28, 2022 Capital increase: 75% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €862,073.95 Debt instruments giving access to equity securities: €50,000,000 — Capital increase: €854,948.95 Debt instruments giving access to equity securities: €50,000,00 Delegation of authority to be granted to the Board of Directors in order to issue share purchase warrants (4) (BSA), purchase and/or subscription warrants for existing and/or new shares (BSAANE) and/or purchase and/or subscription warrants for new and/or existing redeemable shares (BSAAR) with a waiver of the preferential subscription right benefiting categories of persons in accordance with the provisions of Articles L.225-129-2, L.225-138 and L228-91 of the Commercial Code (22nd resolution of the 2021 Shareholders' Meeting). 2% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €22,988.64 919,545 warrants 18 months i.e. until October 28, 2022 Capital increase: 75% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €862,073.95 Date of use by the Board of Directors: October 21, 2021 Number of warrants issued: 30,000 corresponding to approximately 0.07% of the share capital as of the date of the 2021 Shareholders’ Meeting and consisting of a potential capital increase of €750 Date of use by the Board of Directors: December 14, 2021 Number of warrants issued: 65,000 corresponding to approximately 0.17% of the share capital as of the date of the 2021 Shareholders’ Meeting and consisting of a potential capital increase of €1,625 Authorization given to the Board of Directors with a view to the granting of options (5) for the subscription and/or purchase of shares to members of the salaried work force (and/or certain corporate officers) in accordance with the provisions of Articles L.225-177 to L.225-185 of the Commercial Code (24th resolution of the 2021 Shareholders' Meeting). 5% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €57,471.60 2,298,863 options 38 months i.e. until June 28, 2024 Capital increase: 75% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €862,073.95 — Capital increase: €854,948.95 Debt instruments giving access to equity securities: €50,000,00 Authorization to be given to the Board of Directors with a view to allocating free of charges shares to members of the salaried work force and/or certain corporate officers in accordance with the provisions of Articles L.225-197-1 and L.225-197-2 of the Commercial Code (25th resolution of the 2021 Shareholders' Meeting). 5% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €57,471.60 2,298,863 free shares 38 months i.e. until June 28, 2024 Date of use by the Board of Directors: October 21, 2021 Number of free shares issued: 190,000 corresponding to approximately 0.83% of the share capital as of the date of the 2021 Shareholders’ Meeting and consisting of a potential capital increase of €4,750 Delegation of authority to be given to the Board of Directors in order to issue ordinary shares (1) giving right, as the case may be, to ordinary shares or the allocation of debt securities (of the company or a company of the group), and/or securities giving a right to ordinary shares (of the company or a company of the group) without preferential subscription rights by public offering in accordance with the provisions of Articles L.225-129-2, L.225-136 and L.228-92 of the Commercial Code (15th resolution of the 2020 Shareholders’ Meeting). Capital increase: Maximum 60% of the share capital at the date of the 2020 Shareholders’ Meeting i.e. €492,410.43 Debt instruments giving access to equity securities: €50,000,000 26 months i.e. until June 28, 2022 Capital increase: 75% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €862,073.95 Debt instruments giving access to equity securities: €50,000,000 — Delegation of authority given to the Board of Directors in order to issue ordinary shares giving right, as the case may be, to ordinary shares or the allocation of debt securities (of the company or a company of the group), and/or securities giving a right to ordinary shares (of the company or a company of the group) without preferential subscription rights as remuneration for the securities contributed in the context of a public exchange offering in accordance with the provisions of Articles L.225-129-2, L.225-135, L.225-148 and L.228-92 of the Commercial Code (16th resolution of the 2020 Shareholders’ Meeting). Capital increase: Maximum 20% of the share capital at the date of the Shareholders’ Meeting i.e. €164,136.81 Debt instruments giving access to equity securities: €50,000,000 26 months i.e. until June 28, 2022 — Delegation of authority to be given to the Board of Directors in order to issue ordinary shares (1) giving right, as the case may be, to ordinary shares or the allocation of debt securities (of the company or a company of the group), and/or securities giving a right to ordinary shares (of the company or a company of the group) without preferential subscription rights by an offer referred to at section II of Article L.411-2 of the Monetary and Financial Code in accordance with the provisions of Articles L.225-129-2, L.225-135, L.225-136 and L.228-92 of the Commercial Code (17th resolution of the 2020 Shareholders’ Meeting). Capital increase: Maximum 20% of the share capital at the date of the 2020 Shareholders’ Meeting i.e. €164,136.81 Debt instruments giving access to equity securities: €50,000,000 26 months i.e. until June 28, 2022 Capital increase: 75% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €862,073.95 Debt instruments giving access to equity securities: €50,000,000 — Capital increase: €854,948.95 Debt instruments giving access to equity securities: €50,000,00 Delegation of authority to be given to the Board of Directors in order to increase the capital through the issue of ordinary shares and/or securities giving right to the capital, subject to a limitation of 10% of the capital in view of remunerating contributions in kind of shares or securities giving right to the capital in accordance with the provisions of Articles L.225-129-2, L.225-147 and L.228-92 of the Commercial Code (21st resolution of the 2020 Shareholders’ Meeting). Capital increase: 10% of the share capital at the date of the 2020 Shareholders’ Meeting i.e. €82,068.41 26 months i.e. until June 28, 2022 Capital increase: 75% of the share capital at the date of the 2021 Shareholders’ Meeting i.e. €862,073.95 — (1) The issue price should at least be equal to the minimum required by the legal and regulatory provisions applicable at the time when the Board of Directors shall implement the delegation (for reference, to date the weighted average of the listed prices of the share on the regulated Euronext Paris market for the three trading sessions preceding the determination of the subscription price for the increase in capital decreased by a maximum discount of 10%). (2) The issue price of the ordinary shares shall at least be equal, to the average of 5 consecutive trading sessions preceding the determination of the issue price, which may be decreased by a maximum discount of 15%. (3) The present delegation shall be made in favor of the following categories of persons: (i)individual or legal entities (including companies), investment companies, trusts, investment funds, or other investment vehicles of any form whatsoever, whether French or foreign generally investing in the pharmaceutical, bio-technological, ophthalmological, neurodegenerative diseases or medical technologies sectors; and/or (ii)companies, institutions or entities of any form whatsoever, whether French or foreign conducting a significant part of their business in those sectors; and/or (iii)financial service providers, being French or foreign with an equivalent status, capable of guaranteeing that an increase in capital will be successfully placed with the persons referred to in (i) and (ii) hereabove and, in this context, subscribing to the issued securities. (4) The price for the subscription and/or purchase of the shares to which the warrants shall give right shall at least be equal to the weighted average of the closing prices of the Company’s shares for the last 20 trading sessions preceding the date of the decision to issue warrants, deducted by any issue price of the warrant. (5) The price for the subscription and/or purchase of the shares to which the options shall give right shall at least be equal to the weighted average of the closing prices of the Company’s shares for the last 20 trading sessions preceding the date of the decision to issue options. 19.1.7SHARE CAPITAL OF THE COMPANY THAT IS THE SUBJECT OF AN OPTION OR OF AN AGREEMENT TO PUT IT UNDER OPTION. To our knowledge, as of the date of this Universal Registration Document, our share capital is not the subject of any option or any agreement to put it under option. 19.1.8HISTORY OF THE COMPANY’S SHARE CAPITAL SINCE ITS INCEPTION. All the figures (number of shares and amount in €) in the table below are adjusted in order to take into account the reverse stock split which took place on August 17, 2015. All share warrants attached to the Series A preferred shares indicated in the table below (ABSA n°1 and ABSA FBIMR) were cancelled on July 7, 2015. Date Nature of Operation Number of shares issued Nominal value of the share (in €) Issue price per share (in €) Share premium (in €) Issue price (in €) Number of shares representing the share capital Capital increase (in €) Share capital (in €) April 2012 Inception (issuance of ordinary shares) 1,520,000 0.025 0.025 — 38,000.00 1,520,000 38,000.00 38,000.00 February 5, 2013 Share capital increase (issuance of ordinary shares)(1) 268,235 0.025 0.025 — 6,705.88 1,788,235 6,705.88 44,705.88 February 5, 2013 Share capital increase (issuance of Series A preferred shares with warrants attached called ABSA n°1) 1,428,571 0.025 2.800 3,964,285.08 3,999,999.36 3,216,806 35,714.28 80,420.15 February 5, 2013 Share capital increase (issuance of Series A preferred shares) 14,630 0.025 2.800 40,598.25 40,964.00 3,231,436 365.75 80,785.90 March 20, 2013 Share capital increase (issuance of Series A preferred shares with warrants attached called ABSA n°1) 2,364,286 0.025 2.800 6,560,892.54 6,619,999.69 5,595,722 59,107.15 139,893.05 March 20, 2013 Share capital increase (issuance of Series A preferred shares with warrants attached called ABSA n°1) 2,635,714 0.025 2.800 7,314,107.46 7,380,000.31 8,231,436 65,892.85 205,785.90 March 20, 2013 Series A-related costs — — — (337,065.56) — 8,231,436 — 205,785.90 July 8, 2013 Subscription of warrants (BSA2013-02) — — — 656.00 656.00 8,231,436 — 205,785.90 December 19, 2013 Share capital increase (issuance of Series A preferred shares with warrants attached called ABSA FBIMR) 523,253 0.025 3.225 1,674,408.96 1,687,490.29 8,754,689 13,081.33 218,867.23 April 9, 2014 Subscription of warrants (BSA2013-02) — — — 66.00 66.00 8,754,689 — 218,867.23 December 31, 2014 Reversal of share premium to reserves — — — (174,161.35) — 8,754,689 — 218,867.23 February 11, 2015 Share capital increase (issuance of ordinary share through exercise of BCE2013-02 and BSA 2013-02) 229,560 0.025 0.025 — 5,739.00 8,984,249 5,739.00 224,606.23 June 30, 2015 Share capital increase (issuance of Series B preferred shares) 4,624,871 0.025 6.950 32,027,233.06 32,142,854.84 13,609,120 115,621.78 340,228.00 July 7, 2015 Series B-related costs — — — (1,305,561.25) — 13,609,120 — 340,228.00 July 8, 2015 Subscription of warrants (BSA2015-07) — — — 30,250.00 30,250.00 13,609,120 — 340,228.00 July 31, 2015 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 2 0.025 0.025 — 0.05 13,609,122 0.05 340,228.05 July 13, 2016 Share capital increase (Euronext IPO) 5,000,000 0.025 8.000 39,875,000.00 40,000,000.00 18,609,122 125,000.00 465,228.05 July 13, 2016 Euronext IPO-related costs — — (3,571,365.00) — 18,609,122 — 465,228.05 August 10, 2016 Share capital increase (Euronext IPO – Overallotment option) 655,859 0.025 8.000 5,230,475.53 5,246,872.00 19,264,981 16,396.48 481,624.53 August 10, 2016 Euronext IPO overallotment option-related costs — — — (236,109.24) — 19,264,981 — 481,624.53 September 3, 2016 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 112,000 0.025 0.025 — 2,800.00 19,376,981 2,800.00 484,424.53 October 6, 2016 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 31,720 0.025 0.025 — 793.00 19,408,701 793.00 485,217.53 October 6, 2016 Share capital increase (issuance of ordinary share through exercise of BCE2015-07) 1,000 0.025 3.275 3,250.00 3,275.00 19,409,701 25.00 485,242.53 October 31, 2016 Subscription of warrants (BSA2016-07) — 0.025 — 133,250.00 133,250.00 19,409,701 — 485,242.53 January 11, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 117,320 0.025 0.025 — 2,933.00 19,527,021 2,933.00 488,175.53 January 11, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2015-07) 13,432 0.025 3.275 43,654.00 43,989.80 19,540,453 335.80 488,511.33 May 5, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2015-07) 50,000 0.025 3 .275 162,500 163,750 19,590,453 1,250 489,761.33 May 31, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 193,800 0.025 0.025 — 4,845 19,784,253 4,845 494,606.33 June 27, 2017 Share capital increase (Euronext PIPE) 3,750,000 0.025 6.00 22,406,250 22,500,000 23,534,253 93,750 588,356.33 June 27, 2017 Euronext PIPE related costs — — — (1,778,450.20) — 23,534,253 — 588,356.33 June 29, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2015-06) 7,332 0.025 3.275 23,829 24,012.30 23,541,585 183.3 588,539.63 June 29, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 76,120 0.025 0.025 — 1,903 23,617,705 1,903 590,442.63 July 3, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 31,720 0.025 0.025 — 793.00 23,649,425 793 591,235.63 July 26, 2017 Share capital increase (issuance of ordinary share through acquisition of AGA (Performance Tranche 1) 2016) 291,000 0.025 0.025 (7,275) — 23,940,425 7,275 598,510.63 July 26, 2017 Share capital increase (issuance of ordinary share through acquisition of AGA2016) 56,000 0.025 0.025 (1,400) — 23,996,425 1,400 599,910.63 September 18, 2017 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 237,798 0.025 0.025 — 5,944.95 24,234,223 5,944.95 605,855.58 October 2017 Subscription of warrants (BSA2017) — 0.025 — 66,000 66,000 24,234,223 — 605,855.58 July 24, 2018 Share capital increase (issuance of ordinary share through acquisition of AGA2016) 255,000 0.025 0.025 (6,375) — 24,489,223 6,375 612,230.58 July 27, 2018 Share capital increase (issuance of ordinary share through acquisition of AGA2016) 277,500 0.025 0.025 (6,937.5) — 24,766,723 6,937.50 619,168.08 December 14, 2018 Subscription of warrants (BSA2018) — 0.025 — 3,600 3,600 24,766,723 — 619,168.08 December 19, 2018 Share capital increase (issuance of ordinary share through acquisition of AGA2016) 36,250 0.025 0.025 (906.25) — 24,802,973 906.25 620,074.33 February 25, 2019 Share capital increase 3,921,568 0.025 — 7,901,959.52 7,999,998.72 28,724,541 98,039.2 718,113.53 February 25, 2019 Capital increase related costs — — — (94,360) — 28,724,541 — 718,113.53 May 17, 2019 Share capital increase (issuance of ordinary share through acquisition of AGA2017) 263,750 0.025 — (6,593.75) — 28,988,291 6,593.75 724,707.28 September 19, 2019 Share capital increase (issuance of ordinary share through acquisition of AGA2018) 40,000 0.025 — (1,000) — 29,028,291 1,000 725,707.28 December 15, 2019 Subscription of warrants (BSA2018) — 0.025 — 13,650 13,650 29,028,291 — 725,707.28 December 19, 2019 Share capital increase 3,799,071 0.025 2.369 8,905,022.42 8,999,999.2 32,827,362 94,976.78 820,684.05 December 19, 2019 Capital increase related costs — — — (723,683.4) — — — — December 19, 2019 Subscription of warrants (BSA2019 Kreos-A) — 0.025 — 1.00 1.00 32,827,362 — 820,684.05 April 30, 2020 Subscription of warrants (BSA2019-2) — 0.025 — 12,000 12,000 32,827,362 — 820,684.05 July 23, 2020 Share capital increase (issuance of ordinary share through acquisition of AGA2019) 27,500 0.025 — (687,5) — 32,854,862 687,5 821,371.55 July 24, 2020 Share capital increase (issuance of ordinary share through exercise of BCE2015-06) 16,000 0.025 3.275 52,000 52,400 32,870,862 400.00 821,771.55 July 29,2020 Share capital increase (issuance of ordinary share through acquisition of AGA2018 & 2019) 433,750 0.025 — (10,843.75) — 33,304,612 10,843.75 832,615.30 July 31, 2020 Subscription of warrants (BSA 2019 Kreos-B) — 0.025 — 1.00 1.00 33,304,612 — 832,615.30 September 1, 2020 Share capital increase (issuance of ordinary share through acquisition of AGA2018) 160,000 0.025 — (4,000) — 33,464,612 4,000 836,615.30 September 14, 2020 Share capital increase (issuance of ordinary share through acquisition of AGA2019) 273,750 0.025 — (6,843.75) — 33,738,362 6,843.75 843,459.05 October 22, 2020 Share capital increase 5,954,650 0.025 4.20 24,860,663.75 25,009,530 39,693,012 148,866.25 992,325.30 October 22, 2020 Capital increase related costs — — — (1,876,375.61) — — — — December 9, 2020 Share capital increase (issuance of ordinary shares through exercise of 50% OCA Kreos) 668,152 0.025 2.245 1,483,297.44 1,500,001.24 40,361,164 16,703.80 1,009,029.10 December 9, 2020 Share capital increase (issuance of ordinary shares through exercise of 50% of the additional OCA Kreos) 58,275 0.025 2.574 148,542.98 149,999.85 40,419,439 1,456.88 1,010,485.98 December 9, 2020 Share capital increase (issuance of ordinary shares through exercise of BSA Kreos) 456,526 0.025 — (11,413.15) — 40,875,965 11,413.15 1,021,899.13 January 19, 2021 Share capital increase (issuance of ordinary share through exercise of BCE2014-06) 60,000 0.025 0.025 — 1,500 40,935,965 1,500 1,023,399.13 January 22, 2021 Share capital increase (issuance of ordinary share through exercise of BCE2015-06) 12,000 0.025 3.275 39,000 39,300 40,947,965 300 1,023,699.13 January 28, 2021 Share capital increase (issuance of ordinary share through acquisition of AGA2020) 437,500 0.025 — (10,937.5) — 41,385,465 10,937.5 1,034,636.63 February 12, 2021 Share capital increase (issuance of ordinary share through exercise of BCE2013-02) 76,120 0.025 0.025 — 1,903 41,461,585 1,903 1,036,539.63 February 15, 2021 Subscription of warrants (BSA2020) — 0.025 — 28,000 28,000 41,461,585 — 1,036,539.63 March 8, 2021 Share capital increase (issuance of ordinary share through exercise of BSA2013-02) 38,080 0.025 0.025 — 952 41,499,665 952 1,037,491.63 March 26, 2021 Share capital increase 4,477,612 0.025 6,70 29,888,060.10 30,000,000.40 45,977,277 111,940.30 1,149,431.93 March 26, 2021 Capital increase related costs — — — (1,905,800.42) — — — — May 27, 2021 Subscription of warrants (BSA2021) — 0.025 — 25,200 25,200 45,977,277 — 1,149,431.93 June 28, 2021 Share capital increase (issuance of ordinary share through exercise of BSA2016) 30,000 0.025 5.040 150,450 151,200 46,007,277 750.00 1,150,181.93 June 28, 2021 Share capital increase (issuance of ordinary share through exercise of BSA2018) 4,479 0.025 2.220 9,831.41 9,943.38 46,011,765 111.98 1,150,293.90 November 17, 2021 Share capital increase (issuance of ordinary share through exercise of BSA2019) 21,667 0.025 1.450 30,875.48 31,417.15 46,033,423 541.68 1,150,835.58 November 17, 2021 Share capital increase (issuance of ordinary share through exercise of BSA2013-02) 221,960 0.025 0.025 — 5,549.00 46,255,383 5,549.00 1,156,384.58 November 29, 2021 Share capital increase (issuance of ordinary share through exercise of SO2018) 25,208 0.025 2.820 70,456.36 71,086.56 46,280,591 630.20 1,157,014.78 December 14, 2021 Share capital increase (issuance of ordinary share through exercise of SO2018) 20,000 0.025 2.820 55,900 56,400 46,300,591 500.00 1,157,514.78 December 28, 2021 Subscription of warrants (BSA2021) — 0.025 — 17,700 17,700 46,300,591 — 1,157,514.78 February 25, 2022 Share capital increase (issuance of ordinary share through acquisition of AGA 2021) 35,000 0.025 — (875.00) — 46,335,591 875.00 1,158,389.78 April 30, 2022 Subscription of warrants (BSA 2021) — 0.025 — 31,200 24,000 46,335,591 — 1,158,398.78 Total as of the date of this Universal Registration Document 46,335,591 181,205,097.15 194,341,219.0 1,158,389.78 (1) The Company issued 268,235 ordinary shares for the benefit of Novartis in payment for intellectual property rights (see 18.1.2, “License Agreement with Novartis Pharma AG”). In compliance with IFRS 2, the acquired license was valued at the fair value of issued shares, as assessed by an independent expert, at €1.025 per share. 19.1.9FACTORS LIKELY TO HAVE AN IMPACT IN THE EVENT OF A PUBLIC OFFERING. Pursuant to Article L.225-37-5, we call to your attention to the following points likely to have an impact in the event of a public offering: The capital structure as well as the known direct or indirect holdings of the Company and all related matters are described in Section 16.1 of this Universal Registration Document. There are no statutory restrictions on the exercise of double voting rights, apart from abstentions from voting that may be requested by one or more shareholders holding at least 2.5% of the share capital absent a declaration of a breach of the statutory thresholds (Article 12.2 of the Company’s bylaws). There is no statutory restriction on the transfer of shares. There is no instrument containing special control rights. There are no control mechanisms provided in a potential shareholding system for personnel with control rights not exercised by the said personnel. The rules for nominating and removing members of the Board of Directors are the legal and statutory rules provided for in Article 16 of the Company’s bylaws. With regards to authority of the Board of Directors, current delegations are described in paragraph 19.1.3 of this Universal Registration Document (share purchase program) and in the table of delegations for capital increases appearing in Paragraph 19.1.6 of this same document. The Company’s bylaws are changed in accordance with the legal and regulatory provisions. No significant agreement is entered into by the Company that is changed or that terminates in the event of a change of control, except the following: •the Bond Issue Agreement signed with Kreos on December 19, 2019 provides that in the case of a change of control, all moneys outstanding under the Bonds might become immediatly repayable as well as all the interests accrued but unpaid. There are no private agreements providing for severance payments in the event of cessation of duties of members of the Board of Directors or employees if they resign or are laid off without real and serious cause or if their employment is terminated due to a public offering. Details of the severance likely to be paid to the Chief Executive Officer are provided above, as well as in Sections 13.1 and 13.7 of this Universal Registration Document (Table 11). 19.2Constitutive Documents and Bylaws 19.2.1CORPORATE PURPOSE (ARTICLE 2 OF THE BYLAWS). Our corporate purpose in France and abroad includes: •the research and development in the treatment of ophthalmic pathologies and neurodegenerative diseases of any kind; •the technical development, including by way of clinical trials, the production and marketing of any product and material enabling the treatment of ophthalmic pathologies and neurodegenerative diseases; •any services and activities in relation thereto; •the acquisition, operation or sale of any process, patent or other intellectual property rights in relation thereto; •the participation, by any means, whether directly or indirectly, in any operation that could be connected to the activities described above by way of incorporation, contribution, subscription or acquisition of the shares, merger or creation, acquisition, leasing including any management leasing, of any business; and •more generally, all commercial, industrial, real estate, civil and financial transactions, including any guarantee or security, loan, cash transaction in particular the transactions set out in Article L.511-7 of the French Monetary and Financial Code, relating directly or indirectly to any of the aforementioned corporate purposes or any similar or related purpose. 19.2.2ADMINISTRATIVE AND MANAGEMENT BODIES. 19.2.2.1Board of Directors (Articles 15, 16, 17, 18, 20 and 21 of the bylaws) Composition of the Board of Directors, and of the directors The Company is governed by a Board of Directors composed of at least three members and at most 18 members elected by the ordinary shareholders’ meeting pursuant to and subject to the exceptions stated by law. The Board of Directors should reflect a balanced representation of women and men. During the term of the Company, directors are appointed, renewed or dismissed under the conditions provided for by applicable laws and regulations and by the Company’s bylaws. Directors are appointed for a three-year term, by way of exception and in order to exclusively allow for the implementation or the maintenance of the staggering of the mandates, the ordinary shareholders’ meeting may appoint one or several members of the Board of Directors for a term of two years or one year. Directors are eligible for re-election. They can be dismissed at any time by the general shareholders’ meeting. No person who is more than 75 years old may be a director. The number of directors who are also party to employment contracts with us may not exceed one-third of the directors in office. Directors are subject to applicable laws and regulations regarding plurality of offices. Directors may be individual or legal entities. At the time they are elected, legal entities must appoint a permanent representative who is subject to the same conditions and obligations, and who incurs the same civil and criminal responsibilities as he were a director in his own name, without prejudice to the joint liability with the legal entity he represents. The office of permanent representative is given for the duration of the term of office of the legal entity he represents. If the legal entity revokes the appointment of its permanent representative, it must immediately notify the Company, by registered mail, of this dismissal and the name of its new permanent representative. This is also required in the event of the death or resignation of the permanent representative. The shareholders’ meeting can allocate to the directors, as directors’ attendance fees (jetons de présence), a fixed annual amount. The distribution between the directors is determined by the Board of Directors. In addition, the Board of Directors may grant exceptional compensation (rémunérations exceptionnelles) to individual directors on a case-by-case basis for special and temporary assignments. The Board of Directors may also authorize the reimbursement of reasonable travel and accommodation expenses, as well as other expenses incurred by directors in the corporate interest. There are no directors’ share ownership requirements. Deliberations of the Board of Directors The Board of Directors meets as often as necessary in the Company’s interest. The Chairman convenes these meetings. If the Board of Directors has not met in more than two months, at least one-third of its members may request that the Chairman convene it to discuss a particular agenda. The Chief Executive Officer may also request that the Chairman convenes the Board of Directors to discuss a particular agenda. Decisions are taken by a majority of members present or represented. In the event of a tie, the vote of the meeting’s Chairman does prevail. The Board of Directors can only deliberate if at least half of the directors attend the meeting in the manners provided for in our bylaws. In compliance with legal and regulatory provisions, the internal regulations may provide that are considered present for the quorum and the majority, the directors participating to the Board meeting by videoconference or telecommunication means in compliance with technical specifications laid down by the legislative and regulatory provisions in force. Any director may authorize another director to represent him at a meeting of the Board of Directors, each director may hold only one proxy per meeting. The deliberations of the Board are recorded in minutes signed by the Chairman of the meeting and by at least one director who participated in the meeting. In case the Chairman of the meeting is prevented from signing, at least two directors can sign it. The Board of Directors sets up in its internal regulation its operating procedures in accordance with the law and the bylaws. Powers of the Board of Directors The Board of Directors determines the direction of the Company’s business and ensures its implementation. Subject to the powers expressly granted to the shareholders’ meeting, and within the limits of the Company’s purpose, the Board of Directors decides any question concerning the proper functioning of the Company and, through its decisions, settles matters concerning it. It may decide to create committees responsible for studying issues that it itself or its Chairman may submit to them for analysis. The composition and powers of each of these committees, which operate under its responsibility, are set by the Board of Directors by internal regulations. Directors’ voting powers on proposal, arrangement or contract in which any director is materially interested Pursuant to Article L.225-38 of the French Commercial Code, any agreement entered into (directly or through an intermediary) between us and any director that is not entered into (1) in the ordinary course of our business and (2) upon standard market terms is subject to the prior authorization of the Board of Directors (it being specified that the interested director cannot vote on such decision). The same provision applies to agreements between us and another company, provided that the company is not one of our wholly owned subsidiaries, if one of our directors is the owner or a general partner, manager, director, general manager or member of the executive or supervisory board of the other company, as well as to agreements in which one of our directors has an indirect interest. 19.2.2.2Chairman (Article 17 of the bylaws) The Board of Directors elects a Chairman from among the members who are natural persons. No person who is more than 75 years old may be a Chairman. The Chairman represents the Board of Directors. He organizes and manages its work, and reports on such work to the general shareholders’ meeting. He oversees the proper functioning of the Company’s governing bodies and ensures, in particular, that the directors are able to carry out their duties. 19.2.2.3Chief Executive Officer (Article 19 of the bylaws) At the option of the Board of Directors, the Company may be managed either by the Chairman or by another individual appointed by the Board of Directors (among its members or outside) and given the title of Chief Executive Officer. No person who is more than 75 years old may be a Chief Executive Officer. The Chief Executive Officer is granted the broadest powers to act in all circumstances in the Company’s name. He exercises these powers within the limits of the Company’s purpose and subject to the powers that the law and the bylaws grant expressly to the shareholders’ meeting or the Board of Directors. The Chief Executive Officer represents the Company in its relations with third-parties. On the recommendation of the Chief Executive Officer, the Board of Directors may appoint, among its members or outside, one or more individuals in charge of assisting the Chief Executive Officer, who holds the title of Deputy Chief Executive Officer. No person who is more than 70 years old may be a Deputy Chief Executive Officer. There may be no more than five Deputy Chief Executive Officer. The term of office of the Deputy Chief Executive Officer or of the Deputy Chief Executive Officers is determined at the time they are appointed, but this term may not exceed the term of office on the Board, if applicable. The Chief Executive Officer may be dismissed at any time by the Board of Directors. This is also true for the Deputy Chief Executive Officers, on the recommendation of the Chief Executive Officer. If dismissal is decided without grounds, it may result in damages, except when the Chief Executive Officer assumes the position of Chairman of the Board of Directors. When the Chief Executive Officer ceases or is prevented from performing his duties, the Deputy Chief Executive Officers retain their duties and powers, unless decided otherwise by the Board, until the appointment of the new Chief Executive Officer. The Board of Directors determines the compensation of the Chief Executive Officer and the Deputy Chief Executive Officers. 19.2.3RIGHTS, PREFERENCES AND RESTRICTIONS ATTACHING TO ORDINARY SHARES. 19.2.3.1Form of Shares (Article 11 of the bylaws) Fully paid-up shares are in registered or bearer form, at the shareholder’s discretion, under the conditions defined by the regulations in force. The Company may at any time verify the identity of the holders of bearer shares in accordance with applicable laws and regulations. 19.2.3.2Rights and Obligations Attached to Shares (Articles 12 and 14 of the bylaws) Each share gives a right to a share of the profits and corporate assets in proportion to the percentage of capital it represents. Moreover, it gives the right to vote and to representation at shareholders’ meetings under the conditions set by law and the bylaws. By derogation to Article L.225-123 paragraph 3 of the French Commercial Code, the bylaws do not grant double voting rights to the shares of the Company. Shareholders are liable for losses only up to the amount of their contributions. The rights and obligations attached to a share remain with the share when it is transferred. Ownership of a share legally implies compliance with the bylaws and the resolutions of the shareholders’ meeting. Whenever it is necessary to hold several shares to exercise a right, individual shares or a number of shares less than the number required give no rights to their owners against the Company; in this case, it is the responsibility of the shareholders to combine the number of shares necessary. 19.2.3.3Indivisibility of the Shares - Beneficial Ownership (Article 13 of the bylaws) Shares are indivisible with respect to the Company Co-owners of indivisible shares are represented at shareholders’ meetings by one of the owners or by a single agent. If they disagree, the agent shall be designed by court at the request of one of the co-owners. If there is a beneficial owner, the share registration must show the existence of the beneficial ownership. Except where otherwise stipulated in an agreement notified to the Company by registered mail with return receipt, the voting right belongs to the beneficial owner in ordinary shareholders’ meetings and to the bare owner in extraordinary shareholders’ meetings. 19.2.3.4Transfer of Shares (Article 12 of the bylaws) Shares are freely negotiable, except where otherwise stipulated by laws or regulations. They are registered in an account and are transferred, with respect to the Company, by a transfer between accounts, under the conditions defined by the laws and regulations in force. 19.2.4MODIFICATION OF SHAREHOLDERS’ RIGHTS. The rights of shareholders may be modified in accordance with applicable laws and regulations. The bylaws do not contain any particular provisions with respect to modification of the rights of shareholders that are more stringent than the law. 19.2.5GENERAL SHAREHOLDERS’ MEETINGS (ARTICLES 24 TO 31 OF THE BYLAWS). Notice and place of meeting Shareholders’ meetings shall be called and shall deliberate on the terms provided by law. Meetings shall be held either at the registered office or at another place stated in the notice of the call to a meeting. Agenda The meeting agenda is provided on the notices and letters of meeting; it is decided by the author of the notice. The meeting may deliberate only on items indicated on the agenda; however, in all circumstances it may dismiss one or more directors and replace them. One or more shareholders representing at least the percentage of capital required by law, and acting under the statutory conditions and within the statutory time periods, have the option to require the inclusion of proposed resolutions on the agenda. Access to meetings Any shareholder has the right to attend shareholders’ meetings and participate in the deliberations personally or through an agent. Any shareholder may participate at meetings in person or through his agent, under the conditions defined by the regulations in force, with proof of his identity and the ownership of his shares in the form of accounting registration under the conditions defined by the laws and regulations in force. On the decision of the Board of Directors published in the notice of meeting to use such telecommunications methods, shareholders who attend the meeting via videoconference or other telecommunication or electronic transmission methods, including the Internet, which allow identification under the conditions required by the regulations in force, are deemed present for the calculation of quorum and majority. On a decision by the Board of Directors, any shareholder may vote remotely or give his proxy pursuant to the regulations in force using a form prepared by the Company and sent to the Company under the conditions defined by the regulations in force, including electronic or broadcast transmission methods. This form must be received by the Company under the regulatory conditions to be counted. Attendance sheet, officers (bureau), minutes At each meeting, an attendance sheet containing the information required by law shall be kept. Meetings are chaired by the Chairman of the Board of Directors or, in his absence, by a director specifically delegated for this purpose by the Board. If not, the meeting shall elect a Chairman. The duties of tellers (scrutateurs) are performed by the two members of the meeting who are present and accept the duties and who have the largest number of votes. The officers (bureau) name the secretary, who does not have to be a shareholder. The mission of the officers (bureau) is to verify, certify and sign the attendance sheet, to ensure the proper conduct of discussion, to settle incidents at meetings, to count the votes cast, and to ensure the meeting is properly conducted and that minutes are prepared. Minutes are prepared and copies or excerpts of the resolutions are issued and certified as required by law. Ordinary shareholders’ meeting The ordinary shareholders’ meeting is a meeting called to make all decisions that do not amend the bylaws. It meets at least once a year within six months after the closing of each fiscal year to approve the financial statements for the year and the financial statements unless an extension is granted under the conditions provided for by law. On the first notice of meeting, it may legally deliberate only if the shareholders present or represented, or voting by mail and electronically, hold at least one-fifth of the voting shares. On the second notice of meeting, no quorum is required. It rules by a majority of the votes held by the shareholders present, represented or who have voted by mail or means of distance communication. Extraordinary shareholders’ meeting Only the extraordinary shareholders’ meeting is authorized to amend all provisions of the bylaws. It may not, however, increase shareholders’ commitments, subject to operations resulting from a legally performed consolidation of shares without the approval of each shareholder. It legally deliberates only if the shareholders present, represented or who have voted by mail or electronically, hold at least one quarter of the voting shares on the first notice of meeting, and one-fifth of the voting shares on the second notice. If the second quorum is not reached, the second meeting may be moved to a date no more than two months from the date on which it was called. The meeting rules by a two-thirds majority of the votes of the shareholders present, represented or voting by mail or means of distance communication. However, under no circumstances may the extraordinary shareholders’ meeting increase the commitments of the shareholders or damage the equality of their rights unless this is done by unanimous vote of the shareholders. Decisions are made by a two-thirds majority of the votes held by the shareholders present, represented by proxy, or voting by mail. Abstentions will have the same effect as “no” vote. 19.2.6STIPULATIONS THAT ALLOW DELAYING, DEFERRING OR PREVENTING A CHANGE IN CONTROL OF THE COMPANY. There are no provisions either in the Company’s bylaws or in any internal charter or internal rules that could have the effect of delaying, postponing or preventing a change of control of the Company. 19.2.7DECLARATION OF THRESHOLDS (ARTICLE 12 OF THE BYLAWS). In addition to the thresholds provided for by applicable laws and regulations, any natural person or legal entity who comes to hold or ceases to hold, acting alone or in concert within the meaning of Article L.233-10 of the French Commercial Code, directly or indirectly, a number of shares representing at least 2.5% of the share capital or voting rights, including beyond the reporting thresholds provided for by laws and regulations, must inform the Company of the total number of shares and voting rights of the Company that such person holds, by registered letter with return receipt requested sent to the Company’s registered office within four trading days after crossing such threshold(s). Such person shall also indicate the number of securities giving access to the capital and the voting right potentially attached thereto, as well as any other information provided for by law. The notification shall be repeated in the conditions stated above each time an additional fraction of 2.5% of the share capital or voting rights is crossed upward or downward. In the event of failure to comply with the notification requirements described above, shares exceeding the fraction that should have been notified will be deprived of voting rights at shareholders’ meetings if, at such meetings, the notification failure has been recorded and if one or more shareholders jointly holding at least 2.5% of the share capital so request. Loss of voting rights shall be applicable in all shareholders’ meetings that would be held up until two years following proper notification. 19.2.8PARTICULAR STIPULATIONS GOVERNING MODIFICATIONS OF THE SHARE CAPITAL. As the bylaws do not provide any specific stipulations, the share capital may be increased, decreased or amortized by any methods or means authorized by law. 20 MATERIAL CONTRACTS As of the date of this Universal Registration Document, we are a party to the following material contracts: 20.1Collaboration, Partnership and Related Agreements Agreements Relating to LUMEVOQ® •Partnership agreement relating to the research, development and commercialization of LUMEVOQ® between Genethon and the Company dated February 1, 2013, as amended from time to time. In February 2013, we entered into a partnership agreement with Genethon to research, develop and commercialize selected research and development projects for gene therapy products within specific ocular indications using technology licensed by the Company under a license agreement with Inserm Transfert dated October 12, 2012. For more details, see Section 5.5.4, “Collaboration, Partnership and Related Agreements” of this Universal Registration Document. Agreements Relating to GS030 Sight Again Program •Consortium agreement relating to the research and development of complementary therapeutic remedies between Pixium Vision S.A., or Pixium Vision, Fondation Voir et Entendre and the Company dated July 11, 2014. In July 2014, we entered into a consortium agreement with Pixium Vision and FVE. For more details, see Section 5.5.4, “Collaboration, Partnership and Related Agreements” of this Universal Registration Document. •Master agreement relating to the Sight Again Program between Bpifrance Financement, Pixium Vision and the Company dated December 16, 2014. In December 2014, we entered into a master agreement relating to the Program with Bpifrance Financement, Pixium Vision and FVE setting forth the characteristics of the Program, to fix the amount and conditions for awarding funding granted by Bpifrance Financement as well as to clarify the principles and arrangements for monitoring the implementation of the Program by Bpifrance Financement. Pursuant to an amendment dated November 26, 2015, the product candidate known as GS020 has been replaced by the product candidate GS030 for the purpose of the agreement. For more details, see Section 5.5.4, “Collaboration, Partnership and Related Agreements” of this Universal Registration Document. •Financial aid agreement related to the Sight Again Program between Bpifrance Financement and the Company dated December 16, 2014. In December 2014, we entered into a financial aid agreement relating to the Program with Bpifrance Financement setting forth the amounts and conditions upon which Bpifrance Financement shall grant financial aid to the Program. Pursuant to an amendment dated November 26, 2015, the product candidate known as GS020 has been replaced by the product candidate GS030 for the purpose of the agreement. A second amendment redefining the financial conditions was signed in the course of 2021. For more details, see Section 5.5.4, “Collaboration, Partnership and Related Agreements” of this Universal Registration Document. 20.2In-License Agreements Agreements Relating to LUMEVOQ® •License agreement relating to patents used in connection with LUMEVOQ® with Inserm Transfert S.A. and the Company dated October 12, 2012. On October 12, 2012, we entered into a license agreement with Inserm Transfert S.A. (acting as delegate of Inserm). For more details, see Section 5.5.5, “Intellectual Property” of this Universal Registration Document. •License agreement relating to scientific data used in connection with LUMEVOQ® with Association Française contre les Myopathies, Inserm Transfert S.A. and the Company dated December 2, 2013. On December 2, 2013, we entered into a license agreement for use of scientific data with the AFM, Genethon and Inserm Transfert, acting as a delegate of Inserm and on behalf of the UPMC. For more details, see Section 5.5.5, “Intellectual Property” of this Universal Registration Document. •License agreement for the use of Harvard Master CellBank relating to LUMEVOQ® dated June 18, 2019. For more details, see Section 5.5.5, “Intellectual Property” of this Universal Registration Document. Agreements Relating to GS030 •License agreement relating to patents used in connection with GS030 with Adverum Biotechnologies (formerly Avalanche Biotechnologies) and the Company dated February 23, 2014. On February 23, 2014, we entered into a non-exclusive license agreement with Adverum. For more details, see Section 5.5.5, “Intellectual Property” of this Universal Registration Document. Massachusetts Institute of Technology •License agreement relating to patents used in connection with GS030. On January 6, 2016, we entered into a license agreement with M.I.T., upon exercising an option right granted under the patent option agreement between M.I.T. and us, dated January 9, 2015. This license agreement has been amended in April 2017, whereby the Company will provide the M.I.T. with a written research and development plan no later than July 1, 2018. For more details, see Section 5.5.5, “Intellectual Property” of this Universal Registration Document. •License agreement relating to patents used in connection with GS030. On May 6, 2019, we entered into a license agreement with Sorbonne Université, CNRS, Inserm and Satt Lutech. For more details, see Section 5.5.5, “Intellectual Property” of this Universal Registration Document. 20.3Manufacturing Agreement •Services agreement with Brammer Bio dated October 10, 2017. In order to secure the commercial grade manufacturing when GenSight will be ready for submitting the marketing authorization application, GenSight has reconsidered its partnership with Novasep Henogen, and has decided to move on with Brammer Bio. Brammer Bio acquired in 2017 additional facilities dedicated to Phase III and commercial production for Gene Therapy. These facilities are currently under cGMP production. Hence, on October 10, 2017, we entered into a Master Services Agreement (MSA for Development and Manufacturing Services Agreement) with Brammer Bio for the manufacturing and control of our product candidate LUMEVOQ®. The performance of the services under the agreement is split into two work statements. The first work statement (WS1) has been contracted for the process transfer and establishment at Brammer Bio (part A) and the process characterization (part B), with completion timeframes ranging from 6 months to 10 months. The second work statement (WS2) was contracted in August 2018 for the process performance qualification (PPQ) which includes the manufacture of 3-PPQ batches (part C) eligible to market. Each work statement will terminate upon completion of the deliverables. On October 22, 2020, we contracted with Brammer Bio an Amendment to the MSA for Development, Commercial Manufacturing and Supply. This agreement defines the terms of commercial manufacturing and supply such as pricing, payment, and minimum purchase commitment. As per this agreement, GenSight provides to Brammer Bio a rolling twelve- quarter- forecast of batches of LUMEVOQ® drug substance and drug product that shall be manufactured by Brammer. On June 20, 2021, we amended the Product Addendum of the MSA to transfer the release testing of the Drug Product and the related stability studies testing in Europe. A third Work Statement (WS3) was contracted on July 2, 2021 to support (i) the transfer and validation of the analytical methods in Europe, and (ii) the sourcing and bridging study of fetal bovine serum batches for early commercial manufacturing. •Services agreement with Catalent dated March 3, 2022. In 2022, GenSight signed an agreement with Catalent Cell and Gene Therapy (Maryland, Inc., 801 W. Baltimore Street- Baltimore, MD 21201) for scale-up to 400L (2x200L) and manufacturing of the GS030 product required for the Phase III Clinical studies. 20.4Customer Agreement Procurement contract with the CHNO of the Quinze-Vingts dated May 7, 2020.The Company has signed a procurement contract with the CHNO of the Quinze-Vingts Hospital in Paris for the supply of LUMEVOQ® for the treatment of patients under a Temporary Authorization for Use (ATU nominative). 21 DOCUMENTS AVAILABLE Copies of this Universal Registration Document and our bylaws are available free of charge at our registered office. All such legal and financial documents relating to us and made available to shareholders in accordance with applicable regulations may be viewed at our registered office. Once our shares have been admitted to trading on Euronext Paris, regulated information pursuant to the AMF General Regulations will be available on our website (http://www.gensight-biologics.com). 22 GLOSSARY AAAA deno Associated Virus AMD Age-Related Macular Degeneration ANSM Agence nationale de securité du médicament et des produits de santé ATIS Asynchronous Time-Based Image Sensor ATMP Advanced Therapeutic Medicinal Product ATP Adenosine TriPhosphate BCVA Best corrected visual acuity BLA Biological License Application BPCIA Biologics Price Competition and Innovation Act CBER Center for Biological Evaluation & Research CDER Center for Drug Evaluation & Research CAT Committee for Advanced Therapies CE European Conformity cGMP Certified Good Manufacturing Practices CHMP Committee on Human Medicinal Products CMC Chemistry, Manufacturing and Controls CMO Contract Manufacturing Organization CMS Center for Medicare & Medicated Services Cox10 Cytochrome c oxidase assembly homolog 10 CRO Contract Research Organization CTA Clinical Trial Application DNA Deoxyribonucleic acid DSMB Data Safety Monitoring Board EEA European Economic Area EMA European Medicines Agency ETDRS Early Treatment Diabetic Retinopathy Study FDA Food and Drug Administration FD&C Federal Food, Drug, and Cosmetic Act GA Geographic Atrophy GCP Good Clinical Practices GLP Good Laboratory Practices GMP Good Manufacturing Practices GTP Good Tissue Practices HCT/Ps Human Cells, Tissues, and Cellular and Tissue-Based Products HITECH Health Information Technology for Economic and Clinical Health Act HIPAA Health Insurance Portability and Accountability Act IBC Institutional Biosafety Committee ICH International Conference on Harmonization IDE Investigational Device Exemption IND Investigational New Drug IOP Intraocular pressure IRB Institutional Review Board IVT Intravitreal LCA Leber congenital amaurosis LHON Leber hereditary optic neuropathy MAA Marketing Access Authorization MIT Massachusetts Institute of Technology MTS Mitochondrial Targeting Sequence mtDNA Mitochondrial ribonucleic acid mRNA Messenger RNA MTS Mitochondrial Targeting Sequence NDA New Drug Application ND4 NADH dehydrogenase 4 NIH National Institutes of Health NHP Non-human primate OCT Optical coherence tomography PDCO Paediatric Committee PDUFA Prescription Drug User Fee Act PHS Public Health Service PMA PreMarket Approval PPACA Patient Protection and Affordable Care Act RAC Recombinant DNA Advisory Committee rAAV Recombinant adeno-associated Virus REMS Risk Evaluation and Mitigation Strategy RGC Retinal Ganglion Cells RNA Ribo Nucleic Acid RP Retinitis Pigmentosa SOP Standard operating procedure SPC Supplementary Protection Certificate USPTO United States Patent & Trademark Office UTR UnTranslated Region VEP Visual evoked potential Wt Wild type 23 ANNEXES ANNEX 1. OTHER INFORMATION RELATING TO THE FINANCIAL STATEMENTS OF GENSIGHT BIOLOGICS S.A. PARENT COMPANY 1.AGED TRADE ACCOUNT PAYABLES In accordance with the French law on the Modernization of the Economy of August 4, 2008 and the resulting Articles L.441-6-1 and D.441-4 of the French Commercial Code, the aging of the balance of trade accounts payable by GenSight Biologics S.A. parent company at year-end is as follows: Not yet due 0 to 30 days 31 to 60 days 61 to 90 days > 90 days Total overdues Number of invoices 61 Amount of trade account payable(tax included) 3,701 1,262 1 212 503 1,978 % of total purchases (tax included of the period) 10.43% 3.56% 0.00% 0.60% 1.42% 5.58% 2.AGED TRADE ACCOUNTS RECEIVABLES In accordance with the French law on the Modernization of the Economy of August 4, 2008 and the resulting Articles L.441-6-1 and D.441-4 of the French Commercial Code, the aging of the balance of trade accounts receivables by GenSight Biologics S.A. parent company at year-end is as follows: Not yet due 0 to 30 days 31 to 60 days 61 to 90 days > 90 days Total Number of invoices — 1 — — — 1 Total amount of invoices concerned including VAT — 357 — — — 357 Percentage of revenue for the financial year including VAT — 3.85% — — — 3.85% 3.FIVE YEARS FINANCIAL SUMMARY 2021 2020 2019 2018 2017 A – CAPITAL AT YEAR-END (in thousands of euros) 1. Share capital 1,158 1,022 821 821 606 2. Number of ordinary shares outstanding 46,300,591 40,875,965 32,827,362 24,802,973 24,234,223 3. Number of series A shares outstanding — — — — — 4. Number of series B shares outstanding — — — — — B – OPERATIONS AND RESULTS OF THE YEAR (in thousands of euros) 1. Net revenue 4,470 4,070 700 — — 2. Earnings before tax, employee profit-sharing, depreciation, amortization and provisions (27,342) (24,440) (33,250) (36,218) (22,478) 3. Income tax expense / (income) (2,433) (2,764) (4,210) (4,322) (3,692) 4. Employee profit-sharing due for the year — — — — — 5. Earnings after tax, employee profit-sharing, depreciation, amortization and provisions (25,172) (21,911) (29,322) (32,188) (19,045) 6. Distributed earnings (during the year) — — — — — C – EARNINGS PER SHARE (in euros)(1) 1. Earnings per share after tax, employee profit-sharing, but before depreciation, amortization and provisions (0.6) (0.6) (0.9) (1.29) (0.78) 2. Earnings after tax, employee profit-sharing, depreciation, amortization and provisions (0.5) (0.5) (0.9) (1.30) (0.79) 3. Net dividend per ordinary share — — — — — D – PERSONNEL 1. Average number of employees in the year 32 24 27 32 33 2. Total payroll for the year (in KEuros) 4,475 3,625 3,318 3,630 3,315 3. Amounts paid with respect to employee benefits during the year (Social Security, staff benefits, etc.) (in KEuros) 2,207 3,037 1,600 1,209 2,231 (1) The number of shares used for the calculation is as of December 31, 2021. See note 24 to our consolidated financial statements as of and for the fiscal year ended December 31, 2021 for further details on the movements. Designed & published by +33 (0)1 40 55 16 66 74, rue du Faubourg Saint-Antoine 75012 Paris, France (1)In a natural history study conducted by Santhera, 15% of subjects with the ND4 (11778A) mutation achieved the following definition of “clinically relevant recovery” (CRR) from baseline in at least one eye: (i) improved by at least 10 ETDRS letters from their on-chart visual acuity, or (ii) improved from an off-chart level of visual acuity to being able to read at least 5 ETDRS letters (on-chart); Silva et al. (2019), “Natural History of Leber’s Hereditary Optic Neuropathy (LHON): Findings from a Large Patient Cohort”, Poster presented at NANOS March 16-21, 2019; Poster Session II: Scientific Advancements; Poster: 163. (2)Efficacy Endpoint was assessed using a mixed model of analysis of covariance (ANCOVA), with change from baseline at week of interest as the response, and subject, eyes of the subject as random factor, treatment and the baseline LogMAR value as covariates. (3)Silva et al. (2019), “Natural History of Leber’s Hereditary Optic Neuropathy (LHON): Findings from a Large Patient Cohort”, Poster presented at NANOS March 16-21, 2019; Poster Session II: Scientific Advancements; Poster: 163. (4)The estimated amount from the initial payment schedule was €2,675 K. The costs occurred by Company amounted to a lower amount than expected, therefore the amount of this milestone was reduced accordingly. (5)The corresponding milestone occurred in November 2017.