Opthea Ltd — Investor Presentation 2021

Oct 18, 2021

Leading Therapeutic Innovation in Retinal Diseases

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Disclaimer

This presentation includes general background information about the activities of Opthea Limited (ABN 32 006 340 567) (‘Opthea’ or ‘Company’) and its affiliates and subsidiaries (together, the ‘Opthea Group’). The information contained in this presentation is in summary form and does not purport to be complete.

This presentation contains forward-looking statements within the meaning of the U.S. federal securities laws that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements as predictions of future events. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements contained in this presentation reflect our current views with respect to future events, and we assume no obligation to update any forward-looking statements except as required by applicable law. Please refer to information, including risk factors, set forth in Opthea’s filings with the U.S. Securities and Exchange Commission for key factors that could cause actual results to differ materially from those projected in the forward-looking statements contained herein.

This presentation includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. All of the market data used in this presentation involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications and third party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such assumptions.

The information contained in this presentation does not constitute investment or financial product advice (nor taxation or legal advice) and is not intended to be used as the basis for making an investment decision. It does not take into account the investment objectives, financial situation, taxation position or needs of any particular investor, which should be considered when deciding if an investment is appropriate. You must consider your own investment objectives, financial situation and needs and conduct your own independent investigations and enquiries, including obtaining taxation, legal, financial or other professional advice in relation to the information contained in this presentation as appropriate to your jurisdiction. This presentation should not be relied upon by the Recipient in considering the merits of any particular transaction.

This presentation may contain trade marks and trade names of third parties, which are the property of their respective owners. Third party trademarks and trade names used in this presentation belong to the relevant owners and use is not intended to represent sponsorship, approval or association by or with any of the Opthea Group.

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First and only retina asset with strong clinical evidence of better visual outcomes over anti-VEGF-A therapy for wet AMD, with well tolerated safety profile

OPT-302 has the potential to revolutionize the treatment of wet AMD and improve and preserve vision for millions of patients

Currently available treatment options and those in development focus only on reducing burden of care, OPT-302 is designed to transform patient outcomes by improving vision

• OPT-302 expected to be rapidly adopted by patients, physicians and payers globally due to:

• High unmet need

• Established wet AMD market and clinical practice

• Favorable physician and health system economics

We are developing OPT-302, a first-in-class VEGF-C/D ‘trap’, to be used in combination with standard of care anti-VEGF-A therapies

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FDA granted Fast-Track designation based on superior Phase 2b results

Pivotal Phase 3 trials ongoing, on-track for topline data 2H 2023 and commercial launch 2024

OPT-302 represents a multi-billion dollar commercial opportunity

Long-term value opportunity substantial:

• Composition of Matter and Methods of Use Patents through 2034

• • Further opportunity for Patent Term Extension (PTE), Data and Market Exclusivity periods beyond 2034

• Expansion in to DME, RVO and PCV represent blockbuster upside opportunity

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Opthea’s Experienced Leadership Team

Management Team

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Megan Baldwin, PhD CEO & Managing Director[(1)]

• Joined Opthea in 2008 and has been Chief Executive Officer and Managing Director since February 2014

• Selected Experience: Over 20 years of experience focusing on angiogenesis and therapeutic strategies for cancer and ophthalmic indications; prior to Opthea, was employed at Genentech (now Roche) in the US in market planning and research roles. Holds a PhD in Medicine, having conducted doctoral studies on the biology of VEGF-C and VEGF-D.

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Mike Gerometta, PhD Head of CMC Development

• Head of Chemistry, Manufacturing and Controls Development since December 2008

• Selected Experience: Has over 30 years of experience in the Australian biotech industry, working with numerous contract manufacturing organizations overseas and locally in all facets of translational CMC from concept through to Phase 2 studies

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Karen Adams VP Finance & Company Secretary

• VP Finance & Company Secretary since April 2021

• Selected Experience: Directed financial operations at several ASX-Nasdaq listed companies. Formerly CFO of Victor Smorgon group and Director Finance Nexvet Biopharma and Financial Controller of Biota Pharmaceuticals, both companies having listed on the Nasdaq and subsequently been acquired.

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Clare Price Director of Clinical Development

• Director of Clinical Development since July 2016

• Selected Experience: Previously Director of Clinical Development at Commercial Eyes Pty Ltd., and Clinical Programme Director at Starpharma Holdings Ltd. Formerly held roles at SmithKline Beecham and GlaxoSmithKline with project management and clinical operations responsibilities.

Non-Executive Board Members

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Jeremy Levin, DPhil, MB BChir Chairman

• Appointed Chairman in October 2020

• Selected Experience: Has extensive experience in the global biopharma industry. Currently CEO, Chairman and Founder of Ovid Therapeutics. Formerly President & CEO of Teva Pharmaceutical Industries Ltd, and Senior Vice President of Strategy, Alliances & Transactions at Bristol Myers Squibb. Joined BMS from Novartis where he was Global Head of Strategic Alliances. Has served on the board of directors of various public and private companies, including Biocon Ltd, and is currently on the Board of Lundbeck.

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Julia Haller, MD Director

• Appointed in June 2021

• Selected Experience: Internationally recognized ophthalmologist and vitreoretinal surgeon. Ophthalmologist-in-Chief and Endowed Chair at Wills Eye Hospital in Philadelphia. Professor and Chair of the Department of Ophthalmology at the Sidney Kimmel Medical College at Thomas Jefferson University, and a director Bristol Myers Squibb. Previously a director of Celgen Corporation and Professor of Ophthalmology, Johns Hopkins University School of Medicine, The Wilmer Eye Institute. Dr Haller received a BA from Princeton, graduating magna cum laude, and completed her medical training at Harvard Medical School.

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Michael Sistenich, MSc Director, Chair Remuneration Committee

• Appointed in November 2015

• Selected Experience: Healthcare specialist in international investment management and investment banking. Previously led the Bell Potter team which advised the Company through a financing in 2014 and served as Director of international Equities and Head of Global Healthcare Investments at DWS, Deutsche Bank Frankfurt. Currently Chairman of Enlitic Inc. Longstanding capital market connections and experience in the global healthcare investment community.

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Daniel Spiegelman, BA, MBA

Director, Chair Audit & Risk Committee

Appointed in September 2020

• Selected Experience: Former Exec Vice President, CFO and member of the Board of Directors of Biomarin Pharmaceutical Inc. Has provided strategic financial management and insight to life sciences companies, and previously held roles at Genentech, including Treasurer, and CFO of CV Therapeutics. Currently serves as a director of several companies, including Myriad Genetics, Jiya Acquisitions Corp. and Spruce Bioscience.

Judith Robertson, BA, MBA Director

Appointed in June 2021

Selected Experience: Commercial executive with track record of leading commercial organisations and launching multiple ophthalmic products. Previously Chief Commercial Officer of Aerie Pharmaceuticals, Vice President Immunology and Ophthalmology Global Commercial Strategy Leader at Johnson & Johnson and Opthalmology Global Business Franchise Head at Novartis (formerly Alcon). Has also held roles in sales and marketing at Novartis, Bristol Myers Squibb and Searle USA.

Lawrence Gozlan, BSc (Hons) Director, Chair Nomination Committee

• Appointed in July 2020

• Selected Experience: Biotechnology investor and advisor. Life Sciences Investment Manager at Jagen Pty Ltd, an international private investment organization. Chief Investtment Officer and Founder of Scientia Capital providing investment advice for high net-worth individuals, family offices and institutional investors. Previously responsible for the largest biotechnology investment portfolio in Australia as the institutional biotechnology analyst at the Queensland Investment Corporation, QIC

(1) Serves on the Board of Directors

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Pipeline

Product	Clinical Trials & Combination Agent(s)	Research/ Preclinical	Phase 1	Phase 2a	Phase 2b	Phase 3	Anticipated Milestone	Commercial Rights
Wet Age-Related Macular Degeneration (Wet AMD)(Est. patients US and EU: 3.5 million)
OPT-302 Target:VEGF-C/D	Completed Phase 2b: Ranibizumab Two Phase 3 trials: Ranibizumab (ShORe), Aflibercept (COAST)						March 2021: Initiated two concurrent Phase 3 trials 2H 2023:Phase 3 top-line data	(Worldwide)
Diabetic Macular Edema (DME)(Est. patients Worldwide: 2 million)
OPT-302 Target:VEGF-C/D	Phase 1b/2a: Aflibercept						Company may choose to initiate study in DME	(Worldwide)
Co-Formulation (OPT-302 + VEGF-A Inhibitor) (Wet AMD)(Est. patients US and EU: 3.5 million)
Co-Formulated OPT-302 + VEGF-A Inhibitor Target:VEGF-C/D & VEGF-A	TBD						2022:File IND (FDA)	(Worldwide)

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THE PROBLEM

The majority of wet AMD patients experience an incomplete response to VEGF-A inhibitors

• 45% do not achieve meaningful vision gain, >60% have persistent fluid and 25% suffer further vision loss despite anti-VEGF-A treatment

• The majority fail to achieve 20/40 vision and most patients cannot resume routine daily activities such as driving or reading

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THE CAUSE

Wet AMD is a multi-factorial disease and driven by more than just VEGF-A

• VEGF-C and VEGF-D activate validated wet AMD disease pathways, driving angiogenesis and vascular permeability

• VEGF-C and VEGF-D are elevated when VEGF-A is inhibited, which may contribute to suboptimal clinical responses to anti-VEGF-A treatments

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THE SOLUTION

OPT-302 has the potential to be the next transformative step in the treatment of wet AMD

• Strategies to improve clinical outcomes focussed on switching anti-VEGF-A, with limited or no further improvement

• OPT-302 is the most advanced asset targeting a novel mechanism of action with demonstrated evidence of improved visual outcomes

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Improved EFFICACY is the #1 Unmet Medical Need in Wet AMD

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Improved initial & sustained visions
Improved Efficacy
gains and/or lesion morphology
Maintained or improved
Excellent Safety
safety/tolerability
Extended Dosing intervals Less frequent dosing visits
INCREASED IMPORTANCE
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Boulanger-Scemama E, Querques G, About F, Puche, et al. Ranibizumab for exudative age-related macular degeneration: A five year study of adherence to follow-up in a real life setting. J Fr Ophtalmol. 2015 Sep;38(7):620–7. Boyle J, Vukicevic M, Koklanis K, et al. Experiences of patients undergoing repeated intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration. Psychol Health Med. 2018 Feb;23(2):127–40. Mueller S, Agostini H, Ehlken C, Bauer-Steinhusen U, Hasanbasic Z, Wilke T. Patient preferences in the treatment of neovascular age-related macular degeneration: A discrete choice experiment. Ophthalmology. 2016 Apr;123(4):876–83. ClearView Commercial Assessment.

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OPT-302 : A “Trap” Inhibitor of VEGF-C and VEGF-D

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A ‘trap' comprising the extracellular domains 1-3 of VEGFR-3 and the Fc fragment of IgG1

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Potent inhibitor of VEGF-C and VEGF-D

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140 kDa

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Comparable ocular biodistribution and similar ocular PK to Eylea

OPT-302 has characteristics to ‘match’ extended dosing regimens and well tolerated safety profiles of SoC therapies

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OPT-302 Combination Therapy Achieves Broad Blockade of the Validated Pathway in wet AMD

Used in combination with any VEGF-A inhibitor, OPT-302 completely blocks VEGFR-2 and VEGFR-3 signaling, inhibiting the most important pathways driving angiogenesis and vascular leakage

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VEGF-A inhibition elevates VEGF-C and VEGF-D which can contribute to sub-optimal clinical efficacy of anti-VEGF-A treatments

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a Bevacizumab is used ’off-label’ for the treatment of nAMD

Comparison with Other Trials Mean visual acuity higher vs previous VEGF-A inhibitor trials Efficacy at 6 months is typically maintained or greater at 12 months in Phase 3 trials with VEGF-A inhibitors

20 OPT Phase 2b Min. classic & OPT-302 + Ranibizumab Occult lesions only OPT Phase 2b 16.1 All lesions BCVA between Ranibizumab OPT-302 in combination 6 mos – 12 mos ANCHOR 15 14.2 Predominantly Aflibercept OPT Phase 2b classic lesions only All lesions Brolucizumab Control arm MARINA 11.3 10.8 Min. classic & 10 Occult lesions only 10.6 9.4 8.9 8.1 7.9 7.2 6.9 6.6 6.5 5 88 121 119 240 140 304 291 301 306 360 370 0 OPT-302 2.0 OPT-302 2.0 SHAM MARINA ANCHOR VIEW1 VIEW2 VIEW1 VIEW2 HAWK HARRIER + Ran 0.5 q4w + Ran 0.5 q4w + Ran 0.5 q4w Ran 0.5 q4w Ran 0.5 q4w Ran 0.5 q4w Ran 0.5 q4w Aflib 2.0 q8w Aflib 2.0 q8w Brol 6.0 q12w Brol 6.0 q12w

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6 month data

12 month data

All trials shown, excluding Opthea’s Phase 2b data, are Phase 3 registrational studies. Number of patients randomised to treatment group (n, bottom of bars). Mean change in Best Corrected Visual Acuity (BCVA) from baseline shown in ETDRS letters (top of bars). Aflib 2.0, aflibercept 2.0mg; Brol 6.0, brolucizumab 6.0mg; OPT-302 2.0, 2.0mg OPT-302; P2B, Phase 2b study OPT-302-1002; Ran 0.5, ranibizumab, 0.5 mg; administered every four weeks; q8w, administered every 8 weeks (following 3 x 4-weekly loading doses); q12w, administered every 12 weeks

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OPT-302 is the Next Transformational Step in Treatment for Retinal Diseases

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There have been no new targeted therapies with novel mechanisms approved for wet AMD since the approval of the first VEGF-A inhibitor >15 years ago

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New Mechanism
of Action:
OPT-302 targets
VEGF-C/D
Most advanced
product in clinical
development with
demonstrated potential
to IMPROVE patient
visual outcomes
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Off-label
use
Targets VEGF-A,
Target all isoforms
VEGF-B, & PlGF
of VEGF-A
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Isoform-specific
VEGF-A165 inhibition
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Large & Growing Market Opportunity in Retinal Diseases OPT-302 uniquely positioned to tap into entire VEGF-A inhibitor market

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$12B
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$8B

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Total global $4B revenue for Total global Lucentis & Eylea revenue for (wAMD, DME, Lucentis & RVO) ~$12BN Eylea for wAMD alone Market Opportunity

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>$24B OPT-302 to be administered with any antiVEGF-A therapy: Anti-VEGF-A & DURABILITY Off-label use agnostic Total global revenue for Lucentis & Eylea (wAMD, DME, RVO) ~$12BN In addition, ~46% patients worldwide receive Avastin off-label

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Strong OPT-302 Commercial Value Drivers

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1
Large growing patient population
High unmet need
Large market opportunity
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2
Highly differentiated asset
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3
Favorable competitive
landscape
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• 3.5 M wet AMD patients (US & EU)

• 45% of anti-VEGF A treated patients do not achieve meaningful vision gain

• $12B global market opportunity

• First and only VEGF-C/D ‘trap’

• Only current therapy to have demonstrated superior visual outcomes over anti-VEGF–A therapy

• No other asset with potential to disrupt treatment paradigm on basis of EFFICACY for wet AMD in near or long-term pipeline

• Biosimilars will accelerate OPT-302 uptake

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Expedited regulatory pathway
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Commercially scalable
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Financially attractive –
short & long term
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• Fast Track designation granted for OPT-302 combination therapy for nAMD

• Offers earlier and expedited review opportunities

• 1500 centralized retina specialists in USA enables lean commercial organization

• 80 -100 sales reps anticipated (<150 total FTEs across commercial organization)

• Multi-billion dollar peak sales opportunity in USA and EU for wet AMD

• Additional multi-billion dollar peak sales opportunity in DME, RVO, and PCV

• Composition of Matter and Methods of Use Patents till 2034

• Further opportunity for Patent Term Extension (PTE), Data and Market Exclusivity periods beyond 2034

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Strong OPT-302 Stakeholder Value Drivers

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PATIENTS

RETINA SPECIALISTS

PAYERS

• Superior gains in visual acuity over standard of care treatments meaningfully improve quality of life, independence and ability to continue routine daily activities such as driving and reading

• Negligible additional treatment burden

• OPT-302 administered at the same antiVEGF-A injection visit

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• Potential to maximise visual acuity and improve long-term outcomes for patients

• Seamlessly integrates into current antiVEGF-A clinical practice

• OPT-302 injected within minutes following anti-VEGF-A injection

• Utilizes same diagnostics: OCT and Fluorescein Angiography

• OPT-302 is agnostic to anti-VEGF–A treatment type and duration

• Advantageous clinic practice financials:

• No increased staff, visits or diagnostics

• Potential to increase revenue with OPT–302 injections and volume-based discounts

• Payers want better efficacy outcomes from retinal therapy

• VEGF–A therapy represents a significant budget burden to all payers

• Profound cost inefficiency considering limitations of anti-VEGF-A efficacy (>45% of anti-VEGF-A paid treatments are limited in efficacy)

• Payers unlikely to pay for longer durability or convenience; will reimburse for patient efficacy and value to the healthcare system

• Better clinical outcomes represent better health economics

• Biosimilars will increase health cost effectiveness for anti-VEGF–A and OPT– 302 sequential IVT injections

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Clinical Data:

Phase 1/2a trial in treatment naïve and prior treated wet AMD patients (n=51)

Phase 2b randomized, controlled, double-masked & statistically powered wet AMD trial (n=366)

Phase 1b/2a trial in prior-treated DME patients

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OPT-302 Combination Therapy – Clinical Program

Now Recruiting

Completed Completed Completed Phase 1/2a Phase 1b/2a Phase 2b wet AMD DME Wet AMD (n=51) (n=153) (n=366) Comparator Comparator Comparator Ranibizumab Aflibercept Ranibizumab once every month once every month once every month OPT-302 OPT-302 OPT-302 once every month once every month once every month 3 x Monthly Dosing 3 x Monthly Dosing 6 x Monthly Dosing Treatment naïve / Prior-treated Treatment naïve Prior-treated

ShORe COAST Phase 3 Phase 3 wet AMD wet AMD (n=990) (n=990) Comparator Comparator Ranibizumab Aflibercept once every month once every 2 months after 3 monthly doses Standard Dosing Extended Dosing Standard Dosing Extended Dosing OPT-302 OPT-302 OPT-302 OPT-302 once every month once every 2 once every month once every 2 months after 3 months after 3 monthly doses monthly doses Monthly Dosing Every Two Monthly Dosing Every Two Months Dosing Months Dosing Treatment naïve Patients Treatment naïve Patients

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ShORe and COAST Phase 3 pivotal trials incorporate key learnings from our Phase 2b clinical trial in wet AMD patients which demonstrated superior vision outcomes following OPT-302 combination therapy, supporting a high level of confidence in our OPT-302 development program.

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Phase 2b

A multicenter, randomized, double-masked, sham controlled study of intravitreal OPT-302 in combination with ranibizumab, in participants with neovascular (wet) AMD

Conducted at 109 sites across 10 countries: US, EU, Israel OPT-302-1002; NCT ClinicalTrials.gov Identifier: NCT03345082

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Study Overview

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Treatment naïve patients
with neovascular AMD
Key Inclusion Criteria Key Exclusion Criteria
Screening • Active CNV minimally classic / occult > 50% lesion, classic / •• Subfoveal fibrosis or >25% of total lesionHaemorrhage >50% total lesion
• BCVA ≥ 25 and ≤ 60 letters • Other clinically significant ocular disease
Randomised (n=366)
Allocation sham + OPT-302 0.5 mg + OPT-302 2.0 mg +
ITT Population 0.5 mg ranibizumab IVT 0.5 mg ranibizumab IVT 0.5 mg ranibizumab IVT
Q4W x 6 Q4W x 6 Q4W x 6
n=121 n=122 n=123
Completed Study Completed Study Completed Study
Follow-up
n=116 (95.9%) n=112 (91.8%) n=120 (97.6%)
Analysis Analysed Analysed Analysed
n=119 n=122 n=121
mITT Population
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CNV – choroidal neovascularisation; IVT – intravitreal; Q4W – once very 4 weeks

ITT – Intent to Treat Population, all participants who were randomised into the study irrespective of whether study medication was administered or not Safety Population - all participants in the ITT but excluding those who did not receive at least one dose of study medication

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mITT – Modified ITT Population, all participants in the Safety Population but excludes any participant without a Baseline VA score and/or any participant who did not return for at least one post-baseline visit

Study Demographics and Baseline Characteristics

Demographic / Baseline Disease Characteristic	Demographic / Baseline Disease Characteristic	Sham + ranibizumab N=121	0.5 mg OPT-302 + ranibizumab N=122	2.0 mg OPT-302 + ranibizumab N=123
Mean Age – years± SD		76.1±9.48	78.8±8.16	77.8±8.82
Sex – n (%)	Male	48 (39.7%)	49 (40.2%)	45 (36.6%)
	Female	73 (60.3%)	73 (59.8%)	78 (63.4%)
Caucasian Race – n (%)		117 (99.2%)	119 (99.2%)	117 (97.5%)
Mean Visual Acuity (BCVA) – letters± SD		50.7±10.21	51.1±8.96	49.5±10.26
Mean Total Lesion Area - mm2 ± SD		6.08±3.21	6.48±3.30	6.62±3.39
Lesion Type	Predominantly classic – n (%)	15 (12.4%)	15 (12.3%)	16 (13.0%)
	Minimally classic – n (%)	53 (43.8%)	51 (41.8%)	53 (43.1%)
	Occult - n (%)	53 (43.8%)	56 (45.9%)	54 (43.9%)
	PCV detected1 – n (%)	20 (16.5%)	24 (19.7%)	22 (17.9%)
	RAP detected2 – n (%)	15 (12.7%)	22 (18.5%)	14 (11.8%)
Mean central subfield thickness (CST) - mm±SD		412.10±110.62	425.18±120.45	414.12±123.25
Sub-retinal fluid (SRF) present – % participants		89.3%	84.4%	87.8%
Intra-retinal cysts present – % participants		57.9%	63.9%	56.1%

Intent-to-Treat (ITT) population; SD: standard deviation; BCVA: Best Corrected Visual Acuity

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1 PCV - polypoidal choroidal vasculopathy, detected by SD-OCT, FA and fundus photography

2 RAP - retinal angiomatous proliferation, detected by SD-OCT, FA and fundus photography

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Neovascular (wet) AMD Lesion Types Differ in vessel location, leakiness and responsiveness to VEGF-A inhibitors

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OCCULT MINIMALLY CLASSIC PREDOMINANTLY CLASSIC
LEAST RESPONSIVE MODERATELY RESPONSIVE HIGHLY RESPONSIVE
to VEGF-A inhibition to VEGF-A inhibition to VEGF-A inhibition
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A majority of wet AMD patients, 65-80% of the real-world population, have occult and minimally classic lesions

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Best Responders:

Minimally Classic & Occult lesions (RAP Absent)

Achieved greatest vision benefit

Represents primary analysis population in OPT-302 phase 3 program

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Minimally Classic & Occult
20
+16.1
15
Δ = 5.7
p = 0.0002
10 +10.3
5
0
0 4 8 12 16 20 24
Weeks
Sham + 0.5 mg ranibizumab 2.0 mg OPT-302 + 0.5 mg ranibizumab
(letters)
Mean change in BCVA (SEM)
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* Unadjusted p-value

• PCV is highly prevalent in Asian populations (up to ~60%)

• • Described as the most prevalent form of wet AMD worldwide

Polypoidal Choroidal Vasculopathy (PCV)

PCV is a difficult-to-treat wet AMD subtype, with large unmet need

OPT-302 combination therapy has demonstrated potential to improve vision outcomes for patients with PCV

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20
Δ = 6.7
p = 0.0253
15
13.5
10.9
10
6.9
5
20 24 22
0
(letters)
Mean change in BCVA (SEM)
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Sham + 0.5 mg ranibizumab 0.5 mg OPT-302 + 0.5 mg ranibizumab 2.0 mg OPT-302 + 0.5 mg ranibizumab (n=20) (n=24) (n=22)

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* Unadjusted p-value

Mean Change in Best Corrected Visual Acuity Baseline to Week 24

OPT-302 (2.0 mg) Combination Therapy:

Superiority in Visual Acuity over Ranibizumab

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Primary endpoint achieved
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20
15
Δ = +3.4
(p=0.0107)
10
5
0
0 4 8 12 16 20 24
Weeks
Sham + 0.5 mg ranibizumab 0.5 mg OPT-302 + 0.5 mg ranibizumab 2.0 mg OPT-302 + 0.5 mg ranibizumab
(n=119) (n=122) (n=121)
(letters)
Mean change in BCVA (SEM)
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mITT; BCVA – Best Corrected Visual Acuity Left: Difference in Least Square Means, using Model for Repeated Measures (MRM) analysis. Right: Graph represents “as observed” data and SEM

Secondary Endpoints Supportive of Visual Acuity Improvement

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Vision:

• More patients gained ≥ 15, ≥10 and ≥5 letters

• of vision

• Fewer patients lost vision

Retinal anatomical improvements:

Greater reductions in:

• Retinal thickness

• Subretinal fluid

• Intraretinal fluid

• Lesion size

• Neovascular area

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2.0 mg OPT-302 + 0.5 mg ranibizumab

Sham + 0.5 mg ranibizumab

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Safety

OPT-302 well-tolerated with very low incidence of ocular inflammation, comparable to SoC therapy

N Participants (%)	Sham + ranibizumab N=121	0.5 mg OPT-302 + ranibizumab N=120	2.0 mg OPT-302 + ranibizumab N=124
Treatment emergent AEs (TEAEs)	84 (69.4%)	87 (72.5%)	93 (75.0%)
Ocular AEs - Study Eye – related to study product(s)1	17 (14.0%)	17 (14.2%)	19 (15.3%)
Ocular AEs - Study Eye – Severe2	1 (0.8%)	2 (1.7%)	1 (0.8%)
Serious AEs	10 (8.3%)	16 (13.3%)	7 (5.6%)
Ocular SAEs in Study Eye	0 (0.0%)	23 (1.7%)	0 (0.0%)
Intraocular inflammation4 – Study Eye	25,6 (1.7%)	23 (1.7%)	15 (0.8%)
Participants with AEs leading to study IP discontinuation only	2 (1.7%)	3 (2.5%)	0 (0.0%)
Participants with AEs leading to study discontinuation	17 (0.8%)	0 (0.0%)	0 (0.0%)
Any APTC event	0 (0.0%)	18 (0.8%)	0 (0.0%)
Deaths	29 (1.7%)	0 (0.0%)	0 (0.0%)

Safety population analysed according to medication received

• 1 Assessed by investigator to be “possibly related”, “probably related” or “definitely related” to administration of study drug(s)

• 2 Assessed by Investigator to be National Institutes of Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or above, or, if CTCAE grade is unavailable, an AE assessed as “causing an inability to perform normal daily activities” 3 SAE of endophthalmitis, with AEs of hypopyon and anterior chamber cell (n=1), SAE of vitritis (n=1)

• 4 AEs considered to be indicative of intraocular inflammation, defined prior to database lock as: Endophthalmitis, iritis, vitritis, iridocyclitis, uveitis, hypopyon, viral iritis, or anterior chamber inflammation

• 5 Transient anterior chamber cell (trace 1-4 cells)

• 6 Not reported as a TEAE

• 7Squamous cell carcinoma of the lung diagnosed shortly after Baseline visit

• 8 Non-fatal myocardial infarction

• 9 Pneumonia (n=1), infective endocarditis (n=1)

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Phase 2b trial met primary endpoint

• OPT-302 (2.0 mg) combination therapy demonstrated superiority in visual acuity over ranibizumab + sham

Conclusions

OPT-302 Phase 2b wet AMD Trial

• Additional +5.7 letter gain observed in high responder subgroup (minimally classic & occult lesions, RAP absent, >70% study population), represents Phase 3 primary analysis population

• Additional +6.7 letter gain (p=0.025)* in PCV lesions, a difficult-totreat wet AMD subtype, predominant in Asian populations, with large unmet need

• Additional +3.4 letter gain (p=0.0107) in total patient population

Primary endpoint achieved

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• High performing ranibizumab control arm

Secondary outcomes were supportive of the primary endpoint Greater vision gains observed in minimally classic/occult lesions Favorable tolerability profile similar to ranibizumab alone

• Promising treatment option for wet AMD suitable for Phase 3

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Phase 3 Pivotal Trials

Two concurrent, randomized, controlled, 3-arm Phase 3 studies investigating OPT-302 administered every four-weeks and everyeight weeks in combination with standard of care anti-VEGF-A therapy:

ShORe: S OPT-302 in combination with Ra tudy of nibizumab (Study OPT-302-1004) COAST: Combination OPT-302 with Aflibercept STudy (Study OPT302-1005)

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OPT-302 Phase 3 Pivotal Program Topline primary data analysis 2H CY 2023

Opthea intends to submit Biologics License and Marketing Authorization Applications with the FDA and EMA, respectively, following completion of the Primary Efficacy Phase of the trials

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ShORe
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Study of OPT-302 in combination with Ranibizumab

Wet AMD Tx-Naïve Pts

Efficacy Phase

Ranibizumab (0.5 mg) + OPT-302 (2.0 mg) IVT q4w x 52 wks

Ranibizumab (0.5 mg) IVT q4w x 52 wks + OPT-302 (2.0 mg) IVT q4w x 12 wks; q8w x 40 wks Ranibizumab (0.5 mg) + Sham* IVT q4w x 52 wks

Safety Phase

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Ranibizumab (0.5 mg) + OPT-302 (2.0 mg)
Ranibizumab (0.5 mg) + OPT-302 (2.0 mg)
Ranibizumab (0.5 mg) + Sham
Primary Efficacy Endpoint Week 52
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COAST

Combination OPT-302 with Aflibercept STudy

Wet AMD Tx-Naïve Pts

Efficacy Phase

Aflibercept (2.0 mg) IVT q4w x 12 wks; q8w x 40 wks + OPT-302 (2.0 mg) IVT q4w x 52 wks

Aflibercept (2.0 mg) + OPT-302 (2.0 mg) IVT q4w x 12 wks; q8w x 40 wks Aflibercept (2.0 mg) + Sham IVT q4w x 12 wks; q8w x 40 wks

Safety Phase

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Aflibercept (2.0 mg) + OPT-302 (2.0 mg)
Aflibercept (2.0 mg) + OPT-302 (2.0 mg)
Aflibercept (2.0 mg) + Sham
Primary Efficacy Endpoint Week 52
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Design: Multi-centre, double-masked, randomised (1:1:1), sham control Regulatory quality: 90% power, 5% type I error rate

Sample size: 330 patients per arm, 990 per study

•

• Primary Objective: Mean change from Baseline in BCVA at Wk 52

* Sham administered at visits when OPT-302 is not administered

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Opthea’s Phase 3 Program is Optimised for Success

We know the patients which respond best

• Patients with minimally classic & occult lesions are the majority (~80%) of the wet AMD population

OPT-302 positioned for use in combination with any VEGF-A inhibitor

Primary Analysis will be first conducted in the Minimally Classic/Occult population

• Maximises opportunity to demonstrate most compelling vision benefit

Investigates OPT-302 standard and extended dosing regimens:

• Analysis of efficacy on q4w and q8w dosing regimens provides insight into OPT-302 durability

• In Phase 2b, +5.7 letters superior benefit of OPT-302 combination therapy compared to Lucentis[®] alone

Our Phase 3 trials are designed to maximise the commercial opportunity

Meetings to discuss Phase 3 design and analysis plan completed with US (FDA) and European (EMA) regulatory agencies

• Efficacy assessed in minimally classic/occult, followed by ‘all-comer’ total patient population

• OPT-302 investigated in combination with two standard of care treatments respectively

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OPT-302: The potential to revolutionize the treatment of wet AMD and improve and preserve vision

1 2 Market Background

• Large treated (80%) wet AMD market (2.7M patients[#] ) in a US$12B dollar anti-VEGF-A category

• Standard of Care is anti–VEGF-A injections once per month or every two months by intravitreal delivery

2 High Unmet Need

• Highest unmet need in wet AMD is EFFICACY, to improve visual outcomes

• 45% do not achieve meaningful vision gain, >60% have persistent fluid and 25% suffer further vision loss despite antiVEGF-A treatment

• Current innovation is focused on durability rather than improving visual outcomes

• When combined with anti-VEGF–A, OPT-302 broadly shuts down the VEGF/VEGFR pathways driving angiogenesis and vascular leakage

• • Only current therapy demonstrating superior visual outcomes over anti-VEGF–A, with comparable safety

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OPT-302: first in class VEGF-C/D ‘trap’

• Phase 2b results demonstrate visual acuity gains over standard of care:

• Additional +5.7 letter gain (p=0.0002)* in minimally classic and occult lesion patients (80% of patient population)

• Additional +6.7 letter gain (p=0.025)* in PCV lesions, a difficult-to-treat wet AMD subtype, predominant in Asian populations, with large unmet need

• Additional +3.4 letter gain (p=0.0107) in total patient population

• FDA Fast Track status granted based on Phase 2b results

• Two global pivotal Phase 3 trials, ShORe & COAST, currently recruiting, topline data second half calendar year 2023

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Launch
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• USA launch 2024; EU, Japan, and ROW to follow

• Compelling patient, physician and payer value propositions will propel acceptance, adoption and uptake

• Only VEGF-C/D ‘trap’, no viable threat in competitive pipelines

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Financials
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• Multi-billion dollar commercial opportunity in USA and in EU for wet AMD alone

• Additional indications DME, RVO, polypoidal (PCV) wet AMD represent blockbuster upside opportunity

• Strong Composition of Matter and Methods of Use patents till 2034

• Further opportunity for Patent Term Extension (PTE), Data and Market Exclusivity periods beyond 2034

# USA & EU; * Unadjusted p-value

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Megan Baldwin, PhD CEO & Managing Director Opthea Limited Level 4, 650 Chapel Street South Yarra 3141 Victoria Australia P: +61 9826 0399 M: +61 447 788 674 E: megan.baldwin@opthea.com

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