Opthea Ltd — Investor Presentation 2025

Dec 16, 2025

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Investor Update

Dr Jeremy Levin, Executive Chairman 17 December 2025

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Important notice and disclaimer

This presentation has been prepared by Opthea Limited (ABN 32 006 340 567) (“Opthea” or “Company”) to provide summary information about Opthea and its affiliates and subsidiaries (the “Opthea Group”) and their activities. The information contained in this presentation is of general background, does not purport to be complete, is provided as at the date of this presentation and remains subject to change without notice. Except as otherwise required by law, Opthea has no obligation to update or correct this presentation. This presentation should be read in conjunction with Opthea’s other periodic and continuous disclosure announcements lodged with the Australian Securities Exchange (“ASX”), which are available at www.asx.com.au.

The information contained in this presentation does not constitute investment or financial product advice (nor taxation or legal advice) for investors or potential investors, who should consider seeking independent professional advice depending upon their specific investment objectives, financial situation or particular needs. Nothing in this presentation constitutes or forms part of any offer, invitation, solicitation or recommendation to buy or sell securities.

All references to dollar amounts are references to Australian dollars (“A$” or “$”) unless otherwise stated. This presentation is unaudited.

This presentation contains certain forward-looking statements. Forward looking statements can generally be identified by the use of words such as “project”, “foresee”, “forecast”, “plan”, “expect”, “aim”, “ambition”, “aspiration”, “potential”, “goal”, “objective”, “target”, “intend”, “see”, “anticipate”, “expect”, “believe”, “trend”, “estimate”, “may”, “could”, “should”, “would”, “need”, “will”, “must”, “commit”, “guidance” or similar expressions. Indications of, and guidance on, future earnings and financial position and performance are also forward-looking statements. Forward-looking statements may also be made, verbally or in writing, by members of Opthea Group’s management or Opthea’s board in connection with this presentation. Such statements are subject to the same limitations, uncertainties, assumptions and disclaimers set out in this presentation. Forward looking statements, opinions, and estimates provided in this presentation involve a number of risks, assumptions and contingencies, many of which are beyond Opthea’s control and which are subject to change without notice. It is believed that the expectations reflected in these forward-looking statements, opinions and estimates are reasonable at this time, but there can be no assurance that actual outcomes will not differ materially from these statements. Such forward looking statements, opinions and estimates are provided as a general guide only, should not be relied on as an indication or guarantee of future performance. You should not place undue reliance on forward looking statements. An investment in Opthea securities is subject to investment and other known and unknown risks, some of which are beyond the control of the Opthea Group including risks inherent in the regulatory processes, delays in clinical trials, results of clinical trials, contractual risks, risks associated with patent protection, future capital needs or other general risks or factors, along with those factors outlined in the most recent Opthea Annual Report. Opthea does not guarantee any particular rate of return or the performance of the Opthea Group nor does it guarantee the repayment of capital from Opthea or any particular tax treatment.

This presentation may include statistical and other industry and market data obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. Such data 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 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.

No representation or warranty, express or implied, is made as to the accuracy, completeness or reliability of the information. To the fullest extent permitted by law, neither Opthea nor any other member of the Opthea Group nor any of their or its directors, officers, employees and advisers accept any liability for any loss arising from reliance on this presentation or its contents. This presentation may contain trademarks and other 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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Our intention:

Opthea is relaunching, using all the assets and knowledge we have in VEGF-C/D, to target Lymphangioleiomyomatosis (LAM) – a rare disorder with major unmet medical need, which fits the biology of OPT-302

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Agenda

CURRENT STATUS

STRATEGIC REVIEW

OUTCOME OF REVIEW

WHY LYMPHANGIOLEIOMYOMATOSIS (LAM)

REINSTATEMENT OF QUOTATION ON ASX

CONCLUSION AND Q&A

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Current status:

Strong IP, experienced team and cash reserves

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Drug development | Local operations | Local ASX listing | Global outlook

STRONG IP

AN EXPERIENCED TEAM

CASH RESERVES

Patents

• Global portfolio of IP that could extend protection to 2046

OPT-302 package

• Registration ready-data

• • Manufacturing data

• Non-clinical and clinical package

• Known safety profile

Board

• Jeremy Levin (Chair)

• • Kathy Connell

• Lawrence Gozlan

• Hamish George (Joint CoSec)

• • Stephanie Vipond (Joint CoSec)

Management

• Jeremy Levin (Exec Chair)

• • Stuart Mudge (COO)

• • Mike Gerometta (CTO)[1]

• • Hamish George (CFO)

Cash

• A$37.6m[2]

• Significant runway

Tax credit

• A$10.8m R&D Tax incentive received

Fiscal discipline

• Committed to disciplined capital management and transparent investor communication

• Chief Technical Officer, responsible for CMC and other related technical aspects.

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1. Pro-forma cash balance representing A$26.8M as at 30 Sept plus A$10.8M R&D Tax Incentive rebate received 06 October 2025.

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A disciplined strategic review:

Prioritised feasibility, shareholder value and ROI

The Board explored several strategic and value creating options for Opthea and the underlying shareholder capital

ACQUISITION OF ASSETS OR RETURN OF CAPITAL MERGER Minimal ROI Medium ROI IP written off Long lead time Value leaking Asset risk Upside forfeited Shareholder dilution Execution Execution

RETURN OF CAPITAL OPTION

ASSESSMENT

REPURPOSE OPT-302 ASSETS AND EVALUATE OTHER VEGF ASSETS ROI potential if successful Shorter lead times Asset well understood No near-term shareholder dilution Ability to leverage existing body of data towards another disease mediated by VEGF C/D

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Outcome of review:

Targeting high need indications for Opthea’s portfolio with path to commercial viability

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Identifying the
most promising
Market opportunity
re-purposing of and limited
OPT-302
competition
Lymphangioleiomyomatosis
(LAM)
This rare, chronic lung disease
affecting women of reproductive
age with high unmet need meets
all the criteria for the promising re-
purposing of OPT-302
Clear biology and
High unmet
relevance of OPT-
medical need
302 mechanism
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About LAM:

A rare disease with significant unmet needs affecting young women

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one 3-8 women in every million worldwide[1, 2]

Genetic condition Not caused by lifestyle choices

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35
Average age of diagnosis
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• Abnormal smooth-muscle–like cells (“LAM”) cells infiltrate lungs and lymph channels

• LAM cells overproduce VEGF-C and VEGF-D, driving abnormal lymphatics and fluid problems[2]

• Multiple cysts form throughout the lung[3] , trapping air, destroying tissue and creating air leaks

• Over time this leads to a steady loss of breathing capacity, incapacitation and reduced lifespan

• mTOR inhibitors can stabilise disease on treatment, but do not cure LAM and progression often returns off therapy

• Patients may face progressive lung loss and lymphatic complications, with tolerability limits. Creating the need for an add-on biologic targeting complementary biology

No existing cure

1. Prevalence is reported as 3.4-7.8 cases per million women but newer Northern Europe data suggest 20.9–26.04 per million adult women, consistent with underdiagnosis. 2. Issaka, R. B., et al. (2009). See Appendix for full citation.

2. LAM can also be present elsewhere in the body including the kidneys for 40% of women with LAM. Source: Living with LAM.

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LAM market and commercial logic:

Concentrated rare-disease pathway with limited disease-modifying therapy

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Prevalence reported as 3.4–7.8 cases per million adult women; but newer data suggests 20.9– 26.04 per million , consistent with underdiagnosis[1]

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Patients are concentrated and managed by a finite specialty footprint, with ~70 global LAM clinics[3]

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Current disease-modifying therapy is not curative : in the pivotal randomised trial[2] , sirolimus stabilised lung function on treatment, but decline resumed after discontinuation

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Standardised patient identification for a rare lung disease: ATS/JRS guidelines recommend using serum VEGF-D with an 800 pg/mL threshold to support

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Commercial reality: orphan-drug pricing spans a wide, well-established range with orphan treatment annual costs range up to $500,000 per treated patient[4]

1. Updated Prevalence of Lymphangioleiomyomatosis in Europe. See Appendix for full citation.

2. Lynn et al (2011) Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis, The New England Journal Of Medicine. See Appendix for full citation. 3. The LAM Foundation.

3. Launch Price and Access Report: Drug Approvals from 2022–2024 (Final Report). See Appendix for full citation.

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Existing patient journey:

Current limitations and unmet clinical needs

Current patient journey

EARLY SYMPTOMS MISDIAGNOSIS

DIAGNOSIS

• Often mistaken • CT-scans for asthma, • Spirometry

• emphysema and bronchitis, • Blood tests – or chronic elevated VEGFobstructive D is a strong lung disease indicator of LAM[1]

• Non-specific: breathlessness in exertion, cough, fatigue

• Chest pain, lung collapse and/or coughing up blood

DETERIORATION

• Quality of life falls as daily activities become harder

• Hospital visitations increase

• LUNG

• DISEASE TRANSPLANT OR

• MANAGEMENT INCAPACITATION

• • • Rapamycin[2] Quality of life can stabilise and lifespan are some patients, significantly but not all impacted without a

• • True disease double lung

• control and transplant

• restoration remains unmet

• ATS/JRA guidelines recommend using serum VEGF-D with an 800 pg/mL threshold to support diagnosis. 2. Drugs derived from rapamycin are not curative but are capable of slowing the destructive progress of LAM in some patients.

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Scientific rationale:

Targeting VEGF-C/D pathway in LAM

“Lock and key” system

VEGF-C and VEGF-D are growth signals that tell lymphatic vessels to grow and become more permeable.

VEGFR-3 is the receptor on lymphatic cells that receives these signals.

When VEGF-C or VEGF-D bind to VEGFR-3, the lymphatic system gets a strong “expand and remodel” message. In LAM, this leads to abnormal, dilated, and leaky lymphatic vessels.

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The problem[1] In LAM, excess VEGF-D (and VEGF-C) activates VEGFR-3 on lymphatic vessels, driving abnormal, leaky lymphatics in the lungs and accelerating disease progression.

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The mechanism By trapping VEGF-C/D with OPT-302 before they activate VEGFR-3, we aim to dampen the lymphatic signaling that fuels LAM, aiming to stabilise lung function and slow disease progression.

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1. Issaka, R. B., et al. (2009). See Appendix for full citation.

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Why OPT-302:

A VEGF-C/D “trap” suited to LAM[1, 2]

Fitting the Mechanism of Action with the underlying pathology

a VEGF-C/D “trap” designed to bind and sequester VEGF-C and VEGF-D, preventing activation of VEGFR-3– OPT-302 mediated lymphatic signaling

What is de-risked What still must be proven

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Why it fits LAM

• • •

• Target biology and mechanism Optimal route and exposure target Targets the VEGF-C/D → VEGFR-3 are well characterised in including lung/lymphatic axis implicated in lymphatic lymphatic biology. distribution. remodeling/leakage and

• • OPT-302 has an established • Chronic dosing safety/tolerability at lymphatic manifestations in LAM. •

• molecular mechanism and data LAM-relevant exposures (including Intended to complement current informing manufacturability and immunogenicity risk management). therapy mTOR inhibition: safety monitoring. • Clear clinical benefit in LAM with a o mTOR inhibitors address LAM

• Clear clinical benefit in LAM with a regulatory-aligned endpoint strategy.

• mTOR inhibitors address LAM cell growth

• o OPT-302 is positioned to address the lymphatic biology.

• Jackson TL. (2023), See Appendix for full citation. 2. McCormack FX (2016). See Appendix for full citation.

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Delivery paths: Evaluating optimal delivery for efficacy and safety

Exploring a nebulised formulation of OPT-302 for Inhaled direct delivery to the lung and thoracic lymphatics Pathways Would provide broad access to lymphatic vessels under Intravenous throughout the body, but may increase the risk of consideration systemic side effects

Allows gradual systemic absorption and may reach Subcutaneous lymphatic vessels throughout the body, but may offer limited direct access to lung lymphatics

The final delivery path for OPT-302 will be determined by data from large-animal models and early human studies.

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Regulatory strategy:

Will seek orphan designation when appropriate

Orphan drug designation may unlock

Market exclusivity

Orphan designation would grant 7-10 years of market exclusivity post-approval, across jurisdictions (US, EU, Japan & Australia) reducing competitive risk and supporting premium pricing

Regulatory incentives

Opportunity for accelerated regulator review timelines, reduced or waived filing fees, and potential tax credits to lower development costs and shorten time to market

Pricing power

Orphan drugs often command high per-patient pricing (up to $500,000 per treated patient annually[1] ) due to rarity and unmet need, which can transform a small patient base into meaningful revenue.

• Competitive protection

• Lower development costs

• Reduced time to market  Premium pricing power

 Addressing a critical, long-neglected need in women’s health

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1. Launch Price and Access Report: Drug Approvals from 2022–2024 (Final Report). See Appendix for full citation.

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Stage-gated plan:

Rigorous data-driven milestones and stop criteria

Pre-defined stop criteria at each gate

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Preclinical biology and Clinical proof-of-concept in
GATE 1
inhalation in large LAM: GATE 3
animals: meaningful signals in:
• •
LAM-relevant effects lung function
• •
acceptable safety lymphatic outcomes
~18
months
Supportive OPT-302 data: Early human
•
Preclinical data pharmacodynamic (PD) and
•
Nonclinical data tolerability data:
• Clinical data TODAY • OPT-302 well tolerated GATE 2
• • Modulates VEGF-C / D as
Manufacturing
expected
Build strong relationships with
LAM Foundations globally
Funded via existing cash reserves
Continued operations in Australia, leverage R&D tax credits
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LAM organisations:

A family of networks and resources for individuals with LAM across the globe

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Opthea will build on the substantial work completed and ongoing with the global LAM foundations, clinics and communities, establishing long-term partnerships

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~70 global LAM clinics, patient data bases, biospecimen repository, focused International LAM research conference & LAMposium

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…and more

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Reinstatement on ASX:

Rebuilding market confidence through transparency

Opthea plans to seek reinstatement of its securities on the ASX in the first half of calendar year 2026[1]

• Strategic review completed.

• In this presentation, Opthea has communicated the outcome of that strategic review and its intentions in respect of its operations and plans.

• Opthea therefore intends to re-engage with ASX with a view to making adequate market disclosure to ASX’s satisfaction sufficient for ASX to permit reinstatement of Opthea’s securities to quotation on ASX.

• Opthea plans to seek re-instatement of its securities to quotation on ASX without a public offer.

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Conclusion:

Focused execution to unlock value in rare disease affecting women

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Clearly defined problem in women’s health with unmet need and suboptimal treatment options

OPT-302 has been through substantial clinical testing – the remaining focus is to determine its effect on a specific lung disease

Specialist LAM centres, registries and patient groups are well developed, which supports efficient studies and rapid learning from early data

Rare diseases come with market protection and attractive pricing

A convincing result could justify a family of programs in related lymphatic or VEGF-C/D–linked conditions

The family of future opportunity

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Market opportunity
and limited
competition
Clear biology
and relevance High unmet
of OPT-302 medical need
mechanism
Other VEGF-C/D
linked conditions
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Q&A

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Appendix:

Full citations

• Baldwin M. OPT-302: A novel therapy for Wet AMD. Corporate Presentation (Opthea Limited; ASX PDF). January 2017. p. 11 (slide 11) (states “OPT-302 (soluble VEGFR-3, VEGF-C/-D ‘Trap’)”).

• Issaka, R. B., et al. (2009). Vascular Endothelial Growth Factors C and D Induce Proliferation of Lymphangioleiomyomatosis Cells through Autocrine Crosstalk with Endothelium. The American Journal of Pathology, 175 (4), 1410–1420. https://doi.org/10.2353/ajpath.2009.080830

• Jackson TL et al. A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2023 Jun; 130(6):588–597. Epub 2023 Feb 6.

• Launch Price and Access Report: Drug Approvals from 2022–2024 (Final Report). Institute for Clinical and Economic Review (ICER). Report. 2025 Oct 23. p. 11 (Table 3.2: inflation-adjusted median annual list and net launch prices for 2022–2024 approvals).

• Lynn E et al . Am J Respir Crit Care Med. 2024 Feb 15;209(4):456–459. doi:10.1164/rccm.202310-1736LE.

• McCormack FX et al . Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med. 2016 Sep 15;194(6):748–761.

• McCormack FX. et al (2011) Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis, The New England Journal Of Medicine Vol 364 No 17.: Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis | New England Journal of Medicine

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