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Ocular Therapeutix 2025 Investor Day September 30, 2025
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2 Forward Looking Statements and Disclaimers Any statements in this presentation about future expectations, plans, and prospects for the Company, including the development of, regulatory status of, and regulatory submissions regarding the Company’s product candidates, including the timing, design, enrollment, randomization, and conduct of the Company’s ongoing Phase 3 clinical trials and long-term extension study of AXPAXLI (also called OTX-TKI) for the treatment of wet AMD and the Company’s planned Phase 3 clinical trials of AXPAXLI for the treatment of diabetic retinopathy; the Company’s plans to advance the development of AXPAXLI, OTX-TIC and its other product candidates; the size of potential markets for the Company’s product candidates; the potential utility of any of the Company's product candidates; the sufficiency of the Company’s cash resources; and other statements containing the words "anticipate", "believe”, "estimate”, "expect”, "intend", "goal”, "may", "might”, "plan”, "predict”, "project”, "target”, "potential”, "will”, "would”, "could”, "should”, "continue”, and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors. Such forward-looking statements involve substantial risks and uncertainties that could cause the Company’s preclinical and clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the timing and costs involved in commercializing DEXTENZA or any product or product candidate that receives regulatory approval; the ability to retain regulatory approval of DEXTENZA or any product or product candidate that receives regulatory approval; the initiation, design, timing, conduct, and outcomes of clinical trials, including the SOL-1 trial, the SOL-R trial, the SOL-X trial, the planned HELIOS-2, and the planned HELIOS-3 trial; the risk that the FDA will not agree with the Company’s interpretation of the written agreement under the SPA for the SOL-1 or HELIOS-2 trials; the risk that even though the FDA has agreed with the overall design of the SOL-1 and HELIOS-2 trials, the FDA may not find that the data generated by the applicable trial supports potential marketing approval; the risk that the FDA might not agree to the Company’s proposed design for the planned HELIOS-3 trial; uncertainty as to whether the data from earlier clinical trials will be predictive of the data from later clinical trials, particularly later clinical trials that have a different design or utilize a different formulation than the earlier trials, whether preliminary or interim data from a clinical trial (including masked safety or masked rescue data from the Company’s SOL-1 trial) will be predictive of final data from such trial, or whether data from a clinical trial assessing a product candidate for one indication will be predictive of results in other indications; uncertainty as to whether data from the Company’s SOL-X clinical trial will demonstrate clinically meaningful, long-term benefits, including better long-term outcomes as compared to standard of care; uncertainties regarding the potential commercial advantages and/or position of the Company’s product candidates; availability of data from clinical trials and expectations for regulatory submissions and approvals; the Company’s scientific approach and general development progress; the availability or commercial potential of the Company's product candidates; uncertainties inherent in estimating the Company’s cash runway, future expenses, and other financial results, including its ability to fund future operations, including clinical trials; the Company’s existing indebtedness and the ability of the Company’s creditors to accelerate the maturity of such indebtedness upon the occurrence of certain events of default; the Company’s ability to enter into strategic alliances or generate additional funding on a timely basis, on favorable terms, or at all; and other factors discussed in the “Risk Factors” section contained in the Company’s quarterly and annual reports on file with the Securities and Exchange Commission. In addition, the forward-looking statements included in this presentation represent the Company’s views as of the date of this presentation. The Company anticipates that subsequent events and developments will cause the Company’s views to change. However, while the Company may elect to update these forward- looking statements at some point in the future, the Company specifically disclaims any obligation to do so, whether as a result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this presentation. This presentation discusses investigational product candidates in development. Their efficacy and safety profiles have not been established, and they have not been approved for marketing by the FDA or any other regulatory agency.
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3 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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4 Retina experience redefined Our retina experience is redefining your retina experience Introduction & Overview Pravin U. Dugel, M.D. Executive Chairman, President & CEO Redefining treatment Redefining development Redefining outcomes
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55 Positioned to Redefine Retina AXPAXLI
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66 Positioned to Redefine Retina Superiority AXPAXLI
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77 Positioned to Redefine Retina Market Size AXPAXLI
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88 Positioned to Redefine Retina Market Size AdoptabilitySuperiority AXPAXLI
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99 Positioned to Redefine Retina AXPAXLI Superiority
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10 Single Hydrogel1 Highly Potent TKI2,3 Durability up to 12 months4 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs AXPAXLI AMD (age-related macular degeneration); DME (diabetic macular edema); NPDR (non-proliferative diabetic retinopathy); SPA (Special Protocol Assessment); TKI (tyrosine kinase inhibitor); VEGF (vascular endothelial growth factor) 1. Blizzard CD, Driscoll A, El-Hayek R, et al. inventors; Ocular Therapeutix, Inc., assignee. Ocular implant containing a tyrosi ne kinase inhibitor. US patent 11,439,592 B2. September 13, 2022. 2. Gross-Goupil M, et al.Clin Med Insights Oncol.2013;7:269-277. 3. Liang C, et al. Mol Ther Oncolytics. 2022;24:577-584. 4. Khanani A, et al. 12-Month Update on Randomized, Controlled, Trial of OTX-TKI (Axitinib Intravitreal Implant) for the Treatment of Wet AMD. Presented at Clinical Trials at the Summit. June 10, 2023. Park City, UT.
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11 Single Hydrogel1 Highly Potent TKI2,3 Durability up to 12 months4 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs Wet AMD AXPAXLI SOL-1 Superiority Trial AMD (age-related macular degeneration); DME (diabetic macular edema); NPDR (non-proliferative diabetic retinopathy); SPA (Special Protocol Assessment); TKI (tyrosine kinase inhibitor); VEGF (vascular endothelial growth factor) 1. Blizzard CD, Driscoll A, El-Hayek R, et al. inventors; Ocular Therapeutix, Inc., assignee. Ocular implant containing a tyrosi ne kinase inhibitor. US patent 11,439,592 B2. September 13, 2022. 2. Gross-Goupil M, et al.Clin Med Insights Oncol.2013;7:269-277. 3. Liang C, et al. Mol Ther Oncolytics. 2022;24:577-584. 4. Khanani A, et al. 12-Month Update on Randomized, Controlled, Trial of OTX-TKI (Axitinib Intravitreal Implant) for the Treatment of Wet AMD. Presented at Clinical Trials at the Summit. June 10, 2023. Park City, UT.
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12 Single Hydrogel1 Highly Potent TKI2,3 Durability up to 12 months4 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs SOL-1 Superiority Trial HELIOS-2 & HELIOS-3 Superiority Trials Wet AMD NPDR/DME AXPAXLI AMD (age-related macular degeneration); DME (diabetic macular edema); NPDR (non-proliferative diabetic retinopathy); SPA (Special Protocol Assessment); TKI (tyrosine kinase inhibitor); VEGF (vascular endothelial growth factor) 1. Blizzard CD, Driscoll A, El-Hayek R, et al. inventors; Ocular Therapeutix, Inc., assignee. Ocular implant containing a tyrosi ne kinase inhibitor. US patent 11,439,592 B2. September 13, 2022. 2. Gross-Goupil M, et al.Clin Med Insights Oncol.2013;7:269-277. 3. Liang C, et al. Mol Ther Oncolytics. 2022;24:577-584. 4. Khanani A, et al. 12-Month Update on Randomized, Controlled, Trial of OTX-TKI (Axitinib Intravitreal Implant) for the Treatment of Wet AMD. Presented at Clinical Trials at the Summit. June 10, 2023. Park City, UT.
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13 Single Hydrogel1 Highly Potent TKI2,3 Durability up to 12 months4 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs AXPAXLI SPA Agreements for SOL-1 & HELIOS-2 Trials Support Regulatory Path for Superiority Label Wet AMD NPDR/DME SOL-1 Superiority Trial HELIOS-2 & HELIOS-3 Superiority Trials AMD (age-related macular degeneration); DME (diabetic macular edema); NPDR (non-proliferative diabetic retinopathy); SPA (Special Protocol Assessment); TKI (tyrosine kinase inhibitor); VEGF (vascular endothelial growth factor) 1. Blizzard CD, Driscoll A, El-Hayek R, et al. inventors; Ocular Therapeutix, Inc., assignee. Ocular implant containing a tyrosi ne kinase inhibitor. US patent 11,439,592 B2. September 13, 2022. 2. Gross-Goupil M, et al.Clin Med Insights Oncol.2013;7:269-277. 3. Liang C, et al. Mol Ther Oncolytics. 2022;24:577-584. 4. Khanani A, et al. 12-Month Update on Randomized, Controlled, Trial of OTX-TKI (Axitinib Intravitreal Implant) for the Treatment of Wet AMD. Presented at Clinical Trials at the Summit. June 10, 2023. Park City, UT.
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14 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs Superiority to Anti-VEGF Subject to step therapy, pricing wars Potential to bypass step therapy, pricing wars Non-inferiority to Anti-VEGFs
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15 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs ALL EYLEA Biosimilars ALL LUCENTIS Biosimilars ALL Competitive wet AMD Clinical Programs Subject to step therapy, pricing wars Non-inferiority to Anti-VEGFs Potential to bypass step therapy, pricing wars Superiority to Anti-VEGF
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16 Targeting the FIRST SUPERIORITY LABEL vs. anti-VEGFs ALL EYLEA Biosimilars Non-inferiority to Anti-VEGFs ALL LUCENTIS Biosimilars ALL Competitive wet AMD Clinical Programs Subject to step therapy, pricing wars Potential to bypass step therapy, pricing wars AXPAXLI Designed to become the only wet AMD product with a superiority claim at launch AXPAXLI Superiority to Anti-VEGF
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1717 Positioned to Redefine Retina Market Size AXPAXLI
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18 AXPAXLI’s Promising Commercial Potential $15B $2.9B $2.0B $1.2B $9.6B $9.4B $9.5B $0.6B $2.6B $4.4B 2022 2023 2024 LUCENTIS EYLEA VABYSMO 2024 Global Branded Anti-VEGF Revenue1 1. Data aggregated from company reports. Captures revenue across all labeled indications. Figure excludes BEOVU®. EYLEA® HD F DA approved in August 2023 captured in EYLEA® sales figures. 2. Real-World Evidence (TRUCKEE Study): VABYSMO® offers 1 -2 week extension over EYLEA® in switch patients. Study Results presented at Roche Ophthalmology Day, July 2024. 3. Evans RN, et al. JAMA Ophthalmol. 2020;138(10):1043-1051.
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19 AXPAXLI’s Promising Commercial Potential $15B 2024 Global Branded Anti-VEGF Revenue1 Retina Market Rewards Durability 57 Days2 After 6 Injections Compared to EYLEA +2 Weeks VABYSMO DURABILITY: Marginal improvements in durability $4.4B WW sales three years post-launch However, pulsatile dosing may lead to fibrosis / atrophy3 LUCENTIS EYLEA VABYSMO 1. Data aggregated from company reports. Captures revenue across all labeled indications. Figure excludes BEOVU®. EYLEA® HD F DA approved in August 2023 captured in EYLEA® sales figures. 2. Real-World Evidence (TRUCKEE Study): VABYSMO® offers 1 -2 week extension over EYLEA® in switch patients. Study Results presented at Roche Ophthalmology Day, July 2024. 3. Evans RN, et al. JAMA Ophthalmol. 2020;138(10):1043-1051. $2.9B $2.0B $1.2B $9.6B $9.4B $9.5B $0.6B $2.6B $4.4B 2022 2023 2024
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20 AXPAXLI’s Promising Commercial Potential $15B 2024 Global Branded Anti-VEGF Revenue1 Retina Market Rewards Durability 57 Days2 After 6 Injections Compared to EYLEA +2 Weeks VABYSMO DURABILITY: Marginal improvements in durability $4.4B WW sales three years post-launch However, pulsatile dosing may lead to fibrosis / atrophy3 LUCENTIS EYLEA VABYSMO 1. Data aggregated from company reports. Captures revenue across all labeled indications. Figure excludes BEOVU®. EYLEA® HD F DA approved in August 2023 captured in EYLEA® sales figures. 2. Real-World Evidence (TRUCKEE Study): VABYSMO® offers 1 -2 week extension over EYLEA® in switch patients. Study Results presented at Roche Ophthalmology Day, July 2024. 3. Evans RN, et al. JAMA Ophthalmol. 2020;138(10):1043-1051. $2.9B $2.0B $1.2B $9.6B $9.4B $9.5B $0.6B $2.6B $4.4B 2022 2023 2024 Superiority Label Up to 12 Month Durability Better Long-Term Outcomes Our hope for AXPAXLI
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21 AXPAXLI’s Opportunity to Significantly Expand $15B Global Retina Market Wet AMD 1.8M people with wet AMD in U.S.1 40% discontinue treatment in the first year 2 AMD (age-related macular degeneration); NPDR (non-proliferative diabetic retinopathy). 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Khanani AM, et al. Ophthalmol Retina. 2020;4(2):122-133. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025.
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22 AXPAXLI’s Opportunity to Significantly Expand $15B Global Retina Market Wet AMD Redefine the Treatment Attrition Curve GOAL 1.8M people with wet AMD in U.S.1 40% discontinue treatment in the first year 2 AMD (age-related macular degeneration); NPDR (non-proliferative diabetic retinopathy). 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Khanani AM, et al. Ophthalmol Retina. 2020;4(2):122-133. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025.
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23 Redefining the Treatment Attrition Curve in Wet AMD Anti-VEGF Discontinuation in wAMD Illustrative Years on Tx % Continuing Tx Mortality wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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24 Redefining the Treatment Attrition Curve in Wet AMD Anti-VEGF Discontinuation in wAMD Illustrative Years on Tx % Continuing Tx Anti-VEGF Attrition Mortality wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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25 Redefining the Treatment Attrition Curve in Wet AMD Anti-VEGF Discontinuation in wAMD Illustrative Years on Tx % Continuing Tx Anti-VEGF Attrition Mortality Poor Durability of Today’s anti-VEGF Treatment High Treatment Burden wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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26 Redefining the Treatment Attrition Curve in Wet AMD Anti-VEGF Discontinuation in wAMD Illustrative Years on Tx % Continuing Tx Anti-VEGF Attrition Mortality Poor Durability of Today’s anti-VEGF Treatment High Treatment Burden Sub-Optimal Treatment1 Treatment Discontinuation1 wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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27 Redefining the Treatment Attrition Curve in Wet AMD Anti-VEGF Discontinuation in wAMD Illustrative Years on Tx % Continuing Tx Anti-VEGF Attrition Mortality Poor Durability of Today’s anti-VEGF Treatment High Treatment Burden Sub-Optimal Treatment1 Treatment Discontinuation1 Poor Long-Term Outcomes1 wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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28 Redefining the Treatment Attrition Curve in Wet AMD Need for Next-Gen Therapy Anti-VEGF Discontinuation in wAMD Illustrative Years on Tx % Continuing Tx Anti-VEGF Attrition Mortality Poor Durability of Today’s anti-VEGF Treatment High Treatment Burden Sub-Optimal Treatment1 Treatment Discontinuation1 Poor Long-Term Outcomes1 wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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29 Redefining the Treatment Attrition Curve in Wet AMD Anti-VEGF Discontinuation in wAMD Opportunity AXPAXLI Anti-VEGF Attrition Mortality AXPAXLI Opportunity Illustrative Years on Tx % Continuing Tx Poor Durability of Today’s anti-VEGF Treatment High Treatment Burden Sub-Optimal Treatment1 Treatment Discontinuation1 Poor Long-Term Outcomes1 wAMD (wet age-related macular degeneration); Tx (treatment); aVEGF (anti-vascular endothelial growth factor). 1. Wykoff CC, et al. Ophthalmol Sci. 2023;4(2):100421.
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30 AXPAXLI’s Opportunity to Significantly Expand $15B Global Retina Market Wet AMD Redefine the Treatment Attrition Curve GOAL 1.8M people with wet AMD in U.S.1 40% discontinue treatment in the first year 2 AMD (age-related macular degeneration); NPDR (non-proliferative diabetic retinopathy). 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Khanani AM, et al. Ophthalmol Retina. 2020;4(2):122-133. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025.
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31 AXPAXLI’s Opportunity to Significantly Expand $15B Global Retina Market 6.4M people with NPDR in U.S.1 <1% patients currently treated today 3 Wet AMD NPDR Redefine the Treatment Attrition Curve GOAL 1.8M people with wet AMD in U.S. 1 40% discontinue treatment in the first year 2 AMD (age-related macular degeneration); NPDR (non-proliferative diabetic retinopathy). 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Khanani AM, et al. Ophthalmol Retina. 2020;4(2):122-133. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025.
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32 AXPAXLI’s Opportunity to Significantly Expand $15B Global Retina Market Establish a Standard of Care 6.4M people with NPDR in U.S.1 Wet AMD NPDR GOAL Redefine the Treatment Attrition Curve GOAL 1.8M people with wet AMD in U.S. 1 40% discontinue treatment in the first year 2 <1% patients currently treated today 3 AMD (age-related macular degeneration); NPDR (non-proliferative diabetic retinopathy). 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Khanani AM, et al. Ophthalmol Retina. 2020;4(2):122-133. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025.
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3333 Positioned to Redefine Retina Adoptability AXPAXLI
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34 AXPAXLI is Designed for Seamless, Immediate Adoption Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity Ideal Target Product Profile
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35 AXPAXLI is Designed for Seamless, Immediate Adoption Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity No mandated steroids No remnants after drug depletion No surgery for administration Ideal Target Product Profile Single Bioresorbable Hydrogel
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36 AXPAXLI is Designed for Seamless, Immediate Adoption Familiar IVT injection Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity No mandated steroids Predictable fixed schedule for patients Designed for improved treatment adherence No remnants after drug depletion No surgery for administration Ideal Target Product Profile Single Bioresorbable Hydrogel Optimizing Retina Practices
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37 AXPAXLI is Designed for Seamless, Immediate Adoption Familiar IVT injection Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity No mandated steroids Predictable fixed schedule for patients Designed for improved treatment adherence No remnants after drug depletion No surgery for administration Ideal Target Product Profile Single Bioresorbable Hydrogel Optimizing Retina Practices Would Allow Retina Specialists to See More Patients, Less Frequently
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38 What You’ll Hear Today SPA (Special Protocol Agreement); DR (Diabetic Retinopathy). Improved Adherence Global wAMD Opportunity SOL-1 SOL-R HELIOS-2 & HELIOS-3 SOL-X SPA for SOL-1 & HELIOS-2 HELIOS-2 & HELIOS-3DR Opportunity Market Size Adoptability Superiority
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39 Joined by Global Retina Leaders Eleonora (Nora) M. Lad, MD, PhD Duke University Durham, North Carolina Patricio G. Schlottmann, MD Organización Médica de Investigación Buenos Aires, Argentina Prof. Adnan Tufail, MBBS, MD, FRCOphth Moorfields Eye Hospital London, England Arshad M. Khanani, MD, MA, FASRS Sierra Eye Associates Reno, Nevada
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40 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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41 Retina experience redefined Our retina experience is redefining your retina experience SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH Chief Medical Officer Redefining treatment Redefining development Redefining outcomes
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42 SOL-1 Trial Design Superiority Label Trial Execution
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43 SOL-1 Trial Design
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44 *Trial subjects and designated personnel will remain masked through end of year 2. AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study) SOL-1 Design: AXPAXLI First Registration Study in Wet AMD Superiority Study Comparing a Single AXPAXLI Dose to a Single Aflibercept (2 mg) Dose Two-arm trial with 344 total subjects randomized 1:1 Design Proportion of subjects who maintained visual acuity, defined as <15 ETDRS letters of BCVA loss from baseline at Week 36 Primary Endpoint (Week 36) R 1:1-4-8 AXPAXLI Aflibercept (2 mg) Week 4 20 4412 288 24 40 4816 32 36 Randomization (Day 1) Loading End of year 2 76… …52 Safety follow-up* 0 Primary Endpoint Topline Readout SOL-1 Monthly Visits AXPAXLI Aflibercept (2 mg) Study visit
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45 *Trial subjects and designated personnel will remain masked through end of year 2. AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study) SOL-1: Only Ongoing Superiority Trial in Wet AMD SOL-1 Topline Data Expected 1Q 2026 4440 4836 End of year 2 76… …52 Safety follow-up* Primary Endpoint Topline Readout R 1:1-4-8 AXPAXLI Aflibercept (2 mg) Week 4 2012 288 2416 32 Randomization (Day 1) Loading 0 SOL-1 Monthly Visits AXPAXLI Aflibercept (2 mg) Study visit
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46 mo (month) *Trial subjects and designated personnel will remain masked through end of year 2. AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study) SOL-1: Only Ongoing Superiority Trial in Wet AMD Week 36 Primary Endpoint Superiority 9 mo durability 4440 4836 End of year 2 76… …52 Safety follow-up* Primary Endpoint Topline Readout R 1:1-4-8 AXPAXLI Aflibercept (2 mg) Week 4 2012 288 2416 32 Randomization (Day 1) Loading 0 SOL-1 Monthly Visits AXPAXLI Aflibercept (2 mg) Study visit SOL-1 Topline Data Expected 1Q 2026
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47 SOL-1: Only Ongoing Superiority Trial in Wet AMD Week 36 Week 52 Primary Endpoint Superiority 9 mo durability Secondary Endpoint 52 wk assessment 12 mo durability 4440 4836 End of year 2 76… …52 Safety follow-up* Primary Endpoint Topline Readout R 1:1-4-8 AXPAXLI Aflibercept (2 mg) Week 4 2012 288 2416 32 Randomization (Day 1) Loading 0 SOL-1 Monthly Visits AXPAXLI Aflibercept (2 mg) Study visit SOL-1 Topline Data Expected 1Q 2026 mo (month) *Trial subjects and designated personnel will remain masked through end of year 2. AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study)
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48 SOL-1: Only Ongoing Superiority Trial in Wet AMD Week 36 Week 52 Year 2 Q6M Re-dosing for Safety Database Primary Endpoint Superiority 9 mo durability Secondary Endpoint 52 wk assessment 12 mo durability 4440 4836 End of year 2 76… …52 Safety follow-up* Primary Endpoint Topline Readout R 1:1-4-8 AXPAXLI Aflibercept (2 mg) Week 4 2012 288 2416 32 Randomization (Day 1) Loading 0 SOL-1 Monthly Visits AXPAXLI Aflibercept (2 mg) Study visit SOL-1 Topline Data Expected 1Q 2026 mo (month) *Trial subjects and designated personnel will remain masked through end of year 2. AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study)
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49 VEGF (vascular endothelial growth factor); wAMD (wet age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study); CSFT (central subfield thickness); SPA (Special Protocol Agreement). SOL-1 Designed for Success FDA Alignment through SPA Randomize Strong anti-VEGF Responders Enable Superiority Claim on Label Screening Criteria Treatment naïve for wAMD CSFT ≤ 500 μm BCVA ETDRS letter score of ≥ 54 (~20/80) Randomization Criteria BCVA ETDRS letter score ≥ 84 (~20/20) – OR – Increase of ≥ 10 ETDRS letters from screening AND: CSFT ≤ 350 μm Patients highly responsive to anti-VEGF Resulting Population Clinical De-risking Elements of SOL-1
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50 SPA (Special Protocol Agreement); wAMD (wet age-related macular degeneration) 1. FDA comments provided in numerous written responses to Ocular Therapeutix (SPA, Type C, others) 2. Neovascular Age -Related Macular Degeneration: Developing Drugs for Treatment Guidance for Industry. US Food and Drug Administration. Published February 6, 2023. Accessed Sept ember 21, 2023. https://www.fda.gov/media/165606/download. No sham injections for masking per FDA guidance1 1 Control arm has same dosing schedule as Active arm per FDA guidance2 2 3 Only ongoing Phase 3 wAMD trial with a SPA SOL-1 Designed for Success Randomize Strong anti-VEGF Responders Enable Superiority Claim on Label FDA Alignment through SPA Regulatory De-risking Elements of SOL-1
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51 SOL-1 Superiority Label
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52 SOL-1 Designed for Success Randomize Strong anti-VEGF Responders FDA Alignment through SPA Potential Superiority Claim on Label All existing and pipeline wet AMD treatments evaluate non-inferiority to anti-VEGF 1 Commercial De-risking Elements of SOL-1 VEGF (Vascular endothelial growth factor); SPA (Special Protocol Agreement); AMD (age -related macular degeneration).
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53 SOL-1 Designed for Success Randomize Strong anti-VEGF Responders FDA Alignment through SPA Potential Superiority Claim on Label All existing and pipeline wet AMD treatments evaluate non-inferiority to anti-VEGF Designed to become the only wet AMD product with a superiority claim at launch 1 2 Commercial De-risking Elements of SOL-1 VEGF (Vascular endothelial growth factor); SPA (Special Protocol Agreement); AMD (age -related macular degeneration).
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54 SOL-1 Designed for Success Randomize Strong anti-VEGF Responders FDA Alignment through SPA Potential Superiority Claim on Label All existing and pipeline wet AMD treatments evaluate non-inferiority to anti-VEGF Allows Retina Specialists to choose the optimal drug, potentially avoiding step therapy 1 2 3 Commercial De-risking Elements of SOL-1 VEGF (Vascular endothelial growth factor); SPA (Special Protocol Agreement); AMD (age -related macular degeneration). Designed to become the only wet AMD product with a superiority claim at launch
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55 SOL-1 Trial Execution
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56 Strong Execution is Ensuring Exceptional Retention and Protocol Compliance RESCUES Ongoing monitoring supports strong protocol compliance >95% of rescue events to date have met protocol-defined criteria Reviewed on a masked basis Ocular Therapeutix data on file as of September 19, 2025
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57 Strong Execution is Ensuring Exceptional Retention and Protocol Compliance >95% retention to date RESCUES RETENTION Strong engagement and minimal attrition >90% statistical powering Ongoing monitoring supports strong protocol compliance >95% of rescue events to date have met protocol-defined criteria Reviewed on a masked basis Ocular Therapeutix data on file as of September 19, 2025
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58 SAFETY Strong Execution is Ensuring Exceptional Retention and Protocol Compliance No new or unexpected safety signals to date Trials conducted under Independent DSMC monitoring Targeting safety profile consistent with SoC therapies >95% retention to date RESCUES RETENTION Strong engagement and minimal attrition >90% statistical powering Ongoing monitoring supports strong protocol compliance >95% of rescue events to date have met protocol-defined criteria Reviewed on a masked basis Ocular Therapeutix data on file as of September 19, 2025
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59 Q6M Repeat Dosing in Year 2 SOL-1 Conducted Under SPA FDA Alignment SPA (Special Protocol Agreement) Potential Impact of Positive SOL-1 Data: First Superiority Label vs EYLEA
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60 Q6M Repeat Dosing in Year 2 SOL-1 Conducted Under SPA FDA Alignment Potential Impact of Positive SOL-1 Data: First Superiority Label vs EYLEA Establish Durability up to 12 Months Potential Superiority Claim Label SPA (Special Protocol Agreement)
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61 Q6M Repeat Dosing in Year 2 SOL-1 Conducted Under SPA FDA Alignment Potential Impact of Positive SOL-1 Data: First Superiority Label vs EYLEA Establish Durability up to 12 Months Potential Superiority Claim Label Translation to SOL-R Success Safety, Efficacy, and Durability of AXPAXLI Confidence in SPA (Special Protocol Agreement)
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62 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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63 Retina experience redefined Our retina experience is redefining your retina experience SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Chief Scientific Officer Redefining treatment Redefining development Redefining outcomes
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64 SOL-R Patient Selection Confidence in Outcomes Immediate Adoption
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65 SOL-R Patient Selection
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66 *Trial subjects and designated personnel will remain masked through end of year 2. † Any anti -VEGF except Beovu AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study). R 2:2:1Week -12 -4-20-24 -8-16 0 8 16 24 32 40 48 564 12 20 28 36 44 52 End of year 2 72… … Q8W Q8W Evaluation Visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading Safety follow-up* Primary Endpoint Monthly Visits SOL-R Design: AXPAXLI Second Registration Study in Wet AMD Non-Inferiority Study Comparing AXPAXLI Q24W to Aflibercept (2mg) Q8W at W56 Three-arm trial with 555 total subjects randomized 2:2:1 Design Demonstrate that AXPAXLI is non-inferior to fixed-dose aflibercept 2mg Q8W with respect to mean change in BCVA at Week 56 from baseline in wet AMD patients Non-inferiority margin for the lower bound is -4.5 letters in BCVA at Week 56 Primary Endpoint (Week 56) AXPAXLI 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Aflibercept 2 mg Study visitAflibercept 8 mg
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67Jaffe GJ, et al. Ophthalmology. 2016;123(9):1856-1864. Patients with Early Persistent Fluid Can Disrupt Non-Inferiority Trials Vision in Patients with Early Persistent Fluid Vision in Patients without Early Persistent Fluid
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68 Vision in Patients with Early Persistent Fluid Patients with Early Persistent Fluid Can Disrupt Non-Inferiority Trials Screening to exclude subjects with early persistent fluid may be critical for trial success Vision in Patients without Early Persistent Fluid Jaffe GJ, et al. Ophthalmology. 2016;123(9):1856-1864.
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69 Vision in Patients with Early Persistent Fluid Screening to exclude subjects with early persistent fluid may be critical for trial success Vision in Patients without Early Persistent Fluid Patients with Early Persistent Fluid Can Disrupt Non-Inferiority Trials Jaffe GJ, et al. Ophthalmology. 2016;123(9):1856-1864.
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70 SOL-R: Methodical Patient Selection R 2:2:1Week -12 -4-20-24 -8-16 0 8 16 24 32 40 48 564 12 20 28 36 44 52 End of year 2 72… … Q8W Q8W Evaluation Visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading Safety follow-up* Primary Endpoint Monthly Visits AXPAXLI 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Aflibercept 2 mg Study visitAflibercept 8 mg *Trial subjects and designated personnel will remain masked through end of year 2. † Any anti -VEGF except Beovu
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71 SOL-R: Methodical Patient Selection R 2:2:1Week -12 -4-20-24 -8-16 0 8 16 24 32 40 48 564 12 20 28 36 44 52 End of year 2 72… … Q8W Q8W Evaluation Visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading Safety follow-up* Primary Endpoint Monthly Visits AXPAXLI 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Aflibercept 2 mg Study visitAflibercept 8 mg *Trial subjects and designated personnel will remain masked through end of year 2. † Any anti -VEGF except Beovu
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72 SOL-R: Methodical Patient Selection r 2:2:1Week -12 -4-20-24 -8-16 Evaluation visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading AXPAXLI Aflibercept 2 mg Study visitAflibercept 8 mg 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† † Any anti-VEGF except Beovu
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73 r 2:2:1Week -12 -4-20-24 -8-16 Evaluation visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading SOL-R: Methodical Patient Selection AXPAXLI Aflibercept 2 mg Study visitAflibercept 8 mg 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Three Doses of any anti-VEGF † aVEGF (anti-vascular endothelial growth factor); CSFT (central subfield thickness), VA (visual acuity) † Any anti-VEGF except Beovu
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74 r 2:2:1Week -12 -4-20-24 -8-16 Evaluation visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading SOL-R: Methodical Patient Selection AXPAXLI Aflibercept 2 mg Study visitAflibercept 8 mg 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† CSFT ≤350 μm at Wk -12 & Wk -8 — AND — CSFT ≤35 µm increase from the lowest CSFT at any prior visits Three Doses of any anti-VEGF † Two Evaluation Visits aVEGF (anti-vascular endothelial growth factor); CSFT (central subfield thickness), VA (visual acuity) † Any anti-VEGF except Beovu
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75 r 2:2:1Week -12 -4-20-24 -8-16 Evaluation visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading SOL-R: Methodical Patient Selection AXPAXLI Aflibercept 2 mg Study visitAflibercept 8 mg 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† CSFT ≤350 μm at Wk -12 & Wk -8 — AND — CSFT ≤35 µm increase from the lowest CSFT at any prior visits Three Doses of any anti-VEGF † Two Evaluation Visits Two Doses of Aflibercept 2mg aVEGF (anti-vascular endothelial growth factor); CSFT (central subfield thickness), VA (visual acuity) † Any anti-VEGF except Beovu
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76 r 2:2:1Week -12 -4-20-24 -8-16 Evaluation visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading SOL-R: Methodical Patient Selection AXPAXLI Aflibercept 2 mg Study visitAflibercept 8 mg 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† CSFT ≤350 μm at Wk -12 & Wk -8 — AND — CSFT ≤35 µm increase from the lowest CSFT at any prior visits SOL-R Run-in Goal Exclude subjects with early persistent fluid Randomize subjects with less VA variability Three Doses of any anti-VEGF † Two Evaluation Visits Two Doses of Aflibercept 2mg aVEGF (anti-vascular endothelial growth factor); CSFT (central subfield thickness), VA (visual acuity) † Any anti-VEGF except Beovu
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77 SOL-R Confidence in Outcomes
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78 SOL-R: Favorable Primary Endpoint Wk 56 Primary EndpointSOL-R T opline Data Expected 1H 2027 5652 End of year 2 72… … Q8W Q8W Safety follow-up* Primary Endpoint R 2:2:1Week -12 -4-20-24 -8-16 0 8 16 24 32 40 484 12 20 28 36 44 Evaluation Visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading Singular Timepoint Monthly Visits AXPAXLI 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Aflibercept 2 mg Study visitAflibercept 8 mg *Trial subjects and designated personnel will remain masked through end of year 2. † Any anti -VEGF except Beovu
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79 SOL-R: Favorable Primary Endpoint Three Active AXPAXLI Doses Wk 56 Primary EndpointSOL-R T opline Data Expected 1H 2027 5652 End of year 2 72… … Q8W Q8W Safety follow-up* Primary Endpoint R 2:2:1Week -12 -4-20-24 -8-16 0 8 16 24 32 40 484 12 20 28 36 44 Evaluation Visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading Singular TimepointPrior to Primary Endpoint Monthly Visits AXPAXLI 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Aflibercept 2 mg Study visitAflibercept 8 mg *Trial subjects and designated personnel will remain masked through end of year 2. † Any anti -VEGF except Beovu
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80 SOL-R: Favorable Primary Endpoint Three Active AXPAXLI Doses Wk 56 Primary EndpointSOL-R T opline Data Expected 1H 2027 5652 End of year 2 72… … Q8W Q8W Safety follow-up* Primary Endpoint R 2:2:1Week -12 -4-20-24 -8-16 0 8 16 24 32 40 484 12 20 28 36 44 Evaluation Visits AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) SOL-R Randomization (Day 1) Loading Singular TimepointPrior to Primary Endpoint Monthly Visits Most Recent Dose of AXPAXLI 8 Weeks Prior to Primary AXPAXLI 2nd evaluation & Aflibercept 2mg Screening Dose, Any Anti VEGF† Aflibercept 2 mg Study visitAflibercept 8 mg *Trial subjects and designated personnel will remain masked through end of year 2. † Any anti -VEGF except Beovu
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81 *Treatment naïve or diagnosed with wet AMD in the study eye within about four months prior to enrollment VEGF (Vascular endothelial growth factor); AMD (age-related macular degeneration); BCVA (best-corrected visual acuity); ETDRS (Early Treatment Diabetic Retinopathy Study); VA (visual acuity); SoC (standard of care). SOL-R De-risking Elements to Increase Chances of Success FDA Alignment with Written Reponses Randomizing reliable anti-VEGF responders Inclusion At Screening Treatment naïve* for wet AMD BCVA ETDRS letter score of ≥34 (~20/200) Inclusion At Randomization Patients with 5 anti-VEGF doses AND: without early persistent fluid Reliable responders to anti-VEGF with less VA variability Resulting Population Clinical De-risking Elements of SOL-R Efficacy & Safety Comparable to SoC
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82VEGF (Vascular endothelial growth factor); AMD (age-related macular degeneration); SoC (standard of care) SOL-R De-risking Elements to Increase Chances of Success Randomizing reliable anti-VEGF responders FDA Alignment with Written Reponses Efficacy & Safety Comparable to SoC No sham injections for masking Only ongoing Phase 3 wet AMD non-inferiority trial designed as per FDA draft guidance Regulatory De-risking Elements of SOL-R 1 2
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83 SOL-R De-risking Elements to Increase Chances of Success Randomizing reliable anti-VEGF responders Target Efficacy & Safety Comparable to SoC Builds on SOL-1 success to provide complementary dataset Only wAMD trial with comparison to Eylea HD Designed to drive immediate adoption Commercial De-risking Elements of SOL-R 1 2 3 FDA Alignment with Written Reponses VEGF (Vascular endothelial growth factor); AMD (age-related macular degeneration); SoC (standard of care)
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84 SOL-1 Success Feeds SOL-R Probability of Success NEED FOR SUPPLEMENTAL INJECTIONS HIGH SOL-1 SOL-R Strong responders to anti-VEGF (increase ≥10 letters OR visual acuity ≥84 letters after 2 aflibercept injections) Vulnerable to treatment withdrawal Highly selective (reliable responders to 5 aflibercept injections) Stable disease control with maintenance treatment (achieved 8-wk dosing interval in loading) LOW VEGF (Vascular endothelial growth factor)
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85 SOL-1 Success Feeds SOL-R Probability of Success SOL-1 success provides strong evidence for the safety, efficacy, and durability of AXPAXLI SOL-1 success shows AXPAXLI 9-month durability in strong responders, vulnerable to treatment withdrawal AXPAXLI should provide longer durability with fewer supplemental injections in well-controlled patients AXPAXLI 6-month durability more likely to be achieved in SOL-R given enriched patient population SOL-R Outcomes SOL-1 SUCCESS Increases Confidence
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86 SOL-R Immediate Adoption
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87 Establish Repeat Dosing at 6 Months Comparable Safety & Efficacy to SoC Label Potential Impact of Positive SOL-R Data SoC (standard of care)
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88 No Sham Injections Type C & Other Written Responses Establish Repeat Dosing at 6 Months Comparable Safety & Efficacy to SoC Label FDA Alignment Potential Impact of Positive SOL-R Data SoC (standard of care)
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89 Redefine Retina Treatment Potential for FDA Approval No Sham Injections Type C & Other Written Responses Establish Repeat Dosing at 6 Months Comparable Safety & Efficacy to SoC Label FDA Alignment Confidence in Potential Impact of Positive SOL-R Data SoC (standard of care)
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90 AXPAXLI NDA Submission Planned Following SOL-R 56-Week Topline Data* NDA (New Drug Application) *AXPAXLI NDA submission to the U.S. FDA in wet AMD pending successful outcomes in SOL-1 and SOL-R trials. AXPAXLI NDA PACKAGE 2-Year Safety w/ Q6M Re-Dosing 36 Week Superiority 52 Week Durability NDA package expected to exceed the requirements for FDA’s safety database at max dose and most frequent cadence 56 Week Non-Inferiority Q6M Re-Dosing SOL-1 SOL-R
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91 AXPAXLI is Designed for Seamless, Immediate Adoption Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity Ideal Target Product Profile
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92 AXPAXLI is Designed for Seamless, Immediate Adoption Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity No mandated steroids No remnants after drug depletion No surgery for administration Ideal Target Product Profile Single Bioresorbable Hydrogel
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93 AXPAXLI is Designed for Seamless, Immediate Adoption Familiar IVT injection Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity No mandated steroids Predictable fixed schedule for patients Designed for improved treatment adherence No remnants after drug depletion No surgery for administration Ideal Target Product Profile Single Bioresorbable Hydrogel Optimizing Retina Practices
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94 AXPAXLI is Designed for Seamless, Immediate Adoption Familiar IVT injection Best-in-class durability up to 12 months Favorable safety profile to date Monotherapy activity No mandated steroids Predictable fixed schedule for patients Designed for improved treatment adherence No remnants after drug depletion No surgery for administration Ideal Target Product Profile Single Bioresorbable Hydrogel Optimizing Retina Practices Would Allow Retina Specialists to See More Patients, Less Frequently
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95 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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96 Retina experience redefined Our retina experience is redefining your retina experience SOL-X: Long-term Outcomes Namrata Saroj, O.D. Chief Business Officer Redefining treatment Redefining development Redefining outcomes
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97 SOL-X Objectives Trial Design Impact
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98 SOL-X Objectives
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99 Redefining Outcomes: Understanding the Long-Term Impact of AXPAXLI SOL-X Designed to evaluate long-term safety of AXPAXLI and explore disease modifying potential of continuous VEGF suppression VEGF (vascular endothelial growth factor)
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100 Redefining Outcomes: Understanding the Long-Term Impact of AXPAXLI SOL-X Designed to evaluate long-term safety of AXPAXLI and explore disease modifying potential of continuous VEGF suppression KEY OBJECTIVES To evaluate reduction in fibrosis associated with chronic exudation VEGF (vascular endothelial growth factor)
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101 Redefining Outcomes: Understanding the Long-Term Impact of AXPAXLI SOL-X Designed to evaluate long-term safety of AXPAXLI and explore disease modifying potential of continuous VEGF suppression KEY OBJECTIVES To explore long- term maintenance of visual acuity To evaluate reduction in fibrosis associated with chronic exudation VEGF (vascular endothelial growth factor)
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102 Redefining Outcomes: Understanding the Long-Term Impact of AXPAXLI SOL-X Designed to evaluate long-term safety of AXPAXLI and explore disease modifying potential of continuous VEGF suppression KEY OBJECTIVES To explore long- term maintenance of visual acuity To investigate effects of delaying AXPAXLI treatment To evaluate reduction in fibrosis associated with chronic exudation VEGF (vascular endothelial growth factor)
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103 Redefining Outcomes: Understanding the Long-Term Impact of AXPAXLI SOL-X Designed to evaluate long-term safety of AXPAXLI and explore disease modifying potential of continuous VEGF suppression KEY OBJECTIVES Potential superiority claim may allow physicians to initiate AXPAXLI early To investigate effects of delaying AXPAXLI treatment VEGF (vascular endothelial growth factor)
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104 SOL-X Trial Design
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105 AXPAXLI vs Control Arm Fluctuations in SOL-1/R heading into SOL-X Primary Trials Initial Treatment Arms SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) SOL-1 CSFT (central subfield thickness); VEGF (vascular endothelial growth factor)
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106 AXPAXLI vs Control Arm Fluctuations in SOL-1/R heading into SOL-X SOL-1 SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) Primary Trials Initial Treatment Arms Expectations Entering SOL-X SOL-1 Constant VEGF suppression with AXPAXLI likely to result in LOWER CSFT fluctuations CSFT (central subfield thickness); VEGF (vascular endothelial growth factor)
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107 AXPAXLI vs Control Arm Fluctuations in SOL-1/R heading into SOL-X SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) Primary Trials Initial Treatment Arms Expectations Entering SOL-X HIGHER CSFT fluctuations in aflibercept arms due to pulsatile treatment1 SOL-1 CSFT (central subfield thickness); VEGF (vascular endothelial growth factor) 1, Fluctuations in CSFT observed with frequent anti-VEGF dosing (Dhoot DS, et al. J Vitreoretin Dis. Published online August 20, 2025. and Evans RN, et al. JAMA Ophthalmol. 2020;138(10):1043-1051.)
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108Q24W (every 24 weeks) SOL-X: Unlocking Long-Term Value with AXPAXLI Designed to evaluate safety and disease modifying potential of AXPAXLI SOL-X Three-year additional follow-up Primary Trials Initial Treatment Arms SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) SOL-1 24 72 120 14448 96 YEAR 1 0Time (weeks) YEAR 2 YEAR 3 AXPAXLI Study visit AXPAXLI Q24W 12 60 108 13236 844
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109 SOL-X: Unlocking Long-Term Value with AXPAXLI Designed to evaluate safety and disease modifying potential of AXPAXLI Potential sustained inhibition with fixed 6-month dosing of AXPAXLI up to 5 years SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) SOL-X Three-year additional follow-up Primary Trials Initial Treatment Arms SOL-1 Q24W (every 24 weeks) 24 72 120 14448 96 YEAR 1 0Time (weeks) YEAR 2 YEAR 3 AXPAXLI Study visit AXPAXLI Q24W 12 60 108 13236 844
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110 SOL-X: Unlocking Long-Term Value with AXPAXLI Designed to evaluate safety and disease modifying potential of AXPAXLI SOL-X Three-year additional follow-up Primary Trials Initial Treatment Arms SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) SOL-1 Q24W (every 24 weeks) 24 72 120 14448 96 YEAR 1 0Time (weeks) YEAR 2 YEAR 3 AXPAXLI Study visit AXPAXLI Q24W 12 60 108 13236 844
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111 SOL-X: Unlocking Long-Term Value with AXPAXLI Designed to evaluate safety and disease modifying potential of AXPAXLI SOL-X Three-year additional follow-up Primary Trials Initial Treatment Arms Impact of delayed treatment with fixed 6-month dosing of AXPAXLI in crossover patients SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) SOL-1 Q24W (every 24 weeks) 24 72 120 14448 96 YEAR 1 0Time (weeks) YEAR 2 YEAR 3 AXPAXLI Study visit AXPAXLI Q24W 12 60 108 13236 844
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112 SOL-X: Unlocking Long-Term Value with AXPAXLI Designed to evaluate safety and disease modifying potential of AXPAXLI SOL-X Three-year additional follow-up Primary Trials Initial Treatment Arms AXPAXLI: Potential to Redefine the Future of Retinal Disease Management SOL-R AXPAXLI Aflibercept (2 mg) Aflibercept (8 mg) AXPAXLI Aflibercept (2 mg) SOL-1 Q24W (every 24 weeks) 24 72 120 14448 96 YEAR 1 0Time (weeks) YEAR 2 YEAR 3 AXPAXLI Study visit AXPAXLI Q24W 12 60 108 13236 844
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113 SOL-X Impact
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114 SOL-X: Strengthens AXPAXLI Position as Potential First-Line Therapy SOL-1 / SOL-R SOL-X Superiority claim may permit AXPAXLI initiation, without delays of step therapy Designed to support superiority claim Crossover patients expected to have suboptimal outcomes SoC (standard of care); VEGF (vascular endothelial growth factor)
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115 SOL-X: Strengthens AXPAXLI Position as Potential First-Line Therapy SOL-1 / SOL-R SOL-X Target comparable safety, efficacy to SoC Potential for sustained benefit and safety with AXPAXLI Superiority claim may permit AXPAXLI initiation, without delays of step therapy Designed to support superiority claim Potential for reduction in fibrosis with consistent VEGF suppression Crossover patients expected to have suboptimal outcomes SoC (standard of care); VEGF (vascular endothelial growth factor)
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116 SOL-X: Strengthens AXPAXLI Position as Potential First-Line Therapy SOL-1 / SOL-R SOL-X Target comparable safety, efficacy to SoC Potential for sustained benefit and safety with AXPAXLI Potential expansion of market opportunity Superiority claim may permit AXPAXLI initiation, without delays of step therapy Designed to support superiority claim Benefits of dosing every 6 to 12 months Potential for reduction in fibrosis with consistent VEGF suppression Reduced injection frequency expected to improve adherence Crossover patients expected to have suboptimal outcomes SoC (standard of care); VEGF (vascular endothelial growth factor)
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117 SOL-X: Strengthens AXPAXLI Position as Potential First-Line Therapy Collectively, data from the SOL program may help AXPAXLI become the preferred drug of choice SOL-1 / SOL-R SOL-X Target comparable safety, efficacy to SoC Potential for sustained benefit and safety with AXPAXLI Potential expansion of market opportunity Superiority claim may permit AXPAXLI initiation, without delays of step therapy Designed to support superiority claim Benefits of dosing every 6 to 12 months Potential for reduction in fibrosis with consistent VEGF suppression Reduced injection frequency expected to improve adherence Crossover patients expected to have suboptimal outcomes SoC (standard of care); VEGF (vascular endothelial growth factor)
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118 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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119 KOL Perspectives: Wet AMD Clinical Strategy PANELISTSMODERATOR Arshad M. Khanani, MD, MA, FASRS Sierra Eye Associates Reno, Nevada Patricio G. Schlottmann, MD Organización Médica de Investigación Buenos Aires, Argentina Prof. Adnan T ufail, MBBS, MD, FRCOphth Moorfields Eye Hospital London, England Jeffery H. Heier, M.D. Chief Scientific Officer Eleonora (Nora) M. Lad, MD, PhD Duke University, Durham North Carolina
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120 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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121 Retina experience redefined Our retina experience is redefining your retina experience AXPAXLI’s Commercial Potential Jay Robins SVP , Finance Redefining treatment Redefining development Redefining outcomes
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122 aVEGF Treatment Burden Leads To Discontinuation of Therapy Today: Wet AMD Treatments1 Up to 12 injections/year Est. US wAMD IVT Injections1 (Millions) 0 250 500 750 1000 0 1 2 3 4 2022 2023 2024 2025 Wet AMD IVT per year Anti-VEGF treated pts Est. US wAMD aVEGF Treated Patients (‘000s) Mature Market with slow unit growth New Products With Modest Durability Gains Achieve Rapid Adoption Price / Share Game Unsustainable Treatment Burden Suboptimal Treatment & Discontinuation Poor Long-Term Outcomes Treatment Dynamic2 Market Dynamic AMD (age-related macular degeneration) IVT (Intravitreal) Pts (patients) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). Ocular Therapeutix Company Estimates
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123 aVEGF Treatment Burden Leads To Discontinuation of Therapy Today: Wet AMD Treatments1 Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Poor Long-Term Vision Outcomes Treatment Discontinuation Spiral Up to 12 injections/year wAMD (wet age-related macular degeneration), aVEGF (anti vascular endothelial growth factor), Tx (treatment) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2
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124 Need For Improved Durability & Adherence Today’s Paradigm: Short-Acting aVEGF Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated DISCONTINUATION2 Treatment Discontinuation Spiral Up to 12 injections/year aVEGF Tx Discontinuation - wAMD Illustrative Years on Tx % Continuing Tx Potential Adherence Improvement wAMD (wet age-related macular degeneration), aVEGF (anti vascular endothelial growth factor), Tx (treatment) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). Today: Wet AMD Treatments1 aVEGF Attrition Mortality Poor Long-Term Vision Outcomes
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125 Need For Improved Durability & Adherence Today’s Paradigm: Short-Acting aVEGF Today: Wet AMD Treatments1 Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Up to 12 injections/year aVEGF Tx Discontinuation - wAMD Opportunity AXPAXLI aVEGF Attrition Mortality AXPAXLI Opportunity Illustrative Years on Tx % Continuing Tx wAMD (wet age-related macular degeneration), aVEGF (anti vascular endothelial growth factor), Tx (treatment) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2 Poor Long-Term Vision Outcomes
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126 Next Generation Long Duration Eluting Therapies (LDETs) Could Break The Negative Feedback Loop & Discontinuation Cycle Today: Wet AMD Treatments1 Future: LDET Paradigm Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Up to 12 injections/year AMD (age-related macular degeneration), Tx (treatment), LDET (Long Duration Eluting Therapy) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2 Poor Long-Term Vision Outcomes
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127 Next Generation Long Duration Eluting Therapies (LDETs) Could Break The Negative Feedback Loop & Discontinuation Cycle Today: Wet AMD Treatments1 Future: LDET Paradigm Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Predictable Durability, Continuous Therapy Up to 12 injections/year AMD (age-related macular degeneration), Tx (treatment), LDET (Long Duration Eluting Therapy) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2 Poor Long-Term Vision Outcomes
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128 Next Generation Long Duration Eluting Therapies (LDETs) Could Break The Negative Feedback Loop & Discontinuation Cycle Today: Wet AMD Treatments1 Future: LDET Paradigm Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Predictable Durability, Continuous Therapy Low Tx Burden Up to 12 injections/year AMD (age-related macular degeneration), Tx (treatment), LDET (Long Duration Eluting Therapy) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2 Poor Long-Term Vision Outcomes
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129 Next Generation Long Duration Eluting Therapies (LDETs) Could Break The Negative Feedback Loop & Discontinuation Cycle Today: Wet AMD Treatments1 Future: LDET Paradigm Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Predictable Durability, Continuous Therapy Low Tx Burden Optimal Tx: Consistent & Sustained Up to 12 injections/year AMD (age-related macular degeneration), Tx (treatment), LDET (Long Duration Eluting Therapy) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2 Poor Long-Term Vision Outcomes
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130 Next Generation Long Duration Eluting Therapies (LDETs) Could Break The Negative Feedback Loop & Discontinuation Cycle Today: Wet AMD Treatments1 Future: LDET Paradigm Poor Durability, Frequent Dosing High Tx Burden Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Predictable Durability, Continuous Therapy Low Tx Burden Optimal Tx: Consistent & Sustained Improved Long-Term Vision Outcomes Up to 12 injections/year AMD (age-related macular degeneration), Tx (treatment), LDET (Long Duration Eluting Therapy) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). DISCONTINUATION2 Poor Long-Term Vision Outcomes
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131 Next Generation Long Duration Eluting Therapies (LDETs) Could Break The Negative Feedback Loop & Discontinuation Cycle Today: Wet AMD Treatments1 Future: LDET Paradigm Poor Durability, Frequent Dosing Sub-Optimal Tx: inconsistent & undertreated Treatment Discontinuation Spiral Predictable Durability, Continuous Therapy Optimal Tx: Consistent & Sustained Improved Long-Term Vision Outcomes RETENTION Up to 12 injections/year Treatment Retention Cycle Low Tx Burden AMD (age-related macular degeneration), Tx (treatment), LDET (Long Duration Eluting Therapy) 1. Ophthalmic Market Trends: Quarterly US Retina Edition: Q4-2024 & Q1 ‘2025 Analysis of Historical Trends and Latest Developments. Market Scope; 2024. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2). High Tx Burden DISCONTINUATION2 Poor Long-Term Vision Outcomes
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132 AXPAXLI Opportunity Significant AXPAXLI Opportunity to Potentially Expand Retinal Treatment Total US Prevalent Patients (2025): 9.6 Million1,2 >60% aVEGF tx’d <~2% tx’d ~20% aVEGF/ Laser tx’d ~25-30% aVEGF tx’d~10% aVEGF / Laser tx’d wAMD 1.8M Mod-Severe NPDR* 2.8M PDR* 1.8M DME 1.7M RVO 1.5M Trials in Planning Trials in Progress Future Opportunities Adherence Expanding Treated Population Share Gains *Excludes patients with DME as some patients have both NPDR/PDR and DME. wAMD (wet age-related macular degeneration); DME (diabetic macular edema); Mod -Severe NPDR (moderate to severe non-proliferative diabetic retinopathy); PDR (proliferative diabetic retinopathy); RVO (retinal vein occlusion); aVEGF (anti vascular endothelial growth factor); tx’d (treated) 1. Downs P. 2024 Retinal Pharmaceuticals Market Report: Global analysis for 2023 to 2029; 2024. 2. Custom Marketscope Report. Company Estimates Market Expansion Superiority Label Adoptability
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133 Real World Adherence Data Highlights The Opportunity For LDETs 100% 89% 56% 3% 14% 5% 17% 3% 13% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Initiation 6 months Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 On Therapy (Up to Max Label Dosing, QM-Q4M) At-Risk (Dosed > Max Label, >Q4 -12M) Discontinuation Lost To Follow-Up 11-13% Patients Lost to follow-up In Year 1 Not Likely To Continue Tx - Mortality, Poor Baseline Vision, Non-Responders, Injection Averse / Intolerant aVEGF Patients That Would Be Candidates for AXPAXLI Therapy LDET (Long Duration Eluting Therapy); Tx (treatment); aVEGF (anti vascular endothelial growth factor); Ocular Therapeutix Analysis of wet age-related macular degeneration anti-VEGF adherence in IRIS Registry & Vestrum Health Retina Databases
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134 -10 -5 0 5 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 1 Peden, M. C., et al (2015). Ophthalmology, 122(4), 803–808. 2. Wykoff, C. C., et al (2023). Ophthalmology science, 4(2), 100421. 3. Khanani, A. M., et al (2020). Ophthalmology. Retina, 4(2), 122–133. Persistent Dosing Provides for Sustained Visual Acuity Change From Peak (Year 1) Visual Acuity Among Registry Studies & Others Peak BCVA Maintained Peak BCVA Lost aVEGF Fixed Dosing Study1 IRIS Registry Outcomes 2 Vestrum Registry Outcomes 3 Mean Change in BCVA From Year 1 (Peak)
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135 AXPAXLI’s Adoptability Could Bend the Attrition Curve Retaining the At-Risk Population With Sustainable Therapy Can Grow The Treated Population Over Time 0% 20% 40% 60% 80% 100% Initiaiton 6 Months Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7Initiation Projected Mortality Real-World VEGF Attrition Potential Adherence Benefit Ocular Therapeutix Analysis of wet age-related macular degeneration anti-VEGF adherence in IRIS Registry & Vestrum Health Retina Databases
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136 AXPAXLI’s Adoptability Could Bend the Attrition Curve Improved Long-Term Outcomes May Provide Second Catalyst For Market Expansion 0% 20% 40% 60% 80% 100% Initiaiton 6 Months Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7Initiation Projected Mortality Real-World VEGF Attrition Potential Adherence Benefit Potential Adherence & LTO Benefit LTO (long-term outcomes) Ocular Therapeutix Analysis of wet age-related macular degeneration anti-VEGF adherence in IRIS Registry & Vestrum Health Retina Databases
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137 *Excludes patients with DME as some patients have both NPDR/PDR and DME. NPDR (non-proliferative diabetic retinopathy); DME (diabetic macular edema); PDR (proliferative diabetic retinopathy); tx (treatment); aVEGF (anti vascular endothelial growth factor) 1. Custom Marketscope Report. Company Estimates Diabetic Retinopathy Represents A Significant Undertreated Opportunity Challenges in Administration and Durability Have Contributed to Limited Adoption Expand The Treated Pool of DR Patients Potential Increased Treatment Pool with Improved Adherence Illustrative Years on Tx % Continuing Tx aVEGF Adherence Today AXPAXLI Opportunity PDR* DME Severe NPDR* Moderate NPDR* Treated Untreated 1.7M 1.7M Total US Patients1 0.8M 1.9M Illustrative Years ~99% ~95% ~80% ~90% AXPAXLI Opportunity
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138 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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139 Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D. Chief Development Officer Retina experience redefined Our retina experience is redefining your retina experience Redefining treatment Redefining development Redefining outcomes
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140 Expansion into Diabetic Retinopathy Strategy Potential Endpoints Registrational Program
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141 Expansion into Diabetic Retinopathy Strategy
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142 15.9 21.1 11.3 12.9 18.1 35.5 31.5 41.1 15.0 26.1 7.0 16.9 4.5 7.0 North America & Caribbean Europe Middle East & North Africa Western Pacific South & Central America Africa South East Asia2020: 103M 2045: 161M Diabetic Retinopathy is a Growing Global Health Burden Estimated number of adults with diabetic retinopathy in millions Teo ZL, Tham YC, Yu M, et al. Ophthalmology. 2021;128(11):1580-1591. Global Adults with DR
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143 DME (diabetic macular edema); DR (diabetic retinopathy); NPDR (non-proliferative DR); PDR (proliferative DR); VTC (vision -threatening complications) 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Mohamed Q, et al. JAMA. 2007;298(8):902-916. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025. Diabetic Retinopathy (DR): Large and Unrealized Market Opportunity DR Patients in US: 9 Million1 Each dot represents ~50,000 patients DME PDR NPDRPDR DR is a leading cause of vision loss in the working-age population2
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144 DME (diabetic macular edema); DR (diabetic retinopathy); NPDR (non-proliferative DR); PDR (proliferative DR); VTC (vision -threatening complications) 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Mohamed Q, et al. JAMA. 2007;298(8):902-916. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025. Diabetic Retinopathy (DR): Large and Unrealized Market Opportunity DR Patients in US: 9 Million1 Each dot represents ~50,000 patients NPDRPDR DR is a leading cause of vision loss in the working-age population2 NPDR = 72% of total DR population1
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145 Diabetic Retinopathy (DR): Large and Unrealized Market Opportunity NPDR = 72% of total DR population1 <1% of NPDR patients treated today3 DR Patients in US: 9 Million1 Each dot represents ~50,000 patients NPDRPDR DR is a leading cause of vision loss in the working-age population2 DME (diabetic macular edema); DR (diabetic retinopathy); NPDR (non-proliferative DR); PDR (proliferative DR); VTC (vision -threatening complications) 1. Market Scope. 2024 Retinal Pharmaceuticals Market Report. 2. Mohamed Q, et al. JAMA. 2007;298(8):902-916. 3. Market Scope. US Retina Quarterly Update: Q4 2024 Analysis of Historical Trends and Latest Developments. Published February 2025.
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146 CI-DME (center-involved diabetic macular edema); DR (diabetic retinopathy); NPDR (non -proliferative DR); PRN (pro re nata [as needed]); VTC (vision-threatening complications); VEGF (vascular endothelial growth factor); q8/16w (every 8/16 weeks) 1. Maturi RK, et al. JAMA. 2023;329(5):376-385. 2. Brown DM, Wykoff CC, Boyer D, et al. JAMA Ophthalmol. 2021;139(9):946-955. 3. Sivaprasad S, et al. Clin Ophthalmol. 2016;10:939-946. 4. Newman D, et al. Ophthalmol Ther. 2025;14(1):1-12. Why Isn’t NPDR Routinely Treated Today? 0 10 20 30 40 50 Sham Aflibercept 2mg Q16W Aflibercept 2mg Q8W/PRN Percentage of Eyes Developing VTC or CI-DME of untreated NPDR patients develop VTC or CI-DME in 1 year2 Proactive anti-VEGF treatment of NPDR has proven benefits1,2… 40%
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147 CI-DME (center-involved diabetic macular edema); DR (diabetic retinopathy); NPDR (non -proliferative DR); PRN (pro re nata [as needed]); VTC (vision-threatening complications); VEGF (vascular endothelial growth factor); q8/16w (every 8/16 weeks) 1. Maturi RK, et al. JAMA. 2023;329(5):376-385. 2. Brown DM, Wykoff CC, Boyer D, et al. JAMA Ophthalmol. 2021;139(9):946-955. 3. Sivaprasad S, et al. Clin Ophthalmol. 2016;10:939-946. 4. Newman D, et al. Ophthalmol Ther. 2025;14(1):1-12. Why Isn’t NPDR Routinely Treated Today? 0 10 20 30 40 50 Sham Aflibercept 2mg Q16W Aflibercept 2mg Q8W/PRN Percentage of Eyes Developing VTC or CI-DME of untreated NPDR patients develop VTC or CI-DME in 1 year2 Proactive anti-VEGF treatment of NPDR has proven benefits1,2… 40% Frequent injections are cumbersome in working age population 3 Physicians and patients desire a better long-term solution 4 …but treating NPDR is burdensome and unsustainable for patients
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148 Safety and tolerability of AXPAXLI Multi-center, double-masked, randomized, parallel group study of AXPAXLI in mod-severe to severe NPDR without CI-DME DRSS changes, rescue therapy, BCVA / CSFT, vision threatening complications (VTCs)*14 patients enrolled in AXPAXLI treatment arm, with one patient death unrelated to treatment. BCVA (best-corrected visual acuity); DRSS (diabetic retinopathy severity scale); CSFT (central subfield thickness); NPDR (non -proliferative diabetic retinopathy); CI - DME (center-involved diabetic macular edema). Marcus D, et al. Safety and Efficacy of OTX-TKI in Moderately Severe to Severe NPDR: One Year Results from the HELIOS Phase 1 Tr ial. Presented at Retina Society. Lisbon, Portugal. September 14, 2024. HELIOS-1 Study of AXPAXLI in NPDR R 2:1 AXPAXLI Sham 0 Year 1 Monthly Study Visits Monthly Study Visits Design Primary Endpoint Secondary Endpoints Screening Randomization AXPAXLI (N=14*) Sham Control (N=8) HELIOS-1 HELIOS-1
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149 0% 0% 54% 23% 23% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% ≥2 Step Worsening 1 Step Worsening No Change 1 Step Improvement ≥2 Step Improvement Percentage of Patients Any Improvement 46% Any Worsening 0% *14 patients enrolled in AXPAXLI treatment arm, with one patient death unrelated to treatment. DRSS (diabetic retinopathy severity scale) Marcus D, et al. Safety and Efficacy of OTX-TKI in Moderately Severe to Severe NPDR: One Year Results from the HELIOS Phase 1 Tr ial. Presented at Retina Society. Lisbon, Portugal. September 14, 2024. HELIOS-1: DRSS Change at 48 Weeks 23.1% 2-step DRSS improvement in AXPAXLI arm at Week 48 compared to 0% in the sham arm 13% 13% 75% 0% 0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% ≥2 Step Worsening 1 Step Worsening No Change 1 Step Improvement ≥2 Step Improvement Percentage of Patients Any Worsening 25% Any Improvement 0% AXPAXLI (N=13)*SHAM CONTROL (N=8) Any Improvement 46% HELIOS-1
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150 HELIOS-1: DME Improvement in all patients with AXPAXLI BASELINE Patient 11-007 Patient 13-001 Patient 15-004 Patient 16-005 Patient 16-006 Patient 11-008 WEEK 48 Patient 12-002 Patient 16-009 AXPAXLI Normal OCT Thickness Map HELIOS-1 AXPAXLI Subjects with Non-CI DME (N=8) DME (diabetic macular edema); OCT (optical coherence tomography); Normal OCT thickness map courtesy of Maine Eye Center. Marcus D, et al. Safety and Efficacy of OTX-TKI in Moderately Severe to Severe NPDR: One Year Results from the HELIOS Phase 1 Tr ial. Presented at Retina Society. Lisbon, Portugal. September 14, 2024. ; non-CI-DME (non-center-involved diabetic macular edema) HELIOS-1
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151 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0 4 8 12 16 20 24 28 32 36 40 44 48 Mean Change from Baseline (mm3) Study Timepoint (Weeks) Total Retinal Fluid Volume (mm3) Sham (N=8) AXPAXLI (N=14)* Baseline mean AXPAXLI, 10.94 mm3 Sham, 10.26 mm3 Mean Change from Baseline at Week 48 Sham, -0.16 mm3 AXPAXLI, -0.92 mm3 HELIOS-1: Improvement in Total Retinal Volume *14 patients enrolled in AXPAXLI treatment arm, with one patient death unrelated to treatment. Ehlers J, et al. Volumetric Macular Fluid Analysis of the Impact of a Single Axitinib Intravitreal Implant (OTX -TKI) from the HELIOS Clinical Trial for Diabetic Retinopathy. Presented at Angiogenesis. Virtual. February 8, 2025. HELIOS-1
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152 HELIOS-1: DME Improvement in all patients with AXPAXLI If replicated in Phase 3, strong case for potential AXPAXLI use in both prevention and treatment of DME All AXPAXLI-treated subjects with non-CI-DME saw improvement from baseline to week 48 None of the Sham subjects with non-CI-DME saw improvement from baseline to week 48 DME (diabetic macular edema); non-CI-DME (non-center-involved diabetic macular edema) Marcus D, et al. Safety and Efficacy of OTX-TKI in Moderately Severe to Severe NPDR: One Year Results from the HELIOS Phase 1 Tr ial. Presented at Retina Society. Lisbon, Portugal. September 14, 2024. HELIOS-1
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153 HELIOS-1: Total Retinal Vascular Leakage BASELINE END OF STUDY AXPAXLI SHAM CONTROL Higher levels of total retinal vascular leakage associated with 1: • More advanced DR • Greater risk of disease progression • Worse visual outcomes 2.9 3.5 -2.8 -3.0 -4 -3 -2 -1 0 1 2 3 4 5 Week 24 End of Study Mean Change from Baseline (%) Total Leakage Index2 Sham (N=8) AXPAXLI (N=14)* *14 patients enrolled in AXPAXLI treatment arm, with one patient death unrelated to treatment. DR (diabetic retinopathy) 1. Writing Committee for the DRCR Retina Network, et al. Ophthalmol Retina. 2025;9(3):243-252. 2. Figures from Ehlers J, et al. Volumetric Macular Fluid Analysis of the Impact of a Single Axitinib Intravitreal Implant (OTX-TKI) from the HELIOS Clinical Trial for Diabetic Retinopathy. Presented at Angiogenesis. Virtual. February 8, 2025. HELIOS-1
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154 T argeting a Broad Indication in Diabetic Retinopathy DR (diabetic retinopathy); DME (diabetic macular edema) 1. Teo ZL, Tham YC, Yu M, et al. Ophthalmology. 2021;128(11):1580-1591. Global DR Patients >100M1 Global DR Prevalence
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155 T argeting a Broad Indication in Diabetic Retinopathy AXPAXLI Strategy Seeking to Unlock the Diabetic Market with a Broad DR Label Global DR Prevalence Global DR Patients >100M1 DR (diabetic retinopathy); DME (diabetic macular edema) 1. Teo ZL, Tham YC, Yu M, et al. Ophthalmology. 2021;128(11):1580-1591.
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156 T argeting a Broad Indication in Diabetic Retinopathy Global DR Prevalence AXPAXLI Strategy Global DR Patients >100M1 Seeking to Unlock the Diabetic Market with a Broad DR Label 1 Aim to treat full spectrum of diabetic retinal disease DR (diabetic retinopathy); DME (diabetic macular edema) 1. Teo ZL, Tham YC, Yu M, et al. Ophthalmology. 2021;128(11):1580-1591.
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157 T argeting a Broad Indication in Diabetic Retinopathy Global DR Prevalence AXPAXLI Strategy Seeking to Unlock the Diabetic Market with a Broad DR Label Global DR Patients >100M1 DME Patients 19M1 1 2 Aim to treat full spectrum of diabetic retinal disease Includes patients with or without DME DR (diabetic retinopathy); DME (diabetic macular edema) 1. Teo ZL, Tham YC, Yu M, et al. Ophthalmology. 2021;128(11):1580-1591.
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158 T argeting a Broad Indication in Diabetic Retinopathy 1 2 3 ~84M more patients globally than DME-only label1 Global DR Patients >100M1 DME Patients 19M1 Aim to treat full spectrum of diabetic retinal disease Includes patients with or without DME Seeking to Unlock the Diabetic Market with a Broad DR Label Global DR Prevalence AXPAXLI Strategy DR (diabetic retinopathy); DME (diabetic macular edema) 1. Teo ZL, Tham YC, Yu M, et al. Ophthalmology. 2021;128(11):1580-1591.
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159 Expansion into Diabetic Retinopathy Potential Endpoints
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160 DR (diabetic retinopathy); DRSS (DR severity score); NPDR (non-proliferative DR) Images from Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House c lassification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):786-806. and Arcadu F, et al. Deep learning algorithm predicts diabetic retinopathy progression in individual patients. NPJ Digit Med. 2019;2:92 1. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):823-833. DRSS – Diabetic Retinopathy Severity Score DR severity is quantified using feature-based, structured grading of fundus color images and allows the designation of the eye into a category based on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS)(Range 10-85)1 DRSS 10 No DR DRSS 43 Moderate NPDR DRSS 47 Moderate- Severe NPDR DRSS 53 Severe NPDR DRSS 61 Mild Proliferative DR DRSS 35 Mild NPDR DRSS 71 High Risk Proliferative DR
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161 DR (diabetic retinopathy); DRSS (DR severity score); NPDR (non-proliferative DR) Images from Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House c lassification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):786-806. and Arcadu F, et al. Deep learning algorithm predicts diabetic retinopathy progression in individual patients. NPJ Digit Med. 2019;2:92 1. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):823-833. ≥2-Step DRSS Improvement Collapses Studies to a Binary Endpoint FDA Validated Regulatory Endpoint FDA Validated Endpoint | Only Detects Binary Changes in Disease Severity Example of ≥2-Step Improvement Example of ≥2-Step Worsening DRSS 10 No DR DRSS 43 Moderate NPDR DRSS 47 Moderate- Severe NPDR DRSS 53 Severe NPDR DRSS 61 Mild Proliferative DR DRSS 35 Mild NPDR DRSS 71 High Risk Proliferative DR
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162 DRSS (diabetic retinopathy severity score) ClinicalTrials.gov and Nair P, et al. Invest Ophthalmol Vis Sci. 2016;57(13):5127-5142. 20 Years of DR Trials Have Used a Binary DRSS Endpoint Only four FDA approvals to date in DR; All based on ≥2-Step DRSS improvement (Binary Endpoint) AKB-9778 Phase 2 BI 1467335 Phase 2 ABBV-RGX-314 Phase 2 RG7774 Phase 2 KSI-301 Phase 3 APX3330 Phase 2 AKST4290 Phase 2 BI 764524 Phase 2 OPL-0401 Phase 2 BAY1101042 Phase 2 EYP-1901 Phase 2 2007 2011 20252017 2019 2021 2023 Binary Endpoint: Captures ≥2 step DRSS Improvement OR Worsening Lucentis RISE & RIDE Eylea PANORAMA Eylea HD PHOTON Susvimo PAVILION
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163 DRSS (diabetic retinopathy severity score) *HELIOS-1 dataset scaled and simulated to illustrate endpoint impact. Ocular Therapeutix data on file. 2025. Simulated Phase 3 Using HELIOS-1 AXPAXLI Data*: ≥2-Step Binary Endpoint 0% 20% 40% 60% 80% 100% AXPAXLI (N=184) Sham (N=184) ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement Simulated Data Set (Illustrative) 23% (N=42) Binary ≥2-Step Improvement 0% (N=0) Using Various DRSS Endpoints AXPAXLI (N=184) SHAM (N=184)
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164 Simulated Phase 3 Using HELIOS-1 AXPAXLI Data*: ≥2-Step Binary Endpoint 0% 20% 40% 60% 80% 100% AXPAXLI (N=184) Sham (N=184) ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement Simulated Data Set (Illustrative) 23% (N=42) Binary ≥2-Step Improvement 0% (N=0) Using Various DRSS Endpoints AXPAXLI (N=184) SHAM (N=184) Binary ≥2-Step Improvement (p < 0.0001) DRSS (diabetic retinopathy severity score) *HELIOS-1 dataset scaled and simulated to illustrate endpoint impact. Ocular Therapeutix data on file. 2025.
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165 0% (N=0) 0% 20% 40% 60% 80% 100% AXPAXLI (N=184) Sham (N=184) ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement Simulated Phase 3 Using HELIOS-1 AXPAXLI Data*: ≥2-Step Binary Endpoint 13% (N=23) Binary ≥2-Step Worsening Binary ≥2-Step Worsening (p < 0.0001) Using Various DRSS Endpoints AXPAXLI (N=184) SHAM (N=184) Binary ≥2-Step Improvement (p < 0.0001) Simulated Data Set (Illustrative) DRSS (diabetic retinopathy severity score) *HELIOS-1 dataset scaled and simulated to illustrate endpoint impact. Ocular Therapeutix data on file. 2025.
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166DRSS (diabetic retinopathy severity score) Binary DRSS Endpoint Has Significant Limitations Binary Analysis Endpoint Captures ≥2-step improvement OR worsening Oversimplifies DRSS to Yes/No question (≥2 step gain or prevention) Easy to interpret, but throws away vital DRSS information Reduced statistical power Substantially more patients to reach statistical significance
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167 Preparing for Phase 3 Diabetic Retinopathy Trial HELIOS-1 data exceptionally consistent: Statistical significance regardless of binary DRSS endpoint used DRSS (diabetic retinopathy severity score)
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168 Significantly Underperforms Preparing for Phase 3 Diabetic Retinopathy Trial HELIOS-1 data exceptionally consistent: Statistical significance regardless of binary DRSS endpoint used Control Arm Hypothetical Drug Significantly Overperforms But what if “Hypothetical Drug” and/or Control responded differently? DRSS (diabetic retinopathy severity score)
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169 Simulated Phase 3 Data for a Hypothetical Drug Simulated Data Set (Illustrative) 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) DRSS (diabetic retinopathy severity score)
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170 Simulated Phase 3 Data for a Hypothetical Drug Hypothetical Drug: Theoretical Phase 3 Observations 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) “Hypothetical Drug” arm has more 2 step improvement and less 2 step worsening Clinically meaningful results Numerically superior outcomes Simulated Data Set (Illustrative) DRSS (diabetic retinopathy severity score)
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171 Simulated Phase 3 Data for a Hypothetical Drug Using Various DRSS Endpoints Binary ≥2-Step Improvement (p = 0.09) 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) Binary ≥2-Step Improvement FAIL Simulated Data Set (Illustrative) DRSS (diabetic retinopathy severity score)
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172 Binary ≥2-Step Worsening (p = 0.09) FAIL Simulated Phase 3 Data for a Hypothetical Drug Using Various DRSS Endpoints Binary ≥2-Step Improvement (p = 0.09) 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) Binary ≥2-Step Worsening Simulated Data Set (Illustrative) DRSS (diabetic retinopathy severity score)
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173 Ocular Therapeutix: Redefining Development Higher risk trial Binary DRSS: Significant Clinical and Practical Limitations Need to choose improvement OR worsening Excludes relevant DRSS data DRSS (diabetic retinopathy severity score)
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174 Ocular Therapeutix: Redefining Development Leverage Data From ALL Patients Account for BOTH disease improvement AND worsening Align with how clinicians think about DR treatment goals A BETTER Clinical Endpoint Would Higher risk trial Binary DRSS: Significant Clinical and Practical Limitations Need to choose improvement OR worsening Excludes relevant DRSS data DRSS (diabetic retinopathy severity score)
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175 Ocular Therapeutix: Redefining Development Leverage Data From ALL Patients Account for BOTH disease improvement AND worsening Align with how clinicians think about DR treatment goals A BETTER Clinical Endpoint Would Higher risk trial Binary DRSS: Significant Clinical and Practical Limitations Need to choose improvement OR worsening Excludes relevant DRSS data Ordinal DRSS Endpoint DRSS (diabetic retinopathy severity score)
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176 Ordinal Analysis Includes Ordinal Endpoint Captures Full Treatment Effect Greater Statistical Power: Smaller sample size, lower risk trials Captures full DRSS scale: Both improvement and worsening ≥2-step DRSS improvement AND No 2-step change in DRSS AND Prevention of ≥2-step DRSS worsening Stronger efficacy signal gives more compelling case for regulators, payers, and physicians DRSS (diabetic retinopathy severity score)
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177 Simulated Phase 3 Data for a Hypothetical Drug Simulated Data Set (Illustrative) Using Various DRSS Endpoints Binary ≥2-Step Improvement (p = 0.09) 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) Binary ≥2-Step Change FAIL Binary ≥2-Step Worsening (p = 0.09) FAIL DRSS (diabetic retinopathy severity score)
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178 Simulated Phase 3 Data for a Hypothetical Drug Using Various DRSS Endpoints Binary ≥2-Step Improvement (p = 0.09) 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) Ordinal captures BOTH improvement AND preventing worsening Binary ≥2-Step Worsening (p = 0.09) Simulated Data Set (Illustrative) DRSS (diabetic retinopathy severity score)
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179 Simulated Phase 3 Data for a Hypothetical Drug Using Various DRSS Endpoints 6% (N=11) 11% (N=20) 83% (N=153) 83% (N=153) 11% (N=20) 6% (N=11) 0% 20% 40% 60% 80% 100% ≥2 Step Worsening No 2 Step Change ≥2 Step Improvement “Drug” (N=184) SHAM (N=184) Ordinal captures BOTH improvement AND preventing worsening Ordinal ≥2-Step Change (p = 0.02) Simulated Data Set (Illustrative) DRSS (diabetic retinopathy severity score) Binary ≥2-Step Improvement (p = 0.09) Binary ≥2-Step Worsening (p = 0.09)
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180 *14 patients enrolled in AXPAXLI treatment arm, with one patient death unrelated to treatment. PDR (proliferative diabetic retinopathy); CI-DME (center involved diabetic macular edema). Marcus D, et al. Safety and Efficacy of OTX-TKI in Moderately Severe to Severe NPDR: One Year Results from the HELIOS Phase 1 Tr ial. Presented at Retina Society. Lisbon, Portugal. September 14, 2024. What About Prevention of VTC as Primary Endpoint? 25% 13% 38% 0% 0% 0% 0% 5% 10% 15% 20% 25% 30% 35% 40% CI-DME PDR PDR or CI-DME ∎ Sham Control (N=8) ∎ AXPAXLI (N=13*) AXPAXLI AXPAXLI AXPAXLI Monotherapy Activity in NPDR Percentage of Patients HELIOS-1
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181 25% 13% 38% 0% 0% 0% 0% 5% 10% 15% 20% 25% 30% 35% 40% CI-DME PDR PDR or CI-DME 0% in the AXPAXLI arm developed PDR or CI-DME at Week 48 compared to 38% in the Sham arm ∎ Sham Control (N=8) ∎ AXPAXLI (N=13*) AXPAXLI AXPAXLI AXPAXLI What About Prevention of VTC as Primary Endpoint? Monotherapy Activity in NPDR Percentage of Patients *14 patients enrolled in AXPAXLI treatment arm, with one patient death unrelated to treatment. PDR (proliferative diabetic retinopathy); CI-DME (center involved diabetic macular edema). Marcus D, et al. Safety and Efficacy of OTX-TKI in Moderately Severe to Severe NPDR: One Year Results from the HELIOS Phase 1 Tr ial. Presented at Retina Society. Lisbon, Portugal. September 14, 2024. HELIOS-1
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182 ANV (angle neovascularization); DME (diabetic macular edema); DR (diabetic retinopathy); DRSS (DR severity score); FDA (U.S. Food and Drug Administration); PDR (proliferative DR); TRD (tractional retinal detachment); VH (vitreous hemorrhage); VTC (vision -threatening complication) Prevention of VTC as Primary Endpoint has Significant Regulatory Limitations Prevention of VTCPrimary Endpoint Regulatory FDA Vision Endpoint ≥15 letter delta (VTC Requires ≥15 letter loss) Study Design Wait for ≥15 letter loss due to VTC (PDR or ANV or DME, not combined) Statistics Low event rate → requires large N and longer follow-up Clinical Relevance Waiting until ≥ 15 letter loss in DR not acceptable because it is often permanent
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183 Redefining Endpoints in DR Prevention of VTCPrimary Endpoint Regulatory FDA Vision Endpoint ≥15 letter delta (VTC Requires ≥15 letter loss) DRSS used for Lucentis, Eylea approvals Study Design Wait for ≥15 letter loss due to VTC (PDR or ANV or DME, not combined) Familiar to investigators and regulators Statistics Low event rate → requires large N and longer follow-up Every patient contributes data → Great statistical sensitivity Clinical Relevance Waiting until ≥ 15 letter loss in DR not acceptable because it is often permanent Measures both improvement (regression) and worsening (progression) Ordinal DRSS Change ANV (angle neovascularization); DME (diabetic macular edema); DR (diabetic retinopathy); DRSS (DR severity score); FDA (U.S. Food and Drug Administration); PDR (proliferative DR); TRD (tractional retinal detachment); VH (vitreous hemorrhage); VTC (vision -threatening complication)
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184 Redefining Endpoints in DR Prevention of VTCPrimary Endpoint Regulatory FDA Vision Endpoint ≥15 letter delta (VTC Requires ≥15 letter loss) DRSS used for Lucentis, Eylea approvals Study Design Wait for ≥15 letter loss due to VTC (PDR or ANV or DME, not combined) Familiar to investigators and regulators Statistics Low event rate → requires large N and longer follow-up Every patient contributes data → Great statistical sensitivity Clinical Relevance Waiting until ≥ 15 letter loss in DR not acceptable because it is often permanent Measures both improvement (regression) and worsening (progression) Ordinal DRSS Change Ordinal DRSS Endpoint: Potential for a smaller, shorter, more relevant, less clinically risky, and less costly trial ANV (angle neovascularization); DME (diabetic macular edema); DR (diabetic retinopathy); DRSS (DR severity score); FDA (U.S. Food and Drug Administration); PDR (proliferative DR); TRD (tractional retinal detachment); VH (vitreous hemorrhage); VTC (vision -threatening complication)
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185 Ordinal DRSS Change Endpoint Has Potential to Drive a More Efficient Trial VTC (≥15-letter Loss) 3 years ~1600 patients Trial Length Sample SizeEndpoint Trial designs are 90% powered. Sample size calculations assume 15% yearly dropout rate. VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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186 Ordinal DRSS Change Endpoint Has Potential to Drive a More Efficient Trial VTC (≥15-letter Loss) Binary DRSS Change 3 years 1 year ~1600 patients Trial Length Sample SizeEndpoint ~650 patients DRSS improvement only ~450 patients DRSS worsening only OR Trial designs are 90% powered. Sample size calculations assume 15% yearly dropout rate. VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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187 Ordinal DRSS Change Endpoint Has Potential to Drive a More Efficient Trial VTC (≥15-letter Loss) Binary DRSS Change 3 years 1 year ~1600 patients Trial Length Sample Size ~350 patients Endpoint Ordinal DRSS Change 1 year ~650 patients DRSS improvement only ~450 patients DRSS worsening only OR Trial designs are 90% powered. Sample size calculations assume 15% yearly dropout rate. VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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188VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score) Why Ordinal DRSS is the PREFERABLE Primary Endpoint? Binary DRSSVTC Ordinal DRSS Mid trial sizeLargest trial size Smallest trial size
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189 Why Ordinal DRSS is the PREFERABLE Primary Endpoint? Binary DRSSVTC Ordinal DRSS Mid trial sizeLargest trial size Shortest trial lengthLongest trial length Smallest trial size Shortest trial length VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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190 Why Ordinal DRSS is the PREFERABLE Primary Endpoint? Mid trial sizeLargest trial size Shortest trial lengthLongest trial length Mid expensiveMost expensive Binary DRSSVTC Smallest trial size Shortest trial length Least expensive Ordinal DRSS VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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191 Why Ordinal DRSS is the PREFERABLE Primary Endpoint? Binary DRSSVTC Ordinal DRSS Mid trial sizeLargest trial size Shortest trial lengthLongest trial length Mid expensiveMost expensive Most clinical riskUnknown clinical risk Smallest trial size Shortest trial length Least expensive Least clinical risk VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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192 Why Ordinal DRSS is the PREFERABLE Primary Endpoint? Mid trial sizeLargest trial size Shortest trial lengthLongest trial length Mid expensiveMost expensive Most clinical riskUnknown clinical risk Binary DRSSVTC Smallest trial size Shortest trial length Least expensive Least clinical risk Ordinal DRSS Ordinal Endpoint Provides Best Opportunity for Success VTC (vision-threatening complication); DRSS (diabetic retinopathy severity score)
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193DR (diabetic retinopathy); DRSS (diabetic retinopathy severity score); DME (diabetic macular edema) AXPAXLI Diabetic Retinopathy Phase 3 Program Smallest trial size Shortest trial length Least expensive Least clinical risk Ordinal DRSS Ordinal Endpoint Provides Best Opportunity for Success Ordinal ≥2-step DRSS as Primary Endpoint in both registrational trials Two Complementary DR Trials Targeting a broad DR label, which would include DME First time ordinal endpoint being used in DR Trials Most clinically relevant endpoint with higher probability of success than VTC or binary DRSS
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194 AXPAXLI Diabetic Retinopathy Phase 3 Program Smallest trial size Shortest trial length Least expensive Least clinical risk Ordinal DRSS Ordinal Endpoint Provides Best Opportunity for Success Ordinal ≥2-step DRSS as Primary Endpoint in both registrational trials Two Complementary DR Trials Targeting a broad DR label, which would include DME First time ordinal endpoint being used in DR Trials Most clinically relevant endpoint with higher probability of success than VTC or binary DRSS FDA Alignment on Primary Endpoint (Included in HELIOS-2 SPA Agreement) DR (diabetic retinopathy); DRSS (diabetic retinopathy severity score); DME (diabetic macular edema)
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195 Expansion into Diabetic Retinopathy Registrational Program
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196 *Trial subjects and designated personnel will remain masked through end of year 2. DRSS, diabetic retinopathy severity scale; NPDR, non-proliferative diabetic retinopathy; CI-DME center involved diabetic macular edema. Planned HELIOS-2 Study Design Superiority Study Comparing AXPAXLI to a Single Ranibizumab (0.3 mg) Dose Design Primary Endpoint (Week 52) Ordinal DRSS 2-step change status at Week 52 from baseline (≥ 2 step improvement, ≥ 2-step worsening, less than 2-step change in either direction) Study of AXPAXLI in ~432 subjects with moderately-severe to severe NPDR without CI-DME HELIOS-2 AXPAXLI Ranibizumab 0.3 mg Week AXPAXLI Ranibizumab 0.3 mg Study visit 4 20 4412 288 24 40 4816 32 36 End of Year 2 …520 104 Primary endpoint Randomization (Day 1) Screening Monthly Study Visits HELIOS-2 R 1:1 Safety follow-up*
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197 HELIOS-3 AXPAXLI AXPAXLI Planned HELIOS-3 Study Design Superiority Study Comparing AXPAXLI to Sham R 1:1:1Week 4 20 4412 288 24 40 4816 32 36 Randomization (Day 1) Screening 52 Study Visits 0 Design 52 Sham AXPAXLI Sham injection Study visit Primary endpoint HELIOS-3 *Trial subjects and designated personnel will remain masked through the primary endpoint at Week 52. DRSS, diabetic retinopathy severity scale; NPDR, non-proliferative diabetic retinopathy; CI-DME center involved diabetic macular edema. Primary Endpoint (Week 52) Ordinal DRSS 2-step change status at Week 52 from baseline (≥ 2 step improvement, ≥ 2-step worsening, less than 2-step change in either direction) Study of AXPAXLI in ~930 subjects with moderately-severe to severe NPDR without CI-DME
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198 HELIOS Program: AXPAXLI Registrational Program in DR Both trials leverage novel primary endpoint aligned with FDA Two Complementary Trials Designed to UNLOCK the Diabetic Market and Support a Broad DR Label DR, diabetic retinopathy; FDA, U.S. Food and Drug Administration; SPA, Special Protocol Assessment
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199 HELIOS Program: AXPAXLI Registrational Program in DR Planned Design Comparator T arget Label Implications Superiority Study Conducted Under FDA SPA Single Ranibizumab 0.3 mg 12-month durability label Superiority to Ranibizumab 0.3mg Repeat dosing HELIOS-2 Both trials leverage novel primary endpoint aligned with FDA Two Complementary Trials Designed to UNLOCK the Diabetic Market and Support a Broad DR Label DR, diabetic retinopathy; FDA, U.S. Food and Drug Administration; SPA, Special Protocol Assessment
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200 HELIOS Program: AXPAXLI Registrational Program in DR Planned Design Comparator T arget Label Implications Superiority Study Conducted Under FDA SPA Superiority Study Single Ranibizumab 0.3 mg Sham 12-month durability label Superiority to Ranibizumab 0.3mg Repeat dosing 6 and 12-month dosing intervals Superiority to Sham 6-month repeat dosing HELIOS-2 HELIOS-3 Both trials leverage novel primary endpoint aligned with FDA Two Complementary Trials Designed to UNLOCK the Diabetic Market and Support a Broad DR Label DR, diabetic retinopathy; FDA, U.S. Food and Drug Administration; SPA, Special Protocol Assessment
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201DME, diabetic macular edema; DR, diabetic retinopathy; FDA, U.S. Food and Drug Administration; Positioning AXPAXLI for the Broader DR Opportunity DR Market Opportunity DME represents only a fraction of DR patients AXPAXLI’s potential broad DR label could unlock significant market in diabetic retinal disease
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202DME, diabetic macular edema; DR, diabetic retinopathy; FDA, U.S. Food and Drug Administration; Positioning AXPAXLI for the Broader DR Opportunity DR Market Opportunity DME represents only a fraction of DR patients AXPAXLI’s potential broad DR label could unlock significant market in diabetic retinal disease AXPAXLI Phase 3 Strategy Planned trial design seeks to support superiority label Evaluating yearly and Q6M dosing of AXPAXLI De-risking, novel, ordinal primary endpoint to capture improvement and worsening of DR Ordinal endpoint supported by HELIOS-1 and included in HELIOS-2 SPA with FDA
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203DME, diabetic macular edema; DR, diabetic retinopathy; FDA, U.S. Food and Drug Administration; Positioning AXPAXLI for the Broader DR Opportunity DR Market Opportunity DME represents only a fraction of DR patients AXPAXLI’s potential broad DR label could unlock significant market in diabetic retinal disease AXPAXLI Phase 3 Strategy Planned trial design seeks to support superiority label Evaluating yearly and Q6M dosing of AXPAXLI De-risking, novel, ordinal primary endpoint to capture improvement and worsening of DR Ordinal endpoint supported by HELIOS-1 and included in HELIOS-2 SPA with FDA Registrational DR Program to Initiate Imminently
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204 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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205 KOL Perspectives: DR Clinical Strategy PANELISTSMODERATOR Arshad M. Khanani, MD, MA, FASRS Sierra Eye Associates Reno, Nevada Patricio G. Schlottmann, MD Organización Médica de Investigación Buenos Aires, Argentina Prof. Adnan T ufail, MBBS, MD, FRCOphth Moorfields Eye Hospital London, England Peter K. Kaiser, MD Chief Development Officer Eleonora (Nora) M. Lad, MD, PhD Duke University, Durham North Carolina
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206 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.
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207 Retina experience redefined Our retina experience is redefining your retina experience Summary & Takeaways Pravin U. Dugel, MD Executive Chairman, President & CEO Redefining treatment Redefining development Redefining outcomes
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208 AXPAXLI Positioned to Redefine Retina Market Size AdoptabilitySuperiority
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209 Agenda: Ocular Therapeutix 2025 Investor Day SOL-1: Significance of Superiority Nadia K. Waheed, M.D., MPH SOL-R: Immediate Adoptability Jeffrey S. Heier, M.D. Intro & Overview Pravin U. Dugel, M.D. SOL-X: Long-term Outcomes Namrata Saroj, O.D. KOL Perspectives: Wet AMD Clinical Strategy Moderator: Jeffrey S. Heier, M.D. Wet AMD SOL Program AXPAXLI’s Promising Commercial Potential Jay Robins Audience Q&A All KOL Perspectives: DR Clinical Strategy Moderator: Peter K. Kaiser, M.D. Summary & Takeaways Pravin U. Dugel, M.D. Expansion into Diabetic Retinopathy Peter K. Kaiser, M.D.