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Preserving Sight for Life ® Corporate Presentation December 2024
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Forward-Looking Statements Statements contained in this document and any accompanying presentation regarding matters, events, statistics, or clinical or financial results that may occur in the future are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements regarding plans and milestones related to Adverum’s product candidates, clinical studies and trials (including the anticipated timing of initiation of a Phase 3 trial), and regulatory filings; Adverum’s cash sufficiency and runway; the therapeutic and commercial potential of Adverum’s product candidates; potential benefits of Ixo-vec as a one-time IVT injection for the treatment of wet AMD, including the potential best-in-class product profile, clinical activity and favorable safety profile of Ixo-vec; expectations regarding the size of the market for Ixo-vec; and other statements containing the words “anticipates,” “may,” “potential,” “will” and similar expressions, all of which are based on certain assumptions made by Adverum on current conditions, expected future developments and other factors Adverum believes are appropriate under the circumstances. Adverum may not consummate any of these plans or these product, clinical development, process development, manufacturing, or regulatory goals in a timely manner, or at all, or otherwise carry out the intentions or meet the expectations or projections disclosed in its forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, the risk that Adverum’s resources will not be sufficient for Adverum to conduct or continue planned development programs and planned clinical trials, the risk that preliminary or interim data from Adverum’s clinical trials may change as more patient data become available, the risk of a delay in the enrollment of patients in Adverum’s clinical studies or in the manufacturing of products to be used in such clinical studies, risks and uncertainties inherent in the product development and the regulatory approval process, the risk that Adverum will not be able to successfully develop, manufacture, or commercialize any of its product candidates and the risk that Adverum will be delayed in receiving or fail to receive required regulatory approvals. Additional risks and uncertainties facing Adverum are set forth under the caption “Risk Factors” and elsewhere in Adverum’s Securities and Exchange Commission (SEC) filings and reports, including Adverum’s most recent Annual Report on Form 10- K for the year ended December 31, 2023 filed with the SEC on March 18, 2024 and in our Quarterly Reports on Form 10-Q for the quarterly periods ended subsequent to our filing such Annual Report on Form 10-K, as well as any amendments thereto reflected in subsequent filings with the SEC. All forward-looking statements contained in this document speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. This document contains, and any accompanying presentation may contain, estimates, projections and other information concerning Adverum’s industry, business and the markets for certain drugs, including data regarding the estimated size of those markets, their projected growth rates and the incidence of certain medical conditions. Information that is based on estimates, forecasts, projections or similar methodologies is inherently subject to uncertainties and actual amounts may differ materially from amounts reflected in this information. Unless otherwise expressly stated, Adverum obtained this industry, business, market and other data from reports, research surveys, studies and similar data prepared by third parties, industry, medical and general publications, government data and similar sources believed to be reliable, but the accuracy or completeness of such information is not guaranteed by, and should not be construed as representations made by, Adverum. 2
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Ixo-vec ARTEMIS Phase 3 Study and Commercial Profile Ixo-vec has a derisked potential best-in-class product profile in broad population • >50% injection free and >80% treatment burden reduction in hard-to-treat patients • 10x safety margin Follow-up >4 years at doses 10x higher than 6E10 Phase 3 dose No 2E11 patients had inflammation at Year 1 and through Year 4 in OPTIC • No patients at 6E10 had inflammation at 52 weeks or any subsequent visit in LUNA Favorable safety profile with local prophylaxis • LUNA patient survey demonstrates strong patient preference for Ixo-vec ≥93% prefer Ixo-Vec over prior anti-VEGFs, would recommend it to family and friends No inflammation: no ≥ 1 AC/V cells; OPTIC 2E11 participant with inflammation at year 2.5 underwent a cataract surgery near the start of OPTIC EXT; EOP2: End of Phase 2 Meeting DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 3 6E10 With steroid eyedrops $153M Cash into H2’25 Broad Patient population; 284 patients US Study Incorporates FDA EOP2 feedback ARTEMIS Phase 3 Trial
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5+ Years of Clinical Experience Establish 10x Safety Margin 4 Ixo-vec 6E10 with extended prophylaxis de-risks Phase 3 & commercialization 6E11 N=15 2E11 N=15 2E11 N=30 6E10 N=30 Phase 3 Dose Enhanced Safety Steroid Eye Drop Prophylaxis Potential Best-in-Class Profile Dose (vg/eye) 10x Safety Margin 4+ Years Clinical Data DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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6E10 Dose Selected to Maximize Phase 3 and Commercial Success Demonstrated potential best-in-class product profile 6E11 (n = 15) 2E11 (n = 15) 2E11 (n = 29) 6E10 (n = 28) Benefit Safety Ph3 Go-Forward Dose Treatment Reduction ≤ 1 Injection Injection Free % With AC ≥1+ % Receiving Steroids for IOI 88% 75% 54% 0% 4% 92% 79% 69% 3% 7% 84% 73% 60% 0% 27% 97% 87% 87% 0% 60% Benefit comparison provided for outcomes measured over the initial 52 weeks of LUNA and OPTIC. Safety comparison provided for outcomes measured at 52 weeks for LUNA and OPTIC. Potential best-in-class clinical activity with enhanced safety profile of 6E10 for pivotal studies N=1 DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 5
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Ixo-vec & Wet AMD
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Khabou et. al. Biotechnology and Bioengineering, 113:12, December 2016 Ixo-vec Delivers Aflibercept via Single Intravitreal Injection 7 7m8 capsid enables delivery of stable aflibercept levels into the retina AAV.7m8: Created by Directed Evolution • Engineered for IVT administration; peptide loop enables 7m8 to cross the inner limiting membrane (ILM) • AAV.7m8 delivers aflibercept to the retina AAV.7m8 for IVT Gene Therapy • Validated in 3 clinical programs • Published in peer reviewed journals IVT injection Aflibercept secretion by retina Durable suppression of CNV CNV Ixo-vec Promoter Aflibercept PolyA Retina IVT injection ILM Ganglion Cells Inner Nuclear Membrane Photoreceptors RPEAAV.7m8 AAV.7m8 monomer Loop IV Loop IV 7m8 insert AAV.7m8 AAV.7m8 monomer Loop IV Loop IV 7m8 insert Loop IV Loop IV 7m8 insert AAV.7m8 AAV.7m8 monomer
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Ixo-Vec’s Target Product Profile May Enable True Paradigm Shift 8 4-year OPTIC & 52-week LUNA data underscore Ixo-vec’s reliable and predictable profile 88% of patients who were injection free through year 2 remained injection free through year 4 78% of patients who were injection free through year 1 remained injection free through year 4 100% of inflammation resolved by year 1 NO new onset of inflammation after week 30 Demonstrated Reliable Long-Term Benefit Demonstrated Predictable Safety Profile with Extended Local Prophylaxis No inflammation: no ≥ 1 AC/V cells; OPTIC results refer to 2E11 dose DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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Large and Growing Global Market Opportunity 9 Wet AMD physicians and patients embrace innovation Up to 42% of patients develop bilateral disease within 2-3 years of initial diagnosis ~200K US patients diagnosed annually 20M Worldwide Wet Age-Related Macular Degeneration A leading cause of vision loss among older adults 2015 2025E 2035E ~$6B ~$9B ~$13B Multi-Billion Dollar Market Opportunity Growth driven by aging population and product innovation Global Wet AMD Sales 1.5M US Patients Sources: Bright Focus Foundation. Age-Related Macular Degeneration: Facts & Figures.; Wong WL, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:106–16.; Gangnon RE et al. (2015) JAMA Ophthalmol; 133 (2): 125–132.; 2023 Cowen Equity Research – Therapeutic Categories Outlook.; Company estimates based on Cowen figure for 2025E, epidemiology and primary market research conducted by a third party on behalf of Adverum
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Undertreatment Often Results from Barriers to Treatment Hahn P, ed. ASRS 2023 Preferences and Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2023. 10 ASRS physician survey underscores need for more durable treatments 30% 47% 50% 79% 46% 58% 55% 74% Stable Anatomy Longer VEGF Suppression Improved Vision Greater Durability International US Physician Survey: Unmet Needs In Treating Wet AMD and DME Barriers to Treatment Ixo-vec: designed to address unmet need in wet AMD by delivering stable aflibercept Missed Injections Needle Anxiety Comorbidities Lack of TransportationLife Events More Durable Treatment Options Are Needed
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Real-World Vision Declines Due to Chronic Undertreatment 11 Up to ~40% STOP anti-VEGF over 2 years and up to 57% stop over 5 years IRIS Gilles, al CATT HORIZON SEVEN-UP (N>160,000) (N=1,212) (N=647) (N=600) (N=65) Sources: https://futureofvision.global/home/the-reality-of-retinal-disease.html. Adapted from Singer MA, et al. Ophthalmology. 2012;119(6):1175-1183. Adapted from Gillies MC, et al. Ophthalmology. 2015;122(9):1837-1845. Adapted from Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, et al. Ophthalmology. 2016;123(8):1751-1761. Adapted from Rofagha S, et al.; Ophthalmology. 2013;120(11):2292-2299. Wykoff CC, Garmo V, Tabano D, et al, Ophthalmol Sci. 2023;4(2):100421. -15 -10 -5 0 5 10 0 1 2 3 4 5 6 7 Mean Letter Change From Baseline Years
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Ixo-vec: Designed to Deliver Stable Aflibercept to Maintain Long-Term Vision After Vision Gains 12 Ixo-vec -15 -10 -5 0 5 10 0 1 2 3 4 5 6 7 Mean Letter Change From Baseline Years Up to ~40% STOP anti-VEGF over 2 years and up to 57% stop over 5 years IRIS Gilles, al CATT HORIZON SEVEN-UP (N>160,000) (N=1,212) (N=647) (N=600) (N=65) Sources: https://futureofvision.global/home/the-reality-of-retinal-disease.html. Adapted from Singer MA, et al. Ophthalmology. 2012;119(6):1175-1183. Adapted from Gillies MC, et al. Ophthalmology. 2015;122(9):1837-1845. Adapted from Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, et al. Ophthalmology. 2016;123(8):1751-1761. Adapted from Rofagha S, et al.; Ophthalmology. 2013;120(11):2292-2299. Wykoff CC, Garmo V, Tabano D, et al, Ophthalmol Sci. 2023;4(2):100421.
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Ixo-vec Positioned to Transform Treatment Paradigm In contrast, 2nd generation wet AMD treatments are only incremental advancements 4D-150 (Investigational ) Q4W Q8W Q8-Q16W Q8-Q16W Q26W Ixo-vec Q26W 2Y1YQ12W 5Y+ Potential 2024 US Revenue Paradigm Shift % Injection Free >50% 0% Ixo-vec designed to deliver stable and continuous aflibercept 5+ years [Discontinued and Relaunched] $1.6B $4.3B $4.6B $23M Potential 2024 US revenue is extrapolated from Q3 2024 public filings of each company’s reported financial results and is for all indications 2nd Generation 1st Generation 13
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4-Year OPTIC & 52-Week LUNA Results
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OPTIC First-in-Human Trial Design 15 6E11 & 2E11 with short prophylaxis in hard-to-treat population Study timelines not to scale. *Participants in Cohorts 1 and 2 received prophylaxis of 60 mg oral prednisone for 6 days starting at Day –3 followed by 7-day taper; participants in Cohorts 3 and 4 received prophylaxis of QID difluprednate eye drops for 3 weeks starting at Day 1 followed by a 3-week taper. QID, four times daily. OPTIC: NCT03748784; OPTIC EXT: NCT04645212. Primary Objective Secondary Objectives Long-term safety and efficacy of Ixo-vec IVT in treatment experienced patients • Vision maintenance (BCVA) • Anatomy (SD-OCT) • Need for supplemental therapy 2-Year OPTIC Study 3-Year Extension Study 2-Year Safety and Efficacy 5-Year Safety and EfficacyDay 1: Ixo-vec Corticosteroid Prophylaxis* Ixo-vec Dose Corticosteroid Prophylaxis Extension Scheduled Visits Supplemental Aflibercept (2 mg IVT) Criteria: Cohort 1 (n=6) 6E11 Oral, 13d Quarterly assessments following completion of 2- year OPTIC parent study • ≥10 letters BCVA (ETDRS) loss from baseline OR, • CST >75 μm increase from baseline OR, • New vision-threatening hemorrhage due to AMD • After initial supplemental injection subsequent injections administered at investigator discretion Cohort 2 (n=6) 2E11 Oral, 13d Cohort 3 (n=9) 2E11 Eye Drops, 6 wks Cohort 4 (n=9) 6E11 Eye Drops, 6 wks Day -15 to -7: Baseline IVT Aflibercept Screening Period Current Update: 4-Year DATA CUT-OFF: OPTIC 21AUG2024
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Baseline Characteristics Cohort 1 6E11 Cohort 2 2E11 Cohort 3 2E11 Cohort 4 6E11 Mean (range) Age, Years 79.0 (62–88) 79.8 (74–90) 77.4 (65–90) 79.9 (68–88) Mean (range) Years Since nAMD Diagnosis 4.5 (0.9–10.6) 4.1 (0.5–6.8) 3.3 (0.7–8.0) 3.3 (0.2–8.0) Mean (range) Number anti-VEGF Injections Since Initial Diagnosis* 38.2 (7–109) 34.0 (4–69) 24.8 (9–70) 28.5 (2–58) Mean (range) Annualized anti-VEGF Injections Prior to Ixo-vec 9.7 (8.4–11.2) 10.5 (8.5–11.7) 9.6 (7.9–12.8) 9.9 (6.3–13) Mean (range) BCVA, ETDRS Letters Approximate Snellen Equivalent 65.8 (57–77) 20/50 64.7 (53–72) 20/50 65.9 (53–75) 20/50 65.0 (54–77) 20/50 Mean (range) CST, µm 369.2 (293–561) 307.7 (235–339) 473.4 (301–857) 398.6 (255–538) Participant Status Follow-up (Years) 4–5 (median 4.5) 4 (median 4.0) 3–4 (median 3.7) 3 (median 3.0) *Not including the mandated aflibercept at Screening. BCVA, best corrected visual acuity: CST, central subfield thickness; ETDRS, Early Treatment Diabetic Retinopathy Study; neovascular age-related macular degeneration; VEGF, vascular endothelial growth factor 16 OPTIC evaluated hard-to-treat patients Demographics and Baseline Characteristics DATA CUT-OFF: LUNA 29AUG2024
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Mean CST (90% CI) by Dose Over Time 100 150 200 250 300 350 400 450 500 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 Mean CST μm (90% CI) Years Mean CST (μm) change from baseline to last visit (90% CI) 0 -117.7 (-225.0, -10.5) 2E11 0 4 OPTIC EXTOPTIC 30 40 50 60 70 80 90 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 Mean BCVA (90% CI) 0 0.5 1 1.5 2 2.5 3 3.5 4 Mean BCVA (90% CI) by Dose Over Time Mean BCVA (letters) change from baseline to last visit (90% CI) -2.9 (-12.3, 6.5) 2E11 * *Cataract surgery Ixo-vec Maintains BCVA & CST through 4 Years Demonstrated robust and durable activity 11 1213 12 13 12(N) 12 11 12 1115 13 14 13 12(N) 12 11 0 0.5 1 1.5 2 2.5 3 3.5 4 15 17 DATA CUT-OFF: OPTIC 21AUG2024
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Nearly 50% of Patients Remain Injection-Free through 4 Years Proportion of injection-free patients consistent in each year of follow-up *Supplemental aflibercept injections after the first one could be administered at physician’s discretion. All patients terminated due to loss to follow up, death or other reasons included for calculations across all periods [% Injection Free = (Total Cohort – Patients Rescued in Period) / (Total Cohort) * 100]. **Mean Annualized Injection Rate was calculated for the one-year period prior to Ixo-vec administration. All treatment burden reduction figures are calculated against this initial reference rate. Aflibercept Bevacizumab Ranibizumab Visit with no supplemental injection administered Unknown Years 2E11 (n = 15) Early Termination Injection Free By Year * OPTIC EXT -1 0 1 3 42 OPTIC 60% 53% 67% 73% 18 DATA CUT-OFF: OPTIC 21AUG2024
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Through Year 1 | 2 | 3 | 4 | | | Ixo-vec Reduced Treatment Burden Through 4 Years 2E11 shows >80% reduction in annualized anti-VEGF injections in every year Annualized rate (Prior) = (number of IVTs in 12 months prior to Ixo-vec) / (days from the first IVT in the past 12 months to Ixo-vec / 365.25). Annualized rate (Post) = (number of aflibercept IVTs since Ixo-vec) / (days from Ixo-vec to the last study follow-up / 365.25). Analysis includes all participants from the OPTIC study. 9.9 1.6 1.9 1.6 1.4 0 1 2 3 4 5 6 7 8 9 10 11 Mean Annualized Number of anti-VEGF Injections (per patient) 81% 84% 86%84% Mean Prior Annual Rate Mean Post Ixo-vec Annual Rate 2E11 Participants N=15 60% Injection Free 53% Injection Free 53% Injection Free 47% Injection Free 19 DATA CUT-OFF: OPTIC 21AUG2024
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0 5 10 15 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 Count of Participants Years OPTIC 2E11 Well Tolerated through 4 Years OPTIC 2E11 20 100% of patients who had inflammation resolved by year 1 2E11 was generally well tolerated through 4 years of follow up Inflammation was dose dependent, did not impact vision and, when present, was responsive to local corticosteroids 100% inflammation resolved by year 1 2E11 *2E11 participant with inflammation at year 2.5 underwent a cataract surgery near the start of OPTIC EXT. At the next scheduled visit (3 months later—2.5 year visit), inflammation was detected that was responsive to topical corticosteroids. Cell grades as assessed by slit lamp, Grade categories are based on the Standardization of Uveitis Nomenclature (SUN) criteria for aqueous cells and National Institutes of Health guidelines for vitreous cells.; no inflammation: no ≥ 1 AC/VC cells DATA CUT-OFF: OPTIC 21AUG2024 OPTIC EXTOPTIC *0 0.5 1 1.5 2 2.5 3 3.5 4 * VC Cells ≥1+ AC Cells ≥1+ Short prophylactic regimen was 13 days oral prednisone or 6 weeks of topical drops
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Central Retinal Thickness Fluctuations Have Been Associated with Poorer Visual Outcomes during Bolus anti-VEGF Therapy 1Evans, et al. JAMA Ophthalmol. 2020;138(10):1043-1051. 2Chen, et al. Ophthalmol Retina. 2020;4:1158-1169. 3Ciucci, et al. EUR J Ophthalmol 2021 Aug 14;11206721211037820.2021.4Chakravarthy, et al. Eye (2021) 35:2983–2990. 21
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100 200 300 400 500 600 -55 -43 -31 -19 -7 5 17 29 41 53 65 77 89 101 113 125 137 149 161 173 Years CST (µm) -1 Anti-VEGF injection Study visit, no supplemental injection Day 0 Ixo-vec administration -2 wks (baseline) BCVA: 53 letters CST: 358 µm -56 weeks 40 50 60 70 80 90BCVA (ETDRS) 0 2 1 Years Baseline 3 0 2 1 3 Case Study: Ixo-vec 2E11 Reduces Fluctuations in Fluid and Central Subfield Thickness (CST) Aflibercept Q5W prior to Ixo-vec 90-Year-Old Female with 9 IVTs in the 12 Months Prior to Ixo-vec DATA CUT-OFF: OPTIC 23AUG2023, EXCEPT 4Y INJECTION-FREE RATE AS OF 21AUG2024 22
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100 200 300 400 500 600 -55 -43 -31 -19 -7 5 17 29 41 53 65 77 89 101 113 125 137 149 161 173 1 Year BCVA ∆: +16 letters CST ∆: -132 µm 2 Years BCVA ∆: +5 letters CST ∆: -93 µm Years CST (µm) -1 Anti-VEGF injection Study visit, no supplemental injection 9 Months BCVA ∆: +18 letters CST ∆: -127 µm Day 0 Ixo-vec administration -2 wks (baseline) BCVA: 53 letters CST: 358 µm -56 weeks 40 50 60 70 80 90BCVA (ETDRS) 0 2 1 Years Ixo-vec Ixo-vec Baseline 3 0 2 1 3 2.2 Years BCVA ∆: +13 letters CST ∆: -135 µm Case Study: Ixo-vec 2E11 Reduces Fluctuations in Fluid and Central Subfield Thickness (CST) Aflibercept Q5W prior to Ixo-vec 100% anti-VEGF injection free following Ixo-vec 90-Year-Old Female with 9 IVTs in the 12 Months Prior to Ixo-vec Supplemental injection free through 4 years DATA CUT-OFF: OPTIC 23AUG2023, EXCEPT 4Y INJECTION-FREE RATE AS OF 21AUG2024 23
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100 200 300 400 500 600 700 -55 -43 -31 -19 -7 5 17 29 41 53 65 77 89 101 113 125 137 149 161 173 Years CST (µm) -1 Anti-VEGF injection Study visit, no supplemental injection Case Study: Control of Macular Fluid and Stabilized CST 3 Years After Ixo-vec 2E11 Day 0 Ixo-vec administration -2 wks (baseline) BCVA: 75 letters CST: 664 µm -30 weeks Persistent fluid despite frequent anti- VEGF injections 40 50 60 70 80 90BCVA (ETDRS) 0 2 1 Years Aflibercept Q5W prior to Ixo-vec Ixo-vec Baseline 3 0 2 1 3 Historical BCVA data was not collected. 81-Year-Old Male with 9 IVTs in the 12 Months Prior to Ixo-vec DATA CUT-OFF: OPTIC 23AUG2023, EXCEPT 4Y INJECTION-FREE RATE AS OF 21AUG2024 24
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100 200 300 400 500 600 700 -55 -43 -31 -19 -7 5 17 29 41 53 65 77 89 101 113 125 137 149 161 173 1 Year BCVA ∆: +8 letters CST ∆: -383 µm 2 Years BCVA ∆: +9 letters CST ∆: -394 µm Years CST (µm) -1 Anti-VEGF injection Study visit, no supplemental injection Case Study: Control of Macular Fluid and Stabilized CST 3 Years After Ixo-vec 2E11 0.5 Years BCVA ∆: +8 letters CST ∆: -392 µm Day 0 Ixo-vec administration -2 wks (baseline) BCVA: 75 letters CST: 664 µm -30 weeks Persistent fluid despite frequent anti- VEGF injections 40 50 60 70 80 90BCVA (ETDRS) 0 2 1 Years Aflibercept Q5W prior to Ixo-vec Ixo-vec Ixo-vec Baseline 100% anti-VEGF injection free following Ixo-vec 3 0 2 1 3 3 Years BCVA ∆: +5 letters CST ∆: -403 µm 81-Year-Old Male with 9 IVTs in the 12 Months Prior to Ixo-vec Supplemental injection free through 4 years DATA CUT-OFF: OPTIC 23AUG2023, EXCEPT 4Y INJECTION-FREE RATE AS OF 21AUG2024Historical BCVA data was not collected. 25
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100 200 300 400 500 600 700 -55 -43 -31 -19 -7 5 17 29 41 53 65 77 89 101 113 125 137 149 161 173 1 Year BCVA ∆: +8 letters CST ∆: -383 µm 2 Years BCVA ∆: +9 letters CST ∆: -394 µm Years CST (µm) -1 Anti-VEGF injection Study visit, no supplemental injection Case Study: Control of Macular Fluid and Stabilized CST 3 Years After Ixo-vec 2E11 0.5 Years BCVA ∆: +8 letters CST ∆: -392 µm Day 0 Ixo-vec administration -2 wks (baseline) BCVA: 75 letters CST: 664 µm -30 weeks Persistent fluid despite frequent anti- VEGF injections 40 50 60 70 80 90BCVA (ETDRS) 0 2 1 Years Aflibercept Q5W prior to Ixo-vec Ixo-vec Ixo-vec Baseline 100% anti-VEGF injection free following Ixo-vec 3 0 2 1 3 3 Years BCVA ∆: +5 letters CST ∆: -403 µm 81-Year-Old Male with 9 IVTs in the 12 Months Prior to Ixo-vec Supplemental injection free through 4 years Illustrative fluid fluctuations DATA CUT-OFF: OPTIC 23AUG2023, EXCEPT 4Y INJECTION-FREE RATE AS OF 21AUG2024Historical BCVA data was not collected. 26
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Learnings from OPTIC Informed LUNA Phase 2 Trial 27 LUNA goal: optimize Ixo-vec benefit / risk going into pivotal trials Objective I Objective II Optimize Phase 3 Prophylaxis Determine the Optimal Dose for Phase 3
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Corticosteroid Prophylaxis Regimen Supplemental Injection Criteria • Difluprednate 22 wks ± prednisone oral 10 wks • Ozurdex IVT + difluprednate after week 4 ± prednisone oral 10 wks* • Randomized 2:1 local versus local + oral • Increase in CST > 75 μm from BL confirmed by the CRC OR • Loss of ≥ 10 letters in BCVA from BL due to new/worsening IRF or SRF OR • New vision-threatening hemorrhage due to nAMD LUNA Phase 2 Trial Design 28 6E10 & 2E11 with extended prophylaxis in hard-to-treat patients Key inclusion criteria: demonstrated response to anti-VEGF therapy and under active treatment for CNV secondary to nAMD (received a minimum of 2 injections within 4 months of entry), study eye BCVA in the range of 25 – 83 ETDRS letters Study timeline and length of arrows depicted are not to scale. Baseline is defined as the day screening aflibercept is administered. *Protocol amended early in study to include difluprednate starting at week 4 to match the taper in difluprednate regimens; if initiated after week 4 visit, difluprednate may be adjusted at the discretion of investigator in consult with medical monitors (6 participants did not receive difluprednate as part of prophylaxis). Long-term extension ends at year five Screening Period 2E11 (n=30) 6E10 (n=30) Corticosteroid prophylaxis (21+ weeks post-dose) WEEK 52: Primary Endpoints WEEK 26: Interim Analysis DAY 1: IVT Ixo-vec DAY -7: Randomization Day -21 to -14: Baseline IVT Aflibercept 2mg FIVE YEAR: EXT Completion Multicenter, double-masked, randomized, parallel-group Phase 2 study DATA CUT-OFF: LUNA 29AUG2024
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Demographics and Baseline Characteristics OPTIC & LUNA evaluated hard-to-treat patients Demographics and Baseline Characteristics LUNA 6E10 N = 30 LUNA 2E11 N = 30 LUNA Total N = 60 OPTIC Total N = 30 Mean age, years (SD) 75.4 (8.2) 77.7 (7.4) 76.6 (7.8) 79.0 (7.3) Female, n (%) 16 (53%) 18 (60%) 34 (57%) 15 (50%) Race, n (%) White Asian 27 (90%) 2 (7%) 28 (93%) 2 (7%) 55 (92%) 4 (7%) 30 (100%) 0 Mean years since nAMD diagnosis in the study eye (SD) 3.0 (2.9) 3.0 (3.1) 3.0 (2.9) 3.7 (2.8) Mean annualized anti-VEGF injections in year prior to Day 1 (SD) 10.2 (1.7) 10.0 (3.3) 10.1 (2.6) 9.9 (1.9) Mean BCVA, ETDRS letters (SD) 72.9 (8.8) 71.8 (6.4) 72.3 (7.7) 65.4 (7.2) Mean CST, µm(SD) 360.6 (112.0) 340.5 (119.3) 350.6 (115.2) 397.0 (137.3) Phakic lens status, n (%) 11 (37%) 11 (37%) 22 (37%) 10 (33.3%) DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 29
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52-Week LUNA and OPTIC Injection Burden Reduction are Consistent >80% reduction in annualized anti-VEGF injections, >50% injection free Annualized rate (Prior) = (number of IVTs in 12 months prior to Ixo-vec) / (days from the first IVT in the past 12 months to Ixo-vec / 365.25). Annualized rate (Post) = (numbers of aflibercept IVTs since Ixo-vec) / (days from Ixo-vec to last follow-up within the interim analysis period / 365.25). Mean Annualized Number of anti-VEGF Injections (per patient) 10.2 10.1 9.9 1.3 0.8 1.6 0 1 2 3 4 5 6 7 8 9 10 11 6E10 Participants Through Week 52 N=30 2E11 Participants Through Week 52 N=30 2E11 N=29 6E10 N=28 54% Injection Free 75% ≤ 1 Injection 69% Injection Free 79% ≤ 1 Injection -88% -92% 2E11 N=15 60% Injection Free 73% ≤ 1 Injection -84% Mean Prior Annualized Rate Mean Post Ixo-vec Annualized Rate: LUNA OPTIC 30 DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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Potential Best-in-Class Injection-Free Rates 52-week LUNA data demonstrate >50% injection free in hard-to-treat patients Study Week Week 91Week 52Week 26 All Participants (N=60) Week -26Week -52 LUNA 52 Weeks Overall (N = 57) 6E10 (n = 28) 2E11 (n = 29) Injection Free 61% 54% 69% ≤1 Injection 77% 75% 79% ≤2 Injections 89% 89% 90% Supplemental injection administered out of protocol Other Aflibercept Bevacizumab RanibizumabNo supplemental injection given Faricimab Early Termination Doses pooled in swim lane plot to preserve investigator masking in an ongoing double masked study. Early termination patients not included in injection calculations. [% Injection Free = (Total Cohort - Early Termination Patients – Rescued Patients) / (Total Cohort – Early Termination Patients) * 100] DATA CUT-OFF: LUNA 29AUG2024 31
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75% Injection Free in 6E10 Patients with Less Treatment Burden Treatment-experienced patients with ≤6 injections in year prior Ixo-vec Experienced Participants w/ ≤ 6 Prior Injections (N=13) Study Week Week 91Week 52Week 26Week -26Week -52 Overall (N = 13) 6E10 (n = 4) 2E11 (n = 9) Injection Free 69% 75% 67% ≤1 Injection 92% 100% 89% ≤2 Injections 92% 100% 89% Supplemental injection administered out of protocol Other Aflibercept Bevacizumab RanibizumabNo supplemental injection given Faricimab Early Termination Doses pooled in swim lane plot to preserve investigator masking in an ongoing double masked study. Early termination patients not included in injection calculations. [% Injection Free = (Total Cohort - Early Termination Patients – Rescued Patients) / (Total Cohort – Early Termination Patients) * 100]. Experienced patients: diagnosed at least one year prior to administration of Ixo-vec. MEAN INJECTION RATE: 4.7 Only one patient required supplemental injection through their Week 52 visit. 32 DATA CUT-OFF: LUNA 29AUG2024 LUNA 52 Weeks
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Ixo-vec Maintains BCVA & CST Both doses demonstrate robust and durable activity, consistent with OPTIC 33 Least Squares Means are based on Mixed Model Repeated Measures (MMRM) including dose group, baseline value, visit and visit dose group. *Excludes 1 participant at each dose with letter loss due to cataract Least Squares Means Change in Best Corrected Visual Acuity (BCVA) Over Time by Dose* LS Means BCVA Change from Baseline at Week 52, Letters (95% CI) -2.1 (-4.8, 0.7) 6E10 -1.8 (-4.6, 0.9) 2E11 -15 -10 -5 0 5 10 15 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 LS Means Change BCVA (95% CI) Week 6E10 (n=29) 2E11 (n=29) // BL -150 -100 -50 0 50 100 150 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 LS Means Change CST μm (95% CI) Week 6E10 (n=30) 2E11 (n=30) Least Squares Means Change in Central Subfield Thickness (CST) Over Time by Dose LS Means CST Change from Baseline at Week 52, μm (95% CI) -10.2 (-29.0, 8.5) 6E10 -21.9 (-40.4, -3.3) 2E11 BL // DATA CUT-OFF: LUNA 29AUG2024
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Consistent Anatomic Benefit in Broad Population 34 Fluid reduction in patients with baseline CST >300 μm; maintenance in ≤300 μm -150 -100 -50 0 50 100 150 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 Mean CST Change from Baseline, μm (95% CI) Week Mean CST Change from Baseline at Week 52, μm (95% CI) 2.9 (-14.3, 20.2) BL ≤300 μm, All -34.4 (-64.9, -3.9) BL >300 μm, All BL // DATA CUT-OFF: LUNA 29AUG2024 Baseline Characteristic for Subgroup CST ≤300 μm All Participants CST >300 μm All Participants Mean CST, μm (SD) 269.9 (18.7) 416.6 (119.1)
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Consistent Anatomic Benefit in Broad Population 35 Anatomic stability with reduction and maintenance of CST in injection-free patients -150 -100 -50 0 50 100 150 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 Mean CST Change from Baseline, μm (95% CI) Week Mean CST Change from Baseline at Week 52, μm (95% CI) 2.9 (-14.3, 20.2) BL ≤300 μm, All -34.4 (-64.9, -3.9) BL >300 μm, All BL // -7.6 (-20.7, 5.5) BL ≤300 μm, Inj-Free -38.0 (-67.0, -9.0) BL >300 μm, Inj-Free All Participants Injection Free DATA CUT-OFF: LUNA 29AUG2024 Baseline Characteristic for Subgroup CST ≤300 μm All Participants CST >300 μm All Participants CST ≤300 μm Injection Free CST >300 μm Injection Free Mean CST, μm (SD) 269.9 (18.7) 416.6 (119.1) 273.8 (16.7) 417.6 (142.0)
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36 Least Squares Means are based on Mixed Model Repeated Measures (MMRM) including dose group, baseline value, visit and visit dose group *Excludes 1 participant at each dose with letter loss due to cataract, ** Excludes 1 participant with letter loss due to cataract Least Squares Means Change in Best Corrected Visual Acuity (BCVA) Over Time by Dose* LS Means BCVA Change from Baseline at Week 52, Letters (95% CI) -2.1 (-4.8, 0.7) 6E10 -1.8 (-4.6, 0.9) 2E11 -15 -10 -5 0 5 10 15 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 LS Means Change BCVA (95% CI) Week 6E10 (n=29) 2E11 (n=29) // BL -15 -10 -5 0 5 10 15 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 LS Means Change BCVA (95% CI) Week 6E10 (n=15) 2E11 (n=20) Least Squares Means Change in Best Corrected Visual Acuity (BCVA) Over Time by Dose in Supplemental Injection Free Participants** LS Means BCVA Change from Baseline at Week 52, Letters (95% CI) +1.1 (-2.7, 4.9) 6E10 -2.2 (-5.5, 1.2) 2E11 BL // Ixo-vec Maintained Visual Outcomes BCVA maintenance demonstrated in overall population and injection-free patients DATA CUT-OFF: LUNA 29AUG2024
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Ixo-vec Demonstrates Durable Therapeutic Levels After One Injection Sustained aqueous aflibercept levels up to 5 years 1 10 100 1,000 10,000 100,000Aflibercept in Aqueous Humor (ng/mL) Early aflibercept levels are associated with sustained long-term protein expression LUNA 2E11 (n=18) LUNA 6E10 (n=13) LUNA Week 14 aflibercept levels plotted for 31 of 60 individual participants. LUNA revised to stop collection of AH samples. Measurements below the level of quantification of the assay (25ng/ml) are not shown. NHP data: Kiss, Szilárd et al, Molecular Therapy Methods & Clinical Development, Volume 18, 345 - 353 DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 OPTIC 6E11 (n=7) OPTIC 2E11 (n=10) 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years NHP studies suggest aflibercept levels are ~ 7x higher in the back of the eye 37
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1 10 100 1,000 10,000 100,000Aflibercept in Aqueous Humor (ng/mL) Ixo-vec Demonstrates Durable Therapeutic Levels After One Injection Sustained therapeutic aflibercept levels with 6E10 DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 LUNA Week 14 aflibercept levels plotted for 31 of 60 individual participants. LUNA revised to stop collection of AH samples. Measurements below the level of quantification of the assay (25ng/ml) are not shown. NHP data: Kiss, Szilárd et al, Molecular Therapy Methods & Clinical Development, Volume 18, 345 - 353 38 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Years LUNA 2E11 (n=18) LUNA 6E10 (n=13) OPTIC 6E11 (n=7) OPTIC 2E11 (n=10) Early aflibercept levels are associated with sustained long-term protein expression NHP studies suggest aflibercept levels are ~ 7x higher in the back of the eye
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Safety Summary: LUNA 52-Week 1Anterior chamber cell, anterior chamber pigmentation, iris transillumination defect, iritis. 2No inflammation: no ≥ 1 AC/VC cells. 3Topical difluprednate with or without IVT dexamethasone (N=34). 4Topical difluprednate alone (N=10). Ixo-vec continues to be well tolerated, with potential best-in-class product profile Ixo-vec had a favorable safety profile and was well tolerated in total LUNA population • No Ixo-vec-related serious adverse events. All Ixo-vec-related adverse events (AEs) were either mild or moderate • No episcleritis, vasculitis, retinitis, choroiditis, vascular occlusion, or hypotony • Most common Ixo-vec-related AEs were dose-dependent anterior inflammation responsive to local corticosteroid and anterior pigmentary changes with no impact on vision1 • No 6E10 patients had inflammation at week 52 or at any subsequent visit2 Local corticosteroids alone effectively minimized inflammation at both doses3 • No patients had inflammation at week 52 or at any subsequent visit 6E10 + topical steroid eyedrops selected for pivotal program • No patients had inflammation at week 52 or at any subsequent visit4 • Only a single patient had inflammation at any timepoint, which resolved prior to week 52 DATA CUT-OFF: LUNA 29AUG2024 39
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0 0 0 0 0 tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p 0 0 0 1+ tr p 0 p p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p p p p p 0 0 0 0 0 0 0 0 tr 0 0 0 0 0 0 2+ 0 1+ 0 2+ 0 tr 0 0 0 0 2+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p p 0 p 0 0 p p p p 0 0 0 0 0 0 0 0 p p p 0 p 0 p p p p p 0 p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr tr tr tr tr tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1+ 0 0 0 p p p p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr tr tr tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr tr tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p p p p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1+ 1+ tr 0 tr tr 1+ 1+ tr tr tr tr tr tr 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr 1+ 0 0 1+ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p p p 0 0 0 p p p p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p 0 p 0 0 p 0 p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 p p p p p p p p p p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Extended Local Prophylaxis Effective in Minimizing Inflammation Patients receiving prophylaxis with difluprednate with or without dexamethasone ANTERIOR CHAMBER CELLS VITREOUS CELLS IVT DEX + DFBA (N=7) DFBA (N=10) 2E11 IVT DEX + DFBA (N=7) DFBA (N=10) 6E10 IVT DEX + DFBA (N=7) DFBA (N=10) 6E10 IVT DEX + DFBA (N=7) DFBA (N=10) 2E11 Prophylactic Steroid Usage** Initial IVT DEX Injection DFBA Prophylaxis Period (DFBA Only) IVT DEX + DFBA * * * SCRN RAND D1 D3 D8 W2 W4 W6 W8 W10 W14 W18 W22 W26 W30 W34 W38 W42 W48 W52 W65 W78 * * * * * * et et 40 None 1+ 2+ 3+ 4+ Prophylactic Steroid Usage** Initial IVT DEX Injection DFBA Prophylaxis Period (DFBA Only) IVT DEX + DFBA SCRN RAND D1 D3 D8 W2 W4 W6 W8 W10 W14 W18 W22 W26 W30 W34 W38 W42 W48 W52 W65 W78 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 tr 0 0 0 0 0 0 0 0 p p p 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 No inflammation: no ≥ 1 AC/V cells. IVT DEX = Ozurdex, DFBA = dilfuprednate, tr = Trace, p = Pigmented Cells, * = Mixed Pigmented / Non-Pigmented Cells, et – Early Termination. **IVT DEX + DFBA: protocol amended early in study to include difluprednate starting at week 4 to match the taper in the difluprednate only regimen; if initiated after week 4 visit, difluprednate may be adjusted at the discretion of investigator in consult with medical monitors. Due to this, difluprednate prophylaxis with IVT DEX + DFBA may have lasted up to week 34. No patients had inflammation at week 52 or at any subsequent visit None 1+ 2+ 3+ 4+ DATA CUT-OFF: LUNA 29AUG2024
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Both LUNA Steroid Regimens Result in Enhanced Safety Profile Topical eyedrops effective at minimizing inflammation & long-term steroid need 0% 25% 50% 75% 100% 0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354 Proportion of Participants Receiving Steroids within Scheduled Prophylaxis or for Inflammation Treatment 6E10 Weeks DFBA (n=10) IVT DEX + DFBA (n = 7) Treatment of inflammation defined as non-pigmented or mixed pigmented AC/V, including trace cells, or iritis, or vitritis. IVT DEX = Ozurdex, DFBA = dilfuprednate, Ozurdex injections are represented as 8 weeks of treatment. Initial IVT DEX Injection DFBA Only IVT DEX + DFBA 3 participants were treated with steroids for inflammation at any point through week 52 0% 25% 50% 75% 100% 0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354 1 participant treated at week 52 with trace AC cells 2 participants were treated with steroids for inflammation at any point through week 52 DFBA (n=10) IVT DEX + DFBA (n = 7) Prophylactic Regimens: Weeks 2E11 No additional participants began receiving steroids for inflammation beyond 52 weeks 1 participant treated at week 52 with trace VC cells 41 DATA CUT-OFF: LUNA 29AUG2024
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Extended Prophylaxis in LUNA Improves Upon OPTIC Experience Phase 3 regimen enhances overall safety profile & reduces long-term steroid need 0% 25% 50% 75% 100% 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 Weeks Proportion of Participants Receiving Steroids within Scheduled Prophylaxis or for Treatment of Inflammation LUNA: DFBA Only 6E10 (n = 10) 2E11 (n = 10) 2E11 (n = 9) 6E11 (n = 9) OPTIC: DFBA Only Treatment of inflammation defined as non-pigmented or mixed pigmented AC/V cells, iritis, or vitritis. DFBA = difluprednate. DFBA Prophylaxis Period LUNA OPTIC 42 DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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Pre-specified Patient Preference Survey 43 Designed to understand patient needs & commercial potential Adverum’s pre-specified patient preference survey asked whether patients: 1. Found prophylaxis was easy to manage 2. Would want Ixo-vec in their other eye if they had bilateral wet AMD 3. Prefer Ixo-vec over their prior treatment with IVT injections 4. Would recommend Ixo-vec to family or friends Source: Montori VM, et Al. Decision making and the patient. Manual for Evidence-Based Clinical Practice 2008. “Patient preference refers to a patient’s perspective, expectations, and goals for health, as well as the processes involved in evaluating the potential benefits, harms, and costs of each treatment option offered to the patient…”
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Topical Steroid Eyedrops were Easy or Very Easy to Manage 44 Was the steroid treatment you received easy to manage? Easy or Very Easy to Manage Undecided Difficult or Very Difficult to Manage 95% 5% Ozurdex + Difluprednate (n=16) Difluprednate Only (n=20) 88% 13% 60% 35% 5% Oral Prednisone + Difluprednate +/- Ozurdex (n=20) 52-week results from LUNA pre-specified Patient Preference Survey DATA CUT-OFF: LUNA 29AUG2024
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45 93% 7% Would you prefer Ixo-vec over the prior treatment(s)? Total Study (n=56) Yes No 52-week results from LUNA pre-specified Patient Preference Survey >90% of Patients Preferred Ixo-vec over Today’s Standard of Care DATA CUT-OFF: LUNA 29AUG2024
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95% 5% 46 93% 7% Would you prefer Ixo-vec over the prior treatment(s)? Would you want Ixo-vec in your other eye if you bilateral AMD? Total Study (n=56) Total Study (n=56) Yes No 52-week results from LUNA pre-specified Patient Preference Survey >90% of Patients Preferred Ixo-vec over Today’s Standard of Care DATA CUT-OFF: LUNA 29AUG2024
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95% 5% >90% of Patients Preferred Ixo-vec over Today’s Standard of Care 47 93% 7% Would you prefer Ixo-vec over the prior treatment(s)? Would you want Ixo-vec in your other eye if you bilateral AMD? Total Study (n=56) Total Study (n=56) Yes No 96% 4% Total Study (n=56) Would you recommend Ixo-vec to your family or friends? DATA CUT-OFF: LUNA 29AUG2024 52-week results from LUNA pre-specified Patient Preference Survey
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93% 95% 100% of 6E10 + Steroid-Eyedrops-Only Patients Preferred Ixo-Vec to Prior Treatments 48 Yes No 100%100% 100% 6E10 + Difluprednate (n=10) 6E10 + Difluprednate (n=10) 6E10 + Difluprednate (n=10) DATA CUT-OFF: LUNA 29AUG202452-week results from LUNA pre-specified Patient Preference Survey Would you prefer Ixo-vec over the prior treatment(s)? Would you want Ixo-vec in your other eye if you bilateral AMD? Would you recommend Ixo-vec to your family or friends?
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5+ Years of Clinical Experience Establish 10x Safety Margin 49 Ixo-vec 6E10 with extended prophylaxis de-risks Phase 3 & commercialization 6E11 N=15 2E11 N=15 2E11 N=30 6E10 N=30 Phase 3 Dose Enhanced Safety Steroid Eye Drop Prophylaxis Potential Best-in-Class Profile Dose (vg/eye) 10x Safety Margin 4+ Years Clinical Data DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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6E10 Dose Selected to Maximize Phase 3 and Commercial Success Demonstrated potential best-in-class product profile 6E11 (n = 15) 2E11 (n = 15) 2E11 (n = 29) 6E10 (n = 28) Benefit Safety Ph3 Go-Forward Dose Treatment Reduction ≤ 1 Injection Injection Free % With AC ≥1+ % Receiving Steroids for IOI 88% 75% 54% 0% 4% 92% 79% 69% 3% 7% 84% 73% 60% 0% 27% 97% 87% 87% 0% 60% Benefit comparison provided for outcomes measured over the initial 52 weeks of LUNA and OPTIC. Safety comparison provided for outcomes measured at 52 weeks for LUNA and OPTIC. Potential best-in-class clinical activity with enhanced safety profile of 6E10 for pivotal studies N=1 DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 50
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Ixo-Vec’s Target Product Profile May Enable True Paradigm Shift 51 4-year OPTIC & 52-week LUNA data underscore Ixo-vec’s reliable and predictable profile 88% of patients who were injection free through year 2 remained injection free through year 4 78% of patients who were injection free through year 1 remained injection free through year 4 100% of inflammation resolved by year 1 NO new onset of inflammation after week 30 Demonstrated Reliable Long-Term Benefit Demonstrated Predictable Safety Profile with Extended Local Prophylaxis No inflammation: no ≥ 1 AC/V cells; OPTIC results refer to 2E11 dose DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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Ixo-vec Pivotal Program
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Ixo-vec Pivotal Program for Wet AMD in Broad Patient Population Designed to maximize probability of clinical, regulatory, and commercial success Ixo-vec Global Pivotal Program Two double-masked randomized Phase 3 trials Noninferiority design vs. on-label aflibercept ARTEMIS U.S. study based on EOP2 feedback 2nd study to be conducted globally 5+ Years of Clinical Experience 10X Safety Margin Advised by Global KOLs Addressing Unmet Needs + Patient Preference Regulatory Agreement Broad Wet AMD Population Ixo-vec Phase 3 53
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ARTEMIS Phase 3 Wet AMD Study Design 54 Noninferiority trial designed to enable regulatory approval, drive commercial success Primary Endpoint Mean change in BCVA from Baseline to average of Weeks 52 and 56 To demonstrate that a single intravitreal injection of Ixo-vec 6E10 achieves comparable visual outcomes to on-label aflibercept, while significantly reducing the treatment burden Randomized, Double Masked, On-Label Aflibercept-Controlled Phase 3 Trial in Broad Population Trial Design Objective • Two-arm noninferiority trial in US • Ixo-vec 6E10 • Aflibercept control 2mg Q8W • 284 treatment-naïve and previously treated patients with wet AMD • Sham injections for masking • One-year primary endpoint with - 4.5 letter noninferiority margin Endpoints Secondary Endpoint Treatment burden reduction
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ARTEMIS Phase 3 Wet AMD Study Design Patients randomized after 3 aflibercept loading doses, assessed every 4 weeks for disease activity Ixo-vec 6E10 n = 142 Aflibercept 2mg (Q8w) n = 142 Supplemental aflibercept criteria are consistent with LUNA and apply to both arms Week Difluprednate prophylaxis -8 -4 D1 1 4 8 12 16 20 24 28 32 36 40 44 48 52 56 LTFU Baseline Response Randomize Primary Endpoint Treatment-naïve and previously treated wet AMD BCVA: 35 – 78 letters Anti-VEGF responsive: After two aflibercept loading doses Key Inclusion Criteria Aflibercept IVT Ixo-vec IVT Supplemental injection if criteria met Sham Sham or supplemental injection if criteria met Designed to Maximize Probability of Clinical, Regulatory, and Commercial Success LTFU: Long-term follow-up 55
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Ixo-vec is the Only Investigational Gene Therapy in Wet AMD Granted Enhanced Regulatory Designations in the US, EU and UK Provides eligibility for intensive FDA guidance on efficient drug development and Rolling Review and potential eligibility for Priority Review 56 United States (FDA): RMAT and Fast Track Offers enhanced interactions and additional opportunities for scientific advice as well as eligibility for accelerated assessment. European Union (EMA): PRIME Grants enhanced regulatory and market access interactions and a potentially faster path to approval in the U.K. United Kingdom (MHRA): ILAP RMAT, Regenerative Medicines Advanced Therapy; PRIME, Priority Medicines; ILAP, Innovation Passport under the Innovative Licensing and Access Pathway.
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Conclusion & Takeaways
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Highest Injection-Free Rates in Hard-to-Treat Patients from 6 Months to > 4 Years 58 Among IVT and suprachoroidal gene therapy for wet AMD; excludes ABBV-RGX-314 subretinal. ABBV-RGX-314 SCS in AAVIATE (NB: 21 of 56 subjects at 1E12 dose received booster shot at wk 4, not included in post RGX-314 mean annualized injections). RGX-314 data as of 3Feb2024. Latest available 4D-150 PRISM Phase 2a Dose Expansion Cohort data as of 18Sep2024 (Phase 1/2a for 1E10 dose as Phase 2a wasn’t reported separately; calculated from swim lane plot). Data are based on a cross-trial comparison and are not based on head-to-head clinical trials. Cross-trial comparisons are inherently limited and may suggest misleading similarities or differences in outcomes. Results of head-to-head comparisons may differ significantly from those set forth herein. 29% 37% 50% 50% 63% 73% 76% 83% 25% 37% 54% 60% 69% 53% 53% 47% Month 6 Year: 3 421 % Injection-Free 4D-150 (1E10) 4D-150 (3E10) RGX-314 SCS (1E12) RGX-314 SCS (5E11) RGX-314 SCS (2.5E11) LUNA (2E11) LUNA (6E10) OPTIC (2E11) 45% DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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Ixo-Vec’s Target Product Profile May Enable True Paradigm Shift 59 4-year OPTIC & 52-week LUNA data underscore Ixo-vec’s reliable and predictable profile 88% of patients who were injection free through year 2 remained injection free through year 4 78% of patients who were injection free through year 1 remained injection free through year 4 100% of inflammation resolved by year 1 NO new onset of inflammation after week 30 Demonstrated Reliable Long-Term Benefit Demonstrated Predictable Safety Profile with Extended Local Prophylaxis No inflammation: no ≥ 1 AC/V cells; OPTIC results refer to 2E11 dose DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024
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Adoption over time 60 Market Leadership in Wet AMD May Require Best-in-Class Profile that First Demonstrates Success in Hard-to-Treat Patients >9 Injections 7-9 Injections 4-6 Injections 1-3 Injections Adapted from Wykoff CC, Garmo V, Tabano D, et al. Ophthalmol Sci. 2023;4(2):100421. Annual Injection Burden (IRIS Registry, Weighted Average) Proportion of Patients Early Adopters Hard-to-Treat Patients Subsequent Expansion Less Severe Patients
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Ixo-vec ARTEMIS Phase 3 Study and Commercial Profile Ixo-vec has a derisked potential best-in-class product profile in broad population • >50% injection free and >80% treatment burden reduction in hard-to-treat patients • 10x safety margin Follow-up >4 years at doses 10x higher than 6E10 Phase 3 dose No 2E11 patients had inflammation at Year 1 and through Year 4 in OPTIC • No patients at 6E10 had inflammation at 52 weeks or any subsequent visit in LUNA Favorable safety profile with local prophylaxis • LUNA patient survey demonstrates strong patient preference for Ixo-vec ≥93% prefer Ixo-Vec over prior anti-VEGFs, would recommend it to family and friends No inflammation: no ≥ 1 AC/V cells; OPTIC 2E11 participant with inflammation at year 2.5 underwent a cataract surgery near the start of OPTIC EXT; EOP2: End of Phase 2 Meeting DATA CUT-OFF: OPTIC 21AUG2024, LUNA 29AUG2024 61 6E10 With steroid eyedrops $153M Cash into H2’25 Broad Patient population; 284 patients US Study Incorporates FDA EOP2 feedback ARTEMIS Phase 3 Trial
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