Full Press Release Details
LUNA and 4- Year OPTIC Results and Pivotal Program th November 18 , 2024
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Today's Agenda Welcome & Key Takeaways Patient Preference
Survey 01 05 Laurent Fischer, MD Laurent Fischer, MD President & Chief Executive Officer President & Chief Executive Officer Ixo-vec & Wet AMD Commercial Opportunity 02 06 Laurent Fischer, MD Jason Mitchell President & Chief
Executive Officer Chief Commercial Officer 4-Year OPTIC & 52-week 03 07 KOL Panel LUNA Results Moderator: Star Seyedkazemi, PharmD Star Seyedkazemi, PharmD Chief Development Officer Chief Development Officer Key Pivotal Program Elements 04
Conclusions & Q&A 08 Rabia Gurses Ozden, MD Adverum Management Chief Medical Officer 3
Adverum Participants Laurent Fischer, MD Rabia Gurses Ozden, MD Star
Seyedkazemi, PharmD President and Chief Medical Officer Chief Development Officer Chief Executive Officer Linda Rubinstein Mike Zanoni Jason Mitchell Peter Soparkar Chief Financial Officer Head of Investor Relations Chief Commercial Officer Chief
Key Opinion Leader Participants Szil rd Kiss, MD Charles C. Wykoff,
MD, PhD Mark Barakat, MD Distinguished Professor of Ophthalmology, Director of Research, Director of Clinical Research Director of Retina Service Retina Consultants of Texas Retina Macula Institute of Arizona Cornell University Adverum Board Member
Ixo-vec's Derisked Phase 3 and Commercial Profile Clinical updates
underscore Ixo-vec's potential best-in-class product profile Potential best-in-class product profile >50% injection free and >80% treatment burden reduction in hard-to-treat patients 10X safety margin with >4 years
follow-up No OPTIC 2E11 patients had inflammation at Year 1 and through Year 4 No LUNA 6E10 patients had inflammation at 52 weeks or any subsequent visit Favorable safety profile with local prophylaxis LUNA patient survey
demonstrates strong patient preference for Ixo-vec Broad 6E10 EOP2 284 1H25 ARTEMIS Patient population With topical US study, incorporates Patients Expected Phase 3 Phase 3 Trial steroid eyedrops FDA feedback initiation 7 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: OPTIC 21AUG2024, LUNA 29AUG2024
5+ Years of Clinical Experience Establish 10x Safety Margin Ixo-vec 6E10
with extended prophylaxis de-risks Phase 3 & commercialization 6E11 N=15 2E11 N=15 4+ Years Clinical Data 8 DATA CUT: OPTIC 21AUG2024, LUNA 29AUG2024 Dose (vg/eye) 10x Safety Margin
5+ Years of Clinical Experience Establish 10x Safety Margin Ixo-vec 6E10
with extended prophylaxis de-risks Phase 3 & commercialization 6E11 Phase 3 Dose N=15 Enhanced Safety Profile Extended Steroid Prophylaxis Potential Best-in-Class Efficacy Profile 2E11 2E11 N=15 N=30 6E10 N=30 4+ Years
Clinical Data 9 DATA CUT: OPTIC 21AUG2024, LUNA 29AUG2024 Dose (vg/eye) 10x Safety Margin
6E10 Dose Selected to Maximize Phase 3 and Commercial Success
Demonstrates potential best-in-class product profile Benefit Safety Treatment Burden % Receiving 1 Injection Injection Free % With AC 1+ Ph3 Go-Forward Dose Reduction Steroids for IOI 6E10 88% 75% 54% 0% 4% (n = 28) N=1 2E11 92% 79%
69% 3% 7% (n = 29) 2E11 84% 73% 60% 0% 27% (n = 15) 6E11 97% 87% 87% 0% 60% (n = 15) Potential best-in-class clinical activity with enhanced safety profile of 6E10 for pivotal studies 10 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. DATA CUT: OPTIC 21AUG2024, LUNA 29AUG2024
Reliable Benefit & Predictable Safety Profile Enable True Paradigm
Shift 4-year OPTIC & 52-week LUNA data underscore Ixo-vec's profile Demonstrated Reliable Long-Term Benefit 78% of patients who were injection free through year 1 remained injection free through year 4 88% of patients who were injection
free through year 2 remained injection free through year 4 Demonstrated Predictable Safety Profile with Extended Local Prophylaxis NO new onset of inflammation after week 30 100% of inflammation resolved by year 1 11 No inflammation: no 1
AC/V cells; OPTIC results refer to 2E11 dose DATA CUT: OPTIC 21AUG2024, LUNA 29AUG2024
Large and Growing Global Market Opportunity Wet AMD physicians and
patients embrace innovation Wet Age-Related Macular Degeneration Multi-Billion Dollar Market Opportunity A leading cause of vision loss among older adults Growth driven by aging population and product innovation Global Wet AMD Sales 20M 1.5M ~$13B
US Patients Worldwide ~$9B ~$6B ~200k US patients diagnosed annually Up to 42% of patients develop bilateral disease within 2-3 years of initial diagnosis 2015 2025E 2035E 13 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.
Real-World Vision Declines Due to Chronic Undertreatment 10 5 0 IRIS
(N>160,000) -5 HORIZON (N=600) Gilles, al (N=1,212) CATT (N=647) -10 SEVEN-UP (N=65) -15 0 1 2 3 4 5 6 7 Years Up to ~40% STOP anti-VEGF over 2 years and up to 57% stop over 5 years 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- 14 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. Mean Letter Change From Baseline
Real-World Vision Declines Due to Chronic Undertreatment Ixo-vec
designed to deliver stable aflibercept to maintain long-term vision Ixo-vec 10 5 0 IRIS (N>160,000) -5 HORIZON (N=600) Gilles, al (N=1,212) CATT (N=647) -10 SEVEN-UP (N=65) -15 0 1 2 3 4 5 6 7 Years Up to ~40% STOP anti-VEGF over 2 years and up
to 57% stop over 5 years 15 *Potential long-term vision outcome with Ixo-vec. 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. Mean Letter Change From Baseline
Undertreatment Often Results from Barriers to Treatment Physician ASRS
survey underscores need for more durable treatments Barriers to Treatment More Durable Treatment Options Are Needed Physician Survey: Unmet Needs In Treating Wet AMD and DME Needle Anxiety Comorbidities 74% Greater Durability 79% 55% Improved Vision
50% Missed Injections 58% Longer VEGF Suppression 47% 46% Stable Anatomy Life Events Lack of Transportation 30% International US Ixo-vec may address unmet need in wet AMD by delivering stable aflibercept 16 Hahn P, ed. ASRS 2023 Preferences and
Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2023.
Ixo-vec Positioned to Transform Treatment Paradigm In contrast, 2nd
generation wet AMD treatments are only incremental advancements Ixo-vec designed to deliver stable and continuous aflibercept 5+ years % Injection Potential 2024 Free US Revenue 4D-150 (Investigational) Paradigm Shift Ixo-vec >50% [Discontinued
Q26W and Relaunched] nd Q8-Q16W $1.6B 2 Generation Q8-Q16W $4.3B 0% Q8W $4.6B st 1 Generation Q4W $23M Q12W Q26W 1Y 2Y 5Y+ 17 Potential 2024 US revenue is extrapolated from Q3 2024 public filings of each company's reported financial results
and is for all indications
Ixo-vec Delivers Anti-VEGF Aflibercept via Single Intravitreal
Injection 7m8 capsid enables delivery of stable aflibercept levels into the retina AAV.7m8 AAV.7m8 ILM Ganglion Inner Nuclear Photoreceptors RPE IVT injection monomer Cells Membrane Loop IV Retina Loop IV 7m8 insert Promoter Aflibercept PolyA
AAV.7m8: Created by Directed Evolution Engineered for IVT administration; peptide loop enables Ixo-vec 7m8 to cross the inner limiting membrane (ILM) AAV.7m8 delivers aflibercept to the retina AAV.7m8 for IVT Gene Therapy CNV
Validated in 3 clinical programs Aflibercept secretion IVT injection Durable suppression by retina of CNV Published in peer reviewed journals 18 Khabou et. al. Biotechnology and Bioengineering, 113:12, December 2016
4-Year OPTIC & 52-week LUNA Results
OPTIC First-in-Human Trial Design 6E11 & 2E11 with short
prophylaxis in hard-to-treat population Primary Objective Secondary Objectives Vision maintenance (BCVA) Long-term safety and efficacy of Ixo-vec IVT in Anatomy (SD-OCT) treatment experienced patients Need for supplemental
therapy Day -15 to -7: Day 1: Ixo-vec 2-Year Safety and Efficacy Current Update: 5-Year Safety and Efficacy Baseline 4-Year IVT Aflibercept Screening 2-Year OPTIC Study 3-Year Extension Study Period Corticosteroid Prophylaxis* Corticosteroid
Extension Scheduled Ixo-vec Dose Supplemental Aflibercept (2 mg IVT) Criteria: Prophylaxis Visits Cohort 1 (n=6) 6E11 Oral, 13d 10 letters BCVA (ETDRS) loss from baseline OR, Quarterly assessments CST >75 m increase
from baseline OR, Cohort 2 (n=6) Oral, 13d 2E11 following completion of New Vision-threatening hemorrhage due to AMD 2-year OPTIC parent Cohort 3 (n=9) Eye Drops, 6 wks 2E11 study After initial supplemental injection subsequent
injections Cohort 4 (n=9) Eye Drops, 6 wks 6E11 administered at investigator discretion 20 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. DATA CUT: OPTIC
Preclinical Data Suggest Best-in-Class Potential of Ixo-vec at 6E10
Dose NHP studies demonstrate consistent aflibercept production with low inflammation Less-than-dose-proportional aflibercept levels across 3 logs Improved inflammation scores with lower doses (no prophylaxis) Aqueous Humor Aflibercept Levels
Inflammation Scores 8 * 6 4 2 0 I I Vehicle 3E10 1E11 2E11 4E11 6E11 2E12 6E12 2E13 NHP 3E10 1E11 2E11 4E11 6E11 2E12 6E12 2E13 NHP Vehicle 3E10 1E11 2E11 4E11 6E11 2E12 6E12 2E13 Dose (vg/eye) Human equivalent Vehicle 6E10 2E11 4E11 8E11 1E12 4E12
1E13 4E13 Human equivalent 6E10 2E11 4E11 8E11 1E12 4E12 1E13 4E13 Dose (vg/eye) Dose (vg/eye) *Scale is cumulative of two parameters for maximum score of 8. 21 Schaefer-Swale K. Non-Clinical Data Support Efficacy and Tolerability of a Human
Equivalent Dose of 6E10 vg/eye of ADVM-022 for the Treatment of Neovascular Age-Related Macular Degeneration. Poster presented at ASGCT 2023. Human Equivalent Dose (HED) is approximately twice the corresponding NHP dose based on eye volume. E.g.,
2E11 is the HED of 1E11 NHP dose. NOAEL established at NHP dose of 1E11 vg/eye. Aflibercept (ng/l) Hackett-McDonald peak score (AC + VC)
Learnings from OPTIC Informed LUNA Phase 2 Trial LUNA goal: optimize
Ixo-vec benefit / risk going into pivotal trials Objective I Objective II Determine the Determine the Optimal Phase 3 Prophylactic Dose for Phase 3 Regimen 22
LUNA Phase 2 Trial Design 6E10 & 2E11 with extended prophylaxis in
hard-to-treat patients Multicenter, double-masked, randomized, parallel-group Phase 2 study 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 FIVE YEAR: Day -21 to -14: DAY -7: DAY 1: WEEK 26: WEEK 52: Baseline Randomization IVT Ixo-vec Primary Endpoints EXT Completion Interim Analysis IVT Aflibercept
2mg Long-term 2E11 (n=30) extension ends Screening Period 6E10 (n=30) at year five Corticosteroid prophylaxis (21+ weeks post-dose) Corticosteroid Prophylaxis Regimen Supplemental Injection Criteria Difluprednate 22 wks prednisone
oral 10 wks Increase in CST > 75 m from BL confirmed by the CRC OR Ozurdex IVT + difluprednate after week 4 prednisone oral 10 wks* Loss of 10 letters in BCVA from BL due to new/worsening IRF or SRF OR
Randomized 2:1 local versus local + oral New vision-threatening hemorrhage due to nAMD 23 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). DATA CUT: LUNA 29AUG2024
Demographics and Baseline Characteristics OPTIC & LUNA evaluated
hard-to-treat patients LUNA LUNA LUNA OPTIC Demographics and Baseline 6E10 2E11 Total Total Characteristics N = 30 N = 30 N = 60 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