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Gaining Momentum in Gene TherapyOIS@AAO Annual MeetingOctober 10, 2019
Aaron Osborne, MBBS MRCOphthChief Medical Officer
Forward-looking Statements
Statements contained in this document 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 regulatory filings, the therapeutic and commercial potential of Adverum’s product candidates and the sufficiency of Adverum’s resources to fund lead programs, 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 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 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 or commercialize any of its product candidates, and the risk that Adverum will be delayed in receiving or fail to receive required regulatory approvals. Risks and uncertainties facing Adverum are described more fully in Adverum’s periodic reports filed with the SEC, including its Form 10-Q filed with the SEC on August 8, 2019, particularly in the section titled “Risk Factors.” 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.This document contains 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 events or circumstances may differ materially from events and circumstances 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.
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Pioneering Novel Gene Therapies for Ocular Diseases
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Well positioned to execute:§ Leadership team with extensive ophthalmology, drug development expertise§ ~$177.6M in cash* to fund operations into 2021
Industry-leading AAV platform and capabilities§ AAV.7m8 vector optimized for IVT delivery; next-generation vectors developed through proprietary directed
evolution platform§ Robust patent portfolio§ Scalable manufacturing process
*Cash, cash equivalents, and short-term investments as of June 30, 2019 (unaudited)
ADVM-022 in wet AMD§ OPTIC phase 1 trial conducted in patients who require frequent injections to manage their wet AMD§ Zero rescue injections required, durable efficacy signal observed, through week 24 in Cohort 1 (n=6)§ Cohort 1 (52-week) and Cohort 2 (24-week) data releases planned 1H20
ADVM-022: Intravitreal gene therapy for VEGF-driven retinal diseases§ Advanced AAV.7m8 candidate designed to deliver long-lasting efficacy in a single intravitreal injection§ Long-term efficacy from a single injection can address the greatest unmet clinical needs in:
§ Wet AMD – serious lifelong disease affecting 1.2M patients in the US§ Diabetic retinopathy – the leading cause of vision loss in working age people; 8M patients in US
1. Brown DM, et al. N Engl J Med. 2006;355:1432-1444. 2. Busbee DM, et al. Ophthalmology. 2013;120:1046-1056. 3. Heier JS, et al. Ophthalmology.2012;119:2537-2548. 4. Martin DF,et al. N Engl J Med. 2011;364:1897-1908. 5. Rosenfeld PJ, et al. N Engl J Med. 2006;355:1419-1431. 6. Cohen SY, et al. Retina. 2013;33:474-481. 7. Holz FG, et al. Br J Ophthalmol.2015;99:220-226. 8. Holz FG, et al. Br J Ophthalmol. 2013;97:1161-1167.
Real-world Anti-VEGF Patient Outcomes:Treatment Burden Results in Suboptimal Vision from Under-dosing
› Burden of frequent intravitreal (IVT) injections for patients and caregivers
› Real-world visual acuity outcomes fall short of clinical trial results due to under-dosing
› A solution is needed to reduce treatment burden and improve real-world patientoutcomes while providing clinical benefit to patients with wet AMD
Clinical trials1-5 vs Real-world Studies6-81-Year Outcomes With Ranibizumab 0.5 mg
11.3
7.2
10.1
8.1
9.48.5
2.4 3.2
-0.8
-10123456789
101112
ANCHOR MARINA HARBOR VIEW 1 VIEW 2 CATT AURA LUMIERE WAVE
Mea
n BC
VA C
hang
e F
rom
Ba
selin
e, E
TDR
S L
ette
rs
12 12 11.3 12 12 11.7 5.0 5.1 4.3# of injections
Clinical Trials Real World
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IntravitrealInjection
Outpatient Visit
5
Ocular Gene Therapy Approaches: Intravitreal Offers Benefits over Subretinal
› Intravitreal injection is the current standard-of-care for wet AMD
› Potential for wide distribution of vector, thus able to transduce a broader tissue area
SubretinalInjection
Requires Surgical Setting
1 Hossein S, et al. Overview of retinal differentiation potential of mesenchymal stem cells: A promising approach for retinal cell therapy. Annals of Anatomy - Anatomischer Anzeiger,Vol 210, 2017: 52
› Surgical procedure is complex and time-consuming
› Risks associated with vitrectomy surgery
› Not all retinal specialists are equipped or trained to do procedure
› Limited vector distribution, transduction is localized to cells under or near the bleb
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ADVM-022 is Specifically Designed for Long-term Intraocular VEGF Suppression With a Single Intravitreal Injection
ADVM-022AAV.7m8 capsid
ITR aflibercept ITRC11
Aflibercept expression cassette
Target retinal cell expresses aflibercept
AfliberceptRNA
ITR, inverted terminal repeatSource: Grishanin, R. et al. Mol. Ther. 2019;27:118–29
AAV.7m8 was developed using directed evolution to:
› Enable efficient intravitreal delivery› Increase transduction of retinal cells› Increase protein expression
AAV.7m8 Unique Properties
Preclinical Data Demonstrate the Potential for Long-term Efficacy with a Single Intravitreal Injection of ADVM-022
0
5
10
15
20
25
30
35
40
45
50
Vehicle Aflibercept ADVM-022
Perc
enta
ge g
rade
IV le
sion
s, %
Administered at time of
lesion
*p<0.0001CNV, choroidal neovascularizationIVT, intravitreal therapy OD, right eye; OS, left eye1. Kiss, S. Ann Meeting of the Am. Soc. Gene Cell Ther.; May 2019; Washington, DC2. Grishanin, R. et al. Mol. Ther. 2019;27:118–29
5%*
ADVM-022 given 13 months prior to laser CNV is as effective as aflibercept at the time of laser2
Sustained aflibercept protein expression at pharmacologically relevant levels through 30 months1
0.1
1
10
0 5 10 15 20 25 30
Aflib
erce
pt, µ
g/m
L
Months
Vitreous humor OSVitreous humor OD
6%*IVT ADVM-022
40%
13 months post-injection
(2x1012 vg/eye)
7
ADVM-022 OPTIC Phase 1 Trial for Wet AMD –Dosing Completed in Cohorts 1 and 2
†Patients receive rescue aflibercept (2mg IVT) if any of the following criteria are met: 1. Loss of ≥10 letters in BCVA from baseline due to intraretinal or subretinal fluid observed by SD-OCT; 2. Increase in central subfield thickness >75μm from baseline as assessed by SD-OCT; 3. Presence of vision-threatening hemorrhage due to macular degeneration
Day 1: ADVM-022
Baseline assessment Treatment evaluation Follow-up
Day -14 to -7: aflibercept
244 8 12 16 20 104Weeks:
24-week safety and efficacy assessment
52-week safety and efficacy assessment
52
Treatment evaluation
Rescue at any time if disease activity meets retreatment criteria†
Prophylactic oralcorticosteroid taper
(13 days total)Primary endpoint (Safety) 24 weeks
Secondary endpoints (efficacy)
Cohort 2: 2x1011 vg
n=6
Cohort 1: 6x1011 vg
n=6
üDMC safe to proceed
Additional Cohorts, If
Needed
Assess tolerability and efficacy
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OPTIC Cohort 1 Baseline Patient Characteristics
Characteristic ValueMean age, years 79Mean time since nAMD diagnosis, years 3.3Mean number anti-VEGF injections since initial diagnosis (range) 35.3 (7–109)Mean number anti-VEGF injections in 8 months prior to screening 6.2Average annualized injection frequency 9.3Mean BCVA study eye, mean ETDRS letters Approximate Snellen equivalent
65.8 20/50
Mean CST study eye, mean µm 369
Cohort of subjects requiring frequent injections to maintain vision
BCVA, best corrected visual acuity: CST, central subfield thickness; ETDRS, Early Diabetic Retinopathy Study; nAMD, neovascular age-related macular degeneration; VEGF, vascular endothelial growth factor
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Cohort 1: Safety Results through Week 24
*CTCAE v5.0 AE severity grading system, general guidelines
Systemic Adverse Events Ocular Adverse Events(potentially related to ADVM-022)
› No serious adverse events (AEs)
› No adverse events met criteria for
dose-limiting toxicity
› No drug-related non-ocular adverse events
› Inflammation observed in all patients
› 14 mild* AEs
› 5 moderate* AEs
› Anterior chamber cells x2
› Intermediate uveitis x2
› Vitreous cells
› No severe* AEs
Cohort 1: Mean BCVA Stable and Mean CST Reduced through 24 Weeks (Six Subjects)
BCVA, best corrected visual acuity; BL, baseline; CST, central retinal subfield thickness; D, day; W, weekDay 1 visit is 7–15 days after baseline visit90% CIs on mean change in BCVA and CST were calculated using the T-distribution.
-15.0
-10.0
-5.0
0.0
5.0
10.0
Mea
n C
hang
e in
BC
VA,
ETD
RS
lette
rs
BL D1 W4 W8 W12 W16 W20 W24
–2 letters90% CI (-9.1, 5.1)
-150.0
-100.0
-50.0
0.0
50.0
–52.7μm90% CI (-86.5, -18.8)
Mea
n ch
ange
inC
ST, µ
m
BCVA Mean Change
CST Mean Change
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Sentinel Subject: Prior AMD Treatment Experience
Optical coherence tomography (OCT) scans and treatment intervals from most recent 5 anti-VEGF injections visits prior to OPTIC
7 weeks
5 weeks
6 weeks
6 weeks
76 year old malePrevious IVT, n 18
IVT in last 8 months, n 5
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Sentinel Subject: OCT Images in OPTIC
Aflibercept IVT
Week 4
Week 8
Day 1: ADVM-022
Week 12
Week 16
Week 20
Week 24
No rescue injection received over 24 weeks
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Anti-VEGF centurion: Prior nAMD Treatment Experience
Optical coherence tomography (OCT) scans and treatment intervals from most recent 5 anti-VEGF injections visits prior to OPTIC
62 year old malePrevious IVT, n 109
IVT in last 8 months, n 6
5 weeks
5 weeks
6 weeks
6 weeks
15
Anti-VEGF centurion: OCT Images in OPTIC
No rescue injection received over 24 weeks
Aflibercept IVT
Week 4
Week 8
Day 1: ADVM-022
Week 12
Week 16
Week 20
Week 24
OPTIC Cohort 1: 24-Week Conclusions
§ Zero rescue injections required for any patient§ ADVM-022 was safe and well tolerated§ Mean BCVA stable§ Mean CST reduced§ 5/6 subjects showed complete anatomic response
BCVA, best-corrected visual acuity; nAMD, neovascular age-related macular degeneration; OCT, optical coherence tomography
ADVM-022 offers transformative potential to greatly reduce treatment burden and improve retinal anatomy with a single intravitreal injection in nAMD
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ADVM-022 is the Only Intravitreal Injection that has Potential to be a One-time Treatment for wet AMD
Anti-VEGF Intravitreal Injections
Advantages:• Office administration per current
SoC• Proven efficacy and safety profile• Potential for some patients to be
extended to longer treatment intervals
Limitations:• Short duration within eye• ~50% of patients require 4–8 weekly
injections to control disease• Real world outcomes fail to match
clinical trials due to undertreatment• Treatment burden unmanageable
for patients and healthcare systems
ADVM-022 Intravitreal Injection
Advantages:• Office administration per current
SoC• Potential long lasting VEGF
suppression with a single injection• Potential for anatomic
improvements in refractory patients• Could dramatically reduce treatment
burden and improve real-world vision outcomes
Limitations:• May be unsuitable for some patients
(eg history of uveitis)• May need neutralizing antibody
screening• Steroid prophylaxis may be required
Surgical
Advantages:• Potential long lasting VEGF
suppression with a single surgical procedure
Limitations:• Invasive surgical procedure in
operating room setting• Implant device requires refills
alongside rescue injections• Subretinal surgery requires
vitrectomy and steroid prophylaxis• Risks of surgical complications:
• Early: vitreous hemorrhage, retinal detachment; Later: cataract, endophthalmitis
Current and future Wet AMD Treatments
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MilestonesADVM-022 for Wet AMD – OPTIC Phase 1 Clinical Trial
ü Dosed first patient in second cohort (n=6, 2x1011 vg/eye) 2Q19ü Completed patient dosing in second cohort (n=6, 2x1011 vg/eye) 3Q19ü Positive 24-week data from first cohort (n=6, 6x1011 vg/eye)
Podium presentation at Retina SocietyLate-breakers podium presentation at AAO
9/201910/2019
Provide update on development plans for OPTIC 4Q1952-week data from first cohort expected to be presented 1H2024-week data from second cohort expected to be presented 1H20
ADVM-022 for Diabetic Retinopathy (DR)
Plan to submit IND in diabetic retinopathy 1H20
In-house Process Development Capabilities
Be able to occupy new facility with expanded in-house process development capabilities to 1000L YE19
Nasdaq: ADVM