A Phase 2, Multi-Center, Randomized, Double-Masked, Active Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects With Diabetic Macular Edema [INFINITY]
Phase: PHASE2
Conditions: Diabetic Macular Edema, Diabetic Retinopathy
Sponsor: Adverum Biotechnologies, Inc.

CLINICAL STUDY PROTOCOL 
Study ID 
ADVM-022-04 
Study Title 
A Phase 2, Multi-Center, Randomized, Double-Masked, 
Active Controlled Study of ADVM-022 (AAV.7m8-
aflibercept) in Subjects with Diabetic Macular Edema 
[INFINITY] 
Indication Studied 
Diabetic Macular Edema (DME) 
Sponsor 
Adverum Biotechnologies, Inc. 
800 Saginaw Drive 
Redwood City, CA 94063 
Protocol Version 
Document Identifier / Effective Date 
Original  
ADVM-022-04 / 19 March 2020 
Amendment 1.0 
Amendment 2.0 
Amendment 3.0 
Amendment 4.0 
Amendment 5.0 
Amendment 6.0 
Amendment 7.0 
ADVM-022-04 v1.0 / 16 April 2020 
ADVM-022-04 v2.0 / 04 May 2020 
ADVM-022-04 v3.0 / 02 September 2020 
ADVM-022-04 v4.0 / 17 February 2021 
ADVM-022-04 v5.0 / 04 May 2021 
ADVM-022-04 v6.0 / 14 July 2021 
ADVM-022-04 7.0 / 05 August 2021 
Confidentiality Statement 
This document contains confidential and proprietary information of Adverum Biotechnologies, Inc., that must not 
be disclosed to anyone other than the recipient, study staff, and members of the Institutional Review Board/Ethics 
Committee. This information cannot be used for any other purpose other than the evaluation or conduct of the 
clinical study without the prior written consent of Adverum Biotechnologies Inc. 
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Protocol No. ADVM-022-04 (Amendment 7.0)
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A-DVERUM 
BIOTECHNOLOGIES 

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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INVESTIGATOR AGREEMENT 
Study ID 
ADVM-022-04 
Study Title 
A Phase 2, Multi-Center, Randomized, Double-Masked, 
Active Controlled, Study of ADVM-022 (AAV.7m8-
aflibercept) in Subjects with Diabetic Macular Edema 
[INFINITY] 
Version 
Amendment 7.0, 05 August 2021 
I have read this clinical protocol as set forth below.  On behalf of myself and the study staff, I 
agree to conduct Study ADVM-022-04 in compliance with the terms of the protocol as outlined 
herein and in compliance with Good Clinical Practice (GCP) and all applicable legal and 
regulatory requirements.  Furthermore, I understand that the Sponsor, Adverum Biotechnologies, 
Inc. (Adverum), and the Institutional Review Board/Institutional Biosafety Committee 
(IRB/IBC) must approve any changes to the protocol in writing before implementation, except 
where it may be necessary to eliminate an immediate hazard to a subject enrolled in this study.  I 
agree not to divulge to anyone, either during or after the study, any confidential information 
acquired regarding the investigational medicinal product and processes or methods of Adverum.  
All data pertaining to this study will be provided to Adverum.    
 
 
 
Principal Investigator (signature) 
 
Date 
Printed Name: 
 
Institution: 
 
 
 
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Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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STUDY CONTACTS 
Sponsor  
Adverum Biotechnologies, Inc. 
800 Saginaw Drive 
Redwood City, CA 94063 
Sponsor’s Medical Monitor  
  
Medical Director 
phone: 
 
email: 
 
SAE Reporting 
Phone:  
 
  
Fax:  
 
  
Email:  
 
 
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Protocol No. ADVM-022-04 (Amendment 7.0)
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Adverum Biotechnologies, Inc.

Advernm Biotechnologies, Inc. 
ADVM-022 (AA V.7m8-aflibercept) 
Protocol No. ADVM-022-04 (Amendment 7.0) 
Adverum Biotechnologies, Inc. 
Clinical Protocol No. ADVM-022-04 
ADVM-022 (AA V.7m8-aflibe1·cept) 
Amendment 7.0, 05 August 2021 
PROTOCOLAPPROVAL-ADVERUM SIGNATORY 
Study ID 
Study Title 
Version 
ADVM-022-04 
A Phase 2, Multi-Center, Randomized, Double-Masked, Active 
Controlled Study of ADVM-022 (AA V.7m8-aflibercept) in 
Subjects with Diabetic Macular Edema [INFINITY] 
Amendment 7.0, 05 August 2021 
Study ADVM-022-04 will be conducted in accordance with the International Council for 
Harmonisation of Technical Requirements for Pha1maceuticals for Human Use (ICH) and 
Harmonised T1ipaitite Guidelines for Good Clinical Practices (E6), with applicable local 
regulations (including US Code of Federal Regulations [CFR] Title 21, and the ethical p1inciples 
outlined in the Declaration of Helsinki). 
Protocol approved by: 
Advemm Biotechnologies, Inc. 
Signature 
Date 
CONFIDENTIAL 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
INVESTIGATOR AGREEMENT ...............................................................................................2 
STUDY CONTACTS .....................................................................................................................3 
PROTOCOL APPROVAL—ADVERUM SIGNATORY .........................................................4 
1.0 
STUDY SYNOPSIS ...........................................................................................................9 
2.0 
LIST OF ABBREVIATIONS .........................................................................................21 
3.0 
BACKGROUND ..............................................................................................................25 
3.1 
Introduction ............................................................................................................25 
3.2 
Investigational Medicinal Product (ADVM-022) ..................................................25 
3.3 
Preclinical Summary for ADVM-022 ....................................................................26 
3.4 
Other Clinical Studies of ADVM-022 ...................................................................26 
3.5 
Formulation ............................................................................................................31 
3.6 
Dose Justification ...................................................................................................31 
4.0 
CLINICAL STUDY OBJECTIVES AND ENDPOINTS .............................................32 
4.1 
Objectives ..............................................................................................................32 
4.1.1 
Primary Objective .................................................................................32 
4.1.2 
Secondary Objectives ............................................................................32 
4.2 
Endpoints ...............................................................................................................33 
4.2.1 
Primary Endpoints .................................................................................33 
4.2.2 
Secondary Endpoints .............................................................................33 
5.0 
CLINICAL INVESTIGATION PLAN ..........................................................................33 
5.1 
Study Design ..........................................................................................................33 
5.1.1 
: ...................................................34 
5.1.2 
Rescue Treatment: .................................................................................35 
5.1.3 
Data Monitoring Committee (DMC): ...................................................35 
5.1.4 
Stopping Rules: .....................................................................................35 
5.2 
Study Duration .......................................................................................................36 
5.3 
Study Population ....................................................................................................36 
5.4 
Allocation to Treatment .........................................................................................36 
5.5 
Masking and Minimization of Bias........................................................................36 
5.5.1 
Masked Roles ........................................................................................37 
5.5.2 
Unmasked Roles ...................................................................................37 
5.6 
Emergency Unmasking ..........................................................................................38 
5.7 
Dispensing Instructions ..........................................................................................38 
5.8 
Investigational Medicinal Product Accountability and Reconciliation .................38 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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5.9 
Method of Administration......................................................................................38 
5.10 
 ..................................................................38 
5.11 
 ...39 
5.11.1
5.11.2
5.11.3
6.0 
SUBJECT SELECTION CRITERIA AND WITHDRAWAL ....................................40 
6.1 
Selection Criteria ...................................................................................................40 
6.2 
Screening Records .................................................................................................40 
6.3 
Inclusion Criteria ...................................................................................................41 
6.4 
Exclusion Criteria ..................................................................................................41 
6.4.1 
General Exclusion Criteria ....................................................................41 
6.4.2 
Ocular Exclusion Criteria (Study Eye) .................................................43 
6.4.3 
Ocular Exclusion Criteria (Fellow or Study Eye) .................................44 
6.5 
Subject Withdrawal ................................................................................................45 
7.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................45 
7.1 
Informed Consent...................................................................................................46 
7.2 
Confirm Eligibility .................................................................................................46 
7.3 
Medical History, Ophthalmic History, and Demographics ...................................46 
7.4 
General Physical Examination and Vital Signs .....................................................46 
7.5 
ECG Evaluation .....................................................................................................46 
7.6 
Laboratory Tests ....................................................................................................47 
7.6.1 
Clinical Laboratory Tests ......................................................................47 
7.6.2 
 ..............47 
7.7 
Full Ophthalmic Examination ................................................................................47 
7.8 
Refraction and Visual Acuity.................................................................................48 
7.9 
Imaging ..................................................................................................................49 
7.9.1 
Spectral Domain Optical Coherence Tomography - SD-OCT 
(Retinal and Optional Anterior Segment Imaging) ...............................49 
7.9.2 
Optional Optical Coherence Tomography Angiography (OCT-A) ......49 
7.9.3 
Ultra-wide Field Fundus Photography and Iris Photography ...............49 
7.9.4 
Ultra-wide Field Fluorescein Angiography ..........................................49 
7.9.5 
Optional Ultrasound Biomicroscopy (UBM) ........................................50 
7.10 
Laboratory, Biomarker and Other Biological Specimens ......................................50 
7.10.1 
Optional Aqueous Humor Sampling .....................................................50 
7.10.2 
Optional Vitreous Humor and Other Ocular Tissue Sampling .............50 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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8.0 
REQUIRED, CONCOMITANT AND EXCLUDED MEDICATIONS .....................50 
8.1 
Required Medications ............................................................................................50 
8.1.1 
 
) .......................................................................50 
8.1.2 
Eylea® (aflibercept) ...............................................................................50 
8.2 
Concomitant Treatments ........................................................................................51 
9.0 
ADVERSE EVENT HANDLING AND SAFETY REPORTING ...............................52 
9.1 
Assessment of Safety .............................................................................................52 
9.2 
Adverse Events ......................................................................................................52 
9.3 
Definition of Serious Adverse Event .....................................................................52 
9.4 
Adverse Events of Special Interest (Immediately reportable to Sponsor) .............53 
9.5 
Pregnancy-Related Event .......................................................................................53 
9.6 
Eliciting Adverse Events ........................................................................................54 
9.7 
Reporting and Documenting Adverse Events ........................................................54 
9.8 
Assessment of Severity ..........................................................................................55 
9.9 
Assessment of Causality ........................................................................................55 
9.10 
Follow-Up of Subjects Reporting Adverse Events ................................................56 
9.11 
Overdose and Reporting ........................................................................................56 
10.0 
ASSESSMENT OF EFFICACY .....................................................................................56 
11.0 
STATISTICAL CONSIDERATIONS ...........................................................................57 
11.1 
Sample Size Determination ....................................................................................57 
11.2 
Analysis Populations ..............................................................................................58 
11.3 
Statistical Methods .................................................................................................58 
12.0 
ETHICAL CONSIDERATIONS ....................................................................................59 
12.1 
Institutional Review Board / Institutional Biosafety Committee ...........................59 
12.2 
Ethical Conduct of the Study .................................................................................59 
12.3 
Subject Information and Consent...........................................................................60 
13.0 
INVESTIGATOR’S RESPONSIBILITIES ..................................................................60 
14.0 
SPONSOR RESPONSIBILITIES ..................................................................................61 
14.1 
Modification of the Protocol ..................................................................................61 
14.2 
Protocol Deviations ................................................................................................61 
14.3 
Confidentiality .......................................................................................................61 
14.4 
Investigator’s Report to the IRB/IBC ....................................................................62 
14.5 
Records Retention ..................................................................................................62 
14.6 
Financial Disclosure and Obligations ....................................................................62 
14.7 
Liability and Insurance ..........................................................................................63 
14.8 
Publication Policy ..................................................................................................63 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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15.0 
STUDY MANAGEMENT ...............................................................................................63 
15.1 
Monitoring of the Study .........................................................................................63 
15.2 
Data Quality Assurance .........................................................................................64 
15.3 
Data Management ..................................................................................................64 
16.0 
STUDY COMPLETION .................................................................................................65 
17.0 
REFERENCES .................................................................................................................66 
18.0 
APPENDICES ..................................................................................................................67 
18.1 
18.2 
18.3 
 
LIST OF TABLES  
Table 1: 
Number of Patients (Events) with ADVM-022 Related Adverse Events 
in the Study Eye by Preferred Term and ADVM-022 Dose in Clinical 
Protocol No. ADVM-022-01 [OPTIC] ......................................................29 
Table 2:  
Safety Factors of Proposed ADVM-022 Clinical Doses for the DME 
Study Over the Safe Nonhuman Primate Dose ..........................................32 
Table 3: 
Study Arms ................................................................................................34 
Table 4: 
 ..............................................................................39 
Table 5: 
Power for 1-Sided Fisher Exact Tests at Various Rate Assumptions ........58 
 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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1.0 
STUDY SYNOPSIS 
Title of Study: 
A Phase 2, Multi-Center, Randomized, Double-Masked, Active 
Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects 
with Diabetic Macular Edema [INFINITY] 
Sponsor: 
Adverum Biotechnologies, Inc. 
Phase of 
Development: 
Phase 2 
Study Sites: 
Approximately 15 sites in the United States 
Objectives: 
Primary Objective:  
• To assess the durability of a single intravitreal (IVT) injection of 
ADVM-022  
Secondary Objectives: 
• To assess the safety and tolerability of ADVM-022 
• To evaluate the effect of ADVM-022 on macular edema  
• To evaluate the effect of ADVM-022 on Best Corrected Visual 
Acuity (BCVA)  
• To evaluate the effect of ADVM-022 on Diabetic Retinopathy 
Severity Scale (DRSS) score 
• To assess the need for rescue aflibercept (2 mg IVT)  
• To assess the effect of a preceding dose of aflibercept (2 mg IVT) 
prior to ADVM-022 administration 
• To evaluate the effect of ADVM-022 on development of vision 
threatening complications (including anterior segment 
neovascularization, vitreous hemorrhage, or tractional retinal 
detachment) 
Primary Endpoint: 
• Time to worsening of DME disease activity in the study eye  
Secondary 
Endpoints: 
Unless specified otherwise, the secondary endpoints are based on 
outcome measures for the study eye. 
• Incidence and severity of ocular and non-ocular adverse events 
(AEs) 
• Change from Baseline in central subfield thickness (CST) and 
macular volume over time through Week 96 
• Change from Baseline in BCVA over time through Week 96   
• Frequency of rescue aflibercept (2 mg IVT) in the study eye over 
time during the study  
• Incidence of 2-step and 3-step improvement in DRSS score over 
time through Week 96  
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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• Incidence of 2-step and 3-step worsening in DRSS score over 
time through Week 96 
• Occurrence of vision threatening complications (anterior segment 
neovascularization, vitreous hemorrhage, or any other high-risk 
proliferative DR or tractional retinal detachment) over time through 
Week 96 
• Incidence of CST <300 μm over time through Week 96 
• Incidence of clinically significant findings via physical 
examinations, ocular examinations, imaging, and laboratory 
evaluation 
Investigational 
Product and Dosage: 
ADVM-022 (AAV.7m8-aflibercept) investigational medicinal product 
is a genetically engineered, replication incompetent, capsid variant of 
the adeno-associated viral vector of serotype 2 (AAV2).  
A single 0.10 mL IVT administration of ADVM-022 will be evaluated 
at two dose levels: 2 × 1011 vg/eye and 6 × 1011 vg/eye. 
Reference Therapy: 
Name: Eylea® (aflibercept) 
Dosage, Route, Frequency: 0.05 mL of 2 mg administered via IVT for a 
single injection.  
Study Design: 
This is a multi-center, randomized, double-masked, controlled, parallel-
group study to evaluate the efficacy, safety and tolerability of a single 
IVT injection of ADVM-022. Two doses of ADVM-022 will be 
investigated.  
Subjects with initial diagnosis of DME within 6 months of screening 
and have received up to 2 prior injections of anti-VEGF therapy are 
eligible for enrollment.  
Approximately 33 eligible subjects will be randomized to one of 5 
arms.  Arm 1 (n=6) will receive ADVM-022 6 × 1011 vg/eye with a 
preceding aflibercept dose. Arm 2 (n=6) will receive ADVM-022 
6 × 1011 vg/eye of without a preceding aflibercept dose. Arm 3 (n=6) 
will receive ADVM-022 2 ×1011 vg/eye with a preceding aflibercept 
dose. Arm 4 (n=6) will receive ADVM-022 2 × 1011 vg/eye of without a 
preceding aflibercept dose. Arm 5 (n=9) will receive aflibercept only 
(active control).  To maintain masking of the treatment assignment, 
subjects assigned to the arms with no preceding aflibercept on Day 1 or 
to the arm with no ADVM-022 on Day 8 will receive a sham ocular 
injection on the corresponding visit.  Only one eye per subject will be 
selected as the study eye.  If both eyes are eligible, the eye with the 
worse BCVA will be the study eye.    
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Advernm Biotechnologies, Inc. 
ADVM-022 (AA V.7m8-aflibercept) 
Protocol No. ADVM-022-04 (Amendment 7.0) 
Adverum Biotechnologies, Inc. 
Clinical Protocol No. ADVM-022-04 
ADVM-022 (AA V.7m8-aflibe1·cept) 
Amendment 7.0, 05 August 2021 
Subjects will be randomized to the following treatment aims in the 
following table: 
Day l 
Day s 
IVT Aflibercept or 
IVT ADVM-022 Dose 
Arm 
N 
Sham 
(vg/eye) 
1 
6 
Aflibercept 
6 X 1011 
2 
6 
Sham 
6 X 1011 
3 
6 
Aflibercept 
2 X 1011 
4 
6 
Sham 
2 X 1011 
5 
9 
Aflibercept 
Sham 
After the assigned IVT injections on Day 1 and Day 8, all subjects will 
return to the clinic on Week 2, Week 4, and then eve1y 4 weeks up to 
Week 96. To maintain masking, both subjects and the site personnel 
who conduct outcome assessments will be masked to the treatment 
assignment throughout the study. Emergency unmasking for all 
subjects may be required, as dete1mined by the Sponsor with input from 
the Data Monito1ing Committee, to prese1ve subject safety. In the event 
of unmasking of all subjects prior to the end of the study, the study will 
in effect become an open-label study, in which all prior masked roles 
will be able to continue study pruticipation in an unmasked manner. 
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Advernm Biotechnologies, Inc. 
ADVM-022 (AA V.7m8-aflibercept) 
Protocol No. ADVM-022-04 (Amendment 7.0) 
Adverum Biotechnologies, Inc. 
Clinical Protocol No. ADVM-022-04 
ADVM-022 (AA V.7m8-aflibe1·cept) 
Amendment 7.0, 05 August 2021 
Rescue Treatment: 
Starting at Week 8, subjects will receive rescue aflibercept (2 mg IVT) 
if they meet any of the following: 
• Increase in CST > 50 µm as assessed by SD-OCT compared to the 
lower of the two CST measurements recorded at Day 1 or Week 4 
• Loss of> 5 letters in BCVA due to worsening DME disease activity 
compared to the higher of the two BCVA measurements recorded at 
Day 1 or Week 4. 
After the initial rescue treatment administration, subsequent rescue 
treatment may be administered PRN per the discretion of the Primary 
Investigator. 
Only intravitreal aflibercept injection (Eylea) is to be used for any 
rescue treatment unless prior approval by medical monitor. 
Aflibercept should not be injected in eyes with active inflammation. A 
minimum of21 days is required between rescue aflibercept injections. 
Independent Data Monitoring Committee (DMC) 
An independent DMC will monitor safety and study conduct on an 
ongoing basis. Members of the DMC will be independent from the 
Sponsor and will follow a charter that outlines the DMC's roles and 
responsibilities. The DMC will meet every 3-6 months (frequency 
adjustable as required) to evaluate unmasked ocular· and non-ocular 
safety events, with emphasis on the evaluation of the rate of ocular· 
inflammation, increased intraocular· pressure (IOP), endophthalmitis, 
and clinically significant decreases in BCV A. The DMC will also meet 
on an ad hoc basis if stopping rnles ar·e met as outlined below. The 
DMC may recommend stopping the study early for safety reasons. After 
reviewing the data, the DMC will provide a recommendation to the 
Sponsor as described in the DMC Charter. Any outcomes of these data 
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reviews that affect study conduct will be communicated in a timely 
manner to the investigators for notification of their respective 
Institutional Review Boards (IRBs). 
Stopping Rules:  
Enrollment will be suspended if any of the following sight threatening 
events occur:  
• A decrease of ≥ 30 letters in BCVA in the study eye compared with 
the prior visit  
• A surgical intervention (i.e., conventional surgery, vitrectomy) to 
prevent permanent loss of sight 
• Severe intraocular inflammation (i.e., endophthalmitis, 4+ anterior 
chamber cell/flare, or 4+ vitreous cells)  
In addition, enrollment will be suspended if any serious adverse event 
potentially related to ADVM-022 occurs.  
Any event that meets any of the above safety stopping criteria will be 
reported immediately to the Sponsor and enrollment and dosing will be 
suspended until the DMC has reviewed the data and made a 
recommendation to the Sponsor. 
The regulatory authorities and the Investigators, and each site’s IRB and 
other appropriate institutional regulatory bodies will be promptly 
notified if a decision to suspend enrollment is made. 
• If study enrollment is suspended, all subjects who have already been 
treated will remain in the study and will continue to be monitored 
through their completion or withdrawal from the study. 
Study Duration: 
Duration of subject’s participation in the study will be approximately 
100 weeks for each subject (including up to 4-week screening period)   
Number of Subjects: Approximately 33 subjects   
Study Population: 
Subjects with newly diagnosed DME (diagnosis within 6 months of 
screening) that have received up to 2 prior injections of anti-VEGF 
therapy in the study eye.   
Randomization 
Criteria:   
Subjects must meet the following criteria to be included in this study:   
Inclusion Criteria: 
1) Male or female subjects, age ≥ 18 years of age 
2) Type 1 or 2 diabetes mellitus 
3) Ability and willingness to provide informed consent to participate in 
the study requirements and visits prior to any study procedure 
4) Vision at Screening visit: 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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a) Study Eye-BCVA 78 to 50 ETDRS letters, inclusive 
(approximate Snellen equivalent 20/32 to 20/100)  
b) Non-study eye-BCVA 35 ETDRS letters or more (approximate 
Snellen equivalent of 20/200 or better)  
5) CST of study eye at Screening visit of ≥ 325μm using Heidelberg 
Spectralis® with center involving intraretinal fluid (IRF) 
6) A decrease in vision in the study eye determined by the investigator 
to be primarily due to DME 
7) Initial DME diagnosis within 6 months from screening  
8) Up to 2 prior injections (0, 1 or 2) of anti-VEGF in the study eye  
• If a prior anti-VEGF has been administered to the study eye, in 
the judgement of the Investigator, there must have been a 
meaningful CST response (e.g., ≥ 10% reduction) and no adverse 
reaction to anti-VEGF (e.g., inflammation). 
9) A minimum 60-day interval is required between the last anti-VEGF 
IVT injection in the study eye and randomization on Day 1 
Exclusion Criteria: 
Participants with any of the following conditions are ineligible: 
General Exclusion Criteria 
 
 
 
2) Any condition that, in the opinion of the investigator, could 
contraindicate the use of the investigational drug or that might affect 
interpretation of the study results or that renders the subject at high 
risk for treatment complications.   
3) Received an investigational medicinal product within 60 days or 5 
half-lives prior to dosing with ADVM-022, whichever is longer  
4) Prior ocular gene therapy 
5) History of allergy to aflibercept, corticosteroid, or fluorescein dye or 
sodium fluorescein used in angiography (mild allergy amenable to 
treatment is allowable) 
6) Pregnancy 
a) Women who ever intend to become pregnant 
b) Women who are currently or ever intend to breastfeed 
c) For women of childbearing potential (a woman is considered to 
be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (>12 continuous months of 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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amenorrhea with no identified cause other than menopause), and 
has not undergone surgical sterilization (removal of both ovaries 
and/or uterus). The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements): 
i) May participate only if they have a negative pregnancy test 
at screening  
ii) Must agree to remain abstinent (refrain from heterosexual 
intercourse) or use acceptable contraceptive measures that 
result in failure rate < 1% per year  
(1) Examples of acceptable contraceptive methods include 
bilateral tubal ligation, male sterilization; hormonal 
contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices; and copper intrauterine devices. 
(2) Contraception methods that do not result in a failure rate 
of < 1% per year such as male or female condom with or 
without spermicide; and cap, diaphragm, or sponge with 
spermicide are not acceptable. The reliability of sexual 
abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle 
of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 
7) History or evidence of any of the following cardiovascular disease 
within 6 months of dosing: 
a) Severe cardiac disease (e.g., New York Heart Association 
[NYHA] Functional Class III or IV) or clinical evidence of 
unstable angina 
b) Acute coronary syndrome, myocardial infarction or coronary 
artery revascularization  
c) Ventricular tachyarrhythmias requiring ongoing treatment, or 
uncontrolled arrhythmia  
d) Uncontrolled hypertension defined as systolic blood pressure 
(SBP) >160 mmHg or a diastolic blood pressure (DBP) >100 
mmHg, despite using BP–lowering medication within the 
screening period. If BP-lowering medications are required, 
subject should be on a stable dose of the same medication 
continuously for 30 days prior to randomization. 
e) History of cerebrovascular accident or transient ischemic attack  
8) Any history of ongoing bleeding disorders.  The use of aspirin or 
other anticoagulants (e.g., Factor Xa inhibitors) is not an exclusion.   
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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9) HbA1C >10%; or history of diabetic ketoacidosis within 3 months 
prior to randomization; or subjects who, within the last 3 months, 
initiated intensive insulin treatment (a pump or multiple daily 
injection) or plan to do so in the next 3 months 
 
 
 
 
 
12) History of malignancy within the last 5 years except for the 
following adequately treated: 
a) Local basal cell or squamous cell carcinoma of the skin  
b) Carcinoma in situ of the cervix or breast  
c) Papillary, noninvasive bladder cancer  
d) Prostate cancer Stage 1 and 2 for which observation is clinically 
indicated with stable prostate-specific antigen (PSA) for 6 
months  
e) Any other cancer that has been in complete remission for at least 
2 years or considered surgically cured 
13) Known to be positive for HIV or active viral hepatitis (unless 
documented cure after treatment for Hepatitis C)  
14) Known history of syphilis  
15) Known severe renal impairment, as indicated by estimated CrCl <30 
mL/min (by Cockcroft-Gault calculation); need or anticipated need 
for hemodialysis during the study period 
16) Other significant laboratory abnormalities that the Investigator feels 
may compromise the subject’s safety 
17) Any febrile illness within 1 week prior to randomization. 
Ocular Exclusion Criteria (Study Eye) 
18) High-risk PDR at time of screening, defined as: any vitreous or 
preretinal hemorrhage, neovascularization elsewhere >1/2-disc area 
within an area equivalent to standard ETDRS 7-field on clinical 
examination, or neovascularization of disc > 1/3-disc area on 
clinical examination 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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19) Any prior focal or grid laser photocoagulation or any prior PRP in 
the study eye 
 
 
  
 
 
  
 
 
 
23) History of retinal disease in the study eye other than diabetic 
retinopathy including age-related macular degeneration (in either 
eye), retinal vein occlusion, retinal arterial occlusion, pathologic 
myopia etc.) 
24) Any current or history of ocular disease other than DME that, could 
reduce the potential for visual improvement, confound assessment 
of the macula or require medical or surgical intervention during the 
study (e.g. significant cataract, macular traction) or any evidence of 
posterior subcapsular cataract   
25) History of cataract extraction or YAG capsulotomy within 3 months 
before Day 1 
26) History of retinal detachment (with or without repair) in the study 
eye 
27) History of trabeculectomy or glaucoma shunt or minimally invasive 
glaucoma surgery (MIGS) 
 
 
 
 
 
 
 
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Advernm Biotechnologies, Inc. 
ADVM-022 (AA V.7m8-aflibercept) 
Protocol No. ADVM-022-04 (Amendment 7.0) 
Adverum Biotechnologies, Inc. 
Clinical Protocol No. ADVM-022-04 
ADVM-022 (AA V.7m8-aflibe1·cept) 
Amendment 7.0, 05 August 2021 
Minimization of 
Bias: 
Method of 
Administration: 
Ocular Exclusion Criteria (Fellow or Study Eye) 
36) Known histo1y of ocular HSV, VZV, or CMV including viral 
uveitis, retinitis or keratitis 
37) Evidence of external ocular infection, including conjunctivitis, 
chalazion or significant blepha1itis 
38) Histo1y of ocular toxoplasmosis 
Subjects will be randomized to one of 5 arms. The treatment assignment 
will be masked to the subject, the physician and/or staff conducting 
outcome assessments, the central reading center and the sponsor. At the 
study site, only the site staff that prepares the study diug for 
administration and the physician administe1ing the study diug will be 
unmasked. See the IMP manual for additional details. 
An independent review of OCT images, fluorescein angiography (FA) 
and fundus photographs, will be perfo1med at a central reading center to 
provide an objective assessment of these evaluations. 
Safety and disease activity assessment will be perfo1med by the masked 
physician. 
Unmasking of subject treatment assignments was planned to be 
rese1ved until the end of the study. Emergency unmasking for all 
subjects has been required, as dete1mined by the Sponsor with input 
from the Data Monitoring Committee, to preserve subject safety. The 
study in effect has become an open-label study, in which all prior 
masked roles will be able to continue study paiticipation in an 
unmasked manner. 
Both ADVM-022 and aflibercept will be administered via IVT 
injection. Aseptic technique with povidone-iodine will be employed. 
Topical and/or subconjunctival anesthesia will also be used. Post-
injection cai·e and medication regimen will be given based as 
institutional standai·d of care. 
The sham ocular injection procedure will also be done under the same 
conditions but with an empty syiinge without a needle (using the blunt 
end) pressed against the eye to mimic an injection. 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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Safety Assessments: 
The safety of ADVM-022 will be assessed through the collection of 
AEs, vital signs, physical examinations, ocular examinations, imaging, 
and laboratory evaluations.  
Statistical Methods 
and Data Analysis: 
No formal statistical testing is planned for the study. All safety and 
efficacy variables will be summarized descriptively by treatment arm. 
Mean, standard deviation (SD), median and range will be provided for 
continuous variables; and frequency counts and percentages will be 
provided for categorical variables.  Kaplan-Meier survival analysis will 
be utilized to derive median time to the first occurrence of DME disease 
worsening. All rescue aflibercept injections received by each subject 
during the study will be summarized using statistical models for 
recurrent events.  Mean cumulative function (MCF) curve over time 
will be plotted for the mean cumulative number of injections. Mixed-
effect models for repeated measures (MMRM) will be employed to 
explore the treatment effect on the change over time in BCVA and CST. 
The treatment effect on DRSS changes over time will be explored using 
generalized mixed models for categorical outcomes.  Interim analysis is 
planned after all subjects have been followed 24 weeks.  As unmasking 
of all subjects has occurred prior to the end of the study, the study in 
effect has become an open-label study.   
 
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Protocol No. ADVM-022-04 (Amendment 7.0)
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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2.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AAV 
Adeno-Associated Virus 
AE 
Adverse Event 
AMD  
Age-Related Macular Degeneration 
BCVA 
Best Corrected Visual Acuity 
BID 
Two times a day 
cDNA 
Complementary DNA 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations  
CIOMS 
Council of International Organizations of Medical Sciences 
CMV 
Cytomegalovirus 
CNV 
Choroidal Neovascularization 
CRF 
Case Report Form 
CrCl 
Creatinine Clearance 
CRO 
Clinical Research Organization 
CST 
Central Subfield Thickness 
CTA 
Clinical Trial Agreement 
DBP 
Diastolic Blood Pressure  
DM 
Diabetes Mellitus 
DMC 
Data Monitoring Committee 
DME 
Diabetic Macular Edema 
DR 
Diabetic Retinopathy 
DRSS 
Diabetic Retinopathy Severity Scale 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture  
 
 
 
 
EOS 
End of Study  
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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Abbreviation or Term 
Definition/Explanation 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FA 
Fluorescein Angiography 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HED 
Human equivalent dose 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HEENT 
Head, ears, eyes, nose, and throat 
HIV 
Human Immunodeficiency Virus 
HbA1c 
Glycated hemoglobin 
HSV 
Herpes Simplex Virus 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
IUD 
Intrauterine Device  
IVT 
Intravitreal 
 
 
 
KPs 
Keratic Precipitates 
MCF 
Mean cumulative function 
MIGS 
Minimally invasive glaucoma surgery 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measures 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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Abbreviation or Term 
Definition/Explanation 
 
 
nAMD 
Neovascular (wet) Age-Related Macular Degeneration  
NSAID 
Nonsteroidal anti-inflammatory drug 
NHP 
Nonhuman Primate 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OCT-A 
Optical Coherence Tomography Angiography 
OTC 
Over the counter 
OU 
Oculus Uterque (both eyes) 
PASS 
Power and Sample Size (a proprietary software) 
PDR 
Proliferative Diabetic Retinopathy 
PE 
Physical Examination 
PRP 
Pan Retinal Photocoagulation 
PSA 
Prostate-specific antigen  
PT 
Preferred term 
Q2hr 
Every 2 hours 
QD 
Once a day 
QID 
Four times a day 
QoD 
Once every other day 
rAAV 
Recombinant Adeno-Associated Virus 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure  
SD 
Standard deviation 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SE 
Study Eye 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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Abbreviation or Term 
Definition/Explanation 
Sf9 
Clonal isolate of Spodoptera frugiperda Sf21 commonly used in 
insect cells culture for recombinant protein production using 
baculovirus 
sFLT-1  
Soluble FLT-1 Receptor / Soluble VEGFR1 Receptor 
SOC 
System Organ Class 
sVEGFR 
Soluble Vascular Endothelial Growth Factor Receptor  
TID 
Three times a day 
UBM 
Ultrasound Biomicroscopy 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR1 
Vascular Endothelial Growth Factor Receptor 1 
VEGFR2 
Vascular Endothelial Growth Factor Receptor 2 
VZV 
Varicella-zoster virus 
YAG 
Yttrium Aluminum Garnet   
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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3.0 
BACKGROUND 
3.1 
Introduction  
Diabetic Retinopathy (DR) is a major complication of diabetes mellitus (DM) and is a leading 
cause of visual loss in the working age population (Wang 2018).  Diabetic Macular Edema 
(DME) is a complication of DR that affects central vision and can lead to a decline in vision 
ranging from slight visual blurring to blindness, substantially affecting independence and quality 
of life (Varma 2014). Anti-vascular endothelial growth factor (anti-VEGF) agents such as 
aflibercept (Eylea®), approved by the Food and Drug Administration (FDA), have demonstrated 
effectiveness at improving and maintaining vision in patients with DR and DME.  However, 
patients with DR and DME can struggle to adhere to treatment regimens with Eylea that call for 
monthly or bimonthly intravitreal (IVT) injections often leading to suboptimal outcomes in the 
real world.  This may be because diabetic patients are subject to significant lapses in follow-up 
because of illness, financial hardship or noncompliance. In patients treated with currently 
available anti-VEGF therapy alone, unintentional treatment interruptions can result in blinding 
complications including vitreous hemorrhage and tractional retinal detachment (Wubben 2019).  
There is, therefore, an unmet need for a long-acting anti-VEGF agent that can reduce the risks 
associated with lapses in follow-up. 
Gene-based delivery of anti-VEGF proteins has the potential to provide sustained intraocular 
anti-VEGF protein expression following a single administration, addressing this unmet medical 
need.  ADVM-022 is a gene therapy product that uses an adeno-associated viral vector capsid 
(AAV.7m8) encoding DNA for aflibercept and is administered as a single IVT injection.  
ADVM-022 is designed to provide sustained therapeutic levels of aflibercept and to minimize 
the burden of frequent anti-VEGF injections in the treatment of DME.  
3.2 
Investigational Medicinal Product (ADVM-022) 
The investigational medicinal product (IMP), ADVM-022 (AAV.7m8-aflibercept), is a 
recombinant, replication-deficient adeno-associated viral (rAAV) vector containing the 
AAV.7m8 protein capsid derived by in-vivo directed evolution on the AAV2 capsid 
(Dalkara 2013).  ADVM-022 carries an expression cassette of a codon-optimized version of the 
aflibercept complementary DNA (cDNA) under the control of a ubiquitous promoter.  ADVM-
022 is manufactured using the baculovirus expression vector system in Sf9 cells where two 
different baculoviruses are used, one encoding the genes for AAV2 Rep and AAV.7m8 Cap 
proteins, and the other encoding the human aflibercept cDNA expression cassette. 
ADVM-022 offers the potential for sustained intraocular expression of aflibercept, an anti-VEGF 
protein following a single IVT administration, the same route of administration that is standard 
for anti-VEGF drugs currently administered to patients. 
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Clinical Protocol No. ADVM-022-04 
 
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3.3 
Preclinical Summary for ADVM-022 
Results from nonhuman primate (NHP) preclinical pharmacology studies of ADVM-022 
conducted in a clinically relevant animal model of ocular neovascularization, laser-induced 
choroidal neovascularization (CNV), demonstrated the robust pharmacologic effects of 
ADVM-022 (Grishanin 2019).  A single IVT injection of ADVM-022 administered 2 months or 
13 months prior to laser photocoagulation reduced Grade IV lesion development to the same 
extent as a 1.2 mg IVT bolus of aflibercept recombinant protein (a current standard of care for 
nAMD and DR including DME) administered at the time of lesioning.  The effect of ADVM-022 
treatment on Grade IV CNV lesion incidence (as measured by FA) correlated with smaller size 
of fibrovascular CNV complexes (as measured by SD-OCT).  Notably, the effects on CNV 
development were identical whether the lesions were induced 2 months or 13 months post-
ADVM-022 administration, demonstrating the durability of the protective effect of this 
treatment.   
Analysis of aflibercept levels demonstrates that IVT injection of ADVM-022 provides sustained 
intraocular expression that results in high levels of aflibercept in the tissue in which DR and 
nAMD, i.e., retina and choroid.  Aflibercept levels found in the aqueous and vitreous humor, as 
well as ocular tissues of African green monkeys plateaued by one-month post-dose and were 
maintained out to 30 months post-administration, the last time point assessed (Johnston 2013).  
ADVM-022 administration was well-tolerated, showing transient intraocular inflammation that 
generally resolved over time.  The preclinical pharmacology studies provide a strong 
demonstration of the potential efficacy of IVT-delivered ADVM-022. 
3.4 
Other Clinical Studies of ADVM-022  
Clinical Protocol No. ADVM-022-01 (also referred to as the OPTIC study, ClinicalTrials.gov 
Identifier: NCT03748784) is a Phase 1, open-label, multi-center study to evaluate the safety and 
tolerability of a single IVT injection of ADVM-022 in subjects with nAMD.  Secondary 
objectives include evaluating the effect of ADVM-022 on best corrected visual acuity (BCVA), 
central subfield thickness (CST), macular volume, the need for rescue therapy, and presence of 
subretinal or intraretinal fluid.  
To be eligible for the study, subjects needed to be older than 50 years of age, have had prior or 
current evidence of active subfoveal CNV secondary to Age-Related Macular Degeneration 
(AMD), have received a minimum of 2 anti-VEGF injections within 4 months prior to screening, 
have vision in the study eye between 78 to 25 Early Treatment of Diabetic Retinopathy Study 
(ETDRS) letters, have vision in the non-study eye of ≥ 35 ETDRS letters, have demonstrated a 
meaningful anti-VEGF response defined as a reduction from diagnosis in CST by 30% or a 
reduction from screening in CST by 20% or normalization of CST with no wet AMD activity.  
Eligible subjects enrolled in the first two cohorts (Cohorts 1 and 2) received a dose of ADVM-
022 at 6 × 1011 vg/eye and 2 × 1011 vg/eye, respectively, with a prophylactic oral prednisone 
regimen.  Cohorts 3 and 4 subjects received a dose of ADVM-022 at 2 × 1011 vg/eye and 6×1011 
vg/eye, respectively, with a prophylactic topical difluprednate regimen. 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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The OPTIC study is ongoing as of the data cut-off date for this submission of March 10, 2021, 
with the planned 4 cohorts fully enrolled 
 all of whom have been dosed 
with ADVM-022. Patients completing OPTIC are encouraged to enroll in an ongoing 3-year 
long-term extension study at the last study visit (104 weeks), with similar ongoing assessments, 
Clinical Protocol No. ADVM-022-07 [OPTIC-EXT] (ClinicalTrials.gov: NCT04645212), 
initiated in November 2020.  
 
 
The OPTIC study population consisted of patients who previously required frequent injections to 
maintain vision. The mean years since diagnosis per cohort were 4.5 years, 4.1 years, 3.3 years, 
and 3.2 years for Cohorts 1-4 respectively. The mean number of anti-VEGF injections in the 12 
months prior to receiving ADVM-022 were 9.2, 9.2, 9.1, and 7.1 in Cohorts 1-4 respectively.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Adverum Biotechnologies, Inc. 
 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
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Clinical Protocol No. ADVM-022-04 
Amendment 7.0, 05 August 2021 
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3.5 
Formulation 
ADVM-022 drug product is formulated in a buffer composed of 180 mM NaCl, 5 mM Na2HPO4, 
5 mM NaH2PO4, and 0.001% Poloxamer 188 at pH 7.3.  The ADVM-022 drug product is 
supplied as a sterile-filtered, frozen suspension in a sterile, ready-to-use 0.5 mL Crystal Zenith® 
vial which contains approximately 0.25 mL of investigational medicinal product.  The vial is 
stoppered with a sterile, ready-to-use stopper made of chlorobutyl and sealed with a sterile 
aluminum seal.  The filled vials are placed in an outer carton and stored at ≤ -60°C. 
3.6 
Dose Justification 
 
  Other anti-VEGF treatments such as aflibercept 
have been studied using the same doses from their nAMD studies in their DME studies.  These 
studies subsequently demonstrated that those treatments were also safe and efficacious in DME. 
 
      
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 32 of 74 
 
 
 
  
 
 
 
 
 
 
 
4.0 
CLINICAL STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
4.1.1 
Primary Objective 
• To assess the durability of a single IVT injection of ADVM-022  
4.1.2 
Secondary Objectives 
Secondary Objectives: 
• To assess the safety and tolerability of ADVM-022 
• To evaluate the effect of ADVM-022 on macular edema  
• To evaluate the effect of ADVM-022 on Best Corrected Visual Acuity (BCVA)  
• To evaluate the effect of ADVM-022 on Diabetic Retinopathy Severity Scale (DRSS) score 
• To assess the need for rescue aflibercept (2 mg IVT)  
• To assess the effect of a preceding dose of aflibercept (2 mg IVT) prior to ADVM-022 
administration 
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Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
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Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 33 of 74 
• To evaluate the effect of ADVM-022 on development of vision threatening complications 
(including anterior segment neovascularization, vitreous hemorrhage, or tractional retinal 
detachment) 
4.2 
Endpoints 
4.2.1 
Primary Endpoints 
Time to worsening of DME disease activity in the study eye, as defined by the occurrence of 
either: 
• An increase in CST > 50 μm as assessed by SD-OCT compared to the lower of the two CST 
measurements recorded at Day 1 or Week 4 
• A loss of > 5 letters in BCVA due to worsening DME disease activity compared to the higher 
of the two BCVA measurements recorded at Day 1 or Week 4 
4.2.2 
Secondary Endpoints   
Unless specified otherwise, the secondary endpoints are based on outcome measures for the 
study eye. 
• Incidence and severity of ocular and non-ocular adverse events (AEs) 
• Change from Baseline in central subfield thickness (CST) and macular volume over time 
through Week 96 
• Change from Baseline in BCVA over time through Week 96   
• Frequency of rescue aflibercept (2 mg IVT) in the study eye over time during the study 
• Incidence of 2-step and 3-step improvement in DRSS score over time through Week 96  
• Incidence of 2-step and 3-step worsening in DRSS score over time through Week 96  
• Occurrence of vision threatening complication (anterior segment neovascularization, vitreous 
hemorrhage, or any other high-risk proliferative DR, or tractional retinal detachment) over 
time through Week 96 
• Incidence of CST <300 μm over time through Week 96 
• Incidence of clinically significant findings via physical examinations, ocular examinations, 
imaging, and laboratory evaluation 
5.0 
CLINICAL INVESTIGATION PLAN  
5.1 
Study Design 
This is a multi-center, randomized, double-masked, controlled, parallel-group study to evaluate 
the efficacy, safety and tolerability of a single IVT injection of ADVM-022.  Two doses of 
ADVM-022 will be investigated.  
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 34 of 74 
Subjects with initial diagnosis of DME within 6 months of screening and have received up to 2 
prior injections of anti-VEGF therapy are eligible for enrollment.  
Approximately 33 eligible subjects will be randomized to one of 5 arms.  Arm 1 (n=6) will 
receive ADVM-022 6 × 1011 vg/eye with a preceding aflibercept dose. Arm 2 (n=6) will receive 
ADVM-022 6 × 1011 vg/eye of without a preceding aflibercept dose. Arm 3 (n=6) will receive 
ADVM-022 2 × 1011 vg/eye with a preceding aflibercept dose. Arm 4 (n=6) will receive 
ADVM-022 2 × 1011 vg/eye of without a preceding aflibercept dose. Arm 5 (n=9) will receive 
aflibercept only (active control).  To maintain masking of the treatment assignment, subjects 
assigned to the arms with no preceding aflibercept on Day 1 or to the arm with no ADVM-022 
on Day 8 will receive a sham ocular injection on the corresponding visit.  Only one eye per 
subject will be selected as the study eye.  If both eyes are eligible, the eye with the worse BCVA 
will be the study eye.    
Subjects will be randomized to the following treatment arms in Table 3. 
Table 3: 
Study Arms 
Arm 
N 
Day 1 
IVT Aflibercept or Sham 
Day 8 
ADVM-022 Dose (vg/eye) 
1 
6 
Aflibercept 
6 × 1011 
2 
6 
Sham 
6 × 1011 
3 
6 
Aflibercept 
2 × 1011 
4 
6 
Sham 
2 × 1011 
5 
9 
Aflibercept 
Sham 
 
After the assigned IVT injections on Day 1 and Day 8, all subjects will return to the clinic on 
Week 2, Week 4, and then every 4 weeks up to Week 96.  To maintain masking, both subjects 
and the site personnel who conduct outcome assessments were originally masked to the 
treatment assignment throughout the study.   Emergency unmasking for all subjects has been 
required, as determined by the Sponsor with input from the Data Monitoring Committee, to 
preserve subject safety. The study has in effect become an open-label study, in which all prior 
masked roles will be able to continue study participation in an unmasked manner. 
5.1.1 
: 
 
 
    
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
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Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 35 of 74 
5.1.2 
Rescue Treatment: 
Starting at Week 8, subjects will receive rescue aflibercept (2 mg IVT) if they meet any of the 
following:  
• Increase in CST > 50 μm as assessed by SD-OCT compared to the lower of the two CST 
measurements recorded at Day 1 or Week 4 
• Loss of > 5 letters in BCVA due to worsening DME disease activity compared to the higher 
of the two BCVA measurements recorded at Day 1 or Week 4 
After initial rescue treatment administration, 
 
 Primary Investigator.  
Only intravitreal aflibercept injection (Eylea) is to be used for any rescue treatment unless prior 
approval by medical monitor.  
Aflibercept should not be injected in eyes with active inflammation. A minimum of 21 days is 
required between rescue aflibercept injections. 
5.1.3 
Data Monitoring Committee (DMC): 
An independent DMC will monitor safety and study conduct on an ongoing basis. Members of 
the DMC will be independent from the Sponsor and will follow a charter that outlines the DMC's 
roles and responsibilities. The DMC will meet every 3-6 months (frequency adjustable as 
required) to evaluate unmasked ocular and non-ocular safety events, with emphasis on the 
evaluation of the rate of ocular inflammation, increased IOP, endophthalmitis, and clinically 
significant decreases in BCVA. The DMC will also meet on an ad hoc basis if stopping rules are 
met as outlined below. The DMC may recommend stopping the study early for safety reasons. 
After reviewing the data, the DMC will provide a recommendation to the Sponsor as described in 
the DMC Charter. Any outcomes of these data reviews that affect study conduct will be 
communicated in a timely manner to the investigators for notification of their respective 
Institutional Review Boards (IRBs). 
5.1.4 
Stopping Rules: 
Enrollment will be suspended if any of the following sight threatening events occur:  
• 
A decrease of ≥ 30 letters in BCVA in the study eye compared with the prior visit  
• 
A surgical intervention (i.e., conventional surgery, vitrectomy) to prevent permanent loss of 
sight. 
• 
Severe intraocular inflammation (i.e., endophthalmitis, 4+ anterior chamber cell/flare, or 4+ 
vitreous cells)  
In addition, enrollment will be suspended if any serious adverse event potentially related to 
ADVM-022 occurs.  
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 36 of 74 
Any event that meets any of the above safety stopping criteria will be reported immediately to 
the Sponsor and enrollment and dosing will be suspended until the DMC has reviewed the data 
and made a recommendation to the Sponsor. 
The regulatory authorities and the Investigators, and each site’s IRB and other appropriate 
institutional regulatory bodies will be promptly notified if a decision to suspend enrollment is 
made. 
If study enrollment is suspended, all subjects who have already been treated will remain in the 
study and will continue to be monitored through their completion or withdrawal from the study    
5.2 
Study Duration 
Duration of subject’s participation in the study will be approximately 100 weeks for each subject 
(including up to 4-week screening period).  
5.3 
Study Population 
Subjects with newly diagnosed DME (diagnosis within 6 months of screening) that have 
received up to 2 prior injections of anti-VEGF therapy in the study eye. 
5.4 
Allocation to Treatment 
Each subject will be assigned a unique subject number after signing the informed consent.  
Subjects who complete the study screening assessments and meet all the eligibility criteria will 
be scheduled to enroll into the study and randomly assigned to one of the 5 treatment arms on 
Day 1. The planned allocation targets to have 6 subjects each for the four ADVM-022 arms.  
5.5 
Masking and Minimization of Bias 
This is a double-masked study.  Subjects and the designated masked study personnel will be 
masked to subject’s treatment assignment throughout the study.  There must be a minimum of 
two physicians per site to fulfill the masking requirements of the study.  A masked and 
unmasked investigator are required to be present for the Day 1 and Day 8 visits, thereafter only 
the masked investigator is required to be present.  
The roles and responsibilities for masked and unmasked personnel at the investigational site will 
be clearly documented on the Delegation of Authority Log.  Once assigned and executed, these 
roles should not be switched during the conduct of the study.  In unforeseen circumstances, a site 
can notify the Sponsor or designee for a switch of the study staff member from the masked role 
to the unmasked role but not vice versa. 
As unmasking of all subjects has occurred prior to the end of the study, the study in effect has 
become an open-label study, in which all prior masked roles will be able to continue study 
participation in an unmasked manner. 
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______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 37 of 74 
5.5.1 
Masked Roles 
If qualified, the study site personnel with masked role can take on any other masked role tasks 
except for tasks performed by the BCVA examiner. The designated roles for masked study site 
personnel include: 
• Assessor physician (typically the principal investigator) who evaluates all pre-treatment 
assessment as well as all safety and disease activity assessment at all visits 
• Photographer(s) and OCT technician(s) 
• Study Coordinator(s) who have any interaction with study subjects including assessments 
• BCVA examiner who will be masked to both the assigned treatment and the location (OD, 
OS) of the study eye.  The BCVA examiner will have no access to subjects’ medical record 
or the BCVA score from subjects’ previous visits and may have access only to a subject’s 
refraction data from previous visits.  The BCVA examiner is not allowed to perform any 
other task involving direct subject care. 
Additionally, study CRO staff (except those who are responsible for drug accountability or 
randomization), sponsor clinical study team, the Central Reading Center and the Central Lab 
personnel will be masked. 
5.5.2 
Unmasked Roles 
Every effort should be made to limit the number of unmasked study personnel to ensure the 
integrity of this masked study.  There should be no more than six unmasked personnel at a study 
site at one time.  In certain circumstances, the total number of unmasked personnel might be 
increased after discussion with and approval by the Sponsor.  Any other study personnel not 
listed below will be in the masked roles. 
• Treatment administrator: a retina specialist or a qualified ophthalmologist who is designated 
to perform the study treatment administration at Day 1 and Day 8.  He/she can conduct 
assessment prior to randomization visit as well as the post-treatment procedure (i.e., IOP, 
indirect ophthalmic examination and slit lamp) including the optional aqueous humor sample 
collection.  The person in this role will treat any adverse events that occur during or shortly 
after the study treatment administration; however, will not evaluate the causality of adverse 
events which is the responsibility of the masked assessor physician.  
• Either the assessor physician or the treatment administrator can administer rescue aflibercept 
(2 mg IVT). 
• Coordinator(s) and Pharmacist: A designated personnel who receives IMP and prepares the 
study treatment at Day 1 and Day 8.  The person in this role, if qualified, can be assigned to 
measure post-dose IOP.  If the site uses a pharmacy, then the unmasked role is also assigned 
to the pharmacist who performs study treatment related tasks per the Delegation of Authority 
Log. 
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______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 38 of 74 
5.6 
Emergency Unmasking 
If unmasking a particular subject is necessary for a medical emergency (e.g., in the case of a 
serious adverse event for which patient management might be affected by knowledge of 
treatment assignment) the investigator should contact the medical monitor directly.  
Emergency unmasking for all subjects has been required, as determined by the Sponsor with 
input from the Data Monitoring Committee, to preserve subject safety. The study has in effect 
become an open-label study, in which all prior masked roles will be able to continue study 
participation in an unmasked manner.  The unmasking process and sharing of subject treatment 
assignments will be communicated by the Sponsor or designee and must be documented properly 
at the site and sponsor levels.     
5.7 
Dispensing Instructions 
Each subject that has met the eligibility criteria will be assigned a treatment arm based on a 
randomization procedure. The unmasked site staff is responsible for dispensing the proper 
treatment per the assigned treatment arm. 
 
. 
5.8 
Investigational Medicinal Product Accountability and Reconciliation 
The unmasked designee will perform ADVM-022 accountability at the investigational site which 
requires reconciliation between the amount of ADVM-022 shipped to the investigational site, 
treatment assignment and dispensation.  
5.9 
Method of Administration 
Both ADVM-022 and aflibercept will be administered via IVT injection, as per the IMP Manual. 
IVT injection should not be administered if active inflammation is present. Aseptic technique 
with povidone-iodine should be used with topical or subconjunctival anesthesia.  Other than 
specified in the protocol, post-injection care and medication regimen will be performed as per 
institutional standard of care.  
5.10 
  
 
 
 
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 40 of 74 
6.0 
SUBJECT SELECTION CRITERIA AND WITHDRAWAL  
6.1 
Selection Criteria 
Subjects must meet the following criteria to be included in this study.  The subject must have an 
initial diagnosis of DME within 6 months of screening and have received a maximum of 2 prior 
anti-VEGF injections to be potentially eligible for this study. 
6.2 
Screening Records 
All screened subjects will be assigned a unique number.  A screening log or system will record 
the following minimum information: 
• Subjects screening number  
• Randomization Status  
• Screen Fail reason (if applicable) 
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 41 of 74 
6.3 
Inclusion Criteria  
1) Male or female subjects, age ≥ 18 years of age 
2) Type 1 or 2 diabetes mellitus 
3) Ability and willingness to provide informed consent to participate in the study requirements 
and visits prior to any study procedure 
4) Vision at Screening visit: 
a) Study Eye-BCVA 78 to 50 ETDRS letters, inclusive (approximate Snellen equivalent 
20/32 to 20/100)  
b) Non-study eye-BCVA 35 ETDRS letters or more (approximate Snellen equivalent of 
20/200 or better) 
5) CST of study eye at Screening visit of ≥ 325μm using Heidelberg Spectralis® with center-
involving IRF (center 1 mm) 
6) A decrease in vision in the study eye determined by the investigator to be primarily due to 
DME 
7) Initial DME diagnosis within 6 months from screening  
8) Up to 2 prior injections (0, 1, or 2) of anti-VEGF in the study eye 
a) If a prior anti-VEGF has been administered to the study eye, in the judgement of the 
Investigator, there must have been a meaningful CST response (e.g. ≥ 10% reduction) and 
no adverse reaction to anti-VEGF (e.g. inflammation) 
9) A minimum 60-day interval is required between the last anti-VEGF injection in the study eye 
and randomization on Day 1 
6.4 
Exclusion Criteria  
Participants with any of the following conditions are ineligible: 
6.4.1 
General Exclusion Criteria 
 
 
2) Any condition that, in the opinion of the investigator, could contraindicate the use of the 
investigational drug, ADVM-022, or that might affect interpretation of the study results or 
that renders the patient at high risk for treatment complications   
3) Received an investigational medicinal product within 60 days or 5 half-lives prior to dosing 
with ADVM-022, whichever is longer  
4) Prior ocular gene therapy 
5) History of allergy to aflibercept, corticosteroid, or fluorescein dye or sodium fluorescein used 
in angiography (mild allergy amenable to treatment is allowable) 
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.
I 

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 42 of 74 
6) Pregnancy 
a) Women who ever intend to become pregnant  
b) Women who are currently or ever intend to breastfeed  
c) For women of childbearing potential (a woman is considered to be of childbearing 
potential if she is postmenarcheal, has not reached a postmenopausal state (>12 continuous 
months of amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of both ovaries and/or uterus). The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
requirements): 
i) May participate only if they have a negative pregnancy test at screening 
ii) Must agree to remain abstinent (refrain from heterosexual intercourse) or use 
acceptable contraceptive measures that result in failure rate <1% per year:  
(1) Examples of acceptable contraceptive methods include bilateral tubal ligation, 
male sterilization; hormonal contraceptives that inhibit ovulation, hormone-
releasing intrauterine devices; and copper intrauterine devices  
(2) Contraception methods that do not result in a failure rate of < 1% per year such as 
male or female condom with or without spermicide; and cap, diaphragm, or 
sponge with spermicide are not acceptable. The reliability of sexual abstinence 
should be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.   
7) History or evidence of any of the following cardiovascular disease within 6 months of 
dosing: 
a) Severe cardiac disease (e.g., New York Heart Association [NYHA] Functional Class III or 
IV) or clinical evidence of unstable angina    
b) Acute coronary syndrome, myocardial infarction or coronary artery revascularization    
c) Ventricular tachyarrhythmias requiring ongoing treatment, or uncontrolled arrhythmia    
d) Uncontrolled hypertension defined as systolic blood pressure (SBP) >160 mmHg or a 
diastolic blood pressure (DBP) >100 mmHg, despite using BP–lowering medication 
within the screening period. If BP-lowering medications are required, subject should be on 
a stable dose of the same medication continuously for 30 days prior to randomization.  
History of cerebrovascular accident or transient ischemic attack     
8) Any history of ongoing bleeding disorders.  The use of aspirin or other anticoagulants (e.g., 
Factor Xa inhibitors) is not an exclusion.     
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Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Advernm Biotechnologies, Inc. 
ADVM-022 (AA V.7m8-aflibercept) 
Protocol No. ADVM-022-04 (Amendment 7.0) 
Adverum Biotechnologies, Inc. 
Clinical Protocol No. ADVM-022-04 
ADVM-022 (AA V.7m8-aflibe1·cept) 
Amendment 7.0, 05 August 2021 
9) HbAlC >10%; or histo1y of diabetic ketoacidosis within 3 months p1ior to randomization; or 
subjects who, within the last 3 months, initiated intensive insulin treatment (a pump or 
multiple daily injection) or plan to do so in the next 3 months. 
12) Histo1y of malignancy within the last 5 years except for the following adequately treated: 
a) Local basal cell or squamous cell carcinoma of the skin 
b) Carcinoma in situ of the ce1vix or breast 
c) Papillaiy, noninvasive bladder cancer 
d) Prostate cancer Stage 1 and 2 for which obse1vation is clinically indicated with stable 
prostate-specific antigen (PSA) for 6 months 
e) Any other cancer that has been in complete remission for at least 2 years or considered 
surgically cured 
13) Known to be positive for HIV or active viral hepatitis (unless documented cure after 
treatment for Hepatitis C) 
14) Known histo1y of syphilis 
15) Known severe renal impai1ment, as indicated by estimated CrCl <30 mL/min (by Cockcroft-
Gault calculation); need or anticipated need for hemodialysis during the study period 
16) Other significant laborato1y abno1malities that the Investigator feels may compromise the 
subject's safety 
17) Any feb1ile illness within 1 week prior to randomization 
6.4.2 
Ocular Exclusion Criteria (Study Eye) 
18) High-risk PDR at time of screening, defined as: any vitreous or preretinal hemoIThage, 
neovasculai·ization elsewhere > 1/2-disc ai·ea within an area equivalent to standard ETDRS 7-
field on clinical examination, or neovasculai·ization of disc > 1/3-disc ai·ea on clinical 
examination 
19) Any prior focal or giid laser photocoagulation or any prior PRP in the study eye 
CONFIDENTIAL 
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ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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23) History of retinal disease in the study eye other than diabetic retinopathy including age-
related macular degeneration (in either eye), retinal vein occlusion, retinal arterial occlusion, 
pathologic myopia, etc. 
24) Any current or history of ocular disease other than DME that, could reduce the potential for 
visual improvement, confound assessment of the macula or require medical or surgical 
intervention during the study (e.g. significant cataract, macular traction) or any evidence of 
posterior subcapsular cataract 
25) History of cataract extraction or YAG capsulotomy within 3 months before Day 1 
26) History of retinal detachment (with or without repair) in the study eye 
27) History of trabeculectomy or glaucoma shunt or minimally invasive glaucoma surgery 
(MIGS) 
 
 
 
 
 
 
 
 
6.4.3 
Ocular Exclusion Criteria (Fellow or Study Eye) 
 
 
 
36) Known history of ocular HSV, VZV, or CMV including viral uveitis, retinitis or keratitis 
37) Evidence of external ocular infection, including conjunctivitis, chalazion or significant 
blepharitis 
38) History of ocular toxoplasmosis 
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Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 45 of 74 
6.5 
Subject Withdrawal 
Subjects have the right to withdraw their informed consent to participate in the study at any time. 
However, every effort should be made to retain subjects in the study to monitor their safety.  If a 
subject chooses to discontinue, the subject is encouraged to return to clinic to be followed up on 
subject’s disease status and complete study assessment as specified by protocol.  Any missing 
assessment will be recorded as the protocol deviation. 
A subject may discontinue the study for the following reasons: 
• Withdrawal of consent by the subject 
• Lost to follow-up 
• Investigator’s decision (such as chronic noncompliance, adverse event(s) that put the safety of 
the subject at risk, significant protocol deviation, or best interest of the subject) 
• Study termination by the Sponsor 
• Death  
Subjects who withdraw prior to receiving the study treatment (ADVM-022 IVT or Sham ocular 
injection) on Day 8 after randomization will not be replaced directly.  However, the treatment 
allocation will be adjusted accordingly for subsequently enrolled subjects to achieve a target of 6 
treated subjects/arm for the 4 ADVM-022-treated arms and 9 treated subjects in Arm 5. 
If a subject is lost to follow-up, every reasonable effort should be made by the study site 
personnel to contact the subject.  At least two phone calls and a registered letter should be 
documented before considering subject lost to follow-up.  When a subject withdraws before 
completing the study, attempts of follow-up information should be documented in the source 
documents to include reasons of withdrawal. 
7.0 
STUDY ASSESSMENTS AND PROCEDURES  
The study assessments and procedures are outlined in the Schedule of Assessments, Section 18.1. 
In the event of an event that limits the ability of a site to conduct in-person clinic visits (e.g., in 
the case of a pandemic), certain safety assessments including medical history and concomitant 
medication information can be collected via phone calls. The contact should be documented in 
the subject’s source document and the CRF should be updated accordingly. Additional ocular 
examination and imaging assessments should be captured in the presence of active intraocular 
inflammation and/or significant vision loss (greater than or equal to 15 letters loss from 
Baseline), refer to the management of i
 (Section 5.11) and schedule of 
assessments (Section 18.1 and Section 18.2). Additional assessment requirements may be 
reduced based on severity and location of the inflammation on any subsequent follow-up visits. 
The procedure descriptions are as follows:   
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ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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7.1 
Informed Consent 
Informed consent confirming a subject’s willingness to participate in the study must be obtained 
before performing any study-specific screening tests, evaluations, or procedures.  Subjects will 
be provided with an IRB-approved informed consent form (ICF) detailing the IMP, study 
assessments, and study procedures.  Prior to being asked to sign the ICF, subjects will be given 
time to review the study information and ask questions. Acceptable remote methods of consent 
include mailing, emailing, and faxing of consent documents and telephone or video contact. 
7.2 
Confirm Eligibility 
All necessary procedures and evaluations must be performed to document that the subject meets 
the inclusion/exclusion criteria prior to randomization on Day 1 (Section 6.3 and Section 6.4).  In 
addition to the Investigator, the Central Reading Center will review imaging as part of eligibility 
assessment. 
7.3 
Medical History, Ophthalmic History, and Demographics 
The subject’s relevant medical and ophthalmic history will be collected and recorded.  The 
medical history collection period is defined as disease history up until screening.  Concurrent 
medical signs and symptoms must be documented to establish baseline severities.  A disease 
history, including the date of initial diagnosis, prior treatments, dates administered, and 
responses will be recorded. 
7.4 
General Physical Examination and Vital Signs 
The general physical examination (PE) will be conducted at screening and End of Study 
(EOS)/or Early Termination visit.  It consists of body system examination for general 
appearance, neurologic, HEENT (head, eyes, ears, nose, and throat), neck, cardiovascular, 
respiratory, abdomen, extremities, skin, and weight.  Height will be measured at screening only.  
At the EOS/or Early Termination visit, the physical examination will assess if any changes in the 
subject’s physical condition have occurred since the Screening examination. A targeted physical 
examination should be conducted as needed for the evaluation of AEs.  
Vital signs will consist of blood pressure, pulse rate, body temperature, and respiratory rate.  
Systolic and diastolic blood pressure and pulse rate will be measured after subjects have been at 
rest (seated) for at least 5 minutes. 
7.5 
ECG Evaluation 
A 12-lead Electrocardiogram (ECG) will be taken for each subject at Screening and EOS/or 
Early Termination Visit.  The Investigator will assess whether the ECG is normal, abnormal and 
not clinically significant, or abnormal AND clinically significant.   
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Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 47 of 74 
7.6 
Laboratory Tests 
Clinical Laboratory, Vector Expression and Immune Response tests will be performed centrally 
as specified in the Schedule of Assessments. The procedures for sample collection, process and 
shipment are described in the Study Laboratory Manual.  
7.6.1 
Clinical Laboratory Tests 
The following Clinical Laboratory Tests will be conducted for the study:  
• Chemistry  
• CBC  
• HbA1C 
• Urinalysis 
• Serum or urine Pregnancy Testing (females of child-bearing potential) 
• HLA-B27 genotyping   
A detailed listing of clinical laboratory tests is outlined within the Study Laboratory Manual. 
Laboratory reports will be made available to the Investigator in a timely manner to ensure 
appropriate clinical review.   
7.6.2 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
   
7.7 
Full Ophthalmic Examination 
The assessment will include an ophthalmologic exam, Intraocular Pressure (IOP), and indirect 
ophthalmoscopy.   
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Adverum Biotechnologies, Inc.
I 
I 
I 
I 
I 

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 48 of 74 
The ophthalmic examination will consist of an external examination of the eye and adnexa, 
routine screening for eyelid/pupil responsiveness (including but not limited to blepharoptosis, 
abnormal pupil shape, unequal pupils, abnormal reaction to light, and afferent pupillary defect), 
and slit-lamp examination (eyelids, conjunctiva, cornea, lens, iris, anterior chamber).  The slit-
lamp examination will examine the anterior ocular structures and will be used for grading any 
findings.  If any finding is noted during the slit-lamp examination, at any visit, the severity will 
be graded by the Investigator and the finding should be described as clinically significant or not 
clinically significant. 
The IOP measurements will be performed using a Goldmann applanation tonometer or Tono-
pen™, as specified in the Schedule of Assessments. The same method of IOP measurement must 
be used throughout the study for each individual subject.  IOP measurements will be performed 
prior to any IVT injection and prior to dilating eyes, using the same method throughout the 
study.  Every effort should be made to have IOP measurements performed at approximately the 
same time of day and using the same type of instrument for a given subject throughout the study, 
whenever possible.  Day 1 and Day 8 visits will require pre-injection and post-injection (30 
minutes after injection) IOP measurements. Study eye post injection IOP measurement is also 
required following any rescue aflibercept injection.  Any post injection IOP measurements of the 
fellow eye are optional. 
The dilated indirect ophthalmoscopy examination will include an evaluation of posterior segment 
abnormalities of the vitreous, optic nerve, peripheral retina, and retinal vasculature.  If any 
finding is noted during the ophthalmoscopy, at any visit, the severity will be graded by the 
Investigator and the finding should be described as clinically significant or not clinically 
significant.  Day 1 and Day 8 visits will require pre-injection and post-injection indirect 
ophthalmoscopy assessments. Post injection indirect ophthalmic exam of the study eye is also 
required following any rescue aflibercept injection.  Post injection indirect ophthalmic 
examinations of the fellow eye are optional. 
7.8 
Refraction and Visual Acuity 
Refraction and BCVA will be measured by a trained and certified visual acuity examiner(s) at 
the study sites.  
Visual acuity measurements will be measured at a starting distance of 4 meters, prior to dilating 
eyes.  A visual acuity specifications document, procedure manual, and training materials will be 
provided to the investigational sites, and examiner certification will be obtained.  The visual 
acuity examination room must be certified prior to any visual acuity examinations.  The full 
refraction and VA procedure will be provided in the 
. 
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Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 49 of 74 
7.9 
Imaging 
All imaging procedures will be described in a 
 
. All images should be taken according to the Schedule of Assessments. All 
images should be kept at the site with copies sent to the Central Reading Center.  
7.9.1 
Spectral Domain Optical Coherence Tomography - SD-OCT (Retinal and 
Optional Anterior Segment Imaging) 
SD-OCT is an interferometric technique that provides depth-resolved tissue structure information 
encoded in the magnitude and delay of the back-scattered light by spectral analysis of the 
interference fringe pattern.  The same machine should be used for all study visits. Anterior 
segment images are optional if a site does not have the capability to take images of the anterior 
segment.  
If a subject received anti-VEGF injections at visits prior to study randomization, OCTs from 
those visits should be collected and delivered to the central reading center.   
7.9.2 
Optional Optical Coherence Tomography Angiography (OCT-A) 
OCT-A is an imaging technology that provides volumetric, three-dimensional maps of the retina 
and choroid as well as information on blood flow. This procedure is optional and will only be 
utilized at sites with OCT-A instruments.  There are two types of OCT-A, swept-source and 
spectral-domain.  Swept-source imaging should be used where available. If a swept-source 
instrument is not available and a spectral-domain instrument is available, then the spectral 
domain instrument should be used.  
7.9.3 
Ultra-wide Field Fundus Photography and Iris Photography 
A standardized procedure for the collection of ultra-wide field fundus digital photographic 
images of the retina, optic disc, and macula will be followed. In addition, photographs of the iris 
will be taken prior to dilation.  
7.9.4 
Ultra-wide Field Fluorescein Angiography 
A standardized procedure for examining the retinal circulation and vessel permeability using a 
dye-tracing method will be followed.  This involves injection of sodium fluorescein into the 
systemic circulation, after which an angiogram is obtained by digitally photographing the 
fluorescence emitted after illumination of the retina with blue light at a wavelength of 490 nm.  
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 50 of 74 
7.9.5 
Optional Ultrasound Biomicroscopy (UBM) 
Ultrasound Biomicroscopy (UBM) is a technique primarily used for imaging the anatomy and 
associated pathologies of the anterior segment (AS) of the eye.  UBM uses a higher frequency 
transducer (35-100 MHz) than conventional ultrasound. UBM has utility in diagnosis and 
management of uveitis. UBM is optional at sites that have access to the appropriate equipment. 
Both eyes should be imaged, according to the Schedule of Assessments. 
7.10 
Laboratory, Biomarker and Other Biological Specimens 
All laboratory specimens should be collected as indicated in the Schedule of Assessments. 
Sample collection and handling guidelines will be described in the laboratory manual.  
7.10.1 
Optional Aqueous Humor Sampling 
If the subject consents, the aqueous humor sample should be collected by a qualified study staff, 
using aseptic procedure according to local guidelines. As indicated in the schedule of 
assessments, aqueous humor samples should also be obtained on visits in which a rescue 
aflibercept injection is administered. Aqueous humor samples should be collected prior to 
injection of aflibercept. Collection of aqueous humor samples is not required from subjects 
randomized to Arm 5 (sham treatment) following the unmasking of the study. 
Aqueous humor samples may be analyzed for levels of aflibercept, 
.  
Remaining samples will be analyzed for additional biomarkers. 
7.10.2 
Optional Vitreous Humor and Other Ocular Tissue Sampling 
If vitrectomy is medically necessary and the subject consents, an optional vitreous humor sample 
can be obtained.  Vitreous humor samples will be analyzed primarily for aflibercept 
concentrations. If any other surgical procedures become medically necessary in the study and/or 
fellow eye during the course of the study, other ocular tissues may be provided, including 
aqueous or vitreous humor and lens to be analyzed for other biomarkers. The remaining samples 
may be analyzed for other biomarkers.   
8.0 
REQUIRED, CONCOMITANT AND EXCLUDED MEDICATIONS 
8.1 
Required Medications 
8.1.1 
 
 
 
8.1.2 
Eylea® (aflibercept) 
Eylea (aflibercept) is indicated for the treatment of patients with DME; it is commercially 
available (Eylea USPI). 
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 51 of 74 
8.2 
Concomitant Treatments 
Concomitant treatments are any prescription or over-the-counter drugs and medical procedure 
other than protocol specified procedural medications and pre- and post- IVT injection 
medications used by a subject 30 days before Day 1 until the subject’s end of study or early 
termination visit. 
At the discretion of the evaluating physician, subjects may continue to receive all medications 
and standard treatments administered for other conditions except for treatments noted in the 
exclusion criteria described above and as noted in the prohibited medications section below. 
Prohibited Medications and Treatments 
The following medications are prohibited during the study: 
• Any systemic anti-VEGF agent including bevacizumab 
• Systemic drugs known to cause macular edema (e.g., fingolimod, tamoxifen, 
chloroquine/hydroxychloroquine)  
• Any anti-VEGF agent in the study eye other than the study drug or aflibercept IVT 2 mg, as 
defined in this protocol 
• 
 
 
• Systemic Immunosuppressive drugs (e.g., intravenous steroids, methotrexate, azathioprine, 
cyclosporin, adalimumab, infliximab, etanercept).  Inhaled or topical steroids and NSAIDs 
are allowed 
• Use of any other investigational study treatment or device 
Note:  Subjects who develop high-risk PDR in the study eye may receive panretinal 
photocoagulation (PRP) after receiving rescue aflibercept. 
Note:  Subjects with visually significant cataract cannot be enrolled in the study but if a 
cataract develops during the study, cataract surgery in the study eye may be performed if 
clinically indicated and is scheduled > 90 days after ADVM-022 administration and/or 
> 7 days after the last injection of aflibercept.   
Note:  Subjects who develop DME in the fellow (non-study) eye may receive standard of 
care therapy.  
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Protocol No. ADVM-022-04 (Amendment 7.0)
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 52 of 74 
9.0 
ADVERSE EVENT HANDLING AND SAFETY REPORTING 
9.1 
Assessment of Safety 
The Investigator or site staff is to be responsible for detecting, documenting, and reporting all 
events that meet the definition of an AE or an SAE, regardless of relationship to ADVM-022.  
For AEs and SAEs, the reporting period begins at the time the subject signs the informed consent 
and ends at 30 days after the last study visit.  Between the time of informed consent and study 
treatment administration on Day 1, only AEs (non-serious and serious) assessed as related to 
study procedures should be reported.  Events that occurred after the informed consent but prior to 
Day 1 treatment administration that are not related to study procedures should be recorded as 
Medical History Events.  After treatment administration, all clinically significant AEs should be 
reported.  Unless a subject withdraws consent for follow-up, each subject must be followed until 
a) the end of the AE reporting period at 30 days after the last study visit or b) for any ongoing 
IMP related AEs and/or SAEs until they are considered resolved or stable.    
The Investigator should use appropriate judgment in ordering additional tests as necessary to 
monitor the resolution of events.  The Adverum Medical Monitor may request that certain 
SAE/AE be followed longer.  
However, any clinically significant safety assessment that is associated with DME shall not be 
reported as an AE or SAE, unless judged by the Investigator to be more severe than expected for 
the subject’s condition.  Progression of the disease under study will be captured as an efficacy 
outcome. 
9.2 
Adverse Events 
An AE is any untoward medical occurrence in an enrolled subject regardless of its causal 
relationship to the IMP including but not limited to: 
• Any new disease or exacerbation of an existing condition 
• Constellations of individual signs, symptoms and laboratory values should be reported as the 
underlying diagnosis when possible (e.g., elevated WBC, cough and fever associated with 
pneumonia should not be reported as individual AEs but rather as the unifying condition of 
pneumonia) 
• Recurrence of a sporadic medical condition (e.g., fever) not present at Baseline 
• Adverse events related to a protocol-mandated intervention, including those that occur prior 
to study treatment (e.g., aflibercept injection) 
9.3 
Definition of Serious Adverse Event  
An SAE is any untoward medical occurrence in an enrolled subject, regardless of its causal 
relationship to the ADVM-022, that results in:  
• death 
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
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• a life-threatening condition 
• inpatient hospitalization or prolongation of existing hospitalization 
• persistent or significant disability or incapacity or is a congenital anomaly or birth defect 
Important medical events that may not meet these criteria may be considered SAEs when, based 
on appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.   
9.4 
Adverse Events of Special Interest (Immediately reportable to Sponsor) 
Adverse events of special interest for this study are as follows: 
• Sight-threatening adverse events: An adverse event is considered to be sight-threatening and 
should be reported expeditiously if it meets one or more of the following criteria: 
– It causes a decrease of ≥ 30 letters in BCVA compared with the prior visit  
– It requires surgical or medical intervention (i.e., conventional surgery, vitrectomy) to 
prevent permanent loss of sight 
– It causes severe intraocular inflammation (i.e., endophthalmitis, 4+ anterior chamber 
cell/flare, or 4+ vitreous cells)  
All of the above-listed sight-threatening adverse events should be reported as serious adverse 
events, listing the underlying cause (if known) of the event as the primary event term. 
9.5 
Pregnancy-Related Event 
Pregnancy is not regarded as an AE unless there is a suspicion that an ADVM-022 may have 
interfered with the effectiveness of a contraceptive medication.   
To ensure subject safety, any pregnancy must be recorded on a clinical study pregnancy form; 
the form must be sent to CRO within 2 weeks of the study visit during which the pregnancy was 
reported.  The pregnancy must be followed-up to determine outcome (including spontaneous 
miscarriage, elective termination, normal birth, or congenital abnormality) and status of mother 
and child, even if the subject withdrew.   
Any pregnancy complication and elective terminations for medical reasons must be reported as 
an AE or SAE.  Spontaneous miscarriage must be reported as an SAE.  Any SAE occurring in 
association with a pregnancy, brought to the Investigator’s attention after the subject has 
completed the study, and considered by the Investigator as possibly related to the study treatment 
must be promptly reported to CRO.   
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Protocol No. ADVM-022-04 (Amendment 7.0)
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 54 of 74 
9.6 
Eliciting Adverse Events 
At every study visit, the subject is to be asked a standard non-leading question to elicit any 
medically related changes in their well-being; and if they have been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication regimens (prescription 
and OTC).   
9.7 
Reporting and Documenting Adverse Events 
AEs identified from any study data (e.g., laboratory values, PE findings, ophthalmic 
examination) for from review of other documents relevant to subject safety during the study are 
to be documented on the AE eCRF.  Information to be collected includes event term, time of 
onset; Investigator assessment of seriousness, severity, and relationship to ADVM-022; time of 
resolution of the event; any required treatment or evaluations; and outcome.  An AE resulting 
from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, 
or progression of comorbidities must be reported.  All AEs are to be followed to adequate 
resolution.  The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
AEs.   
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be recorded as an AE.  However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
Any SAE or AE of Special Interest must be reported to the Sponsor or its designee immediately 
e.g., within 24 hours after the time site personnel first learn about the event.  An event of interest 
reported will warrant further investigation by the Sponsor prior to dosing additional subjects.  
The following contact information is to be used for SAE reporting: 
CRO: 
Contact Information for Submission of SAE Report Form 
 
Phone:  
 
 
Fax:  
 
 
Email:
 
 
Prompt notification of SAEs by the Investigator to Adverum/CRO is essential so that legal and 
ethical responsibilities towards the safety of subjects are met.   
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Protocol No. ADVM-022-04 (Amendment 7.0)
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Adverum Biotechnologies, Inc.
-

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 55 of 74 
Adverum/CRO has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of ADVM-022.  Adverum/CRO will comply with country-
specific regulatory requirements relating to safety reporting to the regulatory authority, IRB, and 
Investigators.   
Investigator safety reports are prepared for suspected unexpected SAEs according to local 
regulatory requirements and Adverum/CRO policy and are forwarded to Investigators, as 
necessary.   
Any Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from Adverum/CRO is to file it with the 
IRB and notify the IRB, if appropriate according to local requirements.  
9.8 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’s daily 
activities.  The intensity of the AE will be rated on the following scale: 
Mild: The AE is noticeable but does not significantly impair the subject’s daily activities. 
Moderate: the AE reduces or impairs normal daily activity but is not incapacitating.  
Severe: the AE is incapacitating and results in an inability to perform normal daily activity.   
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of severity.  AEs characterized as intermittent do not require 
documentation of onset and duration of each episode. 
9.9 
Assessment of Causality 
The Investigator’s assessment of relationship of an AE to study treatment is part of the 
documentation process, but it is not a factor in determining what is or is not reported.  If there is 
any doubt as to whether a clinical observation is an AE, the event is to be reported. 
Investigator should assess potential causes of each adverse event and events should be 
considered related if there is “a reasonable possibility of a causal relationship” rather than if “a 
causal relationship cannot be ruled out.”  When assessing causality, Investigators should assess 
biological balancing — the probability that the suspect drug caused the Adverse Event (AE) 
must be weighed against the probability that an alternative candidate caused it.  The relationship 
or association of study treatment in causing or contributing to the AE is to be characterized using 
the following classification and criteria: 
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 56 of 74 
Definitely 
Related:  
A definite causal relationship exists between the study treatment and the 
AE; including a plausible time relationship to study treatment, and it 
cannot be explained by underlying or concurrent disease or other drugs/ 
exposures. 
Likely Related: 
There is a reasonable possibility that study treatment caused the adverse 
event; the event is unlikely attributed to underlying or concurrent disease 
or other drugs/exposures (i.e., alternative explanation).  There is a 
reasonable time sequence to administration of the study drug. 
Unlikely Related: 
Underlying or concurrent disease or other drugs/exposures provide 
plausible alternative explanations.  Temporal relationship to study 
treatment administration makes a causal relationship improbable. 
Not Related: 
There is no association between the study treatment and the reported 
event; there is a clear alternative explanation; a causal relationship is non-
plausible.  
 
9.10 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the Investigator deems the event to be chronic, or not clinically 
significant, or until the subject is considered stable. 
In the event of a subject death while participating in the study, the Investigator should request a 
full autopsy report, if available.  
9.11 
Overdose and Reporting 
An overdose is any dose of study treatment given that exceeds the dose described in the protocol.  
Any overdose, with or without associated AEs, must be promptly reported to the Medical 
Monitor.  An overdose without signs or symptoms is not to be recorded as an AE; any AEs 
associated with the overdose is to be reported on the eCRF.  There is no specific antidote for 
overdose of study treatment.  In the event of a suspected overdose, it is recommended that 
supportive clinical care be instituted as considered appropriate by the Investigator, based on the 
subject’s clinical symptoms. 
10.0 
ASSESSMENT OF EFFICACY 
The efficacy of ADVM-022 in the treatment of DME will be assessed by the following 
measures.  Baseline values for BCVA and SD-OCT endpoints refer to pre-treatment 
measurements taken on the Day 1 visit when aflibercept IVT or Sham ocular injection was 
administered.   
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 57 of 74 
• BCVA – Vision will be assessed primarily through the BCVA expressed as an ETDRS score 
(number of letters correctly read).  Maintenance of vision is classified if the subject has lost 
fewer than 15 letters in the ETDRS score compared to Baseline.  Calculated endpoints will 
include the mean change from Baseline, the percent gaining at least 15 letters compared to 
Baseline, and the percent losing 15 or more letters compared to Baseline. 
• Central subfield thickness – SD-OCT will be performed using approved equipment and 
standard techniques to evaluate thickness and fluid compared to Baseline values.  Endpoints 
will include CST and macular volume and be assessed by the Central Reading Center. 
• Aflibercept re-treatments – The incidence and timing of aflibercept injections given post 
ADVM-022 treatment over time. 
• For each timepoint, DRSS will be determined by the Central Reading Center using ultra-wide 
field color fundus photography and compared to Day 1.   
• Vision threatening complications (anterior segment neovascularization, diabetic macular 
edema, high-risk PDR development, vitreous hemorrhage, or tractional retinal detachment) 
as determined by ultra-wide field imaging and clinical examination by the Investigator. 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Sample Size Determination 
The durability of ADVM-022 will primarily be assessed through evaluation of the need for 
rescue aflibercept (2 mg IVT) due to worsening of DME disease activity.   Disease activity and 
rescue aflibercept (2 mg IVT) received will be summarized descriptively.  However, with 12 
subjects at a given dose level of ADVM-022 versus 9 subjects receiving aflibercept only 
(Control), there is a 93.1% power for a 1-sided Fisher Exact Test at an alpha level of 0.05 to 
claim a significant reduction in the rate (in terms of proportion of subjects) of disease worsening 
(or of receiving any rescue aflibercept 2 mg IVT) during a given follow-up time (say, 24, or 48 
weeks) when the true rate is 90% for the Control and 20% for the ADVM-022 treated.  Table 5 
summarizes the powers for the same hypothesis tests under several different assumptions in the 
rate of receiving any aflibercept injection. 
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Protocol No. ADVM-022-04 (Amendment 7.0)
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Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 58 of 74 
Table 5: 
Power for 1-Sided Fisher Exact Tests at Various Rate Assumptions 
Sample Size a 
Rate: 
Control 
Rate: 
ADVM-022 Treated 
Power b 
(1-sided Fisher Exact, 
α = 0.05) 
N=12 ADVM-022 Treated 
versus 
N=9 Control 
90% 
17% 
95.3% 
20% 
93.1% 
25% 
88.3% 
95% 
17% 
98.6% 
20% 
97.7% 
25% 
95.5% 
N=6 ADVM-022 Treated 
versus 
N=9 Control 
90% 
17% 
88.8% 
20% 
85.6% 
25% 
79.6% 
95% 
17% 
95.2% 
20% 
93.2% 
25% 
89.0% 
a 
The sample sizes are not adjusted for dropouts. 
b 
Power for the Fisher Exact test was based on binomial enumeration of all possible outcomes, which was 
performed using PASS 2019 v19.03.    
 
This study was also designed to assess safety and tolerability of ADVM-022 in subjects with 
DME.  If none of the subjects in a group have any untoward event, the 95% upper confidence 
limit of the event rate is 11.7% for a group size of 24 (the target number of subjects to receive 
ADVM-022), or 22.1% for a group size of 12 (the target number of subjects to receive each dose 
level of ADVM-022).  
11.2 
Analysis Populations 
The main analysis population will include all randomized subjects who receive the study 
treatment on Day 8 (ADVM-022 IVT or Sham ocular injection).  The summary will be based on 
the actual treatment received by the subject. 
11.3 
Statistical Methods 
No formal statistical tests are planned for the study.  All safety and efficacy variables will be 
summarized descriptively by treatment arm.  Mean, standard deviation (SD), median and range 
will be provided for continuous variables; and frequency counts and percentages will be 
provided for categorical variables.  Confidence intervals of the means and percentages will be 
provided at both 90% and 95% levels.  Kaplan-Meier survival analysis will be utilized to derive 
median time to the first occurrence of DME disease worsening.  All rescue aflibercept (2 mg 
IVT) received by each subject during the study will be summarized using statistical models for 
recurrent events.  Mean cumulative function (MCF) curve over time will be plotted for the mean 
cumulative number of injections.  Mixed-effect models for repeated measures (MMRM) will be 
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CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 59 of 74 
employed to explore the treatment effect on the change over time in BCVA and CST.  The 
treatment effect on DRSS changes over time will be explored using generalized mixed models 
for categorical outcomes.   
An interim analysis (IA) is planned after all subjects have been followed for 24 weeks.  The 
detailed IA plan will be described in the Statistical Analysis Plan (SAP).  As unmasking of all 
subjects has occurred prior to the end of the study, the study in effect has become an open-label 
study.   
12.0 
ETHICAL CONSIDERATIONS 
12.1 
Institutional Review Board / Institutional Biosafety Committee 
Federal regulations and the ICH guidelines require that approval be obtained for each clinical site 
from an IRB/IBC before participation of human subjects in research studies.  Before study onset, 
the protocol, informed consent form, and any other written information regarding this study to be 
provided to the subject or the subject’s legal guardian must be approved by the IRB/IBC, and 
written confirmation of such approval must be received by the site.  Documentation of all 
approvals and of the IRB/IBC compliance with ICH Guideline for Good Clinical Practice (E6) 
will be maintained by the site and will be available for review by the Sponsor or its designees. 
All approvals should be signed by the IRB/IBC chair or designee and must identify the IRB/IBC 
by name and address, the clinical protocol by title or protocol number or both, and the date 
approval or favorable opinion was granted.  
12.2 
Ethical Conduct of the Study 
The study is to be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and Council of International Organizations of Medical Sciences 
(CIOMS) Ethical Guidelines, and in accordance with the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), 
Harmonised Tripartite Guideline E6: Good Clinical Practice; 21 Code of Federal Regulations 
(CFR); and applicable laws and regulations. 
This study will be conducted in compliance with the protocol approved by the IRB/IBC, and 
according to GCP standards.  No deviation from the protocol will be implemented without the 
prior review and approval of the Sponsor and the IRB, except where it may be necessary to 
eliminate an immediate hazard to a subject enrolled in this study.  In such case, the deviation will 
be reported to the IRB as soon as possible. 
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CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 60 of 74 
12.3 
Subject Information and Consent 
The study specific ICF and the informed consent process must comply with the Declaration of 
Helsinki, US Title 21 Code of Federal Regulations (CFR) Part 50, Health Insurance Portability 
and Accountability Act of 1996 (HIPAA) (if applicable), and local laws.  The Investigator will 
draft the ICF, assent, and HIPAA authorization (if applicable) and submit the draft for review 
and comment by the Sponsor, and Investigator will submit the mutually agreed upon ICF, ascent, 
and HIPAA authorization (if applicable) to the IRB/IBC for approval.   
The Investigator or designee (designee listed on the Delegation of Responsibilities log) must 
explain in terms understandable by the subject the content of the ICF including the purpose and 
nature of the protocol, procedures, anticipated benefit, potential risks, possible AEs, and any 
discomfort that participation in the protocol may entail.  This process must be documented in the 
subject’s source record.  Each subject or legally acceptable representative must be allowed to 
read the ICF under conditions where there is adequate time to consider the risks and benefits 
associated with participation.   
Before any study-specific procedure or test is performed, the Investigator must be certain that the 
subject or legally acceptable representative understands the implications of participation in the 
study.  The subject or legally acceptable representative and the Investigator must sign and date 
the ICF before such subject is entered into the trial.  The Investigator is to retain the signed ICF 
and give a copy of the signed form to the subject or legally acceptable representative.  The 
process of obtaining informed consent is to be documented in the subject’s records. 
The Investigator or designee shall maintain a log of all subjects who have signed the ICF, or 
whose legally acceptable representative has signed the ICF; and indicate whether the subject was 
enrolled or the reason for non-enrollment.  
If the ICF is revised during the course of the study, any institution-specific modifications 
proposed by the site should be reviewed and approved by the Sponsor or designee before IRB 
submission.  
13.0 
INVESTIGATOR’S RESPONSIBILITIES  
A complete list of Investigator responsibilities is outlined in the Clinical Trial Agreement and the 
Statement of Investigator Form FDA 1572, both of which are signed by the Investigator before 
commencement of the study.  In summary, the Investigator will conduct the study according to 
the current protocol, the Statement of Investigator, the general investigational plan, and 
applicable laws and regulations; will read and understand the Investigator’s Brochure; will obtain 
IRB/IBC approval to conduct the study; will obtain informed consent from each study participant 
prior to their participation in the study; will maintain and supply to the Sponsor or designee, 
auditors, and regulatory agencies adequate and accurate records of study activity and drug 
accountability for study-related monitoring, audits, IRB/IBC reviews and regulatory inspections; 
will report SAEs to the Sponsor or designee and IRB/IBC according to the specifics outlined in 
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CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 61 of 74 
this protocol, which reports shall include an assessment of whether there is a reasonable 
possibility that the study drug caused the AE; will personally conduct or supervise the study; and 
will ensure that colleagues participating in the study are informed about their obligations in 
meeting the above commitments. 
14.0 
SPONSOR RESPONSIBILITIES 
A complete list of the Sponsor responsibilities is outlined in the Clinical Trial Agreement and in 
the laws and regulations of the country in which the research is conducted.  In summary, the 
Sponsor will select qualified Investigators, provide them with the information they need to 
properly conduct the study, ensure adequate monitoring of the study, ensure that each 
Investigator conducts the study in accordance with the general investigational plan and protocol, 
and promptly inform Investigators and health and regulatory agencies as appropriate of 
significant new adverse effects or risks with respect to the drug.  
14.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to a subject, must be reviewed and approved by the Sponsor prior to implementation. 
Protocol Amendments must be approved by the IRB/IBC before any subject can be enrolled into 
an amended protocol. 
14.2 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the procedures and processes 
as specified in the protocol.  A significant protocol deviation occurs when there is nonadherence 
to the protocol that might significantly (a) impact the completeness, reliability, and/or accuracy 
of the study data, or (b) affect a subject’s rights, safety, or well-being.  The Investigator or 
designee must document and explain any protocol deviation in the subject’s source 
documentation.  Any significant protocol deviation will be investigated and reported by the 
Sponsor and may lead to the subject being withdrawn from the study, termination of the 
Investigator’s participation in the study, and/or other actions. 
The Sponsor or designee will be notified of known significant protocol deviations by the 
Investigator. Protocol deviations found throughout the course of monitoring visits are to be 
documented by the clinical monitor.  The IRB/IBC should be notified of all applicable protocol 
deviations, in accordance with reporting requirements of the IRB/IBC, in a timely manner by the 
Investigator. 
14.3 
Confidentiality  
Investigators must comply with all applicable privacy laws and regulations (e.g., HIPAA).  
Information on maintaining subject confidentiality in accordance with individual local and 
national subject privacy regulations must be provided to each subject as part of the informed 
consent process, either as part of the ICF or as a separate signed document.  In the United States, 
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CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 62 of 74 
a site-specific HIPAA-compliant authorization form may be used.  The Investigator or designee 
must explain to each subject that for the evaluation of study results and potential marketing 
approval, the subject’s protected health information obtained during the study may be disclosed 
to the Sponsor and its designees, regulatory agencies, and the IRB/IBC.  
It is the Investigator’s or designee’s responsibility to obtain written permission to use protected 
health information from each subject.  If a subject withdraws permission to use protected health 
information, it is the Investigator’s responsibility to obtain the withdrawal request in writing 
from the subject and to ensure that no further data will be collected from the subject or used or 
disclosed except as necessary to protect the integrity of the study.  Any data collected on the 
subject before withdrawal will be used by Sponsor (and/or its designees) in the analysis of study 
results to protect the integrity of the study.  During the review of source documents by the 
monitors or auditors, the confidentiality of the subject will be respected in accordance with 
applicable professional standards and regulations. 
14.4 
Investigator’s Report to the IRB/IBC 
The Investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IBC.  
Upon completion of the study, the Investigator, where applicable, should submit to the IRB/IBC 
the summary of the study outcome.  
14.5 
Records Retention  
The Investigator is responsible for retaining documents as required by local law and applicable 
regulations, as well as ICH standards.  Essential documents should be retained until at least 
2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region; or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the ADVM-022.  These 
documents should be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator or institution as to when these documents no longer need to be retained. 
14.6 
Financial Disclosure and Obligations 
A separate financial agreement will be made between each Investigator and the Sponsor or its 
authorized representative. For this study, each principal Investigator and sub-Investigator (as 
designated on the Form FDA 1572) will provide a personally signed Financial Disclosure Form 
in accordance with 21 CFR Part 54.  Each Investigator will notify the Sponsor or its authorized 
representative of any relevant changes in financial disclosure information during the conduct of 
the study and for 1 year after the study has been completed. 
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CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 63 of 74 
Neither the Sponsor nor its designee is financially responsible for further testing or treatment of 
any medical condition that may be detected in the subject at the time of the informed consent 
process.  In the absence of specific arrangements, neither the Sponsor nor designee is financially 
responsible for further treatment of the subject’s disease. 
14.7 
Liability and Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the treating 
physician/designee will be provided.  The ICF will include a description of treatment in the event 
of a protocol-related injury and handling of the costs associated therewith, incorporating country- 
specific national regulations and / or local laws.  Allocation of financial responsibility as 
between Sponsor and each individual participating site for the costs associated with such 
treatment will be as specified in the relevant CTA.  Financial compensation for the lost wages, 
disability, or discomfort due the treatment with the ADVM-022 is not available.  Insurance has 
been undertaken according to the laws of the countries where the treatment protocol will be 
conducted.  An insurance certificate will be made available to the participating sites at the time 
of protocol initiation.  
14.8 
Publication Policy  
The study data may be considered for reporting at a scientific meeting or for publication in a 
scientific journal.  Authorship may be adjusted upon mutual agreements and in accordance with 
current standards for authorship as recorded in professional conference and journal submission 
instructions.  The data are the property of Adverum and cannot be published without the 
expressed written authorization of Adverum.  
15.0 
STUDY MANAGEMENT  
15.1 
Monitoring of the Study  
All aspects of the study will be monitored by the Sponsor or designee for compliance with 
applicable government regulation with respect to GCP and standard operating procedures.  
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB review, and regulatory agency inspections, including by providing direct access to all study 
records.  
In the event of an audit, the Investigator agrees to allow the Sponsor, representatives of the 
Sponsor, or applicable regulatory agencies an access to all study records.  The Investigator 
should promptly notify the Sponsor or designee of any audits scheduled by any regulatory 
authorities and promptly forward copies of any audit reports to the Sponsor. 
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CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 64 of 74 
15.2 
Data Quality Assurance  
The Sponsor shall implement and maintain quality control and quality assurance procedures to 
ensure that the study is conducted, and that data are generated, documented, and reported in 
compliance with the protocol, GCP, and applicable regulatory requirements.  This study shall be 
conducted in accordance with the provisions of the Declaration of Helsinki (October 2013) and 
all revisions thereof, and in accordance with the FDA regulations (21 CFR Parts 11, 50, 54, 56, 
and 312, Subpart D—Responsibilities of Sponsors and Investigators) and with the ICH 
guidelines on GCP (ICH E6). 
15.3 
Data Management  
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug. 
The Investigator or other study personnel will enter information from the source documents onto 
case report forms (CRFs) that will be used to collect the clinical study data.  A CRF must be 
completed for each enrolled subject with all required study data accurately recorded such that the 
information matches the data contained in medical records (e.g., physicians’ notes, nurses’ notes, 
clinic charts, and other study-specific source documents).  
Authorized study site personnel (e.g., listed on the Delegation of Authority log) will complete 
CRFs designed for this study according to the completion guidelines that will be provided.  The 
Investigator will ensure that the CRFs are accurate, complete, legible, and completed within a 
reasonable period of time.  At all times, the Investigator has final responsibility for the accuracy 
and authenticity of all clinical data.  The CRFs exist within an electronic data capture (EDC) 
system with controlled access managed by the Sponsor or its authorized representative for this 
study.  
Study staff will be appropriately trained in the use of CRFs and application of electronic 
signatures before the start of the study and before being given access to the EDC system.  
Original data and any changes of data will be recorded using the EDC system, with all changes 
tracked by the system and recorded in an electronic audit trail.  The Investigator attests that the 
information contained in the CRFs is true by providing electronic signature within the EDC 
system.  
After database lock, the Investigator will receive a copy of the subject data (e.g., paper, CD, or 
other appropriate media) for archiving at the study site. 
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______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 65 of 74 
16.0 
STUDY COMPLETION  
The study is expected to be completed at the time point when all subjects have exited the 
protocol for any reason, or the protocol is terminated at the sponsor’s discretion, whichever 
occurs first.  
The Sponsor has the right to terminate this study at any time at its discretion.  In terminating the 
study, the Sponsor and the Investigator will assure that adequate consideration is given to the 
protection of the subjects’ interests. 
65 of 74
CONFIDENTIAL
______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.

Adverum Biotechnologies, Inc. 
 
ADVM-022 (AAV.7m8-aflibercept) 
Clinical Protocol No. ADVM-022-04 
 
Amendment 7.0, 05 August 2021 
 
CONFIDENTIAL 
Page 66 of 74 
17.0 
REFERENCES 
Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated 
virus for therapeutic outer retinal gene delivery from the vitreous. Sci Transl Med. 
2013;5(189):189ra76. 
 
 
Eylea® Prescribing Information, Regeneron Pharmaceuticals, Inc. Tarrytown, NY. 
Grishanin R, Vuillemenot B, Sharma P, et. al. Preclinical Evaluation of ADVM-022, a Novel 
Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration. Molecular Ther. 
2019 Jan 2;27(1):118-129. 
Johnston SS, Wilson K, Huang A, et al.  Retrospective Analysis of First-Line Anti-Vascular 
Endothelial Growth Factor Treatment Patterns in Wet Age-Related Macular Degeneration. Adv 
Ther. 2013;30:1111–1127. DOI 10.1007/s12325-013-0078-4. 
Varma R, Bressler NM, Doan QV, et al.  Prevalence of and Risk Factors for Diabetic Macular 
Edema in the United States. JAMA Ophthalmol. 2014;132(11):1334-1340. 
Wang W and Lo ACY. Diabetic Retinopathy: Pathophysiology and Treatments. International 
Journal of Molecular Sciences. 2018;19(1816).  
Wubben, TJ and Johnson MW. Anti-Vascular Endothelial Growth Factor Therapy for Diabetic 
Retinopathy: Consequences of Inadvertent Treatment Interruptions. American J Ophthal. 
2019;204:13–18. https://doi.org/10.1016/j.ajo.2019.03.005 
 
 
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______________________________________________________________________________________________
ADVM-022 (AAV.7m8-aflibercept)
Protocol No. ADVM-022-04 (Amendment 7.0)
______________________________________________________________________________________________
IND 019849 / Sequence No. 0018
Adverum Biotechnologies, Inc.
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