A Phase I/IIa (Phase 1/Phase 2a), Open-label, Multiple-cohort, Dose-escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With RGX-314 in Subjects With Neovascular AMD (nAMD)
Phase: PHASE1
Conditions: Neovascular Age-related Macular Degeneration, Wet Age-related Macular Degeneration
Sponsor: REGENXBIO Inc.

 
 
 
CONFIDENTIAL                                                                Page 1 of 1 
 
STUDY PROTOCOL COVER PAGE 
 
Official Title of the study / Protocol Title: A Phase I/IIa, Open-label, Multiple-cohort, Dose-
escalation Study to Evaluate the Safety and Tolerability of Gene Therapy with RGX-314 in 
Subjects with Neovascular AMD (nAMD) 
 
Protocol Number: RGX-314-001 
NCT Number: NCT03066258 
Document Date: 10 February 2020; Version 10 
 
 
 

Protocol Number: RGX-314-001 
 
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A Phase I/IIa, Open-label, Multiple-cohort, Dose-escalation Study to Evaluate the 
Safety and Tolerability of Gene Therapy with RGX-314 in Subjects with 
Neovascular AMD (nAMD) 
 
Protocol Number: 
RGX-314-001 
Original Protocol: 
02 August 2016 
Current Protocol: 
10 February 2020; Version 10 
Indication: 
Neovascular age-related macular degeneration 
(nAMD) 
IND Number: 
17280 
EudraCT Number: 
N/A 
Sponsor: 
REGENXBIO Inc. 
9600 Blackwell Road, Suite 210 
Rockville, MD, USA 20850 
Sponsor’s Responsible  
Medical Director: 
 
 
 
 
This study is to be performed in compliance with the protocol, International Council 
on Harmonisation E6: Good Clinical Practice: Consolidated Guideline (ICH E6), and 
applicable regulatory requirements. 
 
Confidentiality Statement: This document contains confidential business and commercial information and 
trade secrets of REGENXBIO Inc. (REGENXBIO), and is being submitted solely in support of applicable 
regulatory approvals. No other use or disclosure of this document and of the information contained herein is 
permitted without the prior written consent of REGENXBIO. In accordance with 5 USC §552(b), esp. 5 USC 
§552(b)(4) REGENXBIO must be notified in writing of any requests for access to the information in this 
Protocol to enable REGENXBIO to make submissions about any potential disclosure. 

Protocol Number: RGX-314-001 
 
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1 
SYNOPSIS 
PROTOCOL TITLE:  
A Phase I/IIa, Open-label, Multiple-cohort, Dose-escalation Study to Evaluate the Safety and Tolerability 
of Gene Therapy with RGX-314 in Subjects with Neovascular AMD (nAMD) 
PROTOCOL NUMBER: 
RGX-314-001 
RATIONALE: 
Excessive vascular endothelial growth factor (VEGF) plays a key part in promoting neovascularization 
and edema in neovascular (wet) age-related macular degeneration (nAMD). Counteracting the effects of 
VEGF provides significant therapeutic benefit to subjects suffering from this disorder (AAO PPP, 2015). 
VEGF inhibitors (anti-VEGF), including ranibizumab (LUCENTIS®, Genentech) and aflibercept 
(EYLEA®, Regeneron), have been shown to be safe and effective for treating nAMD and have 
demonstrated improvement in vision. However, anti-VEGF therapy is administered frequently via 
intravitreal injection and can be a significant burden to the patients. The heavy treatment burden can lead 
to noncompliance, which can result in vision decline over time (Cohen et al, 2013; Holekamp et al, 2014). 
When given as needed according to a flexible dosing regimen, patients on average receive around 
7 injections of ranibizumab in the 1st year of disease and 4 to 5 injections in the 2nd year (CATT Research 
Group, 2012; Ho et al, 2014). Frequent intravitreal injections are associated with increased cumulative 
risk of vision-threatening adverse events (AEs) (Day et al, 2011).  
RGX-314 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a coding sequence 
for a soluble anti-VEGF protein. The long-term, stable delivery of this therapeutic protein following a 
1-time gene therapy treatment for nAMD could potentially reduce the treatment burden of currently 
available therapies while maintaining vision with a favorable benefit:risk profile. 
PHASE OF DEVELOPMENT:  
Phase I/IIa 
INVESTIGATIONAL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
RGX-314: AAV8.CB7.CI.amd42.RBG  
Up to 5 dose levels: 3 × 109 genome copies (GC)/eye (1.2 × 1010 GC/mL), 1 × 1010 GC/eye 
(4 × 1010 GC/mL), 6 × 1010 GC/eye (2.4 × 1011 GC/mL), 1.6 × 1011 GC/eye (6.2 × 1011 GC/mL), and  
2.5 × 1011 GC/eye (1 × 1012 GC/mL). 
Single-dose subretinal delivery after pars plana vitrectomy under local anesthesia. 
REFERENCE THERAPY, DOSE, AND MODE OF ADMINISTRATION: 
Ranibizumab (LUCENTIS, Genentech) 0.5 mg will be administered by intravitreal injection on Visit 1, 
14 days prior to RGX-314 subretinal delivery. 
RESCUE THERAPY, DOSE, AND MODE OF ADMINISTRATION: 
Starting at 4 weeks post-RGX-314 administration, the subject may receive intravitreal ranibizumab rescue 
therapy at the Investigator’s discretion in the study eye for disease activity if 1 or more of the following 
rescue criteria apply:  
 
Vision loss of ≥5 letters (per Best Corrected Visual Acuity [BCVA]) associated with 
accumulation of retinal fluid on Spectral Domain Optical Coherence Tomography (SD-OCT) 

Protocol Number: RGX-314-001 
 
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 
Choroidal neovascularization (CNV)-related increased, new, or persistent subretinal or 
intraretinal fluid on SD-OCT 
 
New ocular hemorrhage 
Further rescue injections may be deferred per the Investigator’s discretion if one of the following 
sets of findings occur: 
 
Visual acuity is 20/20 or better and central retinal thickness (CRT) is “normal” as assessed by 
SD-OCT 
 
Visual acuity and SD-OCT are stable after 2 consecutive injections.  
If injections are deferred, they will be resumed if visual acuity or SD-OCT get worse per the criteria above. 
OBJECTIVES: 
Primary Objective: 
 
To evaluate the safety and tolerability of RGX-314 through Week 26 (24 weeks post a single 
dose administered by subretinal delivery to subjects with nAMD) 
Secondary Objectives: 
 
To evaluate the long-term safety and tolerability of RGX-314 
 
To evaluate the concentration of RGX-314 protein levels in aqueous humor 
 
To evaluate the effect of RGX-314 on BCVA 
 
To evaluate the effect of RGX-314 on CRT as measured by SD-OCT 
 
To assess the need for rescue therapy 
 
To evaluate the effect of RGX-314 on CNV lesion growth and leakage as measured by fluorescein 
angiography (FA) 
ENDPOINTS: 
Primary Endpoint:  
 
Safety through Week 26 (24 weeks following RGX-314 administration): incidence of ocular and 
non-ocular AEs and serious AEs (SAEs) 
Secondary Endpoints:  
 
Ocular and non-ocular safety over 106 weeks 
 
Mean change from baseline in aqueous RGX-314 protein over time 
 
Mean change from baseline in BCVA over time 
 
Proportion of subjects gaining or losing ≥15 letters compared to baseline as per BCVA at 
Week 26, Week 54, and Week 106 
 
Mean change from baseline in CRT as measured by SD-OCT over time 
 
Mean number of anti-VEGF rescue injections over time  
 
Time to first anti-VEGF rescue injection 
 
Mean change from baseline in CNV lesion size and leakage area based on FA over time 
 
Immunogenicity measurements (neutralizing antibodies to adeno-associated virus serotype 8 
[AAV8], binding antibodies to AAV8, antibodies to RGX-314 protein, and Enzyme-Linked 
ImmunoSpot) 
 
Vector shedding analysis in serum and urine  
  
 
 
  

Protocol Number: RGX-314-001 
 
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INVESTIGATIONAL SITES: 
Approximately 8 sites in North America will participate in this study. 
NUMBER OF SUBJECTS PLANNED: 
Approximately 42 previously treated (with an anti-VEGF therapy) nAMD subjects meeting the 
inclusion/exclusion criteria (Cohorts 1 to 3: 6 subjects per dose cohort; Cohorts 4 and 5: approximately 12 
subjects per dose cohort) will be treated with RGX-314. At the discretion of the Sponsor, additional 
subjects may be enrolled if a subject(s) does not receive a full 250 μL dose in the subretinal space. 
DIAGNOSIS AND CRITERIA FOR INCLUSION AND EXCLUSION: 
Subjects must have a diagnosis of nAMD that is recurrent and persistent, responsive to anti-VEGF therapy, 
and requires frequent injections and meet the following criteria in order to be eligible for this study: 
Inclusion Criteria: 
1. Males or females aged ≥ 50 years and ≤ 89 years. 
2. Sentinel (1st) subject for each dose cohort must have a BCVA ≤20/63 and ≥20/400 (≤63 and ≥19 
Early Treatment Diabetic Retinopathy Study [ETDRS] letters) in the study eye. Following the 
sentinel subject evaluation, the rest of the subjects in the dose cohort must have a BCVA between 
≤20/40 and ≥20/400 (≤73 and ≥19 ETDRS letters) 
3. In the case both eyes are eligible, study eye must be the subject’s worse-seeing eye, as determined 
by the Investigator. 
4. Must have a documented diagnosis of subfoveal CNV secondary to AMD in the study eye. 
a. 
CNV lesion characteristics: lesion size needs to be less than 10 disc areas (typical disc 
area is 2.54 mm2), blood <50% of the lesion size. 
5. Must have received at least 4 intravitreal injections of an anti-VEGF agent for treatment of nAMD 
in the study eye in approximately 8 months (or less) prior to Visit 1, with anatomical response 
documented on SD-OCT.  
6. Must have subretinal or intraretinal fluid in the center subfield present at Visit 1 in the study eye, 
evidenced on SD-OCT unless the subject is a re-screen. 
a. 
Subjects who have previously met all inclusion criteria including the Visit 2 
responsiveness criterion on OCT, but did not receive RGX-314 within the window, may 
be re-screened and do not need to have fluid on entry or meet the Visit 2 responsiveness 
criterion again subject to discussion with and approval by Sponsor’s Medical Director. 
7. Must be pseudophakic (status post cataract surgery) in the study eye. 
8. Must be willing and able to comply with all study procedures and be available for the duration 
of the study. 

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9. Females of childbearing potential must have a negative urine pregnancy test at the screening visit, 
have negative serum results by Day 8, and be willing to have additional pregnancy tests during 
the study. 
10. Sexually active subjects (both female and male) must be willing to use a medically accepted 
method of barrier contraception (eg, condom, diaphragm, or abstinence) from screening visit until 
24 weeks after vector administration. Cessation of birth control after this point should be 
discussed with a responsible physician. 
11. Must be willing and able to provide written, signed informed consent. 
Exclusion Criteria: 
1. CNV or macular edema in the study eye secondary to any causes other than AMD.  
2. Blood occupying ≥50% of the AMD lesion or blood >1.0 mm2 underlying the fovea of the study 
eye. 
3. Any condition preventing visual acuity improvement in the study eye, eg, fibrosis, atrophy, or 
retinal epithelial tear in the center of the fovea. 
4. Active or history of retinal detachment in the study eye. 
5. Advanced glaucoma in the study eye. 
6. Any condition in the study eye that, in the opinion of the Investigator, may increase the risk to 
the subject, require either medical or surgical intervention during the course of the study to 
prevent or treat vision loss, or interfere with study procedures or assessments. 
7. History of intraocular surgery in the study eye within 12 weeks prior to the screening visit. 
Yttrium aluminum garnet capsulotomy is permitted if performed >10 weeks prior to the screening 
visit. 
8. History of intravitreal therapy in the study eye, such as intravitreal steroid injection or 
investigational product, other than anti-VEGF therapy, in the 6 months prior to screening. 
9. Presence of an implant in the study eye at screening (excluding intraocular lens). 
10. History of malignancy requiring chemotherapy and/or radiation in the 5 years prior to screening. 
Localized basal cell carcinoma will be permitted. 
11. Receipt of any investigational product within the 30 days of enrollment or 5 half-lives of the 
investigational product, whichever is longer. 
12. Participation in any other gene therapy study. 
13. History of therapy known to have caused retinal toxicity, or concomitant therapy with any drug 
that may affect visual acuity or with known retinal toxicity, eg, chloroquine or 
hydroxychloroquine. 
14. Ocular or periocular infection in the study eye that may interfere with the surgical procedure. 
15. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks within the past 
6 months. 
16. Uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg, diastolic BP >100 mmHg) 
despite maximal medical treatment. 
17. Any concomitant treatment that, in the opinion of the Investigator, may interfere with ocular 
surgical procedure or healing process. 
18. Known hypersensitivity to ranibizumab or any of its components or past hypersensitivity (in the 
Investigator’s opinion) to agents like RGX-314. 
19. Has a serious, chronic, or unstable medical or psychological condition that, in the opinion of the 
Investigator, may compromise the subject’s safety or ability to complete all assessments and 
follow-up in the study. 
Criteria for continuing study after receiving ranibizumab: 
At Visit 2, subjects (with the exception of re-screens who have met this criterion in the past) will be 
assessed for initial anti-VEGF response to ranibizumab. Subjects will undergo both SD-OCT and BCVA, 
which will be compared by the Investigator with the Visit 1 values: 

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1. Responsive (subjects will continue in the study): response is defined as reduction in CRT >50 µm 
or >30% improvement in  central fluid by SD-OCT.  
2. Non-responsive (subjects will exit the study as early withdrawals): non-response is defined as 
not meeting the criteria above. Additional subjects will continue to be enrolled until up to 
6 subjects (Cohorts 1 to 3) or up to 12 subjects (Cohorts 4 and 5) in each cohort receive a single 
dose of RGX-314. 
At this visit central lab results will be reviewed. Any subjects with the following values will be withdrawn: 
3. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 × upper limit of normal 
(ULN) 
4. Total bilirubin >1.5 × ULN unless the subject has a previously known history of Gilbert’s 
syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin 
5. Prothrombin time (PT) >1.5 × ULN 
6. Hemoglobin <10 g/dL for male subjects and <9 g/dL for female subjects 
7. Platelets <100 × 103/µL 
8. Estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 
STUDY DESIGN AND METHODOLOGY: 
In this Phase I/IIa, first-in-human, open-label, multiple-cohort, dose-escalation study, approximately 
42 nAMD subjects will be enrolled into up to 5 dose cohorts of RGX-314. Subjects who meet the 
inclusion/exclusion criteria will be enrolled and receive a 0.5 mg intravitreal injection of ranibizumab in 
the study eye (Visit 1). At Visit 2 (7 days after ranibizumab injection), subjects will be evaluated by 
SD-OCT to confirm anatomic response to the initial anti-VEGF activity associated with the ranibizumab 
injection compared with their baseline assessment. Subjects who do not have an anatomic response will 
be withdrawn from the study. For withdrawn subjects, anyone who has an AE associated with the 
ranibizumab injections on Visit 1 will be followed until the AE resolves (up to 30 days post-injection). At 
Visit 3 (Week 2), subjects will receive a single dose of RGX-314 administered in an operating room by 
subretinal delivery. 
The sentinel subject in each cohort will have vision of ≤20/63 and ≥20/400 (≤63 and ≥19 ETDRS letters). 
After RGX-314 administration to the sentinel subject, there will be a minimum of 4-week observation 
period for safety. The Internal Safety Committee will review the safety data for this subject and if there 
are no safety concerns, up to 5 (Cohorts 1 to 3) or up to 11 (Cohorts 4 and 5) additional subjects (with 
expanded vision criteria of ≤20/40 and ≥20/400 [≤73 and ≥19 ETDRS letters]) may be treated with RGX-
314, one per day on consecutive calendar days. If no safety review triggers (SRTs) are observed, then 
4 weeks after the last subject is dosed (with the exception of Cohort 4 which had an Independent Data 
Monitoring Committee (IDMC) review 4 weeks after the sixth subject was dosed, prior to cohort 
expansion to 12 subjects), all available safety data will be evaluated by the IDMC. Given that gene therapy 
studies in nAMD to date (Campochiaro et al, 2016; Constable et al, 2016; Rakoczy et al, 2015) have had 
events either related to the procedure or occasional inflammation that is mild and transient (resolving in a 
few weeks), 4 weeks will be adequate to assess these acute events in the sentinel subject. Additionally, if 
any event meets the criteria of a Stopping Rule, dosing of any new subjects will be suspended until a 
complete review of all safety data has been performed by REGENXBIO and the IDMC. At any given 
IDMC meeting, whether called for by an SRT or at the planned IDMC meeting, the IDMC may 
recommend to stop the study, proceed to the next dosing cohort, or proceed at a lower dose (up to a half 
log).  
Subjects will have 3 visits within the first 4 weeks after treatment with RGX-314 (1 day post-procedure 
and 1 week and 4 weeks post-procedure). Starting 4 weeks after RGX-314 administration, subjects may 
receive intravitreal ranibizumab rescue therapy at the Investigator’s discretion if they meet predefined 
rescue injection criteria. Immunogenicity to the vector and transgene product of RGX-314 will be assessed 
throughout the study. 

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Safety will be the primary focus for the initial 24 weeks after RGX-314 administration (primary study 
period). Following completion of the primary study period, subjects will continue to be assessed until 104 
weeks following treatment with RGX-314 (Week 106). At the end of the study, subjects will be invited to 
participate in a long-term follow-up study. 
The safety and tolerability of RGX-314 will be assessed in each dosed subject and will be monitored 
through assessment of ocular and non-ocular AEs and SAEs, chemistry, hematology, coagulation, 
urinalysis, immunogenicity, ocular examinations and imaging (BCVA, intraocular pressure, slit lamp 
biomicroscopy, 
indirect 
ophthalmoscopy, 
SD-OCT, 
fluorescein 
angiography 
[FA], 
fundus 
autofluorescence [FAF], and color fundus photography [CFP]), and vital signs.  Because of pigmentary 
changes observed in some subjects, starting with Protocol Version 10, additional ophthalmic assessments 
will include Optos Ultra-widefield FAF (in addition to Heidelberg Spectralis FAF), electroretinography if 
available, visual field test (Humphrey Full Field 120 or microperimetry), and, if applicable, additional SD-
OCT in the area of pigmentary change.  
All Investigators will be preselected based on their previous experience with subretinal delivery in clinical 
practice and will be further trained on the procedure as part of the proposed clinical study. A detailed 
description of the procedures can be found in the Administration Manual. 
STATISTICAL METHODS: 
All data will be presented in subject data listings. Categorical variables will be summarized using 
frequencies and percentages, and continuous variables will be summarized using descriptive statistics 
(number of non-missing observations, mean, standard deviation, median, minimum, and maximum). 
Graphical displays will be presented as appropriate.  
Safety and efficacy will be reported by dose cohort and may also be reported for all the dose cohorts 
combined.  
Sample Size and Power Calculation: 
No formal calculation was performed to determine sample size. 

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2 
TABLE OF CONTENTS 
1 
SYNOPSIS ............................................................................................................................. 2 
2 
TABLE OF CONTENTS .................................................................................................... 13 
LIST OF IN-TEXT TABLES ..................................................................................................... 16 
LIST OF IN-TEXT FIGURES ................................................................................................... 16 
3 
ABBREVIATIONS ............................................................................................................. 17 
4 
INTRODUCTION ............................................................................................................... 20 
4.1 Disease Background and Current Therapeutic Options ................................................. 20 
4.2 Brief Overview of the Development of the Investigational Product ............................... 21 
4.2.1 Nonclinical Data ............................................................................................................... 21 
4.2.2 Clinical Data ..................................................................................................................... 39 
4.3 Summary of Potential Risks and Benefits ......................................................................... 39 
4.3.1 Observed and Potential Risks ........................................................................................... 39 
4.3.2 Potential Benefits .............................................................................................................. 44 
4.4 Study Rationales .................................................................................................................. 44 
4.4.1 Rationale for Proposed Doses ........................................................................................... 44 
4.4.2 Rationale for use of a Sentinel Subject ............................................................................. 47 
5 
STUDY OBJECTIVES ....................................................................................................... 48 
5.1 Primary Objective ............................................................................................................... 48 
5.2 Secondary Objectives .......................................................................................................... 48 
6 
INVESTIGATIONAL PLAN ............................................................................................. 49 
6.1 Endpoints ............................................................................................................................. 49 
6.1.1 Primary Endpoints ............................................................................................................ 49 
6.1.2 Secondary Endpoints ........................................................................................................ 49 
6.1.3 Exploratory Endpoints ...................................................................................................... 49 
6.2 Study Design ........................................................................................................................ 50 
7 
SUBJECT POPULATION AND SELECTION ............................................................... 52 
7.1 Selection of Study Population ............................................................................................. 52 
7.1.1 Inclusion Criteria .............................................................................................................. 52 
7.1.2 Exclusion Criteria ............................................................................................................. 53 
7.1.3 Criteria for Continuing Study After Receiving Ranibizumab .......................................... 54 
7.2 Subject Recruitment and Screening .................................................................................. 54 
7.3 Withdrawal of Subjects ...................................................................................................... 55 

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8 
TREATMENTS ADMINISTERED .................................................................................. 56 
8.1 Ranibizumab ........................................................................................................................ 56 
8.1.1 Initial Treatment in the Study Eye .................................................................................... 56 
8.1.2 Rescue Therapy ................................................................................................................. 56 
8.2 Investigational Product ....................................................................................................... 56 
8.3 Method of Assigning Subjects to Treatment ..................................................................... 58 
8.4 Stopping Rules ..................................................................................................................... 58 
8.5 Investigational Product Accountability ............................................................................. 59 
8.6 Prior and Concomitant anti-VEGF Medications and Therapeutic Procedures ............ 59 
8.6.1 Prohibited Medications and Procedures ............................................................................ 60 
8.6.2 Permitted Medications and Procedures ............................................................................. 60 
8.7 Precautions ........................................................................................................................... 60 
9 
VISION AND SAFETY ASSESSMENTS ......................................................................... 61 
9.1 Schedule of Events ............................................................................................................... 61 
9.2 Demographics ...................................................................................................................... 61 
9.3 Medical and Medication History ........................................................................................ 61 
9.4 Ophthalmic Assessments .................................................................................................... 61 
9.5 Safety Assessments .............................................................................................................. 62 
9.5.1 Adverse Events ................................................................................................................. 62 
9.5.2 Pregnancy Testing ............................................................................................................. 62 
9.5.3 Clinical Laboratory Tests .................................................................................................. 62 
9.5.4 Vital Signs......................................................................................................................... 63 
9.6 Appropriateness of Measures ............................................................................................. 63 
10 
ADVERSE EVENT HANDLING AND SAFETY REPORTING................................... 64 
10.1 Definitions ............................................................................................................................ 64 
10.1.1 
Definition of an Adverse Event ................................................................................ 64 
10.1.2 
Definition of a Serious Adverse Event ..................................................................... 65 
10.2 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs 66 
10.3 Evaluation of Adverse Events/Serious Adverse Events ................................................... 66 
10.3.1 
Relationship to Study Treatment and/or Study Procedures...................................... 66 
10.3.2 
Severity or Intensity Grading of Adverse Event Scoring ......................................... 66 
10.4 Serious Adverse Events, Serious Adverse Drug Reactions, and Requirements for 
Immediate Reporting ................................................................................................................... 67 
10.5 Pregnancy Reporting .......................................................................................................... 68 

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10.6 Urgent Safety Measures ...................................................................................................... 68 
10.7 Safety Contact Information ................................................................................................ 69 
11 
STATISTICAL METHODS AND PLANNED ANALYSES .......................................... 70 
11.1 Determination of Sample Size ............................................................................................ 70 
11.2 Analysis Populations ........................................................................................................... 70 
11.3 Disposition ............................................................................................................................ 70 
11.4 Demographics and Baseline Characteristics ..................................................................... 70 
11.5 Safety Analyses .................................................................................................................... 70 
11.5.1 
Adverse Events......................................................................................................... 70 
11.5.2 
Clinical Laboratory Tests ......................................................................................... 71 
11.5.3 
Vital Signs ................................................................................................................ 71 
11.6 Efficacy Analyses ................................................................................................................. 71 
11.7 Other Statistical Issues ........................................................................................................ 71 
11.7.1 
Significance Levels .................................................................................................. 71 
11.7.2 
Missing or Invalid Data ............................................................................................ 71 
11.8 Interim Analysis .................................................................................................................. 71 
12 
SPECIAL REQUIREMENTS AND PROCEDURES ...................................................... 72 
12.1 Ethical Conduct of the Study ............................................................................................. 72 
12.1.1 
Institutional Review Board ...................................................................................... 72 
12.1.2 
Subject Information and Informed Consent ............................................................. 72 
12.2 Data Handling and Record Keeping .................................................................................. 73 
12.2.1 
Monitoring and Access to Study Records ................................................................ 73 
12.2.2 
Source Documents and Case Report Forms ............................................................. 73 
12.2.3 
Data Quality Assurance ............................................................................................ 74 
12.2.4 
Record Retention ...................................................................................................... 74 
12.3 Independent Data Monitoring Committee ........................................................................ 74 
12.4 Internal Safety Committee ................................................................................................. 74 
12.5 Financing and Insurance .................................................................................................... 74 
12.6 Provision of Study Results and Information to Investigators and Publication ............. 74 
13 
REFERENCES .................................................................................................................... 76 
14 
APPENDICES ..................................................................................................................... 83 
14.1 Guide to Signs and Symptoms of Toxicity ........................................................................ 83 
14.2 Ocular Inflammation Grading Scales................................................................................ 84 
15 
SIGNATURE PAGE ........................................................................................................... 86 

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LIST OF IN-TEXT TABLES 
TABLE 1: SCHEDULE OF EVENTS THROUGH THE END OF YEAR 1 (52 WEEKS 
AFTER RGX-314 ADMINISTRATION) ................................................................... 8 
TABLE 2: SCHEDULE OF EVENTS AFTER END OF YEAR 1 THROUGH YEAR 2 
(104 WEEKS AFTER RGX-314 ADMINISTRATION) .......................................... 11 
TABLE 3:  TABULAR SUMMARY OF PRECLINICAL STUDIES ........................................ 23 
TABLE 4: RGX-314 DOSE, VOLUME, AND CONCENTRATION ........................................ 46 
TABLE 5: RGX-314 PRODUCT DESCRIPTION ..................................................................... 57 
TABLE 6: SAFETY REVIEW TRIGGER EVENTS AND ACTIONS ..................................... 58 
TABLE 7: GRADING SCALE FOR OCULAR INFLAMMATION: ANTERIOR CHAMBER 
CELLS AND ANTERIOR CHAMBER FLARE ...................................................... 84 
TABLE 8: GRADING SCALE FOR VITREOUS HAZE .......................................................... 85 
 
LIST OF IN-TEXT FIGURES 
FIGURE 1: ANTERIOR CHAMBER CONCENTRATION OF ANTI-VEGF FAB .................. 28 
FIGURE 2:  ANTERIOR CHAMBER CONCENTRATION OF ANTI-VEGF FAB – 36 
MONTHS .................................................................................................................. 29 
FIGURE 3: DOSE-DEPENDENT REDUCTION IN NEOVASCULAR AREA IN RHO/VEGF 
MICE ADMINISTERED SUBRETINAL INJECTIONS OF RGX-314 .................. 30 
FIGURE 4: DOSE-DEPENDENT REDUCTION IN THE INCIDENCE AND SEVERITY OF 
RETINAL DETACHMENT IN TET/OPSIN/VEGF MICE ADMINISTERED 
SUBRETINAL INJECTIONS OF RGX-314 ............................................................ 31 
FIGURE 5: CONCENTRATION OF RGX-314 TRANSGENE PRODUCT BY DOSE ............ 32 
FIGURE 6: LEVELS OF MRNA FOR RGX-314 IN RETINA DETERMINED BY RT-QPCR 34 
FIGURE 7: CONCENTRATION OF ANTI-VEGF FAB IN ANTERIOR CHAMBER FLUID, 
VITREOUS, AND RETINA ..................................................................................... 35 
FIGURE 8: DOSE BY CONCENTRATION ............................................................................... 47 
FIGURE 9: SCHEMATIC REPRESENTATION OF RGX-314 VECTOR GENOME ............... 57 
FIGURE 10: 
GRADATIONS OF VITREOUS HAZE ............................................................. 85 
 

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3 
ABBREVIATIONS  
Abbreviation 
Term 
AAV 
Adeno-associated virus 
AAV2 
Adeno-associated virus serotype 2 
AAV8 
Adeno-associated virus serotype 8 
AC 
Anterior chamber 
ACF 
Anterior chamber fluid 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMD 
Age-related macular degeneration 
AST 
Aspartate aminotransferase 
ATPA 
Anti-transgene product antibody 
BCVA 
Best Corrected Visual Acuity 
BP 
Blood pressure 
C 
Celsius 
CB7 
Hybrid of cytomegalovirus immediate-early enhancer and the chicken 
β-actin promoter 
CFP 
Color fundus photography 
CFR 
Code of Federal Regulations 
CNV 
Choroidal neovascularization 
CMV 
Cytomegalovirus 
CRF 
Case report form 
CRT 
Central retinal thickness 
CTCAE 
Common Terminology Criteria for Adverse Events 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-Linked ImmunoSpot 
ERG 
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein angiography 
Fab 
Antigen-binding fragment 
FAF 
Fundus autofluorescence 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GC 
Genome copies 
GLP 
Good Laboratory Practice 

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HIPAA 
Health Insurance Portability and Accounting Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL2 
Interleukin 2 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRES 
Internal ribosome entry site 
mAb 
Monoclonal antibody 
MED 
Minimum effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
NAb 
Neutralizing antibodies 
nAMD 
Neovascular (wet) age-related macular degeneration  
NCI 
National Cancer Institute 
NIR-FAF 
Near infrared reflectance fundus autofluorescence 
NHP 
Nonhuman primate 
NOAEL 
No observed adverse effect level 
OCT 
Optical Coherence Tomography 
OD 
Right eye 
ONL 
Outer nuclear layer 
OS 
Left eye 
PBS 
Phosphate buffered saline 
PK 
Pharmacokinetic 
PT 
Preferred term/Prothrombin time 
RGX-314 
AAV8.CB7.CI.amd42.RBG; also referred to as  
AAV8.CB7.CI.amd42.rBG 
RT-qPCR 
Reverse transcription quantitative polymerase chain reaction 
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 

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SD-OCT 
Spectral Domain Optical Coherence Tomography 
SDV 
Source document verification 
SOC 
System Organ Class 
SRT 
Safety review trigger 
TPA 
Tissue plasminogen activator 
UbC 
Ubiquitin C gene promoter 
µL 
Microliter 
ULN 
Upper limit of normal 
US 
United States 
USM 
Urgent Safety Measure 
UWF 
Ultra-widefield 
VA 
Visual acuity 
VEGF 
Vascular endothelial growth factor 

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4 
INTRODUCTION 
4.1 
DISEASE BACKGROUND AND CURRENT THERAPEUTIC OPTIONS 
Age-related macular degeneration (AMD) is a progressive degenerative macular disease 
attacking the region of highest visual acuity (VA), the macula. The neovascular or “wet” 
(nAMD) form of the disease is characterized by choroidal neovascularization (CNV), 
which is marked by proliferation of blood vessels and cells including those of the retinal 
pigment epithelium (RPE) (Carmeliet, 2005). Ultimately, photoreceptor death and scar 
formation result in a severe loss of central vision and the inability to read, write, recognize 
faces, or drive. Many patients can no longer maintain gainful employment or carry out 
daily activities and consequently report a diminished quality of life (Mitchell and Bradley, 
2006). Preventive therapies have demonstrated little effect, and therapeutic strategies have 
focused primarily on treating the neovascular lesion.  
Excessive vascular endothelial growth factor (VEGF) plays a key part in promoting 
neovascularization and edema in nAMD. Counteracting the effects of VEGF provides 
significant therapeutic benefit to subjects suffering from this disorder (AAO PPP, 2015). 
Currently available anti-VEGF agents approved for nAMD treatment, such as ranibizumab 
(LUCENTIS®, Genentech) or aflibercept (EYLEA®, Regeneron), have been shown to 
increase Best Corrected Visual Acuity (BCVA) over time (Schmidt-Erfurth et al, 2014a), 
but their effects may be limited in duration of effectiveness (CATT Research Group, 2016; 
Rofagha et al, 2013).  
While long-term anti-VEGF therapies may improve vision or slow the progression of 
vision loss, none of these treatments prevent neovascularization from recurring (Brown et 
al, 2006; Rofagha et al, 2013). Therapy typically must be re-administered to prevent the 
disease from worsening. The need for repeat treatments can incur additional risks 
(ie, endophthalmitis) and is inconvenient for patients (LUCENTIS USPI). Patients treated 
with ranibizumab as needed were given an average of 13.3 injections over 2 years 
(5.6 injections in year 2). In the Phase III VIEW studies for aflibercept, in the second year 
of the studies (Weeks 52 to 96), patients treated with aflibercept 2.0 mg as needed received 
4.1 injections on average and patients treated with ranibizumab 0.5 mg as needed received 
4.7 injections on average (Schmidt-Erfurth et al, 2014b). In real-life conditions, outside 
clinical studies, patients seem to be generally undertreated because of challenges with 
compliance (CATT Research Group, 2012; CATT Research Group, 2016; Cohen et al, 
2013; Holekamp et al, 2014). Thus, there is significant need for a long-acting therapeutic. 
An effective gene therapy product with a long duration of action may have a significant 
benefit for patients by substantially reducing the number of injections required to maintain 
a positive treatment effect, providing the potential for a profound impact on the treatment 
of this disease. 
Ranibizumab is a recombinant, humanized immunoglobulin G1 kappa isotype monoclonal 
antigen-binding fragment (Fab) that binds and inhibits the biological activity of human 
VEGF-A (LUCENTIS USPI). The binding of ranibizumab to VEGF-A prevents the 
interaction of VEGF-A with its receptors VEGFR-1 and VEGFR-2 on the surface of 
endothelial 
cells. 
This 
binding 
inhibits 
endothelial 
cell 
proliferation 
and 
neovascularization, as well as vascular leakage, all of which are thought to contribute to 

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the progression of the nAMD. Ranibizumab has been approved by the United States (US) 
Food and Drug Administration (FDA) for intravitreal injection treatment in patients with 
nAMD (initially approved in 2006). From the studies supporting the ranibizumab approval, 
as well as studies and clinical experience since the approval, the activity (efficacy) and 
safety of this anti-VEGF therapy in treating nAMD have been established. 
4.2 
BRIEF 
OVERVIEW 
OF 
THE 
DEVELOPMENT 
OF 
THE 
INVESTIGATIONAL PRODUCT 
Gene therapy is considered an approach that, with a single intervention, could potentially 
lead to long-term anti-VEGF activity. Adeno-associated viruses (AAVs) are considered 
promising candidates for ocular gene therapy due to their lack of human pathogenicity, low 
toxicity, and (in particular) their long-term expression while remaining episomal. Adeno-
associated virus serotype 2 (AAV2)- and adeno-associated virus serotype 8 (AAV8)-based 
gene therapy vectors are currently being evaluated in many ocular gene therapy studies 
(www.clinicaltrials.gov), including: choroideremia (NCT02341807), achromatopsia 
(NCT02599922, NCT02610582), Leber’s congenital amaurosis (NCT00821340, 
NCT00481546, NCT00999609, NCT00643747), retinitis pigmentosa (NCT01482195, 
NCT01505062), 
Stargardt’s 
disease 
(NCT01367444), 
X-linked 
retinoschisis 
(NCT02416622, 
NCT02122952, 
NCT02317887), 
and 
nAMD 
(NCT01024998, 
NCT01301443, NCT01494805). In recent studies, AAV was used to deliver a therapeutic 
gene to nAMD patients, including GeMCRIS Protocol #1501-1380, in which a subretinal 
injection of AAV2 was used to deliver sFlt-1, a naturally occurring anti-VEGF Fab protein; 
in GeMCRIS Protocol #0810-948, an intravitreal injection of AAV2 was used to deliver 
sFLT-01, an engineered sFlt protein fused to an immunoglobulin constant region and the 
GEM study in which a subretinal injection of equine infectious anemia virus was used to 
deliver endostatin and angiostatin (Campochiaro et al, 2016). 
RGX-314 gene therapy is a recombinant AAV8 viral vector containing a transgene that 
leads to the production of a soluble anti-VEGF Fab protein. RGX-314 is administered via 
a subretinal delivery and could potentially provide long-term treatment with a single 
intervention. The AAV8 vector was selected because studies have shown that it is more 
efficient than the AAV2 vector in transducing the RPE cells following subretinal injections 
(Vandenberghe et al, 2011). 
 
 
 
. To maximize 
expression of the protein from the retina pigment epithelium, subretinal delivery of 
RGX-314 directly into the subretinal space will be employed in clinical studies, as 
subretinal delivery has been shown to produce optimal expression in animal models 
(Lebherz et al, 2008) and in nonhuman primates (NHP) (Bennett et al, 1999; Schmidt-
Erfurth et al, 2014b; Stieger et al, 2009).  
4.2.1 Nonclinical Data 
 
 

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(
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 

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4.2.1.1 Primary Pharmacology 
AAV8 was selected for initial studies based on its efficiency in transducing retinal cells. 
 
. The 
genes of the heavy and light chains were separated by an encoded furin cleavage site-F/F2A 
linker to assure equal molar expression of both chains. Initial studies to optimize other 
vector characteristics were performed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.2.2 Clinical Data 
This is the first-in-human study of RGX-314. Preliminary safety data from this study that 
support the safety of continued subject dosing may be found in the IB.  
4.3 
SUMMARY OF POTENTIAL RISKS AND BENEFITS 
4.3.1 Observed and Potential Risks 
AAV serotypes (2, 8, and 9) have been studied in several clinical studies such as 
hemophilia B (Nathwani et al, 2011b; Nathwani et al, 2014), Leber’s congenital amaurosis 
(Maguire et al, 2008), and spinal muscular atrophy (NCT02122952), and appear to be safe. 

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However, direct clinical data addressing long-term benefits and risks of AAV-mediated 
gene transfer are limited, and the long-term risks remain unknown.  
No studies have been conducted to evaluate the genotoxicity or carcinogenicity of RGX-
314. The persistence of RGX-314 vector DNA was observed in the eye and was not seen 
in any non-ocular tissue in the NHP studies conducted. The genome of recombinant AAVs 
does not undergo site-specific integration in the host DNA, but remains episomal in the 
nucleus of transduced cells and the risk of insertional mutagenesis in cells of the retina is 
considered low. From a TP perspective, genotoxicity or carcinogenicity studies are not 
considered relevant, as with other anti-VEGF Fabs or monoclonal antibodies (mAbs).  
RGX-314 gene therapy is a recombinant AAV8 viral vector containing a transgene that 
leads to the production of an anti-VEGF Fab protein. 
 
 
 
 
 
 
 
 
 
). 
 
 
 
With gene therapy, there is a possibility that the eye may overexpress 
anti-VEGF Fab, resulting in levels higher than that currently given in intravitreal therapy. 
Patients receiving RGX-314 should be monitored for any ocular AEs that could be 
considered indicative of toxicity (and not expected as a result of the surgical procedure). 
Potential signs and symptoms of ocular toxicity are listed in Appendix, Section 14.1. 
As with all therapeutic proteins, there is a potential for an immune response. The subretinal 
space within the eye is considered immune privileged (ie, it is able to tolerate the 
introduction of antigens without eliciting an inflammatory immune response), and AAV 
NAbs have not had effects on subretinally delivered gene therapies (Bennett et al, 2012; 
Constable et al, 2016; Kotterman et al, 2015). For the proposed clinical study, samples to 
be assayed for AAV8 NAbs will be collected from within the eye prior to RGX-314 
administration to assess for any correlation with outcomes, but subjects will not be 
excluded based on the presence of AAV8 NAbs at baseline, as these are not expected to 
have a clinically relevant effect. If a subject were to experience an immune response, 
inflammation may occur. The symptoms of inflammation will be monitored closely in the 
proposed clinical study and treated if necessary (Appendix, Section 14.1). 
 
 
 
 
 
 
 
 
 

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For this study, an injection site away from the macula was selected for gene therapy 
delivery and retinal anatomy including the site of injection/bleb area is  monitored regularly 
with SD-OCT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Since bleb area SD-OCT scans were performed monthly since treatment, these SD-OCTs 
were reviewed by the reading center consultant. 
 
 
 
 
 
 
 
   
For subjects with inferior retina findings, crosshair (radial) SD-OCT scans are being 
collected to review over time. Similar findings to those described for SD-OCTs in the bleb 

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area were observed. 
 
 
 
 
 
 
 
 
 
  
Additional functional assessments, including Humphrey visual field test or microperimetry 
and electroretinography (ERG), have been obtained in some of these subjects.  To date no 
clear visual function deficit has been observed on any of these assessments, though these 
subjects will be assessed to confirm no significant change over time.  Regarding underlying 
nAMD status and central vision, the majority of these subjects have improved BCVA 
compared to baseline with greatly decreased anti-VEGF intravitreal injection frequency 
compared to treatment burden prior to RGX-314 administration, and no subjects have had 
significant BCVA decrease.  The lone subject with pigmentary changes in the perimacular 
area (Cohort 5) as of the Month 6 visit has gained +6 letters compared with baseline without 
need for anti-VEGF injections.   
Following subretinal delivery of AAV gene therapy, pigmentary changes in the area of the 
bleb have been noted previously (Dimopoulos et al, 2018; Xue et al, 2018; Weleber et al, 
2016). This appears as hyperpigmentation of the RPE cells and has been noted to have 
hyper and hypo fluorescence on FA. Additionally, hyperpigmentation inferior to the bleb 
has been described following subretinal delivery of tissue plasminogen activator (TPA) 
(Hesse et al, 1999). No clinical consequence has been reported in the literature as a result 
of these findings. Background pigmentary changes in the periphery on UWF imaging has 
recently been reported to be highly prevalent in the nAMD population, and the potential 
significance of such peripheral imaging findings is unknown (Forshaw et al, 2019). 
All subjects administred in RGX-314 in clinical trials will have retinal imaging performed 
at baseline and periodically thereafter including UWF CFP, SD-OCT, FAF, and FA.  Post-
treatment SD-OCTs of the bleb area(s) and any area developing pigmentary changes will 
also be performed. To assess visual function, BCVA, visual field test (Humphrey Full Field 
120 or microperimetry) and (if available) ERG will be performed.   
The potential for the vector transgene to spread to unintended recipients from shedding 
(release of vectors that did not infect the target cells and were cleared from the body via 
feces or bodily fluids), mobilization (transgene replication and transfer out of the target 
cell), or germ line transmission (genetic transmission to offspring through semen) is 
considered to be low. Refer to the protocol-specified precautionary measures for use of 
appropriate birth control in sexually active female and male subjects from screening 
through 24 weeks after vector administration and for precluding any use in pregnant 
females or in females planning to become pregnant within 24 weeks after administration. 

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The vector can be handled under BSL-1 conditions (or RG1). 
RGX-314 will be administered subretinally by a trained retinal surgeon with the subject 
under local anesthesia. The procedure will involve standard 3-port pars plana vitrectomy 
with a core vitrectomy followed by subretinal delivery. Pars plana vitrectomy is considered 
to be part of usual retina care and is not part of an experimental protocol. It is a routine 
retinal surgery that can usually be performed safely as an outpatient procedure.  
Vitrectomy-related complications include inflammation or redness, swelling, pain, 
increased or reduced IOP, bleeding, cataract (not applicable to pseudophakic subjects), 
retinal tears, retinal detachments, retinal and vitreous incarceration, vitreous hemorrhage, 
and endophthalmitis. The procedure is also associated with risks for the long-term 
development of open-angle glaucoma due to increased oxygen tension in the eye and 
potential oxidative damage to the trabecular meshwork. Very rarely, vitrectomy also 
increases the risks of developing a visual field defect, visual loss due to macular toxicity 
of light or dye (if used) or manipulation, and optic neuropathy (AAO, 2015-2016). The 
vitrectomy performed in this study will not include the use of dyes and will be performed 
in pseudophakic eyes.  
Subretinal delivery is a less common technique performed by vitreoretinal surgeons. Most 
retinal surgeons have experience with the technique for the delivery of TPA for the 
treatment of submacular hemorrhage. More recently, the technique is being used in several 
other gene therapy studies for inherited retinal diseases (Bainbridge et al, 2008; Gil-Farina 
et al, 2016; Hauswirth et al, 2008; MacLaren et al, 2014; Maguire et al, 2008; and ongoing 
studies noted in Section 4.2) and results previously reported from 2 nAMD programs 
(Campochiaro et al, 2016; Constable et al, 2016; Rakoczy et al, 2015). No serious adverse 
events (SAEs) related to investigational product were observed in these studies; mild 
adverse events (AEs) consistent with vitrectomy were noted, and 1 patient developed a 
macular hole of which the patient was unaware (Maguire et al, 2008). The serious risks 
associated with subretinal delivery include retinal and vitreous hemorrhage, inflammation, 
increases in IOP, retinal tear, macular hole, retinal detachment, or severe endophthalmitis. 
As described above, subretinal delivery of gene therapy and TPA has been associated with 
pigmentary changes in the area of the bleb and/or inferior retina. All Investigators will be 
preselected based on their previous retinal surgery experience in complex retinal 
procedures (such as subretinal delivery) and experience with surgical clinical studies. 
Surgeons will receive further training on the study procedure as part of the proposed 
clinical study. A detailed description of the procedure can be found in the Administration 
Manual.  
A theoretical administration risk to subjects stems from transfer of silicone from the inner 
coating of the syringe into the subject’s eye during the administration procedure (Melo et 
al, 2019). While this risk is considered to be low because of the air-fluid exchange at the 
end of the vitrectomy, low flow rate of injection of RGX-314, and single RGX-314 
administration, investigators should monitor subjects for signs of inflammation or floaters 
and record any change from the subjects‘ baseline condition as an AE. 
Detailed discussion of the risks of RGX-314 and its administration can be found in the IB. 

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4.3.2 Potential Benefits 
RGX-314 delivers a transgene that leads to the production of an anti-VEGF Fab protein. 
Anti-VEGFs are currently approved for the treatment of nAMD. Ranibizumab, aflibercept, 
and more recently brolucizumab (Brolucizumab Prescribing Information) have provided 
evidence for the ability of anti-VEGFs in improving vision and macular edema in patients 
with nAMD. However, these therapies require frequent injections for extended periods, 
often for years.  
The proposed treatment with RGX-314 is a single administration expected to provide 
continuous levels of anti-VEGF activity in the range where established efficacy has been 
seen in ranibizumab models. A long-term duration of efficacy following a single 
intervention will be a significant benefit to patients who currently must undergo monthly 
or otherwise frequent injections. RGX-314 may offer patients an alternative treatment to 
approved anti-VEGF therapies and may provide a similar benefit but with less need for 
repeated intravitreal injections.  
4.4 
STUDY RATIONALES 
4.4.1 Rationale for Proposed Doses 
RGX-314 will be administered as a single subretinal delivery to the subretinal space. This 
replicates the route of administration used in the nonclinical studies. Dose scaling from 
animals to humans took into consideration approximate differences in retinal surface area 
and injection volume.  
When selecting a starting human dose, one key consideration was that the ability to 
readminister the vector may not be possible due to potential immune responses. Given that 
subsequent administration of a higher dose in an individual subject may not be feasible due 
to anatomic and manufacturing constraints, it is necessary to select a starting clinical dose 
that is both safe and carries a reasonable expectation of benefit in this patient population. 
The proposed starting dose in the present study is based on the MED and MTD as 
determined in mouse models of disease and in NHPs, respectively.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

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In order to reduce the risk of toxicity, doses at or below the MTD will be used; additional 
risk will be mitigated by the location of administration. Subretinal delivery in this study 
will be targeted to the area superior to the fovea within the vascular arcades, which will 
avoid the macula with all blebs to remain outside the fovea by at least 2 disc diameters to 
mitigate any potential risk. As an additional clinical safety assessment, the protocol 
includes SD-OCT imaging of the bleb area to evaluate retinal thickness over time. 
The proposed doses represent an acceptable benefit:risk profile, where the dose is expected 
to be in the therapeutic range (and, therefore, may offer clinical benefit) and potential risks 
are managed through targeted administration and regular SD-OCT monitoring. 
 
 
 

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4.4.2 Rationale for use of a Sentinel Subject 
For each dose cohort, a sentinel subject with BCVA of ≤20/63 and ≥20/400 (≤63 and 
≥19 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) will be assessed out to 
4 weeks post-RGX-314 administration prior to dosing anyone further in the dose cohort. 
The doses chosen in this study are considered safe based on the nonclinical animal data. 
Because this is a first-in-human study to explore safety, a subject with worse vision will be 
treated initially and assessed for safety at that dose before expanding the vision criteria for 
the remainder of the subjects in a given cohort. Given that gene therapy studies in nAMD 
to date (Campochiaro et al, 2016; Constable et al, 2016; Rakoczy et al, 2015) have had 
events either related to the procedure or occasional inflammation that were mild and 
transient (resolving in a few weeks), 4 weeks will be adequate to assess these acute events 
in the sentinel subject. Following the sentinel subject evaluation, the remaining subjects in 
the dose cohort must have BCVA ≤20/40 and ≥20/400 (≤73 and ≥19 ETDRS letters). 

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5 
STUDY OBJECTIVES 
5.1 
PRIMARY OBJECTIVE 
 To evaluate the safety and tolerability of RGX-314 through Week 26 (24 weeks 
post a single dose administered by subretinal delivery to subjects with nAMD) 
5.2 
SECONDARY OBJECTIVES 
 To evaluate the long-term safety and tolerability of RGX-314 
 To evaluate the concentration of RGX-314 protein levels in aqueous humor 
 To evaluate the effect of RGX-314 on BCVA 
 To evaluate the effect of RGX-314 on central retinal thickness (CRT) as measured 
by SD-OCT 
 To assess the need for rescue therapy 
 To evaluate the effect of RGX-314 on CNV lesion growth and leakage as measured 
by fluorescein angiography (FA) 

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6 
INVESTIGATIONAL PLAN 
6.1 
ENDPOINTS 
6.1.1 Primary Endpoints 
 Safety through Week 26 (24 weeks following RGX-314 administration): incidence 
of ocular and non-ocular AEs and SAEs 
6.1.2 Secondary Endpoints 
 Ocular and non-ocular safety over 106 weeks 
 Mean change from baseline in aqueous RGX-314 protein over time  
 Mean change from baseline in BCVA over time 
 Proportion of subjects gaining or losing ≥15 letters compared to baseline as per 
BCVA at Week 26, Week 54, and Week 106 
 Mean change from baseline in CRT as measured by SD-OCT over time 
 Mean number of anti-VEGF rescue injections over time 
 Time to 1st anti-VEGF rescue injection  
 Mean change from baseline in CNV lesion size and leakage area based on FA over 
time 
 Immunogenicity measurements (NAb to AAV8, binding antibodies to AAV8, 
antibodies to RGX-314 protein, and Enzyme-Linked ImmunoSpot [ELISpot]) 
 Vector shedding analysis in serum and urine  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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6.2 
STUDY DESIGN 
In this Phase I/IIa, first-in-human, open-label, multiple-cohort, dose-escalation study, 
approximately 42 nAMD subjects will be enrolled into up to 5 dose cohorts of RGX-314. 
Subjects who meet the inclusion/exclusion criteria will be enrolled and receive a 0.5 mg 
intravitreal injection of ranibizumab in the study eye (Visit 1). At Visit 2 (7 days after 
ranibizumab injection), subjects will be evaluated by SD-OCT to confirm anatomic 
response to the initial anti-VEGF activity associated with the ranibizumab injection 
compared with their baseline assessment. Subjects who do not have an anatomic response 
will be withdrawn from the study (response defined in Section 7.1.3). For withdrawn 
subjects, anyone who has an AE associated with the ranibizumab injections on Visit 1 will 
be followed until the AE resolves (up to 30 days post-injection). At Visit 3 (Week 2), 
subjects will receive a single dose of RGX-314 administered in an operating room by 
subretinal delivery.  
The 1st subject in each cohort (sentinel subject) will have vision of ≤20/63 and ≥20/400 
(≤63 and ≥19 ETDRS letters). After RGX-314 administration to the 1st subject, there will 
be a minimum of 4-week observation period for safety. The Internal Safety Committee will 
review the safety data for this subject and if there are no safety concerns, up to 5 (Cohorts 
1 to 3) or up to 11 (Cohorts 4 and 5) additional subjects (with expanded vision criteria of 
≤20/40 and ≥20/400 [≤73 and ≥19 ETDRS letters]) may be treated, one per day, on 
consecutive calendar days. If no safety review triggers (SRTs) are observed, then 4 weeks 
after the last subject is dosed (with the exception of Cohort 4 which had an Independent 
Data Monitoring Committee [IDMC] review 4 weeks after the sixth subject was dosed, 
prior to cohort expansion to 12 subjects), all available safety data will be evaluated by the 
IDMC. Given that gene therapy studies in nAMD to date (Campochiaro et al, 2016; 
Constable et al, 2016; Rakoczy et al, 2015) have had events either related to the procedure 
or occasional inflammation that were mild and transient (resolving in a few weeks), 4 
weeks will be adequate to assess these acute events in the sentinel subject. Additionally, if 
any event meets the criteria of a Stopping Rule, dosing of any new subjects will be 
suspended until a complete review of all safety data has been performed by REGENXBIO 
and the IDMC. At any given IDMC meeting, whether called for by an SRT or at the planned 
IDMC meeting, the IDMC may recommend to stop the study, proceed to the next dosing 
cohort, or proceed at a lower dose (up to a half log).  
Subjects will have 3 visits within the first 4 weeks after treatment with RGX-314 (1 day 
post-procedure and 1 week and 4 weeks post-procedure). Starting 4 weeks after RGX-314 
administration, subjects may receive intravitreal ranibizumab rescue therapy at the 
Investigator’s discretion if they meet predefined rescue injection criteria (Section 8.1.2). 
Immunogenicity to the vector and transgene product of RGX-314 will be assessed 
throughout the study. 
Safety will be the primary focus for the initial 24 weeks after RGX-314 administration 
(primary study period). Following completion of the primary study period, subjects will 
continue to be assessed until 104 weeks following treatment with RGX-314 (Week 106). 
At the end of the study, subjects will be invited to participate in a long-term follow-up 
study. 

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The safety and tolerability of RGX-314 will be assessed in each dosed subject as shown in 
Section 8.4. The safety and tolerability of RGX-314 will be monitored through assessment 
of ocular and non-ocular AEs and SAEs, chemistry, hematology, coagulation, urinalysis, 
immunogenicity, ocular examinations and imaging (BCVA, IOP, slit lamp biomicroscopy, 
indirect ophthalmoscopy, SD-OCT, FA, Heidelberg Spectralis FAF, and CFP), and vital 
signs. Because of pigmentary changes observed in some subjects, starting with Protocol 
Version 10, additional ophthalmic assessments will include Optos UWF FAF (in addition 
to Heidelberg Spectralis FAF), ERG if available, visual field test (Humphrey Full Field 
120 or microperimetry), and, if applicable, additional SD-OCT in the area of pigmentary 
change. 
All Investigators will be preselected based on their previous experience with subretinal 
delivery in clinical practice and will be further trained on the procedure as part of the 
proposed clinical study. A detailed description of the procedures can be found in the 
Administration Manual. 

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7 
SUBJECT POPULATION AND SELECTION 
7.1 
SELECTION OF STUDY POPULATION 
Subjects must have a diagnosis of nAMD that is recurrent and persistent, responsive to 
anti-VEGF therapy, and requires frequent injections and meet the criteria below in order 
to be potentially eligible for this study. 
7.1.1 Inclusion Criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
1. Males or females aged ≥ 50 years and ≤ 89 years. 
2. Sentinel subject for each dose cohort must have a BCVA ≤20/63 and ≥20/400 (≤63 
and ≥19 ETDRS letters) in the study eye. Following the sentinel subject evaluation, 
the rest of the subjects in the dose cohort must have a BCVA between ≤20/40 and 
≥20/400 (≤73 and ≥19 ETDRS letters). 
3. In the case both eyes are eligible, study eye must be the subject’s worse-seeing eye, 
as determined by the Investigator. 
4. Must have a documented diagnosis of subfoveal CNV secondary to AMD in the 
study eye. 
a. CNV lesion characteristics: lesion size needs to be less than 10 disc areas 
(typical disc area is 2.54 mm2), blood <50% of the lesion size. 
5. Must have received at least 4 intravitreal injections of an anti-VEGF agent for 
treatment of nAMD in the study eye in approximately 8 months (or less) prior to 
Visit 1, with anatomical response documented on SD-OCT.  
6. Must have subretinal or intraretinal fluid in the center subfield present at Visit 1 in 
the study eye, evidenced on SD-OCT unless the subject is a re-screen. 
a. Subjects who have previously met all inclusion criteria including the Visit 
2 responsiveness criterion on OCT, but did not receive RGX-314 within the 
window, may be re-screened and do not need to have fluid on entry or meet 
the Visit 2 responsiveness criterion again subject to discussion with and 
approval by Sponsor’s Medical Director. 
7. Must be pseudophakic (status post cataract surgery) in the study eye. 
8. Must be willing and able to comply with all study procedures and be available for 
the duration of the study. 
9. Females of childbearing potential (defined in Section 9.5.2) must have a negative 
urine pregnancy test at the screening visit, have negative serum results by Day 8, 
and be willing to have additional pregnancy tests during the study. 

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10. Sexually active subjects (both female and male) must be willing to use a medically 
accepted method of barrier contraception (eg, condom, diaphragm, or abstinence) 
from screening visit until 24 weeks after vector administration. Cessation of birth 
control after this point should be discussed with a responsible physician. 
11. Must be willing and able to provide written, signed informed consent. 
7.1.2 Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible to participate 
in the study: 
1. CNV or macular edema in the study eye secondary to any causes other than AMD.  
2. Blood occupying ≥50% of the AMD lesion or blood >1.0 mm2 underlying the fovea 
in the study eye. 
3. Any condition preventing VA improvement in the study eye, eg, fibrosis, atrophy, 
or retinal epithelial tear in the center of the fovea. 
4. Active or history of retinal detachment in the study eye. 
5. Advanced glaucoma in the study eye. 
6. Any condition in the study eye that, in the opinion of the Investigator, may increase 
the risk to the subject, require either medical or surgical intervention during the 
course of the study to prevent or treat vision loss, or interfere with study procedures 
or assessments. 
7. History of intraocular surgery in the study eye within 12 weeks prior to the 
screening visit. Yttrium aluminum garnet capsulotomy is permitted if performed 
>10 weeks prior to the screening visit. 
8. History of intravitreal therapy in the study eye, such as intravitreal steroid injection 
or investigational product, other than anti-VEGF therapy, in the 6 months prior to 
screening. 
9. Presence of an implant in the study eye at screening (excluding intraocular lens). 
10. History of malignancy requiring chemotherapy and/or radiation in the 5 years prior 
to screening. Localized basal cell carcinoma will be permitted. 
11. Receipt of any investigational product within the 30 days of enrollment or 5 half-
lives of the investigational product, whichever is longer.  
12. Participation in any other gene therapy study. 
13. History of therapy known to have caused retinal toxicity, or concomitant therapy 
with any drug that may affect visual acuity or with known retinal toxicity, eg, 
chloroquine or hydroxychloroquine. 
14. Ocular or periocular infection in the study eye that may interfere with the surgical 
procedure. 
15. Myocardial infarction, cerebrovascular accident, or transient ischemic attacks 
within the past 6 months. 

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16. Uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg, diastolic BP 
>100 mmHg) despite maximal medical treatment. 
17. Any concomitant treatment that, in the opinion of the Investigator, may interfere 
with ocular surgical procedure or healing process. 
18. Known hypersensitivity to ranibizumab or any of its components or past 
hypersensitivity (in the Investigator’s opinion) to agents like RGX-314. 
19. Any serious, chronic, or unstable medical or psychological condition that, in the 
opinion of the Investigator, may compromise the subject’s safety or ability to 
complete all assessments and follow-up in the study. 
7.1.3 Criteria for Continuing Study After Receiving Ranibizumab 
At Visit 2, subjects (with the exception of re-screens who have met this criterion in the 
past) will be assessed for initial anti-VEGF response to ranibizumab. Subjects will undergo 
both SD-OCT and BCVA, which will be compared by the Investigator with the Visit 1 
values: 
1. Responsive (subjects will continue in the study): Response is defined as reduction 
in CRT >50 µm or >30% improvement in central fluid by SD-OCT. 
2. Non-responsive (subjects will exit the study as early withdrawals): Non-response 
is defined as not meeting the criteria above. Additional subjects will continue to be 
enrolled until up to 6 subjects (Cohorts 1 to 3) or up to 12 subjects (Cohorts 4 and 
5) in each cohort receive a single dose of RGX-314. 
At this visit central lab results will be reviewed. Any subjects with the following values 
will be withdrawn: 
3. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 × upper 
limit of normal (ULN) 
4. Total bilirubin >1.5 × ULN unless the subject has a previously known history of 
Gilbert’s syndrome and a fractionated bilirubin that shows conjugated bilirubin 
<35% of total bilirubin 
5. Prothrombin time (PT) >1.5 × ULN 
6. Hemoglobin <10 g/dL for male subjects and <9 g/dL for female subjects 
7. Platelets <100 × 103/µL 
8. Estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 
7.2 
SUBJECT RECRUITMENT AND SCREENING 
Subjects will be recruited from the population of patients with nAMD by participating 
clinical sites.  
Subjects meeting eligibility that do not make RGX-314 administration (Visit 3) due to 
unforeseen circumstances may be considered for re-screen at a later time by the Sponsor’s 
Medical Director. Refer to the Study Reference Manual for additional information. 

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At the discretion of the Sponsor, additional subjects may be enrolled if a subject(s) does 
not receive a full 250 μL dose in the subretinal space. 
7.3 
WITHDRAWAL OF SUBJECTS 
Every effort should be made to keep subjects in the study. However, subjects are free to 
withdraw consent and/or discontinue participation in the study at any time, without 
prejudice to further treatment. 
A subject may be withdrawn from the study for the following reasons: 
 Considered non-responsive to ranibizumab (per Section 7.1.3) 
 Lost to follow-up 
 Termination of study by REGENXBIO 
 Protocol deviation 
 Noncompliance with study visits 
 Subject or Investigator decides to discontinue the subject’s participation in the 
study 
The term “Early Withdrawal” is used for subjects who dropped out prior to dosing with 
RGX-314, including those who are considered nonresponsive (per Section 7.1.3). An Early 
Termination Visit is not required for these subjects. The term “Early Termination” is used 
for subjects who exit the study after receiving a dose of RGX-314. These subjects should 
complete all tests of the Early Termination Visit. (See Table 2:  Schedule of Events After 
End of Year 1 Through Year 2.) 
At the end of the subject’s participation, the Investigator will complete the discontinuation 
page of the case report form (CRF) and document the reason(s) for study discontinuation. 

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8 
TREATMENTS ADMINISTERED 
8.1 
RANIBIZUMAB 
8.1.1 Initial Treatment in the Study Eye 
All subjects will receive a single intravitreal injection of ranibizumab 0.5 mg on Visit 1 
(14 days prior to RGX-314 delivery). 
8.1.2 Rescue Therapy 
Starting at 4 weeks post-RGX-314 administration, the subject may receive intravitreal 
ranibizumab rescue therapy in the study eye at the Investigator’s discretion for disease 
activity if 1 or more of the following rescue criteria apply: 
 Vision loss of ≥5 letters (per BCVA) associated with accumulation of retinal fluid 
on SD-OCT 
 CNV-related increased, new, or persistent subretinal or intraretinal fluid on 
SD-OCT 
 New ocular hemorrhage 
Injection may be deferred at the Investigator’s discretion if 1 of the following sets of 
findings occur: 
 VA is 20/20 or better and CRT is “normal” as assessed by SD-OCT 
 VA and SD-OCT are stable after 2 consecutive injections. 
If injections are deferred, they will be resumed if VA or SD-OCT get worse per the criteria 
above. 
With approval from the Sponsor’s Medical Director, the Investigator may recommend 
changing the study eye rescue therapy from ranibizumab to aflibercept. Only ranibizumab 
will be provided as part of the study. 
8.2 
INVESTIGATIONAL PRODUCT 
RGX-314 
 is a non-replicating recombinant AAV8 viral 
vector containing a transgene that leads to the production of an anti-VEGF Fab protein 
 

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Final investigational product is supplied as a frozen solution of the AAV vector active 
ingredient 
 in a formulation buffer 
 
 
 
 
 
  
The investigational product (RGX-314) will be given as a single dose via subretinal 
delivery in the subject’s worse-seeing eye (ie, designated “study eye”) as decided by the 

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Investigator. 
 
  
RGX-314 is given by a single subretinal delivery by a retinal surgeon with the subject 
under local anesthesia. The procedure will involve a standard 3-port pars plana vitrectomy 
with a core vitrectomy followed by subretinal delivery of RGX-314 into the subretinal 
space by a subretinal cannula (38 gauge). 
 
 
 
 
 
8.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT 
This is an open-label study. Refer to Section 6.2 for a description of a plan to sequentially 
dose subjects, including review of safety data after the 1st subject in each cohort and after 
at least 6 subjects in each cohort have been dosed at any dose level prior to dose escalation. 
The rationale for the proposed dose levels is provided in Section 4.4.1. 
8.4 
STOPPING RULES 
The safety and tolerability of RGX-314 will be assessed in each dosed subject as shown in 
Table 6. 
Table 6: 
Safety Review Trigger Events and Actions 
Safety Review Trigger (SRT) Event 
Safety Review Action 
A Stopping Rule is met 
An external IDMC will review all available safety data and 
provide a recommendation on whether to enroll additional 
subjects. 
Any Grade 4 or 5 AE  
regardless of relationship to treatment 
The chairs of the Internal Safety Committee and the 
external IDMC will review and decide whether to allow 
enrollment to continue or convene a full IDMC review of 
all available safety data which will then provide a 
recommendation on whether to enroll additional subjects. 
Any Grade 3 AE  
considered treatment-related (by the 
Investigator) 
Any Grade 3 AE  
considered unrelated to treatment (by the 
Investigator) 
An Internal Safety Committee will review all available 
safety data. If safety concerns arise while a cohort is being 
enrolled, the committee may ask the IDMC to review and 
make a recommendation on whether to keep enrolling 
subjects in that cohort. 
Any report by the Investigator of 
technical issues with the surgical 
procedure that may warrant modifications 
to the procedure 
AE = adverse event; IDMC = Independent Data Monitoring Committee. 
If any of the following events occur, a Stopping Rule will be considered to have been met 
and dosing of any new subjects will be suspended until a complete review of all safety data 
has been performed by REGENXBIO and the IDMC: 
 The subject dies, and the Investigator considers the death to be related to the 
investigational product or procedure. 

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 Any occurrence of a treatment-emergent AE of arterial thromboembolism. 
 An ocular AE listed in the Appendix, Section 14.1 reported as a Grade 4 or 5 AE 
regardless of relationship to treatment or reported as a Grade 3 AE that is 
considered treatment-related (by the Investigator). 
 An acute or near-term severe vision loss defined as a 15 letter loss in vision within 
4-weeks after RGX-314 administration that the PI considers related to gene therapy. 
Stopping Rules and SRTs must follow the reporting requirements for SAEs as defined in 
Section 10.4. 
8.5 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
While at the clinical site, investigational product must be stored in a secure limited access 
location at a controlled temperature as described in the IB, Pharmacy Manual, and 
according to product packaging. The storage facility must be available for inspection by 
the Study Monitor at any time during the study. 
An investigational product accountability log must be maintained for all investigational 
product received, dispensed, returned, destroyed, and/or lost during the study, as 
applicable. The record must be kept current and made available to the Study Monitor for 
inspection. Following the closeout of the study, all unused investigational product must be 
returned to REGENXBIO and/or its designee unless other instructions have been provided 
for final disposition of the investigational product. 
8.6 
PRIOR AND CONCOMITANT ANTI-VEGF MEDICATIONS AND 
THERAPEUTIC PROCEDURES 
Prior anti-VEGF therapy and ocular history for the subject from 12 months prior to 
providing informed consent will be recorded into the CRF after retrospective chart review.  
Prior medications will be defined as medications that are taken prior to providing informed 
consent. 
Concomitant medications will be defined as medications that are taken at the time of or 
after providing informed consent and will be recorded in the CRF. All medications, other 
than RGX-314, received as part of any study procedures will also be recorded on the CRF. 
The initial ranibizumab injection and any injections as rescue medication will be recorded 
on the CRF also. 
Anti-VEGF treatment of nAMD in the fellow eye will be at the discretion of the 
Investigator but restricted to ranibizumab or aflibercept. Ranibizumab will be provided for 
the fellow eye as part of the study. 
 
 

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8.6.1 Prohibited Medications and Procedures 
Subjects may not: 
 Receive rescue treatment of the study eye or treatment of the fellow eye with 
bevacizumab (Avastin®, Genentech).  
 Receive any experimental medication or therapy within 4 weeks of screening or 
within 5 half-lives of the investigational product, or at any time during the study. 
 Receive any concomitant treatment that, in the opinion of the Investigator, may 
interfere with ocular surgical procedure or healing process 
8.6.2 Permitted Medications and Procedures 
Treatment of the fellow eye will be at the discretion of the Investigator but restricted to 
ranibizumab or aflibercept. Ranibizumab will be provided for the fellow eye as part of the 
study.  
8.7 
PRECAUTIONS 
The replication defective recombinant AAV8 vector to be used in this program is a 
non-infectious and non-pathogenic material as defined by the NIH (NIH, 2016) and the 
vector can be handled under biosafety level-1 conditions (or Risk Group 1). Risk Group 1 
agents are not associated with disease in healthy adult humans. Staff who may come into 
contact with any bodily fluids of subjects treated with RGX-314 should use appropriate 
precautions (eg, gloves, masks, lab coats) to prevent direct contact. Labs handling these 
bodily fluids should use their normal standard operating procedures, and personnel should 
wash their hands with soap and clean running water. 

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9 
VISION AND SAFETY ASSESSMENTS 
9.1 
SCHEDULE OF EVENTS 
The parameters to be assessed for this study, along with the timing of assessments, are 
provided in the Schedule of Events (Table 1 [Year 1] and Table 2 [Year 2]). Refer to the 
Study Reference Manual for additional information. Additional assessments not specified 
in the Schedule of Events needed for pre-operative evaluations may be performed per 
institutional standards. 
9.2 
DEMOGRAPHICS 
Demographic data such as age, sex, and race will be collected in the CRF. 
9.3 
MEDICAL AND MEDICATION HISTORY 
The Investigator or designee will collect a relevant medical and surgical history. Medical 
history will include information on the subject’s concurrent medical conditions. Medical 
history will include a complete ocular history. Prior anti-VEGF therapy and ocular history 
from the previous 12 months will be recorded on the medical history CRF. 
Medication history will include information on the subject’s current medications. 
Medication history will include previous treatments for nAMD including other anti-VEGF 
therapy. All findings will be recorded on the prior medication CRF. 
9.4 
OPHTHALMIC ASSESSMENTS 
At study visits specified in the Schedule of Events (Table 1 [Year 1] and Table 2 [Year 2]), 
the following ocular assessments may be performed. When applicable, assessments should 
be performed in the order listed. Images will be stored in a central imaging repository; refer 
to the Study Reference Manual for additional information: 
 Full ophthalmic exam – slit lamp biomicroscopy, IOP, and dilated ophthalmoscopy  
 BCVA using ETDRS at 4 meters, repeated at 1 meter, if necessary (bilateral) 
 SD-OCT using the Heidelberg Spectralis (bilateral macula and study eye bleb 
area(s))  
 Starting with Protocol Version 10: additional SD-OCT (radial scan if possible) in 
the area of study eye pigmentary change – subjects with pigmentary changes only 
 FAF (study eye) using the Heidelberg Spectralis and, starting with Protocol Version 
10, also Optos UWF  
 Color fundus photography (study eye) 
 FA (study eye) 
 Starting with Protocol Version 10: visual field test consisting of the Humphrey Full 
Field 120 or microperimetry; once a test is selected, the same test must be 
performed at subsequent time points of assessment 
 Starting with Protocol Version 10: ERG if available 

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9.5 
SAFETY ASSESSMENTS 
9.5.1 Adverse Events 
All AEs will be recorded from the time the subject signs the informed consent form (ICF). 
The determination, evaluation, reporting, and follow-up of AEs will be performed as 
outlined in Section 10. At each study visit, subjects will be asked about any new or ongoing 
AEs since the previous visit. AEs for ocular inflammation will be graded based on the 
scales shown in Appendix, Section 14.2. Assessments of AEs will occur at the time points 
shown in the Schedule of Events (Table 1 [Year 1] and Table 2 [Year 2]). 
9.5.2 Pregnancy Testing 
Female subjects of childbearing potential with a positive urine or serum pregnancy test 
prior to RGX-314 administration (Visit 3) do not meet eligibility criteria for enrollment 
and will not be enrolled in the study. Females considered not of childbearing potential 
include those who have had total hysterectomy, have been in menopause for at least 
2 years, or have had tubal ligation at least 1 year prior to Screening. 
Additional urine pregnancy tests will be performed at any visit in which pregnancy status 
is in question. A serum pregnancy test will be performed in the event of a positive or 
equivocal urine pregnancy test result. Refer to the Study Reference Manual for additional 
information. In the case of a confirmed pregnancy, refer to Section 10.5. 
9.5.3 Clinical Laboratory Tests 
The following clinical laboratory and antibody tests will be assessed as specified in the 
Schedule of Events (Table 1 [Year 1] and Table 2 [Year 2]):  
 Chemistry: glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, 
carbon dioxide, calcium, total protein, albumin, total bilirubin, direct bilirubin, 
alkaline phosphatase, ALT, AST, and creatine kinase.  
 Hematology: Complete blood count with differential and platelet count, including 
hematocrit, hemoglobin, and red blood cell, white blood cell, platelet, neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil counts as well as mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular 
hemoglobin concentration 
 Coagulation: PT and partial thromboplastin time 
 Urinalysis: Dipstick for glucose, ketones, protein, and blood (if warranted, a 
microscopic evaluation will be completed) 
 RGX-314 protein concentration in serum and aqueous humor 
 Immunogenicity measurements: 
o NAb to AAV8 (serum and vitreous humor) 
o AAV8 binding antibodies (aqueous humor) 
o Antibodies to RGX-314 protein (aqueous humor, vitreous humor, and serum) 

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o ELISpot (whole blood) 
 Vector shedding analysis in serum and urine  
 VEGF in aqueous humor 
Laboratory reports from the central laboratory will be made available to the Investigator in 
a timely manner to ensure appropriate clinical review. The Investigator is responsible for 
reviewing and signing all laboratory reports. Any abnormal findings that meet the 
definition of an AE per Section 10.1 will be recorded on the AE CRF. 
Procedures for the collection, handling and shipment of all laboratory samples to be sent 
to the central laboratory will be included in a separate manual.  
9.5.4 Vital Signs 
Assessment of vital signs (BP and heart rate) will be obtained/performed at visits specified 
in the Schedule of Events (Table 1 [Year 1] and Table 2 [Year 2]). 
9.6 
APPROPRIATENESS OF MEASURES 
The assessments of safety and efficacy are standard assessments for studies in subjects with 
nAMD treated with anti-VEGF therapy. 

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10 
ADVERSE EVENT HANDLING AND SAFETY REPORTING 
10.1 
DEFINITIONS 
10.1.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product.  
A suspected adverse reaction means any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of expedited reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug. 
Events meeting the definition of an AE include: 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either the 
investigational product or a concomitant medication (overdose per se will not be 
reported as an AE/SAE) 
 Abnormal laboratory findings, as defined in Section 10.2. 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE. 
Events that do not meet the definition of an AE include: 
 Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
 Situations where an untoward medical occurrence did not occur (eg, social and/or 
convenience admission to a hospital) 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen 
 The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition 

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10.1.2 Definition of a Serious Adverse Event 
An AE is considered to be an SAE if, in the view of the Investigator or Sponsor, it results 
in any of the following outcomes: 
 Death 
 Life-threatening AE 
NOTE: Life-threatening AE or life-threatening suspected adverse reaction is an AE 
or suspected adverse reaction that is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate 
risk of death. It does not include an AE or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Persistent or significant incapacity/disability  
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) that may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
 A congenital anomaly/birth defect 
 All events of possible drug-induced liver injury with hyperbilirubinemia having the 
following 3 components termed “Hy’s Law” events. 
1. ALT ≥3× ULN or AST ≥3× ULN 
2. Total bilirubin ≥2× ULN 
3. No other reason can be found to explain the changes observed in #1 and 
#2 above. 
Important medical events that may not result in death, be immediately life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent 1 of the outcomes listed in this definition. Examples of such events are ocular 
inflammation resulting in severe vision loss (>6 lines on ETDRS chart). 

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10.2 
LABORATORY 
AND 
OTHER 
SAFETY 
ASSESSMENT 
ABNORMALITIES REPORTED AS AES AND SAES 
Any abnormal laboratory test results (hematology, chemistry, coagulation, or urinalysis) 
or other safety assessments (eg, vital sign measurements), including those that worsen from 
baseline and are thought to be clinically significant in the medical and scientific judgement 
of the Investigator, are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
10.3 
EVALUATION OF ADVERSE EVENTS/SERIOUS ADVERSE EVENTS 
10.3.1 Relationship to Study Treatment and/or Study Procedures 
The Investigator will assess the potential relationship of the AEs to study treatment or 
procedures using the following definitions: 
 Not Related: This category applies to an AE that is clearly not related to the 
investigational product/procedure, beyond a reasonable doubt. That is, another 
cause of the event is most plausible; and/or a clinically plausible temporal sequence 
is inconsistent with the onset of the event and the exposure to investigational 
product and/or causal relationship is considered biologically implausible. 
 Possibly Related: This category applies to an AE that follows a reasonable 
temporal sequence from administration of the investigational product and that 
follows a known or expected response pattern to the suspected investigational 
product, but that could readily have been produced by a number of other factors. 
 Probably Related: This category applies to an AE that follows a reasonable 
temporal sequence from administration of the investigational product and that 
follows a known or expected response pattern to the suspected investigational 
product and that could not be reasonably explained by the subject’s concurrent 
disease or other drugs or chemicals. 
10.3.2 Severity or Intensity Grading of Adverse Event Scoring 
Wherever possible, the severity of all AEs will be graded using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Version 4.03). 
The majority of AEs can be graded using the CTCAE criteria; however, if an AE cannot 
be graded using the CTCAE criteria, it should be graded according to the following 
definitions: 
 Mild (Grade 1): Awareness of signs or symptoms, but easily tolerated and are of 
minor irritant type causing no loss of time from normal activities. Symptoms do not 
require therapy or a medical evaluation; signs and symptoms are transient.  

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 Moderate (Grade 2): Events introduce a low level of inconvenience or concern to 
the participant and may interfere with daily activities, but are usually improved by 
simple therapeutic measures; moderate experiences may cause some interference 
with functioning. 
 Severe (Grade 3): Events interrupt the participant’s normal daily activities and 
generally require systemic drug therapy or other treatment; they are usually 
incapacitating. 
 Life-threatening (Grade 4): Events that place the subject at immediate risk of 
death or are disabling requiring urgent intervention. 
 Death (Grade 5): Events that result in death. 
The concept of “SAEs” and “Severe Adverse Events” is often confused. Severity is not 
synonymous with seriousness. The term “severe” is often used to describe the intensity 
(severity) of a specific event (eg, mild, moderate, or severe); however, the event itself may 
be of relatively minor medical significance. For example, a headache is severe, if it causes 
intense pain. On the other hand, a headache is not usually serious (but may be in case of 
subarachnoid hemorrhage, subdural bleed, even a migraine may temporally fit “serious” 
criteria), unless it also satisfies the criteria for seriousness as defined in Section 10.1.2. 
Similarly, a severe rash is not likely to be an SAE. However, mild chest pain may result in 
a day’s hospitalization and thus is an SAE. 
An SAE is based on subject/event outcome or action criteria usually associated with events 
that pose a threat to a subject’s life or functioning. Seriousness (not severity) serves as a 
guide for defining regulatory reporting obligations. In other words, an SAE requires an 
additional reporting process (reported to corporate global drug safety group or 
pharmacovigilance 
group, 
regulatory 
authorities, 
Institutional 
Review 
Boards 
[IRBs]/Independent Ethics Committees [IECs]). 
All events of ocular inflammation must additionally be graded according to the Ocular 
Inflammation Grading Scales (Appendix, Section 14.2). 
10.4 
SERIOUS ADVERSE EVENTS, SERIOUS ADVERSE DRUG REACTIONS, 
AND REQUIREMENTS FOR IMMEDIATE REPORTING 
Any SAE that occurs at any time during the study, including a clinically significant 
abnormal laboratory test result that is considered serious, must be reported within 24 hours 
of knowledge of the event to REGENXBIO or its designee. These requirements apply 
equally to all subjects, regardless of the study phase or the subject’s treatment assignment 
or dose. The reporting requirement for SAEs is from the time of signing the ICF through 
30 days following the last study visit. 
A death occurring during the study and within 30 days after the last study visit must be 
reported to REGENXBIO or its designee within 24 hours of knowledge of the death 
whether or not it is considered treatment-related.  
Initial SAE reports must be followed by detailed descriptions. These should include copies 
of hospital case records and other documents when requested. In addition, the Investigator 

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must notify the IRB/IEC of the SAE occurrence in accordance with the IRB/IEC reporting 
requirements. A copy of this notification must be provided to REGENXBIO or its 
designee. 
REGENXBIO has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. 
REGENXBIO will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators. Investigator safety 
reports are prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and are forwarded to Investigators as necessary. 
10.5 
PREGNANCY REPORTING 
Any pregnancy that occurs during study participation either to a study subject or to the 
female partner of a male subject must be reported using a clinical study pregnancy form. 
To ensure subject safety, each pregnancy must be reported to REGENXBIO within 
24 hours of learning of its occurrence. The pregnancy must be followed up to determine 
outcome (including premature termination) and status of mother and child. Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE. Spontaneous abortions 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 investigational product, must be reported to REGENXBIO within 24 hours 
of knowledge of the event. 
10.6 
URGENT SAFETY MEASURES 
The regulations governing clinical studies state that REGENXBIO and the Investigator are 
required to take appropriate Urgent Safety Measures (USMs) to protect subjects against 
any immediate hazards that may affect the safety of subjects, and that the appropriate 
regulatory bodies should be notified according to their respective regulations.  
USMs are procedures that are not defined by the protocol, which can be put in place with 
immediate effect without needing to gain prior authorization by the IRB (and regulatory 
authorities, where applicable), in order to protect subjects from any immediate hazard to 
their health and safety.  
The reporting period for USMs is from signing the ICF through completion of the last study 
visit. It is the Investigator’s responsibility to notify REGENXBIO or its designee of any 
USMs within 24 hours of occurrence. 

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11 
STATISTICAL METHODS AND PLANNED ANALYSES 
REGENXBIO or its designee will perform the statistical analysis of the data from this 
study. All analyses will be fully described in a statistical analysis plan (SAP), which will 
be finalized before any analyses are conducted.  
All data will be presented in subject data listings. Categorical variables will be summarized 
using frequencies and percentages, and continuous variables will be summarized using 
descriptive statistics (number of non-missing observations, mean, standard deviation, 
median, minimum, and maximum). Graphical displays will be presented as appropriate. 
After all subjects have completed the primary study period (24 weeks following RGX-314 
administration), analyses will be performed for all safety and efficacy for the primary 
period. After all subjects have completed the end of the study period (Week 106), analyses 
will be performed for all safety and efficacy.  
11.1 
DETERMINATION OF SAMPLE SIZE 
No formal calculation was performed to determine sample size. 
11.2 
ANALYSIS POPULATIONS 
 As-treated Population: Includes all subjects who received any dose of RGX-314.  
 Evaluable for Efficacy Population: Includes all subjects with both a baseline and 
24 weeks following RGX-314 administration measurement for the efficacy 
endpoints. 
11.3 
DISPOSITION 
The number of subjects enrolled, the number of subjects who complete the study, and the 
number of subjects who withdraw from the study, along with the reasons for their 
withdrawal, will be summarized by dose cohort and by the study overall. In addition, the 
total number of subjects screened and the number of screen failures, along with the reason 
for screen failure, will be summarized. 
11.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics will be summarized descriptively by dose cohort, 
as well as for the study overall. 
11.5 
SAFETY ANALYSES 
11.5.1 Adverse Events 
AEs occurring prior to administration of RGX-314 or in the fellow eye will be listed and 
presented separately from those that occur during or after investigational product 
administration. The incidence of TEAEs, treatment-related TEAEs, and TEAEs by severity 
(intensity) will be summarized. All AEs will be coded using the most recent version of the 

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Medical Dictionary for Regulatory Activities (MedDRA), and will be summarized by 
System Organ Class (SOC) and Preferred Term (PT).   
11.5.2 Clinical Laboratory Tests 
Observed values and changes from baseline (as applicable) through 104 weeks following 
RGX-314 administration will be summarized descriptively by dose cohort and by the study 
overall for each hematology, chemistry, coagulation, and urinalysis parameter. In addition, 
the incidence of subjects who meet predefined criteria for a clinically significant abnormal 
values (or abnormal change) may also be summarized by dose cohort and by the study 
overall.  
11.5.3 Vital Signs 
Observed values and changes from baseline (as applicable) through 104 weeks following 
RGX-314 administration will be summarized descriptively by dose cohort and by the study 
overall. In addition, the incidence of subjects who meet predefined criteria for clinically 
significant abnormal values (or abnormal change) may also be summarized by dose cohort 
and by the study overall.  
11.6 
EFFICACY ANALYSES 
Observed values and changes from baseline over time (as applicable) will be summarized 
descriptively and a 95% confidence interval will be provided by dose cohort and by the 
study overall for the efficacy endpoints (defined in the SAP).  
11.7 
OTHER STATISTICAL ISSUES 
11.7.1 Significance Levels 
Significance level will be 5% and no multiple comparison adjustment will be performed, 
as all analyses are descriptive. 
11.7.2 Missing or Invalid Data 
Due to the small number of subjects, missing or invalid data will be excluded from 
analyses. Analyses will be based on observed data only. 
11.8 
INTERIM ANALYSIS 
No interim analysis is planned. 

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12 
SPECIAL REQUIREMENTS AND PROCEDURES 
12.1 
ETHICAL CONDUCT OF THE STUDY 
The Investigator will ensure that this study is conducted in full conformity with the 
principles established by the 18th World Medical Association General Assembly 
(Helsinki, 1964) including any subsequent amendments and clarifications to these 
principles, current US FDA regulations, International Council on Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, and local ethical and regulatory requirements. 
Should a conflict arise, the Investigator should follow whichever regulation or guideline 
affords the greater protection to the individual subject. 
12.1.1 Institutional Review Board 
The IRB must be a properly constituted board or committee operating in accordance with 
21 Code of Federal Regulations (CFR) Part 56: Institutional Review Boards and ICH E6: 
Guideline for GCP. This protocol, any protocol amendments, and ICFs must be submitted 
to the IRB for review and must be approved before screening of any subject into the study. 
Investigational product will not be shipped to the Investigator until REGENXBIO or its 
designee has received a copy of the IRB approval letter or certificate of approval from the 
IRB for the protocol, any amendments, and ICFs. Site-specific ICFs must be approved by 
REGENXBIO prior to IRB submission. 
In addition, all subject recruitment and/or advertising materials and subject instructions, if 
applicable, must be submitted to the IRB for review and approval prior to implementation. 
Approval by REGENXBIO is required prior to IRB submission of any subject recruitment 
and/or advertising materials and subject instructions, if applicable. 
IRB approval of any protocol amendment must be received before any of the changes 
defined in the protocol amendment are implemented, except when the protocol amendment 
has been enacted to protect study subjects. In these circumstances, the chair of the IRB 
should be notified immediately and the amendment forwarded to the IRB for review and 
approval. 
12.1.2 Subject Information and Informed Consent  
Informed consent is the process that is initiated prior to the potential subject’s agreement 
to participate in the study and continues throughout the subject’s study participation. It is 
the Investigator’s responsibility to obtain signed written informed consent from each 
potential study subject prior to the performance of any study-related procedure. Written 
informed consent will be obtained only after the nature of the study including potential 
risks have been fully explained to each potential subject. The subject and/or subject’s legal 
guardian(s) will be given the opportunity to ask any questions during informed consent as 
well as throughout the study, and all of the subject’s questions must be answered to the 
subject’s satisfaction. The Investigator must explain to each subject that participation in 
the study is completely voluntary and that the subject can decline participation or withdraw 
from participation at any time. If the subject is unable to provide informed consent, then 
informed assent will be obtained and informed consent must be provided by the subject’s 
legal guardian(s).  

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The process of obtaining and documenting informed consent will comply with 21 CFR 
Part 50: Protection of Human Subjects, ICH GCP guidelines, the Health Insurance 
Portability and Accounting Act (HIPAA), and all other applicable regulatory requirements. 
Subjects will be given a copy of the signed ICF and will be provided any new information 
during their participation in the study that may affect their continued willingness to 
participate in the study. If the protocol is amended and the ICF is revised, each subject will 
be required to provide written informed consent again using the revised IRB/IEC-approved 
ICF. 
Informed consent will be documented in the subject’s study file and in the CRF. The signed 
ICF will remain in each subject’s study file and must be made available to the Study 
Monitor(s) at all times. 
12.2 
DATA HANDLING AND RECORD KEEPING 
12.2.1 Monitoring and Access to Study Records 
A representative of REGENXBIO and/or its designee will perform routine monitoring and 
auditing of the study to ensure compliance with FDA and ICH GCP guidelines. 
REGENXBIO’s designated representative (the Monitor) will visit the Investigator to verify 
the Investigator’s qualifications, to inspect the clinical site facilities, and to inspect study 
records, including adherence to regulatory requirements (ie, IRB/IEC review and approval 
documents). In addition, the Monitor will be responsible for confirming that the study is 
being conducted in adherence to the study protocol, performing Source Document 
Verification (SDV), and ensuring the integrity of the data. 
The Monitor will maintain frequent contact with the study site throughout the course of the 
study. The Investigator and all other site personnel agree to cooperate fully with the 
Monitor and will work collaboratively with the Monitor to resolve all questions and issues 
identified by the Monitor. It is the responsibility of the Investigator to be present or 
available for consultation during these routine monitoring visits. 
The Investigator understands and agrees that regulatory authorities, the IRB, and/or 
REGENXBIO or its designee have the right to access all study-related documents 
(eg, CRFs, source documents, etc) during on-site inspections and routine monitoring visits 
and will retain this right from the beginning of the study until at least 2 years after the last 
approval of a marketing application or for at least 2 years after the discontinuation of the 
clinical development of the investigational product under study. It is the responsibility of 
the Investigator to guarantee access to these documents and to cooperate with and support 
such inspections and routine monitoring visits. 
12.2.2 Source Documents and Case Report Forms  
It is the Investigator’s responsibility to prepare and maintain adequate and accurate case 
histories that record all observations and other data related to the study for each subject. 
Case histories include the CRFs and supporting data (ie, source documents) such as signed 
and dated ICFs, medical records, laboratory reports, etc. Case histories for each subject 
will document that informed consent was obtained prior to participation in the study. 

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A validated Electronic Data Capture (EDC) system will be used for entry of the data into 
electronic CRFs designed and approved by REGENXBIO. All data entered into the CRF 
must be verifiable; therefore, CRFs will be routinely monitored for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source 
documents. 
12.2.3 Data Quality Assurance 
During routine monitoring visits, the Monitor will perform SDV against CRFs to ensure 
data accuracy, completeness, and clarity, including laboratory reports and other subject 
records with the stipulation that subject confidentiality will be strictly maintained in 
accordance with local and federal regulations, including HIPAA requirements. Instances 
of missing or uninterruptable data will be resolved in coordination with the Investigator. 
In addition to routine monitoring of the data by the Monitor, the EDC system will include 
internal quality controls by employing Skip Logics and Edit Checks. Skip Logics are 
programs in the database that restrict entry to particular data fields based on previous 
entered data, thus restricting the entry of irrelevant data. Edit Checks are a set of 
programmed instructions in the database to identify and flag discrepancies in the entered 
data. 
12.2.4 Record Retention 
All study-related documents must be retained for at least 2 years after the last approval of 
a marketing application or until at least 2 years have elapsed since the formal 
discontinuation of the clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with REGENXBIO. All study-related 
documents must be stored in a secure limited access facility. 
12.3 
INDEPENDENT DATA MONITORING COMMITTEE  
This study will be conducted under the auspices of an IDMC. The membership and 
activities are outlined in the IDMC Charter. 
12.4 
INTERNAL SAFETY COMMITTEE 
The Internal Safety Committee will be comprised of REGENXBIO employees and 
designees and be charged with Sponsor oversight for the safe conduct of the study. 
12.5 
FINANCING AND INSURANCE 
Financing and insurance for this study will be addressed in the Clinical Trial Agreement 
with the study site(s). 
12.6 
PROVISION 
OF 
STUDY 
RESULTS 
AND 
INFORMATION 
TO 
INVESTIGATORS AND PUBLICATION 
Study information from this protocol will be posted on www.clinicaltrials.gov within 
21 days of enrollment of the 1st participant. 

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Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study report. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a REGENXBIO site or other mutually 
agreeable location. 
REGENXBIO will also provide the Investigator with the full summary of the study results. 
The Investigator is encouraged to share the summary results with the study subjects, as 
appropriate. The results summary will be posted to clinicaltrials.gov no later than 
12 months after the last subject’s last visit or sooner if required by legal agreement, local 
law, or regulation. A manuscript will be progressed for publication in the scientific 
literature if the results provide important scientific or medical knowledge and will be 
submitted to a peer-reviewed journal for publication within 18 months of the last subject’s 
last visit.  
 

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13 
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14 
APPENDICES 
14.1 
GUIDE TO SIGNS AND SYMPTOMS OF TOXICITY 
AC = anterior chamber; IOP = intraocular pressure; VA = visual acuity. 
 
Acute signs and symptoms of toxicity 
(1-7 days post administration) 
Anterior segment: Corneal edema, acute increase of intraocular 
pressure (IOP) (spike), anterior chamber (AC) inflammatory 
response (flare and cells), iris neovascularization, episcleritis, 
scleritis, and eye pain. 
Posterior segment: acute retinal necrosis, retinal detachment, 
retinal breaks, intra-retinal and subretinal hemorrhage, retinal 
vein thrombosis, cotton wool spots, chorioretinitis and 
inflammation (vitreous cells and haze), retinal edema, retinal 
vascular permeability changes (leakage and edema), sterile 
endophthalmitis, infectious endophthalmitis, macular hole, 
epiretinal membrane, proliferative vitreoretinopathy, retinal 
arterial occlusion, optic nerve edema, optic nerve infarction, 
and retinal vasculitis. 
Functional: acute visual loss, acute visual field loss, and 
metamorphopsia. 
Near-term signs and symptoms of 
toxicity (2-4 weeks post 
administration) 
Anterior segment: corneal endothelial insufficiency, corneal 
epithelial changes, increased IOP, and AC inflammatory 
response (flare and cells). 
Posterior segment: retinal necrosis, retinal detachment, retinal 
breaks, intra-retinal and subretinal hemorrhage, retinal vein 
thrombosis, cotton wool spots, chorioretinitis and inflammation 
(vitreous cells and haze), retinal vascular permeability changes 
(leakage and edema), and retinal atrophic changes. 
Functional: VA decline and visual field defects. 
Long-term signs and symptoms of 
toxicity (months) 
Anterior segment: corneal endothelial insufficiency and 
glaucoma. 
Posterior segment: retinal atrophic changes, retinal vascular 
thinning, retinal thinning, loss of retinal layers, low-grade 
inflammation (chorioretinitis, neuroretinitis), atrophic changes 
in retinal areas, and geographic atrophy. 
Functional: reduced VA, color vision disturbances, visual field 
defects (relative and absolute scotomas), and afferent pupillary 
defect. 

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14.2 
Ocular Inflammation Grading Scales 
Ocular inflammation will be assessed during slit-lamp biomicroscopy and independent 
ophthalmoscopy and graded using the following scales. The standard practice for slit-lamp 
biomicroscopy and indirect ophthalmoscopy assessment should be used. 
Table 7: 
Grading Scale for Ocular Inflammation: Anterior Chamber Cells and 
Anterior Chamber Flare 
Anterior Chamber Cells 
Grade 
Cells in Field (1 mm × 1 mm slit beam) 
0 
None 
+0.5 
1–5 
+1 
6–15 
+2 
16–25 
+3 
26–50 
+4 
>50 
Anterior Chamber Flare 
Grade 
Description 
0 
None 
+1 
Trace 
+2 
Moderate (iris and lens detail clear) 
+3 
Marked (iris and lens detail hazy) 
+4 
Intense (fibrin or plastic aqueous) 
Source: This article was published in Am J Ophthalmol, Vol 140(3). Jabs DA, Nussenblatt RB, Rosenbaum 
JT. Standardization of Uveitis Nomenclature Working Group. Standardization of uveitis nomenclature for 
reporting clinical data. Results of the first international workshop. Pages 509-16. Copyright Elsevier 2005. 
Jabs, 2005 
 
 
 

Protocol Number: RGX-314-001 
 
REGENXBIO INC. 
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Table 8: 
Grading Scale for Vitreous Haze 
Grade 
Amount of Vitreal Haze 
0 
None 
+0.5 
Trace 
+1 
Clear optic disc and vessels; hazy nerve fiber layer 
+2 
Hazy optic disc and vessels 
+3 
Optic disk visible 
+4 
Optic disc not visible 
Source: This article was published in Am J Ophthalmol, Vol 40(3). Jabs DA, Nussenblatt RB, Rosenbaum 
JT. Standardization of Uveitis Nomenclature Working Group. Standardization of uveitis nomenclature for 
reporting clinical data. Results of the first international workshop. Pages 509-16. Copyright Elsevier 2005. 
Nussenblatt, 1985. Refer also to Figure 10. 
 
Figure 10: 
Gradations of Vitreous Haze 
 
Source: Nussenblatt, 1985 
 
 
 
 
 

Protocol Number: RGX-314-001 
 
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PROPRIETARY AND CONFIDENTIAL AND THUS EXEMPTED FROM DISCLOSURE PURSUANT TO 5 USC S552(B), ESP. 5 
USC S552(B)(4) 
15 
SIGNATURE PAGE 
Protocol Title:  
A Phase I/IIa, Open-label, Multiple-cohort, Dose-escalation Study 
to Evaluate the Safety and Tolerability of Gene Therapy with 
RGX-314 in Subjects with Neovascular AMD (nAMD) 
Protocol Number:  RGX-314-001 
 
Investigator Signature: 
I have read Protocol RGX-314-001. I agree to conduct the study as detailed in this protocol 
and in compliance with the Declaration of Helsinki, Good Clinical Practices (GCP), and 
all applicable regulatory requirements and guidelines. 
 
____________________________________________  
 
__________________ 
Investigator Signature 
 
Date 
 
Printed Name: _________________________________________ 
 
Sponsor Signature: 
As the Sponsor representative, I confirm that REGENXBIO will comply with all Sponsor 
obligations as detailed in applicable guidelines and regulations. I will ensure that the 
Investigator is informed of all relevant information in a timely manner that becomes 
available during the conduct of this study. 
___________________________________________  
 
__________________ 
 
 
. 
 

Signature Page for RGX-RIM-003896 v3.0