Conditions: Stargardt's Disease
Keywords: Stargardt's Disease
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
Primary Objective:

To assess the safety and tolerability of ascending doses of SAR422459 in participants with Stargardt's Macular Degeneration (SMD).

Secondary Objective:

To evaluate for possible biological activity of SAR422459.

Detailed description:
The total duration per participant was up to 52 weeks, which included 4 week screening period and 48 weeks study period.

At the end of the study, the participants were invited to enter in an open-label safety study (LTS13588-NCT01736592) for long-term follow-up visits including ophthalmological examinations and recording of adverse events (AEs) for up to 15 years.

Arms:
arm 1: Starting dose of SAR422459 given through subretinal injection arm 2: Escalating dose of SAR422459 given through subretinal injection arm 3: Maximum tolerated dose (MTD) of SAR422459 given through subretinal injection

Interventions: intervention 1: SAR422459
Intervention descriptions: intervention 1: Pharmaceutical form: sterile solution, 100 microliters (μL) aliquots in 0.3 milliliter (mL) type I borosilicate glass 'V' vials with a butyl stopper and aluminum crimp seal.

Route of administration: subretinal injection

Protocol document:
Prot_000.pdf: 
 
SAR422459 is a trademark of Sanofi Group 
This confidential document is the property of Sanofi Group. No unpublished information contained herein may be 
disclosed without the prior written approval of Sanofi Group. 
Page 1 
AMENDED CLINICAL PROTOCOL NO 12 
STUDY NUMBER: TDU13583 
EudraCT number: 2010-023111-34 
IND number: 14639 
A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected SAR422459, 
Administered to Patients with Stargardt’s Macular Degeneration 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SPONSOR 
In France: 
sanofi-aventis Research & Development 
1 avenue Pierre Brossolette 
91380 Chilly-Mazarin (FRANCE) 
 
In the USA: 
Sanofi US Services Inc. 
55 Corporate Drive 
Bridgewater, NJ 08807 (USA) 
 
 
MEDICAL MONITOR 
 
 
 
 
 
  
 
Amended Clinical Protocol NO 12 date 29-Nov-2018 
                               NCT01367444


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended clinical trial protocol 12 
All 
[29 November 2018], version 1 (electronic 10.0) 
Amended clinical trial protocol 11 
All 
[26 September 2017], version 1 (electronic 9.0) 
Amended clinical trial protocol 10 
All 
[28 July 2016], version 1 (electronic 8.0) 
Amended clinical trial protocol 09 
All 
[25 February 2016], version 1 (electronic 7.0) 
Amended clinical trial protocol 08 
All 
[16 December 2015], version 1 (electronic 6.0) 
Amended clinical trial protocol 07 
All 
[10 March 2015], version 1 (electronic 4.0) 
Amended clinical trial protocol 06 
All 
[12 November 2014], version 1 (electronic 3.0) 
Amended clinical trial protocol 05 
All 
[14 April 2014], version 1 (electronic 1.0) 
Amended clinical trial protocol 04 
All 
[24 January 2012], version 1 
Amended clinical trial protocol 03 
All 
[16 June 2011], version 1 
Amended clinical trial protocol 02 
All 
[31 March 2011], version 1 
Amended clinical trial protocol 01 
All 
[14 December 2010], version 1 
Original clinical trial Protocol 
All 
[27 October 2010], version 1 
Amended protocol 12 (29 November 2018)  
This amended protocol is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The protocol is being amended to reduce the dose of administered study drug and to review 
number of patients in cohorts yet to recruit, as well as other changed deemed necessary by the 
Sponsor. 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
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Property of the Sanofi Group - strictly confidential 
Page 3 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Multiple 
sections 
Addition of Cohorts 8 and 9 to be treated with a 
3-fold lower administered dose. 
Due to variability observed in previous batch strength 
patients in Cohort s 6 and 7 have received different doses 
when calculated by measured strength. While strength 
remained within specification, the patients in Cohorts 6 
and 7 (treated with a new batch) received 4.5x106 TU/eye 
dose. Review of safety data in Cohorts 6 and 7 by 
Sponsor and DSMB concluded that due to an increased 
number of IMP related adverse events, treatment dose 
needs to be down-escalated 3 times to ensure more 
safety while preserving transduction potential. 
Multiple 
sections 
 to be used with the IMP. 
 
of product prior to administration is added in relevant 
sections.  
Synopsis, 
multiple 
sections 
Adding information of the administered dose by 
measured strength. 
Due to established need to better control administered 
dose of the IMP, measure of dose is changed from 
referring to dose by target strength to measured QC 
strength. 
Summary, 
Study Flow 
Diagram (3), 
Sections  
4.11 and 7 
Reduction of patient number in Cohorts 6 and 7.  
Due to above observation it is not planned to continue 
recruitment in Cohorts 6 and 7 with previous maximal 
dose.  
9.2.2 
Prophylactic IV methylprednisolone injection will be 
administered 2 hours before surgery instead of 
after surgery.  
In the view of possible early reactions of immune system 
to subretinal injection an anticipated dose of IV 
glucocorticoid is planned to suppress start of any 
inflammatory reaction.  
9.2.2 
Subretinal recommendation shortening. 
This will allow better adaptation of retinotomy and IMP 
injection to individual patient and surgery practices.  
Section 7 
Inconsistency due to edition error in Section 7 
corrected (Cohort 5 data review by DSMB) – to 
match to Summary and other parts of the Protocol.  
Error of edition was done in modifying this part of the text, 
referring to already performed activities in Cohort 5 data 
review. 
 




Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
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Property of the Sanofi Group - strictly confidential 
Page 5 
TABLE OF CONTENTS 
AMENDED CLINICAL PROTOCOL NO 12.................................................................................................... 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .................................................................. 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
1 
LIST OF ABBREVIATIONS .......................................................................................................... 11 
2 
SYNOPSIS ..................................................................................................................................... 14 
3 
STUDY SCHEDULE ...................................................................................................................... 20 
3.1 
COHORT 1 TO 5 ............................................................................................................................ 20 
3.2 
COHORTS 6-9 ............................................................................................................................... 23 
4 
STUDY FLOW DIAGRAM ............................................................................................................. 27 
5 
INTRODUCTION AND RATIONALE ............................................................................................. 28 
5.1 
THERAPEUTIC GENES ................................................................................................................ 28 
5.2 
CLINICAL PATHOLOGY ............................................................................................................... 29 
5.3 
DIAGNOSIS AND MONITORING OF SMD ................................................................................... 30 
5.4 
NON PHARMACOLOGICAL TREATMENT .................................................................................. 31 
5.4.1 
Gene transfer ................................................................................................................................. 31 
5.4.2 
SAR422459 formulation ................................................................................................................. 31 
5.4.3 
Mechanism of action ...................................................................................................................... 32 
5.5 
SUMMARY OF PROOF OF PRINCIPLE NON-CLINICAL STUDIES ........................................... 32 
5.5.1 
Pharmacology studies .................................................................................................................... 32 
5.5.2 
Pharmacokinetic studies ................................................................................................................ 33 
5.5.3 
Toxicology studies .......................................................................................................................... 33 
5.6 
RATIONALE FOR STUDY ............................................................................................................. 33 
5.6.1 
Rationale for SAR422459 .............................................................................................................. 33 
5.7 
RATIONALE FOR INJECTION INTO THE EYE ............................................................................ 34 
5.8 
RATIONALE FOR UNILATERAL ADMINISTRATION ................................................................... 34 
5.9 
RATIONALE FOR THE CLINICAL DOSE ..................................................................................... 34 
5.9.1 
Summary of dosing regimens ........................................................................................................ 35 


Amended Clinical Protocol NO 12  
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5.10 
RATIONALE FOR DOSING INTERVALS ...................................................................................... 35 
5.11 
RATIONALE FOR TARGET PATIENT POPULATION .................................................................. 36 
6 
OBJECTIVES ................................................................................................................................ 38 
6.1 
PRIMARY OBJECTIVES ............................................................................................................... 38 
6.2 
SECONDARY OBJECTIVE ........................................................................................................... 38 
7 
ENDPOINTS .................................................................................................................................. 39 
7.1 
PRIMARY ENDPOINTS ................................................................................................................. 39 
7.2 
SECONDARY ENDPOINTS .......................................................................................................... 39 
7.2.1 
Immunology .................................................................................................................................... 40 
7.2.2 
Laboratory parameters ................................................................................................................... 40 
7.2.3 
Other safety parameters ................................................................................................................ 40 
7.2.4 
Exploratory efficacy parameters .................................................................................................... 40 
7.2.5 
Concomitant medication ................................................................................................................ 40 
7.3 
BIODISTRIBUTION ENDPOINT .................................................................................................... 40 
7.4 
OTHER MEASURES ..................................................................................................................... 41 
7.4.1 
Patient characteristics .................................................................................................................... 41 
8 
STUDY DESIGN ............................................................................................................................ 42 
8.1 
STUDY SITES ................................................................................................................................ 45 
9 
STUDY POPULATION .................................................................................................................. 46 
9.1 
ENTRY CRITERIA ......................................................................................................................... 46 
9.1.1 
Main inclusion criteria..................................................................................................................... 46 
9.1.2 
Specific inclusion criteria Patient Group A ..................................................................................... 46 
9.1.3 
Specific inclusion criteria Patient Group B ..................................................................................... 47 
9.1.4 
Specific inclusion criteria Patient Group C ..................................................................................... 47 
9.1.5 
Specific inclusion criteria Patient Group D ..................................................................................... 47 
9.1.6 
Specific inclusion criteria Patient Group E ..................................................................................... 47 
9.1.7 
Exclusion criteria ............................................................................................................................ 48 
9.2 
WITHDRAWAL CRITERIA ............................................................................................................. 49 
9.3 
STUDY STOPPING CRITERIA ..................................................................................................... 50 
9.4 
DOSE-LIMITING TOXICITIES ....................................................................................................... 50 
10 
TREATMENT PLAN AND METHODS .......................................................................................... 51 


Amended Clinical Protocol NO 12  
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Page 7 
10.1 
ALLOCATION OF TREATMENTS ................................................................................................. 51 
10.1.1 
Dose escalation .............................................................................................................................. 51 
10.2 
STUDY MEDICATION ADMINISTRATION ................................................................................... 51 
10.2.1 
Hospitalization ................................................................................................................................ 51 
10.2.2 
Subretinal injection procedure ....................................................................................................... 51 
10.2.3 
Positioning of the subretinal bleb ................................................................................................... 53 
10.2.4 
SAR422459 preparation ................................................................................................................ 53 
10.2.5 
SAR422459 administration ............................................................................................................ 54 
10.2.6 
Post-surgical monitoring ................................................................................................................ 54 
10.3 
SPECIFIC PROCEDURES ............................................................................................................ 54 
10.3.1 
Screening/baseline procedures ..................................................................................................... 54 
10.3.2 
Screening clinical and laboratory/diagnostic measurements ......................................................... 55 
10.3.3 
Screening clinical laboratory/diagnostic measurements Day -1 .................................................... 56 
10.3.4 
Re-screening .................................................................................................................................. 57 
10.3.5 
Surgery ........................................................................................................................................... 57 
10.3.6 
Follow-up procedures .................................................................................................................... 58 
10.3.7 
Follow-up Day 1 clinical and laboratory/diagnostic measurements ............................................... 58 
10.3.8 
Follow-up Week 1, 2, 4, 12, 24, 36 and 48 clinical and laboratory/diagnostic measurements 
(visit at Week 36 is not performed in Cohorts 6 and 9) .................................................................. 58 
10.3.9 
Samples for PCR ........................................................................................................................... 60 
10.3.10  Samples for immunology ............................................................................................................... 60 
10.3.11  Ophthalmological assessments ..................................................................................................... 61 
10.3.12  Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity ................... 61 
10.3.13  Contrast sensitivity ......................................................................................................................... 61 
10.3.14  Slit lamp examination ..................................................................................................................... 62 
10.3.15  Fundoscopy/indirect ophthalmoscopy............................................................................................ 62 
10.3.16  Intraocular pressure measurement ................................................................................................ 62 
10.3.17  Optical coherence tomography ...................................................................................................... 62 
10.3.18  Fundus photography ...................................................................................................................... 62 
10.3.19  Electroretinogram ........................................................................................................................... 63 
10.3.20  Perimetry ........................................................................................................................................ 63 
10.3.21  Microperimetry ............................................................................................................................... 64 
10.3.22  Fundus Autofluorescence imaging ................................................................................................. 64 
10.3.23  Adaptive optics ............................................................................................................................... 65 
10.3.24  Reading speed ............................................................................................................................... 65 
10.3.25  Visual Function Questionnaires VFQ-25/CVAQC-25 .................................................................... 65 


Amended Clinical Protocol NO 12  
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Page 8 
10.3.26  Medication, adverse event and concomitant medication review ................................................... 66 
10.3.27  Post-surgical ophthalmological adverse events ............................................................................. 66 
10.3.28  Clinical laboratory tests .................................................................................................................. 67 
10.3.29  Flexibility of assessment data capture ........................................................................................... 68 
10.3.30  Surgery video-recording and intra-operative OCT ......................................................................... 69 
11 
STUDY MATERIALS ..................................................................................................................... 70 
11.1 
SAR422459 .................................................................................................................................... 70 
11.1.1 
Packaging and labeling .................................................................................................................. 70 
11.1.2 
Storage and disposition of study medications ............................................................................... 70 
11.1.3 
Precautions/Overdose ................................................................................................................... 71 
11.2 
OTHER STUDY SUPPLIES ........................................................................................................... 71 
12 
OBLIGATIONS OF THE INVESTIGATOR REGARDING SAFETY REPORTING ....................... 72 
12.1 
ADVERSE EVENT DEFINITION ................................................................................................... 72 
12.2 
RELATIONSHIP OF AN ADVERSE EVENT TO THE INVESTIGATIONAL 
PRODUCT/PROTOCOL PROCEDURE ........................................................................................ 72 
12.3 
SEVERITY OF AN ADVERSE EVENT .......................................................................................... 73 
12.4 
SERIOUS ADVERSE EVENT DEFINITION .................................................................................. 73 
12.5 
ADVERSE EVENTS OF SPECIAL INTEREST ............................................................................. 74 
12.6 
GENERAL GUIDELINES FOR REPORTING ADVERSE EVENTS .............................................. 76 
12.6.1 
Instructions for reporting serious adverse events (SAE) ............................................................... 76 
12.6.2 
Guidelines for reporting adverse events of special interest (AESI) ............................................... 77 
12.6.3 
Guidelines for management of specific laboratory abnormalities .................................................. 78 
12.7 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 78 
12.8 
PATIENT WITHDRAWALS FROM THE STUDY ........................................................................... 79 
13 
DATA SAFETY MONITORING BOARD ....................................................................................... 80 
13.1 
ROLE ............................................................................................................................................. 80 
13.2 
RESPONSIBILITIES ...................................................................................................................... 80 
14 
DEVELOPMENT SAFETY UPDATE REPORTS .......................................................................... 81 
15 
DATA MANAGEMENT AND STATISTICAL ANALYSES ............................................................ 82 
15.1 
SAMPLE SIZE ESTIMATES .......................................................................................................... 82 


Amended Clinical Protocol NO 12  
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Page 9 
15.2 
STATISTICAL ANALYSES ............................................................................................................ 82 
15.3 
SAFETY ENDPOINTS ................................................................................................................... 82 
15.3.1 
Adverse events .............................................................................................................................. 82 
15.3.2 
Ophthalmological safety endpoints ................................................................................................ 83 
15.3.3 
Secondary endpoints ..................................................................................................................... 83 
15.3.4 
Immunology endpoint ..................................................................................................................... 83 
15.3.5 
Laboratory parameters ................................................................................................................... 83 
15.3.6 
Other safety parameters ................................................................................................................ 83 
15.3.7 
Concomitant medication ................................................................................................................ 83 
15.4 
BIODISTRIBUTION ENDPOINT .................................................................................................... 83 
15.5 
OTHER MEASURES ..................................................................................................................... 84 
15.5.1 
Patient characteristics .................................................................................................................... 84 
15.5.2 
Withdrawals .................................................................................................................................... 84 
15.5.3 
Deaths ............................................................................................................................................ 84 
15.6 
ELECTRONIC CASE REPORT FORMS AND DATA COLLECTION ........................................... 84 
15.7 
DOUBLE-BLINDED CODES .......................................................................................................... 84 
15.8 
INTERIM ANALYSIS ...................................................................................................................... 85 
16 
ETHICAL CONSIDERATIONS ...................................................................................................... 86 
16.1 
PATIENT INFORMATION LEAFLETS AND INFORMED CONSENT FORMS ............................. 86 
16.2 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD REVIEW ........................................... 87 
17 
REGULATORY REQUIREMENTS AND SPONSOR/INVESTIGATOR OBLIGATIONS ............. 88 
17.1 
STUDY INITIATION ....................................................................................................................... 88 
17.2 
MONITORING ................................................................................................................................ 88 
17.3 
DOCUMENTATION AND RECORD KEEPING ............................................................................. 89 
17.4 
CLINICAL STUDY REPORT .......................................................................................................... 89 
17.5 
TERMINATION OF THE STUDY ................................................................................................... 89 
17.6 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
REQUIREMENTS .......................................................................................................................... 90 
17.7 
PUBLICATION AND COMMUNICATION ...................................................................................... 90 
17.8 
PROTOCOL AMENDMENTS ........................................................................................................ 90 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
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Page 10 
18 
REFERENCES ............................................................................................................................... 91 
19 
APPENDICES ................................................................................................................................ 96 
APPENDIX A 
OCULAR INFLAMMATION GRADING ................................................................................ 97 
APPENDIX B 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI .................................. 99 
APPENDIX C 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 104 
APPENDIX D 
LOW-CONTRAST SLOAN LETTER CHART TESTING ................................................... 110 
APPENDIX E 
RADNER READING CHARTS .......................................................................................... 113 
APPENDIX F 
PROTOCOL AMENDMENT HISTORY ............................................................................. 114 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
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Page 11 
1 
LIST OF ABBREVIATIONS 
 
A2E: 
diretinoid pyridinium-ethanolamine  
AAV: 
adeno-associated virus 
ABC: 
adenosine triphosphate (ATP)-binding cassette 
ABCA4: 
ATP-binding cassette, sub-family A, member 4 
ABCR: 
retina specific ABC transporter  
AE: 
adverse event 
AESI: 
adverse event of special interest  
ALT: 
alanine aminotransferase 
AMD: 
age-related macular degeneration  
ARVO: 
Association for Research in Vision and Ophthalmology 
ATP: 
adenosine triphosphate 
BCVA: 
best-corrected visual acuity  
cDNA: 
complementary deoxyribonucleic acid 
CFR: 
code of federal regulations 
CMV: 
cytomegalovirus 
CRF: 
case report form 
CRO: 
Contract Research Organization 
CS: 
clinically significant 
CVAQC-25: 
25-item Cardiff visual ability questionnaire for children 
DSMB: 
data safety monitoring board  
EC: 
Ethics Committee 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EIAV: 
equine infectious anemia virus 
ERG: 
electroretinogram  
ETDRS: 
early treatment diabetic retinopathy study 
EU: 
European Union 
EVA: 
electronic visual acuity 
FAF: 
fundus autofluorescence  
FDA: 
U.S. Food and Drug Administration 
FIM: 
first in man  
GATE: 
German Adaptive Threshold Estimation (Strategy) 
GCP: 
Good Clinical Practice 
GLP: 
good laboratory practice  
IB: 
investigator brochure 
ICH: 
International Conference on Harmonization 
IMP: 
investigational medical product 
IOP: 
intraocular pressure  
IRB: 
institutional review board 
ISCEV: 
International Society for Clinical Electrophysiology of Vision 
kb: 
kiloBase 




Amended Clinical Protocol NO 12  
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SAR422459-TDU13583 (SG1/001/10) 
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Page 13 
INVESTIGATOR STATEMENT 
I am aware of my responsibilities as an investigator under the guidelines of ICH-Good Clinical 
Practice, The Declaration of Helsinki, the Code of Federal Regulations, Title 21, the applicable 
regulations of the study site and the study protocol and I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control who will be 
involved in the study, ensuring they have access to the study protocol and any amendments and 
are aware of their obligations. 
I, the undersigned, have read and agree with protocol number TDU13583. 
 
Signed 
 
 
Name  
 
 
Date 
 


Amended Clinical Protocol NO 12  
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SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 14 
2 
SYNOPSIS 
 
Official 
Title 
A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected SAR422459, Administered to Patients with 
Stargardt’s Macular Degeneration 
Clinical 
Phase 
Phase I/IIa 
Study Objectives: 
Primary 
Objectives 
To assess the safety and tolerability of ascending doses of SAR422459 in patients with Stargardt’s macular 
degeneration (SMD) 
Secondary 
Objective 
To evaluate for possible biological activity of SAR422459  
Study Endpoints: 
Primary 
Endpoint 
 
The incidence and severity of treatment emergent adverse events. 
 
Clinically important changes from baseline in the following safety assessments: 
- 
Best-corrected visual acuity (BCVA) 
- 
Slit-lamp examination 
- 
Fundoscopy/Indirect ophthalmoscopy 
- 
Fundus photography (color and infrared reflectance) 
- 
Intraocular pressure (IOP) 
- 
Microperimetry 
- 
Full-field static perimetry 
- 
Full-field kinetic perimetry 
- 
Optical Coherence Tomography (OCT)  
- 
Electroretinogram (ERG) 
- 
Laboratory parameters 
- 
Vital signs 
-
Concomitant medications 
Secondary 
Endpoints 
To determine a delay in retinal degeneration following subretinal injection of SAR422459, through changes from 
baseline in visual function and retinal structure relative to the untreated contralateral eye utilizing the following 
retinal analytical techniques: 
 
For visual function: 
- 
BCVA 
- 
Microperimetry 
- 
Full-field static perimetry 
- 
Full-field kinetic perimetry 
 
For retinal structure: 
- 
OCT 
-
Fundus Autofluorescence (FAF) 
Other 
safety 
measures 
SAR422459 distribution in the blood and urine assessed by polymerase chain reaction (PCR) 
Humoral response to SAR422459 administration 
Vital signs, physical examination, hematology, biochemistry, urinalysis and other laboratory data will be 
measured at various time points throughout the study 


Amended Clinical Protocol NO 12  
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Page 15 
Exploratory 
efficacy 
endpoints 
 
Contrast sensitivity  
 
Reading speed (Cohort 1-5; Cohorts 6-7, when possible) 
 
Visual function/Quality of life questionnaires (Cohorts 1-5; Cohorts 6-7, when possible) 
 
Multifocal ERG (Cohorts 1-5 only) 
 
Adaptive optics (Cohorts 1-5 only) 
Study Design 
This is a phase I/IIa open label dose escalation study of subretinally injected SAR422459 in patients with SMD. In this study 
3 doses of SAR422459 will be evaluated over 9 patient cohorts with 5 groups of patients. The first 4 cohorts will evaluate the dose 
escalation phase of the study and will each consist of 4 patients. Cohort 5, consisting of 6 patients, Cohort 6 of 4 patients, 
Cohort 7 having 1 patient receive the highest dose tested from the dose escalation phase. Cohorts 8 and 9, consisting of up to 6 
and up to 8 patients respectively will receive the intermediate dose de-escalated after previous cohorts.  
One study eye will be selected. If both eyes are eligible for the study, the worse eye, as per investigator judgment, will be selected. 
A centralized review will advise on the choice of the study eye if both eyes are clinically similar.  
For Cohorts 6-9, the centralized review will also advise on the area to inject the treatment. 
Five groups of patients (groups A, B, C, D, and E), will be recruited to this study. The advancement of disease for groups A, B, and 
C will be defined according to BCVA and electroretinogram (ERG) recordings, whereas group D will have less advanced disease 
as determined by clinical parameters. 
 
Group A: Patients (18 years or older) with advanced SMD, visual acuity (VA) ≤20/200 in the worst eye and severe 
cone-rod dysfunction with no detectable or severely abnormal full-field ERG responses. 
 
Group B: Patients (18 years or older) with SMD, VA ≤20/200 in the worst eye with abnormal full-field ERG responses.  
 
Group C: Patients (18 years or older) with SMD, VA ≤20/100 in the worst eye with abnormal full-field ERG responses. 
 
Group D: Patients (from 6 to 26 years) with symptomatic early or childhood onset SMD and VA ≥20/200 in both eyes, at 
the time of the screening visit anticipated to experience rapid deterioration in visual function and/or retinal structure (1). 
 
Group E: Patients (from 6 to 17 years) with symptomatic SMD and, VA ≥20/100 in both eyes at the time of the screening 
visit anticipated to experience rapid deterioration in visual function and/or retinal structure. 
Four Group A patients will receive SAR422459 at the lowest dose level (1.8x105 TU/eye dose Cohort 1). An interval of 21 days 
between dosing 2 consecutive patients in the cohort will be observed in order to assess the safety and tolerability of SAR422459 
in these patients. 
If after a minimum interval of 28 days following the dosing of the 4th patient in the cohort the safety and tolerability of Group A at 
the lowest dose is considered satisfactory by the Data Safety Monitoring Board (DSMB) then 4 Group B patients will also be 
enrolled into Cohort 2. These patients will also receive the 1.8x105 TU/eye dose (the same dose of SAR422459 as dose Cohort 1), 
an interval of 21 days between dosing 2 consecutive patients will be observed. 
If after a minimum interval of 28 days the safety and tolerability of group B in Cohort 2 is considered satisfactory by the DSMB the 
dose of SAR422459 will be escalated and 4 group B patients will be enrolled into Cohort 3 and receive a dose of 6x105 TU/eye 
dose of SAR422459. An interval of 21 days between dosing 2 consecutive patients will be observed. 
If after a minimum interval of 28 days from dosing the 4th patient of Group B in Cohort 3, the safety and tolerability of SAR422459 
is considered satisfactory by the DSMB then the dose of SAR422459 will be escalated to the maximal dose (1.8x106 TU/eye), and 
4 Group B patients will be enrolled into the next cohort (Cohort 4). An interval of 21 days between dosing 2 consecutive patients 
will be observed. 
If after a minimum interval of 28 days from dosing the 4th patient of Group B in Cohort 4, the safety and tolerability is considered 
satisfactory by the DSMB then 6 patients in Group C will be enrolled and receive SAR422459 at the maximum tolerated dose 
(MTD) or the highest dose tested (Cohort 5).  
For Cohort 5, an interval of 21 days between dosing the first patient and 2nd patient will be observed; subsequent patients may be 
enrolled in parallel. 
If after a minimum interval of 28 days from dosing the last patient of Cohort 5, the safety and tolerability is considered satisfactory 
by the DSMB then eligible patients will be enrolled in Cohort 6 (group D) and will receive SAR422459 at the highest dose tested. 
Prior to the inclusion of pediatric patients, the DSMB will review all safety data including the available data from all cohorts after 
the last patient of Cohort 5 has completed 12 weeks of follow-up after having been dosed. An interim report including all available 
safety data, preliminary efficacy data and the recommendations from the DSMB will be submitted to the regulatory authorities and 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 16 
institutional review boards/ethics committees for approval before enrolling pediatric patients (<18 years). Additional patient data 
will be submitted to DSMB, if requested so. 
Group D (Cohort 6) plans to enroll and treat patients (from 6 years to 26) with early or childhood onset symptomatic SMD and 
VA ≥20/200 in both eyes at the time of the screening visit anticipated to experience rapid deterioration in visual function and/or 
retinal structure.  
An interval of 28 days between dosing of the first and second pediatric patients will be observed. Thereafter, subsequent pediatric 
patients may be enrolled consecutively. 
Group E (Cohort 7) plans to enroll and treat patients (from 6 years to 17 years old) with symptomatic SMD and VA ≥20/100 in both 
eyes at the time of screening visit, anticipated to experience rapid deterioration in visual function and/or retinal structure. If patient 
is eligible in both - Cohorts 6 and 7 - she/he will be included in Cohort 7. 
Cohort 8 will be treated with the 1.5 x106 TU measured strength dose and will enroll patients corresponding to Group D criteria: 
(from 6 years to 26 years old; early or childhood onset symptomatic SMD and VA ≥20/200 in both eyes at screening; rapid 
deterioration). 
Cohort 9 will be treated with 1.5 x106 TU measured strength dose and will enroll patients corresponding to Group E criteria (from 
6 years to 17 years old; symptomatic SMD and VA ≥20/100 in both eyes at screening; rapid deterioration. If patient is eligible in 
both - Cohorts 8 and 9 - she/he will be included in Cohort 9.  
DSMB review of available data will be performed before starting treating patients younger than 16 years.  
For Cohorts 6-9, to ensure consistency across sites, a centralized review will be conducted prior to Day 0 visit to make 
recommendations on the subretinal injection location and the targeted area of the bleb. 
 
 
 
Subretinal Injection 
Cohort 
Group 
No of patients 
Dilution factor 
Dose by target 
strength  
(TU/eye )*  
Dose by measured 
strength  
(TU/eye )** 
Volume 
1 
A 
4 
1:10 
1.8x105 TU 
0.48x105 TU 
300 µL 
2 
B 
4 
1:10 
1.8x105 TU 
0.48x105 TU 
300 µL 
3 
B 
4 
1:3 
6x105 TU 
3.6x105 TU 
300 µL 
4 
B 
4 
undiluted 
1.8x106 TU 
0.99x106 TU 
300 µL 
5 
C 
6 
undiluted 
1.8x106 TU 
(highest dose 
targeted) 
0.99x106 TU 
300 µL 
6 
D 
4 
undiluted 
1.8x106 TU  
(highest dose 
targeted) 
4.5 x106 TU 
300 µL 
7 
E 
1 
undiluted 
1.8x106 TU  
(highest dose 
targeted) 
4.5 x106 TU 
300 µL 
8 
D 
Up to 6  
1:3 
- 
1.5 x106 TU 
300 µL 
9 
E 
Up to 8 
1:3 
- 
1.5 x106 TU 
300 µL 
Note:  *- calculated from target product strength; **- calculated from dilution (as applicable) of measured strength. 
 
The patients will be followed for up to 48 weeks. After this period they will enter an open-label long term safety study (LTS13588) 
and undergo follow-up visits including ophthalmological examinations and recording of adverse events (AEs).   
 
 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 17 
Main Inclusion Criteria 
Patients must meet ALL of the following criteria to be considered for enrolment into this study: 
 
Signed and dated written informed consent obtained from the patient and/or the patient’s legally acceptable 
representative, if applicable, in accordance with the local regulations. 
 
Diagnosis of SMD, with at least 1 pathogenic mutant ABCA4 allele on each chromosome, confirmed by direct 
sequencing.  Gene mutation analysis results conducted prior to signing the informed consent may be used provided that 
the analysis was conducted by a CLIA (Clinical Laboratory Improvement Amendments) certified laboratory, written 
results are provided to the site, and participants (patients and/or the patient’s parent[s]/legal guardian[s]) give consent to 
utilize the results. For patients genotyped during the screening period, results demonstrating a pathogenic mutant 
ABCA4 allele on each chromosome must be documented prior to the administration of SAR422459. 
 
Women of childbearing potential must have a negative pregnancy test at Day -1 and agree to use an effective form of 
contraception for at least 3 months such as the contraceptive pill or intrauterine device, or be surgically sterile or 
postmenopausal, with the last menstrual period being over 2 years prior to enrolment (partners of study patients must 
agree to use barrier contraception for at least 3 months after SAR422459 administration). 
 
Males must agree with their partner to use 2 forms of contraception, including one barrier method for at least 3 months 
following SAR422459 administration if their partner is of childbearing potential, or must be surgically sterile. 
 
Patients must agree to not donate blood, organs, tissues or cells for at least 3 months following SAR422459 
administration.  
 
Patients enrolled in France must be affiliated to or benefit from a social security regimen. 
Specific Inclusion Criteria Patient Group A 
 
Patients (18 years or older) with advanced SMD. 
 
VA ≤20/200 in the worst eye. 
 
Severe cone-rod dysfunction with no detectable or severely abnormal full-field ERG responses. 
Specific Inclusion Criteria Patient Group B 
 
Patients (18 years or older) with SMD. 
 
VA ≤20/200 in the worst eye. 
 
Abnormal full-field ERG responses. 
Specific Inclusion Criteria Patient Group C 
 
Patients (18 years or older) with SMD. 
 
VA ≤20/100 in the worst eye. 
 
Abnormal full-field ERG responses. 
Specific Inclusion Criteria Patient Group D 
 
Symptomatic patients (from 6 years to 26 years old) with early or childhood-onset SMD (age at disease onset <18 years) 
with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and 
co-segregation analysis within the patient's family. 
 
Visual acuity of ≥20/200 in both eyes at the time of the screening visit. 
 
Patients are anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an 
annual progression rate in at least 1 of the following parameters occurring in at least one eye (assessments recorded up 
to 2 years prior to the screening visit date may be considered to document evidence of rapid deterioration): 
- 
Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters), 
- 
Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry, 
- 
Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by >14 dB-sr as assessed by static 
perimetry, 
- 
Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of ≥0.5 mm2, 
- 
Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a 
rate of ≥0.5 mm2. 
 
All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform 
required study procedures as judged and confirmed by the study investigator. 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
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Property of the Sanofi Group - strictly confidential 
Page 18 
Specific Inclusion Criteria Patient Group E 
 
Symptomatic patients ( from 6 years to 17 years old) with SMD with at least 1 pathogenic mutant ABCA4 allele on each 
chromosome confirmed by direct sequencing and co-segregation analysis within the patient's family. 
 
Visual acuity of ≥20/100 in both eyes at the time of screening visit. 
 
Patients are anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an 
annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded 
up to 2 years prior to the screening visit date may be considered to document evidence of rapid deterioration): 
- 
Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters), 
- 
Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry, 
- 
Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by >14 dB-sr as assessed by static 
perimetry, 
- 
Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of ≥0.5 mm2, 
- 
Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a 
rate of ≥0.5 mm2 . 
 
All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform 
required study procedures as judged and confirmed by the study investigator. 
Exclusion Criteria 
Presence of ANY 1 of the following criteria will exclude patients from being enrolled into the study: 
 
Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study 
endpoints: glaucoma or other primary optic neuropathy that has resulted in significant visual field loss, corneal or 
significant lens opacities, active uveitis, retinopathy and maculopathy (other than that from Stargardt disease) that in the 
opinion of the investigator is causing significant visual loss, myopia greater than 8 diopters spherical equivalent. 
 
Cataract surgery with intraocular lens implantation within 6 months of enrolment. 
 
Aphakia or prior vitrectomy in the study eye. 
 
Concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter 
ocular function. For instance malignancies whose treatment could affect central nervous system function, diabetes, 
juvenile rheumatoid arthritis or sickle cell disease. 
 
Any intraocular surgery (other than study procedure) or laser in either eye planned within 6 months of Day 0. 
 
Any contraindication to pupil dilation in either eye. 
 
Any known allergy to any component of the delivery vehicle or diagnostic agents used during the study (eg, fluorescein, 
dilation drops), or medications planned for use in the peri-operative period particularly topical, injected or systemic 
corticosteroids. 
 
Any injectable intravitreal treatment to the treated eye or intravitreal device in the treated eye within 6 months prior to 
screening. 
 
Any periocular injections of corticosteroids to the treated eye within 4 months prior to screening. 
 
Laboratory test abnormalities or abnormalities in electrocardiogram, chest X-rays that, in the opinion of the principal 
investigator (PI), would make the patient unsuitable for participation in the study. 
 
Significant intercurrent illness or infection during the 28 days prior to enrolment. 
 
Pre-menopausal or non-surgically sterile women who are unwilling to use an effective form of contraception such as the 
contraceptive pill or intrauterine device. 
 
Men or women who do not agree to use barrier contraception as specified in the inclusion criteria. 
 
Alcohol or other substance abuse. 
 
Contraindications to use of anesthesia (local or general, as appropriate). 
 
Concurrent anti-retroviral therapy that would inactivate the investigational agent. 
 
History of any investigational agent within 28 days prior to SAR422459 administration. 
 
Participation in a prior ocular gene transfer therapy study, other than the TDU13583 study. 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 19 
 
Enrolment in any other clinical treatment study, for any condition, including those relating to SMD, throughout the 
duration of the SAR422459 TDU13583 study participation. 
 
Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the 4 weeks prior 
to surgery. 
 
Past medical history of HIV or hepatitis A, B or C infection. 
 
Inability to comply with the demands of the study. 
 
Women who are pregnant or are breastfeeding. 
 
History of or signs consistent with unilateral amblyopia (strabismic, anisometropic or stimulus deprivation). 
Statistical Analysis 
Sample size determination 
This is an exploratory study, the primary objective of which is to evaluate safety and, as a secondary objective, to estimate the 
biological activity. No formal sample size calculation has been performed. 
Analysis population 
All patients with SMD included in the study will be taken into account for the analysis. 
Primary analysis 
The primary analysis will be based on the treatment emergent adverse events (TEAE). 
The number and percentage of patients with treatment emergent adverse events will be summarized. 
An overall summary will include the number and percentage of patients with: 
 
A fatal AE (death). 
 
At least one serious AE. 
 
At least one severe AE. 
 
At least one related AE. 
 
Without any AEs. 
An additional table will show the number and percentage of patients with treatment emergent adverse events broken down by 
System Organ Class, High Level Term and Preferred Term. Related AEs will be summarized separately. 
A specific look will also be done on the ophthalmologic safety endpoints.   
Analysis of secondary endpoints  
Secondary endpoints will be summarized at each visit. Where appropriate, individual profile plots and mean plot of changes in the 
variable against time will be presented.  Key parameters for the estimation of biological activity will be assessments of visual 
function (BCVA, microperimetry, static and kinetic perimetry) and retinal structure (OCT and FAF). 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 20 
3 
STUDY SCHEDULE 
3.1 
COHORT 1 TO 5 
 
Pre SAR422459 
Days 
Weeks 
-28 
(screening 
visit) 
-1 
(baseline 
visit) 
0 
1 
1 
2 
4 
12 
24 
36 
48 l 
Surgery 
Visit windows 
 
±10 days 
-7 days 
N/A 
N/A 
±3 
days 
±3 
days 
±3 
days 
±14 
days 
±14 
days 
±14 
days 
±14 
days 
SAR422459 administration 
 
 
Xo 
 
 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
When available, co-segregation analysis within the patient’s family  
X 
 
 
 
 
 
 
 
 
 
 
Medical history p 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anesthesia assessment 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reproductive status 
 X 
 
 
 
 
 
 
 
 
 
 
Clinical symptoms of SMD 
X 
 
 
 
 
 
 
 
 
 
 
Treatment history 
X 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
 
 
 
 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 21 
 
Pre SAR422459 
Days 
Weeks 
-28 
(screening 
visit) 
-1 
(baseline 
visit) 
0 
1 
1 
2 
4 
12 
24 
36 
48 l 
Surgery 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
Ophthalmological examination 
 
BCVA a 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Intraocular pressure 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Fundoscopy / indirect ophthalmoscopy 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
FAF 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
OCT m 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Microperimetry, Full-Field Kinetic and Static Perimetry 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Fundus photography c 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
Multifocal and Full-Field ERG 
X 
X 
 
 
 
 
X 
X 
X 
 
X 
Adaptive optics 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
Where available: surgery video-recording and/or intra-operative 
OCT 
 
 
X 
 
 
 
 
 
 
 
 
Reading speed 
 
X 
 
 
 
 
 
 
 
 
X 
VFQ-25 
 
X 
 
 
 
 
 
 
 
 
X 
Hematology e 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
Chemistry panel f 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
Kidney function g 
X 
X 
 
 
 
 
X 
 
X 
 
X 
Liver function h 
X 
X 
 
X 
 
 
X 
 
X 
 
X 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 22 
 
Pre SAR422459 
Days 
Weeks 
-28 
(screening 
visit) 
-1 
(baseline 
visit) 
0 
1 
1 
2 
4 
12 
24 
36 
48 l 
Surgery 
Coagulation i 
X 
X 
 
 
 
 
 
 
 
 
 
Urinalysis j 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
Blood for PCR 
X 
 
X b 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test k 
X 
X 
 
 
 
 
 
 
 
 
 
Blood for Immunology 
 
X 
 
 
 
 
X 
X 
X 
Xn 
X n 
Urine for PCR 
X 
 
X b 
X 
X 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Notes: 
If necessary, the screening and baseline assessments can be splitting on different days.  
a BCVA and perimetry (full-field kinetic and static perimetry) will be performed once at the screening visit (Day -28) and on 2 occasions at baseline (Day -1). Microperimetry will be performed once at visits requiring 
full-field kinetic and static perimetry 
b Blood and where possible Urine sample 60 minutes after surgery 
c A pan-retinal photomontage will be taken at the screening visit only 
d Vital signs: blood pressure (BP, sitting), heart rate (HR) and temperature taken and recorded before SAR422459 administration. Following surgery vital signs will be measured every 30 minutes for one hour. Vital 
signs will be obtained on all subsequent follow-up visits 
e Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width 
(RDW), platelets, neutrophils, lymphocytes, monocytes, eosinophils and, basophils 
f 
Chemistry panel: serum electrolytes (phosphorus, calcium, sodium, chloride, bicarbonate and potassium), blood glucose (only at screening), creatine phosphokinase (CPK), lactate dehydrogenase (LDH) 
g Kidney function: Creatinine, blood urea nitrogen (BUN) and uric acid 
h Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (AP), total protein (TP), albumin, gamma glutamic transpeptidase (γGT, GGT), 
cholesterol (CHOL) (only at screening) 
i 
Coagulation: prothrombin time (PT) and partial thromboplastin time (PTT) at screening and baseline only 
j 
Urinalysis: Microscopic or multistick strip urinalysis for protein, blood and ketones 
k Urine pregnancy test if applicable for women of childbearing potential must be negative at Day -1 
l 
Week 48 or early termination procedures 
m Infra-red fundus montage to be performed at each visit 
n Only in patients with positive antibody response at Week 24 
o Patients will not take anything by mouth for a minimum of 8 hours prior to surgery. 
p Past medical history of HIV, hepatitis A, B or C infection will be evaluated. 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 23 
3.2 
COHORTS 6-9 
 
Pre SAR422459  
Days 
Weeks 
-28 
(screening visit) 
-1 
(baseline 
visit) 
0 
1 
1 
2 
4 
12 
24 
48a 
Surgery 
Visit windows 
±10 days 
-7 days 
N/A 
N/A 
±3 
days 
±3 
days 
±3 
days 
±14 
days 
±14 
days 
±14 
days 
SAR422459 administration 
 
 
Xb 
 
 
 
 
 
 
 
Entry criteria 
Xc 
Xc 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
Genotyping d 
X 
 
 
 
 
 
 
 
 
 
Medical history e 
X 
 
 
 
 
 
 
 
 
 
Reproductive status 
 X 
X  
 
 
 
 
 
 
 
 
Clinical symptoms of SMD 
X 
 
 
 
 
 
 
 
 
 
Treatment history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-Operative Assessments 
 
 
 
 
 
 
 
 
 
 
Anesthesia assessment 
Xc 
Xc 
 
 
 
 
 
 
 
 
Height 
Xc 
 
 
 
 
 
 
 
 
 
Weight 
Xc 
Xc 
 
 
 
 
 
 
 
 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG) 
Xc 
Xc 
 
 
 
 
 
 
 
 
Chest X-ray 
Xc 
Xc 
 
 
 
 
 
 
 
 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 24 
 
Pre SAR422459  
Days 
Weeks 
-28 
(screening visit) 
-1 
(baseline 
visit) 
0 
1 
1 
2 
4 
12 
24 
48a 
Surgery 
Physical examination 
Xc 
Xc 
 
 
 
 
 
 
 
X 
Ophthalmological examination 
 
 
 
 
 
 
 
 
 
 
BCVA g, s 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Contrast sensitivity h, s 
X 
X 
 
 
 
 
 
X 
X 
X 
Reading Speed (when possible) s 
 
X 
 
 
 
 
 
 
 
X 
Static Perimetry g, s 
X 
X 
 
 
 
 
 
X 
X 
X 
Full-Field Kinetic Perimetry g, s 
X 
X 
 
 
 
 
 
X 
X 
X 
Slit lamp examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Microperimetry g,t 
Xu 
X 
 
 
 
 
X 
X 
X 
X 
OCT t 
Xv,u 
X 
 
X 
X 
X 
X 
X 
X 
X 
Fundoscopy / indirect ophthalmoscopy t 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Fundus photography i, t 
Xw 
X 
X 
X 
 
X 
X 
 
X 
X 
FAF t 
Xw 
X 
 
 
 
 
X 
X 
X 
X 
Infrared Reflectance Imaging t 
X u 
X 
 
 
 
 
 
X 
X 
X 
Intraocular pressure t 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Full-Field ERG t 
X 
X 
 
 
 
 
 
 
 
X 
Intraoperative video-recording  
(intra-operative OCT, where available) 
 
 
X 
 
 
 
 
 
 
 
VFQ-25/CVAQC (when possible) j 
 
X 
 
 
 
 
 
 
 
X 
Hematology k 
X 
X x 
 
 
 
 
X 
 
X 
X 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 25 
 
Pre SAR422459  
Days 
Weeks 
-28 
(screening visit) 
-1 
(baseline 
visit) 
0 
1 
1 
2 
4 
12 
24 
48a 
Surgery 
Chemistry panel l 
X 
X x 
 
 
 
 
X 
 
X 
X 
Kidney function m 
X 
X x 
 
 
 
 
X 
 
X 
X 
Liver function n 
X 
X x 
 
 
 
 
X 
 
X 
X 
Coagulation  
X 
X x 
 
 
 
 
 
 
 
 
Blood for PCR o 
X 
 
Xo 
X 
X 
 
X 
X 
X 
X 
Blood for Immunology 
 
X 
 
 
 
 
X 
X 
X 
Xp 
Urinalysis q 
X 
X 
 
X 
 
 
X 
 
X 
X 
Urine pregnancy test r 
X 
X 
 
 
 
 
 
 
 
 
Urine for PCR 
X 
 
Xo 
X 
X 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Notes: 
If necessary, the screening and baseline assessments can be carried out over several days.  
a Week 48 or early termination procedures 
b Patients will not take anything by mouth for a minimum of 8 hours prior to surgery. 
c Need to be done prior to surgery between -28 days or Day -1 or by request of anesthesiologist at rescreening. 
d Gene mutation analysis results conducted prior to signing the informed consent may be used provided that the analysis was conducted by a CLIA (Clinical Laboratory Improvement Amendments) certified 
laboratory, written results are provided to the site, and participants (patients and/or the patient’s parent[s]/legal guardian[s]) give consent to utilize the results. For patients genotyped during the screening period 
results must be documented prior to the administration of SAR422459. 
e Past medical history of HIV, hepatitis A, B or C infection will be evaluated. 
f 
Vital signs: blood pressure (BP, sitting), heart rate (HR) and temperature taken and recorded before SAR422459 administration. Vital signs will be measured at 30 and 60 minutes after the surgical procedure. Vital 
signs will be obtained on all subsequent follow-up visits 
g BCVA, Static perimetry, Full-field Kinetic perimetry and Microperimetry will be performed during the screening period. As these measures could be subject to broad intra-individual variability, they must be repeated 
at least twice during the screening period to determine the patient's reliability in the performance of these psychophysical assessments. All of the above screening measures must be completed and final screening 
assessments submitted to the reading center as required in the MOP within 14 days of the planned surgery date.  
h Contrast sensitivity on the Sloan Low contrast Letter Acuity Chart will be performed on Day -28, Day-1, and Weeks 12, 24, and 48. 
i 
For all indicated visits subsequent to the screening visit, a single 50 degree photograph centered on the macula, and including the optic nerve, will be obtained of each eye. 


Amended Clinical Protocol NO 12  
29-Nov-2018 
SAR422459-TDU13583 (SG1/001/10) 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 26 
j 
VFQ-25 for adults ≥18 years/CVAQC for children <18 years 
k Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width 
(RDW), platelets, neutrophils, lymphocytes, monocytes, eosinophils and, basophils 
l 
Chemistry panel: serum electrolytes (phosphorus, calcium, sodium, chloride, bicarbonate and potassium), blood glucose (only at screening), creatine phosphokinase (CPK), lactate dehydrogenase (LDH) 
m Kidney function: Creatinine, blood urea nitrogen (BUN) and uric acid 
n Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (AP), total protein (TP), albumin, gamma glutamic transpeptidase (γGT, GGT), 
cholesterol (CHOL) (only at screening) 
o Blood 60 minutes after surgery and first urine sample that occurs after 60 minutes post-surgery  
p Only in patients with positive antibody response at Week 24 
q Urinalysis: Microscopic or multistick strip urinalysis for protein, blood and ketones 
r Urine pregnancy test if applicable for women of childbearing potential will be performed at Day -28 and Day -1 and must be negative  
s Assessment performed before dilatation 
t 
Assessment performed after dilatation 
u OCT and infrared images, required for the centralized review, must be performed on day -28 (the first day of the screening visit, if screening is conducted over several days).  The OCT volume maps and montaged 
infrared reflectance images must be forwarded to the reading center within 2 days of collection during screening visit as instructed in the MOP.  
v OCT is to be performed prior to Microperimetry at Screening (Day -28) to obtain the OCT overlay to determine the location of the anatomical fovea. 
w Fundus photography and FAF screening images must be submitted to the reading center as required in the MOP within 14 days of the planned surgery date.  
x To be repeated just in case of re-screening, if previous screening was earlier, than 38 days before surgery. 
 


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4 
STUDY FLOW DIAGRAM 
 
 
 
 


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5 
INTRODUCTION AND RATIONALE 
Stargardt macular degeneration (SMD), (which is also known as fundus flavimaculatus or 
Stargardt disease) was described in 1909 by Karl Stargardt, an ophthalmologist in Strasbourg. 
 It is the most common form of inherited juvenile macular degeneration and affects approximately 
one in 10 000 worldwide with around 26 000 sufferers in the United States. 
SMD is characterized by a deterioration of central vision, and the presence of bilateral atrophic 
appearing foveal lesions, eventually leading to legally defined blindness most commonly in 
children and young adults (VA of ≤20/200) (2). 
This disease is nearly always inherited as an autosomal recessive trait that produces a severe form 
of macular degeneration, similar to age-related macular degeneration (AMD), but which begins in 
childhood; it is the most common autosomal recessive juvenile onset macular dystrophy (2). Less 
than 1% of cases may result from a dominant mode of inheritance. The autosomal recessive trait 
for SMD in affected children means that both parents were carriers, having 1 mutated gene for the 
disease paired with one normal gene. Children where both parents are carriers have a one in 
4 chance of inheriting both the mutated genes (one from each parent) leading to Stargardt disease 
(3, 4). 
Carriers are unaffected. The gene which is mutated in patients with autosomal recessive SMD was 
isolated and identified by Allikmets and colleagues (5). The gene identified is a retina-specific 
ABC transporter (6) (ABCR) gene, part of the subfamily adenosine triphosphate (ATP)-binding 
cassette (ABC) transporters (ATP-binding cassette, sub-family A, member 4 [ABCA4], also 
known as ABCR). 
SAR422459 is a gene therapy product developed by Oxford BioMedica (UK) Ltd, designed to 
introduce the correct ABCA4 cDNA to photoreceptors (PR) and thereby attenuate and possibly 
reverse the pathophysiology which leads to SMD. 
SAR422459 is a non-replicating, recombinant lentiviral vector derived from the genome of the 
nonprimate lentivirus, equine infectious anemia virus (EIAV). SAR422459 contains 
approximately 10% (861 nucleotides) of the wild type EIAV genome and there are no functional 
viral proteins or viral coding regions in the recombinant EIAV vector. This LentiVector® 
technology platform for gene delivery is currently in use in an on-going Phase I/II studies for 
Parkinson’s disease wet age-related macular degeneration and retinitis pigmentosa associated with 
Usher syndrome, type 1B. 
5.1 
THERAPEUTIC GENES 
In 1997, the gene for SMD, coding for a member of the ABC transporter family was isolated and 
characterized (4, 7, 8). 


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The ABCA4 gene encodes for a ~250 kDa ATP-binding cassette transporter localized to the disk 
margins of vertebrate PR outer segments and is involved in the transport of toxic by-products of 
the visual cycle out of the PRs. The ABCA4 gene is relatively large containing 50 exons which 
may explain its susceptibility to frequent mutations (9, 10). The ABCA4 (ABCR) protein is 
organized as 2 tandem-arranged halves, each containing a trans-membrane segment, followed by a 
large extracellular domain, a multi-spanning membrane domain and a nucleotide binding domain 
(11, 12). 
Expression of the ABCA4 gene is restricted to retinal rod and cone PRs and the Abcr4 protein is 
localized to the rim and incisures of outer segment discs, where it is present at a molar ratio of 
approximately 1:120 with rhodopsin (9, 13, 14). Abcr4 has been implicated in the active transport 
of retinoid compounds across the outer segment disk membrane following the photo-activation of 
rhodopsin and requires the presence of ATP (15). 
Disease-associated ABCA4 alleles show an extraordinary heterogeneity with over 400 currently 
identified mutations most of which represent missense substitutions. In SMD the mutant ABCR 
protein is unable to fully perform its transport function leading to progressive irreversible loss of 
central vision and delayed dark adaptation due to degeneration of PRs and the underlying retinal 
pigmented epithelium (RPE) within and near the macula. The degeneration of the PRs thought to 
be secondary to the loss of RPE due to the accumulation of an age related pigment lipofuscin 
containing toxic by-products of the visual cycle including elevated levels of 
diretinoid-pyridinium-ethanolamine (A2E). 
5.2 
CLINICAL PATHOLOGY 
Stargardt Macular Degeneration, caused by mutations in the ABCA4 gene is inherited as an 
autosomal recessive trait, is the most frequent cause of juvenile macular degeneration. There is 
variation in the clinical course of the disease but typically central visual failure begins in 
childhood with later onset of peripheral visual constriction in some cases. The consequence of the 
condition is frequently legal blindness. 
SMD pathophysiology is characterized by the accumulation of lipid rich subretinal deposits 
(lipofuscin) that frequently appear as yellowish-tinted flecks on ophthalmoscopic examination. As 
the disease progresses, atrophy of the RPE develops with subsequent loss of the adjacent PRs. 
Symptoms of SMD usually appear before age 20, but may present as early as age 5. Diagnosis is 
initially characterized by sensitivity to glare, even during overcast days and there is decreased 
central vision, peripheral vision is maintained. The disease may also manifest with wavy vision, 
blind spots and blurriness. Patients may also notice difficulty with reading and seeing in dim light 
before being referred to an ophthalmologist for diagnosis. However, the disease is often 
misdiagnosed, or not diagnosed in the first few years of onset, and this may be the result of little 
evidence of the disease being found during eye examinations. The deterioration in vision is 
variable and can decrease rapidly (especially in children) (16). By age 50, approximately half of 
all SMD subjects who were being studied in clinical trials had visual acuities that had deteriorated 
to 20/200 or worse (17). 


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5.3 
DIAGNOSIS AND MONITORING OF SMD 
In early stages of SMD the macula may appear normal, resulting in a delay in diagnosis. 
Characteristic changes occur with disease progression which aid diagnosis. 
In latter stages, SMD is often diagnosed in patients who exhibit bilateral visual loss, following the 
observation of characteristic atrophic-appearing macular lesions surrounded by yellowish-white 
legions or flecks. The appearance of a “beaten-metal” macula in conjunction with the appearance 
of flecks is typical of SMD (18). 
Despite the early work performed by Fishman and colleagues classification of phenotypic 
subtypes in SMD has been problematic because neither duration of disease, nor the extent and 
distribution of fundus lesions correlate well with retinal function (19, 20). However, there appears 
to be good concordance with respect to electrophysiological attributes and on this basis SMD can 
be divided broadly into 3 groups: 
 Patients with normal scotopic ERG and photopic ERG abnormalities. 
 Patients that have preserved scotopic but abnormal photopic ERG. 
 Patients with abnormal scotopic and photopic ERG. 
Patients with normal scotopic and photopic ERG abnormalities tend to have better VA and 
preserved peripheral visual fields over the course of the disease than patients that have preserved 
scotopic but abnormal photopic ERG or abnormal scotopic and photopic ERG. Despite there 
being overlap between the groups, patients with preserved scotopic and photopic ERG b-wave 
activity tend to have better VA (1). It is not known whether these differences represent different 
stages of the disease or are related to the nature of the mutation of the ABCR gene (21). 
Due to the heterogeneity of this disease, there is considerable overlap in clinical phenotype of 
SMD whilst electrophysiological, morphological or clinical predictors of outcome are still to be 
established. In the current study the clinical criterion of VA will be used in conjunction with ERG 
to assess overall pan-retinal function and act as a measure for advancement of SMD to select 
patients for the early study groups (A-C). For the final study group (D), a number of imaging 
modalities and functional assessments will also be used throughout the study to document disease 
prior to treatment, monitor ocular safety and any signs of treatment benefit. 
SMD is a complex retinal degenerative disease with variable disease presentation and progression. 
In the present study, in addition to routine ophthalmic examinations, a number of modalities will 
be used to monitor safety and any signs of bioactivity. Each technology has value in identifying 
disease severity and monitoring progression, but as each has intrinsic limitations others can 
complement, ERG to detect the electrophysiology of the retina, FAF to track lipofuscin 
accumulation and RPE atrophy, OCT will visualize cross sectional retinal structure, perimetry will 
give a measure of retinal function and adaptive optics will visualize cone PR morphology. 
Regular measurements combining these techniques throughout the study will ensure the treated 
eye is effectively monitored for safety and may detect any early signs of bioactivity in this patient 
population. 






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 Subretinal administration of EIAV CMV ABCA4 vector expressing human ABCR protein 
significantly reduces the accumulation of A2E/isoA2E, the primary component of 
lipofuscin, in the Abca4-/- mouse model. 
 The 12-month efficacy data from the Abca4-/- mice injected with SAR422459 
(EIAV CMV ABCA4) provides proof of principle for the use of EIAV vectors expressing 
ABCA4 as a long-term therapeutic strategy to treat patients with SMD. 
5.5.2 Pharmacokinetic studies 
A series of pharmacokinetic studies have been performed in vivo to assess gene transfer and 
biodistribution. Following subretinal delivery of the EIAV lentiviral vector gene delivery and 
expression is observed most evidently in rod and cone PRs and retinal pigment epithelial cells in 
both mice, rabbits and 3 different NHP species; cynomolgus macaques, baboons and 
rhesus macaques. Further details of these studies can be found in the IB. 
5.5.3 Toxicology studies 
Non-clinical toxicology studies have been performed to assess acute and chronic effects of 
SAR422459. The studies demonstrate no significant findings and provide safety data for the 
proposed clinical dose levels. Full details of these studies can be found in the IB. 
5.6 
RATIONALE FOR STUDY 
The primary objective of the present study is to assess the safety and tolerability of ascending 
doses of SAR422459 in patients with SMD. The secondary objective is to evaluate for possible 
biological activity. 
This is a First in Man (FIM), Phase I/IIa open-label, paired-eye, dose escalation study to enable 
the treatment of sufficient number of patients in this rare indication to establish a safe and active 
dose level. The data from this study will facilitate the appropriate design of efficacy studies in a 
Phase II/III clinical development program. 
5.6.1 Rationale for SAR422459  
There is currently no marketed safe and effective therapy for SMD. As the pathophysiology is 
now being understood in molecular detail and the disease has been attributed to mutations within 
the ABCA4 gene, the most likely successful route to preventing or halting disease progression is 
through gene therapy. SAR422459 is a lentiviral vector therapy which delivers the normal 
ABCA4 cDNA and so is able to restore retinal transport function preventing build-up of the 
non-degradable toxic lipofuscin component A2E. Effective PR cell transduction and gene 
expression has been demonstrated in mice and non-human primates following subretinal delivery 
of the EIAV lentiviral vector. 


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5.7 
RATIONALE FOR INJECTION INTO THE EYE 
The eye is an ideal target organ for gene therapy. 
 Local gene therapy is ideal for the eye since it is anatomically separated from the rest of 
the body and creates a natural barrier between itself and surrounding tissues. Therefore, it 
is unlikely that the SAR422459 vector would gain access to and affect tissues other than 
the eye. 
 The eye is easily accessible to the surgeon compared to other organs, both in terms of 
administering the treatment and in terms of evaluating the effect. 
 The treatment approach is designed to correct the underlying genetic abnormality. 
Administration of SAR422459 directly into the eye via subretinal injection provides a 
convenient means of delivering the normal ABCA4 cDNA to restore retinal transport 
function and resulting in a permanent restoration of ABCR protein function in 
photoreceptors. 
5.8 
RATIONALE FOR UNILATERAL ADMINISTRATION 
In this study, one study eye will be selected. If both eyes are eligible for the study, the worse eye, 
as per investigator judgment, will be selected. For Cohorts 6-9, the centralized review will advise 
on the choice of the study eye if both eyes are clinically similar. The rationale for unilateral 
administration is to minimize the risk to the less advanced eye and thus minimize any risk to the 
patient's remaining vision. For patients in Cohorts 1-4 with advanced SMD the study eye will 
have a maximum BCVA of 20/200. In Cohort 5 with slightly less advanced SMD the study eye 
will have a maximum BCVA of 20/100. Cohort 6 and 8 will enroll patients with a much less 
advanced stage of the disease with a minimum BCVA of 20/200 or better in the worse eye at the 
time of the screening exam. Cohort 7 and 9 will enroll pediatric patients with even less advanced 
stage of the disease with a minimum BCVA of 20/100 or better in the worse eye at the time of the 
screening exam. 
5.9 
RATIONALE FOR THE CLINICAL DOSE 
The rationale for the clinical dose is based on the number of transducing units delivered per eye in 
a fixed volume of formulation buffer. Using ocular allometric scaling and information from the 
published literature (Table 2) it was anticipated that a volume of 100 µL of SAR422459 could be 
safely subretinally dosed to both rabbits and NHPs without the need for vitrectomy (which is 
technically difficult in these species). Therefore, a total volume of 100 µL was used to deliver 
SAR422459 subretinally in the rabbit and NHP GLP combined toxicology/biodistribution studies. 
Absorption and retinal re-attachment was complete by 1-2 weeks following subretinal 
administration in NHP and by 4 weeks in the rabbit, there were no observed long-term 
morphological changes to the retinal structures examined at 4 and 6 weeks post-dosing. The 
relative difference in ocular volume between rabbit, NHP and human is around 3-fold, therefore a 
total volume of up to 300 µL will be delivered subretinally in the FIM study following a partial 
vitrectomy. 


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Table 2 - Allometric scaling of approximate ocular volumes and safe subretinal injection volumes 
Species 
Approximate 
axial ocular 
diameter (cm) 
Approximate 
orbital 
volume (cm3) 
Relative ocular 
volume as 
compared to 
mouse 
Safe maximal 
subretinal 
volume (μL) 
Allometric scale-
up based on size 
relative to mouse 
safe volumes 
Mouse 
0.34 (23) 
0.16 
- 
2 (24) 
- 
Rat 
0.64 (22, 25)  
1.1 
7 
10  
5 
Rabbit 
1.5 (26)-1.6 (27) 
5 (28)-14.1 
88 
100 (29) 
50 
Macaque 
1.7 (30) 
20.6 
129 
100 (31)-150 (32)   
50-75 
Human 
2.4 (32)   
57.9 
362 
1000 (33, 34) 
500 
The dose selection for the FIM study was based on the MTD used in the rabbit and NHP GLP 
combined toxicology/biodistribution studies. 
The MTD in the rabbit that was used in the GLP safety study is 1.4 x 106 TU/eye. The MTD in 
the NHP that was used in the GLP safety study is 4.7 x 105 TU/eye. Based on the average 3-fold 
ocular allometric scaling of ocular volume between rabbit/NHP and the human eye the expected 
MTD in man is 1.4 x 106 TU/eye up to 4.2x106 TU/eye based on the MTD in the NHP and rabbit, 
respectively. 
In the current study, injected doses are below the MTD predicted by the rabbit toxicology data 
and are either below or almost equivalent to the MTD predicted in the NHP studies. 
5.9.1 Summary of dosing regimens 
The design is a dose escalation in terms of viral vector particles (transducing units, [TU]), in a 
fixed volume. The study will evaluate 3 target dose levels of SAR422459 1.8 x 105 TU/eye (1:10), 
6 x 105 TU/eye (1:3), 1.8 x 106 TU/eye (undiluted) in a volume of 300 µL. As production process 
results in certain variability of strength - doses per measured strength vary from 0.48x105 to 
4.5x106 TU/eye).  Details of the formulation are provided in Table 1. 
5.10 
RATIONALE FOR DOSING INTERVALS 
SAR422459 will be administered unilaterally on one occasion only per patient in this study. 
Patients with the most advanced disease will be included in the early cohorts; subsequent cohorts 
will include patients with less advanced macular degeneration and pediatric patients in the last 
cohort. In the first cohorts (Cohorts 1-4), allowing 21 days between dosing patients and 28 days 
between cohorts will permit adequate time to assess short-term safety prior to dose escalation or 
the inclusion of patients with less advanced disease. In addition, the long-term safety data 
(approximately 6 months) from the patients with advanced disease dosed early in the study 
(Cohorts 1-3) will be available at the time of treating the later cohorts (Cohorts 5, 6 and 7). 


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Prior to the inclusion of pediatric patients, the DSMB will review all safety data including the 
available data from all cohorts after the last patient of Cohort 5 has completed 12 weeks of 
follow-up after having been dosed. An interim report including all available safety data, 
preliminary efficacy data and the recommendations from the DSMB will be submitted to the 
regulatory authorities and institutional review boards/ethics committees for approval before 
enrolling pediatric patients (<18 years). Following the dosing of the first pediatric patient a 28 day 
interval will be observed prior to the dosing of the second pediatric patient.  Thereafter, 
subsequent pediatric patients may be enrolled consecutively. 
5.11 
RATIONALE FOR TARGET PATIENT POPULATION 
It is inappropriate to administer a gene therapy investigational product to healthy normal 
volunteers. Therefore when determining an initial patient population in which to assess the safety 
and tolerability of SAR422459 careful consideration was given to identifying a patient population 
with the optimal risk:benefit profile. Data from clinical and non-clinical studies have 
demonstrated that the lentiviral vector system is safe and well tolerated. Therefore the potential 
risk to patients is limited to the possible effects of the administration of the normal human 
ABCA4 gene directly into the retina. 
Three phenotypic subtypes of SMD have been identified based upon ERG attributes (Lois et 
al. 2001, (1): 
 Category 1: Severe pattern ERG abnormality with normal scotopic and [photopic] 
full-field ERG. 
 Category 2: Severe pattern ERG abnormality with loss of photopic function but normal 
scotopic and full-field ERG. 
 Category 3: Severe pattern ERG abnormality with loss of both photopic and scotopic 
function. 
Four patient groups with a differing level of advancement of SMD will be included in this study.  
 Group A: Patients (18 years or older) with advanced SMD, VA ≤20/200 in the worst eye 
and severe cone-rod dysfunction with no detectable or severely abnormal full-field ERG 
responses. These will be patients with severe pattern ERG abnormality and loss of both 
photopic and scotopic function, with loss of photopic responses to no more than 70% of 
the category 3 ERG criteria in the Lois et al. classification, and very poor VA. 
 Group B: Patients (18 years or older) with SMD, VA ≤20/200 in the worst eye with 
abnormal full-field ERG responses. These will be patients with very abnormal pattern 
ERG and loss of both scotopic and photopic responses, with loss of photopic responses to 
no more than 85% of the category 3 ERG criteria in the Lois et al. classification, and very 
poor VA. 
 Group C: Patients (18 years or older) with SMD, VA ≤20/100 in the worst eye with 
abnormal full-field ERG responses. These will be patients with severe pattern ERG 
abnormality and loss of both photopic and scotopic function, and have photopic b-wave 
amplitude within the range of category 3 criteria in the Lois et al. classification.  
These patients will also have more preserved VA. 


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 Group D: Patients (from 6 years to 26 years old) with symptomatic early or 
childhood-onset SMD (age at disease onset <18 years), and VA ≥20/200 in both eyes at 
the time of the screening visit anticipated to experience rapid deterioration in visual 
function and/or retinal structure. 
 Group E: Patients (from 6 years to 17 years old) with symptomatic SMD and VA ≥20/100 
in both eyes at the time of the screening visit anticipated to experience rapid deterioration 
in visual function and/or retinal structure. 
Patients thus treated in the first cohort will have advanced disease with the most severe loss of 
photopic retinal function on ERG and very poor VA. Therefore, whilst this patient group is 
unlikely to experience any significant clinical benefit from treatment in terms of improvement in 
BCVA, any deleterious local effects of SAR422459 will be detectable through regular safety 
monitoring. Following clinical experience in patients with advanced disease a further 3 cohorts 
(Cohorts 2-4) in patients with less advanced disease will be evaluated. 
In Cohorts 2-4, all patients will have less advanced disease but will still have extensive retinal 
involvement, abnormal ERG and very poor VA. These patients still may have islets of functional 
retina and may receive clinical benefit from treatment with SAR422459.  
The dose evaluation phase and identification of a MTD or the highest dose tested will be 
completed.  The dose of 4.5x106 TU per measured strength was administered in 4 patients in 
Cohort 6 and up to 1 patient in Cohort 7, it will be down-escalated in subsequent cohorts for better 
safety.  Cohorts 1-5 included patients with less advanced disease with abnormal ERG and reduced 
VA.  
Cohort 6 and 8 will include symptomatic patients (from 6 years to 26 years old) with SMD who 
are anticipated to experience rapid deterioration in visual function and/or retinal structure, with 
VA of ≥20/200 in both eyes at the time of the screening visit.  The previous cohorts must have 
demonstrated acceptable safety and tolerability in the patients with more advanced disease prior to 
treatment of this patient group.   
Cohort 7 and 9 will enroll pediatric patients (from 6 to 17 years old) with SMD who are 
anticipated to experience rapid deterioration in visual function and/or retinal structure, with VA 
of ≥20/100 in both eyes at the time of the screening exam - population expected to benefit most 
from this type of treatment, based on natural history data on SMD (35).  In case patients pass 
eligibility criteria in both Cohort 6 and Cohort 7, they will be included in Cohort 7; the patients, 
who match criteria of Cohorts 8 and 9, will be enrolled into Cohort 9.  


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6 
OBJECTIVES 
6.1 
PRIMARY OBJECTIVES 
To assess the safety and tolerability of ascending doses of SAR422459 in patients with SMD. 
6.2 
SECONDARY OBJECTIVE 
To evaluate for possible biological activity of SAR422459.  


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7 
ENDPOINTS 
For all endpoints with repeated measures, the primary time point will be considered the Week 48 
visit unless otherwise specified. Last available measures before surgery will be considered as 
baseline value. 
7.1 
PRIMARY ENDPOINTS 
The primary endpoint will be considered the Week 48 visit. 
 The incidence and severity of treatment emergent adverse events. 
 Clinically important changes from baseline in the following safety assessments: 
- 
Best-corrected visual acuity,  
- 
Slit lamp examination, 
- 
Fundoscopy/Indirect ophthalmoscopy, 
- 
Fundus photography (color and infrared reflectance), 
- 
Intraocular pressure, 
- 
Microperimetry, 
- 
Full-field static perimetry, 
- 
Full-field kinetic perimetry, 
- 
Optical coherence tomography,  
- 
Electroretinogram,  
- 
Laboratory parameters, 
- 
Vital signs, 
- 
Concomitant medications. 
7.2 
SECONDARY ENDPOINTS 
Secondary Endpoints 
 To determine a delay in retinal degeneration following subretinal injection of SAR422459 
through changes from baseline in visual function and retinal structure relative to the 
untreated contralateral eye utilizing the following retinal analytical techniques: 
For visual function: 
- 
Best-corrected visual acuity,  
- 
Microperimetry, 
- 
Full-field static perimetry, 
 
Full-field kinetic perimetry.  


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For retinal structure: 
- 
Optical coherence tomography,  
- 
Fundus autofluorescence.  
7.2.1 Immunology 
Humoral response to SAR422459 vector components. 
7.2.2 Laboratory parameters 
Hematology, biochemistry, urinalysis and other laboratory data will be measured at various time 
points throughout the study. Values will be flagged as High or Low if outside the laboratory 
normal range. Out of range values will be assessed as clinically significant (CS) or not clinically 
significant (NCS) by the investigator. Clinically significant out of range values will be recorded as 
AEs. Blood for immunology and blood for PCR will also be taken at multiple time points 
throughout the study, as will urine samples for biodistribution assessment. 
7.2.3 Other safety parameters 
Other safety parameters (vital signs, physical examination) will be measured. New abnormalities 
will be recorded under adverse events. 
7.2.4 Exploratory efficacy parameters 
Contrast sensitivity will be performed using the Sloan Low Contrast Acuity Chart.  Reading speed 
and visual function questionnaires (visual function questionnaire-25 [VFQ-25]/25-item Cardiff 
visual ability questionnaire for children [CVAQC-25]) will be recorded in patients when possible 
and if the age of the patient allows.  Multifocal ERG and adaptive optics are performed only in 
Cohorts 1-5 and not required for Cohorts 6-9. 
7.2.5 Concomitant medication 
Changes to concomitant medication will be recorded at all visits. 
7.3 
BIODISTRIBUTION ENDPOINT 
SAR422459 distribution in the blood and urine assessed by polymerase chain reaction (PCR).  
For Cohorts 1-5 blood samples will be taken at Day -28 (Screening), Day 0 (60 minutes 
post-surgery), Day 1, Weeks 1, 2, 4, 12, 24, 36 and 48 and urine samples will be taken at 
Day -28 (Screening), Day 0 (60 minutes post-surgery), Day 1 and Weeks 1 and 2. For Cohorts 6-9 
blood samples will be taken at Day -28 (Screening), Day 0 (60 minutes post-surgery), Day 1, 
Weeks 1, 4, 12, 24, and 48 and urine samples will be taken at Day -28 (Screening), Day 0 
(60 minutes post-surgery), Day 1 and Week 1 only. 


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7.4 
OTHER MEASURES 
7.4.1 Patient characteristics 
During screening, height, weight, sex, vital signs, inclusion/exclusion criteria, medical history 
(including reproductive status, clinical symptoms of SMD and treatment history), 
electrocardiogram (ECG), chest X-ray and anesthesia assessment will be recorded. 


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8 
STUDY DESIGN 
This is a Phase I/IIa, open-label, dose escalation study of subretinally injected SAR422459 in 
patients with SMD. In this study, 3 doses of SAR422459 will be evaluated over 6 patient cohorts 
with 5 groups of patients. The first 4 cohorts will evaluate the dose escalation phase of the study 
and will each consist of 4 patients. Cohorts 5, consisting of 6 patients, Cohorts 6, consisting of 
4 patients and Cohort 7, having 1 patient each, receive the highest dose tested from the dose 
escalation phase. Cohorts 8 and 9 and will be treated with intermediate dose de-escalated from 
previous cohorts and evaluate the safety and biological activity of SAR422459. It is considered to 
be more probable to detect biological activity from the Cohorts 6-9 patients which are patients at a 
less advanced stage of the disease. 
One study eye will be selected. If both eyes are eligible for the study, the worse eye, as per 
investigator judgment, will be selected. The centralized review will advise on the choice of the 
study eye if both eyes are clinically similar. 
Five groups of patients (groups A, B, C, D and E) will be recruited to this study. The advancement 
of disease for groups A, B and C will be defined according to BCVA and ERG recordings, 
whereas group D will have less advanced disease as determined by clinical parameters (please see 
Section 5.11 for further information): 
 Group A: Patients (18 years or older) with advanced SMD, VA ≤20/200 in the worst eye 
and severe cone-rod dysfunction with no detectable or severely abnormal full-field ERG 
responses. 
 Group B: Patients (18 years or older) with SMD, VA ≤20/200 in the worst eye with 
abnormal full-field ERG responses. 
 Group C: Patients (18 years or older) with SMD, VA ≤20/100 in the worst eye with 
abnormal full-field ERG responses. 
 Group D: Patients (from 6 years to 26 years old) with symptomatic early or childhood-
onset SMD (age at disease onset <18 years), and VA ≥20/200 in both eyes at the time of 
the screening visit anticipated to experience rapid deterioration in visual function and/or 
retinal structure.  
 Group E: Patients (from 6 years to 17 years old) with symptomatic SMD, VA ≥20/100 in 
both eyes at the time of the screening visit and anticipated to experience rapid 
deterioration in visual function and/or retinal structure. 
An independent data safety monitoring board (DSMB) will be convened to monitor safety and 
will meet regularly either at face-to-face meetings or by teleconference once the first patient has 
been enrolled. Based on accrual of the data, the committee will comprehensively review the safety 
and tolerability of the treatment for each individual patient and make the decisions regarding dose 
escalation, study continuance and recommended amendments to the protocol. 


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Four group A patients will receive SAR422459 at the lowest dose level SAR422459, 
1.8 x 105 TU/eye (1:10), Cohort 1). An interval of 21 days between dosing 2 consecutive patients 
will be observed in order to assess the safety and tolerability of SAR422459 in these patients. 
If after a minimum interval of 28 days after the 4th patient has been dosed, the safety and 
tolerability of group A at the lowest dose is considered satisfactory by the DSMB then 4 Group B 
patients will also be enrolled into Cohort 2. These patients will also receive SAR422459,  
1.8 x 105 TU/eye (1:10) (the same dose of SAR422459 as dose Cohort 1), an interval of 21 days 
between dosing 2 consecutive patients will be observed. 
If after a minimum interval of 28 days the safety and tolerability of group B in Cohort 2 is 
considered satisfactory by the DSMB the dose of SAR422459 will be escalated and 4 Group B 
patients will be enrolled into dose Cohort 3 and receive the SAR422459  dose of 6x105 TU/eye 
(1:3). An interval of 21 days between dosing 2 consecutive patients will be observed. 
If after a minimum interval of 28 days from dosing the 4th patient of group B in Cohort 3, the 
safety and tolerability of SAR422459 is considered satisfactory by the DSMB then the dose of 
SAR422459 will be escalated to the maximal dose 1.8x106 TU/eye (undiluted), and 4 Group B 
patients will be enrolled into the next dose cohort (Cohort 4). An interval of 21 days between 
dosing 2 consecutive patients will be observed. 
If after a minimum interval of 28 days from dosing the 4th patient of Group B in Cohort 4, the 
safety and tolerability is considered satisfactory by the DSMB then 6 Group C patients will be 
enrolled into the next dose cohort (Cohort 5) and receive SAR422459 at the MTD or the highest 
dose tested (either SAR422459 1.8 x 105 TU/eye (1:10), 6 x 105 TU/eye (1:3) or 1.8 x 106 TU/eye 
(undiluted) in a volume of 300 µL). 
For Cohort 5, an interval of 21 days between dosing the first patient and second patient will be 
observed; subsequent patients may be enrolled in parallel. 
If after a minimum interval of 28 days from dosing the last patient of Cohort 5, the safety and 
tolerability is considered satisfactory by the DSMB then adult patients will be enrolled in 
Cohort 6 (Group D) and receive SAR422459 at the MTD or the highest dose tested. 
Prior to the inclusion of pediatric patients, the DSMB will review all safety data including the 
available data from all cohorts after at least 4 patients of Cohort 5 has completed 12 weeks of 
follow-up after having been dosed. An interim report including all available safety data, 
preliminary efficacy data, analysis of benefit/risk balance of enrolling pediatric patients (with 
regard to US 21 CFR Part 50 Subpart D ‘Additional Safeguards for Children in Clinical 
Investigations’ for FDA specifically and the recommendations from the DSMB will be submitted 
for approval to the regulatory authorities and institutional review boards/ethics committees, before 
enrolling pediatric patients (<18 years). Additional patients’ data may be submitted to the DSMB 
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9 
STUDY POPULATION 
Patients with SMD meeting all of the study inclusion criteria and none of the exclusion criteria 
will be recruited following EC/IRB and regulatory approval. 
9.1 
ENTRY CRITERIA 
9.1.1 Main inclusion criteria 
Patients must meet ALL of the following criteria to be considered for enrolment into this study: 
1. Signed and dated written informed consent obtained from the patient and/or the patient’s 
legally acceptable representative, if applicable, in accordance with the local regulations. 
2. Diagnosis of SMD, with at least one pathogenic mutant ABCA4 allele on each 
chromosome, confirmed by direct sequencing.  Gene mutation analysis results conducted 
prior to signing the informed consent may be used provided that the analysis was 
conducted by a CLIA (Clinical Laboratory Improvement Amendments) certified 
laboratory, written results are provided to the site, and participants (patients and/or the 
patient’s parent[s]/legal guardian[s]) give consent to utilize the results.  For patients 
genotyped during the screening period results demonstrating a pathogenic mutant ABCA4 
allele on each chromosome must be documented prior to the administration of 
SAR422459. 
3. Women of childbearing potential must have a negative pregnancy test at Day -1 and agree 
to use an effective form of contraception for at least 3 months such as the contraceptive 
pill or intra uterine device, or be surgically sterile or postmenopausal, with the last 
menstrual period being over 2 years prior to enrolment (partners of study patients must 
agree to use barrier contraception for at least 3 months after SAR422459 administration). 
4. Males must agree with their partner to use 2 forms of contraception, including one barrier 
method for at least 3 months following SAR422459 administration if their partner is of 
childbearing potential, or must be surgically sterile. 
5. Patients must agree to not donate blood, organs, tissues or cells for at least 3 months 
following SAR422459 administration 
6. Patients enrolled in France must be affiliated to or benefit from a social security regimen.  
9.1.2 Specific inclusion criteria Patient Group A 
 Patients (18 years or older) with advanced SMD. 
 VA ≤20/200 in the worst eye. 
 Severe cone-rod dysfunction with no detectable or severely abnormal full-field ERG 
responses. 


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9.1.3 Specific inclusion criteria Patient Group B 
 Patients (18 years or older) with SMD. 
 VA ≤20/200 in the worst eye. 
 Abnormal full-field ERG responses. 
9.1.4 Specific inclusion criteria Patient Group C 
 Patients (18 years or older) with SMD. 
 VA ≤20/100 in the worst eye. 
 Abnormal full-field ERG responses. 
9.1.5 Specific inclusion criteria Patient Group D 
 Symptomatic patients (from 6 years to 26 years old) with early or childhood-onset SMD 
(age at disease onset <18 years) with at least one pathogenic mutant ABCA4 allele on each 
chromosome confirmed by direct sequencing and co-segregation analysis within the 
patient’s family. 
 Visual acuity of ≥20/200 in both eyes at the time of the screening visit. 
 Patients are anticipated to experience rapid deterioration in visual function and/or retinal 
structure as determined by an annual progression rate in at least one of the following 
parameters occurring in at least one eye (assessments recorded up to 2 years prior to the 
screening visit date may be considered to document evidence of rapid deterioration): 
- 
Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters), 
- 
Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry, 
- 
Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by 
>14 dB-sr as assessed by static perimetry, 
- 
Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate 
of ≥0.5 mm2, 
- 
Enlargement in the area of central macular retinal thinning/photoreceptor loss by 
ocular coherence tomography at a rate of ≥0.5 mm2. 
 All eligible patients must demonstrate an ability to understand, willingness to cooperate 
and ability to reliably perform required study procedures as judged and confirmed by the 
study investigator.  
9.1.6 Specific inclusion criteria Patient Group E 
 Symptomatic patients (between 6 years and 17 years old) with early or childhood-onset 
SMD with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed 
by direct sequencing and co-segregation analysis within the patient's family. 
 Visual acuity of ≥20/100 in both eyes at the time of screening visit. 


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 Patients are anticipated to experience rapid deterioration in visual function and/or retinal 
structure as determined by an annual progression rate in at least one of the following 
parameters occurring  in at least one eye (assessments recorded up to 2 years prior to the 
screening visit date may be considered to document evidence of rapid deterioration): 
- 
Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters), 
- 
Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry, 
- 
Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by  
>14 dB-sr as assessed by static perimetry, 
- 
Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate 
of ≥0.5 mm2, 
- 
Enlargement in the area of central macular retinal thinning/photoreceptor loss by 
ocular coherence tomography at a rate of ≥0.5 mm2. 
 All eligible patients must demonstrate an ability to understand, willingness to cooperate 
and ability to reliably perform required study procedures as judged and confirmed by the 
study investigator. 
9.1.7 Exclusion criteria 
Presence of ANY one of the following criteria will exclude patients from being enrolled into the 
study: 
1. Pre-existing eye conditions that would preclude the planned surgery or interfere with the 
interpretation of study endpoints: glaucoma or other primary optic neuropathy that has 
resulted in significant visual field loss, corneal or significant lens opacities, active uveitis, 
retinopathy and maculopathy (other than that from Stargardt disease) that in the opinion of 
the investigator is causing significant visual loss, myopia greater than 8 diopters spherical 
equivalent. 
2. Cataract surgery with intraocular lens implantation within 6 months of enrolment. 
3. Aphakia or prior vitrectomy in the study eye. 
4. Concomitant systemic diseases including those in which the disease itself, or the treatment 
for the disease, can alter ocular function. For instance malignancies whose treatment could 
affect central nervous system function, diabetes, juvenile rheumatoid arthritis or sickle cell 
disease. 
5. Any intraocular surgery (other than study procedure) or laser in either eye planned within 
6 months of Day 0. 
6. Any contraindication to pupil dilation in either eye. 
7. Any known allergy to any component of the delivery vehicle or diagnostic agents used 
during the study (eg, fluorescein, dilation drops), or medications planned for use in the 
peri-operative period particularly topical, injected or systemic corticosteroids. 
8. Any injectable intravitreal treatment to the treated eye or intravitreal device in the treated 
eye within 6 months prior to screening. 


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9. Any periocular injections of corticosteroids to the treated eye within 4 months prior to 
screening. 
10. Laboratory test abnormalities or abnormalities in electrocardiogram, chest X-rays that in 
the opinion of the PI would make the patient unsuitable for participation in the study. 
11. Significant intercurrent illness or infection during the 28 days prior to enrolment. 
12. Pre-menopausal or non-surgically sterile women who are unwilling to use an effective 
form of contraception such as the contraceptive pill or intrauterine device. 
13. Men or women who do not agree to use barrier contraception according to the inclusion 
criteria. 
14. Alcohol or other substance abuse. 
15. Contraindications to use of anesthesia (local or general, as appropriate). 
16. Concurrent anti-retroviral therapy that would inactivate the investigational agent 
17. History of any investigational agent within 28 days prior to SAR422459 administration. 
18. Participation in a prior ocular gene transfer therapy study, other than the TDU13583 study. 
19. Enrolment in any other clinical treatment study, for any condition, including those relating 
to SMD, throughout the duration of the SAR422459 TDU13583 study participation. 
20. Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation 
therapy within the 4 weeks prior to surgery. 
21. A past medical history of HIV or hepatitis A, B or C infection. 
22. Inability to comply with the demands of the study. 
23. Women who are pregnant or are breastfeeding. 
24. History or signs consistent with unilateral amblyopia (strabismic, anisometropic or 
stimulus deprivation). 
9.2 
WITHDRAWAL CRITERIA 
Once SAR422459 has been administered into the eye it cannot be removed, therefore patients are 
unable to withdraw from the study treatment. However, an individual may withdraw consent for 
any study related procedures at any time throughout the study, and this will not affect the standard 
of care (SOC) they receive.  Patients withdrawing from follow-up monitoring before the primary 
endpoints have been established 6 months after surgery may be replaced.  Regardless of the 
reasons for withdrawal below, the sponsor commits to follow the patient for the complete duration 
of the trial. 
Individual patients may also be withdrawn under the following circumstances: 
 The patient requests early discontinuation. 
 Investigator’s request (eg, if the investigator considers that the patient’s health is 
compromised by remaining in the study or the subject is not sufficiently co-operative). 
 The patient is lost to follow-up (all attempts will be made to locate patients lost to 
follow-up). 


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Any patient that is withdrawn from the study will be encouraged to enroll in a long-term 
follow-up study. Long-term follow-up in gene transfer research allows for the collection of 
important information on the long-term safety and effects of the study treatment. The long-term 
follow-up study (LTS13588) will last for up to 15 years. If the patient withdraws/is withdrawn 
from the study prematurely, the Week 48 procedures should be completed, if possible. 
The long-term safety follow-up will be described in a separate protocol which will be submitted to 
regulatory agencies and Institutional Review Boards/Ethics Committees for approval. 
The open-label follow-up study has been designed to capture the essential safety data pertinent to 
gene therapy follow-up, as well as key efficacy assessments, whilst providing the patient with a 
degree of flexibility for minimizing inconvenience. The long-term follow-up protocol will also 
permit patients to receive alternative treatment during their participation while allowing for safety 
follow-up. 
9.3 
STUDY STOPPING CRITERIA 
The following is to be considered stopping enrollment: 
 Prolonged anterior chamber inflammation and/or prolonged posterior chamber 
inflammation continuing without signs of resolution 28 days after SAR422459 
administration. 
Criteria for suspending enrolment or further study conduct are defined in the DSMB charter and 
all events will be reviewed by the DSMB. 
In the event that enrollment is terminated, all patients who have been dosed with SAR422459 will 
continue to be followed up as per protocol until the Week 48 visit has been completed.  Patients 
will be encouraged to enroll in a long-term follow-up study. Long-term follow-up in gene transfer 
research allows for the collection of important information on the long-term safety and effects of 
the study treatment. The long-term follow-up study (LTS13588) will last for up to 15 years.    
9.4 
DOSE-LIMITING TOXICITIES 
Dosing will stop if a dose-limiting toxicity is encountered in a dosing cohort. Events that 
constitute a dose-limiting toxicity will be defined in the DSMB charter. Dose limiting toxicities 
will include: 
 Severe or persistent ocular inflammation.; 
 Other significant ocular toxicity (eg, large retinal detachment, evidence of direct toxicity). 
 Other systemic toxicities (eg, acute allergic reaction). 
 Any safety issue that has been identified that adversely changes the benefit/risk balance to 
study participants. 


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10 
TREATMENT PLAN AND METHODS 
10.1 
ALLOCATION OF TREATMENTS 
10.1.1 Dose escalation 
Patients will be allocated to treatment in the order in which they are enrolled into the study. 
Dose escalation or progression to the next patient cohort will be based on safety from the patients 
of the previous cohorts, including events such as the presence and severity of manifested clinical 
signs and symptoms, laboratory tests including clinical chemistry, hematology, urinalysis and 
antibodies. The DSMB will thoroughly review and discuss the results from the previous cohort(s) 
before proceeding with any subsequent dose escalation. All patients in the previous cohort must 
be observed for a minimum of 28 days before additional participants receive drug at the next dose 
level. 
10.2 
STUDY MEDICATION ADMINISTRATION 
10.2.1 Hospitalization 
Hospitalization is not required but may be necessary for the subretinal injection procedure for 
convenience of some patients. Patients will not take anything by mouth for a minimum of 8 hours 
prior to the ocular surgery. 
10.2.2 Subretinal injection procedure 
After informed consent is completed, patients will have baseline assessments and eligibility will 
be confirmed. For Cohorts 6 to 9, a centralized review of baseline study assessments will be 
performed pre-operatively for the purpose of providing a recommendation on the area of retina to 
be targeted for the subretinal injection to optimize the treatment benefit.  
Eligible patients will be scheduled for surgery, the study eye will be marked prior to entering the 
operating room and once in the operating room the study eye will be reconfirmed. 
Surgery will be performed under general anesthesia or waking sedation at the surgeon’s 
discretion, with additional periocular/retrobulbar injections according to surgeon and 
anesthesiologist preferences. Surgery will be performed under sterile conditions in accordance 
with hospital operating room protocols, according standard practice of subretinal injections and 
following recommendations of Study Manuals. 
Following the administration of SAR422459, the fundus will be examined by fundoscopy/indirect 
ophthalmoscopy and scleral depression to look for peripheral retinal tears. If there are any 
peripheral retinal tears, they will be treated with cryopexy and a fluid-air exchange or other 
appropriate technique at the judgment of the surgeon. The vitreous cavity may be filled with the 
appropriate tamponade at the discretion of the surgeon.  


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To explore further the treatment effect (safety and biological activity) at the bleb level during the 
procedure, intraoperative photos and, where available, video of the surgery and/or intra-operative 
OCT will be collected.  Following the procedure the surgeon will prepare a retinal drawing 
showing the location of the bleb in order to define as precisely as possible the area of the bleb and 
consequently, the zone of cell transduction.  Materials documenting the subretinal bleb location 
will be forwarded to the reading center.  In the event that the subretinal injection is not placed in 
an area recommended by the central review at the completion of the procedure the surgeon will 
make a note in the study source documents indicating the rationale for the location of the 
subretinal bleb. 
The eye will be patched and the patient will be taken to the post-operative observation area. 
For each patient, the following protocol required anti-inflammatory regimen including antibiotics 
and corticosteroid medications must be administered to reduce the possibility of clinically 
significant intraocular inflammation after subretinal injection procedure. 
 Two hours prior to the subretinal injection procedure - administer: 
- 
In Children:  one dose of intravenous methylprednisolone 1 mg/kg for patients  
≥50 kg or 0.5 mg/kg for patients <50 kg. Maximum corticosteroid dose not to exceed 
80 mg for children <16 years, 
- 
In Adults: one dose of intravenous methylprednisolone 1 mg/kg.   
 Immediately following the completion of the subretinal injection procedure: 
- 
At the discretion of the surgeon, a subconjunctival injection of corticosteroids  
(eg Dexamethasone 5 to 10 mg) and/or a subconjunctival injection of antibiotics may 
be given. 
 Starting (post-operative) Day 1 administer/initiate: 
- 
In Children: oral prednisone 1 mg/kg/day for patients ≥50 kg or 0.5 mg/kg/day for 
patients <50 kg daily for 5 days, then reduce dose to 0.5 mg/kg/day for patients ≥50 kg 
or 0.25 mg/kg/day for patients <50 kg daily for 5 days, then reduce dose by 10 daily 
until the corticosteroid taper is complete.  Maximum corticosteroid dose not to exceed 
80 mg for children <16 years, 
- 
In Adults: oral prednisone 1 mg/kg/day for 5 days, then reduce dose to 0.5 mg/kg/day  
for 5 days, then reduce dose by 10 mg daily until the corticosteroid taper is complete, 
- Topical broad-spectrum antibiotic (eg, ofloxacin, ciprofloxacin, moxifloxacin, 
trimethoprim-polymyxin B or similar) QID for 7-10 days, 
- 
Topical prednisolone acetate 1% (or similar) 4 times a day (QID) for 7-10 days, then 
3 times a day (TID) for 7-10 days, then 2 times a day (BID) for 7-10 days, then once 
daily (QD) for 7-10 days. (Note: The frequency of the topical corticosteroid drops and 
the timing for the start of the taper may be adjusted as needed in response to the 
patient’s manifestation of post-operative inflammation with the goal of resolving the 
post-operative ocular inflammatory response within 28 days after the surgical 
procedure), 


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- 
A topical steroid ointment (eg, sterdex, tobradex or similar) may also be given at 
bedtime (qhs) for 7-10 days at the discretion of the surgeon. 
Intraocular inflammation worsening during the course of treatment with the protocol defined 
anti-inflammatory regimen (see Section 10.3.27  Post Surgical Ophthalmological Adverse Events) 
or persisting or occurring after the completion of the above protocol defined anti-inflammatory 
regimen must be recorded as a post-surgical adverse event.  
For the management of intraocular inflammation persisting or occurring after the completion of 
the above protocol defined anti-inflammatory regimen or worsening during the course of the 
regimen see Section 10.3.27 Post-surgical Ophthalmological Adverse Events. 
10.2.3 Positioning of the subretinal bleb 
In all patients, the site for subretinal injection will be selected as to ensure that the existing VA 
will not be impaired and the treated retinal area can be easily monitored for safety after 
SAR422459 administration. Group A will have advanced disease and very poor VA. In this group 
encroachment of the injection bleb to the central macula will be permitted as it is unlikely it will 
further impair VA. However, groups B, C, D and E will have less advanced disease with better 
acuity and group E will include pediatric patients.  
Prior to surgery, the position of the subretinal bleb will be determined based on the baseline 
clinical evaluation, fundus imaging and visual field testing. Clinical evaluation and fundus 
imaging will be used so that the subretinal bleb can be positioned to avoid area(s) of outer retinal 
atrophy. Perimetry will be used so that the bleb avoids area(s) with normal retina sensitivity.  
Patient Group A: The bleb will be allowed to extend into the central macula. If the surgeon 
determines that the bleb is not forming in the correct position, he/she can choose to stop infusing 
and create another retinotomy. This can be done up to twice until the full volume has been 
delivered. 
Patient Group B and C: The positioning of the bleb will be determined pre-operatively based upon 
visual field testing and in an area of retina that has diminished but recordable retinal sensitivity. 
An extramacular bleb will be created at the macular boundary. The bleb may extend into the 
macula but the central macula will not be detached. 
Patient Group D and E: Recommendation of the bleb location will be made by the centralized 
review for the purpose of optimizing the treatment benefit and minimizing the risk to existing VA.   
10.2.4 SAR422459 preparation 
SAR422459 will be provided in 100 µL aliquots in 0.3 mL type I borosilicate glass ‘V’ vials with 
a butyl stopper and aluminum crimp seal. Each vial of SAR422459 will be issued in a white 
plastic tamper evident container secured in packaging. The vial and plastic tamper-evident 
container will be labeled appropriately. 
Further details of the preparation of SAR422459 for administration are provided in the study 
pharmacy manual. 


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10.2.5 SAR422459 administration 
All disposable surgical supplies; including gloves, masks, gowns, dressings and swabs used 
during the surgical procedure will be destroyed by incineration according to hospital policy at the 
end of the operation. The first dressings removed from the patient’s wounds following surgery 
will also be disposed of by incineration or local equivalent in accordance with the local hospital 
policy on genetically modified materials. 
10.2.6 Post-surgical monitoring 
Post-surgical monitoring will be conducted according to SOC according to the clinical sites usual 
protocols. 
Before the patient is discharged, blood and urine samples will be obtained for PCR assay for viral 
particles. 
10.3 
SPECIFIC PROCEDURES 
Ophthalmic procedures will be conducted on both the treated and untreated eye at all visits. 
10.3.1 Screening/baseline procedures 
A screening log must be maintained for all patients screened for entry to the study, reasons for 
screen failure will be documented. 
Patient screening will take place in the 28 days prior to SAR422459 administration. Full-field 
Kinetic and Static perimetry and BCVA will be performed during the screening period. As these 
measures are subject to broad intra-individual variability, they may be repeated during the 
screening period to determine the patient's reliability in the performance of these psychophysical 
assessments.  
A pan-retinal photomontage image will be taken at screening to document the whole retina prior 
to the beginning of the study.  
At screening, a 7-field fundus photos series will be taken of each eye to document the whole 
retina.  At subsequent visits a standard 50˚ photograph centered on the macula and including the 
optic nerve will be obtained to document the appearance of the posterior pole with specific 
emphasis on recording the area of the retina that will be or was treated.  Images should be evenly 
illuminated, well focused and free of artifacts (please see the Technical Manual of Procedures for 
more details).  If opacities of the anterior ocular structures compromise image quality, an external 
red-reflex image focused on the iris plane should also be taken. 
Screening procedures are detailed in the study schedule in Section 3. 


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10.3.2 Screening clinical and laboratory/diagnostic measurements 
The following assessments are required 28 ± 10 days prior to administration of SAR422459.  If 
necessary, the screening assessments can be carried out over several days. Screening urine 
pregnancy tests must be negative. 
 Informed consent 
 Entry criteria 
 Demographic data 
 Genotyping 
 Medical history 
- 
Clinical symptoms of SMD 
- 
Treatment history 
- 
Past medical history of HIV, hepatitis A, B or C infection will be evaluated. 
- 
Reproductive status 
 Concomitant medications 
 Pre-operative assessments 
- 
Anesthesia assessment 
- 
Height 
- 
Weight 
- 
Vital signs 
- 
Electrocardiogram (ECG) 
- 
Chest X-ray 
- 
Physical examination 
 Ophthalmological examination 
- 
BCVA  
- 
Contrast sensitivity  - Cohorts 6-9 only 
- 
Reading speed (when possible) - Cohorts 6-9 only 
- 
Slit lamp examination 
- 
Intraocular pressure (IOP) 
- 
Fundoscopy/indirect ophthalmoscopy 
- 
FAF 
- 
OCT 
- 
Infra-red imaging - Cohorts 6-9 only 


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- 
Microperimetry 
 
Full-field kinetic and static perimetry  
- 
Full-field ERG  
- 
Multifocal ERG (Cohort 1-5) 
- 
Adaptive optics (Cohort 1-5)  
- 
Fundus photography 
 Laboratory samples  
- 
Hematology 
- 
Chemistry panel 
- 
Kidney function 
- 
Liver function 
- 
Coagulation 
 Urinalysis 
 Urine pregnancy test for women of childbearing potential 
 Blood for PCR 
 Urine for PCR 
 Adverse events (since consent). 
10.3.3 Screening clinical laboratory/diagnostic measurements Day -1 
The following assessments must either be completed on Day-1 or in the preceding 7 days with the 
exception of the urine pregnancy test that must be negative on Day -1. 
 Concomitant medications 
 Vital signs 
 Ophthalmological examination 
- 
BCVA  
- 
Contrast sensitivity- Cohorts 6-9 only 
- 
Slit lamp examination 
- 
Intraocular pressure (IOP) 
- 
Fundoscopy/indirect ophthalmoscopy 
- 
FAF 
- 
OCT 
- 
Infra-red imaging 


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- 
Microperimetry 
 
Full-field kinetic and static perimetry  
- 
Fundus photography 
- 
Multiphocal ERG (Cohort 1-5) 
- 
Full-field ERG  
- 
Adaptive optics (Cohort 1-5) 
- 
Reading speed (when possible) 
- 
VFQ-25/CVAQC-25 (when possible) 
 Clinical laboratory samples 
 Urinalysis 
 Urine pregnancy test for women of childbearing potential 
 Blood for immunology 
 Adverse events 
10.3.4 Re-screening 
Re-screening will be allowed once within 90 day period from initial informed consent, in case 
patient was eligible by all inclusion – exclusion criteria, but was not treated. Previous evaluation 
of rapid deterioration will be accepted. All other eligibility criteria need to be reviewed.  Patient 
will undergo a baseline visit (if was not done) or repeat it within a 7 day period before surgery. 
Additional (standard) examinations/ tests can be needed during such visit: 
 laboratory tests of hematology, chemistry panel, kidney function, liver function and 
coagulation will be repeated if done earlier than 38 days before surgery, or - by a request 
of anesthesiologist.  
 anesthesia assessment will be repeated if outside of the Day-28 to Day-1 window before 
surgery. Weight, ECG, chest X-ray may be repeated by a request of anesthesiologist. 
10.3.5 Surgery 
The following assessments are performed on the day of surgery. 
 SAR422459 administration. 
 Fundus photography will be performed in the operating room during surgery. This will be 
post bleb placement and will record the position of the bleb relative to the retinal anatomy 
 Where available, intraoperative video recording of the surgical procedure and/or 
intraoperative OCT will also be performed. 
 Vital signs 30 and 60 minutes after surgery 


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 Blood 60 minutes after surgery and first urine sample that occurs after 60 minutes post-
surgery  
 Adverse events 
 Concomitant medications 
10.3.6 Follow-up procedures 
Patient follow-up visits are outlined in the study schedule in Section 3. 
10.3.7 Follow-up Day 1 clinical and laboratory/diagnostic measurements 
 Concomitant medications 
 Vital signs 
 Ophthalmological examination 
- 
BCVA 
- 
Slit lamp examination 
- 
Intraocular pressure (IOP) 
- 
Fundoscopy/indirect ophthalmoscopy 
- 
OCT 
- 
Fundus photography 
 Clinical laboratory samples (except coagulation and kidney function) (for Cohorts 1-5 
only) 
 Blood for PCR 
 Urine for PCR 
 Urinalysis 
 Adverse events 
10.3.8 Follow-up Week 1, 2, 4, 12, 24, 36 and 48 clinical and laboratory/diagnostic 
measurements (visit at Week 36 is not performed in Cohorts 6 and 9) 
 Concomitant medications 
 Vital signs 
 Ophthalmological examination 
- 
BCVA 
- 
Contrast sensitivity (Weeks 12, 24 and 48) - Cohorts 6 to 9 only 
- 
Slit lamp examination 
- 
Intraocular pressure (IOP) 


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- 
Fundoscopy/indirect ophthalmoscopy 
- 
FAF: 
- 
Cohorts 1-5: Weeks 4, 12, 24 and 48 only 
- 
Cohorts 6-9: Weeks 4,12, 24 and 48 only 
- 
Infrared reflectance imaging: 
- 
Cohorts 6-9: Weeks 12, 24 and 48 
- 
OCT: 
- 
Cohorts 1-5: at each visit 
- 
Cohorts 6-9: at each visit 
- 
Microperimetry: 
- 
Cohorts 1-5: Weeks 2, 4, 12, 24, 36 and 48 only 
- 
Cohorts 6-9: Weeks  4, 12, 24, and 48 only 
- 
Full-field Kinetic and Static Perimetry 
- 
Cohorts 1-5: Weeks 2, 4, 12, 24, 36 and 48 only 
- 
Cohorts 6-9: Weeks 12, 24, and 48 only 
- 
Fundus photography: 
- 
Cohorts 1-5: Weeks 2, 4, 24, 36 and 48 only 
- 
Cohorts 6-9: Weeks 2, 4, 24 and 48 only 
- 
Full-field ERG: 
- 
Cohorts 1-5: Weeks 4, 12, 24 and 48 only 
- 
Cohorts 6-9: Week 48 only 
- 
Multifocal ERG:  
- 
Cohorts 1-5: Weeks 4, 12, 24 and 48 only  
- 
Adaptive optics: 
- 
Only for Cohorts 1-5 (Weeks 12, 24, 36 and 48 only) 
- 
Reading speed  
- 
Cohorts 1-5: Week 48 only 
- 
Cohorts 6-9: Week 48 only, when available 
- 
VFQ-25/CVAQC-25: 
- 
Cohorts 1-5: Week 48 only 
- 
Cohorts 6-9: Week 48 only, when available 
 Clinical laboratory samples (except coagulation) (Weeks 4, 24 and 48 only) 
 Urinalysis (Weeks 4, 24 and 48 only) 
 Blood for PCR  
- 
Cohorts 1-5: Week 1, 2, 4, 12, 24, 36 and 48 
- 
Cohorts 6-9: Week 1, 4, 12, 24 and 48 


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 Urine for PCR   
- 
Cohorts 1-5: Week 1 and 2 
- 
Cohorts 6-9: Week 1 only 
 Blood for immunology: 
- 
Cohorts 1-5: Week 4, 12 and 24. For patients with positive antibody response at 
Week 24, additional blood sampling will be performed at Week 36 and 48. 
- 
Cohorts 6-9: Week 4, 12 and 24. For patients with positive antibody response at 
Week 24, additional blood sampling will be performed at Week 48. 
 Adverse events 
 Physical examination (Week 48 only) 
10.3.9 Samples for PCR 
Blood samples for PCR are required to be taken at the Screening visit (28 Days prior to surgery) 
and at the following visits post-administration of SAR422459; 60 minutes after surgery, Day 1, 
Weeks 1, 2, 4, 12, 24, 36 and 48. In Cohorts 6-7, blood samples are not required at Week 2 and 
Week 36. 
Urine samples for PCR are required to be taken at the Screening visit (28 Days prior to surgery) 
and at following visits, Day 0 (first urine sample that occurs after 60 minutes post-surgery), Day 1 
and Weeks 1 and 2 only. In Cohorts 6-7, urine samples are not required at Week 2. 
The processing of blood samples for PCR analysis will be performed at the designated hospital by 
a person designated by the PI. The samples will be labeled with the patient number, date of 
collection and visit number. They will then be stored in the freezer at ≤-70°C prior to shipment to 
the Sponsor designated company for analysis. The shipment of samples will be on dry ice. The 
Sponsor clinical project manager or designee will be notified at least 24 hours in advance of any 
shipment. 
10.3.10 Samples for immunology 
Samples for immunology are required to be taken at the baseline visit (Day -1) and at the 
following visits post administration of SAR422459; Weeks 4, 12 and 24 (and Week 36 for 
Cohorts 1-5). In patients with positive antibody response at Week 24, additional blood sampling 
will be performed at Week 36 and 48 for Cohorts 1-5 and only at Week 48 for Cohorts 6-7.  
The processing of the blood samples for immunology analysis will be performed at the designated 
hospital by a person designated by the PI. The samples will be labeled with the patient number 
and initials, date of collection and visit number. They will then be stored in the freezer at ≤-70°C 
prior to shipment to the Sponsor designated company for analysis. The shipment of samples to the 
Sponsor designated company will be on dry ice. The Sponsor clinical project manager or designee 
will be notified at least 24 hours in advance of any shipment. 


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Blood samples collected for immunology will be analyzed using either ELISA and/or Western 
blot analysis. 
Future use of samples 
For subjects who have consented to it, the samples that are unused or left over after testing may be 
used for other research purposes (excluding genetic analysis) related to ophthalmology.  
These sample(s) will be transferred to a Sanofi site (or subcontractor site) and will be handled and 
stored at a secure site specialized for such investigations under the responsibility of the sponsor up 
to 15 years after completion of the final report of the main clinical. Thereafter, all samples will be 
destroyed. 
10.3.11 Ophthalmological assessments 
Ophthalmological assessments will be carried out by certified individuals at the study site. As far 
as possible, for each patient, assessments will be performed by the same individual at each visit. 
Technical details of all ophthalmological assessments will be provided in the investigator site file. 
All findings will to be documented in the source documentation and the appropriate electronic 
Case Report Form (eCRF). 
Studies have shown that a number of psychophysical measures and imaging modalities provide a 
sensitive method of monitoring disease progression and response in SMD. 
10.3.12 Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) Visual 
Acuity 
A BCVA examination will be performed using the EVA (electronic VA) testing system according 
to the recommended protocol. Early Treatment Diabetic Retinopathy Study (ETDRS) chart testing 
will be used as a back-up in case the EVA is not functioning or available.  In such cases the same 
method used to record BCVA at the screening visit for a given patient should be used throughout 
the study. 
For young patients, not knowing to read letters - adapted equivalent charts will be used BCVA 
evaluation.  Use of such charts for rapid deterioration for inclusion will be agreed with Sponsor 
beforehand, loss equivalent to Snellen / ETDRS criteria will be established for each chart. 
10.3.13 Contrast sensitivity 
A contrast sensitivity assessment will be performed using the Sloan Low Contrast Letter acuity 
chart according to the recommended protocol/manual.  In low vision patients, functional vision, 
eg, the ability to recognize faces and read moderate size print and the orientation and mobility 
capacities were better correlated to contrast sensitivity levels than visual acuity measurements. 
(36, 37).  The 100%, 2.5%, and 1.5% contrast level Sloan Low Contrast Acuity charts will be 
used for testing. Contrast sensitivity in the study will be tested on each eye separately; it is not 
required to test both eyes together. For detailed instructions see Appendix D. 


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Special other charts may be used for young patients not knowing to read letters. 
10.3.14 Slit lamp examination 
Slit lamp examination will be performed using the investigator’s standard procedure. 
This procedure will be the same for all patients examined. Observations will be made to indicate 
the absence or presence of findings for ocular adnexa, anterior and posterior segments. Intraocular 
inflammation will be graded using a standard scale (see Appendix A). 
10.3.15 Fundoscopy/indirect ophthalmoscopy 
Dilated fundoscopy/indirect ophthalmoscopic will be performed according to the investigator’s 
standard practice. Investigators will specifically document the presence or absence of retinal 
detachment, retinal tears or holes, subretinal hemorrhage, exudation, fluid or fibrosis. Additional 
observations will also be documented. 
10.3.16 Intraocular pressure measurement 
Applanation tonometry is the preferred method to be used for IOP measurements after dilation, 
however, for Cohorts 6-9, Tonopen or noncontact methods are acceptable.  The same method of 
IOP measurement must be used in each subject throughout the study. 
10.3.17 Optical coherence tomography 
OCT is a non-invasive technique that provides high resolution axial images of the retina. A low 
coherence infrared source is used to image the retina and a portion of coherent backscattered light 
is detected using an optical interferometer (38). Depth and intensity information can be captured 
digitally to visualize the structural morphology of the intraretinal layers. Spectral domain OCT 
(SD-OCT) is the most advanced method available and provides high resolution, rapid scanning, 
high repeatability and the capacity for transverse scans and the 3-dimentional mapping of single 
retinal layers (39). Macular thickness, subretinal fluid, and other architectural OCT features 
provide useful information on the transverse and axial location of retinal lesions. 
OCT will be performed after dilation using the Spectralis SD-OCT imaging system (Heidelberg 
Engineering) to evaluate the cross-sectional anatomy of the macula and document areas of retinal 
atrophy. 
10.3.18 Fundus photography 
Fundus photography (color and infrared reflectance images) remains an invaluable tool to record 
the characteristics of the retina at any one stage of the disease and is used in combination with 
other imaging modalities (eg, autofluorescence) to accurately map the appearance of atrophy. 


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To document the retinal anatomy after adequate dilation, a suitable fundus camera, (Zeiss FF4 
series and the Topcon TRC-50EX or similar) will be used to collect color fundus photos, whereas, 
the Heidelberg Spectralis OCT capable of collecting infrared reflectance images will be used. 
10.3.19 Electroretinogram 
Full-field electroretinography (ERG) measures the electrical responses of various cell types in the 
retina, including the PRs, inner retinal cells bipolar and amacrine cells, and the ganglion cells. It is 
a non-invasive technique in which electrodes are placed on the cornea and the skin near the eye. 
During a recording, the patient's eyes are exposed to standardized light stimuli and the resulting 
ERG signal is displayed showing the time course of the signal's amplitude. The ERG is composed 
of electrical potentials contributed by different cell types within the retina, and the stimulus 
conditions (flash or pattern stimulus, whether a background light is present, and the colors of the 
stimulus and background) can elicit stronger response from certain components. 
If a flash ERG is performed on a dark-adapted eye (scotopic), the response is primarily from the 
rod system and flash ERGs performed on a light adapted eye (photopic) will reflect the activity of 
the cone system. With sufficiently bright flashes, the ERG will contain an ‘a-wave’ (initial 
negative deflection) followed by a ‘b-wave’ (positive deflection). The leading edge of the a-wave 
is produced by the PRs, while the remainder of the wave is produced by a mixture of cells 
including PRs, bipolar, amacrine and Mueller cells. 
A full-field electroretinogram will be conducted after dilation using the standard procedure 
according to the ERG Standardisation Committee of the International Society for Clinical 
Electrophysiology of Vision (ISCEV). Stimulus protocols for both scotopic and photopic function 
will be performed. 
Multifocal electroretinography will be performed using the multifocal ERG according the 
manufacturers protocol. 
10.3.20 Perimetry 
Semi-automated Kinetic Perimetry (SKP) and Full-field Static Perimetry are non-invasive, 
psychophysical tests that can rapidly and accurately assess the visual fields and create a detailed 
map of the retina documenting any scotoma and the level of retinal function at individual loci. 
SKP allows greater standardization, control, and documentation of how the testing is performed, 
and minimizes the variability normally observed when different perimetrists test the same patient. 
Analysis will be performed at a central reading center. 
The technique of static perimetry has been optimized specifically for glaucoma, however has also 
been shown to be appropriate for retinal disease (40). Using the German Adaptive Threshold 
Estimation (GATE) strategy (41) and radially oriented, centrally condensed grids that extend from 
50° nasally to 80° temporally, the entire full-field is captured. The centrally condensed grid 
captures detail of sensitivity boundaries and gradients within the central portion of the field and 
thus, can more precisely define remaining visual field in advanced disease. The differential 
luminance sensitivities are exported digitally to the central reading center for computation and 
modeling to create a “Hill of Vision”, which is a volumetric estimate of retinal function. 


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Perimetry will be performed prior to dilation using the Haag Streit Octopus 900 (Semi-automated 
Kinetic Perimetry (SKP) and Full-Field GATE Static perimetry).  
Full-field Kinetic and Static perimetry and BCVA will be performed during the screening period. 
As these measures are subject to broad intra-individual variability, they will be repeated to during 
the screening period to determine the patient's reliability in the performance of these 
psychophysical assessments.  
10.3.21 Microperimetry 
Microperimetry will be performed on the MP1 following dilation. The MP1 provides a 
quantitative assessment of fixation by tracking fundus movements while the patient looks steadily 
at the fixation target. The MP1 can also accurately map a scotoma by delineating the absolute or 
relative non-seeing areas within the visual field. This is accomplished by projecting a light 
stimulus onto the patient’s retina until it becomes visible to the patient. With the MP1 it is 
possible to monitor the evolution of a disease and the exact changes it effects on a patient’s vision 
over the long-term, because follow-up examinations are automatically performed in previously 
examined areas. 
10.3.22 Fundus Autofluorescence imaging 
Fundus autofluorescence imaging of the retina will be performed following dilation to document 
the distribution of lipofuscin and degenerative geography using the Spectralis system (Heidelberg 
Engineering). Fundus autofluorescence (FAF) is a non-invasive imaging technique to visualize 
lipofuscin, particularly in the parafoveal area. 
Abnormally increased FAF suggests RPE dysfunction, while decrease FAF indicates RPE atrophy 
and PR death (42). Images are acquired using a confocal laser ophthalmoscope system effectively 
gathering light from a single focal plane and eliminating autofluorescence from sources anterior to 
the retina (43). Studies of early SMD have consistently demonstrated abnormal FAF with a wide 
variation in the pattern and degree of retinal involvement. This technique can detect areas of 
atrophy that may be missed by fundus photography and is therefore useful for detection and 
monitoring of early disease (40). 
Early detectable disease is characterized by diffusely increased FAF in the posterior pole and is 
followed by more focal involvement in the parafoveal region. In late disease, FAF decreases due 
to RPE dysfunction and PR degeneration and death (44). 
Although FAF intensity cannot be directly correlated with lipofuscin accumulation, due to 
absorption of fluorescence by a number of ocular structures (45) and variability in detecting 
systems (46) it remains a useful tool in conjunction with other imaging modalities to document 
the retinal geography in macular degenerative disease. 


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10.3.23 Adaptive optics 
Adaptive optics is a non-invasive technique in which a light–illuminated ophthalmoscope system 
or a scanning laser ophthalmoscope utilizes a deformable mirror to form a high resolution image 
of the retina capable of imaging individual cones and other cellular structures (47). Images from 
patients with inherited retinal degenerative conditions have shown irregular cone mosaic patterns, 
increased cone spacing and reduced density and hyper-reflective areas in regions of atrophy 
compared to normal. Adaptive optics can be used in inherited retinal degenerative disease to 
identify both normal and abnormal areas of cone mosaic. However due to limitations of the 
technique identification and estimation of cone spacing is reliably quantified only where the cone 
mosaic can be identified unambiguously. Adaptive optics (Cohort 1-5 only) is often used in 
conjunction with SD-OCT to ensure the expected laminar appearances of the PR inner and outer 
layer in the SD-OCT cross section corresponds to the adaptive optics image. 
10.3.24 Reading speed 
Reading speed is a good predictor of everyday visual function. As VA tests are poor predictors of 
the real-world function, performance-based tests (eg, reading speed measurements) can be used 
for the determination of visual function. Thus, standard charts have been developed in order to 
evaluate reading acuity as well as reading speed (Appendix E). Print size is defined as the height 
of a lower case x and progresses logarithmically from one phrase to another. With these reading 
charts it is possible to determine reading speed with high reliability and a good reproducibility of 
the reading acuity evaluations (48). VFQ-25 and reading speed assessment will also provide data 
regarding the effect of the disease process on the quality of life of patients in the current study. 
For Cohorts 6-9 reading speed will be performed prior to dilation when possible. 
10.3.25 Visual Function Questionnaires VFQ-25/CVAQC-25  
An individual's own perception of quality of life is perhaps one of the most meaningful measures 
of that individual's level visual function. The National Eye Institute (NEI) Visual Function 
Questionnaire (VFQ-25) was developed to measure vision-specific health-related quality of life. 
The VFQ-25 assess difficulty with near vision activities, difficulty with distance vision activities, 
limitations in social functioning due to vision, role limitations due to vision, dependency on others 
due to vision, mental health symptoms due to vision, future expectations for vision, driving 
difficulties, pain and discomfort in or around the eyes, limitations with peripheral vision and color 
vision. The VFQ-25 questionnaire was developed from patient focus groups representing a 
diverse set of visual conditions, the intention being to develop a scale that can be generalized to 
all patients with vision deficits, regardless of cause. Across the range of developmental conditions 
(cataract, glaucoma, AMD, and diabetic retinopathy), as well as other conditions as diverse as 
corneal diseases and vascular occlusions of the retina, NEI-VFQ scores vary in the expected 
direction with differences in visual performance and disease state. For Cohorts 6-9 visual function 
questionnaires will be performed at sites when possible.  Interviewer-administered versions of the 
instruments will be used in the study; interviewers will read the questionnaire to the patient and 
record only the patient’s response (without interpretation). Each questionnaire is composed of 
25 items each. 


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The Visual Function Questionnaire-25 (VFQ-25) from the National Eye Institute will be 
administered to adult patients (≥18 years old). This patient-reported outcome (PRO) instrument 
measures the influence of visual impairment on quality of life of adult with eye diseases. 
The Cardiff Visual Ability Questionnaire for Children (CVAQC) will be administered to children 
aged 6 to <18 years old. This PRO instrument measures the self-perceived visual ability in 
visually impaired children and young people aged 6 to 18 years.  The 25-item Cardiff Visual 
Ability Questionnaire for Children (CVAQC) is a short, psychometrically robust and a self-
reported instrument that works to form a unidimensional scale for the assessment of the visual 
ability in children and young people with a visual impairment.  A list of 121 items was generated 
from 13 focus groups with children and young people with and without a visual impairment. A 
long 89-item questionnaire was piloted with 45 visually impaired children and young people using 
face-to-face interviews. Rasch analysis was used to analyze the response category function and to 
facilitate item removal ensuring a valid unidimensional scale. The validity and reliability of the 
short questionnaire were assessed on a group of 109 visually impaired children (58.7% boys; 
median age 13 years) using Rasch analysis and intraclass correlation coefficient (ICC). The final 
25-item questionnaire has good validity and reliability as demonstrated by a person separation 
index of 2.28 and reliability coefficient of 0.84. The items are well targeted to the subjects with a 
mean difference of -0.40 logit between item and person means, and an ICC of 0.89 demonstrates 
good temporal stability (49).  
10.3.26 Medication, adverse event and concomitant medication review 
Review of concomitant medication and adverse events will be conducted by an 
ophthalmologist/designee at all visits. 
10.3.27 Post-surgical ophthalmological adverse events 
Patients who develop post-surgical complications such as intraocular inflammation and raised IOP 
should be treated according to local standard of care procedures. 
Intraocular inflammation worsening during the course of treatment with the protocol defined 
anti-inflammatory regimen (see Section 10.2.2 Subretinal Injection) or persisting or occurring 
after the completion of the protocol defined anti-inflammatory regimen must be recorded as a 
post-surgical ophthalmological adverse event.  
In this setting the treatment and follow-up of the patient will be at the discretion of the 
investigator, guided by the severity and longevity of the inflammation, in an effort to minimize 
the risk of loss of visual function as a result of the ongoing inflammatory process.  In the situation 
where the intraocular inflammation is clinically worsening the presence of an intraocular infection 
should be excluded. 
Treatment with high dose, oral corticosteroids (1 mg/kg/day for patients ≥50 kg; 0.5 mg/kg/day 
for patients <50 kg; maximum dose not to exceed 80 mg/day for children <16 years) is 
recommended for any patient manifesting worsening intraocular inflammation (eg, ≥2+ for 
anterior chamber cells, ≥2+ vitreous haze and/or cells, the presence of vitreous snowballs or 
retinal vasculitis).  In such cases, the oral corticosteroids should be continued until the ocular 
inflammation is resolved and then tapered as appropriate. 


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Raised IOP greater than 30 mmHg must be recorded as a post-surgical adverse event and may be 
treated with IOP lowering drops with the patient reviewed within a week. If the IOP remains 
greater than 25 mmHg another pressure lowering drop will be added and the patient reviewed 
again within a week. This sequence will be repeated until the IOP remains below 25 mmHg.  For 
increases in IOP occurring while the patient is receiving topical steroids per the recommended 
protocol defined anti-inflammatory regimen, consideration may be given to reducing the 
frequency of the topical steroids if the intraocular inflammation is controlled.  
10.3.28 Clinical laboratory tests 
Clinical laboratory safety tests will be performed in a clinical laboratory. Urinalysis may be 
performed by microscope in a clinical lab or using a multistick strip for protein, blood and 
ketones. Urine pregnancy tests may be performed at the site using a licensed test (dipstick). 
For blood assays, microvolumes and micro-assays should be used, whenever possible. In 
principle, general and / or local anesthesia should be used as appropriate for painful and/or 
invasive procedures. 
Timing of sampling should be coordinated as far as possible to avoid repeat procedures and to 
avoid repeat sampling during the day in order to minimize pain and distress, and the risk of 
iatrogenic complications. Sampling should be performed by trained staff. The number of attempts 
for sampling should be limited.  It is recommended that after one unsuccessful attempt, another 
experienced person take over the procedure.  The trial-related blood loss (including any losses in 
the maneuver) should not exceed 3 % of the total blood volume during a period of 4 weeks and 
should not exceed 1% at any single time (50). 
The following clinical laboratory tests will be performed. 
Serum chemistry 
 Calcium 
 Lactate dehydrogenase (LDH) 
 Chloride 
 Creatine Phosphokinase (CPK) 
 Phosphorous 
 Blood urea nitrogen (BUN) 
 Bicarbonate 
 Uric acid
 Potassium 
 Creatinine
 Sodium 
 Total bilirubin 
 Aspartate aminotransferase (AST)
 Glucose
 Alanine aminotransferase (ALT)

Albumin
 Alkaline phosphatase (ALP) 

Total protein
 Gamma glutamic transpeptidase (GGT)

Cholesterol


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Hematology 
 White blood cell (WBC) count with 
differential 
 Hematocrit 
 Red blood cell (RBC) count 

Hemoglobin
 Neutrophils  

Platelet count
 Lymphocytes  
 Monocytes  
 Mean corpuscular hemoglobin 
concentration (MCHC) 
 Eosinophils  

Mean corpuscular volume (MCV)
 Basophils 

Red Cell Distribution Width (RDW)
Urinalysis 
 Color 
 Glucose
 Appearance 
 Ketones
 Specific gravity 
 Blood
 pH 
 Bilirubin
 Protein 
 Microscopy including WBC/high power 
field (HPF), RBC/HPF 
Pregnancy test (females of childbearing potential only) 
 Urine human chorionic gonadotropin (hCG) 
Other safety tests 
 Coagulation parameters: prothrombin time (PT), partial thromboplastin time (PTT), 
fibrinogen 
10.3.29 Flexibility of assessment data capture 
A certain degree of flexibility is required for capturing the data at the various time points 
throughout the study primarily as not all tests can be carried out on the same day to reduce burden 
of the study on the patient and investigator availability and time. In addition if a patient is not well 
enough to undertake a certain test on a given day it may need to be postponed. The following time 
windows for carrying out the tests are shown below. If tests are performed outside of this then a 
protocol deviation form must be completed explaining the reason for the delay in the test or if the 
assessment has not been done. 
 Screening (Day -28) tests may be performed up to 38 days prior to surgery. 
 Baseline (Day -1) tests may be performed up to 7 days prior to surgery. 
 Re-screening new baseline visit may be performed if needed - up to 7 days prior to 
surgery. 
 Weeks 1, 2 and 4 tests may be performed ±3 days of the scheduled visit. 
 Follow-up visits for Weeks 12, 24, 36 and 48 may be performed ±14 days of the scheduled 
visit (Week 36 for Cohort 1-5 only). 


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10.3.30 Surgery video-recording and intra-operative OCT 
In addition to intraoperative photographs, to explore further the treatment effect (safety and 
biological activity) at the bleb level, video of the surgery and/or intra-operative OCT will be 
collected, where the equipment is available, in order to define as precisely as possible to the area 
of the bleb and consequently the zone of cell transduction. 
For the patients already enrolled, if video-recording of the surgery was obtained, the patient will 
be asked to consent to allow the video to be collected and used for analysis. 




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Dispensing will be documented by completing a log with the date of dispensing and the patient 
details. Used and unused vials should be returned to the hospital pharmacy (or in accordance with 
local standard operating procedures) and stored in labeled biohazard bags prior to reconciliation 
by the study monitor. Where local procedures require immediate destruction of used and unused 
vials, the process will be witnessed, signed and documented on a destruction log. 
At each visit, the clinical study monitor will review the drug-dispensing log and reconcile it with 
the unused vials/destruction log. 
11.1.3 Precautions/Overdose 
There is no known method of vector removal from the eye should an error occur during 
SAR422459 administration. 
11.2 
OTHER STUDY SUPPLIES 
Electronic case report forms will be used in this study (see Section 15.2 below). The PI and 
Co-Investigators must keep all study supplies and documentation in a secure place. 


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12 
OBLIGATIONS OF THE INVESTIGATOR REGARDING SAFETY 
REPORTING 
12.1 
ADVERSE EVENT DEFINITION 
An adverse event (AE) is any untoward medical occurrence in a patient that develops or worsens 
in severity during the conduct of a clinical study of a pharmaceutical product and does not 
necessarily have a causal relationship to the investigational product. This can, therefore, be any 
unfavorable and unintended physical sign, symptom, or laboratory parameter that develops or 
worsens in severity during the course of the study, whether or not considered related to the 
investigational product. 
All AEs must be described in the appropriate section of the eCRF and their seriousness and 
putative relationship (causality) to the study medication and/or protocol procedures noted. 
Adverse events are recorded following signature of the informed consent; this is to ensure that any 
adverse events associated with the screening procedures are captured. 
12.2 
RELATIONSHIP OF AN ADVERSE EVENT TO THE INVESTIGATIONAL 
PRODUCT/PROTOCOL PROCEDURE 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. 
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met: 
 An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related). 
 A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident). 
 A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease related event). 
An event not meeting any of the above definitions for “not related” will be considered “related” to 
the investigational product. 
“Associated with the use of the drug” means that there is a reasonable possibility” that the event 
may have been caused by the product under investigation (ie, there are facts, evidence, or 
arguments to suggest possible causation). 


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12.3 
SEVERITY OF AN ADVERSE EVENT 
For each AE, the severity must be recorded as one of the following: 
 Mild: Discomfort noticed but does not interfere with the patient’s daily routines (an 
annoyance). 
 Moderate: Some impairment of function, not hazardous to health (uncomfortable or 
embarrassing). 
 Severe: Significant impairment of function, hazardous to health (incapacitating). 
12.4 
SERIOUS ADVERSE EVENT DEFINITION 
Adverse events are classified as either serious or non-serious. 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, or 
 Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect 
 Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent 1 of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered as a medically important event. The 
list is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence fit, etc.). 


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- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the investigators in oncology studies) 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases) 
- 
Suspected transmission of an infectious agent: if any suspected transmission of an 
infectious agent via a medicinal product (eg, product contamination). 
Elective surgeries 
For the purpose of this protocol, the following conventions will apply for SAE reporting of 
elective surgery: 
 A pre-scheduled elective procedure or a routinely scheduled treatment is not to be 
considered an SAE, even if the subject is hospitalized, provided the site stipulates that: 
- 
The condition requiring the pre-scheduled elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress between the patient’s 
consent to participate in the clinical study and the time of the procedure or treatment 
- 
The pre-scheduled elective procedure or routinely scheduled treatment is the sole 
reason for admission and intervention 
- 
Any untoward medical event occurring during the pre-scheduled elective procedure or 
routinely scheduled treatment should be recorded as an AE or SAE. 
12.5 
ADVERSE EVENTS OF SPECIAL INTEREST 
An adverse event of special interest AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the Investigator to the Sponsor may be appropriate. Such events may 
require further investigation in order to characterize and understand them. Adverse events of 
special interest may be added or removed during a study by protocol amendment. Reporting 
guidelines for AESIs are provided in Section 12.6.2. 


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The following AEs are considered as AESI. This list includes all the AESI defined by Sanofi for 
any program, although these events have not been observed with SAR422459. 
 Acute hypersensitivity/ anaphylaxis 
 Pregnancy of a female subject occurring at any time after treatment with SAR422459.  
Pregnancy occurring in a female partner of a male subject if within 3 months of her male 
partner treatment with SAR422459. 
The pregnancy will be qualified as an SAE only if it fulfills 1 of the seriousness criteria 
(see Section 12.4). 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
 Symptomatic overdose (serious or non-serious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
investigator or spontaneously notified by the patient and defined as at least 30% more 
than the intended dose or if the dose is administered in less than half the recommended 
duration of administration. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
 Increase in alanine transaminase (ALT) (see the “Increase in ALT” flow diagram in 
Appendix C of the protocol). 
 In addition to the aforementioned AESI, the following adverse events are defined as 
project specific AESIs:  
- 
Infection, particularly any opportunistic infection 
- 
Immunological reactions (eg, new incidence or exacerbation of rheumatologic or other 
autoimmune disorder) 
- 
New incidence or exacerbation/recurrence of a hematological disorder 
 Ocular AESIs: 
- 
AEs that cause a decrease in VA of ≥15 ETDRS letters or ≥ +0.3 LogMAR (compared 
with baseline or the VA assessment at the latest visit) lasting >1 week or 2 successive 
visits. 
- 
AEs that require surgical intervention (eg, conventional surgery, vitreous tap or biopsy 
with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to 
prevent permanent loss of sight. 
- 
AEs associated with severe intraocular inflammation (ie, >2 step increase in anterior 
chamber cells and flare or a >2 step increase in Vitreous Haze). 
- 
AEs that, in the opinion of the Investigator, may require medical intervention to 
prevent permanent loss of sight. 


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In the event that a patient enrolled in the study experiences any of the above project specific 
AESIs, blood samples for PCR and/or immunological analysis will be taken to investigate the 
involvement of IMP. 
12.6 
GENERAL GUIDELINES FOR REPORTING ADVERSE EVENTS 
 All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of the study as defined by the protocol for that 
patient, are to be recorded on the corresponding page(s) or screen(s) of the CRF. 
 Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). 
 The investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
Patients who experience an ongoing SAE or an AESI, at the pre-specified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected. The duration of post-study follow-up and reporting of AEs will be until 
recovery. 
 When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
12.6.1 Instructions for reporting serious adverse events (SAE) 
In the case of occurrence of an SAE, the Investigator must immediately: 
 ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the investigator within the e-CRF or after a standard delay. 
 SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
 All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 


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 A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
- 
SEND (within 24 hours, preferably by fax or e-mail) the signed and dated 
corresponding page(s) in the case report form to the representative of the monitoring 
team whose name, fax number, and e-mail address appear on the clinical trial protocol. 
- 
ATTACH the photocopy of all examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the patient’s 
identity is protected and the patient’s identifiers in the clinical trial are properly 
mentioned on any copy of source document provided to the Sponsor. For laboratory 
results, include the laboratory normal ranges. 
- 
All further documentation should be sent to the monitoring team within 24 hours of 
knowledge. In addition, every effort should be made to further document within the 
week (7 days) following initial notification any serious adverse event that is fatal or 
life threatening. 
Any SAE brought to the attention of the investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
12.6.2 Guidelines for reporting adverse events of special interest (AESI) 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 12.6.1, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e CRF. 
Instructions for AE reporting are summarized in Table 4 below. 
Table 4 - Summary of adverse event reporting instructions 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case Report Form completion 
AE 
form 
Safety 
Complementary 
Form 
Other 
specific 
forms 
Adverse Event 
(nonSAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI or 
AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion 
per Section 12.4 
Yes 
Yes 
No 
Adverse Event of 
Special Interest 
Expedited (within 
24 hours) 
Acute hypersensitivity/ anaphylaxis 
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT≥3 ULN (if baseline ALT<ULN) and 
ALT≥2 x baseline (if baseline ALT≥ULN) 
Yes 
Yes 
Yes 
 
 
Infection, particularly any opportunistic 
infection 
Yes 
Yes 
No  


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Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case Report Form completion 
AE 
form 
Safety 
Complementary 
Form 
Other 
specific 
forms 
 
 
 
 
 
 
 
 
Immunological reactions (eg, new 
incidence or exacerbation of 
rheumatologic or other autoimmune 
disorder) 
Yes 
Yes 
No  
 
 
New incidence or 
exacerbation/recurrence of a 
hematological disorder 
Yes 
Yes 
No  
 
 
Ocular AESI 
Yes 
Yes 
No 
12.6.3 Guidelines for management of specific laboratory abnormalities 
As for any study protocol conducted by Sanofi with any investigational medicinal products, 
decision trees for the management of certain laboratory abnormalities are provided in  
Appendix C. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices: 
 Neutropenia 
 Thrombocytopenia 
 Acute renal insufficiency 
 Suspicion of rhabdomyolysis 
12.7 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
 All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IECs/IRBs as appropriate and to the investigators. 
 All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected [please refer to the IB]. 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 


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12.8 
PATIENT WITHDRAWALS FROM THE STUDY 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. If 
possible, the patients should be assessed using the Week 48 procedures defined above. Patients 
who withdraw should be explicitly asked about the contribution of possible AEs to their decision 
to withdraw consent, and any AE information elicited should be documented. Preferably the 
patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
If an AE leads to patient withdrawal, the patient will be followed up until the AE is resolved. All 
efforts will be made to encourage the patient to continue in the study and the long-term follow-up.  
Withdrawal from the study and reason for withdrawal must be documented in the eCRF. 


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13 
DATA SAFETY MONITORING BOARD 
13.1 
ROLE 
An independent Data Safety Monitoring Board (DSMB) will be formed to undertake an ongoing 
review of the data from the study, the primary role of the DSMB is to ensure the protection and 
safety of patients participating in the study. The DSMB will review the general progress and 
conduct of the study and assist in resolving any issues that may arise. The composition and 
responsibilities, together with the agreed schedule for reviewing data will be detailed in a 
guidance document (DSMB Charter), approved and signed by all members of the committee. The 
members of this committee will include appropriately qualified medical and if needed statistical 
personnel. 
13.2 
RESPONSIBILITIES 
 Monitor and review safety data of patients participating in the study and advise on study 
termination as appropriate 
 Recommend whether to dose escalate after the patients in each cohort have been dosed 
 Recommend the termination of the study if unforeseen safety issues occur which alter the 
risk assessment of the study 
 Provide advice on any other matters as deemed necessary for the safe conduct of the study 
Detailed responsibilities of the DSMB are provided in the DSMB charter. 


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14 
DEVELOPMENT SAFETY UPDATE REPORTS 
The Sponsor will make provision for a harmonized International Birth date for SAR422459; this 
will serve as a data lock point from which all development safety update reports will be generated. 
This will be the date of the first regulatory authority protocol approval. 


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15 
DATA MANAGEMENT AND STATISTICAL ANALYSES 
15.1 
SAMPLE SIZE ESTIMATES 
This is an exploratory study the primary objective of which is to evaluate safety and, as a 
secondary objective, to estimate the biological activity. No formal sample size calculation has 
been performed. 
15.2 
STATISTICAL ANALYSES 
Due to the small number of patients to be enrolled in this study the data will be analyzed by 
descriptive statistics and exploratory figures. A statistical analysis plan will be finalized prior to 
database lock. It is envisaged that analyses will be performed on all available data. However, it 
may be necessary for specific data points to be excluded if not considered reliable. 
Baseline values will be defined as the last available values collected at study visits (eg, Day -28 or 
Day -1) preceding the date of study treatment. 
15.3 
SAFETY ENDPOINTS 
15.3.1 Adverse events 
The number and percentage of patients with treatment emergent adverse events (ie, started or 
increased in severity after the patient received study treatment and includes abnormal lab results, 
ECGs etc.) will be summarized. The adverse events recorded prior to SAR422459 administration 
will not be summarized and will be separated from the adverse events that are recorded post 
SAR422459 administration in the final listings. 
An overall summary will include the number and percentage of patients with: 
 A fatal AE (death). 
 At least 1 serious AE. 
 At least 1 severe AE. 
 At least 1 related AE. 
 Without any AEs. 
An additional table will show the number and percentage of patients with treatment emergent 
adverse events broken down by System Organ Class, High Level Term and Preferred Term. 
Related AEs will be summarized separately. 


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15.3.2 Ophthalmological safety endpoints 
Changes in other safety endpoints will be summarized at each visit; in addition, where 
appropriate, individual profile plots and mean plot of changes in the variable against time will be 
presented. The primary end points will be considered the 48 week (12-month) visit; the individual 
change at this end point will be plotted against dose received. 
15.3.3 Secondary endpoints 
Secondary endpoints will be summarized at each visit; in addition, where appropriate, individual 
profile plots and mean plot of changes in the variable against time will be presented. The 
secondary end points will be considered the 24 week (6-month) and 48 week (12-month) visit; the 
individual change at this end point will be plotted against dose received. 
15.3.4 Immunology endpoint 
The number and percentage of patients with antibody response to SAR422459 administration at 
all time points will be tabulated. 
15.3.5 Laboratory parameters 
Hematology, biochemistry and other laboratory data will be listed at each time point by treatment 
group and, for appropriate values, will be flagged as ‘High’ or ‘Low’ if outside the laboratory 
normal range. Shift tables for key laboratory parameters out of normal range will be presented for 
the assessed visits. 
An additional listing will be provided for those patients who have laboratory values that are 
abnormal and considered to be clinically significant. Laboratory values that become abnormal will 
also be recorded as an adverse event. 
15.3.6 Other safety parameters 
All other safety parameters (vital signs, physical examination, ECG) will be listed by patient, 
treatment assignment, and cohort. New abnormalities will be recorded and summarized under 
adverse events. 
15.3.7 Concomitant medication 
Concomitant medication will be listed by patient, cohort, and study visit. 
15.4 
BIODISTRIBUTION ENDPOINT 
The number and percentage of patients with SAR422459 detected in the blood and urine by 
polymerase chain reaction (PCR) at all time points will be tabulated. 


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15.5 
OTHER MEASURES 
15.5.1 Patient characteristics 
Patient demographic (height, weight, sex, reproductive status) data will be summarized by cohort. 
The number of patients meeting each inclusion/exclusion criteria will be tabulated. Medical 
history, treatment history, chest x-ray and anesthesia assessment will be listed. 
15.5.2 Withdrawals 
The number (%) of patients who withdraw from the study over time, along with their reasons for 
withdrawal, will be tabulated.  
15.5.3 Deaths 
All deaths occurring during the study and its follow-up period will be listed and included in the 
adverse events summary. 
15.6 
ELECTRONIC CASE REPORT FORMS AND DATA COLLECTION 
Data must be transcribed from the patient’s notes and entered onto the eCRF completely, legibly 
and in a timely fashion by the PI or his designees. He will also verify that all the data contained on 
these forms are accurate and will sign the forms once they are completed. 
Copies of anonymized supporting documentation such as ECG recordings, X-rays etc. necessary 
to support regulatory submissions and reports will be provided to and will remain the property of 
the Sponsor and must be available for review and retrieval by the Sponsor or Contract Research 
Organization (CRO) staff at any time. The Investigators are requested to enter data promptly onto 
eCRFs in order to facilitate review, monitoring, and correction of eCRFs in a timely fashion. 
Any subsequent alterations to the data must be made by striking out the previous entry with a 
single line and by writing the new value next to it. All such change must be initialed and dated by 
the PI (or his designee). Whiting or scribbling out of errors is not acceptable. 
When the monitor reviews the eCRFs, certain queries may arise. These will be tracked and 
documented in the eCRF along with the resolution. 
15.7 
DOUBLE-BLINDED CODES 
Double-blind codes are not required as only one treatment is administered in all patients.  


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15.8 
INTERIM ANALYSIS  
No formal interim analysis is planned.  
An independent DSMB will: 
 Monitor and review safety data of patients participating in the study and advise on study 
termination as appropriate 
 Recommend whether to dose escalate after the patients in each cohort have been dosed 
 Recommend the termination of the study if unforeseen safety issues occur which alter the 
risk assessment of the study 
 Provide advice on any other matters as deemed necessary for the safe conduct of the study 
At a minimum the following individual data and mean data will be plotted against time following 
surgery:   
 Adverse events and concomitant medications will be listed 
 Laboratory results 
 Humoral antibody response and vector distribution data 
 BCVA 
 IOP 
 Slit lamp examination and fundoscopy data 
Furthermore for Cohorts 6-9, a review of the data by the sponsor and the investigators will be 
regularly planned (every 6 months) in order to ensure to capture any signal of biological activity. 
Following these meetings, discussion with health authorities could be requested. 


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16 
ETHICAL CONSIDERATIONS 
16.1 
PATIENT INFORMATION LEAFLETS AND INFORMED CONSENT FORMS 
All patients invited to participate in a clinical study are entitled to make their decision based on 
the maximum amount of information available at the time. In order to make the choice, they will 
be given a written document written in clear concise lay language in their native tongue to read. 
The document will previously have been approved by the relevant ethics committee (EC) or 
institutional review board (IRB) and may be updated as new important information becomes 
available that may affect a patient’s willingness to participate or continue in the study. 
This document will inform potential patients about the nature of the indication and the drug, its 
efficacy and safety profile in animals and man, the human experience to date and the route of 
administration. It will also outline the numbers of patients in the study and the steps of the 
protocol as they will apply to the individual, including number of visits, venipunctures and other 
invasive procedures and types of measurements to be performed so that the individual has a clear 
understanding of the risks, inconveniences and benefits that may accrue from the study. 
Participants (both male and female) must understand the need for reliable contraception if 
appropriate. 
The individual must be made aware that he/she may refuse to join the study or may withdraw at 
any time without prejudicing further medical care which is covered by the Sponsor clinical trial 
insurance in the event of a mishap. A contact with whom suspected trial related injuries may be 
discussed will also be detailed. Individuals must also know that their personal hospital records 
may be reviewed in confidence by the Sponsor (or CRO) staff and by Regulatory Authorities from 
time to time and that personal information about them will be held on a confidential database. 
Conditions for ensuring the security and confidentiality of the database should be explained. 
Consent must be recorded in writing after the patient has had adequate time to reflect on the 
information and to ask further questions if need be. The consent form must be signed and dated by 
the patient (and/or by the patient’s legally acceptable representative, if necessary) and then 
countersigned by the Investigator or delegate. A copy of the signed consent form may need to be 
presented to each of the various hospital departments participating in the study.  
Local regulations need to be followed to ensure compliant consent procedure by 
patients/parents/legal guardians as applicable, re-consent, if needed with the change of age and 
necessary archiving of relevant documents.  


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16.2 
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD REVIEW 
Prior approval must also be obtained by the relevant IRB of the local hospital. The EC/IRB will 
conform to the standards of ICH E6, EU Directives 2001/20/EC and 2005/28/EC or the Code of 
Federal Regulations, specifically 21 CFR Part 56. The EC/IRB will be provided with copies of the 
protocol, any amendments, patient information and consent forms for review. EC/IRB approval 
must always be recorded in writing. The approval documents should clearly identify the protocol 
by title and an EC/IRB identifying number, identify the committee members present when the 
approval was granted and list any required amendments with the reasons for them. If a protocol is 
refused approval, the reasons will be given in writing. Amendments and refusals will be notified 
to all other committees considering the study and refusals will be notified to relevant Regulatory 
Authorities. The EC/IRB will review ongoing studies at appropriate intervals.  
The study will not begin and study supplies will not be shipped to the site until written approval is 
received by the Sponsor. The EC/IRB will also provide a list of its members, their affiliations and 
its written procedures if requested by the Sponsor as part of the pre study documentation. The 
EC/IRB must keep records of all its procedures and decisions for at least 3 years after completion 
of the study and make them available on request to representatives of regulatory authorities. 


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17 
REGULATORY REQUIREMENTS AND SPONSOR/INVESTIGATOR 
OBLIGATIONS 
This study will be conducted in accordance with the GCP Guidelines as issued by the 
International Conference for Harmonisation (ICH 135/95, 1996), the Declaration of Helsinki the 
Code of Federal Regulations Title 21 (see Appendix B), EU Directives 2001/20/EC and 
2005/28/EC. These documents will be provided in the site study file. To ensure compliance with 
the guidelines, the study will be audited by third parties including independent auditors and 
possibly Regulatory Authorities. The Investigators agree, by written consent to this protocol, to 
co-operate fully with compliance checks by allowing access to all documentation by authorized 
individuals. 
The study may not begin and clinical study supplies will not be shipped until the Sponsor receives 
relevant regulatory and ethics written approvals. 
17.1 
STUDY INITIATION 
It is essential that all personnel concerned with the study understand their duties and 
responsibilities fully. In order to facilitate this process, site initiation visits will be conducted by 
the Sponsor or designee prior to first patient recruitment and after EC/IRB has been obtained. It is 
expected that all personnel involved will attend this meeting and will familiarize themselves with 
the protocol, the eCRF and the principles of GCP which will be implemented during the study. 
17.2 
MONITORING 
The purposes of clinical study monitoring are to verify that the rights and wellbeing of patients are 
protected, that reported study data are accurate, complete and verifiable from source documents 
and that the conduct of the study is in accordance with current GCP and regulatory requirements. 
In order to assist with the collection in a timely fashion of accurate, verified data which are in 
accordance with the protocol, monitors will visit the study sites regularly. They will audit source 
documents and compare them with data contained in the eCRF. If inconsistencies occur, these 
queries will be answered by the investigator. The monitors will also check patient accrual, drug 
dispensing logs, lists of persons to whom clinical study related activities have been delegated, 
relevant communications with family physicians, fridges and other equipment where necessary. 
They will also visit associated laboratories to ensure their continuing compliance with the 
protocol and with GCP and deal with any problems arising in the course of the study. The 
investigator and others involved in the study must make adequate time available to be present at 
these visits. 


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17.3 
DOCUMENTATION AND RECORD KEEPING 
Essential records must be retained by the study site for at least 5 years after the last approval in an 
ICH region and until there are no pending or contemplated marketing applications in an ICH 
region OR at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
No records may be destroyed or moved without the Sponsor written permission. The Sponsor will 
archive and retain all documents pertaining to the study for the lifetime of the product under 
investigation and final study reports will be kept for a further 5 years. 
17.4 
CLINICAL STUDY REPORT 
This clinical study will be summarized by the Sponsor (or designated CRO) and a final audited 
report must be retained on file. This report will include discussions of the study objectives, 
methodology, findings, and conclusions. The PI will be asked to review and comment on the draft 
report and will be required to sign the final version. In a multi-center study, other investigators 
will be provided with a copy of the final report for their information. This report must be archived 
with all other study related documents. 
17.5 
TERMINATION OF THE STUDY 
The study may be terminated at any time at the request of regulatory agencies, the EC/IRB or the 
PI. The study may be terminated at any time by the Sponsor on the basis of any safety concern, 
inadequate enrolment or developments in a related study or program which would challenge the 
clinical and ethical justification for continued enrolment. 
The study may be terminated prematurely by the investigator by giving 30 days written notice. 
The Sponsor retains the right to terminate the study immediately upon written notice. If a clinical 
study is terminated early for whatever reason, the investigator will return all samples, supplies, 
and CRFs to the Sponsor and will notify the EC/IRB. Whichever party terminates the study will 
provide a written statement as to the reason for the termination. The Sponsor (or CRO) will notify 
Regulatory Authorities as appropriate of premature terminations. 
At the end of a clinical study, investigators must return to the Sponsor (or CRO) all unused 
clinical trial supplies and loaned equipment unless other arrangements have been made. 
Study completion is defined as the date when the final patient has completed their final visit for 
the study. 
In the event that enrollment is terminated, all patients who have been dosed with SAR422459 will 
continue to be followed up as per protocol until the Week 48 visit has been completed.  Patients 
will be encouraged to enroll in a long-term follow-up study.  Long-term follow-up in gene transfer 
research allows for the collection of important information on the long-term safety and effects of 
the study treatment. The long-term follow-up study (LTS13588) will last for up to 15 years.    


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17.6 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
REQUIREMENTS 
The Sponsor will purchase and maintain no fault compensation for clinical trial insurance 
sufficient to meet local regulatory requirements. In the event of a proven investigational product-
induced injury, proof of guilt or negligence will not be required. Settlements will be decided by 
arbitration and the decision of the arbitrator will be final. 
17.7 
PUBLICATION AND COMMUNICATION 
The Sponsor actively encourages publication of clinical trial data in reputable peer reviewed 
journals. Authorship will be discussed and agreed in advance. 
In this context, no submission for publication and/or written and/or oral disclosure regarding the 
results of the Study shall be made by the Investigator without prior written consent of the 
Sponsor. Therefore, the Investigator agrees to: 
 Submit the draft of any proposed publication and communication to the Sponsor at least 
sixty (60) days prior to submission for publication communication. 
 Submit the draft of any proposed abstract to the Sponsor at least thirty (30) days prior to 
submission for publication. 
As the Study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, first presentation (including any oral presentation) or publication of the 
results of the Study shall be made only as part of a publication of the results obtained by all sites 
performing the Protocol. 
17.8 
PROTOCOL AMENDMENTS 
All items in this protocol must be followed exactly. If any deviations occur, they must be 
documented and explained. If an amendment is required, this will be enacted through a formal 
documented protocol amendment procedure and must receive approval from all the authorities 
who approved the original protocol. The approved amendment will be distributed to all protocol 
recipients with instructions to append them to the protocol (or a revised protocol will be issued). 


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18 
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19 
APPENDICES 


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Appendix A 
Ocular inflammation grading 
Slit lamp examination will be performed throughout the study to monitor for ocular inflammation. 
In addition, BCVA, other clinical examination and the results of other investigations such as FA 
may also assist in the evaluation. 
The objective assessment of inflammation will comprise separate assessment of the anterior 
segment, vitreous and fundus. Active inflammation only will be assessed and any signs of 
previous inflammation (eg, premacular fibrosis, healed old choroidoretinal scars will not be 
included in the evaluation of the severity score.) 
Prelimbal injection will be noted as present or absent, no attempt will be made to assign a severity 
score. Anterior chamber findings will be graded according to cell numbers and the intensity of 
flare using the widest slit beam and luminescence of the slit lamp. (Pigmented cells and red blood 
cells will not be counted). See Table 1. 
Table 1 - Slit Lamp Examination Grading of Anterior Chamber Cells and Flare 
Grade 
Cells/field (Field size is 1 mm x 1 mm) 
0 
≤1 cells/field 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
Grade 
Description of flare 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens detail clear) 
3+ 
Marked (iris and lens detail hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
(The standardization of uveitis nomenclature [SUN] working group. J Ophthalmol 2005;140:509-516) 
Vitreous haze, if present is the most reliable sign of intraocular inflammation and the main 
indicator of response to treatment. Vitreous haze is can be determined using fundoscopy (indirect 
ophthalmoscopy). The scoring system is given in Table 2 but it is important to note that the 
grading system is subjective only and media, corneal or lens opacities may significantly influence 
the score. 


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Table 2 - Grading of Vitreous Haze 
Grade 
Description 
Clinical findings 
0 
nil 
none 
1 
minimal 
posterior pole clearly visible 
2 
mild 
posterior pole detail slightly hazy 
3 
moderate 
posterior pole detail very hazy 
4 
marked 
posterior pole detail barely visible 
5 
severe 
fundal detail not visible 
(Neussenblatt RB, Palestine AG, Chan CC et al. Standardisation of vitreal inflammatory activity in intermediate and posterior 
uveitis. Ophthalmol 1985; 92:467-471 
Inflammation will be assessed by slit lamp examination and fundoscopy at all study visits. The 
inflammation grading data will be reported and monitored by the DSMB. 


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Appendix B 
World Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A) INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. The Declaration is intended to be read as 
a whole and each of its constituent paragraphs should not be applied without consideration 
of all other relevant paragraphs.  
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other 
participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health 
of my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act in the patient's best interest when providing medical 
care." 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 


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7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human subjects 
and protect their health and rights. Some research populations are particularly vulnerable 
and need special protection. These include those who cannot give or refuse consent for 
themselves and those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
A) BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must not 
be allowed to reduce or eliminate any of the protections for research subjects set forth in 
this Declaration. The committee must have the right to monitor ongoing studies. The 
researcher must provide monitoring information to the committee, especially information 
about any serious adverse events. No change to the protocol may be made without 
consideration and approval by the committee. 


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16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are found 
to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well as 
to the methods used to deliver the information. After ensuring that the potential subject has 
understood the information, the physician or another appropriately qualified individual 
must then seek the potential subject's freely-given informed consent, preferably in writing. 
If the consent cannot be expressed in writing, the non-written consent must be formally 
documented and witnessed. 


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25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to 
promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorized representative. The potential subject's dissent should 
be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy of 
their reports. They should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results should be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the principles of 
this Declaration should not be accepted for publication. 


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C) ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: 
- 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
- 
Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available. 
22.10.2008 


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Appendix C 
General guidance for the follow-up of laboratory abnormalities by 
Sanofi 
This General Guidance is provided by Sanofi as a help to ensure the appropriate documentation of 
the following laboratory abnormalities if they are observed during the course of the study. It does 
not infer that these abnormalities have been observed or could be observed using SAR422459. 












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Appendix D 
Low-Contrast Sloan Letter Chart Testing 
The following are instructions for testing patients using the front illuminated Low-Contrast Sloan 
Letter Charts (LCSLC; Precision Vision, LaSalle, IL). A standardized script with instructions to 
be read to the patient by the examiner is included below. The examiner should read through the 
following instructions and practice testing prior to examining study patients. 
Preparation and Set-Up: 
1. Set room lighting level to 80-100 cd/m2 (equivalent is about 80-100 foot-candles). 
2. This level illumination may be achieved in a bright exam room/hallway with fluorescent 
lighting. Having exact lighting is less important than using the same room/area for each 
patient/testing session. 
3. Place the charts at 2 meters distance from the patient’s eyes. An artist’s easel or similar 
device may be used, or use a ledge, stand, or chair to prop the charts perpendicular to the 
floor. Use a pre-measured string or tape to measure the distance from the patient’s eyes 
(bridge of nose) to the testing charts at the beginning of each testing session (each patient). 
4. The 100%, 2.5%, and 1.25% contrast level charts will be used for testing. 
5. Patients should wear their usual distance correction for testing (glasses or contact lenses 
that are used for driving, etc.). The same glasses or contact lenses (same prescription) 
should be used for each testing session throughout the study. 
6. Patients should be asked to read the charts with each eye independently. The eye that is 
not being tested should be covered with an opaque device. 
Vision Testing 
1. Instruct patient to read slowly, letters only, left to right, starting at the top of the chart. 
2. Instruct the patient that they are not allowed to re-read any line. 
3. The patient is allowed to correct a “mis-speak” of a single letter only if he/she does so 
before reading the next letter---instruct the patient of this. 
4. During the chart reading, PUSH (encourage) the patient until he/she cannot read any 
letters after being told to guess. 
5. The patient must guess at each letter, even if he/she cannot easily read it, until he/she 
cannot or does not correctly identify any of the 5 letters on a particular line. 
6. Stopping Rule: Once the patient cannot or does not correctly identify any of the 5 letters 
on a line after attempting it, STOP. Go on to the next chart. 
7. Test all 3 charts in the same order (100%, 2.5%, 1.25%) for each patient. 
8. Scoring the test: During testing, circle all letters read correctly on the data forms for each 
chart for each eye. Put an “X” through each incorrectly identified letter; leave unattempted 
letters unmarked. 
9. Fill in the number of letters correct at the end of each line of 5 letters. Record the total 
number of letters correct for each chart at the bottom of the column. 


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10. If a patient is unable to identify any of the letters correctly on the first line of any of the 3 
charts, please indicate this at the top of the data collection form.  
Script For Testing to be Read to Patient: 
These instructions should be read to the patient once he/she is comfortably seated in front of the 
charts at 2 meters distance (see above for instructions on Preparation and Set-Up): 
1. I am going to show you 3 different eye charts with letters on them. The letters will become 
increasingly lighter for each chart. 
2. For each chart, please begin at the very top of the chart and read each letter slowly, from 
left to right on each line. 
3. If you mis-speak on a letter or feel you have identified it incorrectly, you may correct your 
response only before you read the next letter. 
4. You are not allowed to re-read an entire line. 
5. Please try not to lean forward in the chair while reading the letters. 
After the first chart (100% chart) has been uncovered, say: 
1. You may begin reading the letters. 
2. Please start at the top of the chart. 
For each chart, allow the patient to continue reading letters until he/she either: 
1. Does not identify any of the 5 letters on any given line correctly - say: 
You may stop. We will go on to the next chart now. 
OR 
2. States that they are unable to read any more letters - point to the line which is next for the 
patient to attempt (use the yellow-tipped pointer only) and say: 
Can you read any of the letters on this line? 
a) If patient responds no - say: Please guess if you can. 
If patient responds that they cannot - say: 
You may stop. We will go on to the next chart now. 
b) If patient responds yes or begins reading, then continue to record responses until the 
patient cannot or does not correctly identify any of the 5 letters on a given line. 
Stopping Rule: For each chart, once the patient cannot or does not identify any of the 5 letters 
correctly on a given line, say: You may stop. We will go on to the next chart now. 


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Please use the yellow-tipped pointer only to point to the charts (pens and fingers may leave 
marks). The examiner may point to the chart when requested by the patient to indicate the line that 
they are attempting/should attempt next. 
Repeat the above procedure for each of the 3 charts (100%, 2.5%, and 1.25% in that order) with 
each eye independently. 


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Appendix E 
Radner Reading Charts 
The "Radner Reading Charts" have been developed on the basis of the concept of "sentence 
optotypes" for the standardized examination of reading acuity and reading speed. Print sizes are 
logarithmically scaled (logRAD) to permit statistical analysis, and the results obtained can be 
compared to other logarithmically scaled vision systems (eg, logMAR). 
To guarantee accurate, reproducible and standardized measurements of reading acuity and reading 
speed at every viewing distance, "sentence optotypes" have been created to minimize the 
variations between the test items and to keep the geometric proportions as constant as possible at 
all distances. Through interdisciplinary cooperation, a series of test sentences were developed that 
are highly comparable in terms of the number of words (14 words), as well as the word length, 
number of syllables, position of words, lexical difficulty and syntactical complexity. The most 
similar sentences were statistically selected for the Radner Reading Charts. All testing parameters 
have been standardized in compliance with EN ISO 8596 and the recommendations of the 
Committee on Vision of the National Academy of Sciences-National Research Council. 
Illumination: 80 - 120 cd/m2 
Testing Procedure: 
B) The reading chart is held by the patient; the sentences are covered with a piece of paper. 
C) The patient is instructed to uncover the chart sentence by sentence and to read only one 
sentence per measurement. 
D) "Please read the sentences aloud as quickly and accurately as possible. Read each sentence 
to the end, and do not correct reading errors." 
E) "Please uncover the first sentence and start reading." Start the measurement with the 
stopwatch when the patient starts reading and measure the reading time until the end of the 
sentence. 
F) Write the reading time on the scoring sheet, and record any reading errors on the sheet. 
G) Stop criterion: reading time longer than 20 seconds or severe errors. 
 
Reading Speed: 
Reading speed in words per minute (w/min) is either calculated on the basis of the number of 
words in a sentence (=14) and the time (t=seconds) needed to read the sentence. For research or 
clinical analysis, reading speed can be characterized by 2 parameters: (a) the maximum reading 
speed, and (b) the mean reading speed. 
Reading Speed (w/min): 14/t(s) x 60 = 840/t(s).   


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Appendix F 
Protocol amendment history 
Protocol Amendment 11 
Please see the protocol amendment 11 attached with details on the rationale and updated changes. 
REASON FOR AMENDMENT: 
1. Additional Cohort 7 is added to allow a separate analysis of patients 6-17 years of age with 
visual acuity ≥20/100. Population of such age and vision is a rapidly deteriorating 
population in Stargardt’s macular degeneration natural history - population, who 
potentially could benefit most from the SAR422459 treatment, so analyzing as separate 
cohort to evaluate safety and any signals of efficacy is of interest. Total number of planned 
patients is not changed for the study (ref.: Brun-Strang, ARVO 2017). 
2. Inclusion Criterion of the rapid deterioration was reviewed to better define the period of 
reference assessments and to avoid misinterpretations.  
3. Statistical section has a reworded baseline description to use the same for treatment-
emergent safety and any efficacy signal assessments, also – additional detail for laboratory 
test analysis. 
Some other minor corrections, clarifications and typos have been performed. 
 The Medical Monitor has been changed. 
 Definition of severity for AEs has been updated to be consistent with the other Sanofi 
ophthalmologic gene therapy studies. 
 AESI section, including pregnancy criterion, has been updated to match Sanofi standards 
and eliminate inconsistencies. List of relevant Ocular AESIs has been added. 
 It is clarified that in the absence of or due to the dysfunction of the Electronic Visual 
Acuity (EVA) for the assessment of visual acuity that the Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart will also be accepted as an alternative assessment tool 
for visual acuity. 
 Radner reading chart instructions have been added as appendix E. 
 Rescreening possibility is described.  
 Some inconsistencies have been corrected. 


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Protocol Amendment 10 
Please see the protocol amendment 10 attached with details on the rationale and updated changes. 
REASON FOR AMENDMENT: 
Justification for the change to the protocol defined anti-inflammatory regimen: 
Consequent to the occurrence of 2 cases of severe uveitis reported as serious adverse events 
following administration of the lentiviral vector, the Data Safety Monitoring Board (DSMB), also 
in agreement with the study investigators, have recommended that the protocol defined 
anti-inflammatory regimen be modified to include treatment with systemic corticosteroids 
following the subretinal injection procedure in an effort to reduce the likelihood of additional 
serious adverse events as a result of post-operative ocular inflammation. 
Justification for the new study inclusion criteria: 
The following inclusion criteria was added based on the recommendation of the Netherlands Gene 
Therapy Office after review of the sponsors application to conduct clinical research involving 
gene therapeutics in the Netherlands: “Patients must agree to not donate blood, organs, tissues or 
cells for at least 3 months following SAR422459 administration”. 
Other changes: 
Other administrative changes have been made to correct inconsistencies and grammatical errors 
and to clarify, reinforce or highlight the importance of specific protocol sections to aide study site 
personnel in the proper conduct of the trial.   
The back-up plan in using a paper CRF process is revised and completed to more clearly define 
the process with details. 
 
Protocol Amendment 9 
Please see the protocol amendment 9 attached with details on the rationale and updated changes. 
The major changes are described below: 
Change to the Inclusion/Exclusion Criteria 
In sections:  Section 1; Section 4.11; Section 7; and Section 8.1.5.  
Rationale: 
Changes to the specific inclusion criteria for Cohort 6 are made following recommendations from 
health authorities (the FDA and ANSM) to make the enrollment for the pediatric population more 
homogeneous by incorporating into the inclusion criteria the parameters for rapid progression 
suggested by a panel of experts.   


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The first inclusion bullet point has been revised to more clearly define that we are now only 
targeting children and young adults with childhood onset disease. 
An additional parameter for progression (reduction in hill of vision by > 14 dB-sr as assessed by 
static perimetry) has been added based on recent data obtained from review of prior cohorts by the 
reading center. 
The statement requiring investigators to document the criteria used to identify patients at risk for 
progress has been removed as the criteria are now necessary for inclusion and they must be 
documented in the CRF. 
Change to the Study Design for pediatric patients enrolled in Cohort 6 
In sections:  Section 1; Section 4.10; and Section 7. 
Rationale: 
In response to a recommendation from ANSM, a 28 day observation period will be imposed 
between the first and second pediatric patients enrolled in Cohort 6 in order to assess the safety 
and tolerability of SAR422459 in the pediatric population.  Thereafter, subsequent pediatric 
patients may be consecutively included. 
Change in the perioperative medication regimen 
In sections: Section 9.2.2; Section 9.3.26. 
Rationale: 
Per DSMB recommendation, a high dose, tapering course of oral systemic steroids must be given 
early in subjects in whom there is evidence of more intraocular inflammation than expected 
following a vitreoretinal procedure, and prophylactically in cases which are complicated by a 
retinal tear or spillage of vector into the vitreous.  This recommendation was made following 
DSMB assessment of a single reported serious adverse event of granulomatous uveitis that 
occurred after a patient’s subretinal injection procedure which was complicated by a retinal tear.   
Other corrections 
In sections:  Section 2; Section 6.3; Section 9.3.3; Section 9.3.6; Section 9.3.7; Section 9.3.8; and 
Section 9.3.27. 
Rationale: 
Some inconsistencies between the study schedule and the main text have been corrected. In fact 
the study schedule has been modified during the previous amendments and some of the 
corrections had not been taken into account in the main text. 
 


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Protocol Amendment 8 
Please see the protocol amendment 8 attached with details on the rationale and updated changes. 
The major changes are described below: 
 Every occurrence of StarGen™ shall be replaced in the amended  protocol by SAR422459 
In section(s): Throughout the protocol. 
Rationale: 
In the original title of Study TDU13583, SAR422459 is referred to as StarGen™ which represents 
the first nomenclature of this investigational product (IMP). Of note, SAR422459 was initially 
developed by Oxford BioMedica Ltd. (United Kingdom) and the sponsorship was subsequently 
transferred to sanofi-aventis Research and Development (Sanofi) on 12 June 2014. Sanofi is now 
the sole holder of the Investigational New Drug (IND)/Clinical Trial Application (CTA). 
Therefore, as of 30 June 2015, the Oxford BioMedica trademark name for the SD product 
(StarGen) has been cancelled and will not be used hereafter.    
Change to the Inclusion/Exclusion Criteria 
In section(s): Section 1 - Synopsis, Section 4.11 – Rationale for Target Patient Population, Section 
7 – Study Design, Section 8 – Study Population, Section 8.1.1 – Main Inclusion Criteria, Section 
8.1.5 – Specific Inclusion Criteria Patient Group D 
Rationale: 
Stargardt disease is a rare, inherited juvenile macular degeneration primarily affecting children 
and young adults that results in blindness from central vision loss. Currently there is no effective 
treatment for patients with Stargardt disease.  SAR422459 is a gene therapy product in clinical 
development as a treatment for Stargardt disease to replace the defective ABCA4 gene in the 
photoreceptors of affected patients.  With the approval of the protocol amendment 6 (dated 
12th November 2014) for the ongoing TDU13583 study, the study protocol was changed to allow 
enrollment of an additional cohort of patients (Cohort 6/Group D) with a less advanced stage of 
disease, including children (≥6 years of age) to provide an opportunity to evaluate the safety of 
SAR422459 in a population in which the biological activity of the treatment is also more likely to 
be observed due to the expected rapid progression of the disease course.  Within the protocol 
amendment 6 the requirements to be completed prior to the inclusion of pediatric patients were 
detailed:  "Prior to the inclusion of pediatric patients, the DSMB will review all safety data 
including the available data from all cohorts after the last patient of Cohort 5 has completed 
12 weeks of follow-up after having been dosed. An interim report including all available safety 
data, preliminary efficacy data and the recommendations from the DSMB will be submitted to the 
regulatory authorities and institutional review boards/ethics committees for approval before 
enrolling pediatric patients (<18 years)".  Following the DSMB review of all safety and biological 
activity data including the available data from all cohorts after the last patient from Cohort 5 had 


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completed 12 weeks and the benefit-risk profile for SAR422459, the DSMB recommendation is to 
proceed with the recruitment of children in Cohort 6.  
All of the elements fulfilling the predefined requirements for the enrollment of pediatric patients 
in the ongoing TDU13583 study are now being provided to health authorities and IRBs/HA as an 
accompaniment to the submission of this protocol amendment.   
The rationale for the major changes to the current protocol proposed in this amendment is to make 
the requisite changes to enable the recruitment of children with Stargardt disease in Cohort 6.  
Additional rationale for other major changes to the protocol following discussions with 
investigators and experts includes: 
 Clearer definition of the target patient population to be included in Cohort 6 as well as 
refining the practical guidance to investigators regarding the parameters for determining 
evidence of ongoing rapid disease progression and predicting risk of rapid deterioration. 
 Patients in Cohort 6 will be enrolled consecutively.  As patients with Stargardt disease are 
rare and the targeted patients for Cohort 6 are expected to be rapidly deteriorating, 
imposing a fixed interval between the enrollment of patients could create a situation where 
if more than 1 patient meeting the recruitment criteria would be identified within a narrow 
time window, the subsequent patient(s) could progress and no longer be eligible for the 
trial until after the required interval had expired.  As the safety of SAR422459 highest 
dose has been defined in the previous cohorts and efforts have been established to 
minimize the risks for the subretinal injection procedure in children, the is no longer a 
strong safety rationale to impose a delay between the enrollment of successive patients in 
the protocol particularly as this may compromise the study enrollment.  However, it is 
anticipated based on the slow enrollment projections for the study that an interval of 
21 days or more could reasonably occur between the recruitment of successive patients. 
 Clarification regarding availability and use of prior genotyping results: Note, gene 
mutation analysis could have occurred prior to signing the informed consent and it may be 
used provided that the analysis was conducted by a certified laboratory, written results are 
provided to the site, and participants (patients and/or the patient’s parent[s]/legal 
guardian[s]) give consent to utilize the results. 
 Based on the Ethical Considerations for Clinical Trials on Medicinal Products with the 
Pediatric Population, we have streamlined the routine blood draws to minimize blood loss 
as well as reduce the burden affording the best possible protection for the children. 
Perioperative medication regimen 
In section(s): Section 9.2.2 – Subretinal Injection Procedure, Section 9.3.26 – Post-Surgical 
Ophthalmological Adverse Events 
Rationale: 
Following DSMB recommendations, and consensus among study investigators and surgeons, a 
common/standardized perioperative medication regimen was developed for the use of 
perioperative anti-inflammatory agents. 


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 Duration of the long-term follow up 
In section(s): Section 7 Study Design, 16.5 Termination of the Study 
Rationale: 
The long-term safety follow-up will be described in a separate protocol, LTS13588 where patients 
will be followed for up to 15 years. This protocol will also be submitted to regulatory agencies 
and Institutional Review Boards/Ethics Committees for approval. 
Reasons for withdrawal 
In section(s): 8.2 Withdrawal Criteria 
Rationale: 
The sponsor commits to following the patient for the complete duration of the trial. 
In addition, other changes are listed in the description of changes (next section). 
Protocol Amendment 7 
Justification 
The objective of Amendment 7 is to provide clarification regarding the criteria to be used by 
Investigators to identify patients anticipated to experience rapid deterioration. 
The notion of rapid deterioration is not well described in the literature and neither of the 
ophthalmic tests performed in the clinical evaluation of Stargardt patients listed below alone have 
been shown to determine rapid deterioration with utmost certainty, however, the totality of the 
collected patient information available to the Investigator, in combination with available evidence 
in literature, and collective experience of the Investigator in managing Stargardt patients, should 
provide adequate information to enable the Investigator to identify the most appropriate patient 
for the treatment that meet the inclusion criteria for Group D. 
Asymptomatic patients carrying a mutant ABCA4 gene with normal visual function and retinal 
structure are not eligible for enrollment. The investigators will identify patients anticipated to 
experience rapid deterioration based on consideration of at least the following data that will be 
collected and followed during the course of the study: age, family history, genotype, 
best-corrected visual acuity, ophthalmic examination, fundus photography, fundus 
autofluorescence, electroretinogram, optical coherence tomography, microperimetry, static and 
kinetic perimetry. Investigators will be required to document the criteria they used to identify 
patients at risk of rapid progression.   


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Protocol Amendment 6 
Justification 
Significant central vision loss in patients affected by Stargardt’s Macular Degeneration (SMD) 
may occur as early as in the first or second decade. SMD patients ultimately become blind due to 
the irreversible degeneration of photoreceptors (PR) and retinal pigment epithelial cells in the 
macula due to the loss of ATP-binding cassette, sub-family A, member 4 (ABCA4) protein 
function arising from mutations in the ABCA4 gene. While effective gene therapy for SMD 
promises to restore a normal ABCA4 gene and protein function in viable PR, it is not anticipated 
that the treatment will restore degenerated cells that are no longer viable. Therefore, the optimal 
time for intervention with gene therapy in patients with SMD would seem to be before the onset 
of blindness or advanced macular atrophy. 
To date, available clinical data from StarGen and other ocular gene therapy development 
programs using either the LentiVector® technology or adeno-associated virus platform suggest 
that ocular gene therapy is safe and well tolerated in treated adults and children. Based on this 
premise, this protocol amendment proposes extending the safety evaluation of the current protocol 
to an additional group of patients (Group D/Cohort 6) with a much less advanced stage of the 
disease that can be observed in adults and children (6 years and older). 
Disease course 
The progression of SMD is variable over several years before bilateral blindness with an onset 
(first noticeable symptoms) usually before age 20 (51) but as early as age 5 (52). While no 
publications report the distribution of disease onset by age groups, articles (53, 54, 55, 56) 
document that the median age of disease onset is around 20 years with range between 5 to as late 
as 72 years old. 
As observed in a 95-patient study (57), visual acuity (VA) may decrease slowly at first, accelerate 
and then level off. A survival analysis (58) showed that the median time for patients to progress 
from VA 20/40 or better in their better seeing eye to 20/200 or worse is: 7 years [95% CI: 5 to 
8 years] for patients 20 years or less; 22 years [95% CI: 10-23 years] for patients aged 21to 
40 years; 29 years [95% CI: 12-29 years] for patients 41-60 years. This suggests that the rate of 
central vision decrease could be correlated with disease onset with a younger age at symptoms 
onset being associated with more rapid vision loss and onset of blindness. 
While (distance) VA remains the gold standard for the assessment of visual function, particularly, 
in clinical trials, for patients with SMD, VA alone may not be the best assessment to define the 
disease stage or disease course as it reflects only the function of the foveal PRs. Using other 
clinical assessments such as visual field, microperimetry, electroretinography, fundus 
autofluorescence, and optical coherence tomography, alone or in combination, shows that 
evidence of PR and retinal pigmented epithelium (RPE) degeneration and progressive loss of 
visual function can be observed in SMD patients even if distance VA is maintained.  


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Treatment expectations 
The SMD pathophysiology is due to a defective Rim Protein, a protein encoded by the ABCA4 
gene, which causes an accumulation of N-retinylidene-PE in the PR outer segments. 
N-retinylidene-PE is a precursor of A2E, a major component of lipofuscin. Lipofuscin 
accumulates in the RPE cells and is toxic to them leading to PRs death secondary to loss of the 
RPE support function. The treatment objective of gene therapy for SMD is to introduce the correct 
ABCA4 complementary deoxyribonucleic acid (cDNA) into PRs to halt or slow down the 
degenerative loss of RPE cells and PRs and, therefore, the loss of visual function. From the 
current understanding of the pathophysiological process, it is very unlikely that StarGen reverses 
existing lipofuscin accumulation, and its consequent cell damage. If this assumption is correct, the 
likelihood to observe biological activity in patients in an advanced stage of the disease is low. 
Therefore, to enhance the chance of observing biological activity, it has been recommended by 
experts following a preliminary review of data from Cohorts #1-3 that patients with a much less 
advanced disease stage must be evaluated. 
As an inherited disease, the physiopathological process probably starts at birth although it may 
remain clinically undetectable for several years; this supports the rationale to initiate a treatment 
as earlier as possible to limit physiopathological process. Clinical data derived from ongoing 
clinical trials of gene therapy in inherited ocular disease suggest a better response to treatment in 
children relative to adults, also supporting the benefit of early treatment. 
Safety 
From safety and tolerability data collected from Cohorts #1-4, StarGen appears to be safe and 
well-tolerated. On the 22nd September meeting, the Data Safety Monitoring Board (DSMB) 
evaluated the safety available data and reviewed the proposed study amendment 6.  Following 
discussion, they recommended continuing the study with the inclusion of patients in cohort 5 and 
endorsed the study amendment foreseeing the evaluation of StarGen in adults and children with a 
less advanced stage of SMD. 
A 2014 Association of Research in Vision and Ophthalmology (ARVO) abstract concluded that 
the 4 products using the LentiVector® technology (59) platform (ProSavin in neurological disease 
and RetinoStat, StarGen and UshStat in ocular diseases) are safe and well tolerated in 54 patients 
treated to date. 
Most of ocular gene therapies currently use Adeno-Associated Virus (AAV) as vector and also 
appear well tolerated and safe. In 2013, K. Willett and J. Bennett (60) stated ‘Encouragingly, 
AAV appears safe and effective with clinical follow-up surpassing 5 years in some studies. As 
disease targets continue to expand for AAV in the eye, thorough and deliberate assessment of 
immunologic safety is critical. With careful study, the development of these technologies should 
concurrently inform the biology of the ocular immune response’. 
Overall, the experience gained with ocular gene therapies for inherited retinal diseases using 
either AAV or LentiVector® technology platforms demonstrates the safety ocular gene therapy 
treatments administered subretinally. 


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Specific issues related to enrollment of pediatric patients 
 Immune system 
The immune system in children of 6-18 years can be considered mature and is not 
expected to respond differently to viral particles or gene product from that of adults. At 
birth, the cellular immune system is fully developed. The rate of T cell production by the 
thymus is greatest from birth until puberty. Thus, a diverse T cell repertoire, including 
T cells selected against ‘self’ in the thymus, is generated by puberty. Following puberty, 
the generation of new/naïve T cells decreases with age and although T cell numbers 
remain stable throughout life, the T cell repertoire diminishes, particularly characterized in 
the elderly. Hence, a child of age >6 years up until puberty may have a broader repertoire 
of naïve cells than an ‘adult’. This may suggest that this age group may be able to respond 
to a broader range of antigens (‘non-self’) than that of adults. Experimental work with 
influenza vaccines indicated that more influenza-activated T cells were generated in 
children aged 5 to 9 years than in adults (aged 22 to 49 years) (61). However, the 
blood/ocular-brain barrier is fully developed and access of T cells remains highly restricted 
in children >6 years of age as adults. Similarly, various tolerance mechanisms are active 
within the ocular compartment in both children and adults. 
At birth, the humoral immune system is under developed and remains poor for 
approximately 6 months. Adult levels of IgM are produced by 12 months; however adult 
levels of IgG are not reached until 5 years of age when the responses generated in children 
are equivalent to that in adults. 
There is currently no evidence to suggest that the immune response to vector particles or a 
gene product in children and adolescents will differ from the adult population. In studies 
utilizing AAV vectors subretinal injection was well tolerated in children (62). When 
lentiviral vectors are subretinally injected in mature animals, they have been shown to 
induce low levels of inflammation that are transient and comparable to those observed 
with AAV (63). An increased incidence of adverse immunological reactions in children 
following subretinal delivery of an ocular gene therapy is therefore considered unlikely. 
To ensure effective monitoring of vector and product in children and adolescents, 
biodistribution and immunology samples will be collected at the same intervals as in adult 
patients. In addition, as for the adult population, pediatric patients will be encouraged to 
enter the long-term, follow-up protocol designed to monitor the long-term safety of 
patients treated with StarGen. 


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 Eye anatomy and surgery procedure 
From 6 years of age the human eye is fully developed (64), thus inclusion of pediatric 
patients from 6 years of age will enable evaluation of StarGen in this population using the 
optimal and safe dose identified in the earlier parts of the study (Cohorts 1-5), without a 
need for a change in dose, dose volume or method of administration. Given the dose and 
method of administration will have been deemed to be safe in the first part of the study this 
approach will minimize any risk of administration to the younger population and provide 
an effective comparison of the safety of StarGen between the adult and pediatric 
populations. The risks related to the operative procedure, administration of StarGen in 
pediatric patients and the management of the complications of subretinal surgery are 
considered similar to that in adult patients as there is no significant modification in the 
procedure or factors related to the patient that represent significant differences. Surgery 
will be performed by experienced ophthalmic surgeons. Appropriate measures will be 
implemented to minimize any pain or discomfort associated with study procedures in 
children including administering StarGen under general anesthesia, if deemed necessary, 
and, where appropriate, providing in-patient hospitalization for postoperative management. 
General anesthesia in younger children does represent an additional risk compared to local 
anesthesia; however, the anesthesiologists will be experienced in pediatric anesthesia and 
specific practices for ocular surgery. Accommodation and logistic assistance will be 
provided to family members/caregivers to ensure they can be close to children in the event 
of hospitalization.  
 Experience of ocular gene therapy in pediatric patients 
It is worth noting that recent Phase I/II studies in Leber’s Congenital Amaurosis (LCA) 
conducted in the United States (US) and European Union (EU) enrolled patients as young 
as 5 years and older (NCT00516477, NCT01496040, NCT00643747). These studies 
evaluated subretinally injected adeno-associated virus vectors expressing the human gene 
RPE65 that codes for a normal functional retinal pigment epithelium specific 
65 kiloDalton (kDa) protein. In the study reported by Maguire et al. (65), following 
delivery of the normal functional RPE65 gene, the greatest benefit in terms of 
improvement in vision was seen in the younger patients. This therapy is now being studied 
in LCA patients of 3 years and older (NCT00999609) to further evaluate the population 
and define the optimal time for intervention in the natural history of the disease to 
maximize benefit. 
 Informed consent process 
The process of informed assent of pediatric patients and the consent from their parents, 
guardians or other legal representatives will ensure that all parties understand the unique 
risks associated with gene therapy and the specific risks associated with ocular gene 
therapy and the participation in early clinical research where the safety and efficacy of a 
therapy may not have been fully established. 


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Inclusion of pediatric patients in the study will only occur upon the recommendation of the 
DSMB and further to submission of a data package assessing the early benefit/risk profile 
of StarGen to the competent Health Authorities where the study is conducted. 
Summary 
Current nonclinical and clinical studies from multiple programs (ProSavin in neurological disease 
and RetinoStat, StarGen and UshStat in ocular diseases) have demonstrated the safety profile of 
the lentiviral vectors as a gene therapy platform, as well as the safety of the subretinal injection 
procedure. The proposed protocol change to allow enrollment of patients with a less advanced 
stage of disease, including children (≥6 years of age) in an additional cohort will provide an 
opportunity to evaluate the safety of StarGen in a population in which the biological activity of 
the treatment is also more likely to be observed due to the expected rapid progression of the 
disease course. As currently there is no known effective treatment for SMD to alter the inevitable 
progression to blindness, administering treatment in patients with less advanced stage of the 
disease offers the promise of maintaining patients at a higher level of visual functioning due to the 
expected life-long sustained biological activity of StarGen than patients eligible for treatment in 
previous cohorts. The Sponsor will be closely following Health Authority guidelines for pediatric 
patient enrollment. Furthermore, inclusion of pediatric patients in the study will only occur upon 
the recommendations by the DSMB and approval from the competent Health Authorities and 
IRBs/IECs after the review of adult data and benefit/risk assessment.  
Proposed changes to current protocol 
Overall, Cohorts 1-4 aimed to demonstrate safety of increasing doses of StarGen and Cohort 5 to 
confirm the safety profile of the maximum tolerated dose (MTD) or highest dose tested in slightly 
less severe patients (as displayed in table below) but it is very unlikely that biological activity of 
StarGen will be demonstrated from Cohorts 1-5 patients since these patients are too advanced in 
the disease process. 


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Cohort 
Group 
No of 
patients 
Vector total 
dose per eye 
Eligibility criteria 
1 
A 
4 
1.8x105 TU 
 
Patients (18 years or older) with advanced SMD 
 
VA ≤20/200 in the worst eye 
 
Severe cone-rod dysfunction with no detectable or severely abnormal 
full-field ERG responses 
2 
B 
4 
1.8x105 TU 
 
Patients (18 years or older) with SMD 
 
VA ≤20/200 in the worst eye 
 
Abnormal full-field ERG responses 
3 
B 
4 
   6x105 TU 
4 
B 
4 
1.8x106 TU 
5 
C 
up to 12 
MTD or the 
highest dose 
tested 
 
Patients (18 years or older) with SMD 
 
VA ≤20/100 in the worst eye 
 
Abnormal full-field ERG responses 
TU 
 
Transducing units 
SMD  
Stargardt Macular Degeneration 
VA 
 
Visual Acuity 
ERG  
Electroretinogram 
MTD 
Maximum Tolerated Dose 
In addition to providing additional safety and tolerability data of the MTD or highest dose tested, 
another potential benefit of adding Group D in Cohort 6 is to provide the opportunity to further 
investigate the biological activity of StarGen in patients with a less advanced stage of the disease 
where the likelihood of observing biological activity is more probable. Overall, compared to 
patients in Groups A-C, Group D patients will be pediatric and adult patients with fairly preserved 
VA and mildly abnormal or normal full-field ERG responses at baseline in whom a rapid disease 
progression is expected. Therefore, we propose: 
 To decrease the Cohort 5 sample size from up to 12 to up to 6 patients. Although Cohort 5 
will provide further information on safety and tolerability of the MTD or highest dose 
tested, it is considered unlikely that evidence of biological activity will be observed in this 
cohort due to their advanced disease state. Based on the escalation criteria for previous 
cohorts, up to 6 additional patients in Cohort 5 will be adequate to confirm the safety and 
tolerability of the MTD or highest dose tested to allow the evaluation of the dose in adults 
and children with a much less advanced stage of the disease to be enrolled in Cohort 6.  
 To add an additional cohort to the existing 5 cohorts. This Cohort 6/Group D will be 
enrolling up to 24 adult and pediatric (6 years or older) patients with SMD who are 
anticipated to experience rapid deterioration in visual function and/or retinal structure in 
the opinion of the study investigator, with VA of ≥20/100 in the worst eye (study eye) and 
with mildly abnormal (ie, abnormalities limited to photopic responses) or normal full-field 
ERG responses.  
 Safety and biological data from Cohorts 1-5 will be reviewed by the DSMB, and 
subsequently, an interim report that includes a benefit/risk balance analysis for enrolling 
pediatric patients (with regard to US 21 CFR Part 50 Subpart D ‘Additional Safeguards for 
Children in Clinical Investigations’ for the FDA specifically) and provides a 
recommendation on the acceptability of commencing enrollment of pediatric patients in 
Cohort 6 will be submitted for approval by regulatory authorities and institutional review 
boards/ethics committees (IRB/EC). 


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Other changes 
 Where available, video-recording of surgery and/or intra-operative optical coherence 
tomography (OCT) 
To explore further the treatment effect (safety and biological activity) at the bleb level, video 
of the surgery and/or intra-operative OCT will be collected, where available, in order to 
define as precisely as possible the area of the bleb and consequently, the zone of cell 
transduction. 
For the patients already enrolled, if a video of the surgery was obtained the patient will be 
asked to consent to allow the video to be collected and used for analysis. 
 New centers 
It is planned to open new centers in the US and the EU. 
 Centralized review committee 
For Cohort 6, a centralized review committee will be organized to pre-operatively review 
baseline study assessments for the purpose of providing a recommendation on the area of 
retina to be targeted for the subretinal injection to optimize the treatment benefit. The 
committee may also give a recommendation for the choice of the study eye if both eyes are 
clinically similar. As it is planned to open several new centers in the US and the EU, this 
committee will contribute to the homogenization in the treatment of the new patients. 
 Addition of time-points for immunology blood testing 
- 
In all patients, additional immunology blood testing will be performed at Week 12, to 
assess the antibody response kinetic and possibly to identify the peak. 
- 
In patients with positive antibody response at Week 24, additional immunology blood 
testing will be performed at Week 36 and/or Week 48 to document the antibody 
response kinetic until the value return to baseline in these patients (therefore a 
follow-up beyond Week 48 may be needed). 
 For Cohort 6, removal or addition of certain time points of the different assessments 
- 
Fundus photography: removal of Week 36 assessments 
- 
Fundus autofluorescence: removal of Weeks 4 and 12 assessments 
- 
Optical coherence tomography: removal of Weeks 1, 12 and 36 assessments 
- 
Full-field kinetic and static perimetry: removal of Weeks 12 and 36 assessments 
- 
Full-field electroretinogram: removal of Weeks 4 and 12 assessments 
- 
Multi-focal electroretinogram: removal of Week 12 assessment and addition of Week 
2 assessment 
- 
Microperimetry: removal of Weeks 12 and 36 assessments  
- 
Adaptive optics: removed from the investigations 


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- 
VFQ-25: addition of Week 24 assessment 
- 
Reading speed: addition of Week 24 assessment 
 Addition of secondary endpoints 
New secondary endpoints will be added to evaluate the safety and biological activity at the 
bleb level. 
 The study eye has been defined 
One study eye will be selected. If both eyes are eligible for the study, the worse eye, as per 
investigator judgment, will be selected. The centralized review committee may advise on the 
choice of the study eye if both eyes are clinically similar.  
 Inconsistencies’ corrections 
Some inconsistencies have been corrected. 
 
Protocol Amendment 5 
Justification 
On June 12, 2014, the study sponsorship will be transferred from Oxford BioMedica Ltd. to 
sanofi. Therefore the protocol is updated to reflect this change of sponsorship. 
Amended text 
 The header is modified to change the sponsor name, to add the compound code 
(SAR422459), and the study code (TDU13583), as per the new sponsor coding rules. 
 The cover page is updated with the new sponsor related information 
 Core text: Oxford BioMedica Ltd. or OXB has been replaced by “the Sponsor” where 
appropriate 
Corrections of a wording mistake 
In table 3 in Section 7 and the same table in protocol synopsis, Vector Concentration has been 
replaced by Vector total dose per eye. 
Changes in AESI and SAE process: 
Section 11 has been amended to align the protocol with the Sanofi protocol standards as regards to 
the definition and reporting of adverse events, adverse events of special interest and pre-specified 
lab abnormalities. Decision trees for standard pre-specified lab abnormalities data ie, neutropenia, 
thrombocytopenia, acute renal failure, suspicion of rhabdomyolysis and ALT increase have been 
added as appendices. 


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Other Administrative Updates 
 The protocol has also been reviewed and updated to correct grammatical, administrative 
errors and harmonize formatting and spelling to US English. 
 New Sponsor reference numbers have been added. 
 The names of the principal investigators on the cover page have been deleted as per new 
sponsor rules. A page is added to specify the name of the coordinating investigator, the 
monitoring team’s representative, the new sponsor, and other emergency telephone 
numbers 
 OXB Sponsor signature page has been deleted following the change of Sponsor. As per 
new Sponsor rules, no Sponsor signature page will be included in the protocol 
 The publication policy (Section 16.7) has been updated, in order to harmonize the text 
across all the protocols initially generated by Oxford BioMedica Ltd. 
 
Protocol Amendment 4 
Justification for changes 
The following additions/clarifications have been made to protocol version 4.0 and incorporated in 
protocol version 5.0. 
Section 3. Study Schedule and Sections 9.3.6 and 9.3.7 
The study schedule and associated sections have been updated to remove Autofluorescence 
imaging at visits: Day 1 and Weeks 1, 2 and 36. Fundus photography has been removed from 
visits: Weeks 1 and 12. An infra-red fundus montage has been added to OCT time points to 
provide comparable information to autofluorescence imaging. 
Justification for changes 
The Investigators have recommended that the autofluorescence images and colour fundus 
photography time points are reduced in the early post-operative period, as patients find them 
difficult to tolerate and the images do not provide accurate data so soon after the surgical 
procedure. A reduction in autofluorescence imaging and colour fundus photographs also reduces 
the light exposure that may have a detrimental effect on the retina (66). As an infra-red light 
source is barely visible to the human eye, is more comfortable for the patient and presents no 
concerns about retinal light toxicity, a small montage using infra-red imaging will be included as 
part of the OCT imaging to provide comparable information to the previously specified 
autofluorescence imaging time points (67). Study schedule footnote ‘± Infra-red fundus montage 
to be performed at each visit’ has been added to OCT time points. 


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Section 3. Study Schedule 
 An inconsistency between the study schedule and section 9.3.3 has been rectified. Day -1 
(baseline) has a visit window of -7 days. In addition, Section 9.3.25 has been updated to be 
consistent with Section 9.3.3. 
 An inconsistency between the study schedule and section 9.3.18 has been clarified. 
Microperimetry will be performed at scheduled visits requiring Full field Kinetic and 
Static perimetry. Schedule footnote‘*’ has been updated to read: “BCVA and perimetry 
(full-field kinetic and static perimetry) will be performed once at the screening visit  
(Day -28) and on 2 occasions at baseline (Day -1). Microperimetry will be performed once 
at visits requiring full-field kinetic and static perimetry” 
As a result, section 9.3.2, 9.3.3 and 9.3.7 have been updated to clarify microperimetry time points. 
Section 6.2 Biodistribution Endpoint 
An inconsistency between section 6.2 and the study schedule has been rectified. Blood samples 
for PCR will be taken at visits; Day -28, Day 0 (60 minutes post-surgery), Day 1 and Weeks 1, 2, 
4, 12, 24, 36 and 48. 
Section 9.3.1 Screening/Baseline Procedures 
Below cited paragraph has been amended to clarify that only Full-field Kinetic and Static 
perimetry (not microperimetry) are to be performed in triplicate during screening. 
Amended text 
Patient screening will take place in the 28 days prior to StarGen™ administration. Full-field 
Kinetic and Static perimetry and BCVA will be performed on 3 occasions during the screening 
period, (once at Day -28 and twice at Day -1). These measures are subject to broad intra-
individual variability. Thus to ensure eligibility of the patient, an average of the most reliable 
2 will be used. 
Section 9.3.2 Screening Clinical and Laboratory/Diagnostic Measurements 
An inconsistency between section 9.3.2 and the study schedule has been rectified. Day -28 
(Screening) has a visit window of ±10 days. 
Section 9.3.9 Samples for Immunology 
An inconsistency between section 9.3.9 and the study schedule has been rectified. Blood samples 
for immunology are required to be taken at baseline (Day -1) and Weeks 4 and 24. 
Section 9.3.18 Perimetry 
Below cited paragraph has been amended to clarify the perimetry requirements during the 
screening period. 


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Amended text 
Full-field Kinetic and Static perimetry will be performed 3 times during the screening period 
(once at Day -28 and twice at Day -1). These measures are subject to broad intra-individual 
variability, thus to ensure eligibility of the patient the most reliable 2 will go forward for analysis 
by the reading centre. Microperimetry will be performed once at each visit. Follow-up perimetry 
(micro, full-field kinetic and static) tests will be performed at Weeks 2, 4, 12, 24, 36 and 48/early 
termination visit. 
Following review of the study by the Data Safety Monitoring Board (DSMB), the following 
section has been added as recommended. 
Section 11.3 Adverse Events of Special Interest 
AEs of special interest include the following: 
 Infection, particularly any opportunistic infection 
 Immunological reactions (eg, new incidence or exacerbation of rheumatologic or other 
autoimmune disorder) 
 New incidence or exacerbation/recurrence of a hematological disorder 
In the event that a patient enrolled in the study experiences any of the above, blood samples for 
PCR and/or Immunological analysis will be taken to rule out involvement of Investigational 
Product. 
Section 11.6 Reporting a Serious Adverse Event 
The following paragraph has been amended to clarify that the study will comply with ICH GCP 
and any local pharmacovigilance regulatory reporting requirements. 
OBM’s pharmacovigilance provider will report all suspected unexpected serious adverse reactions 
(SUSARs) to the Regulatory Authorities in accordance with ICH GCP, and any local 
pharmacovigilance regulatory reporting requirements, after the investigator or any agent acting on 
behalf of the sponsor, or the sponsor being notified of the SUSAR. 
Other Administrative Updates 
The Protocol has been reviewed and updated to correct grammatical and administrative errors. 
 


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Protocol Amendment 3 
Justification for changes 
The following additions/clarifications have been made to the study protocol in response to review 
by the French regulatory authority (AFSSAPS) 
Section 2. Synopsis (and throughout document) 
The Primary Evaluation assessment ‘Slit lamp biomicroscopy’ has been updated to ‘slit lamp 
examination’ throughout the protocol as a point of clarification. 
Section 4. Introduction and Rationale (page 23 paragraph 3) 
The below cited paragraph has been updated to correct a typographical error; less than 1% of 
Stargardt cases may result from a dominant mode of inheritance as opposed to 10% previously 
cited in Protocol version 3.0. 
Amended text 
This disease is nearly always inherited as an autosomal recessive trait that produces a severe form 
of macular degeneration, similar to age-related macular degeneration, but which begins in 
childhood; it is the most common autosomal recessive juvenile onset macular dystrophy. In 
addition, less than 1% of cases may result from a dominant mode of inheritance. The autosomal 
recessive trait for SMD in affected children means that both parents were carriers, having 
1 mutated gene for the disease paired with 1 normal gene. Children where both parents are 
carriers have a one in 4 chance of inheriting the both mutated genes (1 from each parent) leading 
to Stargardt disease. 
Section 4.2 Clinical Pathology 
This section has been amended to clarify the later onset of peripheral visual constriction compared 
to central visual failure in SMD patients. 
Amended text 
SMD, caused by mutations in the ABCA4 gene is inherited as an autosomal recessive trait, is the 
most frequent cause of juvenile macular degeneration. There is variation in the clinical course of 
the disease but typically central visual failure begins in childhood together with later onset 
peripheral visual constriction in some cases. The consequence of the condition is frequently legal 
blindness. 
Section 4.11 Rationale for Target Patient Population 
This section has been updated to clarify and more clearly define the patient cohorts in this study. 
The phenotypic subtypes of Stargardt macular dystrophy are described by Lois et al. (currently ref 
number 25) and the paper has been appended to the protocol (Appendix D). Updated section also 
referenced in Section 7. Study Design. 


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Additional/Amended text 
Three phenotypic subtypes of SMD have been identified based upon ERG attributes (Lois et al. 
2001, Appendix D): 
Category 1: 
Severe ERG abnormality with normal scotopic and [photopic] full-field ERG. 
Category 2: 
Severe ERG abnormality with loss of photopic function but normal scotopic and 
full-field ERG. 
Category 3: 
Severe ERG abnormality with loss of both photopic and scotopic function. 
Three patient groups 18 years or older with a differing level of advancement of SMD will be 
included in this study. All 3 patient populations to be studied will be from the most severe 
category (category 3 of the Lois et al. classification) 
 Group A: Patients with advanced SMD, visual acuity ≤20/200 in the worst eye and severe 
cone-rod dysfunction with no detectable or severely abnormal full-field ERG responses. 
These will be patients with severe ERG abnormality and loss of both photopic and 
scotopic function, with loss of photopic responses to no more than 70% of the category 3 
ERG criteria in the Lois et al. classification, and very poor visual acuity. 
 Group B: Patients with SMD, visual acuity ≤20/200 in the worst eye with abnormal full-
field ERG responses. These will be patients with very abnormal ERG and photopic 
responses, with loss of photopic responses to no more than 85% of the category 3 ERG 
criteria in the Lois et al. classification, and very poor visual acuity. 
 Group C: Patients with SMD, visual acuity ≤20/100 in the worst eye with abnormal 
full-field ERG responses. These will be patients with severe ERG abnormality, and have 
photopic B-wave amplitude within the range of category 3 criteria in the Lois et al. 
classification. These patients will also have more preserved visual acuity. 
Patients thus treated in the first cohort will have advanced disease with the most severe loss of 
photopic retinal function on ERG and very poor visual acuity. Therefore, whilst this patient group 
is unlikely to experience any significant clinical benefit from treatment in terms of improvement 
in BCVA, any deleterious local effects of StarGen™ will be detectable through regular safety 
monitoring. Following clinical experience in patients with advanced disease a further 3 cohorts 
(Cohorts 2-4) in patients with less advanced disease will be evaluated. 
Section 8.2 Withdrawal Criteria 
This section has been updated to briefly describe a long term follow-up safety study which will be 
submitted as a separate protocol to regulatory agencies and ethics committees for approval. 
Patients taking part in the current study will be encouraged to participate in the follow-up study. 


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Additional text 
Any patient that is withdrawn from the study will be encouraged to consent to an open-label, long 
term follow-up study. If the patient withdraws/is withdrawn from the study, the Week 48 
procedures should be completed if possible. 
The long term safety follow-up will be described in a separate protocol which will be submitted to 
regulatory agencies and Institutional Review Boards/Ethics Committees for approval. 
The open label follow-up study has been designed to capture the essential safety data pertinent to 
gene therapy follow-up, as well as key efficacy assessments, whilst providing the patient with a 
degree of flexibility for minimising inconvenience. The long term follow-up protocol will also 
permit patients to receive alternative treatment during their participation whilst allowing for safety 
follow-up. 
Section 9.3.1 Screening/Baseline Procedures 
This section has been updated to remove the requirement for 3 ERG assessments during the 
screening period prior to surgery, this requirement was included in error. Only BCVA and 
perimetry assessments will now be required in triplicate during screening. ERG assessments will 
occur once at Day -28 and once at Day -1 per the study schedule. 
Amended text 
Patient screening will take place in the 28 days prior to StarGen™ administration. BCVA and 
perimetry will be performed on 3 occasions during the screening period, (once at Day -28 and 
twice at Day -1). These measures are subject to broad intra-individual variability thus to ensure 
eligibility of the patient an average value in each case will be used. 
Section 9.3.3 Screening Clinical Laboratory/Diagnostic Measurements Day -1 
Updated to reduce the number of ERG assessments at visit. 
- 
ERG (Multifocal and Full-Field) 
Section 9.3.7 Follow-Up Week 1, 2, 4, 12, 24, 36 and 48 Clinical and Laboratory/Diagnostic 
Measurements 
An ERG assessment has been included at Week 4 at the request of AFSSAPS to assess early signs 
of safety and biological activity. 
- 
ERG (Weeks 4, 12, 24 and 48 only) 


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Administrative/other updates 
Study Schedule 
An inconsistency between the Study Schedule Section 3 and Section 9.3.8 Samples for PCR has 
been rectified. Blood and where possible urine samples are required to be taken 60 minutes 
post-surgery. 
Section 2.1.1 and 8.1.1 Main Inclusion Criteria 
For Inclusion criteria 2 and 3, inconsistencies in wording between both sections have been 
rectified. 
Section 10.1.2 Storage and Disposition of Study Medications 
This section has been amended to accommodate local procedures for the destruction of used and 
unused vials post-surgery. 
Amended text 
Dispensing will be documented by completing a log with the date of dispensing and the patient 
details. Used and unused vials should be returned to the hospital pharmacy (or in accordance with 
local standard operating procedures) and stored in labeled biohazard bags prior to reconciliation 
by the study monitor. Where local procedures require immediate destruction of used and unused 
vials, the process will be witnessed, signed and documented on a destruction log. 
At each visit, the clinical study monitor will review the drug-dispensing log and reconcile it with 
the unused vials/destruction log. 
 
Protocol Amendment 2 
Justification for changes 
The following additions have been made to the study protocol in response to review by the FDA: 
Section 4.9 Rationale for the Clinical Dose 
The dose selection for the FIM study will be based on the MTD used in the rabbit and NHP GLP 
combined toxicology/biodistribution studies. 
The MTD in the rabbit that was used in the GLP safety study is 1.4x106 TU/eye. The MTD in the 
NHP that was used in the GLP safety study is 4.7x105 TU/eye. Based on the average 3-fold ocular 
allometric scaling of ocular volume between rabbit/NHP and the human eye the expected MTD in 
man is 1.4x106 TU/eye up to 4.2x106 TU/eye based on the MTD in the NHP and rabbit, 
respectively. 


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In the current study, the first dose in man is equivalent to 1.8x105 TU/eye, the second dose is 
equivalent to 6x105 TU/eye and the highest dose will be undiluted StarGen which is equivalent to 
1.8x106 TU/eye. All 3 of these dose levels are below the MTD predicted by the rabbit and are 
either below or almost equivalent to the MTD predicted in the NHP. 
Section 6.1.4 Laboratory Parameters and Section 8.1.5 Exclusion Criteria 
Blood for immunology and blood for PCR will also be taken at multiple time points throughout 
the study, as will urine samples for biodistribution assessment. 
The normal ranges and the definition of abnormal ranges for screening laboratory tests are now 
provided in Appendix C and the reference to Appendix C is provided in the Exclusion Criteria 
item 10 related to laboratory parameters. 
Section 8.3 Study Stopping Criteria 
Prolonged anterior chamber inflammation and/or prolonged posterior chamber inflammation 
continuing without signs of resolution 28 days after StarGen administration. 
Section 9.2.2 Intraocular Injection 
The retinotomy will be temporal to the optic nerve and located outside the major arcade vessels 
such that the subretinal bleb produced may be expanded towards the macula. 
Section 9.2.3 Positioning of the Subretinal Bleb 
In all patients, the site for subretinal injection will be selected as to ensure that the existing visual 
acuity will not be impaired and the treated retinal area can be easily monitored for safety after 
StarGen™ administration. Group A will have advanced disease and very poor visual acuity. In 
this group encroachment of the injection bleb to the central macula will be permitted as it is 
unlikely it will further impair visual acuity. However, groups B and C will have less advanced 
disease with better acuity. Thus, a more conservative approach will be adopted and the bleb will 
only extend over the macular boundary to minimize the risk of any visual function impairment. 
Prior to surgery, the position of the subretinal bleb will be determined based on the baseline 
clinical evaluation, fundus imaging, microperimetry and visual field testing. 
 
Protocol Amendment 1 
Justification for changes 
Following recommendations from the Data Safety Monitoring Board (DSMB) for this study, 
exclusion criteria 7 has been revised to include any known allergy to topical, injected or systemic 
corticosteroids. 
The DSMB also recommended further guidance on the management of any ocular inflammation. 


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Changes and additions as follows 
Section 2.1.5, Synopsis and Section 8.1.5 Exclusion Criteria 
7. Any known allergy to any component of the delivery vehicle or diagnostic agents used during 
the study (eg, fluorescein, dilation drops), or medications planned for use in the peri-operative 
period particularly topical, injected or systemic corticosteroids. 
Section 9.2.2 
Intraocular inflammation may be treated with 1 or a combination of anti-inflammatory 
medications including topical 1% prednisolone acetate, periocular injection of 20 mg of 
triamcinolone acetate, and systemic steroids (eg, oral prednisolone 0.5 mg/Kg daily for 10 days or 
prednisolone 1 mg/Kg daily for 10 days) The choice of medications will be at the treating 
physicians' discretion and guided by the severity and longevity of the inflammation. 

SAP_001.pdf: 
NCT01367444


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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION ............................................................................................................... 1 
2.0 
STUDY OBJECTIVES ........................................................................................................ 1 
2.1 Primary Objective ........................................................................................................... 1 
2.2 Secondary Objective ....................................................................................................... 1 
3.0 
STUDY DESIGN ................................................................................................................ 1 
3.1 Study Stopping Criteria .................................................................................................. 4 
3.2 Dose Limiting Toxicities ................................................................................................ 4 
4.0 
TARGETED STUDY POPULATION .................................................................................... 4 
5.0 
ENDPOINTS ..................................................................................................................... 5 
5.1 Primary Endpoints .......................................................................................................... 5 
5.2 Secondary Endpoints ...................................................................................................... 5 
5.3 Other Endpoints .............................................................................................................. 6 
5.3.1 
Immunology .......................................................................................................... 6 
5.3.2 
Biodistribution ...................................................................................................... 6 
5.3.3 
Laboratory Parameters .......................................................................................... 6 
5.3.4 
Other Safety Parameters ....................................................................................... 6 
5.3.5 
Exploratory Efficacy Parameters .......................................................................... 6 
5.4 Other Measures ............................................................................................................... 7 
5.4.1 
Concomitant Medication ....................................................................................... 7 
5.4.2 
Patient Characteristics ........................................................................................... 7 
5.4.3 
Withdrawals .......................................................................................................... 7 
5.4.4 
Deaths ................................................................................................................... 7 
6.0 
GENERAL STATISTICAL CONSIDERATIONS ................................................................... 7 
6.1 Sample Size .................................................................................................................... 7 
6.2 Primary Data Set ............................................................................................................ 7 
6.3 Handling Data Irregularities ........................................................................................... 8 
6.4 Interim Analyses ............................................................................................................. 8 
6.5 Analyses Specific to DSMB Reports ............................................................................. 8 
6.6 Software to be used for Analyses ................................................................................... 9 
6.7 Modifications to the statistical section of the protocol ................................................... 9 
6.8 Statistical Modifications made in the Statistical Analysis Plan ................................... 10 
7.0 
STATISTICAL ANALYSES .............................................................................................. 10 
7.1 Patient Flow and Compliance ....................................................................................... 11 
7.2 Baseline Characteristics ............................................................................................... 11 
7.3 Primary Outcome ......................................................................................................... 11 
7.3.1 
Adverse Events ................................................................................................... 11 
7.3.2 
Best-Corrected Visual Acuity (BCVA) .............................................................. 13 
7.3.3 
Ocular Inflammation ........................................................................................... 13 
7.3.4 
Intraocular Pressure (IOP) .................................................................................. 13 
7.3.5 
Microperimetry ................................................................................................... 13 
7.3.6 
Full-field Static and Kinetic Perimetry ............................................................... 14 
7.3.7 
Optical Coherence Tomography (OCT) ............................................................. 14 
7.3.8 
Electroretinogram (ERG) .................................................................................... 14 
7.3.9 
Laboratory Parameters ........................................................................................ 15 
7.3.10 
Vital Signs ....................................................................................................... 15 


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7.3.11 
Concomitant Medications ................................................................................ 16 
7.3.12 
Physical Examinations ..................................................................................... 16 
7.4 Secondary Outcomes .................................................................................................... 16 
7.4.1 
Fundus Autofluorescence (FAF) and Supplementary Reading Center Data ...... 16 
7.5 Exploratory Efficacy Outcomes ................................................................................... 16 
7.5.1 
VFQ-25 ............................................................................................................... 16 
7.5.2 
Reading Speed .................................................................................................... 17 
7.5.3 
Low-Contrast Sloan Letter Chart Testing ........................................................... 17 
7.6 Other Safety Measures ................................................................................................. 17 
7.6.1 
Immunology ........................................................................................................ 17 
7.6.2 
Biodistribution .................................................................................................... 17 
7.7 Safety Analysis ............................................................................................................. 18 
7.7.1 
Determination of Maximum Tolerated Dose (MTD) ......................................... 18 
8.0 
A LIST OF PROPOSED TABLES/LISTINGS/FIGURES ..................................................... 18 
8.1 TOC for all TLFs of the latest DSMB report format proposed for TDU13583 CSR .. 18 
8.2 Patient Flow and Compliance ....................................................................................... 22 
8.3 Baseline Characteristics ............................................................................................... 25 
8.4 Primary Outcome Analyses .......................................................................................... 30 
8.4.1 
Adverse Events ................................................................................................... 30 
8.4.2 
Concomitant Medications ................................................................................... 37 
8.4.3 
BCVA, Ocular Inflammation and IOP................................................................ 37 
8.4.4 
Laboratory Parameters ........................................................................................ 45 
8.4.5 
OCT..................................................................................................................... 46 
8.4.6 
Vital Signs ........................................................................................................... 48 
8.5 Secondary Outcomes .................................................................................................... 49 
8.5.1 
Full-field Kinetic and Static Perimetry ............................................................... 49 
8.5.2 
Microperimetry ................................................................................................... 50 
8.5.3 
ERG..................................................................................................................... 50 
8.5.4 
Fundus Autofluorescence .................................................................................... 54 
8.5.5 
VFQ-25 ............................................................................................................... 54 
8.5.6 
Reading Speed .................................................................................................... 55 
8.5.7 
Low-Contrast Sloan Letter Chart Testing ........................................................... 56 
8.6 Other Endpoints ............................................................................................................ 57 
8.6.1 
Immunology ........................................................................................................ 57 
8.6.2 
Biodistribution Endpoint ..................................................................................... 58 


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1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides details of the proposed statistical analyses for 
the clinical trial entitled “A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected 
SAR422459, Administered to Patients with Stargardt’s Macular Degeneration.” Totally, 12 
protocol amendments have been occurred, but Amendment 12 dated November 29, 2018 has 
not been submitted to study sites for approval. The SAP was updated from Version 2.0 to 
include updates of baseline definition and cohorts from Amendment 11 and revise some 
presentations. This document contains a review of the study objectives and design, general 
statistical considerations, comprehensive statistical analysis methods for safety and biological 
activity (efficacy) outcomes, and a list of proposed tables and graphs. Any deviation from 
this SAP will be described and justified in the final study report, as appropriate. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To assess the safety and tolerability of ascending doses of SAR422459 in patients with 
Stargardt’s Macular Degeneration (SMD). 
2.2 
Secondary Objective 
To evaluate for possible biological activity of SAR422459. 
3.0 
STUDY DESIGN 
This is a phase I/IIa, open-label, dose escalation study to evaluate the safety and tolerability 
of a single subretinal injection of SAR422459. All patients will be followed for up to 
48 weeks. After 48 weeks, patients will enter an open-label, safety study (LTS13588), with 
follow-up visits, including ophthalmological examinations and recording of adverse events 
(AEs) for 240 weeks (five years). For a subsequent 10 years, delayed AEs will also be 
monitored. Details of the assessments and analysis methods for this long-term follow-up 
study will be discussed in a separate SAP and will be based on the same principles. 
 
A projected total of up to 46 patients will be enrolled in this study, consisting of seven 
cohorts from five patient groups. The five groups to be used in this study are as follows: 
• Group A: Patients (18 years or older) with advanced SMD, visual acuity ≤ 20/200 in the 
worst eye and severe cone-rod dysfunction with no detectable or severely abnormal 
full-field ERG responses. 
• Group B: Patients (18 years or older) with SMD, visual acuity ≤ 20/200 in the worst eye 


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with abnormal full-field ERG responses. 
• Group C: Patients (18 years or older) with SMD, visual acuity ≤ 20/100 in the worst eye 
with abnormal full-field ERG responses. 
• Group D: Patients (from six years to 26 years old) with symptomatic early or childhood-
onset SMD (age at disease onset <18 years), and visual acuity ≥ 20/200 in both eyes at 
the time of the screening visit anticipated to experience rapid deterioration in visual 
function and/or retinal structure. 
• Group E: Patients (from six years to 17 years old) with symptomatic SMD and visual 
acuity ≥ 20/100 in both eyes at the time of the screening visit anticipated to experience 
rapid deterioration in visual function and/or retinal structure.  
The first four cohorts will each consist of four patients and they will be enrolled as part of the 
initial dose escalation portion of the study. A minimum interval of 21 days between the 
dosing of the first and subsequent patients in each cohort and a minimum interval of 28 days 
between cohorts has been selected in order for the Data and Safety Monitoring Board 
(DSMB) to assess any acute toxicity, post-operative complications and the safety profile of 
each dose level of SAR422459. The DSMB will be responsible for determining whether to 
proceed enrolling the next cohort. 
 
Based on data accrual, the DSMB will comprehensively review the safety and tolerability of 
SAR422459 and make decisions regarding dose escalation, study continuance and 
recommended amendments to the protocol. If after a minimum interval of 28 days from the 
dosing of the last patient in a given cohort, the safety and tolerability is considered 
satisfactory by the DSMB, then the next cohort of patients will be enrolled.   
 
The initial SAR422459 dose to be studied will be 1.8 × 105 transducing units (TU), in 300 L 
of vehicle. Dose levels will increase to a maximum of 1.8 × 106 TU. 
 
Four patients from Group A will be initially enrolled into the first cohort and receive the 
lowest dose of SAR422459 (1.8 × 105 TU). If safety and tolerability are deemed acceptable 
by the DSMB for this group of patients at the lowest dose (after a minimum of 28 days), then 
four patients from Group B will be enrolled into the second cohort, also receiving the lowest 
dose of SAR422459. Cohorts 3 and 4 will also consist of patients belonging to Group B and 
will receive doses of 6.0 × 105 TU and 1.8 × 106 TU, respectively. 
 
At the end of the dose escalation phase of the study (Cohorts 1-4), if the safety and 
tolerability of SAR422459 is considered acceptable following DSMB review, six additional 
patients from Group C (Cohort 5) will be enrolled. For Cohort 5, an interval of 21 days 




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3.1 
Study Stopping Criteria 
The following is to be considered stopping enrollment: 
• Prolonged anterior chamber inflammation and/or prolonged posterior chamber 
inflammation continuing without signs of resolution 28 days after SAR422459 
administration. 
Criteria for suspending enrollment or further study conduct are defined in the DSMB Charter 
and all events will be reviewed by the DSMB. 
In the event that enrollment is terminated, all patients who have been dosed with SAR422459 
will continue to be followed up as per protocol until the Week 48 visit has been completed. 
Thereafter, patients will be encouraged to enroll in a long-term follow-up study.  
3.2 
Dose Limiting Toxicities 
Dosing will stop if a dose-limiting toxicity is encountered in a dosing cohort. Events that 
constitute a dose-limiting toxicity will be defined by the DSMB Charter. Dose-limiting 
toxicities include: 
• Severe or persistent ocular inflammation; 
• Other significant ocular toxicity (e.g., large retinal detachment, evidence of direct 
toxicity); 
• Other systemic toxicities (e.g., acute allergic reaction); and 
• Any safety issue that has been identified that adversely changes the benefit/risk 
balance to study patients. 
4.0 
TARGETED STUDY POPULATION 
The study is multicenter with sites in EU and the USA. Patients with SMD meeting all of the 
study inclusion criteria and none of the exclusion criteria will be recruited following EC/IRB 
and regulatory approval. Patients will be classified into groups (A, B, C, D, or E) according 
to their disease severities at Screening (Day -28). Details regarding the inclusion and 
exclusion criteria for all patients and by cohort may be found in Section 8.1 of Amendment 
11 of the protocol. 


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5.0 
ENDPOINTS 
5.1 
Primary Endpoints 
The primary objective of this study is to evaluate the safety and tolerability of ascending 
doses of SAR422459 in patients with SMD. Safety and tolerability of the investigational 
medicinal product (IMP) will be evaluated by the following endpoints: 
• The incidence and severity of treatment emergent adverse events (AEs). 
• Clinically important changes from baseline in the following safety assessments: 
o 
Best-corrected visual acuity (BCVA) 
o 
Slit-lamp examination 
o 
Fundoscopy/Indirect ophthalmoscopy 
o 
Fundus photography (color and infrared)  
o 
Intraocular pressure (IOP) 
o 
Microperimetry 
o 
Full-field static perimetry 
o 
Full-field kinetic perimetry 
o 
Ocular Coherence Tomography (OCT) 
o 
Electroretinogram (ERG) 
o 
Laboratory parameters 
o 
Vital signs 
o 
Concomitant medications 
For all primary endpoints with repeated measures, the primary time point will be considered 
the Week 48 visit unless otherwise specified. Last available measures before surgery will be 
considered as baseline value (e.g., Day -1). 
5.2 
Secondary Endpoints 
The secondary objective is to determine a delay in retinal degeneration following subretinal 
injection of SAR422459 through changes from baseline in visual function and retinal 
structure relative to the untreated contralateral eye utilizing the following retinal analytical 
techniques: 
For visual function: 
• BCVA 
• Microperimetry 
• Full-field static perimetry 
• Full-field kinetic perimetry 
 
 


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For retinal structure: 
• Fundus autofluorescence (FAF) 
• OCT 
For all secondary endpoints with repeated measures, the primary time point will be 
considered the Week 48 visit. Last available measures before surgery will be considered as 
baseline value (e.g., Day -1). 
5.3 
Other Endpoints 
5.3.1 Immunology 
Humoral response to SAR422459 vector components. 
5.3.2 Biodistribution 
SAR422459 distribution in the blood and urine assessed by polymerase chain reaction 
(PCR). For Cohorts 1-5, blood samples will be taken at Day -28 (Screening), Day 0 (60 
minutes post-surgery), Day 1, Weeks 1, 2, 4, 12, 24, 36 and 48 and urine samples will be 
taken at Day -28 (Screening), Day 0 (60 minutes post-surgery), Day 1, and Weeks 1 and 2. 
For Cohorts 6-7, blood samples will be taken at Day -28 (Screening), Day 0 (60 minutes 
post-surgery), Day 1, Weeks 1, 4, 12, 24, and 48 and urine samples will be taken at Day -28 
(Screening), Day 0 (60 minutes post-surgery), Day 1, and Week 1 only. 
5.3.3 Laboratory Parameters 
Hematology, biochemistry, urinalysis and other laboratory data will be measured at various 
time points throughout the study (refer to Section 2 of the protocol). Values will be flagged 
as High or Low if outside the laboratory normal range. Out-of-range values will be assessed 
as clinically significant (CS) or not clinically significant (NCS) by the investigator. CS out-
of-range values will be recorded as AEs. Blood for immunology and blood for PCR will also 
be taken at multiple time points throughout the study, as will urine samples for 
biodistribution assessment. Shift tables for key laboratory parameters out of normal range 
will be presented for the assessed visits, if applicable. 
5.3.4 Other Safety Parameters 
Other safety parameters (vital signs, physical examination) will be measured. New 
abnormalities will be recorded as AEs. 
5.3.5 Exploratory Efficacy Parameters 
Contrast sensitivity will be performed using the Sloan Low Contrast Acuity Chart. Reading 
speed and visual function questionnaires (VFQ-25/CVAQC-25) will be recorded in patients 


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when possible and if the age of the patient allows. Multifocal ERG and adaptive optics are 
performed only in Cohorts 1-5 and not required for Cohorts 6-7. 
5.4 
Other Measures 
5.4.1 Concomitant Medication 
Changes to concomitant medications will be recorded at all visits. 
 
5.4.2 Patient Characteristics 
During screening, height, weight, sex, vital signs, inclusion/exclusion criteria, medical 
history (including reproductive status, clinical symptoms of SMD and treatment history), 
ECG, chest X-ray and anesthesia assessment will be recorded. 
5.4.3 Withdrawals 
The number and percentage of patients who withdraw from the study over time, along with 
the reasons for withdrawal, will be tabulated. 
5.4.4 Deaths 
All deaths occurring during the study and its follow-up period will be listed and included in 
the AE summary. 
6.0 
GENERAL STATISTICAL CONSIDERATIONS 
6.1 
Sample Size 
This is an exploratory study the primary objective of which is to evaluate safety and, as a 
secondary objective, to estimate the biological activity. No formal sample size calculation 
has been performed. Up to a total of 46 patients will be enrolled in seven cohorts. The first 
four cohorts will consist of four patients each, six additional patients will be enrolled in 
Cohort 5 at the MTD (1.8 x 106 TU), up to 12 patients will be enrolled into Cohort 6 at the 
MTD (1.8 x 106 TU), and up to 12 patients will be enrolled in Cohort 7 at the MTD (1.8 x 
106 TU). 
6.2 
Primary Data Set 
The primary data set to be used to prepare the final analysis and DSMB reports will include 
data from all eligible patients, regardless of adherence to the protocol. However, since 
patients receive only a single treatment, adherence to the protocol will only be affected if 
patients drop out of the study, are lost to follow-up or if patients are seen outside of the visit 
windows as defined in the protocol. If a patient withdraws from the study, the Week 48 
procedures will be completed where possible. 


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6.3 
Handling Data Irregularities 
Although the study will make efforts to ensure maximum patient compliance, data 
irregularities, including protocol violations, non-compliance, withdrawals, missing values 
and loss to follow-up, may occur and will impact the proposed analyses. However, the 
analyses will be primarily descriptive and formal hypothesis testing is not planned. Data 
which are missing could impact conclusions drawn from even a small number of patients and 
therefore presentations (tabular and graphical) will include an indication of missing values 
and, where possible, explanations will be provided. All available data will be reported in 
DSMB reports. There will be no replacement of missing data and no data will be removed. 
Data from experimental procedures, or procedures in which patients are unable to provide 
reliable results (e.g., poor fixation in perimetry), may be presented separately, footnoted, or 
otherwise indicated in the report.  
6.4 
Interim Analyses 
The DSMB will review accumulating data and evaluate safety of the study prior to escalation 
to the next dose cohort. No formal interim analyses will be performed, but the following 
section provides analyses that are specific to DSMB reports. 
6.5 
Analyses Specific to DSMB Reports 
At a minimum, the following individual data and mean data will be presented against time 
following surgery: 
• Adverse events  
• Concomitant medications (listed in Patient Profiles) 
• Laboratory results 
• Humoral antibody response and vector distribution data (whenever possible) 
• BCVA 
• IOP 
• Slit lamp examination and fundoscopy data 
 
Note that additional outcome data may be provided in DSMB reports when available or at the 
request of the DSMB. Thus, Sections 7 and 8 describe analyses and tables/plots 
(respectively) that will be selected and presented upon final analyses, and, at a minimum, 
those relevant to the above outcomes will be provided in DSMB reports.  


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6.6 
Software to be used for Analyses 
Data analyses will be conducted using SAS version 9.2 or higher. Some graphs may be 
generated in R version 3.2.1 or higher. 
6.7 
Modifications to the statistical section of the protocol 
The protocol history table below gives the timing, rationale, and key details of major changes 
to the protocol statistical sections, including the primary and key secondary 
endpoints/analyses, and the analysis populations associated with these analyses. 
 
Amendment 
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
1 
14DEC2010 
Amended in response to review by 
the DSMB. Updated exclusion 
criteria and management of ocular 
inflammation. 
None 
2 
31MAR2011 
Amended in response to review by 
the FDA. Updated study stopping 
criteria and injection procedure, 
Updated immunology and PCR timepoints. 
3 
16JUN2011 
Amended in response to review by 
the AFSSAPS. 
Clarified patient groups and updated 
screening/baseline procedures for ERG. 
4 
24JAN2012 
Updated to clarify some 
discrepancies and add an 
additional cohort. 
Updated time points for reading center 
endpoints,  
5 
14APR2014 
Updated due to a transfer in study 
sponsorship. 
None 
6 
12NOV2014 
Due to disease progression, 
reduced the size of Cohort 5 and 
added Cohort 6, a pediatric cohort. 
Added an additional cohort and reduced the 
size of Cohort 5. Modified timepoints for 
certain assessments. 
7 
10MAR2015 
Updated definition of rapid 
deterioration. 
None 
8 
16DEC2015 
Clarified target population for 
Cohort 6 and updated endpoints. 
Endpoints updated to be consistent 
throughout. 
9 
25FEB2016 
Amended in response to review by 
Health Authorities to modify cohort 
criteria and address inflammation. 
None 
10 
28JUL2016 
Updated inclusion criteria and anti-
inflammatory regimen. 
None 
11 
26SEP2017 
Added Cohort 7, clarified inclusion 
criteria, and updated definition of 
baseline. 
Updated definition of baseline to last visit 
before surgery. 
Note: Amendment 12 dated 29NOV2018 has not been submitted to study centers for approval. 


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6.8 
Statistical Modifications made in the Statistical Analysis Plan 
 
The statistical analysis plan history table below gives the timing, rationale, and key details 
for major changes to the statistical analysis features in the statistical analysis plan.  
 
SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
1 
18NOV2011 
Developed to define the analyses to 
be conducted for DSMB meetings and 
the CSR. 
 
2 
16SEP2016 
Updated for Amendment 10 of the 
protocol and to add outputs that had 
been requested by the sponsor. 
Added outputs for SAEs, AESIs, AEs by 
inflammation, AEs related to IMP, and AEs 
related to procedure. Separated ophthalmic 
presentation by study and fellow eye and 
added analyses for fellow eye. Updated patient 
profile presentations. 
3 
16SEP2019 
Updated for Amendment 11 of the 
protocol and to include the latest 
DSMB report format for final study 
report. 
Modified presentations of some outputs and 
removed patient profile presentations. Updated 
baseline to be the last visit prior to injection. 
7.0 
STATISTICAL ANALYSES 
In this Phase I/IIa study, statistical analyses will be primarily descriptive and include 
patient-level reports referred to herein as patient profiles. Although SAR422459 is applied to 
only the study eye, where available, ophthalmic results for both the study and fellow eyes 
will be reported and clearly identified as “study” or “fellow.” Comparisons between the study 
and fellow eyes could be biased as the two eyes were not randomized to determine which eye 
received IMP (the worse eye - as per investigator judgment - is selected as study eye). The 
following sections describe data presentations which will be available for review prior to 
proceeding to each cohort and at the end of the study. Some variables (primarily ophthalmic 
variables) may be combined with others in a patient profile. Refer to Sections 8 and 9 for 
sample reports. 
 
Data will be summarized using graphical, tabular and/or listing presentations. In addition to 
patient profiles, continuous-scaled variables will be summarized by mean and standard 
deviation and/or median and range while categorical variables will be summarized in 
frequency tables. Percentages given in the summary tables will be rounded and therefore may 
not always add up to exactly 100 percent. 
 
The primary analysis time point will be 48 weeks following administration of SAR422459, 
but all results contributing to the primary and secondary outcomes and assessments of safety 


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at all study visits will be presented. For all outcomes, the last available measures before 
surgery will be considered as baseline value. 
 
Some data of secondary endpoints and exploratory efficacy endpoints have not been analyzed 
and included in DSMB summary reports; for example, fundus autofluorescence imaging, 
reading speed data, CVAQC, and VFQ-25. Likewise, these data will not be analyzed for the 
final analysis since the abbreviated clinical study report will utilize the latest format of 
DSMB summary report for the patients enrolled under Amendments 1 to 11 with a data 
cutoff on May 23, 2018. 
7.1 
Patient Flow and Compliance 
The number of patients screened for eligibility will be reported in a figure, along with the 
number deemed ineligible at the Screening (Day -28) visit. The reasons for ineligibility will 
be provided in footnotes.  
 
A summary of patients’ compliance to the follow-up schedule and study procedures will also 
be tabulated. The number (%) of patients completing and withdrawing from the study over 
time along with reasons for withdrawal, including death, by cohort will be presented in 
tabular format.   
7.2 
Baseline Characteristics 
Baseline demographic and patient characteristics, including age, height, weight, gender, 
reproductive status, medical history, ocular history, chest X-ray, physical examination 
findings, ECG, ophthalmic examination findings (including IOP and visual acuity), imaging 
parameters and laboratory values, obtained from tests given at Screening (Day -28) and 
Baseline (Day -1) visits will be summarized. Rapid deterioration criteria and the date of 
assessment will be listed in a separate table for Cohort 6-7 patients. 
7.3 
Primary Outcome 
The primary outcome is composed of several outcomes related to safety, each of which will 
be presented at the patient and eye level (refer to Sections 8 and 9). Primary analysis for 
these outcomes, except adverse events, will compare change in parameter values from 
Baseline to Week 48. Graphical presentation of cohort summaries will also be presented as 
described, and clinically important changes from Baseline to Week 48 will be indicated and 
summarized. 
7.3.1 Adverse Events 
Adverse events (AEs) will be coded using MedDRA® (last version available at time of 
database lock). All reported events for all patients, with cohort, event description, event date, 


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resolution date, severity, outcome, relatedness, SAE indication, duration, High Level Term 
(HLT), High Level Group Term (HLGT), System Organ Class (SOC) and Preferred Term 
(PT) will be listed. Specifically, AEs prior to treatment, treatment emergent adverse events 
(TEAEs) (i.e., started or increased in severity after the patient receives IMP, including 
abnormal lab results, ECG, etc.) and treatment emergent adverse events (TEAEs) of special 
interest will be listed separately. An overall summary table of TEAEs will also be provided 
that includes the number and percentage of TEAEs and patients with at least one TEAE in 
each dose cohort with:  
• A fatal TEAE (death) 
• At least one serious TEAE 
• At least one severe TEAE 
• At least one TEAE related to IMP 
• At least one TEAE related to procedure 
• Without any TEAEs 
In addition, tables will present both the number and percentage of TEAEs and patients with 
TEAEs by primary SOC, HLGT, HLT, PT, severity and cohort. Treatment emergent adverse 
events of special interest (TEAESI), detailed in the protocol, will be listed and summarized 
by primary SOC, HLGT, HLT, PT, severity and cohort. TEAESIs will be indicated where 
appropriate in the patient profile listing of AEs. AEs related to the IMP and serious adverse 
events (SAEs) will be indicated in the TEAE listing and described in detail in the body of the 
report. Specific grouping will be done for events inflammatory in nature in the eye. Summary 
tables will be presented both with the inflammatory events grouped and without the events 
grouped. All events with the following preferred terms will be considered inflammatory in 
nature in the eye: 
• Anterior chamber cell 
• Anterior chamber inflammation 
• Choroidal effusion 
• Conjunctivitis 
• Eye inflammation 
• Eye discharge 
• Keratitis 
• Macular edema 
• Subretinal fluid 
• Uveitis 
• Vitreous floaters 


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Patients with at least 1 TEAE will be summarized once by unique MedDRA coded term, 
where multiple incidences of the same coded term will be counted once only by the most 
severe event or the event of extreme relationship to the IMP or to study procedure. 
7.3.2 Best-Corrected Visual Acuity (BCVA) 
BCVA (Early Treatment Diabetic Retinopathy Study [ETDRS] letters read) will be listed by 
visit and eye. Study and fellow eye mean BCVA will be tabulated by visit and cohort. BCVA 
for all patients by eye, visit and cohort group will be presented graphically. Mean changes in 
BCVA by visit and cohort will also be presented graphically. The number of individuals with 
BCVA gain or loss ≥ 5, ≥ 10 and ≥ 15 letters at any point from baseline to Week 48 will be 
tabulated by cohort and visit. 
7.3.3 Ocular Inflammation 
The grading system of ocular inflammation can be found in Appendix A of the study 
protocol. The inflammatory grades will be treated as ordinal variables and plotted by patient 
over time. Scores for ocular inflammation, including anterior chamber cells, flare (slit lamp 
examination) and vitreous cells, haze (indirect ophthalmoscopy) and macular edema, will be 
listed by eye and shown graphically with other ophthalmic outcomes. Summary counts for 
the number of ‘step-up’ and ‘step-down’ changes in the inflammation scale in the study eye 
and fellow eye may be tabulated by cohort and visit. Clinically important changes (i.e., ≥ 2 
step change) as observed in slit lamp examination and/or indirect ophthalmoscopy from 
baseline to Week 48 will be indicated and listed where appropriate. 
7.3.4 Intraocular Pressure (IOP) 
The IOP for each visit will be measured using applanation tonometry. Individual IOP will be 
listed by eye and shown graphically with other ophthalmic outcomes. IOP will be listed, 
tabulated and shown graphically similar to BCVA outcomes. Clinically important changes, 
defined as increases or decreases of ≥ 10 mmHg, and the number of individuals with IOP ≥ 
25, ≥ 30 and ≥ 35 mmHg at any point from baseline to Week 48 will be tabulated by cohort 
and visit. 
7.3.5 Microperimetry 
Microperimetry images will be used to perform a quantitative assessment of fixation and 
document scotoma. These image data will not be summarized for Cohorts 1-5 for DSMB 
meetings; however, appropriate images and/or data values will be reported upon final 
analyses. Image data will be presented for Cohorts 6-7 for DSMB meetings and upon final 
analyses.   


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7.3.6 Full-field Static and Kinetic Perimetry 
Full-field static and kinetic perimetry will be used to document scotoma and the level of 
retinal function for each patient, and clinically significant changes from baseline will be 
highlighted. For assessments in which more than one measurement is taken at a single visit 
(e.g., multiple sessions in GATE), the mean of these measurements will be used in analysis. 
 
Individual and mean total volume loss in visual field as well as total volume of full hill of 
vision will be plotted (dB steradians) over time. Values in each eye will be listed in tabular 
format by patient and visit. For Cohort 6-7 patients, reliability factor in each eye will be 
listed in tabular format by patient and visit.  
 
Semi-automated kinetic perimetry (SKP) will be used to estimate total area (degrees2) of 
visual field sensitivity and total scotoma area (degrees2) (for Cohorts 6-7 only) for different 
stimulus intensity levels (I4e, III4e and V4e isopters). Individual and mean total areas will be 
plotted against time. Values in each eye will be listed in tabular format by patient and visit. 
Mean change from Baseline to Weeks 24 and 48 in static and SKP outcomes will be plotted 
against dose received for each eye (study and fellow). 
7.3.7 Optical Coherence Tomography (OCT) 
Central macular thickness, subretinal fluid, macular volume and other architectural features 
will be measured by OCT. Individual values of macular thickness (in the central sub-field) 
and macular volume will be listed and illustrated graphically similar to other ophthalmic 
outcomes. Macular thickness and volume will be listed by visit and eye. Macular thickness 
and volume for all patients’ study eye and fellow eye will be presented graphically by visit 
and cohort. Mean changes in macular thickness and volume by visit and cohort will be 
summarized in a table and graph by cohort and visit. 
 
Extra parameters will be listed in the patient profiles by patient and visit for Cohort 6-7 
patients. These extra parameters include evidence of treatment efficacy, increases in cystoid 
macular edema from baseline, unfavorable changes in subretinal fluid from baseline, AEs 
related to the visit and modality, presence of an E-Z Band, and description of E-Z band 
changes from baseline. 
7.3.8 Electroretinogram (ERG) 
Full field ERG responses include 30 Hz flicker; photopic single flash a- and b-waves; 
scotopic cone-rod flash a- and b-waves; and scotopic rod, dim white light b-wave. 
Amplitudes and implicit times will be presented in tabular format and graphically by patient 
and cohort as appropriate. Clinically significant changes from baseline in ERG data will be 
indicated and listed where appropriate.  


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Maximum peak amplitudes (nV/deg2) and latency (ms) values for multifocal ERG (mfERG) 
responses at baseline will be tabulated for each of six concentric rings in the visual field by 
patient. To examine change in mfERG responses in the central visual field across visits, the 
mean changes from Baseline across the inner rings (Rings 1-3) will be tabulated and plotted 
against time by patient. In addition, mean changes across the outer rings (Rings 4-6) will also 
be tabulated and plotted by patient against time. Multifocal ERG data will be reported only 
for Cohorts 1-5 and will not be collected for Cohorts 6-7. 
7.3.9 Laboratory Parameters 
Clinical laboratory results, including hematology (WBC, RBC, hemoglobin, hematocrit, 
mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, 
platelets, neutrophils, lymphocytes, monocytes, eosinophils and basophils), blood chemistry 
(phosphorus, calcium, sodium, chloride, bicarbonate, potassium, fasting blood glucose, 
creatine phosphokinase and lactate dehydrogenase), kidney and liver function tests 
(creatinine, blood urea nitrogen, uric acid, ALT, AST, total bilirubin, alkaline phosphatase, 
total protein, albumin and gamma glutamic transpeptidase and cholesterol), coagulation 
(prothrombin time and partial thromboplastin time) and urinalysis (protein, blood and 
ketones) will be listed for each patient and visit in the patient profiles. Individual lab values 
will be flagged as ‘High’ or ‘Low’ if outside the clinical site’s normal ranges.  
 
A summary of the number of patients with abnormal and/or clinically significant laboratory 
values will be provided. The following laboratory values and thresholds will be highlighted 
to indicate their clinical significance for major functions: 
• WBC above 2ULN (upper limit of normal) 
• Neutropenia < 1500 
• Platelets < 100,000 
• Creatinine > 1.5ULN 
• ALT ≥ 3ULN 
• AST ≥ 3ULN 
• Total bilirubin ≥ 2 ULN 
 
The lab values will be assessed by site physicians, and clinically significant abnormal lab 
values will also be recorded as AEs. 
7.3.10 Vital Signs 
Vital signs will be summarized and listed by cohort and visit. In addition, patients’ vital signs 
at each study visit will be listed with other examination results in a patient profile. Any 


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abnormalities that are also clinically significant changes in patients’ vital signs will be 
indicated.   
7.3.11 Concomitant Medications 
Concomitant medications including the WHO drug coding will be listed by patient, cohort 
and study visit. Medications will be coded using the last WHO drug coding version available 
at time of database lock. 
7.3.12 Physical Examinations 
Physical Examinations will be conducted at Day -28 and Week 48 visits. System abnormality 
frequencies and percentages (including head/ear-nose-throat, respiratory, gastrointestinal, 
cardiovascular, musculoskeletal, neurologic, endocrine/metabolic, lymphatic/hematologic, 
dermatologic, psychological and genitourinary) will be tabulated by cohort at each time 
point. 
7.4 
Secondary Outcomes 
The secondary outcomes include changes in the study eye from Baseline to Weeks 24 and 48 
relative to the untreated, contralateral eye in measures of visual function and retinal structure. 
The primary outcomes of BCVA, microperimetry, full field static and kinetic perimetry will 
also serve as secondary outcome measures for visual function. Analysis of these parameters 
will be conducted as outlined in previous Sections 7.3.2, 7.3.3 and 7.3.6, respectively. 
Additionally, OCT, a primary outcome measure, and FAF will serve as secondary outcomes 
measures for retinal structure. 
7.4.1 Fundus Autofluorescence (FAF) and Supplementary Reading Center Data 
Fundus photography photomontage, fundus autofluorescence (FAF), OCT image data, 
adaptive optics and microperimetry data will all be analyzed separately by TCTC, the Central 
Reading Center. These exploratory measures will not be summarized for Cohorts 1-5 for 
DSMB meetings; however, appropriate images and/or data values will be provided by the 
Reading Center upon final analyses. FAF and microperimetry data will be presented for 
Cohorts 6-7 for DSMB meetings and upon final analyses. 
7.5 
Exploratory Efficacy Outcomes 
7.5.1 VFQ-25 
All VFQ-25 responses will be re-coded to a scale of 0 to 100 following the scoring rules 
provided by the questionnaire. The mean of all re-coded scores will determine the score for 
each patient, which will range from 0 to 100. The scores for the 12 VFQ-25 sub-scales will 
also be provided, if appropriate. Change in the VFQ-25 responses from baseline to Week 48 


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will be tabulated by patient and cohort and 95% confidence limits and/or ranges will be 
provided. Meaningful changes from baseline will be highlighted where appropriate. 
 
The CVAQC-25 will be used for patients under the age of 18. The mean of CVAQC-25 
responses will determine the score for each patient. The scores for the seven CVAQC-25 
subscales will also be provided, if appropriate. Change in the CVAQC-25 responses from 
baseline to Week 48 will be tabulated by patient and cohort and 95% confidence intervals 
and/or ranges will be provided. Meaningful changes from baseline will be highlighted where 
appropriate.  
7.5.2 Reading Speed 
Change in reading speed scores (words per minute) as well as changes in log reading acuity 
determination (logRAD) from baseline to Week 48 will be tabulated by study eye and fellow 
eye and cohort and 95% confidents limits will be provided as appropriate. Significant 
changes from baseline to Week 48 will be highlighted where appropriate. 
7.5.3 Low-Contrast Sloan Letter Chart Testing 
Low-contrast total letters read using the Sloan letter chart will be listed by visit and eye. 
Study eye and fellow eye mean low-contrast total letters read will be tabulated by visit and 
cohort. Low-contrast total letters read for all patients by eye, visit and cohort group will be 
presented graphically. Mean changes in low-contrast letters read by visit and cohort will also 
be presented graphically. All low-contrast results will be presented at 100% contrast, 
2.5% contrast and 1.25% contrast. Low-contrast Sloan letter chart testing will only be 
performed for Cohort 6-7 patients. 
7.6 
Other Safety Measures 
7.6.1 Immunology 
The number and percentage of patients with antibody responses to any SAR422459 
component at all time points will be tabulated by dose cohort. 
7.6.2 Biodistribution  
The number and percentage of patients with SAR422459 detected in the blood and urine by 
PCR at all relevant time points will be listed (See Section 2 of protocol for specific visits). 
These data may not be available for review between cohorts but will be reported when 
available. 


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7.7 
Safety Analysis 
The primary, secondary and additional safety measures described in the preceding sections 
pertain mostly to assessing patient safety. The only additional safety assessment will be the 
determination of the MTD. 
7.7.1 Determination of Maximum Tolerated Dose (MTD) 
The MTD will be defined as the highest dose level that has an acceptable safety and 
tolerability and positive benefit/risk profile in the opinion of the DSMB.   
8.0 
A LIST OF PROPOSED TABLES/LISTINGS/FIGURES 
This section contains a list of proposed tables, listings, and figures that will be presented in 
analysis of study data, but not all tables, listings, and figures will be included in DSMB 
reports. At a minimum, tables, listings, and figures from Sections 8.1 through 8.3.4 will be 
included in DSMB reports, but additional tables, listings, and figures from remaining 
sections will be included when possible. 
 
8.1 
TOC for all TLFs of the latest DSMB report format proposed for TDU13583 CSR 
• Table 1A: Screening and Surgery Dates and Visit Completion by Cohort 
• Figure 1B: Patient Flow Diagram 
• Table 1C: Study Follow-up Completion and Withdrawal (including deaths) 
• Table 2A: Demographics Summary by Cohort 
• Listing 2B: Detailed Demographic Listing by Cohort 
• Listing 2C: Rapid Deterioration Assessment for Cohort 6-7 
• Listing 2D: General Medical History by Patient 
• Listing 2E: Study Eye Ocular History by Patient 
• Listing 2F: Fellow Eye Ocular History by Patient 
• Table 2G: Baseline Physical Examination Parameters by Cohort 
• Table 2H: Reproductive Status by Patient 
• Listing 2I: Detailed Surgery Listing by Patient for All Cohorts 
• Listing 2J: Detailed Surgery Listing by Patient for Cohort 6-7 Specific Parameters 
• Table 3A: Number and Percentage of Patients Experiencing TEAEs or No Events by 
Type of Event and Cohort 


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• Table 3B: Number of Patients Experiencing TEAEs by MedDRA SOC, HLGT, HLT, PT, 
and Cohort 
• Table 3C: Number of Patients with TEAEs of Special Interest by MedDRA SOC, HLGT, 
HLT, PT, and Cohort 
• Table 3D: Number of Patients with SAEs by MedDRA SOC, HLGT, HLT, PT, and 
Cohort 
• Table 3E: Number of Patients Experiencing Inflammatory TEAEs by MedDRA SOC, 
HLGT, HLT, PT, and Cohort 
• Table 3F: Number of Patients with TEAEs Related to IMP by MedDRA SOC, HLGT, 
HLT, PT, and Cohort 
• Table 3G: Number of Patients with TEAEs Related to Procedure by MedDRA SOC, 
HLGT, HLT, PT, and Cohort 
• Table 3H: Listing of Adverse Events Prior to Treatment by Patient and Cohort 
• Table 3I: Listing of TEAEs by Patient and Cohort 
• Table 3J: Listing of Treatment Emergent Adverse Events of Special Interest by Patient 
and Cohort 
• Table 3K: Listing of Treatment Emergent Serious Adverse Events by Patient and Cohort 
• Table 3L: Number of Patients Receiving Concomitant Medications by ATC1, ATC2, 
ATC3, ATC4, and Cohort 
• Listing 3M: Ophthalmic Outcome Listing for Study Eye and Fellow Eye by Patient and 
Visit 
• Table 3N: Mean Changes from Pre-surgical BCVA by Cohort and Visit 
• Table 3O: Patients Experiencing a Change in BCVA in the Study Eye at Week 48 
Following Treatment by Cohort 
• Table 3P: Mean Changes from Pre-surgical IOP by Cohort and Visit 
• Table 3Q: Patients Experiencing Elevated IOP in the Study Eye at Week 48 Following 
Treatment by Cohort 
• Table 3R: Patients Experiencing Elevated IOP in the Fellow Eye at Week 48 Following 
Treatment by Cohort 
• Table 3S: Patients Experiencing a Clinically Significant Change in IOP in the Study Eye 
Following Treatment by Cohort 
• Tables 3T-3W: Changes in Ophthalmic Inflammation in the Study Eye by Cohort and 
Visit 
• Figure 3X: BCVA in Study and Fellow Eyes by Patient 
• Figure 3Y: IOP in Study and Fellow Eyes by Patient 


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• Figure 3Z: Mean Changes in BCVA over Time by Cohort 
• Figure 3AA: Mean Changes in IOP over Time by Cohort 
• Listing 3AB: Listing of Patients with Abnormal and/or Clinically Significant Labs 
• Listing 3AC: Abnormal Physical Examination Listing by Patient 
• Table 3AD: Mean Change in Continuous Laboratory Parameters by Cohort and Visit 
• Figures 3AE-3AZ: Change in Laboratory Parameters by Patient 
• Table 3BA: Patients Experiencing Edema or Subretinal Fluid in the study eye by Cohort 
• Listing 3BB: OCT Listing by Patient and Visit 
• Table 3BC: OCT Central Retinal Thickness (µm) by Cohort and Visit 
• Table 3BD: OCT Macular Volume (mm3) by Cohort and Visit 
• Figures 3BE: Central Retinal Thickness (OCT) for Study and Fellow Eyes 
• Figures 3BF: Macular Volume (OCT) for Study and Fellow Eyes 
• Table 3BG: Change from Baseline in Vital Signs by Cohort and Visit 
• Figure 4A: Total Volume Loss Measured by Static (GATE) Perimetry by Patient 
• Figure 4B: Volume of Full Field Hill of Vision Measured by Static (GATE) Perimetry by 
Patient 
• Listing 4C: Static (GATE) Perimetry Data by Cohort, Patient, and Visit 
• Figures 4D: Semi-Automated Kinetic Perimetry Data in Study Eyes by Patient 
• Listing 4E: Kinetic (SKP) Perimetry Data by Cohort, Patient, and Visit 
• Figure 4F: Microperimetry Radius of Fixation Data by Patient 
• Figure 4G: Microperimetry Mean Sensitivity Data by Patient 
• Figure 4H: Microperimetry Eccentricity Data by Patient 
• Listing 4I: Microperimetry Data by Cohort, Patient, and Visit 
• Listing 4J: Full Field ERG Response (Study Eye) Amplitude and Implicit Time Data by 
Cohort, Patient and Visit 
• Listing 4K: Full Field ERG Response (Fellow Eye) Amplitude and Implicit Time Data by 
Cohort, Patient and Visit 
• Figures 4L-4AL: Full-field ERG Response in Patient X 
• Table 4AM: Mean Peak Amplitudes and Latencies at Baseline (mfERG) by Cohort and 
Patient 
• Table 4AN: Central Field (Rings 1-3) Summary mfERG Data by Cohort and Patient 
• Table 4AO: Peripheral Field (Rings 4-6) Summary mfERG Data by Cohort and Patient 


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• Figures 4AP-4AT: Change in Central Field (Rings 1-3) mfERG Response Over Time for 
Cohort X 
• Figures 4AU-4AY: Change in Peripheral Field (Rings 4-6) mfERG Response Over Time 
for Cohort X 
• Table 5A: SAR422459 Positive Immunological Data 
• Listing 5B: Detailed Listing of Immunologic Results from Blood Samples by Cohort and 
Patient 
• Listing 5C: Detailed Listing of PCR by Cohort, Patient, and Specimen 
 
 




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Figure 1B: Patient Flow Diagram 
 
 
 
 
 
Screened at Screening 
Visit 
(N=X) 
Determined to be ineligible 
at 
Screening Visit 
(N=X) 
Reasons: 
Eligible at Baseline Visit and  
received investigational 
product at Day 0  
(N=X) 
Determined to be ineligible at 
Baseline Visit 
(N=X) 
Eligible at Screening Visit 
and screened at Baseline 
Visit 
(N=X) 
Eligible at Week 48 and 
enrolled into LTS13588  
(N=X) 
Eligible at Week 48 and did not 
enroll in LTS13588 
(N=X) 










































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Figure 3.2: Mean Change in Ophthalmic Outcome from Baseline versus Dose Cohort 
 
 
 
 














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Figure 4.1: Full Field ERG Response