Clinical trial NCT03972709
Conditions: Macular Degeneration, Age-Related Geographic Atrophy
Sponsor: Genentech, Inc.
Start date: 2019-06-03; Completion date: 2022-10-27
Enrollment: 372 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, and efficacy of intravitreal injections of galegenimab (FHTR2163) administered every 4 weeks (Q4W) or every 8 weeks (Q8W) for approximately 76 weeks in participants with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) compared with sham control. After completing the study's last visit (Week 76), eligible participants will have the option to enroll in open-label extension study NCT04607148 (GR42558) and receive open-label galegenimab (FHTR2163) injections.

Detailed description:

Arms: arm 1: Participants will receive galegenimab every 4 weeks (Q4W). After completing the study's last visit (Week 76), eligible participants will have the option to enroll in open-label extension study NCT04607148 (GR42558) and receive open-label galegenimab injections. arm 2: Participants will receive Sham-control Q4W. After completing the study's last visit (Week 76), eligible participants will have the option to enroll in open-label extension study NCT04607148 (GR42558) and receive open-label galegenimab injections. arm 3: Participants will receive galegenimab every 8 weeks (Q8W). After completing the study's last visit (Week 76), eligible participants will have the option to enroll in open-label extension study NCT04607148 (GR42558) and receive open-label galegenimab injections. arm 4: Participants will receive Sham-control Q8W. After completing the study's last visit (Week 76), eligible participants will have the option to enroll in open-label extension study NCT04607148 (GR42558) and receive open-label galegenimab injections.
Interventions: intervention 1: Galegenimab intervention 2: Sham Control
Intervention descriptions: intervention 1: Intravitreal (ITV) injections of galegenimab intervention 2: Sham control

Protocol documents:
Prot_SAP_001.pdf: 
 
Official Title:  
 
A PHASE II, MULTICENTER, RANDOMIZED, SINGLE-MASKED, 
SHAM-CONTROLLED STUDY TO ASSESS SAFETY, 
TOLERABILITY, AND EFFICACY OF INTRAVITREAL INJECTIONS 
OF FHTR2163 IN PATIENTS WITH GEOGRAPHIC ATROPHY 
SECONDARY TO AGE-RELATED MACULAR DEGENERATION 
(GALLEGO) 
NCT Number: 
NCT03972709 
Document Date:  Protocol Amendment Version 5: 23 October 2023 
 
 


CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (or under its control) and therefore is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Ethics Committee 
or Institutional Review Board.  It is understood that this information will not be disclosed to others 
without written authorization from Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
FHTR2163
Genentech, Inc. 
Protocol GR40973, Version 5 
PROTOCOL 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, 
SINGLE-MASKED, SHAM-CONTROLLED STUDY 
TO ASSESS SAFETY, TOLERABILITY, AND 
EFFICACY OF INTRAVITREAL INJECTIONS OF 
FHTR2163 IN PATIENTS WITH GEOGRAPHIC 
ATROPHY SECONDARY TO AGE-RELATED 
MACULAR DEGENERATION (GALLEGO) 
PROTOCOL NUMBER: GR40973 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
134632 
NCT NUMBER: 
NCT03972709 
TEST PRODUCT: 
FHTR2163 (RO7171009) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
See electronic signature and date stamp on the final 
page of this document. 
 


FHTR2163
Genentech, Inc. 
2/Protocol GR40973, Version 5 
PROTOCOL HISTORY 
Version 
Date Final 
1 
18 February 2019 
2 
12 September 2020 
3 
3 May 2021 
4 
25 October 2021 
 


 
FHTR2163
Genentech, Inc. 
3/Protocol GR40973, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol GR40973 has been amended primarily to update the NCT number.  Changes to 
the protocol, along with a rationale for each change, are summarized below: 
 
The NCT number has been corrected from NCT04507148 to NCT03972709 (front 
matter) 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


 
FHTR2163
Genentech, Inc. 
4/Protocol GR40973, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND ............................................................................ 21 
1.1 
Background on Geographic Atrophy Secondary to 
Age-Related Macular Degeneration ......................................... 21 
1.2 
Background on HtrA1 .............................................................. 22 
1.3 
Background on FHTR2163 ...................................................... 22 
1.3.1 
FHTR2163 Nonclinical Toxicology Summary ........................... 22 
1.3.2 
FHTR2163 Phase I Safety Summary and Pharmacokinetic 
Preliminary Data ...................................................................... 23 
1.4 
Study Rationale and BenefiT-Risk Assessment ....................... 24 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 24 
2.1 
Efficacy ObjectiveS .................................................................. 25 
2.1.1 
Primary Efficacy Objective ....................................................... 25 
2.1.2 
Secondary Efficacy Objective .................................................. 25 
2.1.3 
Exploratory Efficacy Objectives ............................................... 25 
2.2 
Safety Objective ....................................................................... 25 
2.3 
Pharmacokinetic Objective ...................................................... 26 
2.4 
Immunogenicity Objective ........................................................ 26 
2.5 
Biomarker Objectives ............................................................... 26 
3. 
STUDY DESIGN ........................................................................... 27 
3.1 
Description of the Study ........................................................... 27 
3.1.1 
Open-Label Extension Study and Study Follow-Up ................. 32 
3.1.2 
Internal Monitoring Committee ................................................. 32 
3.2 
End of Study and Length of Study ........................................... 32 
3.3 
Rationale for Study Design ...................................................... 32 
3.3.1 
Rationale for FHTR2163 Dose and Schedule .......................... 33 
3.3.2 
Rationale for Patient Population and Analysis Groups ............ 33 
3.3.3 
Rationale for Sham-Control Group .......................................... 34 
3.3.4 
Rationale for Pharmacokinetic and Pharmacodynamic 
Sampling Schedule .................................................................. 34 


 
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3.3.5 
Rationale for Biomarker Assessments ..................................... 35 
3.3.5.1 
Rationale for Aqueous Humor Samples ................................... 35 
3.3.5.2 
Rationale for Plasma and Whole Blood Samples .................... 35 
3.3.5.3 
Rationale for Collection of Prebaseline FAF Images and 
Historical Ocular Images .......................................................... 36 
3.3.5.4 
Rationale for HtrA1 Risk-Variant Genotyping Assay ................ 36 
4. 
MATERIALS AND METHODS ...................................................... 36 
4.1 
Patients .................................................................................... 36 
4.1.1 
Inclusion Criteria ...................................................................... 36 
4.1.2 
Exclusion Criteria ..................................................................... 38 
4.2 
Method of Treatment Assignment and Masking....................... 42 
4.2.1 
Treatment Assignment ............................................................. 42 
4.2.2 
Masking ................................................................................... 42 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 43 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 43 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 43 
4.3.2.1 
FHTR2163 and Sham Control ................................................. 44 
4.3.3 
Investigational Medicinal Product Accountability ..................... 44 
4.3.4 
Continued Access to FHTR2163 ............................................. 44 
4.4 
Concomitant Therapy .............................................................. 44 
4.4.1 
Permitted Therapy ................................................................... 45 
4.4.2 
Prohibited Therapy .................................................................. 45 
4.5 
Study Assessments ................................................................. 46 
4.5.1 
Informed Consent Forms and Screening Log .......................... 46 
4.5.2 
Medical History and Demographic Data .................................. 46 
4.5.3 
Physical Examinations ............................................................. 46 
4.5.4 
Vital Signs ................................................................................ 47 
4.5.5 
Ocular Assessments ................................................................ 47 
4.5.6 
Ocular Imaging ........................................................................ 48 
4.5.7 
Follow-Up Calls ........................................................................ 48 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples ............ 49 
4.5.9 
Blood Samples for Whole Genome Sequencing (Patients 
at Participating Sites) ............................................................... 50 


 
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4.5.10 
Optional Samples for Research Biosample Repository ........... 51 
4.5.10.1 
Overview of the Research Biosample Repository .................... 51 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 52 
4.5.10.3 
Sample Collection and Storage Timeline ................................. 52 
4.5.10.4 
Confidentiality .......................................................................... 53 
4.5.10.5 
Consent to Participate in the Roche Biosample Repository ..... 53 
4.5.10.6 
Withdrawal from the Roche Biosample Repository .................. 53 
4.5.10.7 
Monitoring and Oversight ......................................................... 54 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 54 
4.6.1 
Study Treatment Discontinuation ............................................. 54 
4.6.2 
Patient Discontinuation from the Study .................................... 55 
4.6.3 
Study Discontinuation .............................................................. 55 
4.6.4 
Site Discontinuation ................................................................. 56 
5. 
ASSESSMENT OF SAFETY ......................................................... 56 
5.1 
Safety Plan .............................................................................. 56 
5.1.1 
Potential Risks Associated with FHTR2163 ............................. 56 
5.1.1.1 
Potential Ocular Risks ............................................................. 56 
5.1.1.2 
Potential Systemic Risks ......................................................... 58 
5.1.2 
Risks Associated with Intravitreal Route of Administration ...... 59 
5.1.3 
Risks Associated with Aqueous Humor Sampling through 
Anterior Chamber Paracentesis ............................................... 59 
5.1.4 
Management of Patients Who Experience Adverse Events 
Associated with Intravitreal Injection ........................................ 60 
5.1.5 
Dose-Interruption and/or Treatment Discontinuation 
Criteria ..................................................................................... 60 
5.2 
Safety Parameters and Definitions .......................................... 62 
5.2.1 
Adverse Events ........................................................................ 63 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 63 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 64 
5.2.4 
Selected Adverse Events ......................................................... 65 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 65 


 
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5.3.1 
Adverse Event Reporting Period .............................................. 65 
5.3.2 
Eliciting Adverse Event Information ......................................... 66 
5.3.3 
Assessment of Severity of Adverse Events ............................. 66 
5.3.4 
Assessment of Causality of Adverse Events............................ 67 
5.3.5 
Procedures for Recording Adverse Events .............................. 68 
5.3.5.1 
Adverse Events of Ocular Infection and Inflammation ............. 68 
5.3.5.2 
Increased Intraocular Pressure Values .................................... 69 
5.3.5.3 
Abnormal Findings on Ocular Imaging ..................................... 69 
5.3.5.4 
Diagnosis versus Signs and Symptoms ................................... 69 
5.3.5.5 
Adverse Events That Are Secondary to Other Events ............. 70 
5.3.5.6 
Persistent or Recurrent Adverse Events .................................. 70 
5.3.5.7 
Abnormal Laboratory Values ................................................... 71 
5.3.5.8 
Abnormal Vital Sign Values ..................................................... 71 
5.3.5.9 
Abnormal Liver Function Tests ................................................ 72 
5.3.5.10 
Deaths ..................................................................................... 72 
5.3.5.11 
Preexisting Medical Conditions ................................................ 73 
5.3.5.12 
Worsening of Geographic Atrophy in Study Eye ...................... 73 
5.3.5.13 
Hospitalization or Prolonged Hospitalization ............................ 73 
5.3.5.14 
Cases of Accidental Overdose or Medication Error ................. 74 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 75 
5.4.1 
Emergency Medical Contacts .................................................. 75 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 76 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 76 
5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 76 
5.4.3 
Reporting Requirements for Pregnancies ................................ 76 
5.4.3.1 
Pregnancies in Female Patients .............................................. 76 
5.4.3.2 
Abortions.................................................................................. 77 
5.4.3.3 
Congenital Anomalies/Birth Defects ........................................ 77 
5.5 
Follow-Up of Patients after Adverse Events............................. 77 
5.5.1 
Investigator Follow-Up ............................................................. 77 
5.5.2 
Sponsor Follow-Up .................................................................. 78 


 
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5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 78 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 78 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 79 
6.1 
Determination of Sample Size ................................................. 79 
6.2 
Summaries of Conduct of Study .............................................. 80 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 80 
6.4 
Efficacy Analyses ..................................................................... 80 
6.4.1 
Primary Efficacy Endpoint ........................................................ 80 
6.4.2 
Secondary Efficacy Endpoints ................................................. 81 
6.5 
Safety Analyses ....................................................................... 81 
6.6 
Pharmacokinetic Analyses ....................................................... 81 
6.7 
Immunogenicity Analyses ........................................................ 81 
6.8 
Biomarker Analyses ................................................................. 82 
6.9 
Optional Interim Analyses ........................................................ 82 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 82 
7.1 
Data Quality Assurance ........................................................... 82 
7.2 
Electronic Case Report Forms ................................................. 83 
7.3 
Source Data Documentation .................................................... 83 
7.4 
Use of Computerized Systems ................................................ 83 
7.5 
Retention of Records ............................................................... 84 
8. 
ETHICAL CONSIDERATIONS ...................................................... 84 
8.1 
Compliance with Laws and Regulations .................................. 84 
8.2 
Informed Consent .................................................................... 84 
8.3 
Institutional Review Board or Ethics Committee ...................... 85 
8.4 
Confidentiality .......................................................................... 86 
8.5 
Financial Disclosure ................................................................. 87 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 87 
9.1 
Study Documentation .............................................................. 87 
9.2 
Protocol Deviations .................................................................. 87 
9.3 
Site Inspections ....................................................................... 87 


 
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9.4 
Administrative Structure ........................................................... 87 
9.5 
Dissemination of Data and Protection of Trade Secrets .......... 88 
9.6 
Protocol Amendments ............................................................. 89 
10. 
REFERENCES.............................................................................. 90 
 
 
LIST OF TABLES 
Table 1 
Dose Interruption and Treatment Discontinuation Criteria and 
Management ............................................................................... 61 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 67 
Table 3 
Causal Attribution Guidance ....................................................... 67 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 27 
Figure 2 
Prebaseline Image Collection Flowchart ..................................... 30 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities:  Q4W Arm .............................................. 93 
Appendix 2 
 Schedule of Activities:  Q8W Arms ............................................ 99 
Appendix 3 
 HtrA1 Risk-Variant Genotyping Assay ..................................... 105 
Appendix 4 
 Best Corrected Visual Acuity Testing ....................................... 106 
Appendix 5 
 Low-Luminance Best Corrected Visual Acuity Testing ............. 107 
Appendix 6 
 Grading Scale for Assessment of Anterior Chamber Flare or 
Cells and Vitreous Cells ............................................................ 108 
Appendix 7 
 Post-Injection Procedures for All Patients ................................ 109 
Appendix 8 
 Color Fundus Photography ...................................................... 110 
Appendix 9 
 Fundus Autofluorescence ........................................................ 111 
Appendix 10 
 Near-Infrared Imaging .............................................................. 112 
Appendix 11 
 Spectral Domain Optical Coherence Tomography ................... 113 
Appendix 12 
 Optical Coherence Tomography Angiography ......................... 114 
Appendix 13 
 Fluorescein Angiography ......................................................... 115 
Appendix 14 
 Anterior Chamber Paracentesis and Aqueous Humor 
Sampling Procedure ................................................................. 116 
Appendix 15 
 WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events ......................................................................... 118 
 


 
FHTR2163
Genentech, Inc. 
10/Protocol GR40973, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, 
SINGLE-MASKED, SHAM-CONTROLLED STUDY 
TO ASSESS SAFETY, TOLERABILITY, AND 
EFFICACY OF INTRAVITREAL INJECTIONS OF 
FHTR2163 IN PATIENTS WITH GEOGRAPHIC 
ATROPHY SECONDARY TO AGE-RELATED 
MACULAR DEGENERATION (GALLEGO) 
PROTOCOL NUMBER: GR40973 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
134632 
NCT NUMBER: 
NCT03972709 
TEST PRODUCT: 
FHTR2163 (RO7171009) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by PPD. 


 
FHTR2163
Genentech, Inc. 
11/Protocol GR40973, Version 5 
PROTOCOL SYNOPSIS
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, SINGLE-MASKED, 
SHAM CONTROLLED STUDY TO ASSESS SAFETY, 
TOLERABILITY, AND EFFICACY OF INTRAVITREAL INJECTIONS 
OF FHTR2163 IN PATIENTS WITH GEOGRAPHIC ATROPHY 
SECONDARY TO AGE-RELATED MACULAR DEGENERATION 
(GALLEGO) 
PROTOCOL NUMBER: 
GR40973 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
134632 
NCT NUMBER: 
NCT03972709 
TEST PRODUCT: 
FHTR2163 (RO7171009) 
PHASE: 
Phase II 
INDICATION: 
Age-related macular degeneration 
SPONSOR: 
Genentech, Inc. 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, tolerability, and efficacy of intravitreal (ITV) injections of 
20 mg FHTR2163 administered every 4 weeks (Q4W) or every 8 weeks (Q8W) in patients with 
geographic atrophy (GA) secondary to age-related macular degeneration (AMD) compared with 
sham control.  Specific objectives and corresponding endpoints for the study are outlined below. 
EFFICACY OBJECTIVES 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of ITV injections of 20 mg 
FHTR2163 administered Q4W or Q8W in patients with GA secondary to AMD compared with 
sham control on the basis of the following endpoint:   
 
Mean change in the GA area from baseline to Week 72 as measured by fundus 
autofluorescence (FAF) 
 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of ITV injections of 
20 mg FHTR2163 administered Q4W or Q8W in patients with GA secondary to AMD compared 
with sham control on the basis of the following endpoints:   
 
Mean change in best corrected visual acuity (BCVA) score from baseline to Week 72 as 
assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) chart under 
low-luminance conditions 
 
Mean change in BCVA score from baseline to Week 72 as assessed by ETDRS chart 
 


 
FHTR2163
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12/Protocol GR40973, Version 5 
Exploratory Efficacy Objectives
The exploratory efficacy objectives for this study are as follows: 
 
To evaluate the efficacy of ITV injections of 20 mg FHTR2163 administered Q4W or Q8W in 
patients with GA secondary to AMD compared with sham control on the basis of the 
following endpoint:  
 
Mean rate of change in the GA area, estimated based on GA area as measured by FAF 
at four timepoints:  baseline, Week 24, Week 48, and Week 72  
 
To evaluate the efficacy of ITV injections of 20 mg FHTR2163 administered Q4W or Q8W in 
patients with foveal-involving GA and in patients with non-foveal involving GA compared 
with sham control on the basis of the following endpoints: 
 
Mean change in the GA area from baseline to Week 72 as measured by FAF 
 
Mean rate of change in the GA area, estimated based on GA area as measured by FAF 
at four timepoints:  baseline, Week 24, Week 48, and Week 72  
 
Safety Objective 
The safety objective for this study is to evaluate the local and systemic safety and tolerability of 
ITV injections of 20 mg FHTR2163 administered Q4W or Q8W relative to sham control on the 
basis of the following endpoints: 
 
Frequency, severity, and timing of ocular and systemic adverse events, serious adverse 
events, adverse events leading to study discontinuation, and adverse events of special 
interest  
 
Frequency, severity, and timing of notable findings in ocular examinations and ocular 
imaging, including those requiring intervention or start of anti-vascular endothelial growth 
factor (anti-VEGF) therapy 
 
Incidence of neovascular AMD diagnosed during the conduct of the study 
 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is to characterize the FHTR2163 PK profile on 
the basis of the following endpoint: 
 
Serum and aqueous humor concentration of FHTR2163 at specified timepoints 
 
The exploratory PK objective for this study is as follows:  To evaluate potential relationships 
between drug exposure and the safety and efficacy of FHTR2163 on the basis of the following 
endpoints: 
 
Relationship between serum and/or aqueous humor concentration or PK parameters for 
FHTR2163 and efficacy endpoints 
 
Relationship between serum and/or aqueous humor concentration or PK parameters for 
FHTR2163 and safety endpoints 
 
Immunogenicity Objective 
The immunogenicity objective for this study is to evaluate the immune response to FHTR2163 
on the basis of the following endpoint: 
 
Prevalence of serum anti-drug antibodies (ADAs) at baseline and incidence of serum ADAs 
during the study  
 
The exploratory immunogenicity objective for this study is to evaluate potential effects of serum 
ADAs on the basis of the following endpoint: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
 
Biomarker Objectives 
The exploratory diagnostic biomarker objective for this study is to evaluate the efficacy as 
defined in the primary efficacy objective in carriers versus non-carriers of the high-temperature 
requirement A1 (HtrA1) AMD risk variant rs10490924. 


 
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The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to FHTR2163, are associated with rate of progression to a more 
severe disease state, are associated with susceptibility to developing adverse events, can 
provide evidence of FHTR2163 activity, or can increase the knowledge and understanding of 
disease biology, on the basis of the following endpoints: 
 
Relationship between biomarkers in blood and aqueous humor and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints 
 
Relationship between retinal imaging measures (i.e., FAF, spectral domain optical 
coherence tomography [SD-OCT], optical coherence tomography angiography [OCT-A]) 
and efficacy, safety, PK, immunogenicity, or other biomarker endpoints 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This is a Phase II, multicenter, randomized, single-masked, sham-controlled study evaluating 
the safety, tolerability, and efficacy of 20 mg FHTR2163 dose administered Q4W or Q8W by 
ITV injections for approximately 76 weeks, in patients with GA secondary to AMD.  
Approximately 360 patients (144 patients in FHTR2163 Q4W arm, 72 patients in FHTR2163 
Q8W arm, and 144 patients in pooled sham arm) will be enrolled in the study at approximately 
77 investigational sites in the United States.  Site investigators will be qualified 
ophthalmologists. 
The study will consist of the following: 
 
Screening period of up to 120 days, divided into a prebaseline screening period (Day 120 
to Day 31) and a baseline screening window (Day 30 to Day 1) 
 
Treatment period of up to 68 weeks (Day 1 to Week 68 for the Q4W treatment arms and 
Day 1 to Week 64 for the Q8W treatment arms) 
 
Primary analysis timepoint visit (Week 72) 
 
Final study visit (Week 76) 
 
To be eligible for the study, patients must satisfy all eligibility criteria at both the screening 
visit(s) and the Day 1 visit (i.e., day patient is enrolled and study drug is administered).  One 
essential eligibility criterion is that patients will be required to have two FAF images, a 
prebaseline image and a baseline image performed on a Heidelberg platform obtained at a 
minimum of ~3 months (84 days) and maximum of ~11 months (336 days) prior to the baseline 
screening visit. 
Patients who fail screening may be eligible for rescreening up to three additional times during 
the enrollment period of the study.  Eligible patients will be randomized in a 2:1:1:1 ratio such 
that approximately 144 patients will receive study drug treatment Q4W, 72 patients will receive 
sham-control treatment Q4W, 72 patients will receive study drug treatment Q8W, and 
72 patients will receive sham-control treatment Q8W.  Patients receiving Q4W dosing will 
receive a total of 18 treatments and patients receiving Q8W dosing will receive a total of 
9 treatments. 
NUMBER OF PATIENTS 
Approximately 360 patients with GA secondary to AMD will be enrolled in this study at 
approximately 77 investigative sites located in the United States. 
TARGET POPULATION 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
General Inclusion Criteria 
 
Signed Informed Consent Form 
 
Age 
 60 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 


 
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Genentech, Inc. 
14/Protocol GR40973, Version 5 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of 
 1% 
per year during the treatment period and for at least 28 days after the final dose of 
FHTR2163.   
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (
 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.  
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not acceptable methods of contraception.  If required per local guidelines or regulations, 
locally recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
Ability and willingness to undertake all scheduled visits and assessments 
 
Ocular Inclusion Criteria:  Study Eye 
One eye will be designated as the study eye.  If both eyes meet the following criteria, the eye 
with the worse visual acuity (VA) and/or least function (as determined by the investigator and 
patient) will be selected for study treatment (study eye).  If both eyes have the same visual 
function, the eye with the larger area of GA will be selected as the study eye. 
 
Visual acuity:  BCVA letter score of  24 letters (Snellen equivalent of 20/320 or better) 
using ETDRS chart at starting distance of 4 m 
If the study eye BCVA letter score is 69 letters (Snellen equivalent of 20/40 or better), 
the non-study eye must have a BCVA letter score of 44 letters (Snellen equivalent of 
20/125 or better). 
 
Well-demarcated area of GA secondary to AMD with no evidence of prior or active 
choroidal neovascularization (CNV) 
 
Prebaseline FAF image obtained via a Heidelberg platform 84 336 days prior to the 
screening visit that meets the following criteria: 
 
Total GA lesion size must be 
 2.54 mm2 (approximately 1 disc area [DA]) and 
17.78 mm2 (approximately 
 7 DA) and must reside completely within the FAF imaging 
field (Field 2 30 degree image centered on the fovea) 
If GA is multifocal, at least 1 focal lesion must be 
 1.27 mm2 
(approximately 0.5 DA).  
 
Presence of hyperautofluorescence of either banded or diffuse patterns adjacent to GA 
area 
Note:  Diffuse-trickling pattern is excluded.  
 
Baseline FAF image obtained during the baseline screening window (Day 30 to Day 1) 
must meet the following criteria: 
 
Total GA lesion size must be 
 2.54 mm2 (approximately 1 DA) and 25.4 mm2 
(approximately 10 DA) and must reside completely within the FAF imaging field 
(Field 2 30 degree image centered on the fovea). 
If GA is multifocal, at least 1 focal lesion must be 
 1.27 mm2 
(approximately 0.5 DA).  


 
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Presence of hyperautofluorescence of either banded or diffuse patterns adjacent to GA 
area 
Note:  Diffuse-trickling pattern is excluded.  
 
Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit quality 
fundus imaging 
 
Ocular anatomy that would allow for safe and uneventful collection of approximately 100 L 
aqueous humor sample in the opinion of the investigator  
 
Ocular Inclusion Criteria:  Non-Study Eye 
 
GA secondary to AMD with no evidence of prior or active CNV 
 
The non-study eye must have a BCVA letter score of 44 letters (Snellen equivalent of 
20/125 or better) if the study eye BCVA letter score is 69 letters (Snellen equivalent of 
20/40 or better).  
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
GA Characteristics Exclusion Criterion 
 
GA in either eye due to causes other than AMD (monogenetic macular dystrophies 
[e.g., Stargardt disease, cone rod dystrophy] or toxic maculopathies 
[e.g., chloroquine/hydroxychloroquine maculopathy]) 
 
Ocular Exclusion Criteria:  Study Eye 
 
Absence of any hyperfluorescence pattern (none) adjacent to GA area in the study eye 
 
Presence of diffuse-trickling, patchy, or minimal (focal) hyperfluorescence pattern adjacent 
to GA area in the study eye 
 
Any concurrent ocular or intraocular condition in the study eye (e.g., cataract or diabetic 
retinopathy) that, in the opinion of the investigator, could result in either of the following: 
 
Require medical or surgical intervention during the study period to prevent or treat 
vision loss that might result from that condition 
 
If allowed to progress untreated, could likely contribute to loss of at least two Snellen 
equivalent lines of BCVA during the study period 
 
Intraocular surgery, including cataract surgery, in the study eye within 3 months prior to 
Day 1 
 
Uncontrolled glaucoma in the study eye, defined as intraocular pressure
 30 mmHg despite 
treatment with anti-glaucoma medication 
 
Current vitreous hemorrhage in the study eye 
 
Aphakia or absence of the posterior capsule in the study eye 
 
Previous laser photocoagulation or ITV anti-VEGF for CNV, diabetic macular edema, retinal 
vein occlusion, or proliferative diabetic retinopathy  
 
Prior treatment with photodynamic therapy, external-beam radiation therapy (for intraocular 
conditions), or transpupillary thermotherapy  
 
Any posterior segment device or implant (e.g., any type of corticosteroid implant/device, 
encapsulated cell therapy, or Argus
 II Retinal Prosthesis System) 
 
ITV, subtenon, or topical (ocular) corticosteroids within 3 months prior to randomization 
A single intraoperative administration of a corticosteroid during cataract surgery for 
cystoid macular edema prophylaxis at least 3 months prior to screening is permitted. 
 
History of vitrectomy surgery, submacular surgery, or any surgical intervention for AMD 
 
History of prophylactic subthreshold laser treatment for AMD 
 
History of glaucoma-filtering (trabeculectomy, valves, or minimally invasive glaucoma 
stents) surgery in the study eye 


 
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History of corneal transplant in the study eye
 
History of retinal tear in the study eye 
Patient may be permitted after appropriate treatment and subsequent determination of 
stability by the investigator. 
 
History of retinal detachment or macular hole (Stage 3 or 4) in the study eye 
 
Any concurrent ocular or intraocular conditions that contraindicate the use of an 
investigational drug, may affect interpretation of the study results, or may render the patient 
at high risk for treatment complications 
Note that medical history (e.g., clinically significant increased intraocular pressure 
meeting sight-threatening criteria) that will require the patient to receive pre-injection 
prophylactic paracentesis prior to the study treatment administration in the study eye is 
exclusionary. 
 
Previous violation of the posterior capsule in the study eye unless it occurred as a result of 
yttrium aluminum garnet (YAG) laser posterior capsulotomy in association with prior 
posterior chamber intraocular lens implantation 
 
Spherical equivalent of the refractive error in the study eye demonstrating 
 8 diopters of 
myopia 
 
For patients who have undergone prior refractive or cataract surgery in the study eye, the 
preoperative refractive error in the study eye should not have exceeded 8 diopters of 
myopia. 
 
Ocular Exclusion Criteria:  Non-Study Eye 
 
Non-functioning non-study eye defined as either: 
BCVA of hand motion or worse 
OR  
No physical presence of non-study eye (i.e., monocular)  
 
Ocular Exclusion Criteria:  Both Eyes 
 
Active uveitis and/or vitritis (grade trace or above) in either eye 
 
Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye 
 
Active or history of ocular melanoma in either eye 
 
Active or history of CNV in either eye 
 
Active or history of optic neuritis in either eye 
 
Retinal pigment epithelium tear that involves the macula in either eye 
 
Moderate or severe non-proliferative diabetic retinopathy in either eye 
Note:  Mild non-proliferative diabetic retinopathy (e.g., occasional hemorrhage or 
microaneurysm) in either eye may be permitted at the discretion of the 
investigator.  Moreover, a patient with the onset of mild non-proliferative diabetic 
retinopathy in either eye during study participation may be permitted to continue study 
treatment at the discretion of the investigator. 
 
Proliferative diabetic retinopathy in either eye 
 
Central serous retinopathy in either eye 
 
Previous participation in an interventional clinical trial for GA or dry AMD trial that tested 
stem cell treatments, gene therapy, long-acting delivery platforms/formulations 
(e.g., biodegradable/non-biodegradable implants or formulations, device implant, 
encapsulated cell technologies), or inhibitors/modulators of the visual cycle 
(e.g., fenretinide, emixustat) regardless of timing of patient participation 


 
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Previous participation in interventional clinical trials for GA or dry AMD, except for vitamins 
and minerals, regardless of the route of administration (i.e., ocular or systemic) within the 
last 6 months 
Note:  If patient participation in an interventional clinical trial for GA or dry AMD was 
 6 months prior to screening, the patient may be eligible for the trial at the discretion of 
the investigator.  
 
History of recurrent infectious or inflammatory ocular disease in either eye  
 
History of idiopathic or autoimmune-associated uveitis in either eye 
 
Concurrent Systemic Conditions Exclusion Criteria 
 
Uncontrolled blood pressure, defined as systolic blood pressure 
 180 mmHg and/or 
diastolic blood pressure 
 110 mmHg while patient is sitting 
If 
tial measurement exceeds these values, a second reading may be taken 
30 or more minutes later.  If 
antihypertensive medication, the patient can be eligible if medication is taken 
continuously for at least 30 days prior to Day 1.  
 
History of cerebral vascular accident or transient ischemic attack 
 
History of other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that gives reasonable suspicion of a disease or condition that 
contraindicates the use of FHTR2163, that might affect interpretation of the results of the 
study, or that renders the patient at high risk of treatment complications 
 
Active cancer within past 12 months except for appropriately treated carcinoma in situ of the 
cervix, non-melanoma skin carcinoma, or prostate cancer with a Gleason score of 
 6 and a 
stable prostate-specific antigen for 
 12 months 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or known 
hypersensitivity to any component of the investigational drug injection 
 
Previous participation in any studies of investigational drugs within the last 6 months, 
excluding vitamins and minerals 
If patient participation in a clinical trial was 
 6 months prior to screening, the patient may 
be eligible for the study at the discretion of the investigator. 
 
Requirement for continuous use of any medications/treatments indicated as a prohibited 
therapy in this study  
 
Medical conditions that may be associated with a clinically significant risk for bleeding 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
28 days after the final dose of FHTR2163 
Women of childbearing potential must have a negative serum pregnancy test result 
within 28 days prior to initiation of study drug.  
 
Active systemic or localized infection requiring medical treatment that, in the opinion of the 
investigator, could interfere with study conduct 
 
END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs.  LPLV 
is expected to occur approximately 76 weeks after the last patient is randomized to the study.  
In addition, the Sponsor may decide to terminate the study at any time. 
LENGTH OF STUDY 
The duration of the study is approximately 76 weeks after the last patient is randomized to the 
study. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal product (IMP) for this study is FHTR2163. 


 
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TEST PRODUCT (INVESTIGATIONAL DRUG AND SHAM CONTROL)
On Day 1, patients will be randomized in a 2:1:1:1 ratio to one of the study treatment arms 
(FHTR2163 Q4W, sham control Q4W, FHTR2163 Q8W, or sham control Q8W).  The first ITV 
injection of 20 mg FHTR2163 or sham control will be conducted by investigators on the same 
day as randomization (i.e., Day 1). 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy analyses will be based on the modified intent-to-treat population (see Data 
Analysis Plan for detailed definition).  Patients will be grouped according to the treatment 
assigned at randomization.  Patients in the sham-control Q4W and sham-control Q8W groups 
will be pooled in the analyses. 
If not otherwise specified, analyses of efficacy outcome measures will be stratified by HtrA1 
risk-variant carrier status (HtrA1 risk-variant carrier vs. HtrA1 risk-variant non-carrier, as 
determined by the HtrA1 risk-variant genotyping assay), baseline GA lesion size (
 9.0 mm2 vs. 
 9.0 mm2), and annualized prebaseline GA progression rate (<1.9 mm2/yr vs. 1.9 mm2/yr).  
A data-as-observed approach with the mixed-effect model will be used to handle missing data in 
the primary analysis.  Sensitivity analyses will be performed to evaluate the effect of missing 
data on the results. 
DETERMINATION OF SAMPLE SIZE 
This study is designed to evaluate the efficacy of FHTR2163 administered ITV Q4W and Q8W 
to patients with GA secondary to AMD.  The focus of the efficacy outcome analyses will be on 
estimation of the magnitude of the treatment effect. 
The primary efficacy endpoint is the mean change in GA area from baseline to Week 72 as 
measured by FAF.  The sample size provides reasonable precision for estimation of the 
treatment effect with respect to the primary endpoint. 
Approximately 360 patients will be randomized in a 2:1:1:1 ratio to one of four treatment groups:  
FHTR2163 Q4W, sham control Q4W, FHTR2163 Q8W, or sham control Q8W.  Patients in the 
sham control Q4W and sham control Q8W groups will be pooled in the analyses. 
Assuming a 15% dropout rate by Week 72 and a standard deviation of 1.82 mm2 for change 
from baseline in GA area at Week 72 (estimated from the lampalizumab Phase II Study 
CFD4870g and the Phase III Studies GX29176 and GX29185), 114 patients in the FHTR2163 
Q4W arm and 114 patients in the pooled sham-control group will provide 80% power to detect a 
targeted difference of 0.56 mm2 (20% reduction relative to sham control) in the change from 
baseline in GA area at Week 72 between the FHTR2163 Q4W arm and the pooled sham-
control arm.  Calculations were based on two-sided t-test at the significance level of 20% and 
resulted in a total sample size of 285.  No multiplicity adjustment is planned for this study.  
A total of 131 patients had enrolled in this study as of 10 April 2020.  As a result of the increase 
in missed visits, missed dosing, and missed assessments as a consequence of the COVID-19 
pandemic, up to approximately 75 patients will be enrolled in addition to the originally planned 
285 patients to help mitigate the potential impact on treatment effect and data. 
OPTIONAL INTERIM ANALYSES 
Given the hypothesis-generating nature of this study, the Sponsor may choose to conduct up to 
two interim analyses.  The decision to conduct an optional interim analysis and the timing of the 
analysis will be documented in the Sponsor's trial master file prior to the conduct of the interim 
analysis.  The interim analysis will be performed by the unmasked internal monitoring 
committee (IMC) and will be interpreted by the IMC and appropriate senior management 
procedures.  The details of the timing and scope of the interim analysis, if any, will be specified 
in the IMC Agreement. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AMD 
age-related macular degeneration 
anti-VEGF 
anti-vascular endothelial growth factor 
BCVA 
best corrected visual acuity 
CARASIL 
cerebral autosomal recessive arteriopathy with 
subcortical infarcts and leukoencephalopathy 
CFP 
color fundus photograph 
CNV 
choroidal neovascularization 
CRO 
contract research organization 
DA 
disc area 
DAP 
Data Analysis Plan 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fluorescein angiography 
FAF 
fundus autofluorescence 
GA 
geographic atrophy 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HRB 
hyper-reflective band 
HtrA1 
high-temperature requirement A1 
ICH 
International Council for Harmonisation 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IOI 
intraocular inflammation 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
ITV 
intravitreal 
IWRS 
interactive web-based response systems 
LPLV 
last patient, last visit 
MD 
multiple dose 
NGS 
next-generation sequencing 
nAMD 
neovascular AMD 
NI 
near infrared 


 
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Abbreviation 
Definition 
OCT-A 
optical coherence tomography angiography 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
Q4W 
every 4 weeks 
Q8W 
every 8 weeks 
RBR 
Research Biosample Repository 
RPE 
retinal pigment epithelium 
SAD 
single ascending dose 
SD-OCT 
spectral domain optical coherence tomography 
ULN 
upper limit of normal 
VA 
visual acuity 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
YAG 
yttrium aluminum garnet 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON GEOGRAPHIC ATROPHY SECONDARY TO 
AGE-RELATED MACULAR DEGENERATION 
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in 
people aged 50 years or older in the developed world (Friedman et al. 2004).  The 
majority of the visual loss occurs in the advanced stage of AMD, which has two clinical 
forms:  a non-exudative form, geographic atrophy (GA), which is characterized by loss of 
photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris; and an exudative 
or wet form, known as neovascular AMD (nAMD), which is characterized by choroidal 
neovascularization (CNV) (Sunness et al. 1999; Lindblad et al. 2009).  The prevalence of 
GA increases exponentially with age and approximately quadruples per decade beyond 
50 years of age (Rudnicka et al. 2012).  The estimated prevalence of GA in populations 
of European ancestry at 70 years of age is 0.70%, rising to 2.91% at 80 years of age 
and 11.29% at 90 years of age (Rudnicka et al. 2012). 
In the early stages of GA, patients typically show minimal changes in central visual 
acuity (VA).  However, while central VA may not yet be affected, patients often still 
experience significant symptoms from visual dysfunction, such as dense parafoveal 
scotomas (e.g., leading to difficulties with face recognition), delayed dark adaptation, 
reduced contrast sensitivity, and a decrease in reading rate (Sunness et al. 1995, 1999; 
Sunness and Applegate 1996).  In the later stages, as the GA lesion expands into the 
fovea, a profound decrease in central VA occurs with a decline in activities of daily living 
(Lindblad and Clemons 2005).  Moreover, GA is bilateral in most patients with advanced 
AMD (Sunness et al. 1999; Lindblad et al. 2009).  As such, GA is a significant cause of 
both moderate and severe central visual loss. 
Currently, there are no approved treatments for GA secondary to AMD, and a significant 
unmet medical need exists for treatment of this serious condition.  In Chroma 
and Spectri, the largest Phase III studies of GA conducted to date, lampalizumab 
(anti complement factor D) did not result in a reduction of GA lesion area versus sham 
during 48 weeks of treatment (Holz et al. 2018).  Other more recent Phase II studies 
have reported positive results:  the BEACON study evaluating the brimonidine drug 
delivery system (Allergan), the FILLY study evaluating APL-2, a synthetic cyclic peptide 
conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b 
(Apellis 2018), and the GATHER1 Study evaluating avacincaptad pegol, an inhibitor of 
the cleavage of C5 and formation of terminal fragments C5a and C5b (Jaffe et al. 2020). 
The Phase II clinical development plan for FHTR2163 (Fab of a humanized monoclonal 
antibody directed against the high-temperature requirement A1 [HtrA1] protein) is 
designed to test the safety, tolerability, and efficacy in patients with GA secondary 
to AMD. 


 
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1.2 
BACKGROUND ON HTRA1 
The high-temperature requirement A1 (HtrA1) gene, located in chromosomal region 
10q26, was one of the first AMD genetic loci identified and has been replicated in 
multiple studies with associations seen in both linkage and genome-wide association 
(Weeks et al. 2001; Fritsche et al. 2016).  A single nucleotide polymorphism in the 
promoter region of HtrA1 is the most likely causal variant, or tags the causal variant, for 
AMD at 10q26 (DeWan et al. 2006; Yang et al. 2006), and is estimated to confer a 
population attributable risk of 49.3% (Yang et al. 2006).  Transcription of HtrA1 has been 
shown to be increased in association with the risk allele (Yang et al. 2006). 
HtrA1 is a member of the mammalian HtrA serine protease family (Clausen et al. 2002).  
HtrA1 has been shown to cleave a large number of potential substrates, many of which 
are extracellular matrix proteins (Grau et al. 2006).  In transgenic mice, overexpression 
of HtrA1 in RPE cells recapitulated cardinal features associated with advanced AMD, 
including choroidal vasculopathy and severe degeneration of elastic laminae of the 
(Jones et al. 2011; Kumar et al. 2014).  At the molecular level, this 
phenotype appears to result from HtrA1-induced breakdown of extracellular matrix 
Jones et al. 2011; 
Vierkotten et al. 2011; Kumar et al. 2014).  In the human retina, HtrA1 is expressed by 
RPE cells (DeWan et al. 2006; Yang et al. 2006), and unpublished studies conducted by 
Genentech revealed that its expression is increased in the area peri-lesional to the GA. 
1.3 
BACKGROUND ON FHTR2163 
FHTR2163 (RO7171009) is a Fab of a humanized monoclonal antibody directed against 
the HtrA1 protein (Tom et al. 2020).  FHTR2163 was shown to bind with an equilibrium 
dissociation constant of 0.13 nM to human HtrA1.  The HtrA1 protease is functional only as 
a trimer.  Full inhibition of the enzymatic activity of trimeric HtrA1 requires three separate 
anti-HtrA1 Fabs to bind each HtrA1 subunit (Ciferri et al. 2015).  By inhibiting HtrA1 
protease activity, treatment with FHTR2163 may represent a novel therapeutic option for 
the treatment of GA.  
1.3.1 
FHTR2163 Nonclinical Toxicology Summary 
In Good Laboratory Practice (GLP) repeat-dose toxicity studies, FHTR2163 was 
generally well tolerated in cynomolgus monkeys following bilateral intravitreal (ITV) 
doses every 2 weeks in studies of up to 6 months in duration at doses of up to 
12.5 mg/eye in a 750 mOsm/kg formulation.  Hyper-reflective bands (HRBs) were noted 
on spectral domain optical coherence tomography (SD-OCT) imaging in the fovea of 
some eyes that were dosed with vehicle or FHTR2163.  HRBs were transient, confined 
to the fovea, and not correlated with functional (full-field electroretinography) or 
histopathologic abnormalities.  These findings suggest that HRBs may be related to the 
volume and/or number of ITV injections, and are not due to FHTR2163 (Covance 
Laboratories Inc. report 2018 [available upon request]; Booler et al. 2019).  Ocular 
effects associated with FHTR2163 were limited to ocular inflammation, which was 


 
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considered to be procedure related and/or secondary to specific immune-mediated 
response to a humanized protein.  Ocular inflammation was associated with the 
presence of systemic anti-drug antibodies (ADAs), was not considered to be related to 
the pharmacologic action of FHTR2163, and showed at least partial reversibility by the 
end of the 1-month recovery periods.  No systemic effects were observed in evaluated 
parameters, including safety pharmacology endpoints (cardiovascular, respiratory, or 
behavioral).  The no-observed-adverse-effect level in the 6-month GLP repeat dose 
toxicity study was considered to be 12.5 mg/eye in a 750 mOsm/kg formulation 
administered as a single 50-µL ITV injection every 2 weeks.   
The toxicology program for FHTR2163 supports both the dose regimens of 20 mg/eye 
every 4 weeks (Q4W) and every 8 weeks (Q8W), and the duration of this Phase II 
clinical trial.  Refer to the FHTR2163 Investigator's Brochure for details on nonclinical 
GLP toxicology studies. 
1.3.2 
FHTR2163 Phase I Safety Summary and Pharmacokinetic 
Preliminary Data 
Study GR39821 was an open-label, multicenter, Phase I, first-in-human study designed 
to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of 
FHTR2163 administered intravitreally in patients with GA secondary to AMD.  The study 
consisted of two stages:  a single ascending dose (SAD) and multiple dose (MD).  The 
SAD stage allowed escalated exposure to FHTR2163 with 5 doses (1, 3, 10, 15, and 
20 mg) in 15 patients (3 patients per dose level).  The MD stage evaluated the maximum 
tested dose in SAD (20 mg) administered every 4 weeks for 3 administrations in 
10 evaluable patients.  The study was completed on 20 November 2018 (last patient, 
last visit). 
In Study GR39821, FHTR2163 was well tolerated.  There were no dose-limiting toxicities 
and no ocular serious adverse events.  Two participants, in the MD stage of the study, 
experienced systemic serious adverse events; none of these events were assessed as 
related to study drug. 
In the SAD cohorts, adverse events reported in 
 1 participant were as follows:  
conjunctival hemorrhage (n 
 5) and conjunctival hyperemia (n 
 2).  In the MD cohorts, 
adverse events reported in 
 1 participant were as follows:  conjunctival hemorrhage 
(n 
 2), conjunctival hyperemia (n 
 2), skin ulcer (n 
 2), and squamous cell carcinoma 
(n 
 2).  None of the systemic or ocular adverse events reported in the SAD or MD 
cohorts were assessed as related to study drug. 
No adverse drug reactions related to FHTR2163 have been identified.  Potential risks 
are discussed in Section 5.1.1. 
Based on preliminary pharmacokinetic (PK) analysis, the aqueous humor and serum PK 
profile of FHTR2163 in humans was generally consistent with other Fabs 


 
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(e.g., Lucentis ) administered via ITV injection.  The estimated ocular elimination half-life 
in humans was 4.9 days.  The systemic FHTR2163 concentrations following ITV 
injection are estimated to be at least 7,500-fold lower than vitreal FHTR2163 
concentrations. 
Based on the results of the Phase I study (GR39821), there has been no change to the 
potential risks or the reference safety information for FHTR2163 as outlined in the 
 
1.4 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
As described in Section 1.1, currently, there are no approved treatments to slow or stop the 
progression of GA secondary to AMD and associated vision loss.  FHTR2163 is a first-in-
class inhibitor of HtrA1 in clinical development and as such there are no published data on 
the clinical benefit of this mechanism for the treatment of GA secondary to AMD.  
This Phase II study will evaluate the efficacy of FHTR2163 and will further investigate 
the ocular and systemic safety, tolerability, and pharmacokinetics of FHTR2163 following 
multiple ITV administrations in patients with GA secondary to AMD.  
The clinical experience with FHTR2163 is limited to one first-in-human study (see 
Section 1.3.2), and the safety profile in humans is not fully understood at this time.  The 
completed nonclinical toxicology studies for FHTR2163 support the continued 
development of the molecule in clinical studies in patients with GA secondary to AMD 
(see Section 1.3.1).  There are no known risks for FHTR2163 to date.  Potential risks are 
described in Section 5.1.1.  Several measures are being taken in this study to mitigate 
possible safety concerns, including strict inclusion and exclusion criteria (see 
Section 4.1), regular ocular assessments (see Section 4.5.5), regular ocular imaging 
(see Section 4.5.6), physical examinations (see Section 4.5.3), and regular safety review 
by an unmasked Internal Monitoring Committee (IMC) (Section 3.1.2).  
Because of the high unmet medical need for new treatments for GA secondary to AMD 
and the safety profile of FHTR2163 observed in both nonclinical and clinical studies to 
date, the benefit-risk of FHTR2163 is favorable and supportive of its use in this clinical 
study. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, tolerability, and efficacy of ITV injections of 20 mg 
FHTR2163 administered Q4W or Q8W in patients with GA secondary to AMD compared 
with sham control.  Specific objectives and corresponding endpoints for the study are 
outlined below. 


 
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2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of ITV injections of 
20 mg FHTR2163 administered Q4W or Q8W in patients with GA secondary to AMD 
compared with sham control on the basis of the following endpoint: 
 
Mean change in the GA area from baseline to Week 72 as measured by fundus 
autofluorescence (FAF) 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of ITV 
injections of 20 mg FHTR2163 administered Q4W or Q8W in patients with GA 
secondary to AMD compared with sham control on the basis of the following endpoints: 
 
Mean change in best corrected visual acuity (BCVA) score from baseline to 
Week 72 as assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) 
chart under low-luminance conditions 
 
Mean change in BCVA score from baseline to Week 72 as assessed by ETDRS 
chart  
 
2.1.3 
Exploratory Efficacy Objectives 
The exploratory efficacy objectives for this study are as follows: 
 
To evaluate the efficacy of ITV injections of 20 mg FHTR2163 administered Q4W or 
Q8W in patients with GA secondary to AMD compared with sham control on the 
basis of the following endpoint: 
 
Mean rate of change in the GA area, estimated based on GA area as measured 
by FAF at four timepoints:  baseline, Week 24, Week 48, and Week 72  
 
To evaluate the efficacy of ITV injections of 20 mg FHTR2163 administered Q4W or 
Q8W in patients with foveal-involving GA and in patients with non-foveal involving 
GA compared with sham control on the basis of the following endpoints: 
 
Mean change in the GA area from baseline to Week 72 as measured by FAF 
 
Mean rate of change in the GA area, estimated based on GA area as measured 
by FAF at four timepoints:  baseline, Week 24, Week 48, and Week 72  
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the local and systemic safety and 
tolerability of ITV injections of 20 mg FHTR2163 administered Q4W or Q8W relative to 
sham control on the basis of the following endpoints: 
 
Frequency, severity, and timing of ocular and systemic adverse events, serious 
adverse events, adverse events leading to study discontinuation, and adverse 
events of special interest (see Sections 5.2.3 and 5.3.3) 


 
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Frequency, severity, and timing of notable findings in ocular examinations and 
ocular imaging, including those requiring intervention or start of anti-vascular 
endothelial growth factor (anti-VEGF) therapy 
 
Incidence of neovascular AMD diagnosed during the conduct of the study 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the FHTR2163 PK profile on the basis 
of the following endpoint: 
 
Serum and aqueous humor concentration of FHTR2163 at specified timepoints 
 
The exploratory PK objective for this study is as follows:  To evaluate potential 
relationships between drug exposure and the safety and efficacy of FHTR2163 on the 
basis of the following endpoints: 
 
Relationship between serum and/or aqueous humor concentration or PK 
parameters for FHTR2163 and efficacy endpoints 
 
Relationship between serum and/or aqueous humor concentration or PK 
parameters for FHTR2163 and safety endpoints 
 
2.4 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to 
FHTR2163 on the basis of the following endpoint: 
 
Prevalence of serum ADAs at baseline and incidence of serum ADAs during the 
study  
 
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
serum ADAs on the basis of the following endpoint: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
 
2.5 
BIOMARKER OBJECTIVES 
The exploratory diagnostic biomarker objective for this study is to evaluate the efficacy of 
FHTR2163 as defined in the primary efficacy objective (see Section 2.1.1) in carriers 
versus non-carriers of the HtrA1 AMD risk variant rs10490924. 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to FHTR2163, are associated with rate of 
progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, can provide evidence of FHTR2163 activity, or can increase 
the knowledge and understanding of disease biology, on the basis of the following 
endpoints: 
 
Relationship between biomarkers in blood and aqueous humor (listed in 
Section 4.5.8) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints 




 
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To be eligible for the study, patients must satisfy all eligibility criteria (see Section 4.1) at 
both the screening visit(s) and the Day 1 visit (i.e., day patient is enrolled and study drug 
is administered). 
One essential eligibility criterion is that patients will be required to have two FAF images, 
a prebaseline image and a baseline image performed on a Heidelberg platform obtained 
at a minimum of ~3 months (84 days) and maximum of ~11 months (336 days) prior to 
the baseline screening visit.  The prebaseline and baseline FAF images may be 
obtained in two different approaches as illustrated in Figure 2 and described below. 
No Preexisting FAF Image 
Patients who do not have a preexisting FAF image available will have an FAF obtained 
along with all other prebaseline assessments listed in Appendix 1 and Appendix 2 to 
assess eligibility.  This FAF image will be designated as the prebaseline FAF image.  If 
the prebaseline FAF image is ungradable by the reading center, a repeat FAF image 
needs to be obtained within 30 days.  Up to an additional 7 business days may be 
permitted for exceptional circumstances after consultation with and approval by the 
Medical Monitor.  If prebaseline eligibility criteria for the FAF image (see Section 4.1) are 
met, the patient will enter the 90 (+30) day prebaseline screening period starting from 
the date the FAF image was obtained.  The patient will then return to the clinic during the 
baseline screening window (Day 30 to Day 1) to perform the screening assessments 
(except for keratometry), including the baseline FAF image (see Appendix 1 and 
Appendix 2 and Figure 2). 
Preexisting FAF Image 
Patients with a preexisting FAF image that was obtained on a Heidelberg platform and 
was obtained 84 336 days prior to the baseline screening visit may have the preexisting 
FAF image designated as the prebaseline FAF image, and the patient may proceed 
directly to the baseline screening window (Day 30 to Day 1) to obtain the baseline 
FAF image along with the other screening assessments (see Figure 2). 
Any preexisting near infrared (NI) image obtained 84 336 days prior to the baseline 
screening visit should also be sent to the central reading center.  Preexisting NI images 
are not necessary for eligibility and absence of a preexisting NI image(s) does not 
exclude a patient from screening. 
If patients have more than one preexisting FAF/NI image (obtained 84 336 days prior to 
the baseline screening visit), all such images should be sent to the central reading 
center. 
In the event the preexisting FAF image is deemed not gradable by the central reading 
center or the measured GA lesion size is smaller than required (
 2.54 mm2), the FAF 
image obtained during the baseline screening window will be considered the prebaseline 
image.  If all other eligibility criteria are met (see Section 4.1), the patient will be allotted 


 
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an additional 90 (+30) days from the date that FAF image was obtained to return to the 
clinic.  The patient then will repeat the baseline screening window assessments (except 
for HtrA1 genotyping whole blood sample and keratometry), including the baseline FAF 
(see Figure 2). 
Prebaseline and baseline screening assessments may be completed on separate days 
provided that all assessments are captured within the prebaseline screening period 
(Day 120 to Day 30) or baseline screening window (Day 30 to Day 1), respectively.  
The baseline screening window may be extended for up to 7 business days for 
exceptional circumstances after consultation with and approval by the Medical Monitor.  
All prebaseline and baseline screening images (see Appendix 1 and Appendix 2 for 
details of images required) must be received and evaluated by the central reading center 
prior to the Day 1 visit. 




 
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eye with the worse visual function as determined by the investigator and the patient will 
be the study eye.  If both eyes have the same visual function, the eye with the larger 
area of GA lesion will be selected as the study eye. 
Eligible patients will be randomized in a 2:1:1:1 ratio such that approximately 
144 patients will receive study drug treatment Q4W, 72 patients will receive sham-
control treatment Q4W, 72 patients will receive study drug treatment Q8W, and 
72 patients will receive sham-control treatment Q8W.  Patients receiving Q4W dosing 
will receive a total of 18 treatments and patients receiving Q8W dosing will receive a 
total of 9 treatments. 
Randomization will be stratified by HtrA1 risk-variant carrier status (HtrA1 risk-variant 
carrier vs. HtrA1 risk-variant non-carrier), baseline GA lesion size (
 9.0 mm2 vs. 
 9.0 mm2), and annualized prebaseline GA progression rate (<1.9 mm2/yr vs. 
1.9 mm2/yr).  HtrA1 risk-variant carriers and HtrA1 risk-variant non-carriers may be 
enrolled in either FHTR2163 or sham-control arms. 
After randomization on Day 1, patients will be administered the first ITV injection of 
FHTR2163 or sham control by the investigator.  If a site has an unexpected issue 
(e.g., 
first study treatment may be administered within 3 working days of the Day 1 visit.  The 
following assessments will be repeated on the day of the study treatment:  slit lamp 
examination, indirect ophthalmoscopy, and pre- and post-treatment intraocular pressure 
(IOP) measurement (and recorded on the Day 1 electronic Case Report Form [eCRF]). 
Subsequent study treatment visits will be scheduled Q4W or Q8W relative to the Day 1 
visit date.  Study treatment should not occur earlier than 22 days after the previous 
treatment.  Missed study treatments will not be made up. 
At the subsequent visits, patients will have safety evaluations performed by the 
investigator prior to receiving study drug or sham control.  Patient self-administered 
anti-microbials pre- and post-
Patients will be educated as to signs and symptoms of post-injection adverse events and 
instructed to contact the investigator at any time if they have any health-related 
concerns.  All assessments for a scheduled visit will be performed on the same day, 
(with the exception of assessments performed during the prebaseline screening period 
or baseline screening window, which may be performed at any time during the 90-day or 
30-day time frame, respectively).  After the Day 1 visit, if a patient misses a study visit 
when ocular images are scheduled to be taken (see Appendix 1 and Appendix 2), the 
images must be obtained at the next scheduled visit. 
Patients who are prematurely discontinued from study treatment (but have not withdrawn 
consent) will be encouraged to undergo as many scheduled visits as possible with 
emphasis on completing Week 72 visit. 


 
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Patients discontinued from the study prior to completion will be asked to return for an 
early termination visit after a minimum of 30 days have elapsed following the final study 
treatment for monitoring of adverse events and the early termination visit assessments.  
Early termination visits not completed after 6 months following the last treatment will be 
w-
 
3.1.1 
Open-Label Extension Study and Study Follow-Up  
enroll in an open-label extension study (GR42558) of GAllego and receive open-label 
FHTR2163 injections.  The Week 76 visit will serve as the final visit for the GAllego study 
(GR40973) and the first (Day 1) visit for Study GR42558.  Dosing frequency will remain 
consistent with each patient's dosing schedule in this study (i.e., Q4W or Q8W). 
Patients who do not enter Study GR42558 will be contacted 7 10 days after the last visit 
by a follow-up call to elicit reports of any decrease in vision, eye pain, unusual redness, 
or other new ocular symptoms in the study eye. 
3.1.2 
Internal Monitoring Committee 
An IMC will monitor safety and study conduct on an ongoing basis.  Members of the IMC 
will be unmasked to treatment allocation and will include Sponsor representatives from 
multiple functions who are not involved in the conduct of the study.  The IMC may 
request that additional Sponsor scientists or other external scientists participate in the 
data analyses and review.  The IMC members will not have direct contact with 
investigational staff or site monitors.  Further details regarding roles and responsibilities 
are outlined in the IMC Agreement. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) 
occurs.  LPLV is expected to occur approximately 76 weeks after the last patient is 
randomized to the study.  In addition, the Sponsor may decide to terminate the study at 
any time. 
3.3 
RATIONALE FOR STUDY DESIGN 
The primary efficacy objective of this Phase II study is an anatomic endpoint, 
specifically, the growth rate of GA lesion area based on FAF imaging (Biarnes et al. 
2015).  The anatomic primary endpoint provides a more sensitive, quantitative, and 
earlier metric of GA progression and serves as a surrogate for vision loss.  The 76-week 
study length was designed because of the slow progressing nature of the disease and to 
maximize the opportunity to ascertain a treatment effect (Fleckenstein et al. 2018). 


 
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3.3.1 
Rationale for FHTR2163 Dose and Schedule 
To provide assessment of the relationship between dosing interval and efficacy, two 
FHTR2163 treatment arms will be evaluated in this Phase II study, a 20-mg dose 
administered ITV Q4W and a 20-mg dose administered ITV Q8W. 
In the Phase I study (GR39821), 20 mg of FHTR2163 was the maximum dose tested 
and was administered ITV Q4W for three doses.  The 20-mg dose and the Q4W interval 
were found to be well tolerated.  The 20-mg dose administered Q4W allows evaluation 
of the highest exposure of FHTR2163. 
The Q8W dosing regimen will be assessed to allow evaluation of a longer dosing 
interval, which is a major priority for patients, caregiver, and physicians in this disease 
indication.  On the basis of the observed serum and aqueous PK data, estimated vitreal 
drug concentrations for a typical patient treated with 20 mg Q8W are maintained above 
the 50% inhibitory concentration of 3.58 nM established in a cynomolgus monkey 
PK/pharmacodynamic (PD) study (16-0265).  In addition, the Q8W dosing interval is 
supported by the observed PD biomarker data from aqueous humor samples collected 
during the Phase I study (GR39821), which suggest inhibition of HtrA1 activity through at 
least 8 weeks following a 20-mg dose. 
3.3.2 
Rationale for Patient Population and Analysis Groups 
Currently, there are no approved treatments to reverse, prevent, or reduce the 
progression of GA secondary to AMD and the associated decrease in visual function.  
Consequently, a significant unmet need exists for treatment of this serious condition. 
This study will enroll a target population of patients with a diagnosis of GA secondary to 
AMD.  Key eligibility criteria were selected to enrich the study population for patients with 
GA who may have more rapid growth of GA lesions to maximize the chances of 
detecting progression of disease and treatment effects over the planned study duration 
as well as to identify patients most likely to potentially benefit from the treatment.  The 
key eligibility criteria and rationale for the criteria are presented below. 
Evidence of Geographic Atrophy in Study Eye and Non-Study (Fellow) Eye 
Bilateral GA represents the majority of the population (approximately 60% 67%) 
diagnosed with GA as reported in two natural history studies (Holz et al. 2007; 
Sunness et al. 2007) and has been associated with an increased rate of GA lesion 
growth compared with unilateral GA (Sunness et al. 2007). 
Presence of Hyperautofluorescence Adjacent to the GA Area in the Study Eye 
(i.e., Banded or Diffuse Junctional Fundus Autofluorescence Patterns) 
Holz et al. (2007) described four major perilesional FAF patterns (none, focal, banded, 
and diffuse) that were correlated with the rate of GA lesion growth in the longitudinal 
natural history arm of patients with GA secondary to AMD in the multicenter FAM study.  


 
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Holz reported that GA lesions with banded or diffuse junctional patterns expanded at a 
significantly higher rate than lesions with focal or no hyperautofluorescence.  Of note, 
approximately 70% of the patients in the FAM study exhibited the banded or diffuse 
junctional perilesional FAF patterns.  Furthermore, the diffuse-trickling pattern of FAF will 
be excluded due to a much faster progression rate relative to the other forms as well as 
the potential for being a distinct form of GA (Holz et al. 2007; Fleckenstein et al. 2014). 
Association between Baseline GA Lesion Size, Historical Rate of GA Progression, 
and Rate of GA Progression 
Sunness et al. (2007) reported that eyes with larger baseline GA area tended to have 
larger subsequent growth.  This association was also suggested by Schmitz-
Valckenberg et al. (2016).  Sunness et al. (2007) also reported that the prior 2-year 
growth of GA was strongly correlated with the subsequent growth over 2 years.  
A similar correlation between prior growth rate and subsequent growth rate was also 
suggested in an analysis of lampalizumab Phase III Studies (GX29176 and GX29185) 
(unpublished data at Genentech). 
3.3.3 
Rationale for Sham-Control Group 
A sham-control group will be used in this study to assess the differences in GA 
progression, change in clinical function measures, and safety in patients who receive 
FHTR2163 compared with patients who receive sham control.  Patients randomized to 
the sham-control group will undergo the same assessments as patients randomized to 
the study drug ITV injection group. 
Sham-control injections were chosen instead of placebo ITV injections to minimize the 
known risk of ITV injection-related adverse events (e.g., endophthalmitis) and because 
no potential patient value would be derived from an ITV injection of placebo. 
3.3.4 
Rationale for Pharmacokinetic and Pharmacodynamic 
Sampling Schedule 
The PK sampling schedule enables characterization of the FHTR2163 
concentration time profile in serum and aqueous humor to understand both ocular and 
systemic PK properties after ITV administration. 
The serum samples collected after dosing will characterize drug absorption from the eye 
as well as the subsequent elimination of FHTR2163 from the systemic circulation.  
Furthermore, the relationship between pharmacokinetics and pharmacodynamics will be 
explored in aqueous humor, and these data will be used to support selection of a 
recommended dose and dose regimen for future clinical trials. 


 
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The aqueous humor sampling schedule aims to characterize PD response throughout 
the treatment period with sampling times to assess change in PD response following 
multiple doses.  In addition, aqueous humor sampling at Week 76 enables 
characterization of PD response at 8 weeks and 12 weeks following the previous dose 
for the Q4W and Q8W arms, respectively.  See Appendix 1 and Appendix 2 for sampling 
schedule details. 
3.3.5 
Rationale for Biomarker Assessments 
3.3.5.1 
Rationale for Aqueous Humor Samples 
Biomarkers in aqueous humor may reflect aspects of pathology or treatment response 
that cannot be detected in blood (Kersten et al. 2018).  In preclinical models and in the 
Phase I study (GR39821), FHTR2163 reduced levels of cleaved DKK3, an aqueous 
humor biomarker related to HtrA1 activity (Tom et al. 2020).  Aqueous humor samples 
will be collected to measure levels of FHTR2163 and biomarkers related to HtrA1 and/or 
GA to support the evaluation of PK and PD effects.  
The method for aqueous humor sample collection in patients receiving ITV injection of 
therapeutic products has been shown to be generally safe and well tolerated when 
performed by ophthalmologists (Van der Lelij and Rothova 1997; Trivedi et al. 2011; 
Kitazawa et al. 2017).  Complication rates were less than 1% with no long-term sequelae 
and no effect on visual acuity.   
3.3.5.2 
Rationale for Plasma and Whole Blood Samples 
AMD is a heterogeneous disease, and HtrA1 expression, as well as associated 
downstream activity, may vary among patients.  Therefore, all patients may not respond 
similarly to treatment with FHTR2163.  Plasma biomarker samples collected at baseline 
and after administration of FHTR2163 will be analyzed to evaluate response to 
FHTR2163.  In addition, biomarker samples will be used in an effort to identify patients 
who may be more likely to respond to FHTR2163 for future studies. 
Whole blood samples will be collected during screening for DNA extraction to enable 
polymerase chain reaction to identify HtrA1 risk-variant carrier status by genotyping 
assay (see Appendix 3).  Whole blood samples will be collected at baseline to find 
potential genetic polymorphisms that may be predictive of response to study drug, may 
be associated with faster progression or progression to a more severe disease state, 
and may be associated with susceptibility to developing adverse events.  At participating 
sites, this sample may also be used for next-generation sequencing (NGS) methods that 
may include whole genome sequencing (WGS) or whole exome sequencing (WES) 
(see Section 4.5.9.) 
Aqueous humor, whole blood, and plasma biomarker data will be analyzed in the context 
of this study but will also be explored in aggregate with data from other studies.  This 
aggregate analysis may increase the knowledge and understanding of GA and inform 
the development of new therapeutic targets. 


 
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3.3.5.3 
Rationale for Collection of Prebaseline FAF Images and 
Historical Ocular Images 
In the general GA population, there is significant variability of GA growth rates.  
However, in the proposed study patient population, GA growth rates are approximately 
linear (Sunness et al. 2007; analysis of the lampalizumab Phase III Studies GX29176 
and GX29185).  Sunness et al. (2007) also reported that the prior 2-year growth of GA 
was strongly correlated with the subsequent growth over 2 years.  A similar correlation 
between prior growth rate (3 11 month timeframe) and subsequent growth rate was also 
suggested in an analysis of lampalizumab Phase III Studies (GX29176 and GX29185) 
(unpublished data at Genentech).  
On the basis of the analyses above, prebaseline GA growth rates have the potential to 
be used as a stratification variable to increase the confidence in study analyses by 
incorporating GA growth rates as a prognostic variable.  The collection and analysis of 
prebaseline FAF will enable quantification of prebaseline GA growth rates. 
Historical ocular images will be used to evaluate correlation between a prior growth rate 
of a duration 
 11 months to subsequent growth rate. 
3.3.5.4 
Rationale for HtrA1 Risk-Variant Genotyping Assay 
Patients will be stratified at enrollment on the basis of carrier versus non-carrier status 
using the HtrA1 risk-variant genotyping assay for the single nucleotide polymorphism 
rs10490924 (see Appendix 3).  rs10490924 is established as one of the most significant 
genetic risk factors for advanced AMD (Fritsche et al. 2016) and the response to 
FHTR2163 treatment will be evaluated in carrier versus non-carrier subgroups. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 360 patients with GA secondary to AMD will be enrolled in this study at 
approximately 77 investigative sites located in the United States. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
General Inclusion Criteria 
 
Signed Informed Consent Form 
 
Age 
 60 years at time of signing Informed Consent Form 
 
Ability to comply with the study protocol, in the investigator's judgment 


 
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For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of 
 1% per year during the treatment period and for at least 28 days after the 
final dose of FHTR2163.   
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (
 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.  
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.  
If required per local guidelines or regulations, locally recognized acceptable 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
Ability and willingness to undertake all scheduled visits and assessments 
 
Ocular Inclusion Criteria:  Study Eye 
One eye will be designated as the study eye.  If both eyes meet the following criteria, the 
eye with the worse VA and/or least function (as determined by the investigator and 
patient) will be selected for study treatment (study eye).  If both eyes have the same 
visual function, the eye with the larger area of GA will be selected as the study eye. 
 
Visual acuity:  BCVA letter score of  24 letters (Snellen equivalent of 20/320 or 
better) using ETDRS chart at starting distance of 4 m 
If the study eye BCVA letter score is 69 letters (Snellen equivalent of 20/40 or 
better), the non-study eye must have a BCVA letter score of 44 letters (Snellen 
equivalent of 20/125 or better). 
 
Well-demarcated area of GA secondary to AMD with no evidence of prior or 
active CNV 


 
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Prebaseline FAF image obtained via a Heidelberg platform 84 336 days prior to the 
screening visit that meets the following criteria: 
 
Total GA lesion size must be 
 2.54 mm2 (approximately 1 disc area [DA]) and 
17.78 mm2 (approximately 
 7 DA) and must reside completely within the FAF 
imaging field (Field 2 30 degree image centered on the fovea) 
If GA is multifocal, at least 1 focal lesion must be 
 1.27 mm2 
(approximately 0.5 DA). 
 
Presence of hyperautofluorescence of either banded or diffuse patterns 
adjacent to GA area 
Note:  Diffuse-trickling pattern is excluded. 
 
Baseline FAF image obtained during the baseline screening window (Day 30 to 
Day 1) must meet the following criteria: 
 
Total GA lesion size must be 
 2.54 mm2 (approximately 1 DA) and 25.4 mm2 
(approximately 10 DA) and must reside completely within the FAF imaging 
field (Field 2 30 degree image centered on the fovea). 
If GA is multifocal, at least 1 focal lesion must be 
 1.27 mm2 
(approximately 0.5 DA). 
 
Presence of hyperautofluorescence of either banded or diffuse patterns 
adjacent to GA area 
Note:  Diffuse-trickling pattern is excluded. 
 
Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit 
quality fundus imaging 
 
Ocular anatomy that would allow for safe and uneventful collection of approximately 
100 L aqueous humor sample in the opinion of the investigator  
 
Ocular Inclusion Criteria:  Non-Study Eye 
 
GA secondary to AMD with no evidence of prior or active CNV 
 
The non-study eye must have a BCVA letter score of 
 44 letters (Snellen equivalent 
of 20/125 or better) if the study eye BCVA letter score is 
 69 letters (Snellen 
equivalent of 20/40 or better). 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry. 
GA Characteristics Exclusion Criterion 
 
GA in either eye due to causes other than AMD (monogenetic macular dystrophies 
[e.g., Stargardt disease, cone rod dystrophy] or toxic maculopathies 
[e.g., chloroquine/hydroxychloroquine maculopathy]) 
 


 
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Ocular Exclusion Criteria:  Study Eye 
 
Absence of any hyperfluorescence pattern (none) adjacent to GA area in the 
study eye 
 
Presence of diffuse-trickling, patchy, or minimal (focal) hyperfluorescence pattern 
adjacent to GA area in the study eye 
 
Any concurrent ocular or intraocular condition in the study eye (e.g., cataract or 
diabetic retinopathy) that, in the opinion of the investigator, could result in either of 
the following: 
 
Require medical or surgical intervention during the study period to prevent or 
treat vision loss that might result from that condition 
 
If allowed to progress untreated, could likely contribute to loss of at least 
two Snellen equivalent lines of BCVA during the study period 
 
Intraocular surgery, including cataract surgery, in the study eye within 3 months 
prior to Day 1 
 
Uncontrolled glaucoma in the study eye, defined as IOP 
 30 mmHg despite 
treatment with anti-glaucoma medication 
 
Current vitreous hemorrhage in the study eye 
 
Aphakia or absence of the posterior capsule in the study eye 
 
Previous laser photocoagulation or ITV anti-VEGF for CNV, diabetic macular 
edema, retinal vein occlusion, or proliferative diabetic retinopathy  
 
Prior treatment with photodynamic therapy, external-beam radiation therapy 
(for intraocular conditions), or transpupillary thermotherapy  
 
Any posterior segment device or implant (e.g., any type of corticosteroid 
implant/device, encapsulated cell therapy, or Argus
 II Retinal Prosthesis System) 
 
ITV, subtenon, or topical (ocular) corticosteroids within 3 months prior to 
randomization 
A single intraoperative administration of a corticosteroid during cataract surgery 
for cystoid macular edema prophylaxis at least 3 months prior to screening is 
permitted. 
 
History of vitrectomy surgery, submacular surgery, or any surgical intervention 
for AMD 
 
History of prophylactic subthreshold laser treatment for AMD 
 
History of glaucoma-filtering (trabeculectomy, valves, or minimally invasive 
glaucoma stents) surgery in the study eye 
 
History of corneal transplant in the study eye  
 
History of retinal tear in the study eye 
Patient may be permitted after appropriate treatment and subsequent 
determination of stability by the investigator. 
History of retinal detachment or macular hole (Stage 3 or 4) in the study eye 


 
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Any concurrent ocular or intraocular conditions that contraindicate the use of an 
investigational drug, may affect interpretation of the study results, or may render the 
patient at high risk for treatment complications 
Note that medical history (e.g., clinically significant increased intraocular 
pressure meeting sight-threatening criteria) that will require the patient to 
receive pre-injection prophylactic paracentesis prior to the study treatment 
administration in the study eye is exclusionary. 
 
Previous violation of the posterior capsule in the study eye unless it occurred as a 
result of yttrium aluminum garnet (YAG) laser posterior capsulotomy in association 
with prior posterior chamber intraocular lens implantation 
 
Spherical equivalent of the refractive error in the study eye demonstrating 
 8 diopters of myopia 
 
For patients who have undergone prior refractive or cataract surgery in the study 
eye, the preoperative refractive error in the study eye should not have exceeded 
8 diopters of myopia. 
 
Ocular Exclusion Criteria:  Non-Study Eye 
 
Non-functioning non-study eye defined as either: 
BCVA of hand motion or worse 
OR  
No physical presence of non-study eye (i.e., monocular) 
 
Ocular Exclusion Criteria:  Both Eyes 
 
Active uveitis and/or vitritis (grade trace or above) in either eye 
 
Active, infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye 
 
Active or history of ocular melanoma in either eye 
 
Active or history of CNV in either eye 
 
Active or history of optic neuritis in either eye 
 
RPE tear that involves the macula in either eye 
 
Moderate or severe non-proliferative diabetic retinopathy in either eye 
Note:  Mild non-proliferative diabetic retinopathy (e.g., occasional hemorrhage 
or microaneurysm) in either eye may be permitted at the discretion of the 
investigator.  Moreover, a patient with the onset of mild non-proliferative 
diabetic retinopathy in either eye during study participation may be permitted to 
continue study treatment at the discretion of the investigator. 
 
Proliferative diabetic retinopathy in either eye 
 
Central serous retinopathy in either eye 


 
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Previous participation in an interventional clinical trial for GA or dry AMD trial that 
tested stem cell treatments, gene therapy, long-acting delivery 
platforms/formulations (e.g., biodegradable/non-biodegradable implants or 
formulations, device implant, encapsulated cell technologies), or 
inhibitors/modulators of the visual cycle (e.g., fenretinide, emixustat) regardless of 
timing of patient participation 
 
Previous participation in interventional clinical trials for GA or dry AMD, except for 
vitamins and minerals, regardless of the route of administration (i.e., ocular or 
systemic) within the last 6 months 
Note:  If patient participation in an interventional clinical trial for GA or dry AMD 
was 
 6 months prior to screening, the patient may be eligible for the trial at the 
discretion of the investigator.  
 
History of recurrent infectious or inflammatory ocular disease in either eye  
 
History of idiopathic or autoimmune-associated uveitis in either eye 
 
Concurrent Systemic Conditions Exclusion Criteria 
 
Uncontrolled blood pressure, defined as systolic blood pressure 
 180 mmHg and/or 
diastolic blood pressure 
 110 mmHg while patient is sitting 
If 
reading may 
be taken 30 or more minutes later.  If 
controlled by antihypertensive medication, the patient can be eligible if 
medication is taken continuously for at least 30 days prior to Day 1. 
 
History of cerebral vascular accident or transient ischemic attack 
 
History of other diseases, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that gives reasonable suspicion of a disease or condition 
that contraindicates the use of FHTR2163, that might affect interpretation of the 
results of the study, or that renders the patient at high risk of treatment 
complications 
 
Active cancer within past 12 months except for appropriately treated carcinoma 
in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with a 
Gleason score of 
 6 and a stable prostate-specific antigen for 
 12 months 
 
History of a severe allergic reaction or anaphylactic reaction to a biologic agent or 
known hypersensitivity to any component of the investigational drug injection 
 
Previous participation in any studies of investigational drugs within the last 
6 months, excluding vitamins and minerals 
If patient participation in a clinical trial was 
 6 months prior to screening, the 
patient may be eligible for the study at the discretion of the investigator.  
 
Requirement for continuous use of any medications/treatments indicated as a 
prohibited therapy in this study (see Section 4.4.2) 
 
Medical conditions that may be associated with a clinically significant risk for 
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Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 28 days after the final dose of FHTR2163 
Women of childbearing potential must have a negative serum pregnancy test 
result within 28 days prior to initiation of study drug. 
 
Active systemic or localized infection requiring medical treatment that, in the opinion 
of the investigator, could interfere with study conduct 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND MASKING 
4.2.1 
Treatment Assignment 
After written informed consent has been obtained, all patients will receive a screening 
number assigned through the interactive web-based response systems (IWRS).  
A patient must satisfy all eligibility criteria (see Sections 4.1.1 and 4.1.2) at both the 
screening and the Day 1 visit (first study treatment) prior to randomization.  As part of 
the screening process, the central reading center (masked to patient treatment 
assignment) will evaluate FAF, color fundus photograph (CFP), NI, SD-OCT, and OCT-A 
(if available) images to provide an objective assessment of patient eligibility.  After all 
patient eligibility requirements are confirmed, site personnel will contact the IWRS during 
the Day 1 visit to randomize the patient.  Patients will be randomized in a 2:1:1:1 ratio to 
one of the study treatment arms (FHTR2163 Q4W, sham control Q4W, FHTR2163 
Q8W, or sham control Q8W).  The study treatment kit number will also be assigned by 
IWRS at that time.  Patients will be randomized on the same day the study treatment is 
to be initiated (Day 1 visit).  Randomization will be stratified by HtrA1 risk-variant carrier 
status (HtrA1 risk-variant carrier vs. HtrA1 risk-variant non-carrier, as determined by 
HtrA1 risk-variant genotyping assay; see Appendix 3), baseline GA lesion size 
(
 9.0 mm2 vs. 
 9.0 mm2), and annualized prebaseline GA progression rate (<1.9 mm2/yr 
vs. 1.9 mm2/yr). 
Details of the randomization procedure will be described in the Data Analysis Plan 
(DAP). 
4.2.2 
Masking 
This is a single-masked study with patients masked to their treatment assignment (study 
drug vs. sham control).  The BCVA examiner will also be masked to the study eye and 
treatment assigned.  The BCVA examiner will only be permitted to perform the 
refraction, BCVA assessment, and pretreatment IOP measurement.  The BCVA 
staff will not be masked to the patient treatment assignments. 
The central reading center review team, consisting of graders and ophthalmologists 
assignment.  They will conduct masked independent review of CFP, FAF, NI, SD-OCT, 
and OCT-A images to provide an objective assessment of image evaluations. 


 
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Contract research organization (CRO) personnel, including clinical research associates, 
will not be masked to the patient treatment assignments. 
Sponsor personnel (except for IMC members) will be masked to treatment assignment 
until after database lock, unless there is a need to unmask as determined by the IMC.  
Furthermore, personnel responsible for PK/PD sample management, assays, and 
analysis may be unmasked as needed (i.e., to evaluate PK relationship to an adverse 
event).  Additionally, for regulatory reporting purposes and if required by local health 
authorities, the Sponsor will break the treatment code for all serious, unexpected 
suspected adverse reactions that are considered by the investigator or Sponsor to be 
related to study drug. 
Patients will be masked to HtrA1 risk-variant carrier status. 
Patients, site study investigator and staff (study coordinators, etc.), and Sponsor 
personnel (except for IMC members) will be masked to prebaseline GA growth rate 
unless there is a need to unmask as determined by the IMC. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is FHTR2163. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
FHTR2163 will be supplied by the Sponsor as a sterile lyophilized powder for 
reconstitution.  Detailed instructions for reconstitution and dilution are provided in the 
pharmacy manual. 
For information on the formulation and handling of FHTR2163, see the FHTR2163 
Investigator's Brochure and pharmacy manual. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Cases of accidental overdose or medication error, along with any associated adverse 
events, should be reported as described in Section 5.3.5.14. 
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.5. 


 
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4.3.2.1 
FHTR2163 and Sham Control 
On Day 1, patients will be randomized in a 2:1:1:1 ratio to one of the study treatment 
arms (FHTR2163 Q4W, sham control Q4W, FHTR2163 Q8W, or sham control Q8W).  
The first ITV injection of 20 mg FHTR2163 or sham control will be conducted by 
investigators on the same day as randomization (i.e., Day 1). 
Subsequent study treatment visits will be scheduled Q4W or Q8W relative to the Day 1 
visit date. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of the IMP supplied by the Sponsor per agreed method 
(e.g., returning the appropriate documentation form or updating IWRS) by the study 
team.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor (or Sponsor representative) before any Sponsor-supplied IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Continued Access to FHTR2163 
Patients may be eligible to receive FHTR2163 as part of an open-label extension study 
offered by the Sponsor (Genentech, a member of the Roche Group), as described in 
Section 3.1.1.  The Roche Global Policy on Continued Access to Investigational 
Medicinal Product is available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter preparations) other than protocol-specified procedural medications (e.g., dilating 
drops) and pre- and post-injection medications (e.g., proparacaine) used by a patient in 
addition to protocol-mandated treatment from 7 days prior to initiation of study drug 
(Day 1) to the study completion/discontinuation visit.  All such medications should be 
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4.4.1 
Permitted Therapy 
In general, investigators may manage patients' preexisting conditions or new-onset 
conditions as clinically indicated and per local standard practice, with the exception of 
prohibited therapies defined in Section 4.4.2.  Patients who use other maintenance 
therapies should continue their use.  Of note, the following are some common therapies 
that are permitted: 
 
Onset of ocular hypertension or glaucoma in the study eye during study participation 
should be treated as clinically indicated 
 
Onset of cataract or posterior capsular opacification in either eye during study 
participation may be treated as clinically indicated 
Dose-interruption criteria (see Section 5.1.5 and Table 1) may apply with 
cataract surgery. 
 
Corticosteroids (ITV, subtenon, topical, device implant, oral, or IV)  
 
Patients who use hormone-replacement therapy or other maintenance therapy 
should continue their use 
 
Anti-VEGF treatment in the non-study eye is permitted 
Intravitreal administration of FDA-approved anti-VEGF agents is permitted at 
the discretion of the evaluating investigator if a patient's non-study eye requires 
treatment for neovascular AMD (nAMD).  Treatment in the non-study eye may 
be administered at the same visit as the study eye treatment; however, all study 
assessments and study eye treatment per protocol should be completed prior to 
anti-VEGF administration in the non-study eye.  Individual trays and sterile 
preparation must be separately prepared for each eye treatment. 
 
Paracentesis in the study eye after study drug administration is permitted per clinical 
judgment for treatment of adverse events 
For patients with a history of repeated paracentesis after study drug 
administration, refer to treatment interruption criteria (see Table 1). 
 
4.4.2 
Prohibited Therapy 
At the discretion of the investigator, patients may continue to receive medications and 
standard treatments administered for other conditions.  However, the following 
medications/treatments are prohibited during the study, and patients who receive any of 
the following therapies may have study treatment interrupted or discontinued and/or may 
be discontinued from the study (see Section 5.1.5): 
 
Systemic anti-VEGF agents 
 
ITV anti-VEGF agents in the study eye  
 
Concurrent non-study eye treatment with unapproved anti-VEGF therapy for nAMD  
 
Systemic or intravenous immunomodulatory therapy (e.g., azathioprine, 
methotrexate, mycophenolate mofetil, cyclosporine, cyclophosphamide, anti-tumor 
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Treatment with photodynamic therapy in either eye 
 
Other experimental therapies including, but not limited to, stem cell treatments, gene 
therapy, and long-acting delivery platforms/formulations 
 
Prophylactic paracentesis in the study eye prior to study treatment administration 
(not including anterior chamber paracentesis to enable collection of aqueous humor 
samples) 
For patients that require prophylactic paracentesis prior to study drug 
administration, refer to treatment interruption criteria (see Table 1). 
 
4.5 
STUDY ASSESSMENTS 
Schedules of activities to be performed during the study are provided in Appendix 1 and 
Appendix 2.  All activities should be performed and documented for each patient. 
See Appendix 1 and Appendix 2 for the schedules of activities performed for Q4W and 
Q8W arms, respectively. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening or re-screening 
evaluations).  Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
All screening evaluations and evaluations at Day 1 must be completed and reviewed to 
confirm that patients meet all eligibility criteria before enrollment.  The investigator will 
maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history, including clinically significant diseases, surgeries, chronic and ongoing 
conditions, (e.g., trauma, cancer, cardiovascular, and ophthalmic history), reproductive 
status, and smoking history, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 7 days prior to initiation of 
study treatment (Day 1 visit) will be recorded.  At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A targeted physical examination should include an evaluation of the head, eyes, ears, 
measured as well.  
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History and Baseline Conditions eCRF.  If any abnormalities are noted during the study, 
the patient may be referred to their primary care physician or an appropriate specialist 
for further evaluation. 
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position after resting for 
5 minutes, and temperature.  Vital signs should be taken during visits as indicated 
(see Appendix 1 and Appendix 2). 
4.5.5 
Ocular Assessments 
Ocular assessments will include the following, to be performed on both eyes (with the 
exception of post-injection safety assessments) at timepoints specified in the schedules 
of activities (see Appendix 1 and Appendix 2).  A detailed examination to evaluate for 
signs of intraocular inflammation (IOI) should be performed prior to any study drug 
administration.  
 
BCVA assessment as determined by ETDRS chart at a starting distance of 4 m 
(see Appendix 4)  
Perform prior to dilating eyes; please refer to instruction manual provided by 
Clinical Edge. 
 
Low-luminance BCVA assessment as determined by ETDRS chart at a starting 
distance of 4 m (see Appendix 5) under low-luminance conditions  
Perform prior to dilating eyes; please refer to instruction manual provided by 
Clinical Edge.  
 
Pre-injection IOP measurement of both eyes  
Perform prior to dilating eyes; the method of IOP measurement used for a patient 
must remain consistent throughout the study. 
 
Slit lamp examination 
Perform prior to dilating eyes; for grading scales for anterior and vitreous cells, 
see Appendix 6. 
 
Dilated binocular indirect high-magnification ophthalmoscopy 
 
Finger-counting test followed by hand motion and light perception tests 
(when necessary) performed within 15 minutes post-injection for the study eye 
(see Appendix 7) 
 
At study treatment visits, post-injection IOP will be measured between 
30 50 minutes after injection.  If there are no safety concerns, the patient will be 
discharged from the clinic.  If the IOP is increased by  
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pre-injection measurement or is of concern to the investigator, the IOP will be 
measured again at 60 80 minutes after injection.  If the IOP value remains a 
concern to the investigator, the patient will remain in the clinic and will be treated as 
 (see Section 5.3.5.2 for guidance on recording adverse events of 
increased intraocular pressure).  The method of IOP measurement used for a 
patient must remain consistent throughout the study. 
 
4.5.6 
Ocular Imaging 
Ocular images to be obtained during screening and study include the following: 
 
Digital CFPs of both eyes (see Appendix 8) 
 
FAF (with keratometry measurements) images of both eyes (see Appendix 9) 
 
NI images of both eyes (see Appendix 10) 
 
SD-OCT images of both eyes (see Appendix 11) 
 
OCT-A images of both eyes (for sites with OCT-A capabilities) (see Appendix 12) 
 
Historical ocular images are defined as FAF and SD-OCT (study eye and/or non-study 
eye) images obtained during the 5-year period prior to the screening visit excluding 
those used for prebaseline FAF (see Section 3.1).  Historical ocular images may be 
collected and submitted to the central reading center any time after enrollment into the 
study. 
Additional details on obtaining these images are included in the Central Reading Center 
Manual. 
4.5.7 
Follow-Up Calls 
After each study treatment visit, the site must contact the patient 14 (
 5) days after each 
treatment visit and query for adverse events; particularly any signs or symptoms of 
decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, scotoma, 
pain).  If the patient reports any concerning signs and/or symptoms, the patient must be 
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4.5.8 
Laboratory, Biomarker, and Other Biological Samples 
At scheduled visits, specimens should be collected prior to study eye treatment.  Fasting 
is not required prior to specimen collection.  The specimens will be forwarded to the 
central laboratory.  The central laboratory will either perform the analysis or forward 
samples to Sponsor or its designee for analysis and/or storage.  Instructions for 
obtaining, processing, storing, and shipping of all specimens are provided in the 
laboratory manual.  Laboratory supply kits will be provided to the sites by the central 
laboratory.  See Appendix 1 and Appendix 2 for sample collection timepoints. 
Samples will be collected for the following analyses: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, and 
other cells) 
 
Chemistry panel (serum):  sodium, potassium, glucose, BUN or urea, creatinine, 
total protein, albumin, total and direct bilirubin, ALP, ALT, and AST 
 
Coagulation:  INR, aPTT, and PT 
 
Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
 
Serum samples for measurement of anti-FHTR2163 antibodies (ADAs) 
 
Serum samples to measure FHTR2163 concentration 
 
Aqueous humor samples to measure FHTR2163 concentration  
 
Aqueous humor samples for determination of biomarkers related to HtrA1 activity 
and disease progression  
 
Plasma samples for exploratory research on biomarkers related to HtrA1 and GA 
 
Screening whole blood sample for polymerase chain reaction genotyping of HtrA1 
risk-variant carrier status (rs10490924) 
 
Whole blood clinical genotyping sample for genomic research aimed at exploring 
inherited genome variations associated with AMD and the response to study drug.  
Analysis may include targeted single-nucleotide polymorphism genotyping or 
sequencing for rare variants.  At participating sites, this sample may also be used 
for NGS methods that may include WGS or WES (see Section 4.5.9). 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 


 
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Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.10), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
Serum samples and aqueous humor collected for PK or immunogenicity analysis 
may be needed for additional immunogenicity characterization and for PK or 
immunogenicity assay development and validation; therefore, serum samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been 
completed.   
 
Blood and aqueous humor samples collected for biomarker research and biomarker 
assay development will be destroyed no later than 15 years after the final Clinical 
Study Report has been completed.   
However, the storage period will be in accordance with the Institutional Review Board 
(IRB)/Ethics Committee (EC)-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements). 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
4.5.9 
Blood Samples for Whole Genome Sequencing (Patients at 
Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
to identify variants that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with acquired resistance to 
study drug, are associated with susceptibility to developing adverse events, can lead to 
improved adverse event monitoring or investigation, or can increase the knowledge and 
understanding of disease biology and drug safety.  Research will be aimed at exploring 
inherited characteristics.  The samples may be sent to one or more laboratories for 
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Collection and submission of blood samples for WGS is contingent upon the review and 
approval of the exploratory research by each site's IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS, this 
section of the protocol (Section 4.5.9) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provide a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches or new methods for monitoring efficacy and safety or predicting which 
patients are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Blood samples collected for WGS are to be stored until they are no longer needed or 
until they are exhausted.  However, the storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
Refer to Section 4.5.8 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.10 
Optional Samples for Research Biosample Repository 
4.5.10.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To increase knowledge and understanding of disease biology 


 
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To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.10.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.10) 
will not be applicable at that site. 
4.5.10.3 
Sample Collection and Storage Timeline 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to FHTR2163, diseases, or 
drug safety: 
 
Leftover blood, serum, plasma, and aqueous humor samples and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods.  Genomics is 
increasingly informing researcher's understanding of disease pathobiology.  WGS and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
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4.5.10.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.10.5 
Consent to Participate in the Roche Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.10.6 
Withdrawal from the Roche Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the Medical 


 
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Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent to the 
testing of his or her RBR samples after closure of the site, the investigator must inform 
the Sponsor by emailing the study number and patient number to the following email 
address: 
global_rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.10.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Pregnancy 
 
Unacceptable toxicity 
 
Any event that meets treatment discontinuation criteria defined in Table 1 in 
Section 5.1.5. 
The primary reason for study treatment discontinuation should be documented on the 
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Patients withdrawn from the study prior to completion will be asked to return for an early 
termination evaluation after a minimum of 30 days following his or her final study 
treatment for monitoring of adverse events and assessments listed for the early 
termination visit (see Appendix 1 and Appendix 2).  The reason for the discontinuation 
should be recorded on the appropriate eCRF.  Discontinued patients will not be replaced 
or allowed to re-enter the study. 
Patients who discontinued treatment will not be allowed to re-start the study treatment.  
However, they should be strongly encouraged to stay in the study and undergo as many 
scheduled visits as possible. 
4.6.2 
Patient Discontinuation from the Study 
Patients discontinued or withdrawn from study will return to the clinic for a study 
discontinuation visit after a minimum of 30 days following his or her final study treatment 
(see Appendix 1 and Appendix 2). 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event  
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
If a patient discontinued the study but has not withdrawn the informed consent, the site 
should make every effort to continue to follow up on serious adverse events, deaths, and 
adverse events of special interest in these patients. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
Incidence or severity of adverse events in this or other studies indicates a potential 
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Patient enrollment is unsatisfactory 
 
Data recording is inaccurate or incomplete 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
FHTR2163 is not approved, and clinical development is ongoing.  The nonclinical 
toxicology and safety studies have revealed minimal ocular inflammation that 
demonstrated complete or partial recovery.  No systemic adverse effects were observed 
in nonclinical studies.  In addition, FHTR2163 was well tolerated in the Phase I study 
(GR39821), with no ocular serious adverse events, dose-limiting toxicities, or adverse 
events of special interest reported.  See Section 1.3.2 and the FHTR2163 Investigator's 
Brochure for further details. 
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  Ongoing review of unmasked safety 
data will be performed by an IMC (see Section 3.1.2). 
The safety plan for patients in this study is based on nonclinical studies, the anticipated 
mechanism of action, and clinical experience with the completed FHTR2163 Phase I 
study, GR39821.  The anticipated important safety risks for FHTR2163 are outlined 
below. 
5.1.1 
Potential Risks Associated with FHTR2163 
5.1.1.1 
Potential Ocular Risks 
Ocular Inflammation 
In repeat-dose GLP toxicology studies of up to 6 months in duration in cynomolgus 
monkeys, an anterior and posterior intraocular inflammatory response was observed in 
animals treated with FHTR2163.  The observed inflammation was consistent with a 
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effects of FHTR2163, because of the character and localization of the inflammation and 
because the incidence and/or severity of inflammation generally lacked a relationship to 
dose.  The inflammation noted during optical coherence tomography, ophthalmic 
examinations, or microscopic examinations also showed complete or partial recovery. 
In the FHTR2163 Phase I clinical study (GR39821), there was one patient with 
2 nonserious Grade 1 iritis events.  Both events resolved with topical treatment and the 
patient completed the study with no changes in study drug administration.  
In the ongoing Phase II clinical study GR40973, there have been reports of inflammation 
of the anterior chamber only, posterior chamber only, as well as combined anterior and 
posterior chamber. These include two serious cases of vitritis and one of serious case of 
uveitis; and nonserious recurrent vitritis events that lead to study discontinuation.  The 
mechanism is not fully understood at this point. 
As of 26 March 2021, there have been no reports of IOI in the ongoing Phase II study 
GR42558.  
Refer to the FHTR2163 Investigator's Brochure for more details on ocular inflammation 
events in the completed and ongoing clinical studies. 
The safety plan includes BCVA, detailed ocular examinations, including slit lamp 
examinations and indirect ophthalmoscopy, as well as SD-OCT imaging at most study 
visits to evaluate any potential ocular adverse event.  A follow-up call 14 (
 5) days after 
all study drug administrations is required to query for adverse events; particularly any 
signs or symptoms of decreased visual acuity and/or inflammation (e.g., painful red eye, 
floaters, scotoma, pain); if the patient reports any concerning signs and/or symptoms, 
the patient must be evaluated by the investigator as soon as possible. 
In case of non-infectious IOI, consider performing CFP/FA (widefield CFP/FA or 
standard CFP/FA with peripheral sweeps is preferred) and SD-OCT.  A uveitis lab 
workup, as per clinical judgment, should also be considered.  Additionally, consider 
treatment with corticosteroids if appropriate, based on the individual patient presentation 
and comorbidities (e.g., diabetes, systemic hypertension), and consider referring patient 
to a uveitis specialist and/or rheumatologist, per clinical judgment. 
Dose interruption and treatment discontinuation criteria for ocular inflammation are 
presented in Section 5.1.5 (see Table 1). 
An IMC will review unmasked data on a regular basis to assess for any imbalances in 
rates of ocular inflammation across different treatment arms (see Section 3.1.2 and the 
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IOI-Associated Retinal Vasculitis 
In the ongoing clinical study GR40973, there have been two investigator-reported cases 
of IOI-associated retinal vasculitis as of 23 March 2021.  One case reported IOI with 
associated retinal sheathing of the arteries, with an initial decrease in visual acuity that is 
subsequently recovering with corticosteroid treatment.  The other case reported uveitis 
with mild vasculitis (retinal venous) and optic nerve head leakage seen on FA, with no 
impact on visual acuity.  These events occurred after administration of a single and of 
two doses of masked study drug, respectively, and were treated with corticosteroids.  
IOI has been reported with other FDA-approved intravitreal agents for the treatment of 
wet AMD; it is typically mild, sterile and resolves with corticosteroid eye drops. 
Brolucizumab was the first approved anti-VEGF therapy associated with noninfectious 
retinal vasculitis after intravitreal therapy.  These events have been reported up to 
8 weeks after the first brolucizumab injection, making a direct toxic or infectious cause 
unlikely, and suggesting an immune-mediated mechanism, potentially autoimmunity 
(Baumal et al. 2020). 
It is important to recognize and diagnose IOI-associated retinal vasculitis and to 
distinguish it from other causes of uveitis, endophthalmitis, and embolic causes of retinal 
artery occlusion.  Patients with IOI should be followed up closely, and treated 
appropriately, realizing that some may progress and potentially show signs of retinal 
vasculitis (Baumal et al. 2020).  
The safety plan is described above for ocular inflammation. 
Dose interruption and treatment discontinuation criteria for IOI-associated retinal 
vasculitis are presented in Section 5.1.5 (Table 1).  
5.1.1.2 
Potential Systemic Risks 
Systemic side effects of FHTR2163 are not anticipated based on data from the 
nonclinical studies and the Phase I clinical study.  Observed systemic levels of 
FHTR2163 following multiple ITV administrations of 20 mg in the Phase I study 
(GR39821; see Section 1.3.2) were less than 0.2 g/mL on average at maximum 
concentration and are estimated to be at least 7,500-fold lower than vitreal FHTR2163 
concentrations.  On the basis of the binding affinity of FHTR2163, baseline systemic 
HtrA1 levels, and the systemic concentrations of FHTR2163 following ITV administration 
of 20 mg, complete inhibition of systemic HtrA1 is not expected. 
Furthermore, there is a rare human disease, characterized by complete loss of HtrA1 
activity due to a loss of function mutation in the HTRA1 gene, called cerebral autosomal 
recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL).  
The main clinical manifestations of CARASIL are ischemic stroke or stepwise 
deteriorations in brain functions, progressive dementia, premature baldness, and attack 
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loss of HtrA1 activity from birth, the onset of clinical signs and symptoms do not manifest 
until 20 to 45 years of age (Hara et al. 2009; Fukutake 2011).  
On the basis of the extended time course for the onset of CARASIL as well as the 
expectation that systemic exposures of FHTR2163 after ITV administration will not result 
in complete inhibition of systemic HtrA1, it is highly unlikely that patients will exhibit signs 
and/or symptoms of CARASIL after ITV administration of FHTR2163. 
As part of the safety plan, masked aggregate adverse event reports will be reviewed 
periodically to assess for any potential systemic safety effect with specific focus on 
adverse events that may be related CARASIL signs and symptoms, and an IMC will 
review unmasked data on a regular basis to assess for any imbalances in rates of 
adverse events across different treatment arms (see Section 3.1.2 and the IMC 
Agreement for further details). 
5.1.2 
Risks Associated with Intravitreal Route of Administration 
Potential ocular safety issues currently thought to be associated with the ITV route of 
administration include decreased BCVA, conjunctival hemorrhage, ocular inflammation 
(see Appendix 6 for anterior chamber and vitreous inflammation grading scales), 
intraocular infection (endophthalmitis), transient and/or sustained elevation of IOP, 
transient vision loss, cataract development or progression, retinal or vitreous 
hemorrhage, and retinal break or detachment.  See Section 5.1.5 for details on 
management and Table 1 for instructions concerning dose-interruption and treatment 
discontinuation criteria. 
An IMC will review unmasked data on a regular basis to assess for any imbalances in 
rates of adverse events due to ITV injections across different treatment arms (see 
Section 3.1.2 and the IMC Agreement for further details). 
5.1.3 
Risks Associated with Aqueous Humor Sampling through 
Anterior Chamber Paracentesis 
Sampling of aqueous humor through anterior chamber paracentesis is a valuable 
procedure in providing samples for assessment of ocular PK and PD parameters of 
FHTR2163.  Potential ocular safety issues may include cataract development or 
progression, anterior chamber hemorrhage, decreased IOP and/or hypotony, and 
decreased BCVA.  There have also been rare reports of serious complications, including 
endophthalmitis and corneal abscess. 
The procedure will be performed by experienced ophthalmologists familiar with aqueous 
humor sampling through anterior chamber paracentesis (see Appendix 14 for anterior 
chamber paracentesis and aqueous humor sampling procedures), and patients will be 
monitored closely for occurrence of any potential adverse event associated with the 
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5.1.4 
Management of Patients Who Experience Adverse Events 
Associated with Intravitreal Injection 
Following the study drug injection, patients will remain at the clinic for at least 
30 minutes.  IOP will be measured in both eyes before injection and in the study eye 
30 50 minutes after injection.  If there are no safety concerns, the patient will be 
discharged from the clinic.  If the IOP is increased by 
 10 mmHg from the pre-injection 
measurement or is of concern to the investigator, the IOP will be measured again at 
60 80 minutes post-injection.  If the IOP value remains a concern to the investigator, the 
patient will remain in the clinic and will be treated as necessary in accordance with 
invest
For guidance on adverse 
event reporting, see Section 5.3.5.2.  During each drug administration visit, finger 
counting will be tested within 15 minutes after study drug injection by the investigator; 
hand motion and light perception will be tested when necessary. 
In addition, patients will be instructed by study site personnel about warning signs and 
symptoms, including decrease in vision, eye pain, unusual redness, or any other new 
ocular symptoms in the study eye.  If warranted, patients will be asked to return to the 
clinic as soon as possible for an unscheduled safety assessment visit (see Appendix 1 
and Appendix 2) and will be instructed to contact the investigator at any time should they 
have any health-related concerns.  Please see Table 1 and Section 5.1.5 for instructions 
concerning dose-interruption and treatment discontinuation criteria, and management of 
IOI. 
5.1.5 
Dose-Interruption and/or Treatment Discontinuation Criteria 
Study-treatment interruption and patient discontinuation from the study treatment for 
adverse events will be determined using the criteria listed in Table 1.  If treatment is 
interrupted, treatment will not be resumed earlier than the next scheduled study visit.  
The reason for study treatment interruption or discontinuation should be recorded on the 
appropriate eCRF and, if applicable, on the Adverse Event eCRF (see Section 5.2.1 for 
definition of an adverse event).  Adverse events should be reported to the Sponsor in 
accordance with instructions provided in Sections 5.2 5.6. 
In addition, for any patient who develops any of the exclusion criteria (Section 4.1.2) 
after study onset, dosing may be interrupted or the patient may be discontinued from 
study treatment after discussion with the Medial Monitor.   
Additionally, patients who receive any of the prohibited therapies (Section 4.4.2) may 
have study treatment interrupted or discontinued and/or may be discontinued from the 
study. 
 
 


 
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Table 1 
Dose Interruption and Treatment Discontinuation Criteria and 
Management 


 
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Table 1 
Dose Interruption and Treatment Discontinuation Criteria (cont.) 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 


 
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protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can, 
therefore, be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), (see Sections 5.3.5.11 and 
Section 5.3.5.12 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test that is associated with 
symptoms or leads to a change in study treatment or concomitant treatment or 
discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs patient hospitalization (see Section 5.3.5.13) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
functions) 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 


 
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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events; see Section 5.3.3); 
the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
 Law (see Section 5.3.5.9) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
Adverse events resulting from medication error (see Section 5.3.5.14) 
Examples of medication errors include, but are not limited to, overdose, 
incorrect dose, incorrect route, incorrect drug, incorrect administration, or 
incorrect kit. 
 
Sight-threatening adverse events   
All sight-threatening adverse events listed below should be reported as serious 
adverse events, with the underlying cause (if known) of the event listed as the 
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An adverse event is considered to be sight threatening and should be reported 
expeditiously if it meets one or more of the following criteria: 
 
It causes a decrease of 
 30 letters in VA score, compared with the most recent 
prior VA assessment, that lasts more than 1 hour and is attributable to study 
drug. 
 
It requires surgical intervention (i.e., conventional surgery, vitreous tap, or 
biopsy with ITV injection of an anti-infective compound; or laser or retinal 
cryopexy with gas) to prevent permanent loss of sight. 
 
It is associated with severe (Grade 4+) IOI and/or IOI-associated retinal 
vasculitis as defined in Section 5.3.5.1 (see Section 5.1.1.1 for further details on 
potential ocular risks, Table 1 for dose-interruption and 
treatment-discontinuation criteria, and Appendix 6 for IOI grading scales). 
An additional ADA and PK sample should be collected as close as possible 
to the time of diagnosis (see Section 5.1.5 and Appendix 1 and 
Appendix 2). 
 
In the opinion of the investigator, it may require medical intervention to prevent 
permanent loss of sight. 
 
5.2.4 
Selected Adverse Events 
Additional data will be collected for the following selected adverse events: 
 
Loss of VA 
 30 letters, compared with the last assessment of VA prior to the most 
recent assessment, lasting more than 1 hour due to study drug treatment 
 
CNV conversion requiring treatment for either the study eye or non-study eye 
 
Any clinically significant ocular imaging finding  
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 


 
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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see 
Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.  After the 28-day period, only serious adverse events (1) 
caused by a protocol-mandated intervention (e.g., invasive procedures such as aqueous 
humor sample), or (2) believed to be related to prior study drug treatment (see 
Section 5.6) should be reported (see Section 5.4.2 for instructions for reporting serious 
adverse events). 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The WHO toxicity grading scale (see Appendix 15) will be used for assessing adverse 
event severity.  Table 2 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale. 
For adverse events of IOI, severity assessment ideally should be aligned with the 
grading scale for assessment of anterior chamber flare or cells and vitreous chamber 
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NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Adverse Events of Ocular Infection and Inflammation 
For the purposes of reporting events of ocular infection and inflammation, the following 
terms and definitions should be used: 
 
Iritis:  the presence of inflammatory cells in the anterior chamber 
The presence of aqueous flare alone will not constitute iritis but should be 
documented as an anterior chamber flare for adverse event reporting purposes. 
 
Iridocyclitis:  the presence of inflammatory cells in both the aqueous and vitreous 
 
Vitritis:  the presence of active inflammation in the vitreous, demonstrated by the 
presence of inflammatory cells (trace or greater) 
Active inflammation in the vitreous should be clinically differentiated from 
cellular debris from prior episodes of inflammation, hemorrhage, or other 
causes. 
 
IOI-associated retinal vasculitis:  ocular inflammation and retinal vascular changes 
(i.e., perivascular sheathing and vascular leakage or occlusion on fluorescein 
angiogram), as defined by the Standardization of Uveitis Nomenclature Working 
Group (Jabs et al. 2005). 
The presence of occlusive retinal vasculopathy, in the absence of visible 
inflammation, should not be considered IOI-associated retinal vasculitis.  
 
Endophthalmitis:  diffuse intraocular inflammation predominantly involving the 
vitreous cavity but also involving the anterior chamber, implying a suspected 
underlying infectious cause. 
A culture is required prior to initiating antibiotic treatment for presumed 
endophthalmitis.  Results of bacterial or fungal cultures, treatment given, and 
final ophthalmologic outcome must be provided in the details section of the 
Adverse Event eCRF. 
 


 
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Note:  Trace benign, aqueous pigmented cells visible on slit lamp examination that are 
caused by the dilation process and are not red blood cells, white blood cells, or the result 
of any ocular disorder should not be recorded as an adverse event. 
5.3.5.2 
Increased Intraocular Pressure Values 
The observation of elevated IOP values measured between 30 50 minutes 
post-injection, in general, should not be reported as an adverse event.  Elevated IOP 
values measured between 30  50 minutes post-injection should be reassessed at 
60 80 minutes post-injection prior to reporting an adverse event.  Medical and scientific 
judgment should be exercised in deciding if an elevated IOP at 30 50 minutes post-
injection that remains elevated at the follow-up 60 80 minute assessment is clinically 
significant and qualifies to be reported as an adverse event. 
5.3.5.3 
Abnormal Findings on Ocular Imaging 
Not every abnormal imaging finding on ocular imaging qualifies as an adverse event.  
An abnormal finding on ocular imaging must be reported as an adverse event if it meets 
any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
 
 
It is the 
judgment should be exercised in deciding whether an isolated imaging abnormality 
should be classified as an adverse event. 
If a clinically significant abnormal image finding is a sign of a disease or syndrome 
(e.g., retinal edema), only the diagnosis (i.e., CNV) should be recorded on the Adverse 
Event eCRF. 
Observations of the same clinically significant abnormal image finding from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.6 for 
details on recording persistent adverse events). 
5.3.5.4 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 


 
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report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.5 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.6 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases in severity will be captured on the Adverse 
Event Intensity or Grade Changes eCRF.  If the event becomes serious, it should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning that the 
event became serious; see Sections 5.2.2 and 5.4.2 for reporting instructions).  The 
Adverse Event eCRF should be updated by changing the event from "non-serious" to 
"serious," providing the date that the event became serious, and completing all data 
fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.3.5.7 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
 
 
It 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 
 upper limit of normal (ULN) associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.6 for 
details on recording persistent adverse events). 
5.3.5.8 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
 
 
It 
ndings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.6 for 
details on recording persistent adverse events). 
5.3.5.9 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (
 3 
 ULN) in combination with either an elevated 
total bilirubin (
 2 
 ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as 
Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST 
 3 
 ULN in combination with total bilirubin 
 2 
 ULN 
 
Treatment-emergent ALT or AST 
 3 
 ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.4) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event (see Section 5.2.2) or adverse event of 
special interest (see Section 5.2.3). 
5.3.5.10 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, 
 should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., 
be replaced by the established cause of death.  The term 
 should not 
be used unless combined with the presumed cause of death (e.g., "sudden cardiac 
death"). 
Deaths that occur after the adverse event reporting period should be reported as 
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5.3.5.11 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.12 
Worsening of Geographic Atrophy in Study Eye 
Medical occurrences or symptoms of deterioration that are anticipated as part of the 
normal progression of GA secondary to AMD of the study eye should be recorded as an 
adverse event only if judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature at any time during the study.  When recording 
an unanticipated worsening of study eye GA secondary to AMD on the Adverse Event 
eCRF, it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., 
requirements for sight-threatening events (listed in Section 5.2.3) apply to these 
unexpected changes in the study eye GA secondary to AMD. 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events. 
5.3.5.13 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below: 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
The patient has not experienced an adverse event 
 


 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
  
5.3.5.14 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
FHTR2163 or sham control, adverse events associated with special situations should be 
recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with FHTR2163 (i.e., wrong drug), 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug administered, expired 
drug administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 


 
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Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information 
Genentech Medical Monitor contact information: 
Medical Monitor: 
, M.D., Ph.D. (Primary) 
Telephone No.: 
 (mobile), United States of America 
Email address:  
 


 
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5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
These events should be reported immediately (i.e., no more than 24 hours after learning 
of the event) on the Adverse Event eCRF and the report submitted via the electronic 
data capture (EDC) system.  A report will be generated and sent to Safety Risk 
Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided below: 
Email address: 
RTPSafety@ppdi.com 
Fax No.: 
+1 888 529 3580 
  
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events, adverse events of special interest, 
should be reported within 24 hours after learning of the event until the final study visit 
(Week 76).  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the EDC system.  A report will be generated and sent to Safety 
Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided in Section 5.4.2.1.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur after the final study visit  
(Week 76) are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 


 
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completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided in Section 5.4.2.1.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a paper Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available. 
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
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During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment or to a protocol-mandated intervention (see Section 5.3.1).  These 
events should be reported through use of the Adverse Event eCRF.  However, if the 
EDC system is not available, the investigator should report these events directly to the 
Sponsor or its designee, either by faxing or by scanning and emailing the Clinical Trial 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the fax 
number or email address provided below: 
Email address: 
us_drug.safety@gene.com 
Fax No.: 
+1 650 225 4682 
 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
 
FHTR2163 Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of data for the 76-week study period will be performed when all randomized 
patients have either completed the 76-week study period or have discontinued from the 
study prior to Week 76, all data from this period are in the database, all data have been 
cleaned and verified, and the database is locked. 
Detailed specifications of the statistical methods will be described in the DAP. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study is designed to evaluate the efficacy of FHTR2163 administered ITV Q4W and 
Q8W to patients with GA secondary to AMD.  The focus of the efficacy outcome 
analyses will be on estimation of the magnitude of the treatment effect. 
The primary efficacy endpoint is the mean change in GA area from baseline to Week 72 
as measured by FAF.  The sample size provides reasonable precision for estimation of 
the treatment effect with respect to the primary endpoint. 
Approximately 360 patients will be randomized in a 2:1:1:1 ratio to one of four treatment 
groups:  FHTR2163 Q4W, sham control Q4W, FHTR2163 Q8W, or sham control Q8W.  
Patients in the sham control Q4W and sham control Q8W groups will be pooled in the 
analyses. 
Assuming a 15% dropout rate by Week 72 and a standard deviation of 1.82 mm2 for 
change from baseline in GA area at Week 72 (estimated from the lampalizumab Phase II 
Study CFD4870g and the Phase III Studies GX29176 and GX29185), 114 patients in the 
FHTR2163 Q4W arm and 114 patients in the pooled sham-control group will provide 
80% power to detect a targeted difference of 0.56 mm2 (20% reduction relative to sham 
control) in the change from baseline in GA area at Week 72 between the FHTR2163 
Q4W arm and the pooled sham-control arm.  Calculations were based on two-sided t-
test at the significance level of 20% and resulted in a total sample size of 285.  No 
multiplicity adjustment is planned for this study. 
A total of 131 patients had enrolled in this study as of 10 April 2020.  As a result of the 
increase in missed visits, missed dosing, and missed assessments as a consequence of 
the COVID-19 pandemic, up to approximately 75 patients will be enrolled in addition to 
the originally planned 285 patients to help mitigate the potential impact on treatment 
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6.2 
SUMMARIES OF CONDUCT OF STUDY 
The clinical database will be used to assess study conduct.  The number of patients who 
enroll, discontinue, or complete the study will be summarized.  Reasons for premature 
study treatment discontinuation and study discontinuation, any eligibility criteria 
deviation, and other major protocol deviations will also be tabulated. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (e.g., age, sex, race), baseline safety 
(e.g., baseline vital signs and laboratory test results), and baseline disease 
characteristics (e.g., baseline GA area, baseline BCVA, annualized prebaseline GA 
growth rate) will be summarized for all randomized patients by treatment group using 
descriptive statistics. 
6.4 
EFFICACY ANALYSES 
The primary and secondary efficacy analyses will be based on the modified 
intent-to-treat population (see DAP for detailed definition).  Patients will be grouped 
according to the treatment assigned at randomization.  Patients in the sham control 
Q4W and sham control Q8W groups will be pooled in the analyses. 
If not otherwise specified, analyses of efficacy outcome measures will be stratified by 
HtrA1 risk-variant carrier status (HtrA1 risk-variant carrier vs. HtrA1 risk-variant 
non-carrier, as determined by the HtrA1 risk-variant genotyping assay; see Appendix 3), 
baseline GA lesion size (
 9.0 mm2 vs. 
 9.0 mm2), and annualized prebaseline GA 
progression rate (<1.9 mm2/yr vs. 1.9 mm2/yr).  A data-as-observed approach with the 
mixed-effect model will be used to handle missing data in the primary analysis.  
Sensitivity analyses will be performed to evaluate the effect of missing data on the results 
(see DAP for details). 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change in GA area from baseline to Week 72 
as measured by FAF.  
Comparison of each active arm versus the pooled sham-control arm will be assessed 
using a linear mixed-effect model with an effect for treatment and with covariate 
adjustments for baseline factors such as HtrA1 risk-variant carrier status, baseline GA 
lesion size, and annualized prebaseline GA progression rate.  The primary analysis will 
be based on all available data up to 72 weeks, with no imputation for missing data.  
Two-sided 80% confidence interval will be provided for the estimated treatment effects.  
Hypothesis testing will be conducted at the two-sided significance level of 20%, and no 
multiple-testing adjustment is planned. 
Detailed specifications of the statistical methods will be described in the DAP. 


 
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6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
 
Mean change in BCVA score from baseline to Week 72 as assessed by ETDRS 
chart under low-luminance conditions 
 
Mean change in BCVA score from baseline to Week 72 as assessed by ETDRS 
chart  
 
The secondary endpoints will be analyzed in a similar manner as the primary endpoint, 
using a linear mixed-effect model.  Additional details regarding the analysis of secondary 
and exploratory efficacy endpoints will be provided in the DAP. 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received at 
least one FHTR2163 injection or sham control, with patients grouped according to 
treatment received.  Safety summaries will be presented for all treated patients. 
Safety will be assessed through descriptive summaries of adverse events, ocular 
assessments (e.g., inflammation, IOP, BCVA), clinical laboratory evaluation, ocular 
imaging, and immunogenicity against FHTR2163. 
Verbatim descriptions of adverse events will be summarized by mapped term, 
appropriate thesaurus level, and toxicity grade (if applicable) (see Section 5.3.3).  
6.6 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of any patient who has at least one FHTR2163 
concentration data point.  Individual and mean serum and aqueous humor FHTR2163 
concentration versus time data will be tabulated and plotted by treatment arm.  The 
serum and aqueous humor pharmacokinetics of FHTR2163 will be summarized by 
estimating total exposure (area under the concentration time curve), maximum 
concentration, and elimination rate as data allow.  Estimates for these parameters will be 
tabulated and summarized.  Interpatient variability will be evaluated.  Additional PK 
analyses will be conducted as appropriate. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) as well as after drug administration (postbaseline 
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The relationship between ADA status and efficacy, safety, and PK, endpoints may be 
analyzed and reported via descriptive statistics. 
6.8 
BIOMARKER ANALYSES 
The primary efficacy analysis described in Section 6.4 will be repeated in the HtrA1 
risk-variant carrier and non-carrier subgroups as an exploratory analysis.  Biomarkers 
will be analyzed together with PK data to explore PK/PD relationships.  Additional 
analyses will be performed to identify biomarkers that are predictive of response to 
FHTR2163, are associated with rate of progression to a more severe disease state, are 
associated with susceptibility to developing adverse events, can provide evidence of 
FHTR2163 activity, or can increase the knowledge and understanding of disease 
biology. 
6.9 
OPTIONAL INTERIM ANALYSES 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two interim analyses.  The decision to conduct an optional interim analysis 
and the timing of the analysis will be documented in the Sponsor's trial master file prior 
to the conduct of the interim analysis.  The interim analysis will be performed by the 
unmasked IMC and will be interpreted by the IMC and appropriate senior management 
standard procedures.  The details of the timing and scope of the interim analysis, if any, 
will be specified in the IMC Agreement. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.  The designated Functional Service 
Provider will be responsible for discrepancy management. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and ocular 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the E
System backups for data stored by the Sponsor and records retention for the study data 
 
The Sponsor will supply eCRF specifications for this study. 


 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, images, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the E.U. 
Clinical Trial Directive (2001/20/EC) and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


 
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submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must be 
available for verification by study monitors at any time. 
Each Consent Form may also include patient authorization to allow use and disclosure 
of personal health information in compliance with the U.S. Health Insurance Portability 
and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate Authorization 
Form for patient authorization for use and disclosure of personal health information 
under the HIPAA regulations, the review, approval, and other processes outlined above 
apply except that IRB review and approval may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  


 
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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5). 


 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by Genentech, Inc.  The Sponsor will maintain 
the medical, safety, data management, statistical programming, statistical analysis, and 
oversight of selected vendors during the study.  A CRO will manage the study, site 
monitoring, and selected vendors.  Genentech will oversee the CRO. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 


 
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Section 4.5.8.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the study. 
An IWRS will be used for patient screening and randomization and for management of 
study drug requests and shipments.  A central laboratory will be used for most laboratory 
assessments and for storage of other laboratory samples prior to being shipped to 
Sponsor or its designee for analysis.  Data will be recorded by an EDC system using 
eCRFs or forwarded to Sponsor electronically (e.g., safety lab data).  A central reading 
center will be used for ocular imaging analyses (e.g., FAF, NI, CFP, OCT-A, and 
SD-OCT) that will be forwarded to Sponsor electronically. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website: 
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 


 
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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
REFERENCES 
[Apellis] Apellis Pharmceuticals, Inc. Data supports biologic activity of APL-2 in reducing 
the growth rate of geographic atrophy [resource on the Internet]. 2018 [updated: 
22 February 2018; cited 7 December 2018]. Available from: 
http://investors.apellis.com/news-releases/news-release-details/apellis-
pharmaceuticals-announces-18-month-results-phase-2-study. 
Baumal CR, Spaide RF, Vajzovic L, et al. Retinal vasculitis and intraocular inflammation 
after intravitreal injection of brolucizumab. Ophthalmology 2020;127:1345 59. 
Biarnés M, Arias L, Alonso J, et al. Increased fundus autofluorescence and progression 
of geographic atrophy secondary to age-related macular degeneration: the gain 
study. Am J Ophthalmol 2015;160:345 53. 
Ciferri C, Lipari MT, Liang W-C, et al. The trimeric serine protease HtrA1 forms a 
cage-like inhibition complex with an anti-HtrA1 antibody. Biochem J 
2015;472:169 81. 
Clausen T, Southan C, Ehrmann M. The HtrA Family Of Proteases: Review Implications 
For Protein Composition And Cell Fate. Mol Cell 2002;10:443 55. 
DeWan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related 
macular degeneration. Science. 2006;314:989 92. 
Fleckenstein M, Mitchell P, Freund KB et al. The progression of geographic atrophy 
secondary to age-related macular degeneration. Ophthalmology 2018;125:369 90. 
Fleckenstein M, Schmitz-Valckenberg S, Lindner M, et al. 
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autofluorescence phenotype in geographic atrophy. Invest  Ophthalmol Vis Sci 
2014;55:2911 20. 
et al. Prevalence of age-related macular 
degeneration in the United States. Arch Ophthalmol 2004;122:564 72. 
Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of 
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variants. Nat Genet 2016;48:134 43. 
Fukutake T. cerebral autosomal recessive arteriopathy with subcortical infarcts and 
leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke 
and Cerebrovasc Dis 2011;20:85 93. 
Grau S, Richards PJ, Kerr B, et al. The role of human HtrA1 in arthritic disease. 
J Biol Chem 2006;281:6124 9. 
Hara K., Shiga A., Fukutake T, et al. Association of HTRA1 mutations and familial 
ischemic cerebral small-vessel disease. N Engl J Med 2009;360:1729 39. 
Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy 
and impact of fundus autofluorescence patterns in age-related macular 
degeneration. Am J Ophthalmol 2007;143:463 72. 


 
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Holz FG, Sadda SR, Busbee B, et al. Efficacy and Safety of lampalizumab for 
geographic atrophy due to age-related macular degenerationchroma. JAMA 
Ophthalmol 2018;136:666 77. 
Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature 
for reporting clinical data. Results of the First International Workshop. Am J 
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Jaffe GJ, Westby K, Csaky KJ, et al. C5 Inhibitor Avacincaptad Pegol for Geographic 
Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 
2/3 Trial. Ophthalmology 2020;20:30845 9. 
Jones A, Kumar S, Zhang N, et al. Increased expression of multifunctional serine 
protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal 
vasculopathy in mice. Proc Natl Acad Sci 2011;108:14578 83. 
Kersten E, Paun CC, Schellevis RL, et al. Systemic and ocular fluid compounds as 
potential biomarkers in age-related macular degeneration. Surv Ophthalmol 
2018;63:9 39. 
Kitazawa K, Sotozono C, Koizumi N, et al. Safety of anterior chamber paracentesis 
using a 30-gauge needle integrated with a specially designed disposable pipette. 
Br J Ophthalmol 2017;101:548 50.  
Kumar S, Berriochoa Z, Ambati BK, et al. Angiographic features of transgenic mice with 
increased expression of human serine protease HTRA1 in retinal pigment 
epithelium. Invest Ophthalmol Vis Sci 2014;55:3842 50. 
Lindblad AS, Clemons TE. Responsiveness of the National Eye Institute Visual Function 
Questionnaire to progression to advanced age-related macular degeneration, 
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Lindblad AS, Lloyd PC, Clemons TE, et al. Change in area of geographic atrophy in the 
Age-Related Eye Disease Study. AREDS report number 26. Arch Ophthalmol 
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Rudnicka AR, Jarrar Z, Wormald R, et al. Age and gender variations in age-related 
macular degeneration prevalence in populations of European ancestry: a 
meta-analysis. Ophthalmology 2012;119:571-80.  
Schmitz-Valckenberg S, Sahel J-A, Danis R, et al. Natural history of geographic atrophy 
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Progression Study). Ophthalmology 2016;123:361 8. 
Sunness JR, Bressler NM, Maguire MG. Scanning laser ophthalmoscopic analysis of the 
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Sunness JS, Applegate CA, Haselwood D, et al. Fixation patterns and reading rates in 
eye with central scotomas from advanced atrophic age-related macular 
degeneration and Stargardt disease. Ophthalmology 1996;103:1458 66. 
Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual 
acuity loss in the geographic atrophy form of age-related macular degeneration. 
Ophthalmology 1999;106:1768 79. 
Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic 
atrophy from age-related macular degeneration: enlargement of atrophy and 
implications for interventional clinical trials. Ophthalmology 2007;114:271 7. 
Tom I, Pham VC, Katschke KJ, et al. Development of a therapeutic anti-HtrA1 antibody 
and the identification of DKK3 as a pharmacodynamic biomarker in geographic 
atrophy. Proc Natl Acad Sci U S A 2020;117;9952 63. 
Trivedi D, Denniston AK, Murray PI. Safety profile of anterior chamber paracentesis 
performed at the slit lamp. Clin Exp Ophthal 2011;39:725 8. 
Van der Lelij A, Rothova A. Diagnostic anterior chamber paracentesis in uveitis: a safe 
procedure. Br J Ophthalmol 1997;81:976 9. 
Vierkotten S, Muether PS, Fauser S. Overexpression of HTRA1 leads to ultrastructural 
changes in the elastic layer of Bruch's membrane via cleavage of extracellular 
matrix components. PloS One 2011;6:e22959. 
Weeks DE, Conley YP, Tsai H-J, et al. Age-related maculopathy: an expanded 
genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 
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Appendix 1: 
Schedule of Activities: Q4W Arms 
  
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b Patients who have an eligible preexisting FAF image may directly enter in the 30-day baseline screening window (see Figure 2).  The 
preexisting FAF will be considered the prebaseline FAF.  See Section 4.1 for GA lesion eligibility criteria.  Baseline screening activities may 
be completed across more than one visit if necessary.  
c After 
-label extension study (GR42558) 
and receive FHTR2163 injections.  The Week 76 visit will serve as the final visit for this study (GR40973; GAllego) and the first (Day 1) visit 
for Study GR42558.  Patients who do not enter Study GR42558 will be contacted 7 10 days after the last visit by a follow-up call to elicit 
reports of any decrease in vision, eye pain, unusual redness, or other new ocular symptoms in the study eye.  
d For patients who discontinue early from the study, early termination assessments will be performed after minimum of 30 days have lapsed 
following the final study treatment. 
e The Informed Consent Form needs to be signed and documented only once during prebaseline screening or screening visit.  
f 
Significant medical and surgical history, including chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, and ophthalmic 
history), and tobacco use, surgeries, cancer history, reproductive status, and all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to Day 1 visit. 
g Demographic data will include age, sex, and self-reported race/ethnicity. 
h Historical ocular images are defined as FAF and SD-OCT images of both eyes obtained up to 5 years prior to the baseline screening window, 
excluding those used to evaluate prebaseline FAF.  Historical ocular images may be collected and submitted any time after enrollment into 
the study.  This assessment is required only for patients who have historical images available. 
i 
Prebaseline FAF and NI images from patients must have been obtained on a Heidelberg platform 84 336 days prior to screening (Day 30 to 
Day 1).  If both eyes have the potential to be eligible for the study, FAF and NI images from both eyes should be sent to central reading 
center. 
j 
If the preexisting FAF image is not gradable or the total GA lesion size is smaller than the required (
 2.54 mm2), the FAF image obtained 
during the baseline screening window will be considered as the prebaseline image.  If all other eligibility criteria are met (see Section 4.1), the 
patient will return to clinic for a repeat screening visit 90 (  30) days from the date of when the prebaseline image was obtained.  During the 
repeat 30-day baseline screening window, all screening visit assessments will be performed except for HtrA1 genotyping whole blood sample 
and keratometry. 
k On Day 1, contact IWRS for study drug kit assignment after all assessments are performed. 
l 
To be performed if clinically indicated.  
m Vital signs consist of measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient is in a seated 
position after resting for 5 minutes, and temperature. 
n For a detailed description of sample collection, see the laboratory manual. 


Appendix 1: 
Schedule of Activities: Q4W Arms 
  
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o Collect and perform urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at each study 
treatment visit.  If positive, collect a serum pregnancy sample and forward to central laboratory for testing; if the serum pregnancy test is 
positive, do not administer the study treatment. 
p At screening, collect serum pregnancy sample for women of childbearing potential, including those who have had tubal ligation.  If positive, 
record the patient as a screen fail.  At early termination visit, collect the serum pregnancy sample and forward to the central laboratory for 
testing. 
q In case of Grade 
 0 non-infectious intraocular inflammation, contact the Medical Monitor to discuss case.  An additional serum ADA and PK 
sample should be collected as close as possible to the time of diagnosis.  Consider performing CFP/FA (Appendix 13; widefield CFP/FA or 
standard CFP/FA with peripheral sweeps is preferred), SD-OCT, and uveitis lab workup as clinically indicated.  Additionally, consider 
treatment with corticosteroids if appropriate, based on the individual patient presentation and comorbidities (e.g., diabetes, systemic 
hypertension), and consider referring patient to a uveitis specialist and/or rheumatologist, per clinical judgment. 
r 
Perform assessment prior to dilating the eyes. 
s Recommend the slit lamp examination be performed prior to dilating eyes; for grading scales for anterior and vitreous cells, see Appendix 6. 
t 
Aqueous humor sample must be collected from the study eye after pretreatment IOP measurement, but prior to study drug administration, 
when applicable.  For a detailed description of the anterior chamber paracentesis and aqueous humor sample collection procedures, see 
Appendix 14 and the laboratory manual. 
u FAF, keratometry, SD-OCT, OCT-A (as applicable), NI images, and color fundus photographs will be obtained from both eyes and will be 
forwarded to the central reading center.  Note:  After randomization, if a patient misses a study visit where ocular images were scheduled to 
be obtained, the images should be obtained at the next scheduled visit. 
v Only one keratometry measurement on each eye (obtained at prebaseline screening or baseline screening) is required. 
w OCT-A is mandatory for sites that have the capability. 
x All assessments (including a detailed examination to evaluate for signs of intraocular inflammation) and sample collection should be 
completed prior to study drug administration except for post-treatment finger-counting and IOP measurement. 
y After study drug administration in the study eye only, a finger-counting test followed by hand motion and light perception tests (when 
necessary) will be performed by the investigator within 15 minutes post study drug injection followed by an IOP measurement that will be 
obtained between 30 50 minutes post-injection.  If there are no safety concerns, the patient may be discharged from the clinic.  If the IOP is 
increased  10 mmHg from pre-injection measurement, the IOP will measured again at 60 80 minutes post-injection.  If the IOP value 
remains a concern to the investigator
judgment prior to discharge.  For guidance on adverse event reporting, see Section 5.3.5.2. 


Appendix 1: 
Schedule of Activities: Q4W Arms 
  
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z Record any concomitant medications (e.g., prescription drugs, over-the-counter preparations other than protocol-specified procedural 
medications [e.g., dilating drops or fluorescein dyes] and pre- and post-injection medications [e.g., proparacaine]) used by the patient from 
7 days prior to Day 1 to until the study completion/discontinuation visit. 
aa After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  Adverse events will be recorded starting on Day 1 after the study treatment until 28 days 
after the final dose of study drug.  After the 28 day period, only serious adverse events caused by a protocol-mandated intervention or 
believed to be related to prior study drug treatment (see Section 5.6) should be reported (see Sections 5.3.1 and 5.4.2 for instructions for 
reporting serious adverse events).  Adverse events assessed by the investigator as related to study drug should be followed until the event 
resolves or the event is assessed 
in the study has ended. 
bb Record all concurrent ocular procedures performed on the study or non-study eye. 
cc  After each study treatment visit, the site must contact the patient 14 (
 5) days after each treatment visit and query for adverse events; 
particularly any signs or symptoms of decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, scotoma, pain); if the patient 
reports any concerning signs and/or symptoms, the patient must be evaluated by the investigator as soon as possible. 
 
 
 
 








Appendix 2: 
Schedule of Activities: Q8W Arms 
  
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f Significant medical and surgical history, including chronic and ongoing conditions (e.g., trauma, cancer, cardiovascular, and ophthalmic 
history), and tobacco use, surgeries, cancer history, reproductive status, and all medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the patient within 7 days prior to Day 1 visit. 
g Demographic data will include age, sex, and self-reported race/ethnicity. 
h Historical ocular images are defined as FAF and SD-OCT images of both eyes obtained up to 5 years prior to the baseline screening 
window, excluding those used to evaluate prebaseline FAF.  Historical ocular images may be collected and submitted any time after 
enrollment into the study.  This assessment is required only for patients who have historical images available. 
i 
Prebaseline FAF and NI images from patients must have been obtained on a Heidelberg platform 84 336 days prior to screening (Day 30 
to Day 1).  If both eyes have the potential to be eligible for the study, FAF and NI images from both eyes should be sent to central reading 
center. 
j 
If the preexisting FAF image is not gradable or the total GA lesion size is smaller than the required (
 2.54 mm2), the FAF image obtained 
during the baseline screening window will be considered as the prebaseline image.  If all other eligibility criteria are met (see Section 4.1), 
the patient will return to clinic for a repeat screening visit 90 (
 30) days from the date of when the prebaseline image was obtained.  During 
the repeat 30-day baseline screening window, all screening visit assessments will be performed except for HtrA1 genotyping whole blood 
sample and keratometry. 
k On Day 1, contact IWRS for study drug kit assignment after all assessments are performed. 
l 
To be performed if clinically indicated.  
m Vital signs consist of measurements of respiratory rate, pulse rate, and systolic and diastolic blood pressures while the patient in a seated 
position after resting for 5 minutes, and temperature.   
n For a detailed description of sample collection, see the laboratory manual. 
o Collect and perform urine pregnancy test for women of childbearing potential, including those who have had tubal ligation, at each study 
treatment visit.  If positive, collect a serum pregnancy sample and forward to central laboratory for testing; if the serum pregnancy test is 
positive, do not administer the study treatment. 
p At screening, collect serum pregnancy sample for women of childbearing potential, including those who have had tubal ligation.  If positive, 
record the patient as a screen fail.  At early termination visit, collect the serum pregnancy sample and forward to the central laboratory for 
testing. 
q In case of Grade 
 0 non-infectious intraocular inflammation, contact the Medical Monitor to discuss case.  An additional serum ADA and 
PK sample should be collected as close as possible to the time of diagnosis.  Consider performing CFP/FA (Appendix 13; widefield CFP/FA 
or standard CFP/FA with peripheral sweeps is preferred), SD-OCT, and uveitis lab workup as clinically indicated.  Additionally, consider 
treatment with corticosteroids if appropriate, based on the individual patient presentation and comorbidities (e.g., diabetes, systemic 
hypertension), and consider referring patient to a uveitis specialist and/or rheumatologist, per clinical judgment. 


Appendix 2: 
Schedule of Activities: Q8W Arms 
  
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r Perform assessment prior to dilating the eyes. 
s Recommend the slit lamp examination be performed prior to dilating eyes; for grading scales for anterior and vitreous cells, see Appendix 6. 
t Aqueous humor sample must be collected from the study eye after pretreatment IOP measurement, but prior to study drug administration, 
when applicable.  For a detailed description of the anterior chamber paracentesis and aqueous humor sample collection procedures, see 
Appendix 14 and the laboratory manual. 
u FAF, keratometry, SD-OCT, OCT-A (as applicable), NI images, and color fundus photographs will be obtained from both eyes and will be 
forwarded to the central reading center.  Note:  After randomization, if a patient misses a study visit where ocular images were scheduled to 
be obtained, the images should be obtained at the next scheduled visit. 
v Only one keratometry measurement on each eye (obtained at prebaseline screening or baseline screening) is required. 
w OCT-A is mandatory for sites that have the capability. 
x All assessments (including a detailed examination to evaluate for signs of intraocular inflammation) and sample collection should be 
completed prior to study drug administration except for post-treatment finger counting and IOP measurement. 
y After study drug administration in the study eye only, a finger-counting test followed by hand motion and light perception tests (when 
necessary) will be performed by the investigator within 15 minutes post study drug injection followed by an IOP measurement that will be 
obtained between 30-50 minutes post-injection.  If there are no safety concerns, the patient may be discharged from the clinic.  If the IOP is 
increased  10 mmHg from pre-injection measurement the IOP will measured again at 60 to 80 minutes post-injection.  If the IOP value 
remains a concern to the investigator, the patient will remain in the clinic and will be treated in accordance wit
judgment prior to discharge.  For guidance on adverse event reporting, see Section 5.3.5.2.  
z Record any concomitant medications (e.g., prescription drugs, over-the-counter preparations) other than protocol-specified medications 
(e.g., dilating drops, proparacaine, and pre and post-injection anti-microbial drops) used by the patient from 7 days prior to Day 1 to until the 
study completion/discontinuation visit. 
aa After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a 
protocol-mandated intervention should be reported.  Adverse events will be recorded starting on Day 1 after the study treatment until 
28 days after the final dose of study drug.  After the 28-day period, only serious adverse events caused by a protocol-mandated intervention 
or believed to be related to prior study drug treatment (see Section 5.6) should be reported (see Sections 5.3.1 and 5.4.2 for instructions for 
reporting serious adverse events).  Adverse events assessed by the investigator as related to study drug should be followed until the event 
resolves or the event is assessed 
 
bb  Record all concurrent ocular procedures performed on the study or non-study eye. 


Appendix 2: 
Schedule of Activities: Q8W Arms 
  
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cc  After each study treatment visit, the site must contact the patient 14 (
 5) days after each treatment visit and query for adverse events; 
particularly any signs or symptoms of decreased visual acuity and/or inflammation (e.g., painful red eye, floaters, scotoma, pain); if the 
patient reports any concerning signs and/or symptoms, the patient must be evaluated by the investigator as soon as possible. 
 
 


 
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Appendix 3  
HtrA1 Risk-Variant Genotyping Assay 
The genotype at the single nucleotide polymorphism 
 is determined using a 
TaqMan  polymerase chain reaction assay (
).  The assay 
has been designed and validated by Life Technologies and is performed in a Clinical 
Laboratory Improvement Amendments certified lab. 
Each assay contains two sequence-specific primers for amplifying and two allele specific 
TaqMan MGB probes (labeled with reporter dyes VIC and FAM) for detecting the alleles 
for the specific polymorphisms of interest.  The fluorescence data are collected and 
analyzed using the ABI Prism  7900HT Sequence Detection Systems software.  The 
software uses Cycle Threshold (Ct) values for mutant and wild-type probes to determine 
genotype 
. 
 


 
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Appendix 4  
Best Corrected Visual Acuity Testing 
SCOPE 
Best corrected visual acuity (BCVA) assessment must be conducted before pupil 
dilation.  BCVA will be measured by trained and certified personnel at the study sites.  
The BCVA 
treatment arm (study drug vs. sham control) assignment.  BCVA will be measured at the 
intervals specified in the protocol (see Appendix 1 and Appendix 2 of the protocol and 
Clinical Edge Instruction Manual). 
EQUIPMENT 
The following are needed to conduct the examination: 
 
Examination lane of adequate dimensions to allow testing at required distances 
 
Standard chair with a firm back 
 
Set of three Precision Vision  or Lighthouse distance acuity charts (modified Early 
Treatment Diabetic Retinopathy Study Charts R, 1, and 2 in the United States) 
 
Retro-Illuminated box 
 
Study frame 
 
Study lens set 
 
TRAINING AND CERTIFICATION 
VA specifications document, procedure manual, and training materials will be provided 
to the investigational sites, and examiner certification will be obtained.  The VA 
examination room also must be certified before any VA examinations are performed. 
 


 
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Appendix 5  
Low-Luminance Best Corrected Visual Acuity Testing 
These are the same requirements as the best corrected visual acuity described in 
Appendix 4; however, low-luminance visual acuity will be measured by placing a 
2.0-log-unit neutral density filter (Kodak Wratten 2.0 neutral density filter) over the best 
correction for the eye and having the participant read the standard illuminated Early 
Treatment Diabetic Retinopathy Study Chart. 
 




 
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Appendix 7  
Post-Injection Procedures for All Patients 
The patient will be monitored with a finger-counting test followed by hand motion and 
light perception tests (when necessary) within 15 minutes of the study treatment by the 
investigator. 
A measurement of intraocular pressure (IOP) in the study eye only will be obtained 
30 50 minutes after study treatment.  If there are no safety concerns, the patient may be 
discharged from the clinic.  If the IOP is increased by 
 10 mmHg from the pre-injection 
measurement or is of concern to the investigator, the IOP will be measured again at 
60 80 minutes post-injection.  If the IOP value remains a concern to the investigator, the 
patient will remain in the clinic and will be treated as necessary in accordance with 
 
As per individual site investigator decision, the investigator may administer antimicrobial 
drops after treatment following study drug injection.  The individual site investigator may 
also instruct patients to self-administer antimicrobial drops pre- and post-injection. 
Unless country regulatory prohibits, the used study drug kit, including the used vial, 
should be stored until the Sponsor representative conducts the study drug accountability 
and the site is instructed to discard or ship to the Sponsor.  Discard all syringes and 
needles in the sharps container. 
 


 
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Appendix 8  
Color Fundus Photography 
SCOPE 
Non-stereo color fundus photographs will be taken by trained personnel at the study 
sites.  Fundus photography will be performed at the intervals specified in the protocol 
(see Appendix 1 and Appendix 2). 
EQUIPMENT 
See the Central Reading Center Manual. 
PROCEDURE 
The central reading center will provide a study manual and the training materials.  The 
fundus photographer and photography equipment will be certified by the reading center 
before any study images are taken.  See the Central Reading Center Manual for further 
details. 


 
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Appendix 9  
Fundus Autofluorescence 
SCOPE 
Fundus autofluorescence (FAF) will be performed at the study sites by trained personnel 
who are certified by the central reading center.  FAF imaging will be performed for each 
patient at the intervals specified in the protocol (see Appendix 1 and Appendix 2) and will 
be forwarded to the central reading center. 
EQUIPMENT 
Equipment used during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required (i.e., no 
printed FAF images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
FAF operators, systems, and software will be certified prior to any evaluation of patients. 


 
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Appendix 10  
Near-Infrared Imaging 
SCOPE 
Near-infrared (NI) imaging will be performed at the study sites by trained personnel who 
are certified by the central reading center.  NI imaging will be performed for each patient 
at the intervals specified in the protocol (see Appendix 1 and Appendix 2). 
The NI images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center. 
EQUIPMENT 
Equipment used during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed NI images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
NI operators, systems, and software will be certified prior to any evaluation of patients. 
  


 
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Appendix 11  
Spectral Domain Optical Coherence Tomography 
SCOPE 
Spectral domain optical coherence tomography (SD-OCT) will be performed at the study 
sites by trained personnel who are certified by the central reading center.  SD-OCT 
imaging will be performed for each patient at the intervals specified in the protocol 
(see Appendix 1 and Appendix 2). 
The SD-OCT images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center. 
EQUIPMENT 
Equipment used during this study is described in the Central Reading Center Manual.  
The SD-OCT equipment used for a patient must remain consistent throughout the study.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed SD-OCT images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  
SD-OCT operators, systems, and software will be certified prior to any evaluation 
of patients. 
 


 
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Appendix 12  
Optical Coherence Tomography Angiography 
SCOPE 
Optical Coherence Tomography Angiography (OCT-A) will be performed at the study 
sites with this capability by trained personnel who are certified by the central reading 
center.  OCT-A imaging will be performed for each patient at the intervals specified in 
the protocol (see Appendix 1 and Appendix 2). 
The OCT-A images of both eyes will be obtained at protocol-specified visits and will be 
forwarded to the central reading center. 
EQUIPMENT 
Equipment used during this study is described in the Central Reading Center Manual.  
The ability to transfer images to electronically exportable digital files is required 
(i.e., no printed OCT-A images will be sent to the central reading center). 
PROCEDURES AND CERTIFICATION 
The central reading center will provide the study manual and training materials.  OCT-A 
operators, systems, and software will be certified prior to any evaluation of patients. 
 


 
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Appendix 13  
Fluorescein Angiography 
SCOPE 
Fluorescein angiography (FA) will be performed at the study sites by trained personnel, 
when non-infectious intraocular inflammation is suspected and investigator considers it 
as an important part of the diagnostic work-up.  Analysis (if applicable) will be performed 
by the central reading center. 
EQUIPMENT AND DIGITAL IMAGING SYSTEMS 
Digital angiograms must be used while conducting an angiographic evaluation for the 
study.  Widefield FA or standard FA with peripheral sweeps is preferred, if available. 
Film-based angiography is not acceptable. 
PROCEDURES 
Refer to the Central Reading Center Manual for details.  


 
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Appendix 14  
Anterior Chamber Paracentesis and Aqueous Humor Sampling 
Procedure 
An aqueous humor sample will be collected before the treatment of the study eye 
(if applicable) as indicated in Appendix 1 and Appendix 2.  The anterior chamber 
paracentesis will be performed by a qualified physician by placing a drop of topical 
anesthetic on the cornea, passing a needle through the limbus into the anterior chamber, 
and removing approximately 100 L of aqueous fluid and more volume if possible 
without endangering patient safety at applicable patient visits.  Samples will be collected 
with the kit provided by central laboratory and shipped on dry ice to the central 
laboratory as soon as possible after the draw. 
The following procedures will be used to minimize the risk of potential adverse events 
associated with aqueous humor sampling (e.g., endophthalmitis, corneal abscess, 
hyphema, cornea, lens, iris trauma). 
Aseptic technique will be performed by clinic staff involved in the aqueous humor 
collection tray assembly, anesthetic preparation, and aqueous humor sample collection.  
In addition to the procedures outlined below, any additional safety measures in 
adherence to specific institutional policies associated with aqueous humor sample 
collection will be observed.  
As per individual site investigator decision, patients may self-administer antimicrobial 
drops prior to treatment and after treatment following the aqueous humor sample 
collection. 
Prepare a sterile field that includes the following supplies: 
 
10% povidone iodine swabs 
 
Sterile surgical gloves 
 
4 
 4 sterile pads 
 
0.5% proparacaine hydrochloride 
 
5% povidone iodine ophthalmic solution 
 
1-cc syringe  
 
27- or 30-gauge needle, 0.5 inches in length 
 
Sterile saline solution 
 
Per individual investigator discretion: 
 Sterile cotton-tipped applicators 
 Eyelid speculum 
 Sterile ophthalmic drape 
 Surgical face mask 


Appendix 14: 
Anterior Chamber Paracentesis and Aqueous Humor 
Sampling Procedure 
 
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Aqueous humor sampling should be performed using an aseptic procedure and sterile 
field as follows: 
 
Instill two drops of 0.5% proparacaine hydrochloride into the study eye 
 
Wait 90 seconds  
 
As per individual investigator discretion, instill two drops of antimicrobial drops 
 
Wait 5 minutes (only if antimicrobial drops are used)  
 
Instill two drops of 5% povidone iodine ophthalmic solution in the study eye 
 
Disinfect the periocular skin and eyelid of the study eye  
Scrub the eyelid, lashes, and periorbital skin with 10% povidone-iodine 
swabs, starting with the eyelid and lashes and continuing with the 
surrounding periocular skin.  Ensure that the eyelid margins and lashes are 
swabbed, and proceed in a systematic fashion from medial to temporal 
aspects. 
 
Instill two additional drops of 5% povidone-iodine ophthalmic solution in the 
study eye 
 
After washing hands, put on sterile gloves 
 
Per investigator discretion, the investigator may place sterile ophthalmic drape to 
isolate the field and place the speculum underneath the eyelid of the study eye 
 
Collect the aqueous humor sample (approximately 100 L) using the 27- or 
30-gauge needle attached to the 1-cc syringe through a paracentesis inserted at the 
temporal paralimbal clear cornea on a horizontal angle in a plane above and parallel 
to the iris with the bevel of the needle facing away from the iris, paying strict 
 
NOTE:  The investigator and patient should refrain from talking, coughing, or 
sneezing during the aqueous sample collection.  A surgical face mask may 
be worn per investigator discretion. 
 
Dispense collected aqueous humor into the appropriately labeled collection tube 
provided and store frozen until shipped as described in the Laboratory Manual 
 
As per individual site investigator decision, patients may self-administer 
antimicrobial drops after treatment following aqueous humor sampling 
 


 
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Appendix 15  
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
ITEM 
Grade 1 Toxicity Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
HEMATOLOGY 
Hemoglobin 
9.510.5 g/dL 
8.09.4 g/dL 
6.57.9 g/dL 
 6.5 g/dL 
Absolute Neutrophil 
Count 
10001500/mm3 
750999/mm3 
500749/mm3 
 500/mm3 
Platelets 
75,00099,000/mm3 50,00074,999/mm3 20,00049,000/mm3 
 20,000/mm3 
Prothrombin Time 
(PT) 
1.011.25  ULN 
1.261.5  ULN 
1.513.0  ULN 
 3  ULN 
Activated Partial 
Thromboplastin 
(aPTT) 
1.011.66  ULN 
1.672.33  ULN 
2.343  ULN 
 3  ULN 
Fibrinogen 
0.750.99  LLN 
0.500.74  LLN 
0.250.49  LLN 
 0.25  LLN 
Fibrin Split Product 
2040 g/mL 
4150 g/mL 
5160 g/mL 
 60 g/mL 
Methemoglobin 
5%9.9% 
10.0%14.9% 
15.0%19.9% 
 20% 
LIVER ENZYMES 
AST (SGOT) 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
ALT (SGPT) 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
GGT 
1.252.5  ULN 
1.65  ULN 
5.110  ULN 
 10  ULN 
Alkaline 
Phosphatase 
1.252.5  ULN 
1.65  ULN 
5.110  ULN 
 10  ULN 
Amylase 
1.11.5  ULN 
1.62.0  ULN 
2.15.0  ULN 
 5.1  ULN 
CHEMISTRIES 
Hyponatremia 
130135 mEq/L 
123129 mEq/L 
116122 mEq/L 
 116 or mental status 
changes or seizures 
Hypernatremia 
146150 mEq/L 
151157 mEq/L 
158165 mEq/L 
 165 mEq/L or mental 
status changes or 
seizures 
Hypokalemia 
3.03.4 mEq/L 
2.52.9 mEq/L 
2.02.4 mEq/L or 
intensive replacement 
Rx required or 
hospitalization 
required 
 2.0 mEq/L or paresis 
or ileus or 
life-threatening 
arrhythmia 
Hyperkalemia 
5.66.0 mEq/L 
6.16.5 mEq/L 
6.67.0 mEq/L 
 7.0 mEq/L or 
life-threatening 
arrhythmia 
Hypoglycemia 
5564 mg/dL 
4054 mg/dL 
3039 mg/dL 
 30 mg/dL or mental 
status changes or coma 


Appendix 15: WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
 
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ITEM 
Grade 1 Toxicity Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
CHEMISTRIES (cont.) 
Hyperglycemia 
(note if fasting) 
116160 mg/dL 
161250 mg/dL 
251500 mg/dL 
 500 mg/dL or 
ketoacidosis or seizures 
Hypocalcemia 
(corrected for 
albumin) 
8.47.8 mg/dL 
7.77.0 mg/dL 
6.96.1 mg/dL 
 6.1 mg/dL or life-
threatening arrhythmia 
or tetany 
Hypercalcemia 
(corrected for 
albumin) 
10.611.5 mg/dL 
11.612.5 mg/dL 
12.613.5 mg/dL 
 13.5 mg/dL or 
life-threatening 
arrhythmia 
Hypomagnesemia 
1.41.2 mEq/L 
1.10.9 mEq/L 
0.80.6 mEq/L 
 0.6 mEq/L or 
life-threatening 
arrhythmia 
Hypophosphatemia 
2.02.4 mg/dL 
1.51.9 mg/dL or 
replacement Rx 
required 
1.01.4 mg/dL 
intensive Rx or 
hospitalization 
required 
 1.0 mg/dL or 
life-threatening 
arrhythmia 
Hyperbilirubinemia 
1.11.5  ULN 
1.62.5  ULN 
2.65  ULN 
 5  ULN 
BUN 
1.252.5  ULN 
2.65  ULN 
5.110  ULN 
 10  ULN 
Creatinine 
1.11.5  ULN 
1.63.0  ULN 
3.16  ULN 
 6  ULN or required 
dialysis 
URINALYSIS 
Proteinuria 
1 or  0.3% or 
 3 g/L or 
200 mg1 g 
loss/day 
23 or 0.3%1.0% 
or 310 g/L or 
12 g loss/day 
4 or  1.0% or 
 10 g/L or 
23.5 g loss/day 
nephrotic syndrome or 
 3.5 g loss/day 
Hematuria 
Microscopic only 
Gross, no clots 
Gross  clots 
Obstructive or required 
transfusion 
CARDIAC DYSFUNCTION 
Cardiac Rhythm 
 
Asymptomatic, 
transient signs, no 
Rx required 
Recurrent/persistent, 
no Rx required 
Requires treatment 
Hypertension 
Transient increase, 
 20 mm, no Rx 
Recurrent, chronic, 
 20 mm, 
Rx required 
Requires acute Rx, 
no hospitalization 
Requires  
hospitalization 
Hypotension 
Transient 
orthostatic 
hypotension, no Rx 
Symptoms 
correctable with 
oral fluids, Rx 
Requires IV fluids, 
no hospitalization 
required 
Requires  
hospitalization 
Pericarditis 
Minimal effusion 
Mild/moderate 
asymptomatic 
effusion, no Rx 
Symptomatic effusion, 
pain, ECG changes 
Tamponade, 
pericardiocentesis, or 
surgery required 


Appendix 15: WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
 
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ITEM 
Grade 1 Toxicity Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
CARDIAC DYSFUNCTION (cont.) 
Hemorrhage, Blood 
Loss 
Microscopic/occult Mild, no transfusion 
Gross blood loss, 
12 units transfused 
Massive blood loss, 
 3 units transfused 
RESPIRATORY 
Cough 
Transient, no Rx 
Treatment 
associated cough, 
local Rx 
Uncontrolled 
 
Bronchospasm, 
Acute 
Transient, no Rx 
 80%70% FEV1 
(or peak flow) 
Requires Rx, 
normalizes with 
bronchodilator, 
FEV1 50%70% 
(or peak Flow) 
No normalization 
with bronchodilator, 
FEV1 25%50% 
(or peak flow 
retractions) 
Cyanosis: FEV1  25% 
(or peak flow) or 
intubated 
GASTROINTESTINAL 
Stomatitis 
Mild discomfort, no 
limits on activity 
Some limits on 
eating/drinking 
Eating/talking very 
limited 
Requires IV fluids 
Nausea 
Mild discomfort, 
maintains 
reasonable intake 
Moderate discomfort, 
intake decreased 
significantly, some 
activity limited 
Severe discomfort, 
no significant intake, 
activities limited 
Minimal fluid intake 
Vomiting 
Transient emesis Occasional/moderate 
vomiting 
Orthostatic 
hypotension or IV 
fluids required 
Hypotensive shock or 
hospitalization required 
for IV fluid therapy 
Constipation 
Mild 
Moderate 
Severe 
Distensions w/vomiting 
Diarrhea 
Transient, 34 
loose stools/day 
57 loose 
stools/day 
Orthostatic 
hypotension or 
 7 loose stools/day or 
IV fluids required 
Hypotensive shock 
or hospitalization for 
IV fluid therapy 
required 
NEURO & NEUROMUSCULAR 
Neuro-cerebellar 
Slight 
incoordination, 
dysdiadochokinesis 
Intention tremor, 
dysmetria, slurred 
speech, nystagmus 
Locomotor ataxia 
Incapacitated 
Mood 
Mild anxiety or 
depression 
Moderate anxiety or 
depression and 
therapy required 
Severe anxiety or 
depression or mania, 
needs assistance 
Acute psychosis, 
incapacitated, requires 
hospitalization 
Neuro Control 
Mild difficulty 
concentrating, no 
Rx, mild 
confusion/agitation, 
ADLs unaffected 
Moderate 
confusion/agitation, 
some limitation of 
ADLs, minimal Rx 
Severe 
confusion/agitation, 
needs assistance 
for ADLs, therapy 
required 
Toxic psychosis, 
requires hospitalization 


Appendix 15: WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events 
 
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121/Protocol GR40973, Version 5 
ITEM 
Grade 1 Toxicity Grade 2 Toxicity 
Grade 3 Toxicity 
Grade 4 Toxicity 
NEURO & NEUROMUSCULAR (cont.) 
Muscle Strength 
Subjective 
weakness, no 
objective 
symptoms/signs 
Mild objective 
signs/symptoms, 
no decrease in 
function 
Objective weakness, 
function limited 
Paralysis 
OTHER PARAMETERS 
Fever: Oral, 
 12 hours 
37.7C38.5C or 
100.0F101.5F 
38.6C39.5C or 
101.6F102.9F 
39.6C40.5C or 
103F105F 
 40.5 C or 
 105 F 
Headache 
Mild,  
no Rx therapy 
Transient,  
moderate, 
Rx required 
Severe,  
responds to initial 
narcotic therapy 
Intractable,  
required repeated 
narcotic therapy 
Fatigue 
No decrease  
in ADLs 
Normal activity 
decreased 
25%50% 
Normal activity 
decreased  50%, 
cannot work 
Unable to care for self 
Allergic Reaction 
Pruritus without 
rash 
Localized urticaria 
Generalized urticaria, 
angioedema 
Anaphylaxis 
Local Reaction 
Tenderness or 
erythema 
Induration  10 cm 
or phlebitis or 
inflammation 
Induration  10 cm 
or ulceration 
Necrosis 
Mucocutaneous 
Erythema, pruritus 
Diffuse, 
maculopapular 
rash, dry 
desquamation 
Vesiculation, moist 
desquamation, or 
ulceration 
Exfoliative dermatitis, 
mucous membrane 
involvement or 
erythema, multiforme or 
suspected 
Stevens-Johnson or 
necrosis requiring 
surgery 
ADLs  activities of daily living; FEV1  forced expiratory volume in 1 second; GGT  gamma-glutamyl 
transferase; LLN  lower limit of normal; Rx  prescription; ULN  upper limit of normal 
 


Signature Page for Protocol - GR40973 - GALEGENIMAB - v5 - Published
System identifier: RIM-CLIN-507689
Approval Task
Company Signatory
23-Oct-2023 17:53:04 GMT+0000