An Open-label Extension (OLE) Phase 3 Trial to Assess the Safety of Intravitreal Administration of Avacincaptad Pegol (Complement C5 Inhibitor) in Patients With Geographic Atrophy Who Previously Completed Phase 3 Study ISEE2008 (GATHER2)
Phase: PHASE3
Conditions: Geographic Atrophy, Age-Related Macular Degeneration
Sponsor: Astellas Pharma Global Development, Inc.

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AN OPEN-LABEL EXTENSION (OLE) PHASE 3 TRIAL TO ASSESS THE 
SAFETY OF INTRAVITREAL ADMINISTRATION OF AVACINCAPTAD PEGOL 
(COMPLEMENT C5 INHIBITOR) IN PATIENTS WITH GEOGRAPHIC 
ATROPHY WHO PREVIOUSLY COMPLETED PHASE 3 STUDY ISEE2008 
(GATHER2)  
 
 
PROTOCOL NO: ISEE2009  
(GATHER2 OLE) 
 
Amendment 01 
 
 
Version Date: 27 Feb 2024 
 
 
SPONSOR: 
Astellas Pharma Global Development, Inc. 
Northbrook, IL 60062, US 
 
FOR MEDICAL EMERGENCIES REFER TO THE 
“SAFETY CONTACT LIST” PROVIDED SEPARATELY 
 
 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
77,902 
EudraCT 
2022-002860-59 
 
 
 
 
 
Confidentiality Statement 
 
The information contained in this document is supplied as a background for clinical investigations. This document contains confidential 
information, which is the intellectual property of Astellas. By accepting or reviewing this document, you agree to hold this information in 
confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as otherwise agreed to in writing; (2) where 
required by applicable law; (3) where disclosure is directly related to the care and safety of the research participant; and (4) where 
disclosure of such information is made to a member of the investigator’s team who agrees to hold this information in confidence.  

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TABLE OF CONTENTS 
1 
GLOSSARY OF ABBREVIATIONS ......................................................................4 
2 
SYNOPSIS OF PROTOCOL ISEE2009 ...............................................................6 
3 
STUDY ASSESSMENTS ......................................................................................8 
4 
INTRODUCTION ..................................................................................................9 
4.1 
GA Disease State Overview ......................................................................9 
4.2 
Avacincaptad Pegol (ARC1905) .............................................................. 11 
4.3 
Nonclinical Development Program .......................................................... 12 
4.4 
Completed and Ongoing Clinical Trials ................................................... 13 
4.5 
Trial Rationale ......................................................................................... 15 
4.6 
Benefit/Risk Assessment......................................................................... 16 
5 
TRIAL OBJECTIVES .......................................................................................... 17 
5.1 
Objectives ............................................................................................... 17 
5.2 
Endpoints ................................................................................................ 17 
6 
TRIAL DESIGN ................................................................................................... 18 
7 
PROCEDURES .................................................................................................. 19 
7.1 
Refraction, Visual Acuity, and Low Luminance Visual Acuity .................. 19 
7.2 
Tonometry ............................................................................................... 19 
7.3 
Ophthalmologic Examination ................................................................... 19 
7.4 
Fundus Photography, Fluorescein Angiography, Fundus 
Autofluorescence, and Optical Coherence Tomography (SD-OCT) ........ 20 
7.5 
Pregnancy Tests and Birth Control ......................................................... 20 
7.6 
Immunogenicity ....................................................................................... 21 
7.7 
Pharmacokinetics .................................................................................... 21 
8 
SUBJECT POPULATION ................................................................................... 22 
8.1 
Sample Size ............................................................................................ 22 
8.2 
Inclusion Criteria ..................................................................................... 22 
8.3 
Exclusion Criteria .................................................................................... 22 
9 
TRIAL MEDICATION .......................................................................................... 23 
9.1 
Drug Supply ............................................................................................ 23 
9.2 
Previous or Concomitant Therapy ........................................................... 25 
10 TRIAL CONDUCT .............................................................................................. 26 
10.1 
Subject Enrollment .................................................................................. 26 
10.2 
Trial Assessments ................................................................................... 26 
10.3 
Development of CNV During the Trial ..................................................... 36 
10.4 
Withdrawal from Trial .............................................................................. 37 

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10.5 
Study Drug Discontinuation ..................................................................... 37 
10.6 
Trial Discontinuation ................................................................................ 37 
11 STATISTICAL METHODS .................................................................................. 39 
11.1 
Study Endpoints ...................................................................................... 39 
11.2 
Determination of Sample Size and Statistical Rationale ......................... 39 
11.3 
Randomization and Masking Procedures ................................................ 39 
11.4 
Analytical Considerations ........................................................................ 39 
11.5 
Immunogenicity and PK Analyses ........................................................... 40 
11.6 
Interim Analyses ...................................................................................... 40 
12 ADVERSE EVENTS ........................................................................................... 41 
12.1 
Definition of Adverse Events ................................................................... 41 
12.2 
Assessment and Reporting of Adverse Events ....................................... 41 
12.3 
Definition of AESIs .................................................................................. 43 
12.4 
Definition of Serious Adverse Events ...................................................... 43 
12.5 
Assessment and Reporting of Serious Adverse Events .......................... 45 
12.6 
Exposure in Utero ................................................................................... 45 
13 RESPONSIBILITIES ........................................................................................... 46 
13.1 
Emergency Equipment ............................................................................ 46 
13.2 
Case Report Forms and Trial Documentation ......................................... 46 
13.3 
Drug Accountability/Storage Conditions .................................................. 47 
13.4 
Protocol Compliance ............................................................................... 47 
13.5 
Ethical Aspects ........................................................................................ 47 
13.6 
Institutional Review Board or Ethics Committee Approval and Informed 
Consent ................................................................................................... 48 
13.7 
Clinical Trial Insurance ............................................................................ 48 
13.8 
Trial Report and Publications .................................................................. 48 
14 MONITORING .................................................................................................... 49 
15 REFERENCES ................................................................................................... 50 
16 SPONSOR SIGNATORY .................................................................................... 54 
17 APPENDICES .................................................................................................... 55 
17.1 
Procedures for Refraction and Vision Testing ......................................... 55 
17.2 
Intravitreous Administration Protocol ....................................................... 65 
17.3 
ISEE2009 Study Schematic .................................................................... 70 
17.4 
Protocol Amendment Summary of Changes ........................................... 71 
 
 

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1 
GLOSSARY OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AMD 
Age-Related Macular Degeneration 
BCVA 
Best Corrected Visual Acuity  
C3 
Cleavage of Complement 3 
CF 
Count fingers 
CI 
Confidence Interval 
CFP 
Color fundus photography 
CFR 
Code of Federal Regulations 
CNV 
Choroidal Neovascularization 
CRA 
Central Retinal Artery 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
EC 
Ethics Committee 
EOS 
End of Study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EW 
Early Withdrawal 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence 
 
FDA 
Food and Drug Administration 
FE 
Fellow Eye 
FSH 
Follicle-stimulating Hormone 
GA 
Geographic Atrophy  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IV 
intravenous 
IVT 
Intravitreous 
LLVA 
low luminance best correct visual acuity 
MAC 
Membrane attack complex 
NF 
National Formulary 
OCT 
Optical Coherence Tomography 
OLE 
Open-label Extension 
OU 
Both Eyes 
PEG 
Polyethylene glycol 
PK 
Pharmacokinetic 

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RC 
Reading Center 
RNA 
Ribonucleic Acid 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SD-OCT 
Spectral-Domain Optical Coherence Tomography 
SE 
Study Eye 
US 
United States 
USP 
United States Pharmacopeia 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 

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2 
SYNOPSIS OF PROTOCOL ISEE2009 
SYNOPSIS 
TITLE: 
An Open-label Extension (OLE) Phase 3 Trial to Assess the Safety of 
Intravitreal Administration of avacincaptad pegol (Complement C5 
Inhibitor) in Patients with Geographic Atrophy Who Previously 
Completed Phase 3 Study ISEE2008 (GATHER2) 
OBJECTIVES: 
The objectives of this trial are to assess long-term safety of 
avacincaptad pegol intravitreal administration for patients with 
geographic atrophy (GA) who completed Study ISEE2008 (GATHER2) 
through the Month 24 visit on study treatment (either avacincaptad 
pegol or Sham). 
TRIAL DESIGN: 
Approximately 280 patients who completed Study ISEE2008 
(GATHER2) through the Month 24 visit on study treatment (either 
avacincaptad pegol or Sham) and consent to participate will be 
administered monthly avacincaptad pegol 2 mg from Month 1 through 
Month 17 (maximum 17 total doses).  
 
All patients will have a final follow up visit at Month 18 or if the study is 
terminated early, Month 18 final follow up procedures will be followed. 
Premature termination of this clinical trial may occur because of a 
regulatory authority decision, change in opinion of the Institutional 
Review Board (IRB)/ Ethics Committee (EC), or at the discretion of 
Astellas. 
ENDPOINTS: 
Primary Endpoint:  
• 
Adverse events (AEs) 
Secondary Endpoints: 
• 
Immunogenicity  
• 
Pharmacokinetics  
Exploratory Endpoints:  
• 
Ophthalmic findings (best corrected visual acuity [BCVA], low 
luminance visual acuity [LLVA], intraocular pressure [IOP], and 
ophthalmic examination) 
PLANNED SAMPLE SIZE: 
Approximately 280 patients will be enrolled. This is based on the 
number of currently enrolled patients in Study ISEE2008 (GATHER2) 
who will have completed Study ISEE2008 (GATHER2) through the 
Month 24 visit on study treatment (either avacincaptad pegol or 
Sham). 

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SYNOPSIS 
SUBJECT SELECTION: 
Male or female patients aged 50 years or greater diagnosed with GA 
inside and/or outside of the fovea who completed Study ISEE2008 
(GATHER2) through the Month 24 visit on study treatment, regardless 
of whether they received treatment with avacincaptad pegol or Sham 
previously. 
FORMULATION: 
Avacincaptad pegol is formulated at a concentration of 20 mg/mL 
(oligonucleotide mass) in phosphate buffered saline as a sterile 
aqueous solution and will be supplied in a sealed vial by the Sponsor. 
The product is preservative -free and intended for intravitreous 
injection only. The product should not be used if cloudy or if particles 
are present. The 2 mg dose will have a total injection volume of 0.1 mL 
(100 µL). 
INVESTIGATIONAL DRUG 
DOSAGE: 
Patients will receive a maximum 17 doses (1 dose/month) of 
avacincaptad pegol at a dose of 2 mg (100 µL injection volume). 
STUDY SITES 
All study sites participating with active patients in the ISEE2008 trial 
will be used for this ISEE2009 OLE trial. 
STATISTICAL METHODS 
The sample size is estimated based on the number of ISEE2008 
patients that completed the study through the ISEE2008 Month 24 visit 
(“ISEE2008 completers”) and the expected number of eligible 
ISEE2008 completers willing to participate in the ISEE2009 study.  
 
Data will be summarized using descriptive statistics or listed. No 
statistical inference will be made.  
 

 
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3 
STUDY ASSESSMENTS  
Assessments 
M1a 
M2 M3 M4 M5 M6 M7 M8 M9 M10 M11 M12 M13 M14 M15 M16 M17 M18/EOS 
(EW) 
Informed Consent 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refraction and ETDRS BCVAc,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LLVAc 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Tonometryc,d,e/Ophthalmologic Examinationc,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Color Fundus Photographyc 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Fluorescein Angiographyc 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Optical Coherence Tomographyc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus Autofluorescencec 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urine Pregnancy (If Applicable)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity Samplingh 
Xi 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
PK Samplingh 
Xi 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Avacincaptad pegol 2 mg Administration  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BCVA = best corrected visual acuity; EOS = end of study; ETDRS = Early Treatment Diabetic Retinopathy Study; EW = early withdrawal; IOP = intraocular pressure; 
LLVA = low luminance visual acuity; M = month; OLE = open-label extension; OU = both eyes; PK = pharmacokinetic; SE = study eye. 
Refer to Section 10.2 Trial Assessments for additional details on assessments.  
aEnrollment into this OLE trial must be within 90 days of the patient’s Month 24 visit in Study ISEE2008. 
bInformed consent must be signed before any other assessments are performed at Month 1 in this OLE trial. 
cOcular assessments are to be performed on both eyes (OU) pre-injection (as applicable) at Month 12 and Month 18/EOS (EW). Ocular assessments at all other trial 
visits are performed only on the study eye (SE).  Refer to Appendix 17.1 for details on procedures for refraction and vision testing.  
dGoldmann applanation tonometry must be performed at Month 12 and Month 18/EOS (EW), pre- and post-injection (as applicable). The Tono-Pen may be used at 
other times; however, Goldmann applanation tonometry must also be used to verify intraocular pressure (IOP) reading of ≥ 30 mmHg occurring at any time. 
eTonometry should be measured prior to the injection and at least 30 minutes after the injection as per Section 10, Trial Conduct. 
fA full ophthalmic examination is performed prior to the injection and again at least 30 minutes after the injection. An abbreviated exam assessing Gross Visual 
Function and Direct Visualization, to ensure the health of the eye post-injection, will be performed 0 to 5 minutes and again at least 30 minutes after injection.    
gUrine Pregnancy Test will be done at each monthly visit for any female subject of childbearing potential.  
hBlood samples will be collected prior to avacincaptad pegol administration and analyzed using validated methods. Two blood samples should be collected at each 
timepoint indicated (one for primary analysis and one for back-up). 
iBlood samples taken at Month 1 will be considered baseline samples for patients crossing over from Sham to avacincaptad pegol (i.e., drug-free baseline). 
jAdverse events are to be recorded starting after the first dose of study drug. 
kBCVA is required at the indicated visits and at any other timepoints in the event of an ocular AE in the study eye. 
VISIT WINDOWS: It is essential that patients adhere to their prescheduled trial visits within the visit window as per Section 10, Trial Conduct. Monthly doses will be 
administered at least 21 days apart. 

 
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4 
INTRODUCTION 
4.1 
GA Disease State Overview 
Geographic atrophy (GA) is a progressive disease characterized by, irreversible, and severe 
loss of functional vision, with a potential loss on average of 22 letters over 5 years, that 
ultimately leads to blindness. GA is associated with a major impact on functional vision, quality 
of life, and independence (Boyer 2017, Mitchell 2018). GA occurs during the late stage of dry 
age-related macular degeneration (AMD) and is the most prevalent form of AMD in the general 
population, accounting for 85% to 90% of AMD cases (Miller 2017). GA may also affect 
patients with the wet (neovascular) form of AMD, even after treatment with anti-vascular 
endothelial growth factor (VEGF) agents, so that development or progression of GA over time 
contributes significantly to vision loss in patients with AMD (Bhisitkul 2015, Abdelfattah 2016, 
Grunwald 2017). Once GA advances to cover the foveal center, vision loss is rapidly 
accelerated (Brown 2005, Bagheri 2019).   
GA causes progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment 
epithelium [RPE], and choriocapillaris) leading to a loss of visual function over time (Lindner 
2019, Lindblad 2009, Bonilha 2008, Sunness 1999). Globally, approximately 5 million people 
have GA, with approximately 1 million patients living in the United States (Wong 2014, 
Chakravarthy 2018, Rudnicka 2012). The prevalence of GA increases exponentially with age 
and approximately quadruples per decade beyond 50 years (Rudnicka 2012). GA is typically a 
condition with about half of patients developing GA in both eyes within 7 years of initial 
diagnosis (Boyer 2017, Lindblad 2009).  
The chronic nature of GA leads to loss of visual function. This often results in difficulties 
performing daily tasks including reading, driving, face recognition, and ultimately, severe 
detriment on independence (Brown 2014, DeCarlo 2003). Initially, patients may present with 
adequate visual acuity (VA) if GA lesions are not involved in the central macular or foveal 
region of the retina (Sadda 2016, Lindner 2015) and standard vision tests can underrepresent 
the visual deficit experienced by GA patients (Sunness 1996). Reading speed is often initially 
unaffected due to foveal sparing but worsens progressively as the area of atrophy enlarges 
(Kunzel 2021, Lindner 2019, Sunness 2008). As the disease progresses, vision-related quality 
of life declines markedly and patients become at higher risk for developing advanced wet AMD 
(Kunzel 2020). 
GA is quantified in terms of the area of RPE atrophy and can be observed clinically by slit-lamp 
biomicroscopy (Fleckenstein 2018). It is documented using multiple imaging modalities, with 

 
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the most common being a combination of color fundus photography (CFP), fundus 
autofluorescence (FAF) imaging, and optical coherence tomography (OCT) (Shi 2021, Pfau 
2017, Schmitz-Valckenberg 2011). GA presents as sharply demarcated atrophic lesions at the 
macula secondary to the loss of photoreceptors, RPE, and choriocapillaris (Fleckenstein 
2018). The atrophic lesions tend to arise in the perifoveal regions initially, preserving the fovea 
('foveal sparing') before these lesions expand and coalesce over time to affect the fovea 
(Fleckenstein 2018). Recent data suggest that photoreceptor degeneration is not limited to the 
area of RPE atrophy but extends beyond this area. These more subtle changes can be 
quantified by volumetric analyses of OCT data (Pfau 2020b, Reiter 2020).  
The pathogenesis of GA is not fully understood and is likely multifactorial, triggered by intrinsic 
and extrinsic stressors of a poorly regenerative RPE including oxidative stress (caused by the 
high metabolic demand of photoreceptors), photo-oxidation, and environmental stressors (e.g., 
cigarette smoke) (Pfau 2020b). Variations in several genes, particularly in the complement 
system, have been implicated in the development of GA (Pfau 2020a). The current hypothesis 
is that with aging, damage caused by stressors accumulates, which coupled with a genetic 
predisposition, results in the appearance of drusen and lipofuscin deposits. These and other 
products of oxidative stress then trigger inflammation via multiple pathways, particularly the 
complement cascade, leading to loss of photoreceptors, RPE, and choriocapillaris, culminating 
in atrophic lesions that spread over time (Abdelfattah 2016, Holz 2014). 
The rate of progression of GA is highly variable, ranging from 0.53 to 2.6 mm2/year depending 
on the technology used to evaluate GA and various patient-related prognostic factors, 
including larger baseline lesion size, presence of multifocal lesions, specific autofluorescence 
patterns, and parafoveal atrophic lesions (Fleckenstein 2018, Lindblad 2009, Sunness 2008, 
Holz 2007). The median time for parafoveal GA to expand into the fovea was determined as 
~2.5 years (Lindblad 2009). In an observational study, 53% of GA participants (initially not 
involving the fovea) suffered a 3-line loss of VA by 4 years. 
4.1.1 Role of Complement in GA 
The complement pathway and C5 have been identified as important mediators of inflammation 
(Brandstetter 2015) with complement proteins identified in the subretinal drusen deposits 
characteristic of GA (Hageman 2001, Cao 2016). 
The complement cascades result in generation of complement C5 convertase which cleaves 
complement C5 into C5a and C5b, the main terminal effector components of the complement 
cascade, leading to cell death (Holers 2014). Physiologically, C5a is involved in inflammasome 
priming and activation leading to pyroptosis, a rapid inflammatory form of lytic programmed cell 

 
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death (Brandstetter 2015), and C5b leads to the generation and accumulation of membrane 
attack complex (MAC; C5b-9) of targeted cell membranes, also leading to cell death (Holers 
2014). 
4.1.2 Unmet Medical Need 
Given the long-term natural history of GA, there is a substantial medical need for new 
therapies that target the underlying cause of disease, alter its progression, and preserve the 
anatomical architecture needed for visual function While there have been  longstanding, 
established anti-VEGF treatments for wet AMD, the absence of or limited availability of 
treatment options for GA represents a major public health concern and unmet medical need for 
the rapidly growing aging population (Brown 2006, Rosenfeld 2006, Heier 2012, Martin 2012, 
Boyer 2017).  
4.2 
Avacincaptad Pegol (ARC1905) 
Avacincaptad pegol is a polyethylene glycol (PEG)-conjugated single-stranded RNA aptamer. 
It is a potent and specific inhibitor of complement activation that acts by binding to human 
complement factor 5 with high affinity (KD = 0.69 ± 0.148 nM at 37°C) and specificity. It 
consists of a 12,882 Da modified nucleotide aptamer that is conjugated at the 5’ terminus to a 
~43 kDa branched PEG moiety. The aptamer portion of avacincaptad pegol is 39 nucleotides 
in length and modified with a primary amine at the 5’ terminus to provide a reactive site for 
site-specific conjugation (“PEGylation”). The nucleotide composition consists of purine 
ribonucleotides and modified 2'‑fluoro pyrimidines and 2’ methoxy purines. The modified 
nucleotides minimize susceptibility to endonuclease digestion. The 3’ terminus is capped with 
an (“inverted”) 3’-3’ phosphodiester linkage to a deoxythymidine nucleotide to maximize 
resistance to 3’-exonuclease degradation. PEGylation is employed to improve residence time 
in vivo. All concentrations and doses for avacincaptad pegol (20 mg/mL = 1.55 mM) are based 
on the mass of the aptamer, exclusive of the PEG mass. 
Avacincaptad pegol inhibits C5 and prevents the formation of key terminal fragments (C5a and 
C5b-9), regardless of which initial activation pathway (classical, alternative, or lectin) is 
induced in their generation. By inhibiting these C5-mediated inflammatory and MAC activities, 
avacincaptad pegol provides a therapeutic approach to treat GA by preserving the anatomical 
architecture needed for visual function and preventing the loss of photoreceptors and disease 
progression inside and outside the fovea. Despite complete inhibition of C5 activation, 
avacincaptad pegol does not inhibit cleavage of complement 3 (C3) to C3a and C3b, the latter 
of which is an important component of host defense mechanisms. Thus, the beneficial effects 
of the complement pathway, such as host defenses against pathogens, can be maintained. 

 
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4.3 
Nonclinical Development Program  
A battery of nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies were 
conducted for avacincaptad pegol. The primary pharmacology studies included binding 
assays, complement activity inhibition assays, and radioligand binding assays. Safety 
pharmacology studies included in vitro human ether-à-go-go channel electrophysiology and 
toxicology assessments in cynomolgus monkeys. Investigations of ocular and systemic 
disposition, as well as chronic toxicity studies, have been performed in rabbits and dogs 
following intravitreal (IVT) administration of avacincaptad pegol. There have been no findings 
in nonclinical studies that would preclude the further development of avacincaptad pegol. 
Specifically, these nonclinical studies demonstrate that avacincaptad pegol has high selectivity 
and specificity for inhibition of complement activation at the C5 activation step without affecting 
other host defense mechanisms. Because avacincaptad pegol is delivered via IVT injection, 
systemic levels following slow egress out of the vitreous cavity are very low, in the nanogram 
per milliliter range, and hence, the inhibition of C5 is likely limited to the eye. Clinical and 
nonclinical PK data have confirmed that avacincaptad pegol migrates slowly out of the eye 
compartment and is associated with very low plasma levels. These systemic concentration 
levels appear to remain below levels that would be of any toxicological concern as evidenced 
by the repeat dose toxicology study results. Additionally, avacincaptad pegol shows no 
deleterious effects with long-term dosing and has not demonstrated concerns for genetic 
toxicity.  
An overview of these extensive studies is presented in the current Investigator Brochure.  
The Sponsor notes that initially the development program for avacincaptad pegol was intended 
for other routes of administration, hence the numerous studies using the intravenous (IV) route 
of administration than typical for an IVT administered therapy. 

 
 
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4.4 
Completed and Ongoing Clinical Trials 
A summary of completed and ongoing intravitreal avacincaptad pegol clinical trials is presented below with additional information 
described in the IB.  
Protocol  
Numbera 
Status 
(Date) 
Study 
Design 
Phase 
of 
Study 
Objectives 
Total Subjects 
Enrolled and/or 
Planned 
Dose (N) 
Study 
Duration 
OPH2000 
Completed 
(final CSR on 
27 Jun 2011) 
OL, PG, 
MD, 
CWA 
Phase 
1 
Safety, tolerability, 
and PK in nAMD 
subjects 
60 subjects 
ARC1905 0.03 mg  (N=3) 
ARC1905 0.3 mg    (N=19) 
ARC1905 1 mg       (N=16) 
ARC1905 2 mg       (N=15) 
ARC1905 3/1 mgb    (N=7) 
3 to 6 
months 
OPH2001 
Completed 
(final CSR on 
26 Jul 2018) 
OL, MD Phase 
1 
Safety and 
tolerability in GA 
AMD 
47 subjects 
ARC1905 0.3 mg (N=24) 
ARC1905 1 mg (N=23) 
12 
months 
OPH2002 
Completed 
(final CSR on 
05 Oct 2018) 
OL, MD, 
CWA 
Phase 
2a 
Safety and 
tolerability in IPCV 
subjects 
4 subjects 
ARC1905 1 mg (N=4) 
3 months 
OPH2003 
Completed 
(final CSR on 
25 Feb 2022) 
R, MC, 
DM, 
SC, MD 
Phase 
2/3 
Efficacy and safety 
in GA AMD 
subjects 
286 subjects 
ARC1905 1 mg (N=26) 
ARC1905 2 mg (N=25) 
Sham (N=26) 
ARC1905 2 mg + Sham (N=42) 
ARC1905 4 mg (2 mg + 2 mg) (N=83) 
Sham + Sham (N=84) 
18 
months 
OPH2004 
Completed 
(final CSR on 
07 Mar 2022) 
OL, MD, 
CWA 
Phase 
2a 
Safety and 
tolerability in nAMD 
subjects 
1 subject 
ARC1905 2 mg (N=1) 
18 
months 

 
 
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Protocol  
Numbera 
Status 
(Date) 
Study 
Design 
Phase 
of 
Study 
Objectives 
Total Subjects 
Enrolled and/or 
Planned 
Dose (N) 
Study 
Duration 
OPH2005 
Ongoing 
R, MC, 
DM, 
SC, MD 
Phase 
2b 
Efficacy and safety 
in patients with 
Stargardt Disease 
121 subjects 
ARC1905 (N=60) 
Induction Phase: ARC1905 2 mg 
Maintenance Phase: ARC1905 4 mg/eye (2 mg + 2 mg) 
Sham (N=61) 
Induction Phase: Sham 
Maintenance Phase: Sham + Sham 
18 
months 
OPH2007 
Completed 
(final CSR on 
10 Jul 2020) 
OL MC, 
MD, 
CWA 
Phase 
2a 
Safety and 
tolerability in nAMD 
subjects 
65 subjects 
Cohort 1 (N=10): 
Lucentis® 0.5 mg + ARC1905 4 mg (2 mg + 2 mg); 
Cohort 2 (N=11): Lucentis® 0.5 mg + ARC1905 2 mg 
Cohort 3 (n=22): 
Induction Phase: D0, Lucentis® 0.5 mg + ARC1905 2 mg; 
D14, ARC1905 2 mg 
Maintenance Phase: Lucentis® 0.5 mg + ARC1905 2 mg 
Cohort 4 (n=22): 
Induction Phase: D0, Lucentis® 0.5 mg + ARC1905 2 mg; 
D14, ARC1905 2 mg 
Maintenance Phase: D0, ARC1905 2 mg; D2, Lucentis® 
0.5 mg + ARC1905 2 mg 
6 months 
ISEE2008 
  
Completed 
(final CSR on 
06 Dec 2023) 
R, MC, 
DM, 
SC, MD 
Phase 
3 
Efficacy and safety 
in GA AMD 
subjects 
448c subjects 
ARC1905 2 mg (N=225) 
Sham (N=222) 
24 
months 
AMD=age-related macular degeneration; CSR=clinical study report; CWA=combined with anti-VEGF therapy; DM=double-masked; GA=geographic atrophy; 
IPCV=idiopathic polypoidal choroidal vasculopathy; MC= Multicenter; MD=multidose; nAMD=neovascular AMD; NDA=new drug application; OL=open-label; PG=Parallel 
Group; PK=pharmacokinetic; R=randomized; SC=Sham-controlled. 
Note: ARC1905 is interchangeable with the name avacincaptad pegol for the purposes of this table. 
aAll studies listed in this table are to be included in NDA. 
bDue to a drug stability matter with the 3 mg/eye dose, subjects in Part 1 originally assigned to 3 mg/eye have been transitioned to the 1 mg/eye dose under Amendment D. 
c447 subjects enrolled and treated; 1 subject randomized to the Sham group never received treatment. 
 

 
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4.5 
Trial Rationale 
In the first pivotal trial (Study OPH2003 [GATHER1]), the primary endpoint was GA measured 
by FAF at 3 time points: Baseline, Month 6, and Month 12. At Month 12, the primary efficacy 
objective was met. The mean rate of GA lesion growth in the avacincaptad pegol 2 mg dose 
group was 0.697 mm2 per year (95% confidence interval [CI] = 0.204; 1.190) less than that of 
the Sham control group (p-value = 0.0059). The avacincaptad pegol treatment effect on GA 
growth was evident at first evaluation time (Month 6) with patients in the avacincaptad pegol 
2 mg dose group, whose GA on average grew 0.323 mm2 (95% CI = 0.068; 0.579) less than 
that of the GA lesions in the Sham group. The treatment differences between the avacincaptad 
pegol groups compared to the corresponding Sham group were maintained through the last 
evaluation time (Month 18), with patients in the avacincaptad pegol 2 mg dose group whose 
GA on average grew 1.156 mm2 (95% CI = 0.480;1.833) less than that of the GA lesions in the 
Sham group. The most frequently reported ocular adverse events (AEs) with avacincaptad 
pegol were related to the injection procedure.  
Study ISEE2008 (GATHER2), the second pivotal trial, was a 24-month study and the primary 
endpoint was GA measured by FAF in at least three timepoints: Baseline, Month 6 and Month 
12. At Month 12, the primary efficacy objective was met. The average GA lesion growth of 
patients in the avacincaptad pegol 2 mg group was 0.376 mm2 per year (95% CI = 0.122; 
0.631) less than that of the GA lesions in the Sham group (p-value = 0.0039). Study ISEE2008 
has completed data analysis. At Month 24, a statistically significant difference of 
0.362 mm2/year (95% confidence interval [CI] = 0.066; 0.657) in the mean GA growth rate was 
demonstrated in favor of avacincaptad pegol 2 mg every month treated group compared to 
sham (p = 0.0165). 
The primary endpoint in both OPH2003 and ISEE2008 as measured by FAF, is reflective of 
loss of photoreceptors and disease progression inside and outside the fovea. As of this 
protocol’s effective date, there are two FDA approved treatments available for patients with GA 
secondary to AMD, each expressing a unique benefit risk profile. IZERVAY™ (avacincaptad 
pegol intravitreal solution) is one of the available treatment options in the US, approved by the 
FDA on August 4, 2023. The limited availability or absence of treatment options for GA 
represents a major public health concern for the rapidly increasing aging population.  
This open-label extension (OLE) trial will continue to assess the long-term safety of monthly 
intravitreal administration of avacincaptad pegol 2 mg, while continuing to allow patients with 
GA, who completed Study ISEE2008 (GATHER2) through the Month 24 visit on study treatment 
(either avacincaptad pegol or Sham), access to avacincaptad pegol treatment. 

 
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4.6 
Benefit/Risk Assessment 
The safety and efficacy of avacincaptad pegol were demonstrated in two pivotal randomized, 
multi-center, double-masked, sham-controlled, 18- and 24-month studies (OPH2003 
[GATHER1] and ISEE2008 [GATHER2], respectively) in patients with GA secondary to AMD. 
A total of 733 patients were treated in these studies. Patient ages ranged from 51 to 97 years 
with a mean of 77 years. In total 26, 292, and 83 patients were treated with avacincaptad pegol 
1 mg, 2 mg, and 4 mg respectively, and 332 patients received sham.  
The most frequently reported Treatment Emergent Adverse Events (TEAEs) in those 
participants receiving avacincaptad pegol 2 mg in the pivotal clinical studies OPH2003 and 
ISEE2008 were related to injection procedure.  The most common adverse reactions (≥ 5% 
and greater than sham) reported up to 12 months were conjunctival hemorrhage (13%), 
increased IOP (9%), and Choroidal Neovascularization (CNV; 7%). 
Both Study OPH2003 and Study ISEE2008 demonstrated robust statistical superiority of 
avacincaptad pegol over sham, through a substantial reduction in GA lesion growth, after one 
year of treatment.  In both pivotal studies, avacincaptad pegol was shown to elicit a treatment 
effect by Month 6 that was persistent and continued to increase over time as measured by the 
absolute difference of GA growth between intervention groups. 
The consistent safety and efficacy results from two independent, randomized, adequately well-
controlled studies in patients with GA secondary to AMD support a favorable benefit/risk profile 
of avacincaptad pegol 2 mg for treatment in patients with GA secondary to AMD, a serious 
progressive disease that leads to irreversible blindness, especially in an increased aging 
population with limited, or no effective and safe treatment options available. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of avacincaptad pegol can be found in the IB. 
Adherence to eligibility criteria and study assessments may minimize potential risks to study 
participants. The safety of study participants will be monitored by the sponsor through remote 
data review and will be facilitated by timely entry of clinical data into the electronic data capture 
system (EDC) and reporting of serious adverse events (SAEs) by the investigator during study 
conduct. 

 
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5 
TRIAL OBJECTIVES 
5.1 
Objectives 
The objectives of this trial are to assess long-term safety of avacincaptad pegol monthly 
intravitreal administration for patients with GA who completed Study ISEE2008 (GATHER2) 
through the Month 24 visit on study treatment (either avacincaptad pegol or Sham). 
5.2 
Endpoints 
Primary Endpoint:  
• AEs 
Secondary Endpoints: 
• Immunogenicity  
• Pharmacokinetics 
Exploratory Endpoints: 
• Ophthalmic variables  
o best corrected visual acuity (BCVA) 
o low luminance visual acuity (LLVA) 
o intraocular pressure (IOP) 
o ophthalmic examination 

 
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6 
TRIAL DESIGN 
This is an open-label, multicenter, 18-month extension study. Approximately 280 patients who 
completed Study ISEE2008 (GATHER2) through the Month 24 visit on study treatment (either 
avacincaptad pegol or Sham) will be administered avacincaptad pegol 2 mg monthly from 
Month 1 through Month 17. All patients, regardless of treatment received in ISEE2008 
(avacincaptad pegol or Sham), will receive avacincaptad pegol 2 mg monthly. 
All patients will have a final follow up visit at Month 18 or if the study is terminated early, 
Month 18 final follow up procedures will be followed. The end of the study is defined as the 
date of the last study assessment (See Section 3) for the last subject in the study globally. 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the Institutional Review Board (IRB)/Ethics Committee (EC), or at the 
discretion of Astellas.   

 
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7 
PROCEDURES 
7.1 
Refraction, Visual Acuity, and Low Luminance Visual Acuity 
Refraction, Vision Testing, and Low Luminance Vision Testing will be performed at all 
time-points specified in Section 10.2 “Trial Assessments”. BCVA is also required at any other 
time-point in the event of an ocular AE in the study eye. Retro-illuminated modified 
Ferris-Bailey Early Treatment Diabetic Retinopathy Study (ETDRS) charts are used starting at 
4 meters (see Appendix 17.1). 
When refraction and ETDRS BCVA measurements are required by the trial protocol, these will 
be performed only by certified VA examiners with access to the previous VA measurement and 
the previous protocol refraction.  
All necessary materials and instructions for these assessments will be provided by Astellas.  
These assessments should always be performed in the following order: Refraction, ETDRS 
BCVA, and Low Luminance Visual Acuity. 
7.2 
Tonometry  
Tonometry will be performed at all time-points specified in Section 10.2 “Trial Assessments”. 
The IOP should be measured and recorded pre-injection and at least 30 minutes after the 
injection and IOP must be < 30 mmHg before the subject leaves the clinic. For the 
post-injection tonometry, proper care should be taken to minimize the risk of contamination. 
Goldmann applanation tonometry must be performed at Month 12 and Month 18/End of Study 
(EOS) or Early Withdrawal (EW), pre- and post-injection (as applicable). Tono-Pen may be 
used at all other timepoints. Goldmann applanation tonometry must also be used to verify IOP 
reading of ≥ 30 mmHg occurring at any time.  
7.3 
Ophthalmologic Examination 
The following examinations will be performed at all time-points specified in Section 10.2 “Trial 
Assessments”. 
• Examination of the eyelids 
• Examination of extra-ocular muscle movement  
• Examination of the cornea 
• Examination of the anterior chamber 
• Examination of the pupils 

 
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• Examination of the iris 
• Examination of the lens 
• Examination of the vitreous body 
• Examination of the retina and optic disc 
7.4 
Fundus Photography, Fluorescein Angiography, Fundus Autofluorescence, 
and Optical Coherence Tomography (SD-OCT) 
Color stereoscopic fundus photographs, fluorescein angiography (FA), FAF, and 
spectral-domain optical coherence tomography (SD-OCT) will be performed at all time-points 
specified in Section 10.2 “Trial Assessments”.  
All color fundus photos, FAs, FAFs, and SD-OCTs that are collected at protocol-specified time 
points must be sent to the reading center (RC) as specified in the RC procedure manual. The 
RC will provide instructions for the CFP, FA, FAF, and SD-OCT procedures. 
7.5 
Pregnancy Tests and Birth Control 
A urine pregnancy test will be performed for women of childbearing potential prior to 
avacincaptad pegol intravitreal administration at the visits as indicated in Section 3, “Study 
Assessments”, and in Section 10.2 “Trial Assessments”. 
For patients who are women of childbearing potential, the same protocol approved highly 
effective contraceptive method must be used for at least one month prior to study entry and 
during the trial until at least 90 days following the last dose of test medication. Protocol 
approved highly effective contraceptive methods are:  
• Hormonal contraceptives (i.e., combined oral contraceptive, patch, vaginal ring, 
injectable, or implant), 
•  Intrauterine devices or intrauterine systems, 
• Vasectomy, and/or tubal ligation, 
• Abstinence, defined as refraining from heterosexual intercourse during the entire period 
of the study and until at least 90 days following the last dose of study medication if in 
accordance with usual lifestyle. 
If the patient is a woman of childbearing potential, she must have no plans to donate ova 
during the duration of the trial and for at least 90 days following the last dose of test 
medication. 

 
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Non-childbearing potential is defined as follows: 
• A woman who has had surgical sterilization (hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy) 
• A woman ≥ 60 years of age 
• A woman ≥ 40 and < 60 years of age who fulfills at least one of the following: 
o A cessation of menses for at least 12 months and a follicle-stimulating hormone 
(FSH) test confirming non-childbearing potential (refer to laboratory reference 
ranges for confirmatory levels) 
o A cessation of menses for at least 24 months without FSH levels confirmed 
Czech Republic, Poland, France, Italy: If the patient is male, he should use a condom and 
not donate sperm during the time of study drug exposure and for 90 days following the last 
exposure of study drug. 
7.6 
Immunogenicity 
Assessments of anti-drug antibodies (ADA) will be performed at pre-dose at Month 1, Month 2, 
Month 4, Month 7, Month 13, and Month 18 as specified in Section 10.2 “Trial Assessments”. 
The pre-dose sample taken at Month 1 will be considered the serum sample taken prior to 
dosing of avacincaptad pegol for Sham patients crossing over to avacincaptad pegol to 
capture a drug-free baseline. 
Two serum samples of 2 mL will be collected at each timepoint specified: one for primary 
analysis and one as a back-up. 
The Sponsor may request ad-hoc ADA sampling in the event of an adverse drug reaction. 
7.7 
Pharmacokinetics 
The concentration of avacincaptad pegol in K2EDTA human plasma samples will be quantified 
using validated electrochemiluminescence dual hybridization assay and expressed in terms of 
ng/mL. Plasma PK samples will be collected at pre-dose at Month 1 (baseline), Month 2, 
Month 4, Month 7, Month 13, and Month 18 as specified in Section 10.2 “Trial Assessments” 
prior to administration of avacincaptad pegol in order to evaluate the effect of ADA on the 
plasma concentrations of avacincaptad pegol.  
 

 
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8 
SUBJECT POPULATION 
8.1 
Sample Size 
Approximately 280 patients will be enrolled. 
8.2 
Inclusion Criteria  
Male or female patients aged 50 years or greater diagnosed with GA inside and/or outside of 
the fovea who completed Study ISEE2008 (GATHER2) through the Month 24 visit on study 
treatment, regardless of whether they received treatment with avacincaptad pegol or Sham 
previously, refer to Section 8.2 of the ISEE2008 protocol for inclusion criteria details. Patients 
must provide new written informed consent for this OLE trial prior to participating and have the 
ability to return for all trial visits for the duration of the 18-month trial. 
Information on the conduct of patients who are or are not women of childbearing potential and 
contraception usage in men and women is provided in Section 7.5. 
8.3 
Exclusion Criteria 
Patients will not be eligible for the trial if: 
1. Patient did not complete Study ISEE2008 (GATHER2) through the Month 24 visit on 
study treatment (either avacincaptad pegol or Sham), 
2. Any patients who had the study drug permanently withdrawn for an AE are not eligible; 
patients who had study drug temporarily withheld for an AE(s) or elective ocular surgery 
will be reviewed on case by case basis for eligibility, 
3. Patient did not enroll into this OLE trial within the 90 days enrollment period. 
4. Patients who are pregnant or nursing 

 
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9 
TRIAL MEDICATION 
9.1 
Drug Supply  
9.1.1 Avacincaptad pegol 
Avacincaptad pegol is a PEGylated RNA aptamer consisting of a 13 kDa modified RNA 
aptamer that is conjugated at the 5’ terminus to a ~43 kDa branched PEG moiety. The aptamer 
portion of avacincaptad pegol is 39 nucleotides in length and modified to a primary amine at 
the 5’ terminus to provide a reactive site for subsequent conjugation (“PEGylation”). The 
nucleotide composition consists of purine ribonucleotides and modified 2’-fluoro pyrimidines 
and 2’-methoxy purines. The modified nucleotides minimize minimize susceptibility to 
endonuclease disgestion. The 3’ terminus is capped with an (“inverted”) 3’-3’ phosphodiester 
linkage to a deoxythymidine nucleotide to maximize resistance to 3’-exonuclease degradation. 
PEGylation is employed to improve residence time in vivo. All concentrations and doses for 
avacincaptad pegol (1 M = 13 g/mL) are based on the mass of the aptamer, exclusive of the 
PEG mass.  
Avacincaptad pegol drug product is formulated at a concentration of 20 mg/mL (oligonucleotide 
mass) in 10 mM phosphate buffered saline at pH 6.8 to 7.8 as a sterile aqueous solution and 
will be supplied in a sealed vial by the Sponsor. Sodium hydroxide or hydrochloric acid may 
have been added for pH adjustment. The product is a preservative-free clear solution and 
intended for intravitreous (IVT) injection only. The product should not be used if cloudy or if 
particles are present.  
Avacincaptad pegol will be supplied in single use sterile glass vials for intravitreal injection. 
Active ingredient: 
avacincaptad pegol 
 
 
Avacincaptad pegol is 
formulated as: 
20 mg/mL solution for injection  
 
 
Excipients: 
Sodium Chloride, United States Pharmacopeia (USP) 
 
Sodium Phosphate Monobasic, Monohydrate, USP 
 
Sodium Phosphate Dibasic, Heptahydrate, USP 
 
Sodium Hydroxide, National Formulary (NF; as needed) 
 
Hydrochloric acid, NF (as needed) 
Water for injection, USP 

 
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9.1.2 Treatment Regimen and Duration 
Patients may receive monthly injections of 0.1 mL (100 µL) avacincaptad pegol 2 mg for up to 
18 months (maximum 17 total doses), starting at Month 1 through Month 17. Monthly doses 
will be administered at least 21 days apart. 
All patients will have a final follow up visit at Month 18. 
Subjects will continue in the trial for up to 18 months or until one of the following occurs: the 
subject withdraws consent and discontinues from the trial, the subject is discontinued from the 
trial at the discretion of the Investigator or the Sponsor, or the trial is terminated. Refer to 
Section 10.4 and Section 10.510.6 for patient withdrawal and trial discontinuation information, 
respectively. 
9.1.3 Administration of Study Drug 
Each study medication kit contains a 5-micron filter needle, a 30 G injection needle, a 1 mL 
empty syringe, and a vial of avacincaptad pegol 2 mg, to be administered by IVT injection. The 
method for IVT administration of avacincaptad pegol is described in detail in Appendix 17.2.  
After administration, discard the contents inside of the carton in accordance with local 
regulations, complete the vial tear-off label, and place in the subject source documents for the 
monitor to conduct study drug reconciliation.  
9.1.4 Drug Accountability  
A drug accountability log will be provided by the Sponsor and must be maintained by the 
clinical site. The drug accountability log must be kept current and must contain the date and 
drug units [lot number, subject number, date of dispensation and initials of the dispenser].  
At the end of the trial or when indicated by the Sponsor, all unused study medication should be 
destroyed locally by the study site. Where local laws or site procedures do not permit local site 
destruction the Sponsor will provide instructions for the return of unused medication to a local 
depot. Sites that destroy study medication locally must be able to produce a certificate of 
destruction upon request of the Sponsor.  
9.1.5 Storage 
The Investigator, or an approved representative (e.g., pharmacist), will ensure that all study 
drugs are stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements. All study medication kits should be stored at all times 
under refrigeration (2 to 8C; 36 to 46F) as per the study medication label; do not freeze. All 
vials should be protected from light and stored in the originally provided carton or clinical kit, 

 
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until the time of use. Any deviations in storage temperature should be reported to the Sponsor 
prior to administering the drug to study subject. The Sponsor will determine if the study drug 
remains stable and can be administered to subjects. 
9.2 
Previous or Concomitant Therapy 
Only patients completing the Month 24 visit of Study ISEE2008 are eligible for this OLE trial, 
patients who discontinued for any reason are not eligible. Therefore, patients enrolled will have 
had no previous treatment for GA except for previous treatment with avacincaptad pegol 2 mg 
in Study ISEE2008.  
If subject has a history of wet AMD or if wet AMD were to develop during the trial, in either the 
study eye (SE) or the fellow eye (FE), please refer to Section 10.3 for guidance on the use of 
concomitant treatment. 
9.2.1 Prohibited Medication 
Use of medications listed in the below table are not permitted after start of study intervention. 
Prohibited Medication 
Medication 
Recommended Action 
Study Eye 
Anti-VEGF therapy (licensed, unlicensed or 
investigational) other than Eylea, Lucentis, or 
Vabysmo; use of other biologics  
Other investigational treatment 
 
Discontinue study treatment 
 
Discontinue study treatment 
Fellow Eye 
Anti-VEGF therapy (licensed, unlicensed or 
investigational) other than Eylea, Lucentis, or 
Vabysmo 
Other investigational treatment 
 
None 
 
Discontinue study treatment 
Systemic 
Anti-complement therapy 
Any new systemic medication known to be toxic to the 
lens, retina, or optic nerve (including, but not limited to 
hydroxychloroquine, tamoxifen) 
Any investigational drug, biologic or device (with the 
exception of over-the-counter vitamins, supplements 
or diets) 
 
Discontinue study treatment 
Discontinue study treatment 
 
 
Discontinue study treatment 
Other concomitant medications may be considered on a case-by-case basis by the 
Investigator in consultation with the medical monitor. 
All treatments administered to the study eye, fellow eye, and systemically must be recorded in 
the case report form (CRF). 

 
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10 
TRIAL CONDUCT 
10.1 Subject Enrollment 
Before recruitment of patients into the trial, written IRB or EC approval of the protocol and 
informed consent must be obtained. 
Enrollment into this OLE trial must be within 90 days of the patient’s Month 24 visit in 
Study ISEE2008.  
Patients who meet the eligibility criteria and have provided written informed consent will be 
enrolled in the trial. If any inclusion or exclusion criteria are not met, treatment with study drug 
should not commence. Waivers are not permitted. 
10.2 Trial Assessments 
Written informed consent must be obtained before any of the procedures listed below are 
performed. An explanation of the trial and discussion of the possible risks and discomforts will 
be given by the Investigator or appropriate designee. Only those patients who fulfill all eligibility 
criteria will be entered into the trial.  
Ocular assessments performed at Month 12 and Month 18 (and at an EW visit, if performed) 
should be performed pre-injection (as applicable) on both eyes (OU). Ocular assessments at 
all other trial visits are performed only on the SE. 
Screening and Day 1 (ISEE2008 Baseline) assessments were performed as part of enrollment 
into Study ISEE2008 (GATHER2), and therefore, are not repeated for this OLE trial. Refer to 
the ISEE2008 (GATHER2) protocol for Screening and Day 1 assessments and corresponding 
procedures (Section 10.2 and Section 7, respectively). 
The following assessments, as outlined in the Study Assessments Chart (see Section 3), will 
be performed on the days specified below. 
Note:  
• IVT injection is contraindicated in patients with active ocular or peri-ocular 
infections and in patients with active intraocular inflammation. 
• Concomitant medications should be assessed at every trial visit. 
• AEs and serious AEs (SAEs) should be assessed starting at Month 1 (first visit of 
this OLE trial) after the first dose of study drug until 30 days after the last dose of 
study drug or until the last follow up visit of the trial, whichever comes later.  

 
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Month 1 
• Pre-Injection: 
o Informed consent (must be signed before any other assessments are performed 
at Month 1) 
o Urine pregnancy test (if applicable) 
o Immunogenicity and PK sampling 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o LLVA 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Color fundus photography (SE) 
o Fundus autofluorescence (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg  
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE):  To ensure that the injection 
procedure has not endangered the health of the eye, the study eye will be 
assessed immediately (0 to 5 minutes) and 30 minutes after an active injection 
with an abbreviated ophthalmic exam. A full ophthalmic examination and 
tonometry will also be performed 30 minutes after injection. Assessments will 
continue to ensure the central retinal artery (CRA) is adequately perfused and 
the IOP is within 10 mmHg of the pre-injection value and stable in the opinion of 
the Investigator.  
▪ Immediately (0 to 5 minutes) post-injection: 
• Examine the gross visual function of the SE: CF, hand motion, light 
perception, no light perception 
• Perform direct visualization to: 
o Verify the status of the CRA: CRA is perfused and not 
pulsating, CRA is perfused and pulsating, CRA is pulsating, 
or CRA is closed.  
o Verify the retina is attached and there are no new intraocular 
hemorrhages. 

 
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▪ At 30 minutes post-injection: 
• If no CF at the previous measurement examine the gross visual 
function of the SE 
• Perform direct visualization to: 
o Verify the status of the CRA: CRA is perfused and not 
pulsating, CRA is perfused and pulsating, CRA is pulsating, 
or CRA is closed.  
o Verify the retina is attached and there are no new intraocular 
hemorrhages. 
• Perform full ophthalmic examination 
• Measure IOP 
▪ Continue beyond 30 minutes post-injection until the CRA is adequately 
perfused and IOP is within 10 mmHg of the pre-injection value and is 
stable in the opinion of the Investigator. 
Month 2 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Immunogenicity and PK sampling 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 3 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 

 
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o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 4 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Immunogenicity and PK sampling 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 5 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 

 
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Month 6 (±7 days)  
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o LLVA 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Color fundus photography (SE) 
o Fundus autofluorescence (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 7 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Immunogenicity and PK sampling 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 8 (±7 days)  
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 

 
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o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 9 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full oophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 10 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 

 
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Month 11 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 12 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o LLVA 
o Goldmann applanation tonometry and full ophthalmologic examination (OU) 
o Color fundus photography (OU)  
o Fluorescein angiography (OU, transit SE) 
o Optical coherence tomography (OU)  
o Fundus autofluorescence (OU) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1 (Note: Goldmann applanation tonometer must be used). 
Month 13 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Immunogenicity and PK sampling 
o Refraction 

 
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o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 14 (±7 days)  
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 15 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 

 
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Month 16 (±7 days)  
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 17 (±7 days) 
• Pre-Injection: 
o Urine pregnancy test (if applicable) 
o Refraction 
o BCVA (4 meters) using ETDRS chart (SE) 
o Tonometry (SE) 
o Full ophthalmologic examination (SE) 
o Optical coherence tomography (SE) 
o Treatment with IVT avacincaptad pegol 2 mg 
• Post-injection: 
o Ophthalmic exam (SE) and Tonometry (SE): Following same procedures as 
outlined at Month 1. 
Month 18/End of Study (Early Withdrawal)  
• Urine pregnancy test (if applicable) 
• Immunogenicity and PK sampling 
• Refraction 

 
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• BCVA (4 meters) using ETDRS chart (OU) 
• LLVA 
• Goldmann applanation tonometry (OU) 
• Full ophthalmologic examination (OU) 
• Color fundus photography (OU)  
• Fluorescein angiography (OU, transit SE) 
• Optical coherence tomography (OU)  
• Fundus autofluorescence (OU) 

 
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10.3 Development of CNV During the Trial 
If the Investigator suspects the development of CNV in the study eye, or if the subject has 
> 5 ETDRS letters of VA loss between the current visit and the immediate past visit where VA 
was assessed, the diagnosis must be assessed with fundus photography, FA and OCT and 
confirmed by the Duke RC prior to initiating anti-VEGF treatment in the study eye. The 
trigger for imaging studies should be the Investigator’s suspicion of CNV. VA change alone 
does not constitute a requirement for imaging studies. 
For patients who develop CNV in the study eye and the diagnosis is confirmed by the Duke 
RC during the trial, the study eye should be treated with either Lucentis® (ranibizumab), Eylea® 
(aflibercept), or Vabysmo® (faricimab) per their label. 
If the Investigator plans to administer the anti-VEGF agent on the day of the diagnosis, the 
Duke RC will confirm the diagnosis within 1 hour after receiving the images. If the anti-VEGF 
agent and avacincaptad pegol are administered in the SE on the same day, avacincaptad 
pegol should be administered first, and the anti-VEGF administered second. The anti-VEGF 
agent may NOT be administered after the avacincaptad pegol injection until the IOP is  
≤ 21 mmHg or within 5 mmHg of the baseline IOP on that day (i.e., the “baseline” IOP is the 
pre-injection IOP before the avacincaptad pegol administration on that day). If the IOP is not  
≤ 21 mmHg or within 5 mmHg of the baseline IOP, the IOP should continue to be monitored 
until it is ≤ 21 mmHg or within 5 mmHg of the baseline IOP before proceeding to the anti-VEGF 
injection.  
For the anti-VEGF agent administration, it is mandatory that, the same injection preparation 
and administration protocol specified for the avacincaptad pegol administration be followed by 
the ophthalmologist. Please refer to Appendix 17.2 Intravitreous Administration Protocol; for 
example, the use of aseptic technique, sterile gloves, anesthesia, eye speculum, and 
povidone-iodine are required.   
IVT injection is contraindicated in patients with active ocular or peri-ocular infections and in 
patients with active intraocular inflammation. 
The subject will continue with the study treatment (avacincaptad pegol) as scheduled. 
For patients who develop CNV in the fellow eye during the trial, the fellow eye should be 
treated with either Lucentis® (ranibizumab), Eylea® (aflibercept), or Vabysmo® (facimab) per 
their label, with no change to trial conduct regarding the study eye. However, if the study eye 
is treated on the same day as the fellow eye, the study eye should be treated before the 
fellow eye. 

 
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10.4 Withdrawal from Trial 
Patients have the right to withdraw from the trial at any time for any reason. The Investigator 
(after consultation with the Sponsor) or Sponsor also have the right to withdraw patients from 
the trial in the event of concurrent illness, AEs (including pregnancy in female patients), 
treatment failure after a prescribed procedure, protocol violations, regulatory authority decision, 
cure, administrative or other reasons. 
Final trial assessments as outlined in the Study Assessments Chart, Section 3, should be 
performed on all patients who withdraw. Patients who withdraw due to an AE should be 
followed until resolution of the AE, or an adequate explanation for the event is obtained. 
Patients who withdraw for any reason should have assessments performed according to the 
Early Withdrawal schedule.  
10.5 Study Drug Discontinuation 
In rare instances, it may be necessary for a subject to permanently discontinue study treatment 
before the planned study duration. If study treatment is permanently discontinued, the subject 
should, if at all possible, remain in the study to be evaluated for safety. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should not be considered discontinued from the study unless they withdraw their 
consent and where possible, they should return for study visits and assessments according to 
the Study Assessments Chart, Section 3.  
10.6 Trial Discontinuation 
The reason for a subject discontinuing from the trial will be recorded in the source 
documentation and CRF. A discontinuation occurs when an enrolled subject ceases 
participation in the trial, regardless of the circumstances, prior to completion of the protocol. 
The Investigator must determine the primary reason for discontinuation. A discontinuation must 
be reported immediately to the clinical monitor or his/her designated representative if it is due 
to an SAE (see Section 12.3). The final evaluation required by the protocol will be performed at 
the time of trial discontinuation. The Investigator will record the reason for trial discontinuation, 
provide or arrange for appropriate follow--up (if required) for such patients, and document the 
course of the subject’s condition. 
Premature termination of this clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or at the discretion of Astellas.  

 
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The trial will be considered completed when the last subject completes the final trial visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator.  
A subject is considered to have completed the study if the subject has completed the final trial 
visit.   

 
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11 
STATISTICAL METHODS 
The following summarizes the statistical methods that will be employed in this trial. 
11.1 Study Endpoints 
Primary endpoint: 
• All AEs reported whether or not deemed related to the injection procedure or study drug 
Secondary endpoints: 
• Immunogenicity 
• Pharmacokinetics 
Exploratory Endpoints: 
• Ophthalmic variables (BCVA, LLVA, IOP, and ophthalmic examination) 
11.2 Determination of Sample Size and Statistical Rationale 
The sample size is estimated based on the number of ISEE2008 subjects that completed the 
ISEE2008 Month 24 visit (“ISEE2008 completers”) and the expected number of eligible 
ISEE2008 completers willing to participate in the ISEE2009 study.  
11.3 Randomization and Masking Procedures 
No randomization or masking procedures are necessary for this trial as it is an open-label trial 
and all eligible patients will be administered avacincaptad pegol 2 mg monthly. 
11.4 Analytical Considerations 
11.4.1 Safety Analysis 
The safety analysis will be conducted on all patients who had at least one administration of 
study drug. 
AEs will be summarized using Medical Dictionary for Regulatory Activities terms. The 
incidence and severity of AEs will be listed and grouped by body system.  
Summary statistics (i.e., mean, median, standard deviation, minimum and maximum for 
continuous variables, counts and proportions for categorical variables) will be presented for all 
endpoints.  

 
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11.5 Immunogenicity and PK Analyses 
Additional details regarding immunogenicity and pharmacokinetic data analyses will be 
provided in the statistical analysis plan (SAP) prior to database lock. 
Immunogenicity: A patient’s overall ADA status will be reported as follows: ADA-negative, 
ADA-positive, ADA-inconclusive and Unevaluable samples.  
Pharmacokinetics: Individual patient concentration-time data will be listed and summarized 
descriptively in tabular format. 
11.6 Interim Analyses 
Interim analyses may be performed if deemed appropriate. Details (if applicable) will be 
described in the SAP. 

 
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12 
ADVERSE EVENTS 
12.1 Definition of Adverse Events 
An AE is defined as follows: Any untoward medical occurrence in a patient or subject including 
unfavorable and unintended signs, symptoms or disease temporally associated with the use of 
a medicinal product and which does not necessarily have to have a causal relationship to this 
treatment. 
AEs include illnesses with onset during the trial, or exacerbations of pre-existing illnesses. 
Exacerbation of pre-existing illness is defined as a significant increase in the severity of the 
illness as compared to the start of the trial and should be considered when a patient requires 
new or additional treatment for that illness. Lack of or insufficient clinical response or efficacy 
should not be recorded as an AE. 
In addition, clinically significant changes in objective findings (e.g., laboratory, 
electrocardiogram, X-ray, physical examination) should also be considered as to whether they 
are AEs. The criteria for determining whether an objective finding should be reported as an AE 
are as follows: 
1. Associated with accompanying symptoms; and/or 
2. Requires medical/surgical intervention; and/or 
3. Leads to a change in trial dosing or discontinuation from the trial, significant additional 
concomitant drug treatment or other therapy; and/or 
4. Leads to any of the outcomes included in the definition of a SAE; and/or 
5. Is considered to be an AE by the Investigator or Sponsor. 
Any abnormal test result that is determined to be an error does not require reporting as an AE. 
12.2 Assessment and Reporting of Adverse Events 
AEs will be recorded starting after the first dose of study drug and continuing until 
30 days after the last dose or until the last follow -up visit required by the protocol, 
whichever comes later. An AE that is ongoing at the last follow up trial visit is required to be 
followed up until the event resolves or stabilizes at a level acceptable to the Investigator and/or 
Sponsor. If the subject still presents with any treatment -related toxicity, the follow-up period 
will be extended until return to baseline status or until the condition has stabilized. 
All AEs spontaneously reported, elicited, or observed by the Investigators will be recorded. The 
events will be recorded in the source documents and onto the AE pages of the CRF, including 

 
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date of onset and resolution, severity, relationship to trial treatment and determination of 
whether the event qualifies as a “serious” AE (Section 12.3). 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
The Investigator will take all therapeutic measures necessary for resolution of the AE. Any 
medication necessary for treatment of the AE must be recorded in the subject’s source 
documents and on the appropriate pages of the subject’s CRF. 
To assist with grading of AE severity, the following definitions are provided: 
Mild 
= 
Aware of sign or symptom, but easily tolerated;  
Moderate 
= 
Discomfort enough to cause interference with usual activity; 
Severe 
= 
Incapacitating with inability to work or do usual activity; 
AEs are assessed as “not related” or “related” to one of the following: (1) the IVT injection 
procedure (including eyelid speculum, anesthetic drops, mydriatic drops, antibiotic drops, 
povidone-iodine, subconjunctival injection of anesthetic, IVT injection of avacincaptad pegol or 
anti-VEGF) or (2) the study drug (avacincaptad pegol).  
The adverse relationship will be assessed using the definitions below. The Investigator will 
choose either “not related”, or chose the most likely cause of the AE (i.e., only one of the 
relationships noted in the above paragraph may be chosen):  
Not Related 
= There is not a reasonable possibility that the AE is related to the IVT 
injection procedure or to the study drug (avacincaptad pegol). 
Related  
=  There is a reasonable possibility that the AE is related to the IVT injection 
procedure or to the study drug (avacincaptad pegol). 

 
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12.3 Definition of AESIs 
The selection of adverse events of special interest (AESIs) are based on medical review of 
avacincaptad pegol AEs throughout the development program and the post-marketing 
environment. These include identified risks for an IVT injection procedure and potential risks 
for avacincaptad pegol mechanism of action, considering the frequency, seriousness, and 
medical plausibility of events.   
The AESIs will include the following: 
• Endophthalmitis 
• Ischemic optic neuropathy 
• Intraocular inflammation; any case of uveitis, retinal vasculitis or retinal occlusive 
vasculitis 
• IOP ≥ 30 mmHg at 30 minutes post injection deemed clinically significant by the 
Investigator  
• Transient loss of light perception immediately after injection  
• Elevation of IOP post-injection requiring surgical/procedural intervention (i.e., 
paracentesis; for instruction regarding paracentesis refer to Appendix 17.2 
• BCVA decrease ≥30 letters from ISEE2009 Month 1 Visit 
• CNV (exudative or nonexudative) 
AEs, as defined in Section 12.1, should be reported as per Section 12.2. 
An AESI, as defined in this Section 12.3, shall be reported if affecting the study eye. When an 
AESI occurs, the Investigator will fill out a standardized questionnaire to report the designated 
event in the same expedited manner as SAEs (Section 12.5). 
Adverse events of CNV, endophthalmitis and intraocular inflammation occurring in the fellow 
eye, while not considered an AESI per protocol, shall be entered in the CRF as expeditiously 
as possible (i.e., within 24 hours of event). 
12.4 Definition of Serious Adverse Events 
A SAE is any event that: 
1. Results in death; 
2. Is life-threatening (immediate risk of death); 
3. Results in inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in a persistent or significant disability/incapacity; or 
5. Results in congenital anomaly/birth defect. 

 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the patient/subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
A life-threatening AE is any event that places the patient/subject at immediate risk of death 
from the reaction as it occurred; i.e., it does not include a reaction that, had it occurred in a 
more severe form, might have caused death. 
Disability is a substantial disruption of a person’s ability to conduct normal life functions. 
Hospitalization is defined as any inpatient admission. For chronic or -long-term inpatients, 
inpatient admission also includes transfer within the hospital to an acute/intensive care 
inpatient unit (e.g., from the psychiatric wing to a medical floor, from a medical floor to the 
coronary care unit).  
• Inpatient admission does not include the following: 
o Emergency Room/Casualty Department visits 
o Outpatient/same -day/ambulatory procedures and observation/short -stay units 
o Hospice facilities and Respite care (e.g., caregiver relief) 
o Rehabilitation facilities, skilled nursing facilities, nursing homes, custodial care 
facilities 
• Inpatient admission in the absence of a precipitating, treatment -emergent, clinical AE 
may meet criteria for “seriousness” but is not an AE and thus is not subject to immediate 
reporting to the Sponsor. For example: 
o Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with a worsening of the pre-existing condition (e.g., 
for work-up of persistent pretreatment lab abnormality) 
o Social admission (e.g., subject has no place to sleep) 
o Optional admission not associated with a precipitating clinical AE (e.g., yearly 
physical, elective cosmetic surgery) 

 
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12.5 Assessment and Reporting of Serious Adverse Events 
SAEs will be recorded starting after the first dose of study drug and continuing until 30 
days after the last dose or until the last follow-up visit required by the protocol, 
whichever comes later. Any SAE occurring at any other time after completion of the trial must 
be promptly reported if a causal relationship to study drug is suspected.  
If a SAE occurs, the Sponsor is to be notified within 24 hours of awareness of the event by the 
Investigator. In particular, if the SAE is fatal or life--threatening, notification to the Sponsor 
must be made regardless of the extent of available AE information. This timeframe also applies 
to additional new information (follow-up) on previously forwarded SAE reports. 
All Serious Adverse Events must be reported by the site 
to the Sponsor or Designee within 24 hours. 
Refer to the “Safety Contact List” provided separately 
12.6 Exposure in Utero 
If any trial patient or the female partner of a male patient becomes or is found to be pregnant 
while receiving study drug, the Investigator must contact the Sponsor. This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
pregnancy. The Sponsor will inform the site of the information to be provided. All pregnancies 
must be followed to conclusion to determine their outcome, as well as the status of the infant 
for a minimum of 8 weeks. 
 

 
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13 
RESPONSIBILITIES 
13.1 Emergency Equipment 
Each center must adhere to their policies regarding emergency equipment and resuscitation 
procedures that may be in effect at the individual site or institution. 
The Sponsor recommends, if applicable for the participating sites, to have emergency 
resuscitation equipment available, including at a minimum, an Ambu bag, IV tubing, D5W IV 
fluid, oxygen, and epinephrine 1:1000, and diphenhydramine hydrochloride (Benadryl) and to 
ensure that all equipment is within specifications for the duration of the trial. If applicable, each 
center should follow their written policies regarding resuscitation procedures. In addition to the 
above, any additional measures in adherence to specific site or institutional policies should be 
followed. 
13.2 Case Report Forms and Trial Documentation 
The Investigator will complete the appropriate CRF pages within 3 business days following 
completion of each procedure or evaluation. 
All data recorded on CRFs will be supported by source documents. For certain trial 
parameters, with prior written agreement by the trial Sponsor and monitor, the CRF may be 
used to record source data. 
All source documents will be made available to Astellas clinical monitors, or its 
representatives, during scheduled monitoring visits, to auditors during any audits requested by 
Astellas, and to regulatory agencies during inspections. 
The Investigator will maintain a Trial File containing all trial related documentation required by 
Good Clinical Practice. This Trial File will be reviewed periodically for completeness by 
Astellas’ clinical monitors, or its representatives, and must be made available to auditors and 
regulatory agencies. 
All CRFs and original source documents including ocular images should be stored for a 
minimum of two years after a marketing application has been approved, or two years after 
formal discontinuation of development of the investigational drug, or five years after completion 
of the trial, whichever is longer. Documents should not be destroyed without the permission of 
Astellas. In the event of the Principal Investigator leaving the clinical site, it is the Principal 
Investigator’s responsibility to notify Astellas in writing and to designate which trial material will 
be transferred at the clinical site. 

 
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13.3 Drug Accountability/Storage Conditions 
The Investigator is responsible for the accountability of all used and unused trial medication 
and for recording and documenting the drug storage temperature at arrival and throughout the 
trial. The Investigator is responsible for reporting all deviations in drug storage temperatures 
and should not administer the drug to any subjects until the stability is approved by Astellas.  
Drug accountability records will be reviewed during monitoring visits. Adequate drug 
accountability records include documentation of all study drug supplies received, dispensed to 
trial patients, and returned to Astellas.  
At the end of the trial, all drug supplies and documentation will be reviewed and verified by the 
trial monitors. The sites will be instructed to destroy unused study drug supplies when the trial 
is completed, or the site may choose to return the drug to an Astellas contracted drug 
management facility for destruction. If the drug is destroyed at the site, the drug accountability 
form must be completed and sent to Astellas for archiving. 
13.4 Protocol Compliance 
Astellas will not compensate the Investigator for evaluation of cases in which the procedures 
and evaluations are conducted in a manner other than that specified by the protocol. 
Prospective approval of protocol deviations to recruitment or enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
13.5 Ethical Aspects 
Local Regulations/Declaration of Helsinki 
The Investigator will ensure that this trial is conducted in full conformance with the principles of 
the “Declaration of Helsinki” (as amended in Tokyo, Venice, Hong Kong, South Africa, and 
Scotland) and with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the individual. The trial must fully adhere to the 
principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite Guideline (May 9th 
1997) and with local law if it affords greater protection to the subject. For studies conducted in 
the USA or under US Investigational New Drug (IND), the Investigator will additionally ensure 
adherence to the basic principles of “Good Clinical Practice” as outlined in the current version 
of 21 CFR, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 50, 
“Protection of Human Patients”, and part 56, “Institutional Review Boards”. 
Expedited reporting will be conducted in accordance with local legislation. 

 
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13.6 Institutional Review Board or Ethics Committee Approval and Informed 
Consent 
The Investigator is responsible for obtaining approval of the trial protocol, informed consent, 
and any advertising used for subject recruitment from the appropriate IRB/EC prior to initiating 
the trial. The Investigator will forward the following documents prior to commencement of 
subject enrollment:  
• IRB/EC approval documentation 
• Approved trial patient informed consent 
• A list of IRB/EC members, or statement of compliance 
Prior to enrollment, written informed consent must be obtained from each patient or his/her 
legally authorized representative. The informed consent must contain all of the elements 
prescribed by the relevant regulatory authorities and must be appropriately signed, dated and 
witnessed. Any changes by the Investigator or local IRB/EC to the sample consent 
provided by the Sponsor must be approved by the Sponsor before initiating enrollment. 
13.7 Clinical Trial Insurance 
Astellas has insurance coverage for medicine induced injury and other liabilities incurred 
during clinical trials with its compounds. 
13.8 Trial Report and Publications 
The trial will be documented in a final report, which will contain appropriate statistical analysis 
and medical overview. No individual site or Investigator may publish or present any results 
from the trial until a joint, multi-center publication of the trial results is made by Sponsor in 
conjunction with various participating Investigators and appropriate sites contributing data and 
comments. Subsequently, individual Investigators may request to publish or present results 
from the trial; however, approval will be at the sole discretion of the Sponsor. Should the 
foregoing language be in conflict with the language addressing publication in the clinical trial 
agreement, the language in the clinical trial agreement will prevail. 

 
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14 
MONITORING 
The Investigator will permit representatives of Astellas to review all CRFs, trial documentation, 
and subject medical records at regular intervals throughout the trial. These monitoring visits 
are for the purpose of verifying protocol compliance, subject safety, and the adequacy of data 
collected. 

 
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15 
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Bagheri, S, Lains, I, Silverman, RF, et al.  Percentage of foveal vs total macular geographic 
atrophy as a predictor of visual acuity in age-related macular degeneration. J Vitreoretin Dis 
(2019); 3(5):278-82. 
Bhisitkul, RB, Mendes, TS, Rofagha, S, et al.  Macular atrophy progression and 7-year vision 
outcomes in subjects from the anchor, marina, and horizon studies: The seven-up study. Am J 
Ophthalmol (2015); 159(5):915-24 e2. 
Bonilha, VL.  Age and disease-related structural changes in the retinal pigment epithelium. Clin 
Ophthalmol (2008); 2(2):413-24. 
Boyer, DS, Schmidt-Erfurth, U, van Lookeren Campagne, M, Henry, EC and Brittain, C.  The 
pathophysiology of geographic atrophy secondary to age-related macular degeneration and 
the complement pathway as a therapeutic target. Retina (2017); 37(5):819-35. 
Brandstetter C, Holz FG, Krohne TU. Complement Component C5a Primes Retinal Pigment 
Epithelial Cells for Inflammasome Activation by Lipofuscin-mediated Photooxidative Damage. J 
Biol Chem. 2015 Dec 25;290(52):31189-98.  
Brown, DM, Kaiser, PK, Michels, M, et al.  Ranibizumab versus verteporfin for neovascular 
age-related macular degeneration. N Engl J Med (2006); 355(14):1432-44. 
Brown, JC, Goldstein, JE, Chan, TL, et al.  Characterizing functional complaints in patients 
seeking outpatient low-vision services in the united states. Ophthalmology (2014); 
121(8):1655-62 e1. 
Brown, MM, Brown, GC, Stein, JD, et al.  Age-related macular degeneration: Economic burden 
and value-based medicine analysis. Can J Ophthalmol (2005); 40(3):277-87. 
Cao S, Wang JC, Gao J, et al. CFH Y402H polymorphism and the complement activation 
product C5a: effects on NF-κB activation and inflammasome gene regulation. Br J Ophthalmol. 
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Chakravarthy, U, Bailey, CC, Johnston, RL, et al.  Characterizing disease burden and 
progression of geographic atrophy secondary to age-related macular degeneration. 
Ophthalmology (2018); 125(6):842-9. 
DeCarlo, DK, Scilley, K, Wells, J and Owsley, C.  Driving habits and health-related quality of 
life in patients with age-related maculopathy. Optom Vis Sci (2003); 80(3):207-13. 
Fleckenstein, M, Mitchell, P, Freund, KB, et al.  The progression of geographic atrophy 
secondary to age-related macular degeneration. Ophthalmology (2018); 125(3):369-90. 

 
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Grunwald, JE, Pistilli, M, Daniel, E, et al.  Incidence and growth of geographic atrophy during 5 
years of comparison of age-related macular degeneration treatments trials. Ophthalmology 
(2017); 124(1):97-104. 
Hageman, G. S., Luthert, P. J., Victor Chong, N. H., Johnson, L. V., Anderson, D. H., Mullins, 
R. F. An integrated hypothesis that considers drusen as biomarkers of immune-mediated 
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Immunol (2014); 32:433-59. 
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Holz, FG, Strauss, EC, Schmitz-Valckenberg, S and van Lookeren Campagne, M.  Geographic 
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121(5):1079-91. 
Kunzel, SH, Lindner, M, Sassen, J, et al.  Association of reading performance in geographic 
atrophy secondary to age-related macular degeneration with visual function and structural 
biomarkers. JAMA Ophthalmol (2021); 139(11):1191-9. 
Kunzel, SH, Moller, PT, Lindner, M, et al.  Determinants of quality of life in geographic atrophy 
secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci (2020); 61(5):63. 
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progression in age-related macular degeneration with foveal sparing. Ophthalmology (2015); 
122(7):1356-65. 
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Mitchell, P, Liew, G, Gopinath, B and Wong, TY.  Age-related macular degeneration. Lancet 
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(2020b); 138(10):1026-34. 
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detecting global and local progression of geographic atrophy by sd-oct imaging. Invest 
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degeneration. N Engl J Med (2006); 355(14):1419-31. 
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degeneration prevalence in populations of european ancestry: A meta-analysis. 
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Schmitz-Valckenberg, S, Brinkmann, CK, Alten, F, et al.  Semiautomated image processing 
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Shi, Y, Zhang, Q, Zhou, H, et al.  Correlations between choriocapillaris and choroidal 
measurements and the growth of geographic atrophy using swept source oct imaging. Am J 
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Wong, WL, Su, X, Li, X, et al.  Global prevalence of age-related macular degeneration and 
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16 
SPONSOR SIGNATORY 
 
Sponsor signatures as required by ICH GCP 4.5.1 are located in the first attachment.  
Attachment 1 
Electronic Sponsor Signatures 
 
 

 
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17 
APPENDICES 
17.1 Procedures for Refraction and Vision Testing 
Refraction and VA measurements will be performed for all patients by a trained vision 
examiner. Another examiner should also be trained to serve as a back-up should the primary 
examiner be absent. The name of the vision examiner should be documented in the subject’s 
source document at each visit. The subject’s chart, previous VA testing results, and previous 
refraction should be made available. 
17.1.1 Refraction 
Refraction may not be required at every study visit to obtain best corrected vision. Refraction 
should be conducted prior to VA testing to obtain best corrected vision at the Month 1, M7, 
M12, and Month 18/EOS (EW) visits. Refraction should be performed on study visits 
immediately following any refractive procedures (cataract extraction) or if greater than 
10 ETDRS letter difference compared to immediate prior visit is observed. 
17.1.2 Equipment 
Refraction equipment required includes: 
1. Retroilluminated light box and Charts R, 1 and 2 from Ferris-Bailey ETDRS distance VA 
chart set 
2. Trial lens frames 
3. Trial lens set with plus or minus cylinder lenses 
4. Jackson cross-cylinders of 0.25, 0.5, and 1.00 diopters 
5. Pinhole occluder 
6. Tissues or eye pads and tape 
7. A 1 meter rigid measuring stick 
17.1.3 Beginning Approximate Refraction 
At the Screening visit (performed at Screening in Study ISEE2008 [GATHER2]), the subject’s 
beginning refraction is determined by one of the following methods: 
a)  If the subject’s VA is 20/100 or better and the subject does not require glasses for distance 
vision, then the beginning approximate refraction should be no lens correction or plano. 
b)  If the subject’s VA is 20/100 or better and the subject requires glasses for distance viewing, 
the glasses should be measured using a lensometer, and these measurements are used 
for the beginning refraction. 

 
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c)  If the subject’s VA is less than 20/100 with or without correction, then retinoscopy or 
autorefraction should be performed. 
d)  If the subject wears contact lenses for refraction, a notation should be made that the 
refraction was over contact lenses. It is suggested that the subject wear the contact lenses 
for future examinations. If the subject is not a regular contact lens wearer and wore the 
lenses in by mistake, they should be removed and you should wait at least 30 minutes 
before beginning the refraction. The subject should be reminded not to wear contact lenses 
at subsequent visits.  
Refractions are performed with either plus or minus cylinder power. Whichever cylinder type is 
used at Screening (minus or plus) must be used for all subsequent visits. Best correction will 
be recorded on an examination form for each subject to be included in the source document. 
At each follow-up visit, the results of the protocol refraction from the previous visit are used as 
the beginning approximate refraction. If the previous refraction is not available for whatever 
reason, the procedure described immediately above should be used. Note: The distance 
prescription worn in glasses should be used only as the starting point for the Screening visit. 
All subsequent visits should use the previous refraction as the starting point. 
The charts used for measuring distance VA must NOT be used for refraction. Refraction for 
each eye should be performed at 4 meters unless the subject’s VA measured at 4 meters on 
the refraction chart (Chart R) is worse than 20/160. If VA is worse than 20/160 the eye is 
refracted at 1.0 meter. If during the refraction process at one meter, the subject is reading 
letters on the eighth line or lower, the refraction should continue at 4 meters. Whenever a 
subject cannot read any letters on the top line of Chart R at 1.0 meter the vision should be 
checked with a pinhole to see whether reduced vision is due, at least in part, to a larger 
refractive error. If there is no improvement with the pinhole, then the eye is exempt from 
refraction. 
Subjective refraction as described below should be performed for corrected aphakic patients, 
including those with intraocular lenses. For uncorrected aphakic patients, a +10.00 diopter 
sphere should be added to the trial frame as the beginning approximate refraction. 
17.1.4 Subjective Refraction 
Subjective refraction allows one to determine the best correction for a subject to perform the 
VA tests at specified distances. The “push plus” approach is used in this trial. Add minus 
diopter spherical corrections only when the subject is able to read at least one more letter on a 
line or a letter on a smaller line.  

 
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17.1.5 Procedure 
1. Measure the distance vision of each eye using Chart R while occluding the FE. Patients 
should be reminded to blink and encouraged to use eccentric fixation, or their side vision, 
when necessary. 
2. All vision testing must be done at 4 meters or 1 meter from Chart R, depending upon the 
VA determined at 4 meters. Distance for 4 meters is 13 feet and 1.5 inches or 157.5 inches. 
The one meter distance is 39 and 3/8 inches. 
3. All patients should be seated for testing. A rigid measuring device should be used to 
measure the distance from the subject to the chart at each visit if testing is done at 1 meter. 
The distance is measured from the outer canthus to the center of the second letter (left 
eye) or fourth letter (right eye) of the third line of the chart. If testing is done at 4 meters, 
clear and permanent floor markings should be used to mark the distance for consistency. 
4. Place and adjust the trial frame on the subject’s face so that the lens cells are parallel to 
the anterior plane of the orbits and centered in front of the pupils. Adjust the lens cells for 
the proper distance from the cornea. 
5. Occlude the left eye by lightly patching with an eye pad or tissue and tape. 
a) Place the spherical lens correction in the compartment closest to the eye. 
b) The cylindrical lens correction, if present, is placed in the compartment in front of the 
spherical correction. Adjust the axis. 
6. Spherical Correction: To determine the highest plus or least minus sphere, refract the 
right eye. The following refraction steps are recommended for visual acuities of 20/10 
to 20/80 with the beginning approximate refraction. For visual acuities less than 
20/80, refer to the refraction table for the appropriate sphere and cylinder powers 
and testing distance (See summary below) and follow a similar procedure. Note: 
Whenever VA is improved to a higher range by improved correction, refraction should be 
performed with the smaller sphere and cylinder powers given for the better VA level (See 
table at end of this appendix). 
a) Hold a +0.50 sphere in front of the subject’s right eye. The subject should be looking at 
the smallest legible line on the VA chart. In these exact words, ask the subject, “Is this 
better, worse, or no change?” 
b) If the subject responds that the vision is worse or blurred, remove the +0.50 sphere from 
in front of the trial frame, record the VA to the nearest letter, and go to Step 6d.  

 
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c) If the subject responds better or no change, remove the +0.50 sphere from in front of 
the trial frame and replace the spherical lens in the trial frame with a spherical lens that 
is one-half diopter more positive. Continue this procedure by returning to Step 6a and 
repeating this process until a +0.50 makes the vision worse or blurred and then go to 
Step 6d. 
d) Hold a -0.50 sphere in front of the subject’s right eye. In these exact words, ask the 
subject, “Is this better, worse or no change?” If the subject replies “worse” or “no 
change”, go to Step 6f. If they reply “better” go to Step 6e. 
e)  Hold the -0.50 sphere in front of the eye. If the subject responds that the vision is 
better, ask the subject to read the VA chart. Whenever the VA is improved, even by one 
letter, you may increase the minus by 0.50 (or decrease the plus) and repeat Step 6d. 
Whenever VA is not improved, go to Step 6f. 
f) Remove the -0.50 sphere from in front of the eye and hold a +0.50 sphere in front of the 
right eye. In these exact words, ask the subject, “Is this better, worse, or no change?” If 
the subject responds that vision is better or unchanged, then return to Step 6c. 
Otherwise, go to Step 7. Spherical testing should always end with a plus lens. 
7. Cylinder Axis: To determine and refine the cylinder axis for PLUS cylinder, proceed as 
follows (If negative cylinders are used, the appropriate technique using minus cylinders 
must be employed and minus cylinder must be used throughout the trial.): 
a) Have the subject look at a line, which is either one or two lines larger than the smallest 
line the subject is able to read. Ask the subject to focus on a rounded letter such as “C”, 
“D”, or “O”. The subject should focus on this same letter throughout this procedure. 
b) If a cylinder is present in the beginning approximate refraction, then go to Step 7c. 
Otherwise, follow one of the options listed below to determine the appropriate cylindrical 
correction. 
Option 1: 
Place a +0.50 diopter cross-cylinder with the positive axis (white) first at 90, then 
at 180, then 45, and 135. If the subject says that vision is improved at any one 
of these axis positions, place a +0.50 cylindrical lens in the trial frame at the 
preferred axis and go to Step 7c. If none of the positions are preferred, then 
proceed to Step 9. 

 
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Option 2 (preferred): 
Place a +0.50 diopter cross-cylinder with the positive axis (white) first at 90, then 
compare this to no cylinder; repeat this procedure for 180, then 45, and 135 
always comparing to no cylinder after each axis position. If the subject says that 
vision is improved at any one of the four axis positions, place a +0.50 cylindrical 
lens in the trial frame at the preferred axis. If the subject prefers no cylinder at all 
four axis positions, then go to Step 9. 
c) Place the +0.25 diopter cross-cylinder (for VA 20/10 to 20/80) first with the positive axis 
45 to the right of the preferred cylinder axis (as determined above), and second with 
the positive axis 45 to the left of the preferred cylinder axis. Ask the subject, “Which do 
you like better, position one, or position two?” Also, tell the subject that both positions 
may blur their vision. The subject must choose the least blurred position, either one or 
two. “Neither” is allowed only if both positions are equally blurred or equally good. 
d) If “neither” position is better and this was the first test of axis position, move the axis of 
the cylinder in the trial frame 15 to the right or left and return to Step 7c. Otherwise, 
proceed to Step 7e. 
e) When one position is preferred over another, move the cylinder to the preferred positive 
axis position in the step sizes noted below and return to Step 7c. If no single position is 
better than another than go to Step 8. 
CYLINDER REFINEMENT AXIS STEP SIZES 
Cylinder Power 
 
Axis Step Sizes 
< 1.00D 
 
15 
1.00 - < 2.00D 
 
10 
2.00 - < 3.00D 
 
5 
3.00 - < 5.00D 
 
3 
5.0 - < 8.00D 
 
2 
8. Cylinder Power: Cylinder power is refined by following the steps: 
a) Ask the subject to look at the smallest line that can be read on the VA chart. 
b) Test the cylinder power by placing the 0.25 diopter cross-cylinder (for vision of 20/10 to 
20/80) first with the positive axis and second with the negative axis coincident with the 

 
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cylinder axis. Ask the subject, “Which is better, position one or position two?” Do not 
give the subject the choice of neither. 
c) If the subject prefers the negative (red) axis coincident with the cylinder axis, the total 
power of the correcting plus cylinder is reduced by 0.25 diopter. Repeat the process 
until the subject cannot choose one of the cross cylinder positions over the other. If the 
subject indicates a change that would introduce negative cylinder power, remove all 
cylinder power and continue testing for positive cylinder power at an axis 90away from 
the previous axis. Otherwise go to Step 8d. 
d) If the subject prefers the positive (white) axis coincident with the cylinder axis, increase 
the power of the cylinder by 0.25 diopters and return to Step 8b. Otherwise proceed to 
Step 8e. 
e) When the subject feels that both positions are equally bad or good, and the cylinder 
power in the trial frame has changed by more than 0.50 diopter, return to Step 7c and 
re-adjust the axis if necessary. Otherwise, proceed to Step 9. 
Note: If the cylinder is changed by more than 0.50 diopter, the spherical equivalent 
should be maintained. (For each 0.50 plus CX increase, add –0.25 to the sphere, for 
each 0.50 minus CX increase, add +0.25 to the sphere). 
9. Spherical Correction Refinement: Recheck the power of the sphere by adding +0.25 
and -0.25 spheres and changing the spherical power by 0.25 diopter increments of the 
appropriate sign until the subject cannot detect any improvement in vision. As a reminder, 
spherical testing should always begin and end with a plus lens. 
10. Record the lens corrections obtained by subjective refraction for the right eye on the 
examination form in the section for VA measurements as the corrections obtained by 
protocol refraction for the right eye. If the corrective power was changed by more than 
2 diopters from the starting refraction, confirm that the subject can read at least as well as 
the beginning approximate refraction. If not, then begin again at Step 1 and repeat the 
process.  
11. Repeat the entire process (Steps 1-10) for the left eye and record the result on the 
examination form. 
17.1.6 Visual Acuity Testing 
Best-corrected VA is measured at all trial visits using standard charts, lighting, and procedures. 
Best correction is determined by careful refraction at that visit according to the standard 

 
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protocol for refraction as described in the previous section. 
17.1.7 Visual Acuity Charts 
Chart 1 is used for testing the VA of the right eye; Chart 2 for testing the left eye; and Chart R 
for testing refraction only. Patients should not be allowed to see any of the charts before the 
examination. 
17.1.8 Visual Acuity Lane and Visual Acuity Box 
A distance of 4 meters is required between the subject’s eyes and the VA chart. With the box 
light off, not more than 15 foot-candles of light (161.4 Lux) should fall on the center of the 
chart. To measure the amount of light, the room is set up for VA testing, but with the box light 
off. The light meter is placed at the fourth line from the top of the chart, with its back against 
the chart and the reading is taken. If more than one lane is available for testing VA, the VA of 
an individual subject should be measured in the same lane at each visit, if possible. If different 
lanes are used to test VA, they must each meet the same standards. 
Retro-illuminated ETDRS charts are used in this trial. The illuminator box will be either 
wall-mounted or mounted on a stand manufactured by the Lighthouse Low Vision Services. 
The light box should be mounted at a height such that top of third row letter is 49 + 2 inches 
from floor. 
The VA light box is equipped with two General Electric Cool Daylight 20-watt fluorescent tubes 
and a ballast which partially covers the tubes. Because the illumination of fluorescent tubes 
diminishes by 5 percent during the first 100 hours and by another 5 percent during the next 
2000 hours, new tubes should be kept on for 4 days (96 hours) continuously, and should be 
replaced once a year. 
A sticker should be placed on the back of the light box, indicating the date on which the 
present tubes were installed. A spare set of burned in bulbs should be available on site. 
Each tube is partly covered by a 14-inch fenestrated sleeve, which is open in the back. This 
serves as a baffle to reduce illumination. Each sleeve should be centered on the tube with the 
opening towards the back. 
17.1.9 Corrected Visual Acuity Measures 
• 
As a reminder, Charts 1, 2, and R are used for testing the right eye, left eye, and refraction, 
respectively. Patients should not see the charts until the test begins. 
• 
All eyes must be tested at 4 meters first, even if the refraction was performed at 1 meter. 

 
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• 
The subject should be seated comfortably directly in front of the chart so that the eyes 
remain at the 4 meter distance. Testing always begins with the right eye. Occlude the 
subject’s left eye. A folded tissue or eye pad lightly taped over the eye behind the trial 
frame serves as an effective occluder that allows eccentric fixation without inadvertent use 
of the covered eye. After testing the right eye, occlusion of the right eye should be done 
BEFORE Chart 2 is put up for testing the left eye. 
• 
The lens correction from the subjective refraction should be in the trial frame worn by the 
subject. 
• 
The subject is asked to read the letters slowly, approximately one letter per second. The 
subject should be told that only one chance is given to read each letter on the chart. If the 
subject is unsure about the identity of the letter, then the subject should be encouraged to 
guess. 
• 
The subject should begin by reading the top line of the chart and continue reading every 
letter on each smaller line, from left to right on each line. The examiner circles every correct 
letter read and totals each line and the whole column (0 if no letters are correct) on the data 
collection form. An X is put through letters read incorrectly. Letters, for which no guess was 
attempted, are not circled. When a subject reaches a level where he/she cannot guess, the 
examiner may stop the test provided that the subject has made errors on previous guesses, 
which is a clear indication that the best VA has been obtained. 
• 
When a subject cannot read at least 20 letters on the chart at 4.0 meters, the subject is 
tested at 1.0 meter. The distance from the subject to the chart should be measured again 
using the rigid one meter stick. The distance is measured from the outer canthus to the 
center of the fourth letter (right eye) or the second letter (left eye) of the third line of the 
chart. The spherical correction in the trial frame should be changed by adding +0.75 to 
correct for the closer test distance. The subject may fixate eccentrically or turn or shake 
his/her head to improve VA. If this is done, the examiner must ensure that the FE remains 
occluded both centrally and peripherally and that the subject does not move forward in the 
chair. Particular care should be taken to make sure the subject does not move forward 
when testing at 1 meter. The subject should be reminded to blink. 
• 
The examiner should not tell the subject if a letter was identified correctly. The subject may 
be encouraged by neutral comments, such as “good”, “next”, and “OK”. 
• 
The examiner should not stand close to the chart during testing. Attention should be 
focused on the subject and the data collection form. If the subject has difficulty locating the 
next line to read, the examiner may go up to the chart and point to the next line to be read, 
but then must move away from the chart. 

 
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• When it is possible to measure the VA of the eye at 4.0 meters (i.e. 20 or more letters read 
at 4 meters), the VA score for that eye is recorded as the number of letters correct plus 30. 
The subject gets credit for the 30 1M letters even though they did not have to read them. 
Otherwise, the VA score is the number of letters read correctly at 1.0 meter plus the 
number, if any, read at 4M. If no letters are read correctly at either 4.0 meters or 1 meter, 
then the VA score is recorded as 0. 
17.1.10 Testing for Count Fingers Vision, Hand Motion Vision and Light Perception/No 
Light Perception Vision 
If the subject’s VA is so poor that he/she cannot read any chart letters when tested at one 
meter then the subject’s ability to count fingers, detect hand motion, or have light perception 
should be evaluated. 
Testing for Count Fingers Vision 
In testing for count fingers vision, the examiner’s hand holding 1, 2, or 5 fingers is held steady 
at a distance of two feet directly in front of the eye being examined. The FE is completely 
occluded with a patch on the face. A light should be shown directly on the hand from behind 
the subject. The examiner’s fingers should be presented in random order and repeated 
5 times. Eccentric fixation, if present, should be encouraged. If the subject correctly identifies 
three of the five presentations, then count fingers vision is noted. If not, then the subject must 
be tested for hand motion vision. 
Testing for Hand Motion Vision 
The examiner’s hand with all fingers spread out should be extended two feet directly in front of 
the eye being examined. The FE should be occluded with a patch on the subject’s face. A light 
should be shone directly on the hand from behind the subject. The examiner’s hand should be 
moved in an up-and-down direction (vertically) or in a side-to-side direction (horizontally) at a 
constant speed of approximately one back and forth presentation per second. The subject is 
instructed that the examiner’s hand will be presented and they will have to respond to the 
question: “What am I doing with my hand?” This should be repeated five times. Three out of 
five correct responses indicate that hand motion vision is present. If the subject does not 
correctly identify three of five presentations, then you must test for light perception. 
Testing for Light Perception/No Light Perception Vision 
Light perception should be tested with an indirect ophthalmoscope in a darkened room. The 
indirect ophthalmoscope light should be in focus at 1 meter with the rheostat set at maximum 
voltage. From that distance the beam should be directed in and out of the eye at least four 
times, and the subject should be asked to respond when he or she sees the light. If the 

 
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examiner is convinced that the subject perceives the light, vision should be recorded as “light 
perception”, if not, vision should be recorded as “no light perception”. 
17.1.11 Procedures for Refraction and Vision Testing under Low Luminance 
Once the subject has been refracted and had their vision measured under normal light 
conditions, a neutral density filter will be added to the trial frame and the ETDRS VA will be 
measured again using the same refraction noted above. Additional specification of the neutral 
density filter and procedures will be provided by the Sponsor. 
17.1.12 Refraction Sequence Chart 
Refraction Protocol Summary 
Vision with Best 
Correction (Refraction 
Distance) 
Sphere 
Cylinder 
Sphere Refinement 
 
Power 
(a) 
Increment 
Axis 
(b) 
Power 
(c) 
Increment 
Power 
(d) 
Increment 
20/10 - 20/80 
(4 meters) 
+.50 
-.50 
+.50 
-.50 
.25 
JCC 
.25 
JCC 
+.25 
-.25 
+.25 
-.25 
+.25 
-.25 
20/10 - 20/160 
(4 meters) 
+1.00 
-1.00 
+1.00 
-1.00 
.50 
JCC 
.50 
JCC 
+.50 
-.50 
+.50 
-.50 
+.50 
-.50 
20/20 - 20/400 
(1 meter) 
+2.00 
-2.00 
+2.00 
-2.00 
1.00 
JCC 
1.00 
JCC 
+1.00 
-1.00 
+1.00 
-1.00 
+1.00 
-1.00 
<20/400 
(1.0 meters) 
+2.00 
-2.00 
+2.00 
-2.00 
No cylinder test 
No refinement 
Sequence of Refraction: (a) - (d) 

 
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17.2 
Intravitreous Administration Protocol 
This protocol applies to avacincaptad pegol injections. 
The injection volume for avacincaptad pegol 2 mg is 0.10 mL (100 µL).  
Only an ophthalmologist who is experienced with IVT injections may perform the IVT 
injection. 
In addition to the procedures outlined, any additional safety measures in adherence to specific 
institutional policies associated with intravitreal injections may be utilized. 
New bottles of topical eye drops should be used for each patient at each visit. 
NOTE: Prior to the IVT injection, direct ocular massage using a sterile cotton-tip applicator at 
the intended site of injection may be utilized at the Investigator’s discretion. However, a 
paracentesis MAY NOT be performed prior to injection of the IVT drug. 
NOTE: Pre-operative antibiotic drops are NOT recommended prior to the scheduled 
injection(s) of IVT drug. In addition, peri-operative and post-operative antibiotic drops are NOT 
recommended at the time of the procedure or after the procedure, respectively. However, if it is 
considered the standard of care at the individual institution, appropriate broad spectrum topical 
antibiotics may be prescribed for subject use at the discretion of the Investigator. 
Before the Injection Day 
1) If pre-operative topical ofloxacin, levofloxacin, or an antibiotic drop with comparable 
antimicrobial coverage therapy is ordered by the Investigator, the subject should be 
instructed to initiate the use of such antibiotic drops according to the regimen selected at 
the discretion of the Investigator. The antibiotic drops should be provided to the subject with 
clear instructions of how to use them at the visit immediately prior to each planned 
injection. 
Preparation on the Day of the Injection 
2) Within one hour prior to injection, topical 1% tropicamide (e.g., Mydriacyl) and 2.5% 
phenylephrine (e.g., Neo-Synephrine) from new bottles should be applied topically to 
achieve adequate pupillary dilation. If 2.5% phenylephrine is not available, another dilating 
drop may be used at the discretion of the Investigator.  
3) Injection preparation (for the following, new povidone-iodine bottles must be used and 
cannot be shared between patients):  
a. Apply single use topical anesthetic drop(s) to the eye. 

 
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b. Apply 2 to 3 drops of povidone-iodine to the injection site. 
c. OPTIONAL: Apply 2 to 3 drops of povidone-iodine to the lower fornix 
and/or use sterile cotton-tipped applicators soaked in 5% or 10% 
povidone-iodine to swab the upper and lower eyelid margins and the 
upper and lower eyelashes.  
4) Place a sterile eyelid speculum to stabilize the eyelids.  
5) Consider additional anesthesia with the application of one or two cotton-tipped applicators 
soaked in topical anesthetic over the intended injection site for at least 30 seconds. 
Subconjunctival anesthesia (0.5 mL of 2% xylocaine without epinephrine subconjunctivally 
at the intended injection site) can be used if the Investigator believes that topical anesthetic 
is not sufficient to minimize discomfort. Lidocaine gel is not permitted. 
6) Encourage the study participant to look superonasally (if injection site is inferotemporal) 
during the application of the povidone-iodine. Apply one of the following to the conjunctiva 
directly over and surrounding the intended injection site: 
a. A cotton-tipped applicator soaked in 5% or 10% povidone-iodine. 
b. A 10% povidone-iodine swab stick. 
c. At least 3 drops of 5% povidone-iodine (at least enough to cover the 
intended injection site). 
7) Allow 30 to 60 seconds for the povidone-iodine to be in contact with the injection site before 
injection. 
NOTE: As indicated above, injection preparation must include the use of 
povidone-iodine either applied directly to the injection site using topical drops, a 
cotton-tipped applicator, or a swab stick. If a study participant experiences an 
adverse reaction to povidone-iodine, other approaches to limit the exposure of 
povidone-iodine may be permitted. However, a study participant may not 
receive a study intravitreal injection without use of povidone-iodine directly 
to the injection site just prior to the injection. 
8) Sterilized calipers should be used to measure the injection site. The entry site of the needle 
for the IVT injection should be 3.0 to 3.5 mm from the limbus in aphakic/pseudophakic 
patients, and 3.5 to 4.0 mm in phakic patients.  
NOTE: During the preparation and injection of the drug, Investigators, 
ancillary staff, and patients should refrain from talking. If talking becomes 

 
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absolutely necessary, the Investigator should face away from the bare 
needle and the injection site to avoid contamination of the needle and 
injection site. Wearing a mask during the preparation and injection of the 
study drug is optional. 
Avacincaptad pegol 2 mg (0.1 mL injection volume) Injection Procedure:  
a. Use sterile gloves during preparation and administration of the injectable drug. 
b. Using aseptic technique, 0.2 mL of the avacincaptad pegol injection vial contents are 
withdrawn through a 5-micron filter needle attached to a 1-mL sterile syringe (supplied). 
Please see the study drug manual for appropriate withdrawal technique. The filter 
needle should be discarded after withdrawal of the vial contents and should not be used 
for intravitreal injection. The filter needle should be replaced with the sterile 30-gauge 
needle (supplied) for the intravitreal injection. The contents and any air bubbles should 
be expelled until the plunger tip is aligned with the line that marks mg 0.10 mL on the 
syringe for avacincaptad pegol 2 mg. 
c. Insert the drug into the vitreous cavity pointing toward the optic nerve via the pars plana. 
Once the needle is in place, continuous pressure should be applied to the syringe for 
approximately 10 seconds to assure slow, even delivery of all drug. 
d. As the needle is withdrawn, a sterile cotton tip applicator should be rolled over the entry 
site to minimize the risk of drug reflux. This should be held in place for a full 10 seconds. 
e. The eye can then be irrigated as per the typical practice pattern of the Investigator to 
minimize irritation from the aseptic procedure. 
f. 
Zero to five minutes following the intravitreal injection, patients should be examined 
with indirect ophthalmoscopy to assure that the optic nerve head is perfused, the retina 
is attached, and there is no new intraocular hemorrhage. 
g. The IOP should be measured and recorded at least 30 minutes after the intravitreal 
injection is administered. Monitor the IOP until it is below 30 mmHg; the subject should 
not be discharged until at least 30 minutes after the injection and the IOP is below 
30 mmHg or at a lower level as determined by the Investigator. 
After All Injections: 
1) Zero to five minutes following intravitreal injection, patients should be examined by 
ophthalmoscopy to verify reperfusion of the central retinal artery in the immediate 
post-injection period. Verify that the retina is attached and that there is no new intraocular 

 
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hemorrhage.  
2) After each intravitreal injection, check the IOP: 
a. The IOP should be measured and recorded at least 30 minutes after the 
injection. Monitor the IOP until it is within 10 mmHg of the pre-injection value; the 
subject should not be discharged until at least 30 minutes after the injection and 
the IOP is within 10 mmHg of the pre-injection value.  
b. If a Tono-Pen is used to check pressure, a clean Tono-Pen condom should be 
placed on the tip before taking each measurement. If applanation tonometry is 
used, the applanator tip should be cleaned as per the standard procedures of the 
site before using it to measure IOP. Sterile fluorescein strips and single use 
proparacaine bottles should be used for all patients. “Fluoracaine” or other 
combination fluorescein sodium and proparacaine HCl mixtures should only be 
used if single use presentation is available, and then only if single use bottles are 
available. IOP may be lowered by pharmaceutical or surgical intervention, if 
required. Treatment should be initiated whenever IOP is increased to the extent 
that the central retinal artery remains closed and the subject has no light 
perception for more than 1 to 2 minutes or as per Investigator judgment. 
Transient graying or obscuration of vision following injection, however, is 
expected and should not be treated. See below for additional information 
concerning paracentesis. 
3) No special precautions are required before discharge of a subject who has had an 
uneventful recovery from the intravitreal injection(s), but patients and/or caregivers should 
be educated to avoid rubbing the eye and to recognize the signs and symptoms of 
endophthalmitis, retinal detachment and intraocular hemorrhage, including eye pain or 
increased discomfort, increased redness of the eye (compared to immediately after 
injection), blurred or decreased vision, and increased ocular sensitivity to light. Patients 
should be informed that some blurring of vision is common post-injection, which is often 
described as seeing spots floating in the eye. Patients who experience post-injection AEs 
that require additional monitoring should remain in the clinic for longer than 30 minutes, and 
treated according to the Investigator’s medical judgment.  
4) After administration, please securely discard the contents inside of the carton, flatten and 
retain the box for the monitor to conduct drug reconciliation.  

 
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Instructions Regarding Paracentesis: 
Paracentesis should be used only in extreme circumstances when the degree of pressure 
elevation poses an imminent and irreversible threat to vision. In the rare situation when a 
paracentesis is warranted, the IOP should be recorded both before and after the procedure. 
Apply single use topical anesthetic drop(s) to the eye. Use a new pair of sterile gloves. Place a 
sterile lid speculum to open the eye lids. Apply 2 to 3 drops of povidone-iodine to the 
paracentesis site, and allow 30 to 60 seconds for the povidone-iodine to be in contact with the 
paracentesis site. A 0.1 mL paracentesis is performed at the temporal limbus using a 27-gauge 
or 30-gauge needle by the Investigator. For repeated paracentesis in the same patient, 
different clock-hour locations along the corneal circumference should be chosen. Further, IOP 
reducing drops can be applied prior to the intravitreal injection at the Investigator's discretion. 
Antibiotic eye drops are applied per discretion of the Investigator. Record pre- and 
post-paracentesis IOP measurements in the source document and on the appropriate CRF 
page. 
NOTE: A paracentesis MAY NOT be performed prior to injection of the IVT drug. 
 
 

 
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17.3 ISEE2009 Study Schematic 
 
 
 
 

 
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17.4 Protocol Amendment Summary of Changes 
 
DOCUMENT HISTORY 
Protocol Version 
Protocol Version Date 
Protocol Amendment 01 
27 February 2024 
Protocol Amendment A (France) 
28 November 2022 
Original Protocol 
27 July 2022 
Amendment 01 dated 27 February 2024 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union and EU Clinical Trial Regulation. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the sponsor and to apply clarifications to the conduct of the study 
throughout the protocol.  
Substantial Changes 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
The sponsor is updated 
from Iveric bio to Astellas 
Pharma Global 
Development (Astellas). 
To reflect the change in sponsor. 
2; 6; 8.1  
The approximate number of 
subjects to be enrolled is 
reduced from 400 to 280 
To update the number of subjects expected to complete the ISEE2008 
study and be eligible to enroll in ISEE2009, based on current data.  

 
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2; 5.2; 11.1 
Study safety endpoints 
clarified as follows: 
Primary Endpoint: 
• Adverse Events (AEs) 
Secondary Endpoints: 
• Immunogenicity 
• Pharmacokinetics 
Exploratory Endpoints: 
• Ophthalmic findings 
(BCVA, LLVA, IOP, 
and ophthalmic 
examination) 
To specify primary, secondary, and exploratory endpoints of existing 
endpoints as required. Study endpoints were originally specified only as 
“safety endpoints”. 
 
Nonsubstantial Changes 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
Regulatory agency 
identifier numbers are 
added. 
To include regulatory agency identifiers as required.  
Title Page 
Sponsor confidentiality 
statement is updated. 
To provide updated confidentiality statement per change in Sponsor.  
2; 6; 9.1.2; 
10.6 
Removal of market 
authorization of study drug 
and commercial availability 
as reason for premature 
study termination 
To reflect that commercial availability of study drug does not impact 
study duration. 
2; 11.2  
The justification for sample 
size is updated 
To clarify that the sample size is based on enrollment and eligible 
subject completion in ISEE2008 

 
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3; 10.2 
Specified “as applicable” 
for ocular assessments at 
Month 12 and Month 18 
performed pre-injection on 
both eyes (OU) 
To provide clarity on pre-injection ocular assessments, given that there 
is no injection at Month 18 
3 
A cross-reference to 
Appendix 17.1 for details 
on procedures for 
refraction and vision testing 
is added.  
To ensure understanding of study procedures.  
3; 10.2  
The requirement to perform 
a full ophthalmic evaluation 
at 0 to 5 minutes post-
injection is revised to an 
abbreviated exam.   
An abbreviated exam is adequate to monitor health of eye immediately 
post-injection.  
3; 7.2; 10.2 
The timepoints for 
performing Goldmann 
applanation tonometry are 
updated to pre- and post-
injection as applicable.  
To clarify the timepoints when this assessment is to be conducted.  
4.1 
Deletion of concluding 
paragraph of Section 4.1 
GA Disease State 
Overview 
To align with current state of unmet medical need 
4.1.2 
Revision of Section 4.1.2 
Unmet Medical Need  
To align with current state of unmet medical need 
4.2 
Description of 
avacincaptad pegol is 
updated 
To align with description in current IB 
4.4 
Updates to Section 4.4 
Completed and Ongoing 
Clinical Trials 
To reflect current information 

 
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4.5 
Clinical data cited in the 
trial rationale is updated to 
reflect current information.  
To provide current information.  
4.6 
A benefit/risk assessment 
is added. 
To summarize the benefits and risks of avacincaptad pegol based on 
current clinical data, and to meet the requirements of European Clinical 
Trial Regulation. The data in the benefit/risk assessment is updated but 
the overall benefit/risk ratio is not significantly changed compared to the 
benefit/risk statement in the most recent IMPD.  
6 
Added statement “This is 
an open-label, multicenter 
18-month extensions 
study.” 
For clarity on trial design and length of study 
6; 10.6 
The end of trial definition is 
added. 
To provide a clear definition of the end of the trial.  
9.1.1 
Avacincaptad pegol 
composition details 
updated 
For clarity and consistency with program level documents 
9.2 
The exclusion of previous 
treatment for CNV in study 
ISEE2008 is removed.  
To align with current requirements for study ISEE2008. Subjects treated 
for CNV in ISEE2008 are eligible for enrolling into ISEE2009. 
9.2 
The exclusion of any 
treatment with 
investigational agent(s) 
during the trial is removed.  
Placed in tabular format in Section 9.2.1 
9.2.1 
A table listing prohibited 
medications is added.  
To specify prohibited medications. Prohibited medications was absent 
from the original protocol 
10.1; 13.4 
References to waivers from 
individual protocol criteria 
are updated to clarify that 
waivers to the protocol, 
including inclusion and 
exclusion criteria, are not 
allowed.  
To preserve trial integrity.  

 
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10.3 
Vabysmo® (faricimab) is 
added as a treatment 
option for CNV. 
To reflect additional treatment option for CNV.  
10.4 
Treatment failure is added 
as an event qualifying for 
withdrawal from trial. 
Subjects with treatment failure should be withdrawn from trial to avoid 
continued exposure to ineffective treatment.  
10.5 
Study drug discontinuation 
section is added to 
describe circumstances 
when a subject may 
discontinue study 
treatment but remain on 
trial for safety evaluation.  
To continue to monitor safety of the subject and collect safety data in 
case of early discontinuation of study treatment.  
10.6 
Added subject study 
completion definition to the 
Section describing Trial 
Discontinuation.  
To clarify the definition of completed subject for analysis purposes.  
11.6 
New section Interim 
Analysis with reference to 
the SAP for details on 
interim analysis is added.  
The full description of interim analysis details is provided in the SAP as 
applicable.  
12.3 
Adverse Events of Special 
Interest are updated as 
follows: 
• Endophthalmitis 
• Ischemic optic 
neuropathy 
• Intraocular 
inflammation; any 
case of uveitis, 
retinal vasculitis or 
retinal vascular 
To add clarity to AESI definitions for the Investigator and to aid in 
management of AESI reporting; Ischemic optic neuropathy added as a 
new AESI to reflect current events included in safety signal monitoring. 

 
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occlusion occlusive 
vasculitis 
• IOP ≥ 30 mmHg at 30 
minutes post 
injection deemed 
clinically 
significant by the 
investigator 
• Transient vision loss 
of light perception  
immediately after 
injection 
• Elevation of IOP 
post-injection 
requiring 
surgical/procedural 
intervention (i.e., 
paracentesis; for 
instruction regarding 
paracentesis refer to 
Appendix 17.2) 
• BCVA decrease ≥30 
letters from 
Screening in the 
ISEE2009 Month 1 
Visit 
• CNV (exudative or 
nonexudative) in the 
SE 
 
Clarification of AESI 
handling for study eye 
versus fellow eye is also 
added.  

 
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12.6 
Included “or the female 
partner of a male patient”  
For clarity of pregnancy reporting requirements for the study. Reporting 
of pregnant partners was not specified in the original protocol. 
16 
Updated Signature Page to 
Sponsor Signatory 
To align with new sponsor standard format 
17.2 
Examination after 
intravitreal injection is 
updated from one to two 
minutes to zero to five 
minutes 
To allow operational flexibility in performing this assessment; to ensure 
consistency throughout document  
17.2 
Included “head” to describe 
optic nerve as part of the 
post-injection assessment 
of the Intravitreous 
Administration Protocol 
For clarity 
17.3 
A schematic of study visits 
is added.  
To ensure understanding of trial visit timing.  
17.4 
New section Protocol 
Amendment Summary of 
Changes added 
To align with new sponsor template 
Throughout 
Minor administrative-type 
changes were made, e.g., 
typos, formatting, definition 
of abbreviations and other 
continuity throughout the 
protocol.  
To provide clarification and proper interpretation of the protocol.  
 

Electronic Signature Page
Document Name: ISEE2009-protocol-incorp-subst-amend-01
Document Type - Subtype: Clinical - Study Report Appendices
Vault Document Number: VV-CLIN-061222 v1.0
Signed By:
Capacity: Therapeutic Area - Medical
Signature Date: 29-Feb-2024 14:39:55 GMT+0000
Signed By:
Capacity: Biostatistician
Signature Date: 29-Feb-2024 15:22:46 GMT+0000
PPD
PPD