A Phase 2 Randomized, Open-Label, Multicenter Study Evaluating Administration of Repeated Intravitreal Doses of ICON-1 in Patients With Choroidal Neovascularization Secondary to Age-related Macular Degeneration
Phase: PHASE2
Conditions: Choroidal Neovascularization, Wet Macular Degeneration
Sponsor: Iconic Therapeutics, Inc.

Protocol Title:  A Phase 2 Randomized, Open-Label, Multicenter Study Evaluating 
Administration of Repeated Intravitreal Doses of ICON-1 in Patients with Choroidal 
Neovascularization Secondary to Age-related Macular Degeneration 
 
Protocol date: 19 January 2018 
 
NCT Number: NCT03452527 

 
 
 
 
CLINICAL STUDY PROTOCOL 
 
PROTOCOL TITLE: 
A Phase 2 Randomized, Open-Label, Multicenter 
Study Evaluating Administration of Repeated 
Intravitreal Doses of ICON-1 in Patients with 
Choroidal Neovascularization Secondary to Age-
related Macular Degeneration 
PROTOCOL NUMBER: 
IT-004 
PHASE OF DEVELOPMENT: 
Phase 2 
INVESTIGATIONAL 
PRODUCT: 
human Immuno-conjugate 1 (ICON-1) 
INDICATION: 
Choroidal Neovascularization Secondary to Age-
related Macular Degeneration 
IND NUMBER: 
102,472 
SPONSOR: 
Iconic Therapeutics, Inc. 
7000 Shoreline Court 
Suite 270 
South San Francisco, CA 94080 
DATE OF PROTOCOL: 
Original:  
19 January 2018 
 
 
Confidentiality Statement 
The information in this document is confidential and will not be disclosed to others without 
written authorization from Iconic Therapeutics, Inc., except to the extent necessary to obtain 
informed consent from persons who are potential participants in the trial or their legal guardians, 
persons participating in the conduct of the trial, appropriate institutional review boards or 
independent ethics committees, or duly authorized representatives of the United States Food and 
Drug Administration (FDA) or national regulatory authority. 

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19 January 2018 
 
 
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1 
SPONSOR SIGNATURE PAGE 
This study will be conducted as outlined herein in accordance with current 
International Council for Harmonisation (ICH) guidelines, Good Clinical Practices 
(GCPs), the Declaration of Helsinki, and complying with the obligations and 
requirements of the Sponsor as listed in Title 21 of the United States Code of Federal 
Regulations. 
 
Approved by: 
 
_____________________________________ 
Wendy Murahashi, MD 
Medical Monitor 
 
 
_________________________ 
Date 
___________________________________ 
_________________________ 
Gabriela Burian, MD 
Chief Medical Officer 
Date 
 
 
 
___________________________________ 
_________________________ 
Debbi Kotlovker 
Biostatistician 
Date 
 
 
 

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2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Title: 
A Phase 2 Randomized, Open-label, Multicenter Study 
Evaluating Administration of Repeated Intravitreal Doses of 
ICON-1 in Patients with Choroidal Neovascularization 
Secondary to Age-related Macular Degeneration 
 
Protocol Number: 
IT-004 
 
I have read and understand all sections of this protocol and commit to conducting the study as 
outlined herein in accordance with the current International Council for Harmonisation (ICH) 
guidelines, Good Clinical Practices (GCPs) and the Declaration of Helsinki, and complying with 
the obligations and requirements of the Clinical Investigator and other requirements as listed in 
Title 21 of the United States Code of Federal Regulations and other applicable regulations.  
I agree to provide the Sponsor with accurate financial information to allow the Sponsor to submit 
complete and accurate certification and disclosure statements as required by applicable 
regulations. 
 
 
 
Principal Investigator’s Name (Printed) 
 
 
 
 
 
Principal Investigator’s Signature 
 
 
Date 
 

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3 
KEY ROLES AND CONTACTS 
Key roles and contact information may be updated by written notification to the clinical sites 
without a protocol amendment. 
Sponsor: 
 
Iconic Therapeutics, Inc. 
7000 Shoreline Court, Suite 270 
South San Francisco, CA 94080 
 
Medical Monitor: 
 
Wendy Murahashi, MD 
Medical Monitor 
 
Sponsor’s Responsible Medical 
Officer: 
 
Gabriela Burian, MD 
Chief Medical Officer 
  
 
 

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4 
PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Randomized, Open-label, Multicenter Study Evaluating 
Administration of Repeated Intravitreal Doses of ICON-1 in Patients 
with Choroidal Neovascularization Secondary to Age-related Macular 
Degeneration 
Protocol Number 
IT-004 
Study Phase 
Phase 2 
Study Sites 
Up to 10 centers located in the United States 
Study Objectives 
To evaluate the safety and efficacy of repeated intravitreal injections 
of ICON-1 0.6 mg administered as maintenance therapy or in 
combination with aflibercept (Eylea®) in patients with neovascular 
(wet) age-related macular degeneration (AMD). 
Study Design 
This is a signal-seeking, Phase 2, randomized, open-label, multicenter 
study to evaluate the safety and efficacy of repeated intravitreal 
injections of ICON-1 0.6 mg in patients with wet AMD who are naive 
to treatment for wet AMD in the selected study eye. 
Eligible patients will be randomly assigned to one of the following 
two treatment arms in the selected study eye in a 1:1 ratio:  
• ICON-1 Maintenance Therapy: Aflibercept (Eylea®) 
monthly during Months 0-2 and ICON-1 0.6 mg monthly 
during Months 2-4, then aflibercept retreatment up to every 8 
weeks as needed during Months 4-8, based on the retreatment 
criteria.   
• ICON-1 + AFL Combination Therapy: Aflibercept (Eylea®) 
monthly and ICON-1 0.6 mg monthly (administered 0-7 days 
after aflibercept) during Months 0-2, then aflibercept 
retreatment up to every 8 weeks as needed during Months 4-8, 
based on the retreatment criteria. 
Patients will receive up to three intravitreal injections in the study eye 
at each injection visit according to the patient’s assigned treatment 
arm.  
During Months 4-8, as needed aflibercept retreatment will be 
administered based on the following pre-specified criteria: 
• Clinically significant anatomical evidence of increased or 
persistent CNV activity (e.g., new or persistent fluid on OCT, 
leakage, hemorrhage on FA) compared to the previous 
scheduled visit, as determined by the investigator 

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Safety will be evaluated by means of occurrence of adverse events, 
clinical laboratory tests (serum chemistry, hematology, and 
coagulation), vital signs measurements, slit-lamp biomicroscopy, 
intraocular pressure (IOP), and dilated ophthalmoscopy. 
Pharmacodynamic and biological activity will be measured by means 
of BCVA by ETDRS, spectral-domain optical coherence tomography 
(sdOCT), optical coherence tomography angiography (OCT-A), color 
fundus photography (CFP), and fundus fluorescein angiography (FA). 
Immunogenicity will be evaluated by anti-drug antibodies (ADA).    
Patients (or their legally authorized representative) may choose to 
withdraw from the study for any reason at any time without prejudice. 
Study assessments for an Early Termination Visit should be 
conducted in the event a subject discontinues from the study 
prematurely. 
Study Duration 
Enrollment is anticipated to take approximately 6 months and patient 
participation will be approximately 10 months including screening, 
treatment and follow-up. 
Number of Patients 
Approximately 20 patients will be enrolled and randomized in the 
study (approximately 10 patients per treatment arm). 
Study Population 
Inclusion Criteria 
Patients must meet all of the following criteria to be included in the 
study: 
1. Verbal and written informed consent obtained from the subject or 
the subject’s legal representative (as applicable). 
2. Males or females of any race, ≥50 years of age. 
3. Clinical diagnosis of treatment-naïve, active primary CNV 
secondary to AMD in the study eye as determined by the 
Investigator.  
4. BCVA of 83 to 24 ETDRS letters (20/25 up to 20/320 Snellen 
equivalent) in the study eye at Screening. 
5. Study eye meets all of the following lesion characteristics at 
Screening as determined by the Investigator: 
a) Total lesion size <4 disc areas based on fundus fluorescein 
angiography (FA) and <10 mm2 on OCT-A 
b) CNV area is >50% of total lesion size based on FA 
6. Adequate clarity of ocular media and adequate pupillary dilation 
to permit good quality imaging of fundus in the study eye as 
determined by the Investigator. 

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7. If a woman of childbearing potential (WOCBP) (i.e., not 
postmenopausal for at least 2 years or not surgically sterile), must 
have a negative serum pregnancy test at Screening, and must use 
adequate birth control with their non-surgically sterile male 
sexual partner throughout the study. Adequate methods of birth 
control include hormonal contraceptives, intrauterine 
contraceptive device (IUD), condom with spermicide, 
contraceptive sponge with spermicide, diaphragm with 
spermicide and cervical cap with spermicide. 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from 
the study: 
1. Monocular patient or patient with BCVA of ≤35 letters (20/200 or 
worse Snellen equivalent) in the better seeing eye.  
2. CNV secondary to other causes in the study eye as determined by 
the Investigator. 
3. Any prior treatment of CNV or advanced AMD in the study eye 
(e.g., laser, pharmacological [e.g., anti-VEGF agents] or surgical 
treatment, or any investigational therapy), except for dietary 
supplements or vitamins. 
4. Presence in the study eye of suspected polypoid choroidal 
vasculopathy (PCV) and retinal angiomatous proliferation (RAP) 
lesion components, hemorrhagic pigment epithelial detachment 
(PED), retinal tears or rips, or vitelliform macular dystrophy as 
determined by the Investigator. 
5. History of recurrent CNV in the study eye as determined by the 
Investigator. 
6. Presence of any of the following lesion characteristics in the study 
eye as determined by the Investigator: 
a) Retinal hemorrhage area >50% of total lesion area based on 
FA 
b) Fibrosis area >50% of total lesion area based on FA 
c) Subfoveal scar, fibrosis or atrophy visible on sdOCT 
7. Chronic, uncontrolled glaucoma or ocular hypertension in the 
study eye defined as an IOP >25mmHg regardless of concomitant 
treatment with IOP-lowering medications.  
8. Previous participation in an investigational study of ICON-1. 
9. Known serious allergy to fluorescein sodium for injection in 
angiography.  

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10. Known hypersensitivity to aflibercept (Eylea®) or any of the 
excipients in Eylea®. 
11. History of intraocular or ocular surface surgery (including 
cataract surgery and YAG laser procedures) in the study eye 
within 3 months prior to Screening. 
12. History of vitrectomy in the study eye. 
13. For a patient receiving chronic anticoagulant treatment (e.g., 
patients with a history of cardiovascular/cerebrovascular diseases 
[events] or hospitalization due to such conditions), the patient is 
without confirmation of stable clotting time using the appropriate 
test (Prothrombin Time (PT), International Normalized Ratio 
(INR) (e.g., Coumadin), or activated partial thromboplastin time 
(aPTT) (e.g., Pradaxa)) over the last 6 months from the patient’s 
treating physician. Some agents do not require PT/INR/aPTT 
monitoring (e.g., aspirin, Eliquis (apixaban)).  
14. Hereditary or chronic hemorrhagic or coagulopathy conditions 
(i.e., hemophilia). 
15. Use of any investigational product or device within 30 days prior 
to Screening, or planned use of an investigational product or 
device during the study. Age-related Eye Disease Study 
(AREDS)-formulated vitamins (which have been under 
investigation) are allowed during the study. 
16. History or presence of other concurrent conditions deemed by the 
Investigator to be likely to impact the subject’s visual acuity in 
the study eye or to interfere with the interpretation of the study 
results, such as optic neuritis or atrophy (related to multiple 
sclerosis or other neurological disease), uveitis, or retinal 
vasculitis in the study eye. 
17. Presence of any other concurrent medical condition, including 
mental illness or substance abuse, deemed by the Investigator to 
be likely to interfere with a subject’s ability to provide informed 
consent, comply with monthly study visits and assessments, or 
interfere with the interpretation of the study results. 
18. Woman who is pregnant or lactating. 
Study Eye 
Determination 
The study eye is defined as the eye that meets all of the inclusion 
criteria and none of the exclusion criteria. If both eyes meet the 
criteria for entry, the eye with the worst BCVA will be selected as the 
study eye.  

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Investigational 
Product  
Investigational Product 
The investigational product is human Immuno-conjugate 1 (ICON-1). 
ICON-1 is a recombinant fusion protein that targets and binds to 
Tissue Factor (TF) overexpressing cells and suppresses the aberrant 
TF signaling that lies at the root of overly vascularized disease states 
like wet AMD. It is a dimeric antibody-like protein with a molecular 
weight of 157 kDa; each monomer has two functional domains joined 
by a linker. The targeting domain of ICON-1 is a mutated FVIIa 
protein conjugated to an Fc effector moiety of a human IgG1 
immunoglobulin.   
Test Article 
Administration 
Patients will be randomly assigned to one of two treatment arms in a 
1:1 ratio:  
• ICON-1 Maintenance Therapy: Aflibercept (2 mg/50 µL) 
monthly during Months 0-2 and ICON-1 0.6 mg (two 
injections of 0.3 mg [300 µg/100 µL]) monthly during Months 
2-4, then aflibercept up to every 8 weeks as needed during 
Months 4-8, based on retreatment criteria.   
• ICON-1 + AFL Combination Therapy: Aflibercept 
(2 mg/50 µL) monthly and ICON-1 0.6 mg (two injections of 
0.3 mg [300 µg/100 µL]) monthly during Months 0-2, then 
aflibercept up to every 8 weeks as needed during Months 4-8, 
based on retreatment criteria. 
Using aseptic technique, ICON-1 or aflibercept will be administered 
by first withdrawing vial contents through a 5-micron 19-gauge filter 
needle attached to a 1-cc tuberculin or Luer Lock syringe and then 
replacing the filter needle with a 30-gauge x ½ inch needle for the 
intravitreal injection. Adequate topical anesthesia and broad-spectrum 
microbicide will be given prior to injection.  
At treatment visits with two injections, both intravitreal injections 
will be administered on the same day. At treatment visits with three 
injections, the three intravitreal injections (first injection: aflibercept 
2 mg, second injection: ICON-1 0.3 mg, and third injection: ICON-1 
0.3 mg) may be administered on the same day OR the three injections 
may be administered across two separate days up to 7 days apart. If 
the three injections will be split across two days, the entire 0.6 mg 
dose of ICON-1 (two injections of 0.3 mg) must be administered on 
the same day.  
IOP will be measured before and after each injection. When multiple 
injections are administered on the same day, the second injection and 
the third injection (if applicable) will be administered following 
stabilization of IOP to the pre-injection level (i.e., within 5 mmHg of 

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the pre-injection IOP) AND a minimum of 30 minutes after the prior 
injection. 
Study Endpoints 
Primary Endpoint: 
• Change in choroidal neovascularization by FA and OCT-A 
over time  
Secondary Endpoints:  
• Time to progression of choroidal neovascularization growth 
• Change in Best Corrected Visual Acuity over time 
• Change in CST by sdOCT over time 
• Percent of patients with “dry retina” over time 
• Time to achieving “dry retina” 
• Time to retreatment during PRN aflibercept retreatment 
period  
• Percent of patients receiving PRN aflibercept retreatment over 
time 
Safety Endpoints: 
• Occurrence of ocular and systemic serious adverse events and 
adverse events 
• Changes in standard clinical laboratory tests (serum 
chemistry, hematology, coagulation) 
• Changes in vital signs and ophthalmic examinations 
• Systemic levels of ADA over time 
Statistical Analyses 
Statistical Methods 
All patients who receive ICON-1 will be considered evaluable and 
will be included in the analysis. This study is exploratory and its 
sample size is not determined by statistical power considerations. 
As descriptors of the two treatment arms, univariate data summaries 
will be provided. For ordinal and continuous endpoints, summary 
statistics will include number of patients, mean, median, standard 
deviation, minimum, and maximum. For categorical endpoints, 
summary statistics will include number of patients, frequency, and 
percentages. 
This Phase 2 trial is a signal-seeking trial to assess effects of ICON-1 
on the biology of the CNV complex. As such, the primary aim for the 

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assessment of biological activity in this trial is to delineate the 
functional and anatomical profiles of ICON-1 in terms of: 
• Function, as tracked through visual acuity and attendant 
treatment implications: 
− temporal changes in BCVA, as measured by actual 
mean changes in BCVA; percent of patients with 
BCVA gain post baseline; percent of patients with 
BCVA >20/40 and <20/200 post baseline; percent of 
patients who remain within BCVA severity level post 
baseline; 
− Signs of CNV activity, as measured by time to re-
treatment with aflibercept and percent of patients 
receiving aflibercept re-treatment 
• Anatomic, as tracked through physical (qualitative and 
quantitative) longitudinal changes in the eye that can be 
imaged through sdOCT, FA, CFP, and OCT-A: 
−  CNV complex changes; 
− Changes in CST;  
− Exudative and fluid changes; 
− Fibrosis/atrophy changes; 
− Retina layers integrity changes.  
Thus, the data analyses for assessing biological activity in this trial 
are geared towards descriptive multifactorial summaries. 
There are no interim analyses planned; however, patient clinical and 
safety data will be examined on an ongoing basis to ensure patient 
safety and compliance.  
 

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5 
TABLE OF CONTENTS 
TITLE PAGE .......................................................................................................................................... 1 
1 
SPONSOR SIGNATURE PAGE .................................................................................................... 3 
2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................................... 4 
3 
KEY ROLES AND CONTACTS ................................................................................................... 5 
4 
PROTOCOL SYNOPSIS ................................................................................................................ 6 
5 
TABLE OF CONTENTS .............................................................................................................. 13 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 17 
7 
ETHICS ......................................................................................................................................... 20 
7.1 
Institutional Review Board or Ethics Committee .............................................................. 20 
7.2 
Ethical Conduct of the Study ............................................................................................. 20 
7.3 
Subject Information and Consent ...................................................................................... 21 
8 
INTRODUCTION ........................................................................................................................ 22 
8.1 
Background ....................................................................................................................... 22 
8.2 
Study Rationale ................................................................................................................. 25 
9 
STUDY OBJECTIVES ................................................................................................................. 27 
10 INVESTIGATIONAL PLAN ....................................................................................................... 28 
10.1 
Overall Study Design and Plan ......................................................................................... 28 
10.2 
Study Sites ......................................................................................................................... 30 
10.3 
Discussion of Study Design, Including the Choice of Control Groups ............................. 30 
10.4 
Appropriateness of Measurements .................................................................................... 30 
11 STUDY POPULATION ............................................................................................................... 31 
11.1 
Target Population .............................................................................................................. 31 
11.2 
Inclusion Criteria ............................................................................................................... 31 
11.3 
Exclusion Criteria .............................................................................................................. 31 
11.4 
Study Eye Determination .................................................................................................. 33 
12 STUDY TREATMENTS .............................................................................................................. 34 
12.1 
Study Drug Dosage and Administration ............................................................................ 34 
12.1.1 
Investigational Product (ICON-1) ..................................................................... 34 
12.1.2 
Comparator Product .......................................................................................... 34 
12.1.3 
Test Article Administration............................................................................... 34 
12.2 
Study Drug Packaging, Labeling and Storage ................................................................... 35 
12.3 
Selection of Doses and Timing of Doses .......................................................................... 35 
12.4 
Criteria for Retreatment with Aflibercept ......................................................................... 35 
12.5 
Measurement of Study Drug Compliance ......................................................................... 36 
12.6 
Study Drug Accountability ................................................................................................ 36 
12.7 
Prior and Concomitant Therapy ........................................................................................ 36 
12.8 
Other Study Supplies ......................................................................................................... 37 
13 RANDOMIZATION AND MASKING ....................................................................................... 38 
13.1 
Enrollment and Subject Identification Numbers ............................................................... 38 
13.2 
Method of Assigning Patients to Treatment Arms ............................................................ 38 
13.3 
Masking ............................................................................................................................. 38 
14 STUDY PROCEDURES .............................................................................................................. 39 
14.1 
Visit 1: Screening (Day -14 to -1) ..................................................................................... 39 
14.2 
Visit 2: Baseline (Month 0/Day 0) .................................................................................... 40 
14.3 
Visit 3: Month 1 (Day 28 ±3 days) .................................................................................... 41 
14.4 
Visit 4: Month 2 (Day 56 ±3 days) .................................................................................... 42 
14.5 
Visit 5: Month 3 (Day 84 ±3 days) .................................................................................... 43 

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14.6 
Visit 6: Month 4 (Day 112 ±3 days) .................................................................................. 44 
14.7 
Visits 7-10: Months 5, 6, 7, 8 (Days 140, 168, 196, 224 ±3 days) .................................... 45 
14.8 
Visit 11: End of Study, Month 9 (Day 252 ±3 days) ......................................................... 46 
14.9 
Early Termination Visit ..................................................................................................... 46 
14.10 Unscheduled Visits ............................................................................................................ 47 
14.11 Subject Withdrawal from Treatment or Study .................................................................. 48 
14.11.1 
Handling of Withdrawals .................................................................................. 48 
14.11.2 
Replacements .................................................................................................... 49 
14.11.3 
Sponsor or Regulatory Agency Termination of the Study ................................ 49 
15 STUDY ASSESSMENTS ............................................................................................................. 50 
15.1 
Informed Consent .............................................................................................................. 50 
15.2 
Eligibility Assessment ....................................................................................................... 50 
15.3 
Demographic Data ............................................................................................................. 50 
15.4 
Medical, Surgical, and Ocular History .............................................................................. 50 
15.5 
Prior and Concomitant Therapy ........................................................................................ 51 
15.6 
Best-corrected Visual Acuity ............................................................................................ 51 
15.7 
Slit-lamp Biomicroscopy ................................................................................................... 51 
15.8 
Intraocular Pressure ........................................................................................................... 51 
15.9 
Dilated Ophthalmoscopy ................................................................................................... 52 
15.10 Color Fundus Photography ................................................................................................ 52 
15.11 Spectral-Domain Optical Coherence Tomography ........................................................... 52 
15.12 Optical Coherence Tomography Angiography ................................................................. 52 
15.13 Fundus Fluorescein Angiography ..................................................................................... 53 
15.14 Vital Signs ......................................................................................................................... 53 
15.15 Clinical Laboratory Evaluations ........................................................................................ 53 
15.16 Measurement of Plasma Anti-drug Antibodies ................................................................. 54 
15.17 Evaluation of Adverse Events ........................................................................................... 54 
15.17.1 
Definition of an Adverse Event......................................................................... 55 
15.17.2 
Serious Adverse Event ...................................................................................... 56 
15.17.3 
AE Severity ....................................................................................................... 56 
15.17.4 
Study Drug Causality ........................................................................................ 57 
15.17.5 
Adverse Event Reporting Procedures ............................................................... 57 
15.17.6 
Reporting Serious Adverse Events to Regulatory Agencies ............................. 58 
15.17.7 
Pregnancy .......................................................................................................... 58 
15.17.8 
Overdose ........................................................................................................... 59 
15.17.9 
Follow-up of Adverse Events............................................................................ 59 
15.17.10 Follow-up of Post-study Serious Adverse Events ............................................. 59 
16 STUDY ENDPOINTS .................................................................................................................. 60 
16.1 
Primary Endpoints ............................................................................................................. 60 
16.2 
Secondary Endpoints ......................................................................................................... 60 
16.3 
Safety Endpoints: .............................................................................................................. 60 
17 STATISTICAL ANALYSIS AND METHODS PLANNED ....................................................... 61 
17.1 
Statistical Analysis Plans ................................................................................................... 61 
17.2 
Analysis of the Conduct of the Study ................................................................................ 61 
17.3 
Handling of Dropouts or Missing Data ............................................................................. 62 
17.4 
Analysis of Treatment Arm Comparability ....................................................................... 62 
17.5 
Treatment Exposure .......................................................................................................... 62 
17.6 
Safety Analyses ................................................................................................................. 62 
17.7 
Analyses of pharmacodynamics effects ............................................................................ 62 
17.8 
Immunogenicity Analyses ................................................................................................. 64 

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17.9 
Interim Analysis ................................................................................................................ 64 
17.10 Sample Size Determination ............................................................................................... 64 
18 DATA HANDLING AND RECORD KEEPING ......................................................................... 65 
18.1 
Case Report Forms and Source Documents ...................................................................... 65 
18.2 
Monitoring of the Study .................................................................................................... 65 
18.3 
Data Management.............................................................................................................. 66 
18.4 
Inspection of Records ........................................................................................................ 66 
18.5 
Study Record Retention ..................................................................................................... 67 
19 ADMINISTRATIVE CONSIDERATIONS ................................................................................. 68 
19.1 
Confidentiality ................................................................................................................... 68 
19.2 
Amendments to the Protocol ............................................................................................. 68 
19.3 
Protocol Deviations ........................................................................................................... 68 
19.4 
Study Reporting Requirements ......................................................................................... 69 
19.5 
Financial Disclosure .......................................................................................................... 69 
19.6 
Investigator Responsibilities ............................................................................................. 69 
19.7 
Clinical Trial Agreement ................................................................................................... 69 
19.8 
Policy for Publication and Presentation of Data ................................................................ 69 
20 REFERENCES .............................................................................................................................. 70 
21 APPENDICES .............................................................................................................................. 72 
21.1 
Appendix A:  Study Flowchart and Assessments .............................................................. 73 
21.2 
Appendix B:  Study Treatment Flowchart ......................................................................... 75 
21.3 
Appendix C: Retreatment Criteria ..................................................................................... 76 
21.4 
Appendix D: Retreatment Decision Tree .......................................................................... 77 
 
 
 

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LIST OF IN-TEXT TABLES 
Table 1:  Categories of Severity for Adverse Events .................................................................... 57 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Study Design Schema.................................................................................................... 29 
 

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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
anti-drug antibodies 
AE 
adverse event 
AFL 
ALT 
aflibercept 
alanine aminotransferase 
AMD 
age-related macular degeneration 
aPTT 
activated partial thromboplastin time 
AREDS 
Age-related Eye Disease Study 
AST 
aspartate aminotransferase 
BCVA 
best-corrected visual acuity 
BUN 
blood urea nitrogen 
CFP 
color fundus photography 
CNV 
choroidal neovascularization 
CO2 
carbon dioxide 
CPK 
creatine phosphokinase 
CrCl 
creatinine clearance 
CRO 
Contract Research Organization 
CST 
central retinal subfield thickness 
DMP 
Data Management Plan 
EC 
ethics committee 
eCRF 
electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
fundus fluorescein angiography 
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FVIIa 
activated Factor VII 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
Hct 
hematocrit 
Hgb 
hemoglobin 

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ICON-1 
human Immuno-conjugate 1 (ICON-1) 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgG 
immunoglobulin G 
INR 
International Normalized Ratio 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IVT 
intravitreal 
kDa 
kilodaltons 
LDH 
lactic dehydrogenase 
MAb 
monoclonal antibody 
MCV 
mean corpuscular volume 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
μg 
microgram 
mg 
milligram 
mL 
milliliter 
MPV 
mean platelet volume 
NK 
natural killer 
OCT-A 
optical coherence tomography angiography 
OTC 
over-the-counter 
OU 
both eyes 
PCV 
polypoid choroidal vasculopathy 
PED 
pigment epithelial detachment 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PRN 
pro re nata, as needed 
PT 
Prothrombin Time 
RAP 
retinal angiomatous proliferation 
RBC 
red blood cell 

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RDW 
red cell distribution volume 
RPE 
retinal pigment epithelium 
SAD 
single ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
sdOCT 
spectral-domain optical coherence tomography 
SE 
study eye 
TF 
tissue factor 
TEAE 
treatment emergent adverse event 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
WOCBP 
women of child-bearing potential 
YAG 
yttrium-aluminum-garnet 
 
In this protocol, Sponsor duties refer to responsibilities that will be performed by the Sponsor, 
the Sponsor’s designee or the Sponsor’s designated CRO. In this protocol, Investigator refers to 
the Principal Investigator or his/her designee who is responsible for performing study 
evaluations. 

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7 
ETHICS 
7.1 
Institutional Review Board or Ethics Committee 
The protocol, Investigator’s Brochure, informed consent form (ICF), advertisements to be used 
for patient recruitment, and any other written information provided to patients for this study, 
including all consent forms translated to a language other than the native language of the clinical 
site must be approved by the Investigator’s Institutional Review Board (IRB) or Ethics 
Committee (EC) before the study is initiated at a site. Documentation of this approval must be 
maintained by the clinical site and provided to the Sponsor (or designee) and must be made 
available during an inspection by the US Food and Drug Administration (FDA) or other 
regulatory agency inspectors. Prior to initiating the study, the Investigator will obtain written 
confirmation that the IRB/EC is properly constituted and compliant with International Council 
for Harmonisation (ICH) and Good Clinical Practice (GCP) requirements, and all applicable 
laws and local regulations. 
The study will not be initiated at a given clinical site until documentation confirming approval of 
the protocol, ICF, and any written materials supplied to the patient are received by the Sponsor 
or its designee. Approval documentation from the IRB/EC should be signed by the IRB/EC 
chairperson or designee, identify the IRB/EC by name and address, refer to the study protocol by 
title and/or protocol number and version or date, identify documents reviewed, and include the 
date of the review and approval or favorable opinion was granted.   
Appropriate reports on the progress of the study will be made to the IRB/EC and to the Sponsor 
(or designee) by the Investigator in accordance with applicable governmental regulations and 
local regulations, and in agreement with policies of the IRB/EC. The Investigator must provide 
written documentation of the following to the Sponsor (or designee): 
• IRB/EC periodic (e.g., semi-annually, annually) re-approval of the protocol as required 
by the site’s IRB/EC 
• IRB/EC approvals of any amendments to the protocol or revisions to the ICF 
• IRB/EC receipt of safety and SAE reports, as appropriate 
• Any additional submissions (including an end of study report) required by the site’s 
IRB/EC 
7.2 
Ethical Conduct of the Study 
This study will be conducted in compliance with GCP as described in FDA regulations (21 CFR 
parts 11, 50, 54, 56, and 312), the ICH document “Guidance for Good Clinical Practice, E6 
(R2),” and the principles of the World Medical Association Declaration of Helsinki – Ethical 
Principles for Medical Research Involving Human Subjects, including all amendments and Notes 
of Clarification. The Investigator is expected to comply with the requirements of the protocol, 
and will conduct all aspects of this study in accordance with all national, state, and local laws or 
regulations. 

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7.3 
Subject Information and Consent 
Written informed consent in compliance with FDA regulations (21 CFR 50.25), the ICH 
document “Guideline for Good Clinical Practice, E6 (R2),” and other applicable local regulations 
shall be obtained from each patient prior to entering the study or performing any study related 
procedure. An ICF template will be provided by the Sponsor (or designee) to clinical sites. The 
ICF will be submitted by the Investigator to his or her IRB/EC for review and approval prior to 
the start of the study. If any modifications to the content are proposed or made by the site, the 
ICF should be reviewed by the Sponsor (or designee) prior to IRB/EC submission. 
The investigator is responsible for obtaining written informed consent from each patient 
participating in the study. If there are any revisions to the ICF during the course of the study, all 
active participating patients must be re-consented using the revised ICF in a timely fashion.   
Informed consent must be obtained from the patient before any study related screening activity 
or treatment is undertaken that is not part of routine care. This includes, but is not limited to, the 
performance of diagnostic or therapeutic procedures and the administration of the first dose of 
the study treatment. All pertinent aspects of the study must be explained to the prospective 
patient and/or the patient’s legally authorized representative before signing the ICF. The patient 
and/or patient’s legally authorized representative will be informed that participation is voluntary 
and he/she can withdraw from the study at any time. The patient and/or patient’s legally 
authorized representative will be allowed to read the IRB/EC approved ICF. Once the 
Investigator or designee is assured the patient/patient’s legally authorized representative agrees 
to participate in the study, the patient/legally authorized representative will be asked to give 
consent by signing the ICF. The ICF must be signed and dated by the patient or by the patient’s 
legally authorized representative, and by the person who conducted the informed consent 
discussion, and witness (if required). The Investigator shall provide a copy of the signed and 
dated ICF to the patient/patient’s legally authorized representative. The original shall be 
maintained in the patient’s medical records at the site. This document should not be displayed or 
made accessible to any third party except the Sponsor, its designee or regulatory agency 
representatives. 
If a patient permanently revokes informed consent and declines further observation and/or 
contact, then this must be clearly documented in the patient’s chart and recording of further data 
will be discontinued. 

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8 
INTRODUCTION 
8.1 
Background 
Age-related macular degeneration (AMD) refers to the chronic, progressive degenerative 
pathology of the macula that results in loss of central vision. According to the Macula Vision 
Research Foundation and the National Eye Institute, as many as fifteen million people in the 
United States suffer from some form of AMD, with similar numbers in Europe and other 
continents. Neovascular AMD (also referred to as exudative or “wet” AMD) is the leading cause 
of severe vision loss and blindness in elderly patients over the age of fifty in the industrialized 
world. In the United States alone, more than 1.5 million people suffer from neovascular AMD 
[1]. It is expected that the AMD incidence and prevalence will further increase with the ageing 
population, thus leading to a significant increase in the number of patients with wet AMD in the 
United States and worldwide. 
AMD has been at the forefront of research in ophthalmology in recent years and significant 
advances were made in the understanding, diagnosis and treatment of the disease. Vascular 
endothelial growth factor (VEGF) has been shown to be a potent stimulator of angiogenesis and 
vascular permeability in the etiology of choroidal neovascularization (CNV) due to AMD [2]. 
The role of the VEGF has been also clinically demonstrated through the recently developed anti-
VEGF therapies which have been successful in substantially improving central visual function in 
approximately one third of the treated patients and stopping severe vision loss in the majority of 
patients [3,4]. The biological anti-VEGF therapies have thus become the currently approved 
standard of clinical care for neovascular AMD.  
However, due to the multifaceted aspects of the AMD pathogenesis [5], targeting VEGF alone is 
likely insufficient to modify or halt the progression of the disease towards the advanced CNV-
associated degenerative processes. Supporting evidence of immune dysfunction is increasingly 
growing and potent pro-angiogenic signaling via macrophages that exacerbate CNV 
pathogenesis have been reported [6,7]. Therefore, beyond blocking neovascular growth and 
leakage, an improved therapy should aim to target additional aspects and mechanisms involved 
in the CNV biology.  
Angiogenesis research first suggested that Tissue Factor (TF) may be implicated in the 
pathophysiology of neovascular AMD. TF was shown to be expressed in retinal pigment 
epithelial (RPE) cells and macrophages of both post-mortem and surgically excised CNV 
specimens, with increased staining in “inflammatory-active” versus “inflammatory-inactive” 
lesions [8]. The potential role of TF in CNV formation was further indicated in human diabetic 
retinas in which TF was associated with pathological neovessels but not with normal capillaries 
[9]. In addition to being the key initiator of coagulation, TF was shown to have other major 
biological functions: TF signaling induces angiogenesis by upregulating VEGF and is involved 
in the inflammatory cascade of cytokine release, both key processes that underlie CNV 
pathogenesis [10]. Increased expression of intraocular TF was demonstrated in AMD eyes versus 
non-AMD eyes and further supports the association with CNV pathogenesis [11]. This collective 
evidence provides the scientific rationale that TF is potentially an important therapeutic target for 
CNV, the pathophysiologic hallmark of wet AMD.  

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Therapeutic proteins are molecules that bind selectively to disease-causing or disease-related 
targets and remove them or their related effect in the affected tissue. They are designed to 
preferentially target pathological cells on which these targets are present at considerably higher 
levels than on normal cells. A well-known example of such a therapeutic protein that targets 
pathological cells through this mechanism is Herceptin®
 
(Genentech/ Roche), a monoclonal 
antibody (MAb) treatment for breast cancer. Herceptin binds to a receptor that is over-expressed 
only on the surface of certain breast cancer cells. 
Iconic Therapeutics, Inc. has developed one such therapeutic protein known as ICON-1 to target 
TF. ICON-1 is a recombinant fusion protein, an Icon molecule (abbreviation for 
Immunoconjugate), a term known to describe an antibody-like protein that has two functional 
domains, one targeting and one effector domain, joined by a linker. The targeting moiety of 
ICON-1 is a mutated factor VIIa (FVIIa) protein conjugated to a Fc effector moiety of a human 
IgG1 immunoglobulin [12]. The physiological role of factor VIIa is to function as an initiator of 
the clotting cascade and begin the clotting process when binding to TF. In ICON-1, however, 
factor VIIa has been mutated such that it is defective as a clotting signal, but retains its specific 
high affinity for TF.  
The mechanism through which ICON-1 is thought to affect the endothelial cells of the 
neovascular complex is probably twofold, thus the therapeutic potential is derived from both 
“protein partners” that are fused in the molecule. Firstly, via the FVIIa targeting moiety, ICON-1 
binds to the TF expressed on the surface of endothelial cells of the CNV interfering with TF’s 
intracellular signaling and its function of inducing angiogenesis and mediating inflammation. 
Secondly, the TF-bound ICON-1 molecule, through its Fc effector region, signals the immune 
system to attract natural killer (NK) cells and initiate a cell-mediated cytotoxicity towards the 
CNV endothelial cells. Thus, in contrast to anti-VEGF agents (such as aflibercept, Eylea®, 
Regeneron/ Bayer) this capability to bind directly with the CNV pathologic biology differentiates 
ICON-1 from these agents and offers a novel therapeutic approach for the treatment of 
neovascular AMD. 
In summary, the neovascular changes that occur in the chorioretinal tissue of patients affected by 
wet AMD constitute a significant pathology to target the overexpressed TF and the properties of 
the ICON-1 molecule, as a targeted immunoprotein, meet the requirements to target the 
choroidal neovascularization-expressed TF. This provides the scientific rationale to evaluate the 
potential of ICON-1 as a therapeutic molecule to affect the CNV pathology. 
The toxicity, safety and tolerability, as well as the efficacy of Icon molecules have been 
evaluated to date in 12 preclinical studies, including wet AMD animal models and four Good 
Laboratory Practice (GLP) toxicology studies; a Phase 1 single ascending dose (SAD) study in 
patients with wet AMD; a Phase 2 repeated dose study in patients with wet AMD; and a Phase 1 
single or repeated dose study in patients with uveal melanoma. A summary of these studies and 
their results is detailed below. 
Preclinical and Toxicity Studies 
The preclinical studies were designed to generate evidence in support of the initial therapeutic 

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indication for ICON-1, namely CNV due to AMD (wet AMD). Because the reaction between 
FVIIa and TF is species-restricted [13-15], both a human (ICON-1) and a murine (mIcon), 
consisting of mutated mFVIIa fused to human IgG1Fc, [16] molecule have been made and used 
to test efficacy in animal models. In each case the active site of the FVIIa moiety has been 
inactivated by mutation of Lys341 to Ala341 to inhibit initiation of the coagulation pathway 
without reduction in the affinity to TF ([17]. Efficacy studies were conducted in wet AMD 
models in mice (using mIcon) and pigs (using ICON-1) and a decrease in lesion size and 
neovascularization was observed in both species.  
GLP toxicology studies were conducted with ICON-1 in pigs and rabbits. Clinical observations 
did not reveal systemic changes nor alteration and laboratory parameters. There was no drug 
effect on ocular tonometry or electroretinogram and no macroscopic finding at necropsy. 
Immunogenicity was observed in most animals, which is expected when performing repeat 
dosing with a human protein in these species. In addition to the toxicology studies, a non-GLP 
ocular toxico-kinetic study was performed in rabbits to assess ocular pharmacokinetic parameters 
following IVT administration of ICON-1 at 300 µg or 600 µg. Administration of 600 µg of 
ICON-1 resulted in higher concentrations in the ocular and plasma compartment than what was 
observed for the 300 µg dose. Within the dose range and dosing frequency examined, ICON-1 
pharmacokinetics (PK) appears to be dose linear. 
The preclinical efficacy, safety and toxicity models results were the basis for conducting a first-
in-human single ascending dose Phase 1 study in patients with wet AMD. A single IVT dose of 
up to 300 μg of ICON-1 was considered to be reasonably safe for a period of 2 to 4 weeks. 
Clinical Studies 
In clinical studies conducted by Iconic Therapeutics, a total of 88 patients have received 
treatment with ICON-1. Seventy-eight (78) patients with wet AMD have been administered 
0.3 mg ICON-1 as single or repeated doses, as monotherapy or in combination with other 
therapies (studies IT-001 and IT-002); and ten (10) patients with uveal melanoma have been 
administered up to 0.6 mg ICON-1 as single or repeated doses one week apart (study IT-003)  
The Phase 1 study (IT-001), was an open-label, single intravitreal (IVT) dose, dose-escalating 
study in 18 patients with CNV due to AMD, including both treatment-naïve patients and patients 
previously treated with chronic anti-VEGF therapy. The safety results showed that ICON-1 was 
safe at all doses tested (0.06 mg, 0.15 mg, and 0.3 mg), and there were no systemic or ocular 
dose limiting toxicities. The serum PK results determined that the systemic absorption of ICON-
1 after a single IVT injection was below the limit of quantification in the majority of patients. 
None of the patients developed detectable anti-drug antibodies up to 12 weeks after receiving an 
IVT injection of up to 0.3 mg of ICON-1. In conclusion, the safety, tolerability and biologic 
activity outcomes established in the completed Phase 1 study were shown to be consistent with 
the preclinical evaluations and supported the further evaluation of the ICON-1 molecule in a 
Phase 2 study.  
The Phase 2 study (IT-002) was a signal-seeking, randomized, double-masked, active-controlled 
study to evaluate the safety and biological activity of repeated IVT injections of ICON-1 0.3 mg 

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in 88 patients with CNV secondary to AMD who were naïve to treatment for CNV in the study 
eye. Patients were randomly assigned to one of three treatment arms (ICON-1 + ranibizumab 
combination therapy, ICON-1 monotherapy + sham injection, or ranibizumab monotherapy + 
sham injection), and received up to 6 monthly administrations of study treatment over a 5-month 
dosing period, with one month of follow up.  
The safety results showed that there were no unexpected ocular and non-ocular safety signals 
with IVT ICON-1 injection administered in monotherapy or in combination with ranibizumab, in 
repeated doses of 0.3 mg up to 6 months. The ICON-1 + ranibizumab combination therapy arm 
had a greater decrease in the CNV lesion size than ranibizumab alone or ICON-1 alone. In 
addition, the mean time from treatment end until the first re-treatment needed was longer in 
patients in the ICON-1 + ranibizumab combination therapy arm than in the ranibizumab 
monotherapy and ICON-1 monotherapy arms. The study met its endpoint to explore the safety of 
ICON-1 0.3 mg as a Tissue Factor antagonist leading to CNV lesion modification and supports 
further study of ICON-1 in higher doses. 
A Phase 1 study in uveal melanoma (IT-003) was an open-label, sequential-group study to 
evaluate the safety, tolerability, biological activity, pharmacokinetics, and pharmacodynamic 
activity of single and repeated escalating intravitreal injections of ICON-1 in 10 patients with 
primary uveal melanoma scheduled to undergo enucleation or brachytherapy. Patients were 
enrolled and administered ICON-1 in one of three dosing cohorts (single dose of 0.3 mg, 
repeated doses of 0.3 mg one week apart, or repeated doses of 0.6 mg one week apart). The 
safety results showed that intravitreal ICON-1 administered as single or repeated doses of up to 
0.6 mg over one week was well tolerated with no notable safety signals observed. 
8.2 
Study Rationale 
The initial Phase 1 study has shown that a single IVT dose of ICON-1 up to 0.3 mg was well 
tolerated and safe in both naïve and previously treated wet AMD patients. The follow-up Phase 2 
study has shown that repeated IVT doses of ICON-1 0.3 mg were well-tolerated and safe in 
treatment naïve wet AMD patients. Additionally, a Phase 1 study in ocular melanoma patients 
has shown that single or repeated IVT doses of ICON-1 up to 0.6 mg were well tolerated. These 
outcomes provide support to further explore a higher dose in both a maintenance and 
combination dosing regimen of 0.6 mg IVT ICON-1 in this Phase 2 study. The safety 
assessments and endpoints are based on both ocular (adverse events, description and follow up of 
the ocular events, such as inflammation) and systemic (adverse events, follow up and description 
of systemic events) clinical safety outcomes. In addition, the immunogenicity evaluation of the 
presence of anti-ICON-1 antibodies in the systemic circulation will be performed.  
The response to the application of ICON-1 in animal models of CNV showed that the CNV 
membranes were no longer visible in the tested animal models in a dose-response fashion, in 
addition to reduced leakage. This observed result is different from the effects produced by the 
anti-VEGF class of drugs alone. In addition to supporting the role of TF as a target in the 
pathogenic cascade of CNV, it also supports the hypothesis of a novel mechanism of action of 
ICON-1 beyond that of anti-VEGF alone, likely via both the inflammatory and immune-
mediated patho-mechanisms. To evaluate how the different mechanism may translate into 

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different biological activity and clinical outcomes, in this Phase 2 study, ICON-1 will be dosed 
as either maintenance or combination therapy with an anti-VEGF agent. 
The biological activity and the pharmacodynamic effect will be measured using both functional 
and anatomical assessments. The anatomical outcomes, in addition to the quantitative measure of 
the central retinal subfield thickness CST change, are an important element of understanding the 
differences in treatment effect and the biologic activity of ICON-1 vs. anti-VEGF (in 
maintenance or in combination). Therefore, an assessment of qualitative anatomical features of 
the CNV complex will also be performed. This Phase 2 study will aim to provide proof of 
concept of the translation of the mechanism of action of ICON-1 by comparing not only the 
reduction in fluid amount, leakage and CNV size, but also additional qualitative anatomical 
features to understand the new and/or additional mechanism of ICON-1 in affecting the CNV 
over time, such as signs of CNV activity and progression of the lesion, dimensions, and other 
morphological characteristics in the chorioretinal space. The anatomical markers will be 
collected via standard practice imaging techniques (color fundus photography [CFP], fundus 
fluorescein angiography [FA], spectral-domain optical coherence tomography [sdOCT], optical 
coherence tomography angiography [OCT-A]).  
Based on historical evidence in treating CNV due to AMD with Eylea, after 3-monthly doses the 
clinical response to treatment can be assessed [20-22], therefore both treatment arms will initiate 
treatment in this study with 3 monthly aflibercept (Eylea®) IVT doses. After Month 3, patients 
remain in their treatment arm and continue to be treated and evaluated until Month 8. Starting at 
Month 4, aflibercept (Eylea®) may be administered based on the individual patient response to 
treatment. As has been observed in previous studies with anti-VEGF treatment administered as 
needed (pro re nata, PRN), after 3 initial injections, there are patients that have an optimal 
BCVA and CST response to treatment and do not require additional dosing for some period of 
time. 
The 9-month duration of the study is considered appropriate in naïve patients with wet AMD to 
demonstrate clinical proof of concept of clinical safety and biological activity. The second and 
final comparative evaluation of both safety and biological activity endpoints will be performed at 
the Month 9, end of study time point.  
To minimize the risk of severe wet AMD progression despite availability of efficacious standard 
of clinical care therapy, in cases in which clinical signs of AMD progression are observed, 
patients will have access to retreatment with standard of care aflibercept (Eylea®) therapy, as 
labeled, during the as needed observation period.  
 
 

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9 
STUDY OBJECTIVES 
The objectives of this study are to evaluate the safety and pharmacodynamics effects of repeated 
intravitreal injections of ICON-1 0.6 mg administered as maintenance therapy or in combination 
with aflibercept (Eylea®) in patients with neovascular (wet) age-related macular degeneration 
(AMD). 
 

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10 INVESTIGATIONAL PLAN 
10.1 
Overall Study Design and Plan 
This is a signal-seeking, Phase 2, randomized, open-label, multicenter study to evaluate the 
safety and pharmacodynamics effects of repeated intravitreal injections of ICON-1 0.6 mg in 
patients with wet AMD who are naive to treatment for wet AMD in the selected study eye.   
Eligible patients will be randomly assigned to one of the following two treatment arms in the 
selected study eye in a 1:1 ratio:  
• ICON-1 Maintenance Therapy: Aflibercept (Eylea®) monthly during Months 0-2 and 
ICON-1 0.6 mg monthly during Months 2-4, then aflibercept retreatment up to every 
8 weeks as needed during Months 4-8, based on the retreatment criteria.   
• ICON-1 + AFL Combination Therapy: Aflibercept (Eylea®) monthly and ICON-1 
0.6 mg monthly (administered 0-7 days after aflibercept) during Months 0-2, then 
aflibercept retreatment up to every 8 weeks as needed during Months 4-8, based on the 
retreatment criteria.  
During Months 0-4, patients will receive up to three intravitreal injections in the study eye at 
each injection visit according to the patient’s assigned treatment arm.  
At treatment visits with two injections, both intravitreal injections will be administered on the 
same day. At treatment visits with three injections, the three intravitreal injections (first 
injection: aflibercept 2 mg, second injection: ICON-1 0.3 mg, and third injection: ICON-1 0.3 
mg) may be administered on the same day OR the three injections may be administered across 
two separate days up to 7 days apart. If the three injections will be split across two days, the 
entire 0.6 mg dose of ICON-1 (two injections of 0.3 mg) must be administered on the same day. 
During Months 4-8, as needed aflibercept retreatment will be administered based on the 
following pre-specified criteria:  
• Clinically significant anatomical evidence of increased or persistent CNV activity (e.g. 
new or persistent fluid on OCT, leakage or hemorrhage on FA) compared to the previous 
scheduled visit, as determined by the Investigator 
 
Safety will be evaluated by means of occurrence of adverse events, clinical laboratory tests 
(serum chemistry, hematology, and coagulation), vital signs measurements, slit-lamp 
biomicroscopy, intraocular pressure (IOP), and dilated ophthalmoscopy. Pharmacodynamic and 
biological activity will be measured by means of BCVA by ETDRS, color fundus photography 
(CFP), spectral-domain optical coherence tomography (sdOCT), optical coherence tomography 
angiography (OCT-A), and fundus fluorescein angiography (FA). Immunogenicity will be 
evaluated by means of measuring plasma anti-drug antibodies. 

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Patients (or their legally authorized representative) may choose to withdraw from the study for 
any reason at any time without prejudice. Study assessments for an Early Termination Visit 
should be conducted in the event a subject discontinues from the study prematurely. 
Figure 1: Study Design Schema 
 
 
 
 
 
 
 
 
 
 
 
 
Months 0-1 
 
 
Month 2 
 
 
Months 3-4 
 
 
Months 4-8 
 
 
 
 
Screening  
(within 14 days prior to Baseline) 
End of Study (Month 9) 
or 
Early Termination 
 
ICON-1 0.6 mg + AFL 2mg q4wk 
ICON-1 Maintenance Therapy 
AFL 2 mg q4wk X 3 months,  
then ICON-1 0.6 mg q4wk X 3 months 
(n=10) 
ICON-1 + AFL Combination Therapy 
ICON-1 0.6 mg + AFL 2 mg 
q4wk X 3 months 
(n=10) 
 
AFL 2 mg q4wk 
 
ICON-1 0.6 mg + AFL 2 mg q4wk 
  
ICON-1 0.6 mg q4wk 
Baseline 
(Day 0) 
1:1 Randomization (n=20) 
Retreatment with AFL 2 mg up to every 8 weeks as needed based on retreatment criteria 
(monthly study visits) 
 
ICON-1 0.6 mg + AFL 2 mg q4wk 

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10.2 
Study Sites 
Up to 10 centers located in the US will participate in this study.   
10.3 
Discussion of Study Design, Including the Choice of Control Groups 
In this Phase 2 Proof of Concept study, the safety and pharmacodynamics effects of ICON-1 
maintenance or combined with an anti-VEGF (aflibercept) will be evaluated. Anti-VEGF therapy 
is the current treatment of choice for CNV secondary to AMD. Aflibercept binds VEGF reducing 
vascular leakage and new blood vessel formation. In contrast to anti-angiogenic agents, ICON-1 
binds directly to specific receptors that are over expressed on the endothelial cells of pathologic 
vasculature and thus may change the biological characteristics of the choroidal neovascular 
complex. This capability to interfere directly with the growth and possibly lead to the destruction 
of the existing pathologic vessels differentiates ICON-1 from the anti-angiogenic agents and 
offers a novel therapeutic approach for the treatment of neovascular, wet AMD. 
Randomization will be used in the study to minimize bias in patient selection and treatment 
assignments but treatment assignments will not be masked. The study duration of 9 months is 
considered to be an adequate treatment and follow up period to assess safety and biologic 
activity of the treatments in patients with treatment-naïve CNV secondary to AMD. 
10.4 
Appropriateness of Measurements 
The choice of safety and biological activity parameters of pharmacodynamics effect to be 
evaluated in this study reflect experience in the non-clinical studies and the completed human 
Phase 1 and Phase 2 clinical trials, including two previous studies in CNV secondary to AMD. 
The immunogenicity assessment in this study is used widely and is generally recognized as 
reliable, accurate, and relevant. 
The primary aim for data analyses in this trial is to characterize the anatomical outcomes after 
ICON-1 administration as assessed by fundus fluorescein angiography (FA) and optical 
coherence tomography angiography (OCT-A) over time. Secondary aims include evaluation of 
the functional and anatomical outcomes after ICON-1 administration as measured by BCVA and 
imaging markers of the retina and subretinal space (via sdOCT and CFP) to longitudinally assess 
changes in the features of the CNV complex, exudative changes, fibrotic and atrophic, and other 
morphology changes over time compared to baseline. 

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11 STUDY POPULATION 
11.1 
Target Population 
The target population for this study is treatment-naïve men and women age 50 years and older 
with a diagnosis of active primary CNV secondary to AMD. The defined population is further 
characterized by parameters of disease characteristics and clinical status that are within the 
severity range that is thought to be reversible and will enable the evaluation of a biological 
response to ICON-1.   
11.2 
Inclusion Criteria 
Patients must meet all of the following criteria to be included in the study: 
1. 
Verbal and written informed consent obtained from the subject or the subject’s legal 
representative (as applicable). 
2. 
Males or females of any race, ≥50 years of age. 
3. 
Clinical diagnosis of treatment-naïve, active primary CNV secondary to AMD in the study 
eye as determined by the Investigator. 
4. 
BCVA of 83 to 24 ETDRS letters (20/25 to 20/320 Snellen equivalent) in the study eye at 
Screening. 
5. 
Study eye meets all of the following lesion characteristics at Screening as determined by the 
Investigator: 
a) Total lesion size <4 disc areas based on fundus fluorescein angiography (FA) and 
<10 mm2 on OCT-A 
b) CNV area is >50% of total lesion size based on FA 
6. 
Adequate clarity of ocular media and adequate pupillary dilation to permit good quality 
imaging of fundus in the study eye as determined by the Investigator. 
7. 
If a woman of childbearing potential (WOCBP) (i.e., not postmenopausal for at least 2 years 
or not surgically sterile), must have a negative serum pregnancy test at Screening, and must 
use adequate birth control with their non-surgically sterile male sexual partner throughout 
the study. Adequate methods of birth control include hormonal contraceptives, intrauterine 
contraceptive device (IUD), condom with spermicide, contraceptive sponge with 
spermicide, diaphragm with spermicide and cervical cap with spermicide. 
 
11.3 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. 
Monocular patient or patient with BCVA of ≤35 letters (20/200 or worse Snellen equivalent) 
in the better seeing eye.  

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2. 
CNV secondary to other causes in the study eye as determined by the Investigator. 
3. 
Any prior treatment of CNV or advanced AMD in the study eye (e.g., laser, 
pharmacological [e.g., anti-VEGF agents] or surgical treatment, or any investigational 
therapy), except for dietary supplements or vitamins. 
4. 
Presence in the study eye of suspected polypoid choroidal vasculopathy (PCV) and retinal 
angiomatous proliferation (RAP) lesion components, hemorrhagic pigment epithelial 
detachment (PED), retinal tears or rips, or vitelliform macular dystrophy as determined by 
the Investigator. 
5. 
History of recurrent CNV in the study eye as determined by the Investigator 
6. 
Presence of any of the following lesion characteristics in the study eye as determined by the 
Investigator: 
a) Retinal hemorrhage area >50% of total lesion area based on FA 
b) Fibrosis area >50% of total lesion area based on FA 
c) Subfoveal scar, fibrosis or atrophy visible on sdOCT 
7. 
Chronic, uncontrolled glaucoma or ocular hypertension in the study eye defined as an IOP 
>25mmHg regardless of concomitant treatment with IOP-lowering medications.  
8. 
Previous participation in an investigational study of ICON-1 
9. 
Known serious allergy to fluorescein sodium for injection in fluorescein angiography.  
10. Known hypersensitivity to aflibercept (Eylea®) or any of the excipients in Eylea®. 
11. History of intraocular or ocular surface surgery (including cataract surgery and YAG laser 
procedures) in the study eye within 3 months prior to Screening. 
12. History of vitrectomy in the study eye. 
13. For a patient receiving chronic anticoagulant treatment (e.g., patients with a history of 
cardiovascular/cerebrovascular diseases [events] or hospitalization due to such conditions), 
the patient is without confirmation of stable clotting time using the appropriate test 
(Prothrombin Time (PT), International Normalized Ratio (INR) (e.g., Coumadin), or 
activated partial thromboplastin time (aPTT) (e.g., Pradaxa)) over the last 6 months from the 
patient’s treating physician. Some agents do not require PT/INR/aPTT monitoring (e.g., 
aspirin, Eliquis (apixaban)).  
14. Hereditary or chronic hemorrhagic or coagulopathy conditions (i.e., hemophilia). 
15. Use of any investigational product or device within 30 days prior to Screening, or planned 
use of an investigational product or device during the study. Age-related Eye Disease Study 
(AREDS)-formulated vitamins (which have been under investigation) are allowed during 
the study. 
16. History or presence of other concurrent conditions deemed by the Investigator to be likely to 
impact the subject’s visual acuity in the study eye or to interfere with the interpretation of 
the study results, such as optic neuritis or atrophy (related to multiple sclerosis or other 
neurological disease), uveitis, or retinal vasculitis 

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17. Presence of any other concurrent medical condition, including mental illness or substance 
abuse, deemed by the Investigator to be likely to interfere with a subject’s ability to provide 
informed consent, comply with monthly study visits and assessments, or interfere with the 
interpretation of the study results. 
18. Woman who is pregnant or lactating. 
 
11.4 
Study Eye Determination 
The study eye will be determined as the eye that meets all of the inclusion criteria and none of 
the exclusion criteria. If both eyes meet the criteria for entry, the eye with the worst BCVA will 
be selected as the study eye. 

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12 STUDY TREATMENTS 
12.1 
Study Drug Dosage and Administration 
12.1.1 Investigational Product (ICON-1) 
The investigational product is human Immuno-conjugate 1 (ICON-1). ICON-1 is a recombinant 
fusion protein that targets and binds to Tissue Factor (TF) overexpressing cells and suppresses 
the aberrant TF signaling that lies at the root of overly vascularized disease states like wet AMD. 
It is a dimeric antibody-like protein with a molecular weight of 157 kDa; each monomer has two 
functional domains joined by a linker. The targeting domain of ICON-1 is a mutated FVIIa 
protein conjugated to an Fc effector moiety of a human IgG1 immunoglobulin.   
 
12.1.2 Comparator Product  
There will be no active comparator in this study.  
12.1.3 Test Article Administration 
Patients will be randomly assigned to one of two treatment arms in a 1:1 ratio:  
• ICON-1 Maintenance Therapy: Aflibercept (2 mg/50 µL) monthly during Months 0-2 
and ICON-1 0.6 mg (two injections of 0.3 mg [300 µg/100 µL]) monthly during Months 
2-4, then aflibercept up to every 8 weeks as needed during Months 4-8, based on 
retreatment criteria.   
• ICON-1 + AFL Combination Therapy: Aflibercept (2 mg/50 µL) monthly and ICON-1 
0.6 mg (two injections of 0.3 mg [300 µg/100 µL]) monthly during Months 0-2, then 
aflibercept up to every 8 weeks as needed during Months 4-8, based on retreatment 
criteria.  
 
Using aseptic technique, ICON-1 or aflibercept will be administered by first withdrawing vial 
contents through a 5-micron 19-gauge filter needle attached to a 1-cc tuberculin or Luer Lock 
syringe and then replacing the filter needle with a 30-gauge x ½ inch needle for the intravitreal 
injection. Adequate topical anesthesia and broad-spectrum microbicide will be given prior to 
injection. 
At treatment visits with two injections of study drug, both intravitreal injections will be 
administered on the same day.  
At treatment visits with three injections of study drug, the three intravitreal injections (first 
injection: aflibercept 2 mg, second injection: ICON-1 0.3 mg, and third injection: ICON-1 
0.3 mg) may be administered on the same day OR the three injections may be administered 
across two separate days up to 7 days apart. If the three injections will be split across two days, 
the entire 0.6 mg dose of ICON-1 (two injections of 0.3 mg) must be administered on the same 
day.  

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IOP will be measured before and after each intravitreal injection. When multiple study drug 
injections are administered on the same day, the second injection and the third injection (if 
applicable) will be administered following stabilization of IOP to the pre-injection level (i.e., 
within 5 mmHg of the pre-injection IOP) AND a minimum of 30 minutes after the prior 
injection. 
12.2 
Study Drug Packaging, Labeling and Storage 
ICON-1 will be provided by the Sponsor, and is supplied in single-use glass vials containing 
0.28 mL of a sterile solution of ICON-1 at a concentration of 3 mg/mL in 15 mM HEPES, 
150 mM NaCl, 25 mM Arginine, pH 7.4 with 0.01% of Polysorbate-80 and 5 mM CaCl2. Each 
vial will be provided in an individual kit box with a foam insert, and kits will be labeled with a 
unique kit number.  
Vials of ICON-1 will be shipped frozen on dry ice and should be stored frozen at ≤ -60ºC until 
just before use. Temporary storage is permitted at -20ºC ± 5ºC for up to 90 days. ICON-1 vials 
should be thawed by removing the vial from the box and foam insert, and leaving at room 
temperature for approximately 10-15 minutes prior to administration. Verify that the study drug 
is completely thawed by taking the vial and gently swirling it. ICON-1 may NOT be refrozen 
once it has been thawed. Time between thawing and administration should be as minimal as 
possible and should not exceed 4 hours. Vials of ICON-1 are for single-use only. 
Commercial aflibercept (Eylea®) will be supplied by the clinical site. Eylea® is provided in 
cartons containing one single-use, sterile, 3-cc glass vial designed to deliver 0.05 mL of 
40 mg/mL of aflibercept. Each carton also contains one 5-micron, 19-gauge x 1-½-inch filter 
needle for withdrawal of vial contents, one 30-gauge x ½-inch injection needle for the 
intravitreal injection, one 1-mL syringe for administration, and one package insert. Eylea® 
should be refrigerated at 2ºC - 8◦C (36ºF - 46ºF). DO NOT FREEZE. Do not use beyond the date 
stamped on the carton and container label. Eylea® should be protected from light, and stored in 
its original carton until time of use. 
12.3 
Selection of Doses and Timing of Doses  
Doses of ICON-1 selected for this study are based on the results of non-clinical efficacy and 
toxicology studies, clinical Phase 1 and 2 studies in patients with wet AMD, and a Phase 1 study 
in patients with uveal melanoma. Results of the Phase 1 and 2 studies in wet AMD showed 
ICON-1 was well tolerated at all doses tested up to 0.3 mg for up to 6 monthly doses, and results 
of the Phase 1 study in uveal melanoma showed ICON-1 was well-tolerated in doses up to 
0.6 mg for up to two weekly doses. These data support further evaluation of repeated doses of 
0.6 mg in this Phase 2 study. ICON-1 administered at monthly intervals for loading doses is 
thought to be an optimal dosing regimen with respect to safety and effectiveness (see Section 8.1 
for information regarding the non-clinical, Phase 1 and Phase 2 studies).  
12.4 
Criteria for Retreatment with Aflibercept 
Patients will be administered aflibercept intravitreal injections in the study eye once every four 
weeks at Months 0, 1 and 2. As of Month 4 (at Months 4, 5, 6, 7 and 8), patients may be retreated 

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with aflibercept up to every 8 weeks as needed, based on their individual observed treatment 
response. The Investigator will use the following retreatment criteria to determine if treatment is 
required at each retreatment visit:  
• Clinically significant anatomical evidence of increased or persistent CNV activity (e.g., 
new or persistent fluid on OCT, leakage, hemorrhage on FA) compared to the previous 
scheduled visit, as determined by the Investigator 
At a given month when retreatment is required, the injection procedure(s) and timing will remain 
the same. See Section 21.2 (Appendix B) for the Study Treatment Flowchart and Section 21.4 
(Appendix D) for the Retreatment Decision Tree. 
12.5 
Measurement of Study Drug Compliance 
All study treatment will be administered by the Investigator or designated physician at each 
clinical site. The date and time of study treatment must be documented for each subject in the 
source record. Treatment assignment and dose must be documented in records with access 
restricted to authorized study personnel only.   
12.6 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining accurate records of study drug 
supplies. Reasons for any departure from the expected dispensing regimen must be recorded. 
Study drug may not be used for any other purpose other than that described in the protocol. All 
study drug supplies and accountability records must be stored in a secure location with limited 
access restricted to authorized personnel only. 
All vials of study drug will be recorded on a Drug Accountability Log accounting for all vials 
received, administered, not used, and destroyed. Drug Accountability will be performed by a 
Study Monitor during site visits. Once reconciled, study drug will be returned to the Sponsor or 
destroyed at the site, as directed by the Sponsor. If study drug is to be destroyed at the site, it is 
the Investigator’s responsibility to ensure arrangements have been made for appropriate 
destruction according to applicable regulations, guidelines and procedures. Appropriate records 
of the destruction must be maintained. 
12.7 
Prior and Concomitant Therapy 
All medications (prescription, over-the-counter (OTC) and herbal) and nutritional supplements 
taken by a subject from 30 days prior to Screening through the completion of the study will be 
recorded. Changes in the dosing and/or frequency of concomitant medication must be captured 
with new start and stop dates indicating the previous and current doses/frequencies. 
Any prior or concomitant treatment of CNV or advanced AMD in the study eye (e.g. laser, 
pharmacological [e.g., anti-VEGF agents] or surgical treatment, or any investigational therapy) is 
prohibited, except for dietary supplements or vitamins.  
Treatment of the fellow eye is allowed during the course of the study, and may be performed by 
any qualified physician in accordance with the site’s standard of care. 

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Use of topical ocular anti-glaucoma medications is allowed during the study. 
Use of any investigational product or device within 30 days before Screening through the 
completion of the study is prohibited. Age-related Eye Disease Study (AREDS)-formulated 
vitamins (which have been under investigation) are allowed during the study. 
In the event of an emergency, any needed medications or therapies may be prescribed without 
prior approval, but the Medical Monitor must be notified of the use immediately thereafter. The 
decision to administer a prohibited medication or therapy should be done with the safety of the 
patient as the primary consideration. If permissibility of a specific medication or therapy is in 
question, the Investigator should contact the Medical Monitor. 
12.8 
Other Study Supplies 
Additional supplies for administering ICON-1 intravitreal injections will include 1-cc tuberculin 
syringes, 5-micron 19-gauge x 1-½ inch filter needles for withdrawal of the study drug vial 
contents, and 30-gauge x ½ inch needles for intravitreal injections of ICON-1.  

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13 RANDOMIZATION AND MASKING 
13.1 
Enrollment and Subject Identification Numbers 
Each subject will be assigned a unique screening number after informed consent is obtained. The 
screening number will be used as the subject ID number throughout the study. Patients will be 
randomized to one of two treatment arms using a central randomization list generated by the 
Sponsor. The screening number and the randomization number will both serve as unique subject 
identifiers throughout the study.  
13.2 
Method of Assigning Patients to Treatment Arms 
The Investigator will evaluate the inclusion and exclusion criteria to determine patient eligibility 
for entry into the study. After the patient is determined to be eligible by the Investigator, study 
site personnel will contact the Sponsor (or designee) for assignment of a subject randomization 
number and treatment arm assignment.  
Patients will be randomized in a 1:1 ratio to receive intravitreal aflibercept (2 mg) and ICON-1 
(0.6 mg) maintenance therapy or ICON-1 (0.6 mg) + aflibercept (2 mg) combination therapy (see 
Section 12.1 for description of ICON-1 or aflibercept injection). Patients will be randomized on 
or before the day treatment is to be initiated (Day 0) based on the Screening visit assessments.  
13.3 
Masking 
This is an open-label study in which treatment assignments will be known to the study patients, 
study site personnel, and the Sponsor and its agents.  

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14 STUDY PROCEDURES 
The Study Flowchart and Assessments is presented in Section 21.1 (Appendix A). A detailed 
accounting of the assessments performed at each study visit is presented below.   
The protocol-specified procedures for a given study visit may be split across 2 days as long as all 
procedures are completed within the visit-specific window; however, for each visit all BCVA 
testing, ophthalmic exams and imaging must be performed on the same day and cannot be split 
across 2 or more days. 
14.1 
Visit 1: Screening (Day -14 to -1) 
Screening must take place within 14 days prior to Baseline (Month 0/Day 0). Patients will 
undergo Screening assessments to determine if they are eligible to enroll in the study.  
An ICF must be signed and dated by the subject or the subject’s legally authorized 
representative, the person who conducted the informed consent discussion, and witness (if 
required) before any Screening assessments or treatment is undertaken that is not part of routine 
care.  
The following procedures will be performed at Visit 1: 
• Obtain written informed consent and then assign a unique Screening Number to the 
subject 
• Obtain demographic data 
• Obtain medical history including surgical history 
• Obtain ocular history 
• Record prior (within the last 30 days) and concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS-like charts (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (study eye only) 
o sdOCT (study eye only) 

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o OCT-A (study eye only) 
o Fundus fluorescein angiography  
• Vital signs 
• Blood samples for clinical laboratory tests (serum chemistry, hematology and 
coagulation), prior to injection of fluorescein for FA 
• Blood sample for serum pregnancy test (women of child-bearing potential only), prior to 
injection of fluorescein for FA 
• Assessment of adverse events 
• Assessment of eligibility (Note: If an eligible subject is not assigned and dosed within the 
14-day screening period the Investigator must confer with the Medical Monitor regarding 
repeating screening procedures.) 
• Schedule subject to return for Visit 2 (Baseline, Month 0/Day 0) within the specified 
window 
14.2 
Visit 2: Baseline (Month 0/Day 0) 
Baseline assessments will be completed on Day 0. The following procedures will be performed 
at Visit 2: 
• Assessment of adverse events 
• Record concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (pre-injection, both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
• Vital signs 
• Assessment of eligibility 

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• Obtain randomization number and treatment assignment from Sponsor (or designee) 
(Note: The subject’s randomization assignment may be requested prior to the Baseline 
visit once the Investigator has determined that the subject is eligible for the study based 
on the Screening visit assessments.)  
• Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation) 
• Pre-dose blood sample for plasma anti-drug antibodies 
• Administration of intravitreal injection(s) (designated physician only) 
• Post-injection IOP after each intravitreal injection, as applicable (designated physician or 
designated site staff member only, study eye only)  
• Assessment of adverse events 
• Instruct patients to contact site study personnel immediately if their treated eye becomes 
red, sensitive to light, painful, or develops a change in vision 
• Schedule subject return for Visit 3 (Month 1) within the specified window 
14.3 
Visit 3: Month 1 (Day 28 ±3 days) 
The following procedures will be performed at Visit 3: 
• Assessment of adverse events 
• Record concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (pre-injection, both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
• Vital signs 

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• Only if patient is in ICON-1 + AFL Combination Therapy arm, pre-dose blood sample 
for plasma anti-drug antibodies, prior to injection of fluorescein for FA  
• Administration of intravitreal injection(s) (designated physician only) 
• Post-injection IOP after each intravitreal injection, as applicable (designated physician or 
designated site staff member only, study eye only) 
• Assessment of adverse events 
• Instruct patients to contact site study personnel immediately if their treated eye becomes 
red, sensitive to light, painful, or develops a change in vision 
• Schedule subject to return for Visit 4 (Month 2) within the specified window 
14.4 
Visit 4: Month 2 (Day 56 ±3 days) 
The following procedures will be performed at Visit 4: 
• Assessment of adverse events 
• Record concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (pre-injection, both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
• Vital signs 
• Only if patient is in ICON-1 + AFL Combination Therapy arm, pre-dose blood sample 
for plasma anti-drug antibodies  
• Administration of intravitreal injection(s) (designated physician only) 
• Post-injection IOP after each intravitreal injection, as applicable (designated physician or 
designated site staff member only, study eye only) 

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• Assessment of adverse events 
• Instruct patients to contact site study personnel immediately if their treated eye becomes 
red, sensitive to light, painful, or develops a change in vision. 
• Schedule subject to return for Visit 7 (Month 3) within the specified window 
14.5 
Visit 5: Month 3 (Day 84 ±3 days) 
The following procedures will be performed at Visit 5: 
• Assessment of adverse events 
• Record concomitant medication 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (pre-injection, both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (study eye only) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
o Fundus fluorescein angiography  
• Vital signs 
• Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation), prior to injection of fluorescein  
• Pre-dose blood sample for plasma anti-drug antibodies, prior to injection of fluorescein 
for FA 
• If the patient is to be treated, administration of intravitreal injection(s) (designated 
physician only) 
• If a patient is treated, perform a post-injection IOP after each intravitreal injection, as 
applicable (designated physician or designated site staff member only, study eye only) 
• Assessment of adverse events 

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• If a patient is treated, instruct patients to contact site study personnel immediately if their 
treated eye becomes red, sensitive to light, painful, or develops a change in vision. 
• Schedule subject to return for Visit 6 (Month 4) within the specified window 
14.6 
Visit 6: Month 4 (Day 112 ±3 days) 
The following procedures will be performed at Visit 6: 
• Assessment of adverse events 
• Record concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (pre-injection, both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
• Vital signs 
• Only if patient is in ICON-1 Maintenance Therapy arm, pre-dose blood sample for 
plasma anti-drug antibodies 
• Determine if patient meets retreatment criteria 
• If a patient is to be treated with ICON-1 and/or retreated with aflibercept, administration 
of intravitreal injection(s) (designated physician only) 
• If a patient is treated/retreated, perform a post-injection IOP after each intravitreal 
injection, as applicable (designated physician or designated site staff member only, study 
eye only) 
• Assessment of adverse events 
• If a patient is treated/retreated, instruct patients to contact site study personnel 
immediately if their treated eye becomes red, sensitive to light, painful, or develops a 
change in vision. 

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• Schedule subject to return for Visit 7 (Month 5) within the specified window 
14.7 
Visits 7-10: Months 5, 6, 7, 8 (Days 140, 168, 196, 224 ±3 days)  
The following procedures will be performed at Visits 7-10: 
• Assessment of adverse events 
• Record concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (pre-injection, both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
o Only at Month 6, color fundus photography (study eye only) 
o Only at Month 6, fundus fluorescein angiography  
• Vital signs 
• Only at Month 5 and if patient is in ICON-1 Maintenance Therapy arm, pre-dose blood 
sample for plasma anti-drug antibodies  
• Determine if patient meets retreatment criteria 
• If a patient is to be retreated with aflibercept, administration of the intravitreal injection 
(designated physician only) 
• If a patient is retreated, perform a post-injection IOP after the intravitreal injection 
(designated physician or designated site staff member only, study eye only) 
• Assessment of adverse events 
• If a patient is retreated, instruct patients to contact site study personnel immediately if 
their treated eye becomes red, sensitive to light, painful, or develops a change in vision. 
• Schedule subject to return for the next scheduled visit within the specified window 

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14.8 
Visit 11: End of Study, Month 9 (Day 252 ±3 days) 
The following procedures will be performed at Visit 11: 
• Assessment of adverse events 
• Record concomitant medications 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (study eye only) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
o Fundus fluorescein angiography  
• Vital signs 
• Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation), prior to injection of fluorescein for FA 
• Blood sample for serum pregnancy test (women of child-bearing potential only), prior to 
injection of fluorescein for FA 
• Blood sample for plasma anti-drug antibodies, prior to injection of fluorescein for FA  
• Assessment of adverse events 
• Exit subject from study 
If follow-up is needed after the End of Study visit, it should occur as a post-study unscheduled 
visit at the discretion of the Investigator. Patients with an ongoing SAE at this visit will be 
followed until the event is resolved or stabilized as described in Section 15.17.9.  
14.9 
Early Termination Visit 
Patients who discontinue study drug or withdraw from the study prematurely will undergo an 
Early Termination (ET) visit. At this visit, the following will be performed: 

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• Assessment of adverse events 
• Record concomitant medication 
• Perform the following ophthalmic procedures: 
o Best-corrected visual acuity by ETDRS (both eyes) 
o Slit lamp biomicroscopy (both eyes) 
o IOP (both eyes) 
o Dilated ophthalmoscopy (both eyes) 
o Color fundus photography (study eye only) 
o sdOCT (study eye only) 
o OCT-A (study eye only) 
o Fundus fluorescein angiography  
• Vital signs 
• Blood samples for clinical laboratory tests (serum chemistry, hematology, and 
coagulation), prior to injection of fluorescein for FA 
• Blood sample for serum pregnancy test (women of child-bearing potential only), prior to 
injection of fluorescein for FA 
• Blood sample for plasma anti-drug antibodies, prior to injection of fluorescein for FA 
• Assessment of adverse events 
If follow up is needed after the Early Termination visit, it should occur as a post-study 
unscheduled visit at the discretion of the Investigator. Patients with an ongoing SAE at this visit 
will be followed until the event is resolved or stabilized as described in Section 15.17.9. 
14.10 Unscheduled Visits 
Unscheduled visits may be necessary due to AEs or other reasons. The Investigator may examine 
a subject as often as is medically necessary while the subject is enrolled in the study. Any 
follow-up that is performed to monitor patient safety should be recorded as an Unscheduled 
Visit. The Investigator is responsible for monitoring patient AEs, and additional assessments 
performed at an unscheduled visit are at the discretion of the Investigator. Additional clinical 
laboratory assessments should be performed by the central laboratory as needed and when 
possible. 

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14.11 Subject Withdrawal from Treatment or Study 
14.11.1 Handling of Withdrawals 
Patients (or their legally authorized representative) may choose to withdraw from the study for 
any reason at any time without prejudice. The study assessments for the Early Termination Visit 
should be conducted in the event a subject discontinues from the study prematurely. If a subject 
withdraws from the study, he or she may not re-enter the study. 
The Principal Investigator or the Sponsor may withdraw a subject from the study for any of the 
following reasons:  
• Adverse event 
• Prohibited therapy (subject requires concomitant medication or a medical procedure 
prohibited by the protocol) 
• Subject noncompliance (subject does not adhere to the requirements specified by the 
protocol) 
• Subject improper entry (subject was enrolled in the study but did not meet the eligibility 
criteria) 
• Subject withdrawal of consent 
• Pregnancy (subject becomes pregnant) 
• Lost to follow-up 
• Death 
At the time of withdrawal, the Principal Investigator should advise the subject of the other 
available options. When a subject is withdrawn from the study for any reason, the reason(s) for 
withdrawal will be recorded in the eCRF. For any subject who withdraws due to an AE, the 
reason for withdrawal must be recorded as an AE and not any other reason. Whenever possible, 
all patients who withdraw from the study prematurely will undergo assessments listed for the 
Early Termination visit.  
If a subject fails to return for a scheduled visit, it is the responsibility of the Principal Investigator 
or designee to document all efforts to contact the subject and to determine the reason the subject 
did not return. After randomization, if a subject cannot be contacted with 3 documented 
telephone call attempts over a period of 2 weeks, followed by a certified letter, and does not have 
a known reason for discontinuation (e.g., withdrawal of consent or an AE), the reason for 
discontinuation will be recorded as “lost to follow-up”. The date that the certified letter was 
mailed will be considered the date of study withdrawal. 
In the event of a subject death during the study, the date of death (as listed on the death 
certificate) will be used as the date of study withdrawal. 

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It is vital to obtain follow-up data on any subject who is withdrawn due to an AE. In such cases, 
every effort must be made to undertake protocol-specified safety follow-up procedures.  
The Medical Monitor should be notified promptly when a subject is withdrawn. 
The Sponsor may terminate the study at any time for clinical or administrative reasons and may 
discontinue participation by an individual Investigator or site for poor enrollment or 
noncompliance. 
14.11.2 Replacements 
Patients who are withdrawn from the study may be replaced at the sponsor’s discretion. 
14.11.3 Sponsor or Regulatory Agency Termination of the Study 
Although the Sponsor intends to complete the study, the right is reserved to discontinue the study 
at any time for clinical or administrative reasons, or if required by the local regulatory authority. 

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15 STUDY ASSESSMENTS 
This section describes the study assessment procedures. See Study Flowchart and Assessments 
(Section 21.1 - Appendix A) for timing of each assessment. 
15.1 
Informed Consent 
Each site will be required to obtain IRB/EC approval of the ICF. Before any study specific 
procedures are performed, the investigator or designee will provide the subject or the subject’s 
legally authorized representative with a copy of the current IRB/EC approved ICF and allow 
adequate time for review and the opportunity to ask any questions regarding the study and/or 
ICF. The Investigator should answer all questions to the best of his ability and to the satisfaction 
of the subject or the subject’s legally authorized representative before performing any study visit 
assessments. The ICF should be signed and dated by the subject or subject’s legally authorized 
representative, the Investigator or his designee, and witness (where applicable) before any study 
specific procedures are performed. 
The consenting process must be conducted in accordance to the ICH GCP and local regulatory 
and/or IRB/EC requirements. A copy of the signed and dated ICF should be given to the subject 
or the subject’s legally authorized representative and a copy should be maintained in the 
subject’s medical records. The consenting process should be documented in the subject’s source 
record including the names of persons participating in the discussions and a brief summary of 
what was discussed including questions and responses. 
If the protocol is amended or new safety information becomes available, and revisions are 
required to the ICF, the subject or subject’s legally authorized representative will be required to 
sign the updated IRB/EC approved ICF. 
If a subject or subject’s legally authorized representative withdraws consent at any time the date 
and time and details of the discussion should be recorded in the subject’s source record along 
with the names of the persons participating in the discussion.  
15.2 
Eligibility Assessment 
Screening assessments will be used to determine eligibility before randomizing a subject for 
entry in the study. The Investigator is responsible for assessing patient eligibility. Patients who 
meet the eligibility criteria will be randomized to one of the two treatment arms. 
15.3 
Demographic Data 
Demographic data will be recorded including date of birth, gender, race and ethnicity. 
15.4 
Medical, Surgical, and Ocular History 
Medical history will be recorded and should elicit all major illnesses, diagnoses, and surgeries 
for the subject. Ocular history will also be recorded and should be specific to which eye as 
appropriate. 

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15.5 
Prior and Concomitant Therapy 
Prior and Concomitant Therapy taken from 30 days prior to Screening through the last study visit 
will be recorded. The subject’s source record should include start and stop dates, dose, route, 
frequency, and indication. 
15.6 
Best-corrected Visual Acuity 
Best-corrected visual acuity (BCVA) will be measured for each eye, pre-treatment prior to 
dilating eyes, using standard Early Treatment Diabetic Retinopathy Study (ETDRS) retro-
illuminated charts. BCVA will be recorded as the total letter score in each eye.  
Visual acuity testing will be performed by designated site personnel, and should occur before 
any examination requiring contact with the eye. In order to provide standardization and well-
controlled measurements of BCVA during the study, all measurements at a single site must be 
consistently done using the same lighting conditions, correction, chart type, and measurement 
procedure for an individual subject throughout the study. 
A study specific refraction and BCVA testing protocol will be provided in a separate BCVA 
manual. 
15.7 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed for each eye by designated site personnel. Slit-lamp 
biomicroscopy, including magnification, will be performed without dilation of the pupil and 
consistent with standard clinical practice. The subject will be seated during the examination. This 
procedure should be conducted in the same manner for all patients and will include an 
assessment of each of the following as normal or abnormal: 
• Eyelids 
• Conjunctiva 
• Cornea 
• Anterior chamber 
• Iris 
• Lens 
All abnormal findings that are clinically significant will be described. A change from normal to 
abnormal for any biomicroscopic variable will be considered clinically significant. 
15.8 
Intraocular Pressure 
At each study visit, IOP will be measured with a Goldmann applanation tonometer or Tono-Pen 
tonometer, consistent with standard clinical practice and consistent over the study visits. At 
injection visits, IOP will be measured by designated site personnel in each eye before the first 
injection, and in the study eye only at least 30 minutes after each intravitreal injection. 
Measurements will be recorded in mmHg (e.g., 19 mmHg). At other study visits, a single IOP 
measurement will be performed in both eyes by designated site personnel.   

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The tonometer must be calibrated for accuracy before the first subject in the study at a given site 
undergoes the first examination, and at least once every 30 days thereafter, until the last subject 
at the site has exited the study. Tonometer calibration may be completed by any qualified site 
personnel, and should be performed in accordance with the manufacturer’s specifications. Only 
adequately calibrated instrument should be used for IOP measurement.   
15.9 
Dilated Ophthalmoscopy 
A dilated fundus examination will be performed pre-treatment for each eye in all patients by 
designated site personnel. The following will be observed for the presence of abnormalities: 
• Vitreous body 
• Retina 
• Macula 
• Choroid 
• Optic nerve 
All abnormal findings that are clinically significant will be described. A change from normal to 
abnormal for any ophthalmoscopic variable will be considered clinically significant. 
15.10 Color Fundus Photography 
Color fundus photography (CFP) will be performed to assess CNV lesion characteristics in the 
study eye at the Screening Visit and at the Month 3, Month 6, and Month 9 or Early Termination 
visits. CFP will be performed pre-treatment during visits in which study treatment is 
administered. 
Color fundus photographs will be obtained using a digital fundus camera, and will be performed 
by designated site personnel. 
15.11 Spectral-Domain Optical Coherence Tomography 
Spectral-domain optical coherence tomography (sdOCT) imaging will be performed to assess 
CNV lesion characteristics in the study eye at all scheduled study visits and at the Early 
Termination visit (if applicable). sdOCT will be performed pre-treatment during visits in which 
study treatment is administered.  
sdOCT imaging will be obtained using a Spectral-Domain (High Definition) OCT device, and 
will be performed by designated site personnel. 
15.12 Optical Coherence Tomography Angiography 
Optical coherence tomography angiography (OCT-A) imaging will be performed to assess CNV 
lesion characteristics and en face chorioretinal space morphology in the study eye at all 
scheduled study visits and at the Early Termination visit (if applicable). OCT-A will be 
performed pre-treatment during visits in which study treatment is administered.  

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OCT-A imaging will be obtained using an FDA-approved OCT-A device, and will be performed 
by designated site personnel. 
15.13 Fundus Fluorescein Angiography 
Fundus fluorescein angiography (FA) imaging (after intravenous administration of fluorescein 
dye) will be performed to examine the circulation of the retina and the CNV lesion 
characteristics in the study eye according to standard FA image capture protocol. Intravenous FA 
must be performed pre-treatment, but after all other scheduled imaging has been completed. FA 
will be performed at the Screening Visit and at the Month 3, Month 6, and Month 9 or Early 
Termination visits.  
Fundus fluorescein angiographic images will be obtained using a digital camera, and will be 
performed by designated site personnel. 
15.14 Vital Signs 
Vital signs should be taken when the subject is adequately rested (after the subject has been 
resting in a seated position for at least 5 minutes). Vital signs measurements include blood 
pressure (systolic and diastolic in millimeter of mercury (mmHg)), heart rate (beats/minute), 
respiratory rate (breaths/minute), and temperature (°C). 
15.15 Clinical Laboratory Evaluations 
Blood samples for routine clinical laboratory tests will be collected at the Screening and Baseline 
visits and at the Month 3 and Month 9 or Early Termination visits. Samples will be collected pre-
treatment during visits in which study treatment is administered. The minimum tests to be 
performed include:  
• Hematology (complete blood count including white blood cell [WBC] count, WBC 
differential, red blood cell [RBC] count, hematocrit [Hct], hemoglobin [Hgb], mean 
corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular 
hemoglobin concentration [MCHC], red cell distribution width [RDW], platelet count, 
and mean platelet volume [MPV])  
• Serum chemistry profile (albumin, alkaline phosphatase, alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], blood urea nitrogen [BUN], calcium, serum chloride, 
carbon dioxide [CO2], creatinine, BUN/creatinine ratio, creatinine clearance [CrCl] using 
Cockcroft-Gault formula, creatine phosphokinase [CPK], direct and total bilirubin, 
triglycerides, gamma-glutamyl transferase [GGT], globulin, glucose, lactic 
dehydrogenase [LDH], phosphorus, potassium, sodium, total cholesterol, total protein, 
and uric acid) 
• Serum pregnancy test for women of child-bearing potential 
• Coagulation (prothrombin time [PT], international normalized ratio [INR], fibrinogen, 
and activated partial thromboplastin time [aPTT]) 

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Any abnormal test results determined to be clinically significant by the Investigator should be 
repeated at the discretion of the Investigator until the cause of the abnormality is determined, the 
value returns to baseline or to within normal limits, or the Investigator determines that the 
abnormal value is no longer clinically significant. Clinical laboratory results should be initialed 
and dated by the Investigator and any abnormal results should be marked as clinically significant 
or not clinically significant. Clinically significant laboratory results should be recorded as an AE, 
preferably as a diagnosis where possible. 
Female patients with a positive pregnancy test at Screening do not meet the eligibility criteria 
and may not enroll in the study. Women must have been in menopause for at least 2 years, or had 
a tubal ligation at least 1 year prior to Screening, or have had a total hysterectomy to be 
considered not of child-bearing potential. 
Laboratory tests will be performed by a central laboratory. For detailed instructions regarding 
collection, storage and handling of laboratory samples, please refer to the Laboratory Manual 
provided separately. 
15.16 Measurement of Plasma Anti-drug Antibodies  
Blood samples will be obtained to measure systemic (plasma) levels of anti-drug antibodies 
(ADA). Blood samples for measurement of ADA will be drawn before the first intravitreal 
injection at the Baseline visit and at the Month 1, Month 2, Month 3, and Month 9 or Early 
Termination visits. Samples will be collected pre-treatment during visits in which study 
treatment is administered. 
ADA samples will be analyzed by a central bioanalytical laboratory. For detailed instructions 
regarding collection, storage and handling of ADA samples, please refer to the Laboratory 
Manual provided separately. 
15.17 Evaluation of Adverse Events 
Adverse events (AEs) will be monitored continuously during the study from the time that the 
subject has provided written informed consent through the subject’s last day of study 
participation. AEs may be reported spontaneously by the subject, discovered by Investigator or 
study staff through questioning, or observed through physical examination or other means. It is 
the responsibility of the Investigator to assess and document all AEs that occur during the course 
of the study, regardless of the causal relationship with the study drug.  
The following information will be collected for all AEs and recorded on the subject’s source 
document and AE eCRF: 
• Event description (diagnosis preferred, if unknown, record the signs/symptoms) 
• Onset and resolution dates 
• Severity (intensity) 
• Frequency (intermittency) 
• Relationship to study drug (causality) as determined by the Investigator 

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• Seriousness 
• Action taken with study drug 
• Corrective action taken 
• Outcome 
15.17.1 Definition of an Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  
An AE can therefore be: 
• Any unfavorable and unintended medical diagnosis, sign or symptom 
• Any new undesirable medical occurrence or unfavorable or unintended change in a pre-
existing condition that occurs during or after study treatment  
• Laboratory abnormality, vital sign or ophthalmic assessment that is assessed as clinically 
significant and different from baseline (e.g., requiring discontinuation of study treatment, 
specific treatment, or a change in subject management). If possible, changes in laboratory 
results or changes in vital signs that meet the definition of an AE should be reported as a 
medical diagnosis rather than as the abnormal value (e.g., “hypertension” rather than 
“blood pressure increased”).  
The following are special considerations when determining and reporting AEs: 
• Whenever possible, the Investigator should group signs or symptoms that constitute a 
single diagnosis under a single AE term (e.g., “cough, rhinitis, and sneezing” might be 
grouped together as “upper respiratory tract infection”).  
• Pre-existing conditions are not considered AEs unless the condition worsens (increase in 
frequency, severity or specificity) during or following study drug administration. 
Fluctuations in a pre-existing condition should be assessed by the Investigator, and those 
that fall within the limits of expected fluctuations for the disease state, and are not 
assessed as worsening of the disease, should not be considered AEs. Any change assessed 
as clinically significant worsening of the disease from baseline must be documented as an 
AE. 
• Elective surgery or routine diagnostic procedures are not considered AEs. However, an 
untoward medical event occurring during the pre-scheduled elective surgery or diagnostic 
procedure should be recorded as an AE. 
• Death itself is not considered an AE; it is instead the outcome of an AE. 
• Pregnancy is not considered an AE, but it is an important medical event that must be 
followed up as described in Section 15.17.7. 

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• Elevated IOP in the study eye following an intravitreal injection should be considered an 
AE if, at least 30 minutes after the injection: (1) two or more follow-up IOP 
measurements (taken at least 15 minutes apart) are required to demonstrate stabilization 
to the pre-injection level (i.e., within 5 mmHg of the pre-injection value), thereby 
delaying the time of the planned subsequent intravitreal injection; or (2) interventional 
therapy is required to return IOP to within 5 mm Hg of the pre-injection value. 
A treatment-emergent AE (TEAE) is any AE with an onset from any time after the subject has 
received study drug through 30 days after the last dose of study drug, whether or not it is 
considered causally related to the study drug.  
15.17.2 Serious Adverse Event 
All AEs will be assessed as either serious or non-serious. A serious adverse event (SAE) is any 
event that results in any of the following outcomes: 
• Death 
• Life-threatening (i.e., if in the view of the Investigator or Sponsor, the event’s occurrence 
placed the subject at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe).  
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
(Hospitalization for elective surgery for a pre-existing condition or for surgery planned 
before study entry is not considered an SAE.)  
• A persistent or significant disability/incapacity (permanent or substantial disruption of the 
subject’s ability to perform normal life functions). This definition is not intended to 
include experiences of relatively minor or temporary medical significance. 
• Congenital anomaly/birth defect (an AE that occurs in the child or fetus of a subject 
exposed to study drug prior to conception or during pregnancy). 
Important medical event or serious medical condition that does not meet any of the above criteria 
may be considered an SAE if, based upon appropriate medical judgment, it may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the outcomes listed 
above. 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. 
15.17.3 AE Severity 
The severity of an AE should be determined by the intensity of the AE and will be assessed using 
the following 3-point scale: 

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Table 1:  Categories of Severity for Adverse Events 
1-Mild 
Discomfort noticed but no limitation in normal daily activities; no medical 
intervention/therapy required 
2-Moderate 
Discomfort sufficient to reduce or affect normal daily activities; some 
assistance may be needed; no or minimal medical intervention/therapy 
required 
3-Severe 
Inability to perform normal daily activities; some assistance usually required; 
medical intervention/therapy required; hospitalization or prolongation of 
current hospitalization possible; may be incapacitating or life-threatening 
 
The term “severe” is a measure of intensity. A severe AE is not necessarily a serious AE. 
15.17.4 Study Drug Causality 
The Investigator will assess the relationship of the AE to the study drug as either “Related” or 
“Not Related”. The following should be taken into consideration when assessing SAE causality: 
• Positive temporal relationship to study drug, such as if the study drug was withdrawn and 
the AE resolved or the event recurred after re-introduction. 
• If there is a reasonable possibility that the AE is associated with an underlying or 
concomitant illness. 
• Possible association with previous or concomitant therapy. 
• No temporal relationship to the study drug and/or a more likely alternative etiology 
exists. 
• If the AE is directly related to study procedures or lack of efficacy. 
15.17.5 Adverse Event Reporting Procedures 
The occurrence of AEs should be sought by non-direct questioning of the subject at each 
scheduled or unscheduled study visit. At each visit, study personnel should ask the following 
question: “Have you had any problems since your last visit?” AEs may also be detected when 
they are volunteered by the subject during and between visits or through physical examination, 
or other assessments. All AEs (serious and non-serious) reported by the subject will be reviewed 
by a qualified physician participating in the study and must be recorded on the subject’s source 
documents and AE eCRF. 
An AE that is classified as “serious” requires expeditious handling and reporting to the Sponsor 
(or designee) within 24 hours of site notification to comply with regulatory requirements.  
All SAEs, whether or not related to study drug, must be reported immediately to the Sponsor (or 
designee) by entering the SAE information directly into the electronic data capture (EDC) 
system (AE eCRF) within 24 hours after the Investigator becomes aware of the event.  

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Note that any SAEs that occur after the subject has provided written informed consent but before 
administration of study drug and are considered related to a protocol procedure must also be 
reported to the Sponsor (or designee) within 24 hours after the Investigator’s awareness of the 
event. 
Investigators should not wait to receive additional information to fully document an SAE before 
reporting the event to the Sponsor (or designee). If only limited information is initially available, 
follow-up information regarding the SAE is required. Additional relevant information such as 
hospital records, laboratory test results, discharge summaries and/or autopsy reports should be 
provided as soon as these are available. These SAE follow-up documents should be uploaded 
into the EDC system for informational purposes; however, if a document cannot be uploaded, it 
should be submitted to Iconic Therapeutics Drug Safety: 
SAE Notification 
Email: drugsafety@iconictherapeutics.com 
Fax: 650-246-9011  
(or to the email or fax number provided on the SAE Notification Cover Sheet) 
 
15.17.6 Reporting Serious Adverse Events to Regulatory Agencies 
An AE, whether serious or non-serious, is considered “unexpected” if the event is not reported in 
the clinical safety section of the reference document (e.g., Investigator Brochure or Package 
Insert) or if the event is of greater severity or frequency than is reported in the reference 
document. 
Expedited SAE reports are those SAEs that are both unexpected based on the reference 
document and considered related to the study drug (i.e., the relationship cannot be ruled out). 
The Sponsor will determine which SAEs qualify for expedited reporting.  
Reports of those SAEs that qualify for expedited reporting will be submitted to regulatory 
agencies in accordance with applicable local regulation (e.g., 21 Code of Federal Regulations 
[CFR] 312.32 and, as applicable, European Union Directive 2001/83/EC and 2001/20/EC).  
Expedited reports will be also distributed to Investigators. Upon receiving such notices, the 
Investigator must review and retain the notice with the Investigator Brochure and immediately 
submit a copy of this information to the governing IRB/IEC in accordance with institutional 
guidelines and local regulations. 
15.17.7 Pregnancy 
Pregnancy alone is not an AE. However, any report of pregnancy that occurs in a female study 
subject within 30 days after the subject’s last administration of study drug, and that becomes 
known to the Investigator, must be reported to the Sponsor even if the subject is withdrawn from 
study.  

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If a subject or Investigator suspects that a subject may be pregnant prior to study drug 
administration, the study drug administration must be withheld until the results of blood serum 
pregnancy tests are available. If pregnancy is confirmed, the subject must not receive the study 
drug and must not be enrolled in the study. If pregnancy is suspected while the subject is 
receiving study treatment, the study drug must be withheld immediately until the result of a 
pregnancy testing is known. If pregnancy is confirmed, the study drug will be permanently 
discontinued and the subject withdrawn from the study. The Investigator must follow the 
pregnancy to conclusion, and collect data on both maternal and fetal outcome including follow-
up information regarding the course of the pregnancy and perinatal and neonatal outcomes.  
A Pregnancy Report form will be submitted to the Sponsor, at a minimum, initially and at the 
end of the pregnancy. The Investigator is also encouraged to submit to the Sponsor trimester 
follow up reports during the pregnancy. The outcome of the pregnancy and any complications 
occurring during the pregnancy or the delivery must be reported to the Sponsor. 
A miscarriage or spontaneous abortion will be considered an SAE, and will be reported to the 
Sponsor according to the procedure described in Section 15.17.5. 
15.17.8 Overdose 
Overdose is defined as any dose higher than the protocol prescribed dose of study drug. 
Occurrences of overdose leading to an AE will be reported on the AE eCRF. An overdose 
leading to an SAE will be reported to the Sponsor according to the procedure described in 
Section 15.17.5. 
15.17.9 Follow-up of Adverse Events  
Patients with an ongoing SAE will be followed until the event is resolved, the significant 
changes return to baseline, the condition stabilizes, the event is no longer considered clinically 
significant by the Investigator, the subject withdraws consent, or the subject is lost to follow-up. 
This may imply that follow-up will continue after the subject has left the study and that 
additional investigation may be requested by the Sponsor. If the severity or relationship to study 
drug worsens for an ongoing SAE, follow-up SAE information should be reported to the Sponsor 
within 24 hours after the Investigator becomes aware of the change in status. 
All non-serious adverse events will be followed through the study exit visit. If a non-serious AE 
is first identified at the last scheduled study contact, the event will be recorded on the AE eCRF 
with the current status noted, but no further follow-up is required. 
15.17.10 Follow-up of Post-study Serious Adverse Events 
Should the Investigator become aware of a new SAE that occurs within 30 days after the last 
scheduled study contact and the event is determined by the Investigator to be related to the study 
drug, the SAE should be reported to the Sponsor and followed in accordance with the procedures 
described in this protocol. 

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16 STUDY ENDPOINTS 
16.1 
Primary Endpoints 
Change in choroidal neovascularization (CNV) by fluorescein angiography (FA) and optical 
coherence tomography angiography (OCT-A) over time 
16.2 
Secondary Endpoints 
• Time to progression of choroidal neovascularization growth 
• Change in Best Corrected Visual Acuity over time 
• Change in CST by sdOCT over time 
• Percent of patients with “dry retina” over time 
• Time to achieving “dry retina” 
• Time to retreatment during PRN aflibercept retreatment period 
• Percent of patients receiving PRN aflibercept retreatment over time 
 
16.3 
Safety Endpoints: 
• Occurrence of ocular and systemic serious adverse events and adverse events 
• Changes in standard clinical laboratory tests (serum chemistry, hematology, coagulation) 
• Changes in vital signs and ophthalmic examinations 
• Systemic levels of ADA over time 
 

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17 STATISTICAL ANALYSIS AND METHODS PLANNED 
17.1 
Statistical Analysis Plans  
This Phase 2 trial is a signal-seeking trial to assess the safety and pharmacodynamic effects of 
ICON-1. As such, the primary aim for data analyses in this trial is to delineate the functional and 
anatomical outcomes after ICON-1 treatment in either maintenance or combination with anti-
VEGF. Thus, the data analyses in this study is geared towards descriptive multifactorial 
summaries and displays of the functional and anatomical parameters. 
As descriptors of the two treatment arms, univariate data summaries will be provided. For 
ordinal and continuous endpoints, summary statistics will include number of patients, mean, 
median, standard deviation, minimum, and maximum. For categorical endpoints, summary 
statistics will include number of patients, frequency, and percentages. 
Safety analyses will include all randomized patients who received at least one dose of ICON-1, 
with patients allocated to the treatment arm associated with the dosing regimen actually received. 
The analyses of pharmacodynamic effects and biological activity will include all randomized 
patients who received at least one dose of ICON-1 and who had at least one post baseline disease 
evaluation, with patients allocated to the treatment arm associated with the regimen actually 
received.   
Exploratory analyses of the data not described in the following subsections may be conducted as 
deemed appropriate. 
The baseline evaluation will be defined as the last evaluation prior to the first study treatment.  
More details of the data analyses will be provided in the Statistical Analysis Plan (SAP). 
17.2 
Analysis of the Conduct of the Study 
The number of patients randomized will be tabulated by study site and treatment arm. Subject 
disposition (the number of patients randomized, treated, and completing the study) will be 
tabulated by treatment arm. The number of patients who complete each scheduled visit and 
treatment will be tabulated by treatment arm and by visit. Subject discontinuations and reasons 
for discontinuation will be summarized. Eligibility criteria exceptions and other major protocol 
deviations will be summarized by treatment arm. 
Treatment compliance (ratio of total dose received to total dose intended) will likewise be 
summarized by treatment arm. 
 

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17.3 
Handling of Dropouts or Missing Data 
All analyses of safety results will be performed on an available-case basis. Available data for all 
treated patients will be summarized by assigned treatment. No imputation for missing data will 
be performed, and no attempt to correct for deviations from assigned treatment will be made. 
Patients who are withdrawn from the study may be replaced at the Sponsor’s discretion. 
17.4 
Analysis of Treatment Arm Comparability 
Summary statistics of the following patient characteristics will be provided by treatment arm to 
assess comparability:  
• Patient demographics, such as age, sex, and race;  
• Baseline disease characteristics, such as BCVA, CST, extent of CNV area;  
• Prior disease-related therapies; and 
• Concomitant medications. 
Other patient baseline characteristics will be summarized as deemed appropriate. 
17.5 
Treatment Exposure 
The total dose received of both study treatments (ICON-1, aflibercept) will be summarized by 
treatment arm. The duration of dosing and number of doses received will also be summarized by 
treatment arm.  
17.6 
Safety Analyses 
Safety will be assessed through summaries of adverse events, changes in laboratory test results 
(serum chemistry, hematology, coagulation), and changes in vital signs and ophthalmic 
examinations. Adverse events will be mapped using MedDRA. 
All collected adverse event data will be listed by treatment, study site and patient number. All 
adverse events occurring on or after treatment on Day 0 (treatment emergent adverse events, 
TEAEs) will be summarized by treatment arm. In addition, all serious adverse events, including 
deaths (if any), will be listed separately and summarized. Finally, all ocular TEAEs will be listed 
and tabulated with events for the study and fellow eye summarized separately. 
Changes in laboratory data will be summarized by treatment arm with shift tables. 
17.7 
Analyses of pharmacodynamics effects 
This Phase 2 trial is a signal-seeking trial to assess the effects of ICON-1 on the biology of the 
CNV complex. As such, the primary aim for the assessment of biological activity in this trial is 

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to delineate the functional and anatomical outcomes of ICON-1 maintenance or combined with 
an anti-VEGF (aflibercept), in terms of: 
• Function, as tracked through visual acuity and attendant treatment implications: 
− temporal changes in BCVA, as measured by actual mean changes in BCVA; 
percent of patients with a BCVA gain post baseline; percent of patients with 
BCVA >20/40 and <20/200 post baseline; percent of patients who remain within 
BCVA severity level post baseline; 
− Signs of CNV activity, as measured by time to retreatment with aflibercept and 
percent of patients receiving aflibercept re-treatment 
• Anatomic, as tracked through physical (qualitative and quantitative) longitudinal changes 
in the eye that can be imaged through sdOCT, FA, CFP, and OCT-A: 
− CNV complex changes; 
− Changes in CST;  
− Exudative and fluid changes; 
− Fibrosis/atrophy changes; 
− Retina layers integrity changes.  
Thus, the data analyses for assessing biological activity in this trial are geared towards 
descriptive multifactorial summaries. The CNV complex anatomical outcomes will be assessed 
by qualitative and quantitative measures, including but not limited to: CNV dimensions (area, 
volume), CNV leakage, fluid presence (or absence of all intraretinal, subretinal and sub-RPE 
fluids, ie defined as “dry retina”), type and location of fluids and exudation and other 
morphological characteristics.  
Initially, descriptive univariate data summaries by treatment arm will be provided for each of the 
biological activity parameters listed above. For ordinal and continuous endpoints (such as 
changes in BCVA and in CST), summary statistics will include number of patients, mean, 
median, standard deviation, minimum, and maximum. For categorical endpoints (such as percent 
of patients receiving retreatment), summary statistics will include number of patients, frequency, 
and percentages.  
To describe the multifactorial functional and anatomical impact of ICON-1, treatment arm 
profiles (ICON-1 maintenance therapy, ICON-1 + aflibercept combination therapy) with 
multiple parameters will be concurrently presented and comprehensively examined.   
• An example of one such profile is as follows: A treatment arm CNV complex anatomy 
profile may be constructed with the following anatomical variables: changes in CST, 
CNV changes, exudation and fibrosis/atrophy changes, with benchmark summary 
descriptors for the corresponding baseline values. 
 

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More patient and treatment arm profiles will be constructed as appropriate, and will be detailed 
in the SAP. 
17.8 
Immunogenicity Analyses 
Systemic levels of anti-drug antibodies (ADA) during the study will be collected for each 
patient. If there are sufficient numbers of patients exhibiting systemic levels of ADA, summary 
statistics by treatment arm will also be provided. 
17.9 
Interim Analysis 
No formal interim analysis is planned for this study. 
17.10 Sample Size Determination 
This study is exploratory and its sample size is not determined by statistical power 
considerations. 
 
 

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18 DATA HANDLING AND RECORD KEEPING 
18.1 
Case Report Forms and Source Documents 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain detailed and accurate case histories of all study patients. Original data will be recorded 
in the subject’s source documents (which may include medical records, hospital charts, clinic 
charts/notes, diagnostics tests such as x-rays, laboratory tests and ECGs, and electronic 
recordings), and transcribed onto electronic case report forms (eCRFs) provided by the Sponsor. 
The Investigator agrees to maintain accurate source documentation as part of the case history for 
each subject. Recorded data should be updated/corrected in a manner that does not obliterate, 
destroy, or render illegible the previous entry (e.g., by drawing a single line through the incorrect 
entry and writing the revision next to the corrected data). An individual who has corrected an 
entry should make clear who made the correction and when, by adding his/her initials and the 
date of the correction. 
Designated site staff must complete the applicable eCRFs as soon as possible after each subject 
visit, and the eCRFs must be available for review at the next scheduled monitoring visit. 
Electronic case report form completion guidelines that describe how to appropriately enter data 
into eCRFs from the source documents will be provided to the study sites. If an item is not 
available or is not applicable, this should be indicated. Blank data fields should not be present 
unless otherwise directed. 
Prior to locking the clinical database, the Investigator must review and approve all completed 
eCRFs to verify their accuracy. 
18.2 
Monitoring of the Study 
Qualified individuals (CRAs or Study Monitors) designated by the Sponsor will follow the study 
closely, and monitor all aspects of the study according to ICH/GCP and standard operating 
procedures for compliance with applicable government regulations. The Principal Investigator 
(PI) agrees to allow the CRAs direct access to study drug accountability records and drug 
supplies, dispensing and storage areas, clinical files of the study patients (including original 
medical records) and the regulatory files. The PI also agrees to assist the CRAs if requested. The 
PI and appropriate site staff are responsible for being present or available for consultation during 
routinely scheduled site visits conducted by the CRAs.  
The CRA will maintain necessary email, telephone, fax, and/or mail contact with the 
Investigators and study site personnel, and will visit the study sites at periodic intervals. The 
CRA will maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
Investigators and study site staff. During those visits, the CRA will compare the subject data 
entered in the eCRFs against original source documents at the clinical site, and evaluate the 
eCRFs for completeness and accuracy. Data that are modified on the eCRFs to resolve any 
discrepancies must be supported by the source documents. The review of subject medical records 

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will be performed in a manner to ensure that subject confidentiality is adequately maintained. 
Further details of the study monitoring will be outlined in a separate Monitoring Plan. 
18.3 
Data Management 
Data management for this study will be contracted to a Contract Research Organization (CRO) 
designated by the Sponsor. All data management procedures will be detailed in separate, 
specifically identified documents that collectively will be referenced as the Data Management 
Plan (DMP).  
The designated site personnel will transcribe the information required by the protocol onto the 
eCRFs that will be provided using a fully validated Electronic Data Capture (EDC) system 
conforming to FDA requirements for the capture of electronic data. The data will be checked for 
missing data or suspect errors upon entry against validation programs, and appropriate flags will 
be displayed on the eCRFs. The Investigator or designee will make the necessary corrections or 
verify the correctness of the data based on these flags. The database will be backed up regularly 
throughout the study by the CRO or EDC vendor.  
Study Monitors representing the Sponsor will review the eCRFs against the source 
documentation at the site for completeness and accuracy, and will discuss the need for further 
corrections with the Investigator or designee. In addition, computerized edit checks and manual 
review processes will also be performed by the CRO on an ongoing basis as outlined in the DMP 
until all data clarifications are resolved.  
In order to classify adverse events, medical and ocular history, and concomitant medications, 
preferred terms will be assigned to the original terms entered on the eCRFs using MedDRA or 
WHO Drug dictionaries.  
After all data are entered and all data queries resolved, the Investigator must certify that the 
subject data are complete and accurate by applying an electronic signature to the eCRF study 
completion page. Once all eCRFs for the study are signed and the analysis populations are 
determined and documented, the clinical database will be locked. 
After the clinical database is locked, disks containing electronic copies of all applicable patients’ 
eCRFs will be provided to each Investigator to be maintained on file by the Investigator. 
18.4 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspection(s) by providing direct access to all study records. The 
Investigator or study site may be audited by the Sponsor or its representatives and/or regulatory 
agencies at any time. In the event of an audit, the Investigator agrees to allow the Sponsor, 
representatives of the Sponsor, the FDA, or other regulatory agency access to all study records. 
The Sponsor will review case report form data and perform electronic edit checks on the data.  

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The Investigator should promptly notify the Sponsor of any audits scheduled by any regulatory 
authorities and promptly forward copies of any received audit reports to the Sponsor. 
18.5 
Study Record Retention 
Government agency regulations and directives require that all study documentation pertaining to 
the conduct of a clinical study must be retained by the Investigator. Original source documents 
for each subject should be included in this documentation. Study documentation should be 
retained by the Investigator until notified by the Sponsor in writing that retention is no longer 
necessary. In addition, the Investigator must notify the Sponsor of any change in the location, 
disposition or custody of the study documentation. Study documentation includes study records, 
subject charts/notes, subject medical records, laboratory tests, and paper or electronic recordings. 
It is the responsibility of the Sponsor to inform the Investigator/institution as to when this 
documentation no longer needs to be retained.  
Records containing subject medical information must be handled in accordance with the 
requirements of the applicable privacy rules and consistent with the terms of the subject 
authorization contained in the ICF for the study. Care should be taken to ensure that such records 
are not shared with any person or for any purpose not contemplated by the ICF. Furthermore, 
eCRFs and other documents to be transferred to the Sponsor should be completed in strict 
accordance with the instructions provided by the Sponsor, including the instructions regarding 
the coding of subject identities.  
Essential study documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. Should the Investigator retire, relocate, or for other reasons withdraw from the 
responsibility of keeping the study records, custody must be transferred by the Investigator to 
another party who will accept the responsibility. The Sponsor must be notified in writing by the 
Investigator of the name and address of the new custodian and receive documented acceptance 
from the new custodian. If requested, the Investigator will provide the Sponsor, applicable 
regulatory agencies, and applicable IRB/IEC with direct access to original source documents. 
 

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19 ADMINISTRATIVE CONSIDERATIONS 
19.1 
Confidentiality 
All records identifying the patient will be kept confidential and to the extent permitted by the 
applicable laws and/or regulations will not be made publicly available. Patient names and other 
identifying information will not be supplied by the Sponsor. Only subject number and/or subject 
initials will be reported in the eCRF. If the patient name or other identifying information appears 
on any other document or study materials, the information must be deleted before a copy of the 
document is supplied to the Sponsor.   
The Investigator (or designee) is responsible to obtain from the patient or patient’s legally 
authorized representative, written permission to use protected health information per country-
specific regulations, such as the HIPAA in the United States. If permission to use protected 
health information is withdrawn, it is the Investigator’s responsibility to document this in the 
patient’s record. 
If the results of the study are published, the subject’s identity will remain confidential. The 
Investigator is responsible for maintaining a list enabling subject’s records to be identified. 
19.2 
Amendments to the Protocol 
Any changes or deviations in the protocol will be made as an amendment to the protocol and 
approved by the Sponsor and the IRB/EC before they are implemented. The Investigator or 
designee must notify the Sponsor or designee of any inadvertent protocol deviations upon their 
discovery, and document the deviations appropriately in the study files. 
When a protocol amendment substantially alters the study design or the potential risks or burden 
to patients, the ICF will be amended and approved by the IRB/EC, and all patients on treatment 
must provide informed consent. 
19.3 
Protocol Deviations 
The Investigator will not deviate from any tests, procedures, eligibility criteria, or the schedule of 
assessments described in the protocol except in the event of a medical emergency. The 
Investigator should contact the Medical Monitor with any questions concerning a subject who 
may not meet the entry criterion. Waivers for protocol eligibility will not be allowed for this 
study.  
All protocol deviations must be documented and explained in the subject’s source 
documentation, and should be reported to the Study Monitor. Protocol deviations should also be 
reported to the site IRB/EC in a timely manner and in accordance with the policies of the 
IRB/EC.  

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19.4 
Study Reporting Requirements 
The Investigator is responsible for submitting progress reports annually, or more frequently if 
required, to their IRB/EC and any applicable institutional committees in accordance with the 
policies of their IRB/EC and institutional committees respectively. The Investigator is 
responsible for maintaining copies of these reports and any acknowledgments from the IRB/EC 
or institutional committees. These reports must be available for review by the Study Monitor and 
any regulatory agency upon request. Any changes significantly affecting the conduct of the study 
and/or risk to the patients should be promptly reported to the Sponsor its designee, the IRB/EC 
and any applicable institutional committees. 
19.5 
Financial Disclosure 
Financial Disclosure Forms must be completed by the Principal Investigator and all Sub-
Investigators listed on the Form FDA 1572 who will directly be involved in the treatment or 
evaluation of patients in this study. 
19.6 
Investigator Responsibilities 
The Investigator should ensure that all persons involved in the conduct of the study are informed 
about the protocol, protocol amendments, study procedures, and any study-related duties. The 
investigator is responsible for assuring that study site staff are properly trained and credentialed 
to perform any delegated tasks. 
The Investigator is responsible for monitoring the safety of patients who have entered this study 
and for providing appropriate medical care. In addition, the Investigator is responsible for 
managing AEs that are serious or that cause the patient to withdraw before completing the study. 
Frequency of follow-up beyond that mandated in the protocol is left to the discretion of the 
Investigator.   
19.7 
Clinical Trial Agreement 
A fully executed (signed and dated by all applicable parties) Clinical Trial Agreement describing 
the responsibilities and terms of collaboration between Iconic Therapeutics and the study site is 
required prior to initiating the study. 
19.8 
Policy for Publication and Presentation of Data 
Iconic Therapeutics recognizes the importance of communicating medical study data and 
therefore encourages their publication in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this study will be described in the Clinical Trial Agreement 
between Iconic Therapeutics and the institution of the Investigator. 

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20 REFERENCES 
1. Friedman DS et al. Prevalence of age-related macular degeneration in the United States. 
Arch Ophthalmol. 2004;122:564-572.  
2. Shams N et al. Role of vascular endothelial growth factor in ocular angiogenesis. 
Ophthalmol Clin North Am. 2006 Sep;19(3):335-44. 
3. Rosenfeld PJ et al. Aflibercept for neovascular age-related macular degeneration. N Engl 
J Med. 2006;355:1419-1431. 
4. Brown DM et al. Aflibercept versus verteporfin for neovascular age-related macular 
degeneration. N Engl J Med. 2006;355:1432-1444. 
5. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. 
Nature Reviews. 2013;13:438-451. 
6. Lopez PF et al. Pathologic features of surgically excised subretinal neovascular 
membranes in age-related macular degeneration. Am J Ophthalmol. 1991;112: 647-656. 
7. Oh H et al. The potential angiogenic role of macrophages in the formation of choroidal 
neovascular membranes. Invest Ophthalmol Vis Sci. 1999;40:1891-1898. 
8. Grossniklaus et al. Macrophage and retinal pigment epithelium expression of angiogenic 
cytokines in choroidal neovascularization. Mol Vis. 2002;8:119-126. 
9. Belting M, Ahamed J, Ruf W. Regulation of angiogenesis by tissue factor cytoplasmic 
domain signaling. Nat Med. 2004;10:502-509. 
10. Cho Y, Rickles FR, Parver LM, Tuo J, Chan CC. The potential pathophysiological role 
of tissue factor in age-related macular degeneration. Expert Rev Ophthalmol. 
2010;5(1):27-34. 
11. Cho Y, Cao X, Shen D, Tuo J, Parver LM, Rickles FR, Chan CC. Evidence for enhanced 
tissue factor expression in age-related macular degeneration. Laboratory Invest. 
2011;91:519-526.  
12. Hu Z, and Garen A. Targeting tissue factor on tumor vascular endothelial cells and 
tumor cells for immunotherapy in mouse models of prostatic cancer. Proceedings of the 
National Academy of Sciences 2001;98.21:12180–85. 
13. Janson TL, Stormorken H, Prydz H. Species specificity of tissue thromboplastin. 
Haemostasis 1984;14:440-4. 
14. Schreiber MA, Holcomb JB, Rojkjaer R. Preclinical trauma studies of recombinant 
factor VIIa. Crit Care 9;2005(5):S25-8. 
15. Petersen LC, Norby PL, Branner S, Sorensen BB, Elm T, Stennicke HR, Persson E, 
Bjorn SE. Characterization of recombinant murine factor VIIa and recombinant murine 
tissue factor: a human-murine species compatibility study. Thromb Res 2005;116:75-85. 
16. Hu Z, Sun Y, Garen A. Targeting tumor vasculature endothelial cells and tumor cells for 
immunotherapy of human melanoma in a mouse xenograft model. Proc Natl Acad Sci 
1999;96:8161–8166. 

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17. Dickinson CD, Kelly CR, Ruf W. Identification of surface residues mediating tissue 
factor binding and catalytic function of the serine protease factor VIIa. Proc Natl Acad 
Sci 1996;93:14379-84. 
18. Bora PS, Hu Z, Tezel TH, Sohn JH, Kang SG, Cruz JM, Bora NS, Garen A, Kaplan HJ. 
Immunotherapy for choroidal neovascularization in a laser-induced mouse model 
simulating exudative (wet) macular degeneration. Proc Natl Acad Sci USA. 
2003;100:2679-84. 
19. Tezel TH, Bodek E, Somnez K, Kaliappan S, Kaplan HJ, Hu Z, Garen A. Targeting 
tissue factor for immunotherapy of choroidal neovascularization by intravitreal delivery 
of factor FVII-Fc chimeric antibody. Ocul Immunol Inflamm. 2007;15:3-10. 
20. Schmidt-Erfurth U, Eldem B, Guymer R, Korobelnik JF, Schlingemann RO, Axer-
Siegel R, Wiedemann P, Simader C, Gekkieva M, Weichselberger A; Efficacy and 
safety of monthly versus quarterly aflibercept treatment in neovascular age-related 
macular degeneration: the EXCITE study. EXCITE Study Group. Ophthalmol. 2011; 
118(5):831-9.  
21. Holz FG, Amoaku W, Donate J, Guymer RH, Kellner U, Schlingemann RO, 
Weichselberger A, Staurenghi G; Safety and efficacy of a flexible dosing regimen of 
aflibercept in neovascular age-related macular degeneration: the SUSTAIN study. 
SUSTAIN Study Group. Ophthalmol. 2011;118(4):663-71. 
22. Simader C, Ritter M, Bolz M, Deàk GG, Mayr-Sponer U, Golbaz I, Kundi M, Schmidt-
Erfurth UM. Morphologic parameters relevant for visual outcome during anti-
angiogenic therapy of neovascular age-related macular degeneration. Ophthalmol. 2014; 
121(6):1237-45. 

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21 APPENDICES 

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21.1 
Appendix A:  Study Flowchart and Assessments 
 
Screening 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Months  
5, 6, 7, 8 
End of 
Study 
Month 9 
Early 
Termi- 
nation 
Study Month/Day 
Day -14 to 
-1 
Month 0/ 
Day 0 
Day 28 
 ±3 days 
Day 56 
 ±3 days 
Day 84 
 ±3 days 
Day 112 
 ±3 days 
Day 140, 
168, 196, 224 
 ±3 days 
Day 252 
 ±3 days 
 
Visit 
1 
2 
3 
4 
5 
6 
7, 8, 9, 10 
11 
ET 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
Medical/Ocular/Surgical/Medication 
History 
X 
 
 
 
 
 
 
 
 
Best-corrected Visual Acuity by ETDRS 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Slit Lamp Biomicroscopy 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Intraocular Pressure1 
 
Pre-injection 
 
Post-injection 1 
 
Post-injection 2 
 
Post-injection 3 
OU 
 
OU 
SE 
SE3 
SE3  
 
OU 
SE 
SE3 
SE3 
 
OU 
SE 
SE 
SE 
 
OU 
SE2 
SE2 
 
OU 
SE2,4 
SE2 
SE2 
 
OU 
SE4 
OU 
OU 
Dilated Ophthalmoscopy 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
OU 
Color Fundus Photography 
SE 
 
 
 
SE 
 
SE5 
SE 
SE 
Spectral-domain Optical Coherence 
Tomography 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
Optical Coherence Tomography 
Angiography 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
SE 
Fundus Fluorescein Angiography 
OU 
 
 
 
OU 
 
OU5 
OU 
OU 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry, Hematology and 
Coagulation Blood Samples 
X 
X 
 
 
X 
 
 
X 
X 
Serum Pregnancy Test (WOCBP only) 
X 
 
 
 
 
 
 
X 
X 

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Screening 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Months  
5, 6, 7, 8 
End of 
Study 
Month 9 
Early 
Termi- 
nation 
Study Month/Day 
Day -14 to 
-1 
Month 0/ 
Day 0 
Day 28 
 ±3 days 
Day 56 
 ±3 days 
Day 84 
 ±3 days 
Day 112 
 ±3 days 
Day 140, 
168, 196, 224 
 ±3 days 
Day 252 
 ±3 days 
 
Visit 
1 
2 
3 
4 
5 
6 
7, 8, 9, 10 
11 
ET 
Anti-drug 
Antibodies 
Plasma Sample 
ICON-1 Maintenance 
Therapy 
 
X 
 
 
X 
X 
X6 
X 
X 
ICON-1 + AFL 
Combination Therapy 
 
X 
X 
X 
X 
 
 
X 
X 
Assessment of Eligibility 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
X7 
 
 
 
 
 
 
 
Study Drug 
Intravitreal 
Injection(s)8 
ICON-1 Maintenance 
Therapy 
 
A 
A 
A + I 
I 
A4 + I 
A4 
 
 
ICON-1 + AFL 
Combination Therapy 
 
A + I 
A + I 
A + I 
 
A4 
A4 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SE=Study Eye, OU=Both Eyes, A=aflibercept 2 mg, I=ICON-1 0.6 mg (2 injections of 0.3 mg) 
1 IOP measured using Goldmann applanation tonometry or Tono-Pen tonometer. For study eyes that receive study drug injections, the post-injection IOP will be measured 
after each study drug injection. 
2 Performed only for patients in ICON-1 Maintenance Therapy arm.  
3 Performed only for patients in ICON-1 + AFL Combination Therapy arm.  
4 Performed for patients requiring aflibercept retreatment at Months 4-8, per the retreatment criteria.  
5 Month 6 only. 
6 Month 5 only. 
7 Subject’s randomization assignment may be requested prior to the Baseline visit once the Investigator has determined that the subject is eligible for the study based on 
the Screening visit assessments. 
8 Study Eye receives up to three injections at each injection visit. When multiple study drug injections are administered on the same day, the second injection and the third 
injection (if applicable) will be administered following stabilization of IOP to the pre-injection level (i.e., within 5 mmHg of the pre-injection IOP) AND a minimum of 
30 minutes after the prior injection.  

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21.2 
Appendix B:  Study Treatment Flowchart 
Treatment 
Arm 
Visit 2 
Month 0/ 
Day 0 
Visit 3 
Month 1 
Visit 4 
Month 2 
Visit 5 
Month 3 
Visit 6 
Month 4 
Visit 7-10 
Months 5-8 
Visit 11 
Month 9 
ICON-1 
Maintenance 
Therapy 
 
 
 
 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICON-1 + AFL 
Combination 
Therapy 
 
 
 
 
* 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 AFL (aflibercept 2 mg/50 µL) injection 
 ICON-1 (ICON-1 0.3 mg/100 µL) injection 
* Retreatment with aflibercept up to every 8 weeks as needed during Months 4-8, based on protocol-specified retreatment criteria. 
Note: The Study Eye receives up to three injections at each injection visit. When multiple study drug injections are administered on the 
same day, the second injection and the third injection (if applicable) will be administered following stabilization of IOP to the pre-
injection level (i.e., within 5 mmHg of the pre-injection IOP) AND a minimum of 30 minutes after the prior injection. 
 
 

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21.3 
Appendix C: Retreatment Criteria 
Retreatment Criteria 
ICON-1 Maintenance Therapy arm: Patients will be administered aflibercept intravitreal injections in 
the study eye once every four weeks at Months 0, 1 and 2, and ICON-1 intravitreal injections once every 
four weeks at Months 2, 3,and 4. As of Month 4 (at Months 4-8) patients may be retreated with 
aflibercept up to every 8 weeks as needed, based on their individual observed treatment response.  
 
Combination Therapy arm: Patients will be administered aflibercept and ICON-1 intravitreal injections 
in the study eye once every four weeks at Months 0, 1 and 2. As of Month 4 (at Months 4-8) patients may 
be retreated with aflibercept up to every 8 weeks as needed, based on their individual observed treatment 
response. 
 
Retreatment Criteria: The investigator will use the following retreatment criteria to determine if 
treatment is required at each retreatment visit: 
• 
Clinically significant anatomical evidence of increased or persistent CNV activity (e.g., new or 
persistent fluid on OCT, leakage, hemorrhage on FA) compared to the previous scheduled visit, 
as determined by the Investigator 
 
 
 
 

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21.4 
Appendix D: Retreatment Decision Tree 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NO 
YES 
Observe  
& evaluate for 
retreatment at next visit 
Re-treat with 
aflibercept 2 mg 
Clinically significant anatomical evidence of increased or 
persistent CNV activity (e.g., new or persistent fluid on 
OCT, leakage, hemorrhage on FA) compared to the 
previous scheduled visit, as determined by the Investigator