A Phase 3 Randomized, Double-masked, Multicenter Study to Compare the Efficacy and Safety of the Proposed Aflibercept FYB203 Biosimilar in Comparison to Eylea® in Patients With Neovascular Age-Related Macular Degeneration
Phase: PHASE3
Conditions: Neovascular Age-related Macular Degeneration
Sponsor: Bioeq GmbH

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
1 
TITLE PAGE 
Protocol Title: A Phase 3 Randomized, Double-masked, Multicenter Study to Compare the Efficacy and 
Safety of the Proposed Aflibercept FYB203 Biosimilar in Comparison to Eylea® in Patients with 
Neovascular Age-Related Macular Degeneration (MAGELLAN-AMD) 
 
Protocol Number: FYB203-03-01 
 
Protocol Version: 15 July 2022/Version 3.0 
 
Amendment Number: Amendment 1.0 
 
Product: Aflibercept FYB203 
 
Short Title: Efficacy and Safety of the Aflibercept FYB203 Biosimilar in Comparison to Eylea® in 
Patients with Neovascular Age-Related Macular Degeneration (MAGELLAN-AMD) 
 
Study Phase: Phase 3 
 
Sponsor Name: bioeq GmbH 
 
Legal Registered Address:  
bioeq GmbH 
Bergfeldstrasse 9 
83607 Holzkirchen 
Germany 
 
Regulatory Agency Identifying Number(s): EudraCT No 2019-003923-39 
 
Date of Protocol: 15 July 2022 
 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
2 
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
 
Document 
Date 
Region 
Amendment 1.0 
15 July 2022 
Global 
 
Amendment 1.0 (15 July 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the planned statistical analyses. 
Section # and Name 
1.1 Synopsis 
10.4 Statistical Analyses 
 
1.1 Synopsis 
10.4 Statistical Analyses 
 
1.1 Synopsis 
10.2 Sample Size 
Determination 
10.5 Interim Analyses 
 
 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
4 
Section # and Name 
1.1 Synopsis 
3. Objectives and 
Endpoints (Table 1) 
1.1 Synopsis 
3. Objectives and 
Endpoints (Table 1) 
1.3 Schedule of 
Activities 
6.1 to 6.13 (Visit 0 to 
Visit 9) 
9.1.1 Best Corrected 
Visual Acuity 
1.3 Schedule of 
Activities 
6.2 Visit 1 (Baseline) 
6.9 Visit 5 
6.11 Visit 7 
6.13 Visit 9 (EOS/Early 
Termination Visit) 
9.1.5 National Eye 
Institute Visual 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
6 
TABLE OF CONTENTS 
TITLE PAGE ...........................................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3 
TABLE OF CONTENTS ........................................................................................................6 
TABLE OF TABLES .............................................................................................................10 
TABLE OF FIGURES ...........................................................................................................11 
1 
PROTOCOL SUMMARY ........................................................................................12 
1.1 
Synopsis ...........................................................................................................12 
1.2 
Schema ............................................................................................................21 
1.3 
Schedule of Activities .....................................................................................22 
2 
INTRODUCTION......................................................................................................25 
2.1 
Eylea: Aflibercept Reference Product .........................................................26 
2.2 
FYB203: Proposed Aflibercept Biosimilar ..................................................27 
2.3 
Study Rationale ..............................................................................................27 
2.4 
Background ....................................................................................................28 
2.5 
Benefit/Risk Assessment ................................................................................29 
3 
OBJECTIVES AND ENDPOINTS ..........................................................................30 
4 
STUDY DESIGN ........................................................................................................32 
4.1 
Overall Design ................................................................................................32 
4.2 
Scientific Rationale for Study Design ...........................................................34 
4.3 
Justification for Dose .....................................................................................34 
4.4 
End of Study Definition .................................................................................34 
5 
STUDY POPULATION ............................................................................................35 
5.1 
Inclusion Criteria ...........................................................................................35 
5.2 
Exclusion Criteria ..........................................................................................37 
5.3 
Lifestyle Considerations ................................................................................39 
5.4 
Screen Failures ...............................................................................................39 
5.5 
Re-screening Procedures ...............................................................................39 
6 
SCHEDULE OF STUDY VISITS ............................................................................41 
6.1 
Visit 0 (Screening) ..........................................................................................41 
6.2 
Visit 1 (Baseline) .............................................................................................42 
6.2.1 
Telephone Safety Call .......................................................................44 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
7 
6.3 
Visit 1a (Subgroup only) ................................................................................44 
6.4 
Visit 1b (Subgroup only) ...............................................................................44 
6.5 
Visit 2...............................................................................................................44 
6.5.1 
Telephone Safety Call .......................................................................45 
6.6 
Visit 3...............................................................................................................45 
6.6.1 
Telephone Safety Call .......................................................................46 
6.7 
Visit 3a (Subgroup only) ................................................................................46 
6.8 
Visit 4...............................................................................................................46 
6.8.1 
Telephone Safety Call .......................................................................47 
6.9 
Visit 5...............................................................................................................47 
6.9.1 
Telephone Safety Call .......................................................................48 
6.10 
Visit 6...............................................................................................................48 
6.10.1 
Telephone Safety Call .......................................................................49 
6.11 
Visit 7...............................................................................................................49 
6.11.1 
Telephone Safety Call .......................................................................50 
6.12 
Visit 8...............................................................................................................51 
6.12.1 
Telephone Safety Call .......................................................................52 
6.13 
Visit 9 (EOS/Early Termination Visit) .........................................................52 
7 
STUDY TREATMENT .............................................................................................53 
7.1 
Study Treatment(s) Administered ................................................................53 
7.2 
Preparation/Handling/Storage/Accountability ...........................................54 
7.3 
Measures to Minimize Bias: Randomization and Masking .......................54 
7.4 
Study Treatment Compliance .......................................................................55 
7.5 
Concomitant Therapy ....................................................................................55 
7.5.1 
Fellow Eye Treatment .......................................................................56 
7.6 
Treatment After the End of the Study .........................................................56 
8 
DISCONTINUATION OF STUDY TREATMENT AND PATIENT 
DISCONTINUATION/WITHDRAWAL ................................................................57 
8.1 
Discontinuation of Study Treatment ............................................................57 
8.1.1 
Temporary Investigational Medicinal Product Withhold ..................58 
8.1.2 
Replacement ......................................................................................59 
8.2 
Patient Discontinuation/Withdrawal from the Study .................................59 
8.3 
Lost to Follow-up ...........................................................................................60 
8.4 
Premature Termination of the Study ...........................................................60 
9 
STUDY ASSESSMENTS ..........................................................................................61 
9.1 
Efficacy Assessments .....................................................................................61 
9.1.1 
Best Corrected Visual Acuity ............................................................61 
9.1.2 
Ophthalmological Examination .........................................................62 
9.1.3 
Color Fundus Photography and Fluorescein Angiography ...............63 
9.1.4 
Spectral Domain Optical Coherence Tomography (SD-OCT) .........63 
9.1.5 
National Eye Institute Visual Function Questionnaire (NEI 
VFQ-25) ............................................................................................64 
9.2 
Safety Assessments .........................................................................................64 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
10 
TABLE OF TABLES 
Table 1 
Study Objectives and Endpoints ......................................................................30 
Table 2 
Study Treatment Details ..................................................................................53 
Table 3 
Analysis Sets ....................................................................................................72 
Table 4 
Study Administrative Structure........................................................................86 
Table 5 
Protocol-required Laboratory Assessments .....................................................89 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
11 
TABLE OF FIGURES 
Figure 1 
Overall Study Design .......................................................................................21 
Figure 2 
Overall Study Design .......................................................................................32 
 
 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
13 
Objectives 
Endpoints 
• 
Evaluate and compare change in total lesion 
size 
• 
Change from baseline in total lesion size to 
Week 24 (Visit 5), Week 40 (Visit 7) and 
Week 56 (Visit 9) 
• 
Evaluate and compare systemic free and total 
aflibercept concentrations in a subgroup of up 
to 60 patients (up to 30 per arm) 
• 
Systemic concentrations (close to maximum 
concentration [Cmax]) of free and total 
aflibercept in a subgroup at selected sites 
− 
48 hours after the 1st dose (Visit 1a) 
− 
48 hours after the 3rd dose (Visit 3a) 
• 
Evaluate and compare change in vision-related 
functioning and well-being measured by 
National 
Eye 
Institute 
Visual 
Function 
Questionnaire 25 (NEI VFQ-25) 
• 
Change from Baseline Visit (Visit 1) in 
vision-related functioning and well-being 
measured by NEI VFQ-25 to Week 24 
(Visit 5), Week 40 (Visit 7), and Week 56 
(Visit 9) 
• 
Evaluate and compare the immunogenic profile 
(anti-drug antibodies [ADAs]) in serum 
• 
Number of patients with ADAs over time 
• 
Evaluate and compare local and systemic 
adverse events (AEs) and serious adverse 
events (SAEs) 
• 
Frequency of local and systemic AEs and 
SAEs  
 
Overall Design: 
This study is a Phase 3 parallel-group, 1:1 randomized, active-controlled, double-masked, 
multicenter study to demonstrate clinical equivalence in terms of clinical efficacy, safety, and 
immunogenicity of FYB203 with EU-approved Eylea over 48 weeks of treatment in patients with 
subfoveal nAMD or wet AMD.  
All eligible patients will receive 1 intravitreal (IVT) injection every 4 weeks for 3 consecutive 
doses starting at Week 0 (Visit 1) through Week 8 (Visit 3) followed by 1 IVT injection every 8 
weeks over a period of approximately 48 weeks (Visit 8). Patients will be randomized in a 1:1 ratio 
to receive either FYB203 or EU-approved Eylea at a dose of 2 mg (0.05 mL of a 40 mg/mL 
solution). Each patient will receive a total of 8 IVT injections. 
Systemic concentrations of free and total aflibercept will be assessed and compared in a subgroup 
of up to 60 patients (up to 30 each for EU-approved Eylea and FYB203) at selected study sites at 
Baseline Visit (Visit 1) prior to 1st IVT dose, 48 hours after 1st IVT dose (Visit 1a) close to Cmax, 
and at 48 hours after the 3rd IVT dose (Visit 3a) close to Cmax. Anti-drug antibodies formation 
against aflibercept will be evaluated in serum in all patients prior to receiving the IVT injections 
at Visit 1, Visit 2, Visit 4, Visit 5, Visit 7 and Visit 9, and in addition in the subgroup 1-week after 
the 1st dose (Visit 1b) and 48 hours after the 3rd dose (Visit 3a). 
 
Number of Investigators and Study Centers: 
Originally 400 patients were planned to be randomized, including 52 patients in Japan. However, 
the actual number of patients randomized are 434 including 33 patients in Japan.  

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
14 
Eighty-five study centers, located in Europe, Israel and Japan  have patients participating in this 
study. 
 
Number of Patients: 
A total of 434 patients have been randomly assigned to study treatment and 433 patients have 
received at least 1 injection of study treatment in the study eye, including 33 patients in Japan, 
such that 433 patients will be included in the Full Analysis Set (FAS) population, where the FAS 
population is defined as all patients randomly assigned to study treatment who receive at least 1 
injection of study treatment in the study eye (SE). The fixed sample size could have been increased 
following the interim masked review of sample size after the first 200 treated patients had 
completed Week 8 (Visit 3) up to a maximal sample size of 800 patients. However, this interim 
masked review of sample size revealed that the observed variability overall does not require an 
increase in sample size to maintain the intended statistical power of 90% for the primary endpoint, 
and of 80% for the key secondary endpoint (EU/Japan only). 
 
Inclusion Criteria: 
General 
1. Age ≥ 50 years at Screening. 
2. Male or female: 
• Male: 
− A male patient must agree to use contraception as defined in this protocol during the 
treatment period (48 weeks) and for at least 4 weeks after the last dose of study 
treatment. 
• Female:  
− A female patient is eligible to participate if she is not pregnant, not breastfeeding, and 
at least 1 of the following conditions applies: 
i) Not a woman of childbearing potential (WOCBP)  
OR 
ii) A WOCBP who agrees to follow the contraceptive guidance during the treatment 
period (48 weeks) and for at least 4 weeks after the last dose of study treatment 
3. Capable of giving signed informed consent, which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in this protocol. 
4. Willingness and ability to undertake all scheduled visits and assessments. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
15 
Ocular (Study Eye) 
5. Newly diagnosed (within 6 months of Screening Visit), angiographically documented, 
treatment-naïve choroidal neovascularization (CNV) lesion secondary to wet AMD:  
a) All subtypes of wet AMD CNV lesions are eligible (classic, occult, some classical 
component, retinal angiomatous proliferation lesions). Treatment-naïve CNV 
secondary to wet AMD must be subfoveal or juxtafoveal with subfoveal component 
related to CNV activity (such as sub- or intraretinal fluid by spectral domain optical 
coherence tomography [SD-OCT] or retinal pigment epithelium [RPE] 
detachment); 
b) Total area of whole lesion must be ≤ 9 disc areas; 
c) Total CNV area encompasses ≥ 50% of total lesion area based on fluorescein 
angiography (FA), including all subtypes of wet AMD. 
Term 
Definition 
Wet AMD 
Clinical signs (including findings by retinal imaging) attributable to wet 
AMD (e.g. pigmentary changes, drusen) and no other likely etiologic 
explanations for the degenerative changes 
Subfoveal 
Including the center of the fovea 
Juxtafoveal 
At least some part of CNV lesion must be in an area up to 199 µm from 
the geometric center of the fovea 
Total area of 
whole lesion 
A contiguous area of abnormal tissue that contains a CNV (as 
documented by FA) with possible additional components of 
hemorrhages, blocked fluorescence not from hemorrhage, serous 
detachment of the RPE, atrophy, and subretinal fibrosis 
6. Sufficiently clear ocular media and adequate pupillary dilation to permit good quality ocular 
imaging. 
7. Best corrected visual acuity (BCVA) in the SE, determined by standardized ETDRS testing, 
between 20/40 and 20/200 Snellen equivalent. 
8. Foveal center point retinal thickness at Screening ≥ 300 µm and < 800 µm. (FCP thickness is 
defined as the distance between the vitreoretinal interface and Bruch’s membrane at the 
geometric center of the fovea). 
Ocular (Fellow Eye) 
9. Best corrected visual acuity (BCVA) in the fellow eye, determined by standardized ETDRS 
testing, at least 20/200 Snellen equivalent. 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
16 
Exclusion Criteria: 
Patients are not eligible for the study if any of the following criteria apply: 
General 
1. Employees of clinical study sites, individuals directly involved with the conduct of the study 
or immediate family members thereof, prisoners, and persons who are legally institutionalized. 
2. Study eye requiring immediate treatment. 
Prior or Current Ocular Treatment 
 
3. Any prior treatment with anti-Vascular Endothelial Growth Factor (VEGF) agent (e.g. 
bevacizumab, aflibercept, ranibizumab) or any investigational products to treat AMD, in either 
eye. 
4. Prior treatment with any investigational products to treat ocular diseases other than wet AMD 
within 30 days or 5 half-lives prior to Randomization, whichever is longer.    
5. History of vitrectomy, macular surgery or other surgical intervention for AMD in the SE; 
6. History of IVT or periocular injections of corticosteroids or device implantation within   
6 months prior to Randomization in the SE. 
7. Prior treatment with verteporfin (photodynamic therapy), transpupillary thermotherapy, 
radiation therapy, or retinal laser treatment (e.g. focal laser photocoagulation) in the SE; 
8. Any other intraocular surgery (including cataract surgery) in the SE within 3 months prior to 
Randomization. 
CNV Lesion Characteristics 
9. Sub- or intra-retinal hemorrhage that comprises more than 50% of the entire lesion in the SE. 
10. Irreversible structural damage involving the center of fovea (e.g. advanced fibrosis > 50% of 
the total lesion in the SE or atrophy) in the SE that is considered sufficient to irreversibly impair 
visual acuity (VA).  
11. CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic 
myopia. 
Current Ocular Conditions 
12. Retinal pigment epithelial tear involving the macula in the SE. 
13. History of or current full-thickness macular hole (stage 2 and above by clinical examination or 
full-thickness macular hole by SD-OCT imaging of any size) in the SE. 
14. History of or current retinal detachment in the SE. 
15. Current vitreous hemorrhage in the SE. 
16. Spherical equivalent of the refractive error in the SE demonstrating more than 6 diopters of 
myopia. 
17. For patients who have undergone prior refractive or cataract surgery in the SE, the preoperative 
refractive error in the SE should not exceed 6 diopters of myopia. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
17 
18. History of or current corneal transplant in the SE. 
19. Aphakia in the SE. Absence of an intact posterior capsule is allowed if it occurred as a result 
of YAG laser posterior capsulotomy in association with prior posterior chamber intraocular 
lens (IOL) implantation. 
20. Active or recent (within 4 weeks prior to Randomization) intraocular inflammation of clinical 
significance in either eye such as active infections of the anterior segment (excluding mild 
blepharitis) including conjunctivitis, keratitis, scleritis, uveitis, or endophthalmitis. 
21. Uncontrolled ocular hypertension or glaucoma in the SE (defined as intraocular pressure [IOP] 
≥ 30 mmHg, despite treatment with anti-glaucomatous medication). 
22. Ocular disorders in the SE (i.e. retinal detachment, pre-retinal membrane of the macula or 
cataract with significant impact on VA) at the time of Screening that may confound 
interpretation of study results and compromise VA. 
23. Any concurrent intraocular condition in the SE (e.g. glaucoma, cataract, or diabetic 
retinopathy) that, in the opinion of the Investigator, would either require surgical intervention 
during the study to prevent or treat visual loss that might result from that condition or affect 
interpretation of study results. 
Systemic Medical History and Treatments and Conditions at Screening 
24. Use of other investigational drugs (excluding vitamins, minerals) within 30 days or 5 half-lives 
prior to Randomization, whichever is longer. 
25. Systemic treatment with anti-VEGF agent (e.g. bevacizumab) within 90 days prior to 
Randomization. 
26. Any type of advanced, severe, or unstable disease, including any medical condition (controlled 
or uncontrolled) that could be expected to progress, recur, or change to such an extent that it 
may bias the assessment of the clinical status of the patient to a significant degree or put the 
patient at special risk. 
27. Stroke or myocardial infarction within 6 months prior to Randomization. 
28. Presence of uncontrolled systolic blood pressure > 160 mmHg or uncontrolled diastolic blood 
pressure > 100 mmHg within 4 weeks prior to Randomization. 
29. Known hypersensitivity to the investigational drug (aflibercept or any component of the 
aflibercept formulation) or to drugs of similar chemical class or to fluorescein or any other 
component of fluorescein formulation. 
30. Current or planned use of systemic medications known to be toxic to the lens, retina, or optic 
nerve, including deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines, 
and ethambutol. 
31. History of recurrent significant infections and/or current treatment for active systemic 
infection. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
18 
Ocular (Fellow Eye) 
32. Any diagnosis and/or signs of wet AMD requiring treatment with an IVT anti-VEGF agent 
(e.g. aflibercept, bevacizumab, ranibizumab) within the Screening period or are expected, in 
the opinion of the investigator, to need such treatment in the fellow eye throughout the study. 
At the time of Screening and Randomization, the Investigator should use best medical 
judgement to exclude patients with a probable FE treatment need during the course of the 
study. 
Treatment Groups and Duration: 
The Investigational Medicinal Products (IMPs) are FYB203 and Eylea. 
Experimental product: FYB203 – proposed aflibercept biosimilar (International Nonproprietary 
Name [INN]: aflibercept) 40 mg/mL solution for IVT injection. 
Comparator: Eylea (INN: aflibercept), EU-approved¸ 40 mg/mL solution for IVT injection.  
All eligible patients will receive 1 IVT injection every 4 weeks for 3 consecutive doses starting at 
Week 0 (Visit 1) through Week 8 (Visit 3) followed by 1 IVT injection every 8 weeks over a period 
of approximately 48 weeks (Visit 8). Each patient will receive a total of 8 IVT injections. 
 
Statistical Methods: 
 
Primary Endpoint: 
The FAS, defined as all randomized patients who receive at least 1 injection of study treatment in 
the SE, will be used for all efficacy analyses. Sensitivity analyses based on the Per Protocol Set 
(PPS; defined as all patients from the FAS with available BCVA assessments at Baseline and 
Week 8 for the SE without major protocol deviations that might influence the BCVA assessments 
at Baseline Visit (Visit 1) or Week 8) will be performed for the primary and secondary efficacy 
endpoints (see below). For the final assessment of bioequivalence, it is essential that the analyses 
of the primary efficacy endpoint based on the FAS and on the PPS as well as other sensitivity 
analyses yield consistent results. 
The primary estimand is the mean difference between the randomized treatment groups, FYB203 
and Eylea for the primary endpoint, i.e. change from Baseline to Week 8 in BCVA, in the SE 
regardless of treatment adherence and usage of concomitant medications and using data on all 
patients within the FAS. Also patients randomized and treated although inclusion or exclusion 
criteria were violated will be analyzed within the FAS according to the randomized treatment 
group. 
The primary estimand will be assessed through a mixed model for repeated measures (MMRM), 
which uses all available data collected until Week 24 (Visit 5) for the SE for all patients for model 
estimation. The difference in the treatment group least square means and the corresponding 
two-sided 90.4% 
 confidence intervals (CI) will be estimated from the MMRM to 
address regulatory requirements in the US 
. If the respective CI is 
completely contained in the interval ]-3.5; 3.5[ ETDRS letters, equivalence of FYB203 and Eylea 
can be concluded (rounded to the next integer, this corresponds to an equivalence margin of 
3 ETDRS letters). 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
19 
Supplemental estimands are defined by excluding patients with major protocol deviations which 
impact the BCVA assessments until Week 8 and/or patients who discontinue treatment before 
Week 8 or do not have a Week 8 BCVA assessment. By excluding all these patients, an estimand 
will be defined that repeats the primary analysis based on the PPS. 
 
Secondary Endpoints: 
Specifically, for the European Medicines Agency (EMA), the endpoint of change in FCP retinal 
thickness from Baseline to Week 4 in the SE will be analyzed as a key secondary endpoint using 
an equivalence interval from [-45; 45] µm. The difference in the treatment group least square 
means and the corresponding two-sided 95.2% CI will be estimated from the MMRM using all 
patients in the FAS. If the CI is completely contained in the interval [-45; 45] µm, equivalence of 
FYB203 and Eylea with respect to the FCP retinal thickness can be concluded. For all non-EU 
regulatory submissions, the CI will not be compared to any equivalence margin and descriptive 
statistical analyses will performed. 
The change from baseline in the SE over time for BCVA, FCP and FCS retinal thickness and total 
lesion area will be analyzed using a similar MMRM model than the one used for the primary 
estimand. The absolute values and the changes from baseline for each parameter will also be 
summarized descriptively by visit and treatment group for all scheduled time points for the SE. 
Data for the fellow eye at Screening Visit, Visit 7, and EOS Visit will be summarized descriptively. 
NEI VFQ-25 total scores will be determined as described in the official manual. The absolute 
values and the change from baseline for each parameter will also be summarized descriptively by 
visit and treatment group for the SE and fellow eye separately. 
The percentage of patients with fluid-free macula at each visit, based on all patients with evaluation 
at each given visit, will be presented in descriptive summary tables. 
 
Interim Analysis: 
An interim masked review of sample size was planned to re-assess the assumptions for the sample 
size calculation with respect to the standard deviation after the first 200 patients had completed 
the primary efficacy endpoint of change in BCVA at Week 8 and the key secondary endpoint for 
the EU-specific analysis of change in FCP retinal thickness at Week 4. Variability of the primary 
and the secondary endpoint were planned to be estimated as the common covariance from the 
MMRM model used for the primary analysis, but with the treatment and treatment-by-time 
interaction terms excluded. This was used to calculate the conditional power for the study to show 
bioequivalence. A target power of 90% to show bioequivalence is intended for the primary efficacy 
endpoint for the PPS (assuming 10% of patients will be excluded from the FAS) and a target power 
of 80% for the EU-specific key secondary endpoint for the FAS. An independent statistician who 
will otherwise not be involved in the planning and performance of the statistical analysis of the 
study data has performed the calculations and  provided recommendations on possible sample size 
adaptations. The recommendation followed the following rules: The sample size will not be 
decreased, even if the conditional power will be higher than targeted. If the conditional power is 
lower than the target power, the sample size will be increased up to a pre-determined maximal 
sample size. If the target power for the primary endpoint can only be reached by including more 
patients than the maximal sample size, the recommendation will indicate this fact and the Sponsor 
will stop the study. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
20 
This interim masked review of sample size was performed in November 2021 and revealed that 
the observed variability overall does not require an increase in sample size to maintain the intended 
statistical power of 90% for the primary endpoint, and of 80% for the key secondary endpoint 
(EU/Japan only). 
 
Main Analyses: 
Three analyses are planned on unmasked data: (1) the final US analysis intended for the US 
regulatory submission (Biologics License Application [BLA]), (2) the main EU, and (3) the final 
EU/Japan analyses intended for the EU and Japan regulatory submissions respectively. Only a 
restricted number of pre-defined persons not otherwise involved in the direct conduct and 
management of the study and the study sites, will have access to any unmasking information to 
perform and review the first two planned analyses. 
The final US analysis intended for the US regulatory submission (BLA) is planned to be performed 
when the first 320 treated patients have completed 40 weeks of treatment (or discontinued the 
study prematurely) and all randomized and treated patients have completed the primary efficacy 
endpoint assessment at Week 8 (or discontinued the study prematurely).  
Due to the geopolitical situation in Ukraine in 2022, more patients than the originally planned 320 
treated patients may be included in the US analysis. The exact number of patients will be 
determined prior to providing any access regarding treatment unmasking information to any 
personnel involved in the analysis of this data and will depend on the extent of missing treatments 
and possibly missing information related to safety and efficacy assessments in affected sites and 
patients. Formal records on this decision will be kept in the blind data review meeting minutes 
together with time points of decision and partial unmasking. 
The main EU analysis intended for initial regulatory submission is planned when all randomized 
and treated patients have completed 24 weeks of treatment or discontinued the study prematurely. 
The final EU/Japan analysis intended for the EU and Japan regulatory submissions is planned 
when all randomized and treated patients have completed the whole study period of 56 weeks. 
 
Data Monitoring Committee (DMC): Yes 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
21 
1.2 Schema 
Figure 1 
Overall Study Design 
 
 
ADA = Anti-drug antibody; EOS = End of Study; IMP = Investigational Medicinal Product; ICF = informed consent form; PC = plasma concentration; V = visit; W = week. 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
24 
12 No significant anatomical change in the SE compared to Screening and visual acuity in the SE within the defined inclusion criteria range (Snellen equivalent 
20/40 [0.5] to 20/200 [0.1]) and within 5 letters of the Screening BCVA.  
13 See 
 for the list of clinical laboratory tests to be performed. 
14  Urine sampling for clinical laboratory test will be collected at Screening, at Visit 5 and Visit 7 prior to IVT injection of IMP and at EOS Visit 
 
Urine samples must be collected before performing FA (when applicable) to avoid false elevations in urine protein values.ADA = Anti-drug antibody; AE = Adverse 
event; BCVA = Best-corrected visual acuity; D = day; EOS = End of Study; ETDRS = Early treatment diabetic retinopathy study;  
FA = Fluorescein angiography; FSH = follicle stimulating hormone; h = hours; hCG = Human chorionic gonadotropin; IMP = Investigational Medicinal Product; IOP = Intraocular 
pressure; IVT = Intravitreal; nAb = neutralizing antibody; NEI VFQ-25 = National eye institute visual function questionnaire 25; SD-OCT = Spectral domain optical coherence 
tomography; SE = Study eye; V = Visit; VA = Visual acuity; W = Week. 
 
All assessments of a particular visit have to be performed during 1 day, except for screening. 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
25 
2 INTRODUCTION 
Age-related macular degeneration (AMD) is a progressive degenerative macular disease affecting 
the region of highest visual acuity (VA) of the eye. Characteristically, it is a disease affecting 
individuals over 50 years of age and is the leading cause of visual loss in developed countries 
(1,2,3,4,5,6). 
In developed countries, AMD is a leading cause of severe visual loss in people 65 years of age and 
older. In the US, an estimated 6% of individuals aged 65 to 74 years, and 20% of those older than 
75 years are affected with some stage of AMD. Also, among white people aged 40 years and older, 
AMD is the number one cause of visual impairment and blindness in the US. 
Although the disease rarely results in complete blindness and peripheral vision may remain 
unaffected, central vision is gradually blurred, severely affecting ordinary daily activities. 
Age-related macular degeneration is classified into 2 general subgroups: the non-neovascular 
(non-exudative or dry) form of the disease and the neovascular (exudative or wet) form of the 
disease. The non-neovascular form of AMD is more prevalent, accounting for approximately 85% 
to 90% of all AMD cases in the US and is often characterized by a slow degeneration of the macula 
resulting in atrophy of the central retina with gradual vision loss over a period of years. By contrast, 
neovascular AMD (nAMD) or wet AMD, although less prevalent, accounts for 10% to 15% of 
clinical forms in the US and commonly causes sudden, often substantial, loss of central vision and 
is responsible for most cases of severe loss of VA in this disease (7). This type of AMD results 
from abnormal blood vessels (neovascularization) proliferation under and/or within the retina. The 
neovascular form develops due to an angiogenic process in which newly formed choroidal vessels 
(choroidal neovascularization; CNV) invade the macular area, resulting in rapid vision loss and 
often total blindness (8,9). 
Choroidal neovascularization can be associated with fibrous replacement of the retinal 
photoreceptors and retinal pigment epithelium (RPE), as well as atrophy of these portions of the 
retina in the macula, leading to severe visual decline with loss of reading vision, driving vision, 
and the ability to recognize faces. Vascular Endothelial Growth Factor (VEGF), a protein growth 
factor that stimulates angiogenesis and increases vascular permeability, is a major pathogenic 
factor in CNV due to AMD. Counteracting these effects of VEGF can provide significant 
therapeutic benefit to patients suffering from this disorder. 
The pathogenesis of AMD is poorly understood. It is characterized by development of focal 
deposits of long-spacing collagen and phospholipid vesicles within and beneath the basement 
membrane of the RPE, called “drusen” which can be accompanied by gradual degeneration of 
photoreceptors and RPE (atrophy), which often results in slow deterioration of central VA. This 
thickening and degeneration of Bruch’s membrane can predispose to abnormal growth of blood 
vessels from the choriocapillaris, termed CNV. The occurrence of CNV heralds the onset of wet 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
26 
AMD. Leakage from the CNV can cause macular edema with collection of fluid and blood beneath 
and within the macula, resulting in loss of vision. Growth of the lesions with accompanying 
fibrovascular or fibroglial tissue further destroys retinal tissue. Over time, the CNV promotes 
scarring that damages photoreceptors and the RPE, resulting in permanent vision loss. 
In addition to wet AMD, ocular neovascularization occurs in various other ocular diseases, 
including proliferative diabetic retinopathy, retinopathy of prematurity, and ocular hemangioma. 
Several lines of evidence have linked VEGF to the development of ocular vascular conditions. 
Vascular endothelial growth factor-A, VEGF-B, and Placental Growth Factor (PlGF) have all been 
detected in choroidal neovascular membranes. Placental Growth Factor may play an important role 
in the pathological angiogenesis, in a coordinated way with other VEGF family members. 
However, the exact effect of PlGF on neovascularization may be case-dependent. 
All pharmacologic therapies currently available for wet AMD target and inhibit VEGF and are 
administered by the intravitreal (IVT) route. These include Lucentis® (ranibizumab), Eylea 
(aflibercept), and Macugen® (pegaptanib sodium) (10,11,12). The primary mode of action (MoA) 
of these anti-VEGF agents is prevention of local angiogenesis and the decrease of the intra-retinal 
and subretinal fluid associated with abnormal blood vessels. Today anti-VEGF therapy is the 
mainstay and gold standard in the treatment of wet AMD (13). 
Aflibercept acts as a soluble decoy receptor that binds VEGF-A and PlGF with higher affinity than 
their natural receptors, thereby inhibiting the binding and activation of these cognate VEGF 
receptors. Aflibercept binds VEGF-dimers 1:1 and cannot form multimeric complexes. Binding 
and neutralization of VEGF dimers inhibits dimerization of the transmembrane receptors, VEGF 
receptor (VEGFR)-1 and VEGFR-2 and prevents activation of vascular endothelial cells. 
Inhibition of VEGF-A, VEGF-B, and PlGF-mediated effects is aflibercept’s exclusive MoA and 
is identical for all indications for which Eylea is licensed (14). 
2.1 Eylea: Aflibercept Reference Product 
Eylea (aflibercept) (15) is a recombinant fusion protein consisting of portions of human VEGFR-1 
and VEGFR-2 extracellular domains fused to the Fc portion of human immunoglobulin (Ig)G1 
formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a homodimeric 
glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, 
constituting an additional 15% of the total molecular mass, resulting in a total molecular weight 
of 115 kDa. Aflibercept is produced in recombinant CHO cells. 
Eylea is a sterile, clear, and colorless to pale yellow solution and supplied as a preservative-free, 
sterile, aqueous solution for intravitreal injection in a single-dose glass vial or a prefilled syringe 
designed to deliver 50 µL of solution containing 2 mg of aflibercept (40 mg/mL in 10 mM sodium 
phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, at pH 6.2). 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
27 
2.2 FYB203: Proposed Aflibercept Biosimilar 
FYB203 is developed as a biosimilar to Eylea as the reference medicinal product. The 
recommended dose of Eylea and FYB203 is 2 mg administered every 4 weeks for the first 
3 months, followed by a 2 mg dose once every 8 weeks (2 months). 
Like the originator Eylea, FYB203 is a glycosylated, disulfide-stabilized homodimeric 
recombinant fusion protein consisting of domain 2 of VEGFR-1) and domain 3 of VEGFR-2 fused 
to the Fc domain of human IgG1.
 
 
 
Like Eylea, FYB203 is supplied as a 40 mg/mL sterile, aqueous solution for IVT injection in a 
glass vial containing the same amount of solution. Each vial contains 100 µL, equivalent to 4 mg 
aflibercept. This provides a usable amount to deliver a single-dose of 50 µL containing 2 mg 
aflibercept.
 
 
 Storage conditions of FYB203 will be same as for the reference product Eylea. 
In vitro data obtained with representative FYB203 drug substance and drug product batches from 
production scale demonstrated similar pharmacological results in binding assays and cell-based 
assays when compared to Eylea. Since the main mechanism of action is through binding of 
aflibercept to members of the VEGF family and consequently blocking of downstream effects, it 
is expected that also the in vivo human pharmacological effects will be highly similar between 
FYB203 and Eylea. 
2.3 Study Rationale 
The reference product Eylea (15) is currently approved in the EU for the treatment of: 
• Neovascular (wet) AMD 
• Visual impairment due to macular edema secondary to retinal vein occlusion (RVO) (branch 
RVO or central RVO) 
• Visual impairment due to diabetic macular edema 
• Visual impairment due to myopic CNV 
In the US, the reference product, Eylea is currently approved for: 
• Neovascular (wet) AMD 
• Macular edema following RVO 
• Diabetic macular edema 
• Diabetic Retinopathy  
In Japan, Eylea is currently approved in the following indications: 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
28 
• Age-related macular degeneration with subfoveal CNV 
• Macular edema secondary to RVO 
• Choroidal neovascularization in pathologic myopia (myopic CNV)  
• Diabetic macular edema 
Regarding the treatment of wet AMD, there is an unmet need for an affordable treatment with a 
highly effective substance and the approved reference product, Eylea, is approaching patent 
expiration. For these reasons, the Sponsor has developed an aflibercept biosimilar version to Eylea. 
A biosimilar is a biological medicinal product that is highly similar to an already authorized 
original biological medicinal product (reference medicinal product) in terms of quality, 
tolerability, and efficacy based on a comprehensive comparability exercise (16, 17, 18). The 
European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have 
developed specific guidelines for a biologic drug to be approved as a biosimilar (16, 18, 19). These 
guidelines recommend a stepwise approach in developing a biosimilar starting with extensive 
physicochemical and biological characterization before initiating clinical studies for the 
comparison of the efficacy, tolerability, plasma concentration properties, and immunogenicity of 
the biosimilar. 
This Phase 3 study aims to demonstrate the biosimilarity between FYB203 (proposed aflibercept 
biosimilar) and Eylea (approved originator medicinal product) in terms of efficacy, safety, and 
immunogenicity, in patients with wet AMD, and to obtain approval in all granted indications for 
the originator biological medicinal product Eylea in the European Economic Area, Japan, and the 
US. 
This study will be conducted in compliance with the clinical study protocol, the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) Topic E6, and all applicable 
regulatory requirements including the principles outlined in the Declaration of Helsinki. 
2.4 Background 
Age-related Macular Degeneration, left untreated, is a leading cause of adult blindness in the 
developed world. Neovascular or wet AMD accounts for only 10% of cases of AMD yet results in 
90% of the severe vision loss. Epidemiological studies suggest that “wet” AMD will develop in 
almost 1 million persons in the US within the next 5 years (20, 21). 
Aflibercept acts as a soluble decoy receptor that binds VEGF-A, VEGF-B, and PlGF with higher 
affinity than their natural receptors and thereby can inhibit the binding and activation of these 
cognate VEGF receptors. Aflibercept has been shown to prevent abnormal, leaky blood vessel 
growth (CNV) observed in wet AMD and other intraocular disease manifestations related to 
exaggerated levels of VEGF which also cause macular edema and impaired vision. Today 
anti-VEGF therapy is the mainstay and gold standard in the treatment of wet AMD (13). 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
29 
A detailed description of the chemistry, pharmacology, nonclinical efficacy, and clinical safety of 
aflibercept is provided in the most recent Investigator’s Brochure (IB). 
2.5 Benefit/Risk Assessment 
As this study is being conducted in patients diagnosed with wet AMD, a benefit to the patient is 
expected. As other compounds of this class are approved for the intended indications, the risks are 
well understood at this time. The potential risks associated with this study are: 
1. Risks related to the intravitreal injection procedure: common risks associated with intravitreal 
injections include conjunctival hyperemia and hemorrhage at the injection site. Uncommon 
risks include endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, 
retinal tear and iatrogenic traumatic cataract, increase in intraocular pressure, and vitreous 
hemorrhage. 
2. Risks related to aflibercept study treatment: hypersensitivity, non-ocular hemorrhages and 
arterial thromboembolic events, and pigment epithelial retinal detachment. 
Based on the physical/chemical and preclinical data, FYB203 is expected to have the same safety 
and efficacy profile as the originator. Intravitreal aflibercept was generally well tolerated and 
without notable differences in ocular or non-ocular treatment-emergent adverse events (TEAEs) 
compared to ranibizumab. The incidence of anti-drug antibodies (ADAs) was low with no 
difference between pre- and post-dose values. 
The potential benefit of FYB203 is to bring new treatment options to patients with retinal diseases 
since there is a need for more easily accessible anti-VEGF therapeutic agents. That need can be 
met by developing biosimilars to approved anti-VEGFs. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of FYB203 may be found in the IB. 
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
31 
• 
Evaluate and compare local and systemic adverse 
events (AEs) and serious adverse events (SAEs) 
• 
Frequency of local and systemic AEs and SAEs  
ADA = Anti-drug antibody; AE = Adverse event; ETDRS = Early treatment diabetic retinopathy study; FCP = foveal central point; 
FCS = foveal central subfield; NEI VFQ-25 = National eye institute visual function questionnaire 25. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
32 
4 STUDY DESIGN 
4.1 Overall Design 
Figure 2 
Overall Study Design 
 
ADA = Anti-drug antibody; EOS = End of Study; IMP = Investigational Medicinal Product; ICF = informed consent form; 
PC = plasma concentration; V = visit; W = week. 
This is a Phase 3, parallel-group, 1:1 randomized, active-controlled, double-masked, multicenter 
study to demonstrate the equivalence of efficacy of FYB203 to Eylea and to evaluate the safety 
and immunogenicity in patients with nAMD. During the Screening period (maximum 28-day 
starting with the informed consent form [ICF] signature), the central reading center will receive 
the patient’s retinal images in order to provide an independent, masked assessment of patient 
eligibility regarding FCP, lesion classification, lesion size, and area of CNV. Patients must meet 
all eligibility criteria during the Screening period, including positive evaluation of the screening 
retinal images performed by the central reading center. After this period, potential patients who 
satisfy the entry criteria will be randomized in a 1:1 ratio to receive either FYB203 or EU-approved 
Eylea at a dose of 2 mg (0.05 mL of a 40 mg/mL solution).  
The treatment will consist of 1 IVT injection every 4 weeks for 3 consecutive doses starting at 
Week 0 (Visit 1) through Week 8 (Visit 3) followed by 1 IVT injection every 8 weeks over a period 
of approximately 48 weeks (Visit 8). Each patient will receive a total of 8 IVT injections.  
This study is designed to be evaluation-masked, neither the patient nor the Investigator(s) 
performing the evaluations and masked study personnel will know which treatment the patient is 
assigned to.   
At each study site there will be at least 2 masked staff members (Investigator and VA examiner) 
and 1 unmasked Injector (who will administer the investigational medicinal product [IMP]). There 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
33 
may be also other masked study site staff (e.g. study coordinator, study nurse, optical coherence 
tomography technician, photographer). The unmasked Injector should have a back-up person. 
The Principal Investigator (PI) (or his/her masked study team to whom tasks have been delegated) 
will do all pre- and post-injection assessments (Tonometry and Ophthalmologic Examination, 
spectral domain optical coherence tomography [SD-OCT], fluorescein angiography [FA] and 
color fundus photography [FP], blood samples collection, and National eye institute visual 
function questionnaire 25 [NEI VFQ-25 questionnaire administration]), except measurements of 
refraction and VA. The masked Investigator(s) will also assess the relationship of all AEs to IMP, 
including those noted by the unmasked Injector. 
Only the masked VA examiners will measure refraction and BCVA. The masked VA examiners 
will not be permitted to have any further roles in obtaining data from a patient; however, they may 
perform additional study support tasks such as read-out of the temperature logger. 
Only the unmasked Injector will perform IVT injections. He/she can also perform the post-dose 
safety check or tonometry, according to the clinical practice of the study site. The systemic 
concentrations of free and total aflibercept will be assessed and compared in a subgroup of up to 
60 patients (up to 30 per arm) at Baseline Visit (Visit 1) prior to 1st IVT dose, 48 hours after 1st 
IVT dose (Visit 1a) close to Cmax, and at 48 hours after the 3rd IVT dose (Visit 3a) close to Cmax. 
Anti-drug antibodies formation against aflibercept will be evaluated in serum in all patients prior 
to the patient receiving the IVT injections administered at Baseline Visit (Visit 1), Week 4 
(Visit 2), Week 16 (Visit 4), Week 24 (Visit 5), Week 40 (Visit 7) and Week 56 (Visit 9), and in 
addition, in patients participating in the subgroup 1 week after the 1st dose (Visit 1b) and 48 hours 
after the 3rd dose (Visit 3a). In case, patients experiencing signals of an unexpected ocular 
inflammation, as this may indicate an immune response, additional sampling of an ADA sample 
should be conducted. 
A follow-up visit for safety (Early Termination Visit/End of Study [EOS]) will occur at Week 56 
(Visit 9) after the administration of 8 IVT doses of IMP. If the patient discontinuation happens 
before the 8 planned IVT doses, an Early Termination Visit should be conducted. 
The total study duration for a patient will be approximately 56 weeks, excluding the Screening 
period. 
A Data Monitoring Committee (DMC) will be established to monitor safety throughout the study. 
The DMC is independent of the Sponsor and of the contract research organization (CRO) and will 
consist of external experts who will review the safety and tolerability data from the study. Details 
of the analysis will be specified in the DMC Statistical Analysis Plan (SAP) and referenced in the 
DMC Charter. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
34 
4.2 Scientific Rationale for Study Design 
The purpose of this study is to demonstrate the biosimilarity between FYB203 and Eylea in 
patients with wet AMD, the most sensitive indication. The planned confirmatory study is expected 
to rule out any clinically meaningful differences between both biological medicinal products. 
FYB203 is developed in the same indications and route of administration as the reference product 
Eylea. 
For supporting the assessment of overall systemic safety of FYB203 relative to Eylea, systemic 
exposures will be collected and compared in the subgroup population (approximately 60 patients, 
30 patients per treatment group) in this study.  
No clinical studies have been performed with FYB203 to date. The clinical development program 
of FYB203 builds on an extensive analytical and functional characterization which compares 
FYB203 and Eylea. Similarity will be confirmed in a parallel-group, 1:1 randomized, 
active-controlled, double-masked, multicenter study to demonstrate clinical equivalence of 
efficacy of FYB203 to Eylea and evaluate the safety and immunogenicity over 56 weeks in patients 
with subfoveal wet AMD. The product characteristics of the reference product Eylea are well 
known for human use. After close to 10 years on the EU and US market, the medicinal product 
continues to be an effective agent for the treatment in all approved indications. 
4.3 Justification for Dose 
The dose of FYB203 and Eylea selected for use in this study is the approved dose for patients with 
subfoveal wet AMD treatment. 
4.4 End of Study Definition 
A patient is considered to have completed the study if he/she has completed the study including 
the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA) 
(Section 1.3). 
The end of the study is defined as the date of the last visit of the last patient in the study or last 
scheduled procedure shown in the SoA (Section 1.3) for the last patient in the study globally. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
35 
5 STUDY POPULATION 
The study population for this study are patients with subfoveal wet AMD.  
Prospective approval of protocol deviations to eligibility criteria, also known as protocol waivers 
or exemptions, will not be granted. 
Eligibility for participation in this study will be based on the inclusion/exclusion criteria. Only 1 
eye will be designated as the study eye (SE). For patients who meet eligibility criteria in both eyes, 
the eye with the worse VA will be selected as the SE. If both eyes have equal VA, the eye with 
better visual prognosis (e.g. clearer lens and ocular media and less amount of subfoveal scar or 
geographic atrophy) will be selected at the Investigator’s discretion. If there is no objective basis 
for selecting the SE, factors such as ocular dominance, other ocular pathology, and patient 
preference should be considered by the Investigator in making the selection. 
5.1 Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for the study: 
General 
1. Age ≥ 50 years at Screening. 
2. Male or female: 
• Male: 
− A male patient must agree to use contraception as detailed in 
 of this 
protocol during the treatment period (48 weeks) and for at least 4 weeks after the last 
dose of study treatment. 
• Female:  
− A female patient is eligible to participate if she is not pregnant 
, not 
breastfeeding, and at least 1 of the following conditions applies: 
i) Not a woman of childbearing potential (WOCBP) as defined in 
 
OR 
ii) A WOCBP who agrees to follow the contraceptive guidance in 
 during the 
treatment period (48 weeks) and for at least 4 weeks after the last dose of study 
treatment 
3. Capable of giving signed informed consent as described in 
, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
4. Willingness and ability to undertake all scheduled visits and assessments. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
36 
Ocular (Study Eye) 
5. Newly diagnosed (within 6 months of Screening Visit), angiographically documented, 
treatment-naïve CNV lesion secondary to wet AMD:  
a) All subtypes of wet AMD CNV lesions are eligible (classic, occult, some classical 
component, retinal angiomatous proliferation lesions). Treatment-naïve CNV 
secondary to wet AMD must be subfoveal or juxtafoveal with subfoveal component 
related to CNV activity (such as sub- or intra-retinal fluid by SD-OCT or RPE 
detachment); 
b) Total area of whole lesion must be ≤ 9 disc areas; 
c) Total CNV area encompasses ≥ 50% of total lesion area based on FA, including all 
subtypes of wet AMD. 
Term 
Definition 
Wet AMD 
Clinical signs (including findings by retinal imaging) attributable to wet AMD 
(e.g. pigmentary changes, drusen) and no other likely etiologic explanations for 
the degenerative changes 
Subfoveal 
Including the center of the fovea 
Juxtafoveal 
At least some part of CNV lesion must be in an area up to 199 µm from the 
geometric center of the fovea 
Total area of 
whole lesion 
A contiguous area of abnormal tissue that contains a CNV (as documented by 
FA) with possible additional components of hemorrhages, blocked fluorescence 
not from hemorrhage, serous detachment of the RPE, atrophy, and subretinal 
fibrosis 
 
AMD = Age-Related Macular Degeneration; CNV = choroidal neovascularization; FA = fluorescein 
angiography; RPE = Retinal pigment epithelium. 
6. Sufficiently clear ocular media and adequate pupillary dilation to permit good quality ocular 
imaging. 
7. Best corrected visual acuity in the SE, determined by standardized ETDRS testing, between 
20/40 and 20/200 Snellen equivalent 
. 
8. Foveal center point retinal thickness at Screening ≥ 300 µm and < 800 µm. (FCP thickness is 
defined as the distance between the vitreoretinal interface and Bruch’s membrane at the 
geometric center of the fovea). 
Ocular (Fellow Eye) 
9. Best corrected visual acuity in the fellow eye, determined by standardized ETDRS testing, at 
least 20/200 Snellen equivalent 
. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
37 
5.2 Exclusion Criteria  
Patients are not eligible for the study if any of the following criteria apply: 
General 
1. Employees of clinical study sites, individuals directly involved with the conduct of the study 
or immediate family members thereof, prisoners, and persons who are legally institutionalized. 
2. Study eye requiring immediate treatment. 
Prior or Current Ocular Treatment 
 
3. Any prior treatment with anti-VEGF agent (e.g. bevacizumab, aflibercept, ranibizumab) or any 
investigational products to treat AMD, in either eye. 
4. Prior treatment with any investigational products to treat ocular diseases other than wet AMD 
within 30 days or 5 half-lives prior to Randomization, whichever is longer. 
5. History of vitrectomy, macular surgery or other surgical intervention for AMD in the SE. 
6. History of IVT or periocular injections of corticosteroids or device implantation within 
6 months prior to Randomization in the SE. 
7. Prior treatment with verteporfin (photodynamic therapy), transpupillary thermotherapy, 
radiation therapy, or retinal laser treatment (e.g. focal laser photocoagulation) in the SE. 
8. Any other intraocular surgery (including cataract surgery) in the SE within 3 months prior to 
Randomization. 
CNV Lesion Characteristics 
9. Sub- or intra-retinal hemorrhage that comprises more than 50% of the entire lesion in the SE. 
10. Irreversible structural damage involving the center of fovea (e.g. advanced fibrosis > 50% of 
the total lesion in the SE or atrophy) in the SE that is considered sufficient to irreversibly impair 
VA.  
11. CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic 
myopia. 
Current Ocular Conditions 
12. Retinal pigment epithelial tear involving the macula in the SE. 
13. History of or current full-thickness macular hole (Stage 2 and above by clinical examination 
or full-thickness macular hole by SD-OCT imaging of any size) in the SE. 
14. History of or current retinal detachment in the SE. 
15. Current vitreous hemorrhage in the SE. 
16. Spherical equivalent of the refractive error in the SE demonstrating more than 6 diopters of 
myopia. 
17. For patients who have undergone prior refractive or cataract surgery in the SE, the preoperative 
refractive error in the SE should not exceed 6 diopters of myopia. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
38 
18. History of or current corneal transplant in the SE. 
19. Aphakia in the SE. Absence of an intact posterior capsule is allowed if it occurred as a result 
of yttrium aluminum garnet laser posterior capsulotomy in association with prior posterior 
chamber intraocular lens (IOL) implantation. 
20. Active or recent (within 4 weeks prior to Randomization) intraocular inflammation of clinical 
significance in either eye such as active infections of the anterior segment (excluding mild 
blepharitis) including conjunctivitis, keratitis, scleritis, uveitis, or endophthalmitis. 
21. Uncontrolled ocular hypertension or glaucoma in the SE (defined as intraocular pressure [IOP] 
≥ 30 mmHg, despite treatment with anti-glaucomatous medication). 
22. Ocular disorders in the SE (i.e. retinal detachment, pre-retinal membrane of the macula or 
cataract with significant impact on VA) at the time of Screening that may confound 
interpretation of study results and compromise VA. 
23. Any concurrent intraocular condition in the SE (e.g. glaucoma, cataract, or diabetic 
retinopathy) that, in the opinion of the Investigator, would either require surgical intervention 
during the study to prevent or treat visual loss that might result from that condition or affect 
interpretation of study results. 
Systemic Medical History and Treatments and Conditions at Screening 
24. Use of other investigational drugs (excluding vitamins, minerals) within 30 days or 5 half-lives 
prior to Randomization, whichever is longer. 
25. Systemic treatment with anti-VEGF agent (e.g. bevacizumab) within 90 days prior 
Randomization. 
26. Any type of advanced, severe, or unstable disease, including any medical condition (controlled 
or uncontrolled) that could be expected to progress, recur, or change to such an extent that it 
may bias the assessment of the clinical status of the patient to a significant degree or put the 
patient at special risk. 
27. Stroke or myocardial infarction within 6 months prior to Randomization. 
28. Presence of uncontrolled systolic blood pressure > 160 mmHg or uncontrolled diastolic blood 
pressure > 100 mmHg within 4 weeks prior to Randomization. 
29. Known hypersensitivity to the IMP (aflibercept or any component of the aflibercept 
formulation) or to drugs of similar chemical class or to fluorescein or any other component of 
fluorescein formulation. 
30. Current or planned use of systemic medications known to be toxic to the lens, retina, or optic 
nerve, including deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines 
and ethambutol. 
31. History of recurrent significant infections and/or current treatment for active systemic 
infection. 
Ocular (Fellow Eye) 
32. Any diagnosis and/or signs of wet AMD requiring treatment with an IVT anti-VEGF agent 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
39 
(e.g. aflibercept, bevacizumab, ranibizumab) within the Screening period or are expected, in 
the opinion of the Investigator, to need such treatment in the fellow eye throughout the study. 
At the time of screening and randomization, the Investigator should use best medical 
judgement to exclude patients with a probable fellow eye treatment need during the course of 
the study.  
5.3 Lifestyle Considerations 
No restrictions are required.  
Please see Section 7.5 for medications that are prohibited during this study. 
5.4 Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
adverse event. 
5.5 Re-screening Procedures 
The decision for re-screening of a patient is at the discretion of the Investigator and may be 
performed under certain circumstances. Re-screening may only be performed once per screened 
patient and 1 of the following criteria has to apply: 
1. The patient was already consented and fulfilled all eligibility criteria but the enrollment 
was delayed due to an unexpected change in the patient’s personal situation (e.g. an issue 
in the family). 
2. The patient did not fulfill all eligibility criteria previously due to an event (e.g. laboratory 
test result, physical exam finding, planned surgery, uncontrolled medical condition) or any 
other technical/logistical reason (e.g. laboratory samples lost by courier, malfunction of a 
device) that has been resolved. 
3. The patient did not fulfill all eligibility criteria previously but becomes eligible due to a 
protocol amendment and change of inclusion and exclusion criteria. 
In cases where previous screening procedures were discontinued, and the patient was not 
randomized, the following procedures have to be undertaken: 
1. The patient has to sign and date a new ICF prior to being re-screened. 
2. A new unique patient identification number will be assigned to the patient. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
40 
3. Data of the patient has to be entered in a new eCRF with the new unique patient 
identification number. 
4. Re-screening has to be documented in the source data. 
The re-screened patient can be randomized if all eligibility criteria are met. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
41 
6 SCHEDULE OF STUDY VISITS 
All assessments of a particular visit have to be performed within 1 day, except for screening. 
6.1 Visit 0 (Screening) 
Prior to participation in the study patients will be informed both verbally and in writing about the 
purpose of the study, its procedures and any potential risks or discomforts resulting from 
participation. Informed consent will be obtained by the patient before any study specific 
procedures. Only those patients who fulfill all eligibility criteria will be enrolled into the study. 
However, if a routine procedure (e.g. FA, SD-OCT) is performed to diagnose AMD independent 
of this clinical study, and subsequently the patient provides informed consent, procedures 
performed prior to informed consent may be used as Screening assessments for this study, provided 
the 28-day period of Screening evaluations is respected. In addition, the assessments must meet 
the standards defined in this protocol and SD-OCT images must be obtained by central reading 
center-certified SD-OCT operators and evaluated by the central reading center. 
At Screening (Visit 0), the following activities and assessments will be performed within 28 days 
prior to Visit 1: 
• Patient information/Informed consent 
• Demographic information (date of birth [or year of birth], gender, race and ethnicity) 
• Medical history:  
− General medical conditions:  
 All conditions present at the time of ICF signature 
 All conditions/surgeries that occurred within 1 year prior to ICF signature 
 History of arterial thromboembolic events (defined as nonfatal stroke or 
nonfatal myocardial infarction) regardless of the time of occurrence 
− Ophthalmologic conditions: all data regardless of the time of occurrence including SE 
and fellow eye information 
• Prior treatments:  
− All medications the patient is receiving until the time of ICF 
− All medications related to ophthalmologic conditions, regardless of the time of 
occurrence 
− All medications related to arterial thromboembolic events (defined as nonfatal stroke 
or nonfatal myocardial infarction) regardless of the time of occurrence 
− Ocular and systemic: ocular and systemic anti-VEGF treatment, regardless of the 
indication 
• Physical assessment 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
42 
• Vital signs (before any blood sample collection on the same day) 
• BCVA (both eyes): refraction and VA testing must be performed by a certified masked visual 
acuity examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (both eyes): Goldmann applanation tonometry must be performed at Screening  
• Slit lamp exam (both eyes) 
• Ophthalmoscopy (both eyes) 
• Verification of inclusion and exclusion criteria 
• Urine sampling 
. Urine samples must be collected before performing FA (when 
applicable) to avoid false elevations in urine protein values. 
• Fluorescein angiography (both eyes) 
• Color FP (both eyes) 
• SD-OCT (both eyes) 
• Laboratory tests 
 
• Pregnancy test, serum human chorionic gonadotropin (hCG) and follicle stimulating hormone 
(FSH) (only women) 
• Concomitant medications 
• AEs recorded from the day the informed consent was signed 
6.2 Visit 1 (Baseline) 
At Visit 1, the following activities and assessments will be performed: 
Prior to randomization: 
• Concomitant medications 
• AEs 
• NEI VFQ-25 (prior to any ophthalmic procedures or any other assessments) 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 
• SD-OCT (SE) 
• Verification of inclusion and exclusion criteria 
To remain eligible for randomization at Day 1 (Visit 1), the following 3 criteria must be met: 
1. There is no significant anatomical change in the SE following ophthalmological and SD-OCT 
examination between the Screening Visit and Visit 1 (i.e. large subretinal hemorrhage, RPE 
tear, pigment epithelial detachment).  

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
43 
2. Visual acuity in the SE is within the defined inclusion criteria range (using ETDRS testing 
Snellen equivalent 20/40 [0.5] to 20/200 [0.1]) and within 5 letters (better or worse) of the 
Screening VA. Thus: 
− If difference in BCVA is greater than 5 ETDRS letters (better or worse) between 
Screening and Visit 1, the patient must NOT be randomized. 
− If the Snellen equivalent at Visit 1 is no longer within the inclusion criteria (Snellen 
equivalent 20/40 to 20/200), the patient must NOT be randomized. 
3. No diagnosis and/or signs of wet AMD requiring treatment during the study with an IVT 
anti-VEGF agent in the fellow eye (e.g. aflibercept, bevacizumab, ranibizumab). The 
Investigator should use best medical judgement to exclude patients with a probable FE 
treatment need during the course of the study. 
Randomization: 
After completing the Screening period and being confirmed eligible for participation in the study 
by the central reading center and the masked Investigator, patients will be centrally randomized 
via Interactive Web Response System (IWRS) into 1 of the two study groups in a 1:1 ratio 
(FYB203:Eylea).  
Post-randomization: 
• Blood sampling for ADAs 
• Blood sampling for systemic evaluation of aflibercept plasma concentration (Subgroup only) 
IVT injection:  
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator  
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
44 
6.2.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs or symptoms of potential complications of the IVT injections such 
as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, the 
masked Investigator or delegated staff member will be responsible for further patient assessments 
and treatment, if applicable. 
6.3 Visit 1a (Subgroup only) 
• Blood sampling for evaluation of systemic aflibercept plasma concentration  
• AEs 
6.4 Visit 1b (Subgroup only) 
• Blood sampling for ADAs 
• AEs 
6.5 Visit 2 
The following activities and assessments will be performed: 
During the visit: 
• Concomitant medications 
• AEs 
Pre-IVT injection: 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 
• SD-OCT (SE) 
• Blood sampling for ADAs 
IVT injection: 
• IVT administration (FYB203 or Eylea) by unmasked IVT administrator 
Post-IVT injection: 
• Safety check including: 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
45 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 
6.5.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
6.6  Visit 3 
The following activities and assessments will be performed: 
During the visit: 
• Concomitant medications 
• AEs 
Pre-IVT injection: 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 
• SD-OCT (SE) 
• Additional ADA sampling and evaluation will be performed in patients experiencing signals 
of unexpected ocular inflammation  
IVT injection: 
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
46 
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 
6.6.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
6.7 Visit 3a (Subgroup only) 
• Blood sampling for evaluation of systemic aflibercept plasma concentration  
• AEs 
• Blood sampling for ADAs 
6.8 Visit 4 
The following activities and assessments will be performed: 
During the visit: 
• Concomitant medications 
• AEs 
Pre-IVT injection: 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
47 
• SD-OCT (SE) 
• Blood sampling for ADAs 
IVT injection: 
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator 
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 
6.8.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
6.9 Visit 5 
The following activities and assessments will be performed: 
During the visit: 
• NEI VFQ-25 (prior to any ophthalmic procedures or any other assessments) 
• Physical assessment 
• Vital signs (before any blood sample collection on the same day) 
• Laboratory tests 
 
• Concomitant medications 
• AEs 
Pre-IVT injection: 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
48 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 
• Urine sampling 
. Urine samples must be collected before performing FA (when 
applicable) to avoid false elevations in urine protein values. 
• Fluorescein angiography (SE) 
• Color FP (SE) 
• SD-OCT (SE) 
• Blood sampling for ADAs 
IVT injection: 
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator  
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 
6.9.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
6.10 Visit 6 
The following activities and assessments will be performed: 
During the visit: 
• Concomitant medications 
• AEs 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
49 
Pre-IVT injection: 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 
• SD-OCT (SE) 
• Additional ADA sampling and evaluation will be performed in patients experiencing signals 
of unexpected ocular inflammation  
IVT injection: 
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator 
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 
6.10.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
6.11 Visit 7 
The following activities and assessments will be performed: 
During the visit: 
• NEI VFQ-25 (prior to any ophthalmic procedures or any other assessments) 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
50 
• Physical assessment 
• Vital signs (before any blood sample collection on the same day) 
• Laboratory tests 
 
• Concomitant medications 
• AEs 
Pre-IVT injection: 
• BCVA (both eyes): refraction and VA testing must be performed by a certified masked visual 
acuity examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (both eyes): the Tonopen or Perkins Tonometer, may be 
used, however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (both eyes) 
• Ophthalmoscopy (both eyes) 
• Urine sampling 
. Urine samples must be collected before performing FA (when 
applicable) to avoid false elevations in urine protein values. 
• Fluorescein angiography (both eyes) 
• Color FP (both eyes) 
• SD-OCT (both eyes) 
• Blood sampling for ADAs 
 
IVT injection: 
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator 
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 
6.11.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
51 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
6.12 Visit 8  
The following activities and assessments will be performed: 
During the visit: 
• Concomitant medications 
• AEs 
Pre-IVT injection: 
• BCVA (SE): refraction and VA testing must be performed by a certified masked visual acuity 
examiner using an ETDRS chart prior to any ophthalmic assessments. 
• Tonometry (prior to the injection) (SE): the Tonopen or Perkins Tonometer, may be used, 
however Goldmann applanation tonometry must be used to verify any IOP ≥ 30 mmHg 
• Slit lamp exam (SE) 
• Ophthalmoscopy (SE) 
• SD-OCT (SE) 
• Additional ADA sampling and evaluation will be performed in patients experiencing signals 
of unexpected ocular inflammation.  
IVT injection: 
• IVT administration (aflibercept biosimilar FYB203 or Eylea) by unmasked IVT administrator 
Post-IVT injection: 
• Safety check including: 
− Check for light perception: within 15 minutes after the injection (SE). Absence of light 
perception may indicate central retinal artery occlusion. In this case, paracentesis is 
indicated as an attempt to restore central retinal artery perfusion immediately. 
− Ophthalmoscopy: within 30 minutes after the injection (SE) to assess central retinal 
artery perfusion and identify injection-related complications (i.e. hemorrhage or retinal 
detachment). 
− Tonometry: 30 to 60 minutes after the injection (SE). The Tonopen or Perkins 
Tonometer, may be used, however Goldmann applanation tonometry must be used to 
verify any IOP ≥ 30 mmHg. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
52 
6.12.1 Telephone Safety Call  
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are signs and symptoms of potential complications of the IVT injections such 
as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, the 
masked Investigator or delegated staff member will be responsible for further patient assessments 
and treatment, if applicable. 
6.13 Visit 9 (EOS/Early Termination Visit) 
The following activities and assessments will be performed: 
During the visit: 
• NEI VFQ-25 (prior to any ophthalmic procedures or any other assessments) 
• Physical assessment 
• Vital signs (before any blood sample collection on the same day) 
• Laboratory tests 
 
• Concomitant medications 
• AEs 
• BCVA (both eyes): refraction and VA testing must be performed by a certified masked visual 
acuity examiner using an ETDRS chart prior to any ophthalmic assessments.  
• Tonometry (both eyes): the Tonopen or Perkins Tonometer, may be used, however Goldmann 
applanation tonometry must be used to verify any IOP ≥ 30 mmHg  
• Slit lamp exam (both eyes) 
• Ophthalmoscopy (both eyes) 
• Urine sampling 
. Urine samples must be collected before performing FA (when 
applicable) to avoid false elevations in urine protein values. 
• Fluorescein angiography (both eyes) 
• Color FP (both eyes) 
• SD-OCT (both eyes) 
• Blood sampling for ADAs 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
53 
7 STUDY TREATMENT 
The IMPs are FYB203 and Eylea. 
The term experimental product refers to FYB203 (aflibercept biosimilar). 
The term comparator refers to Eylea (EU-approved). 
7.1 Study Treatment(s) Administered 
This study is designed to be evaluation-masked, neither the patient nor the Investigator(s) 
performing the evaluations and masked study personnel will know which treatment the patient is 
assigned to.   
The PI (or his/her masked study team to whom tasks have been delegated) will do all pre- and 
post-injection assessments (Tonometry and Ophthalmologic Examination, SD-OCT, FA and color 
FP, blood samples collection and, NEI VFQ-25 questionnaire administration), except 
measurements of refraction and VA. The masked Investigator/s will also assess the relationship of 
all AEs to IMP, including those noted by the unmasked IVT administrator. 
Only the unmasked IVT administrator will perform IVT injections. He/she can also perform the 
post-dose safety check or tonometry, according to the clinical practice of the study center. 
Each eligible patient will receive a total of 8 IVT injections of FYB203 or Eylea according to the 
details in Table 2. 
Table 2 
Study Treatment Details 
Study Treatment Name: 
 
FYB203  
(experimental product) 
Eylea  
(comparator)1 
INN: 
aflibercept 
Pharmaceutical Form: 
Solution for injection; clear, colorless to pale yellow and iso-osmotic 
solution 
Route of Administration  
Intravitreal  
Unit Dose Strength(s): 
2 mg (0.05 mL of 40 mg/mL solution) 
Storage conditions 
Store in a refrigerator (2ºC to 8ºC). Do not freeze. Protect from light 
(keep the outer carton unopened). Prior to usage, the unopened carton 
may be stored at room temperature (below 25°C) for up to 24 hours. 
Dosing Instructions: 
 
IMP is for IVT injection only and may only be administered according 
to medical standards and applicable guidelines by a qualified 
ophthalmologist in IVT injections. 
Packaging and Labeling 
 
Study treatment packaging and labeling will comply with Good 
manufacturing practices regulations and local regulatory requirements.  
1 Eylea® (15) 
IMP = investigational medicine product; IVT = intravitreal. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
54 
7.2 Preparation/Handling/Storage/Accountability 
1. Detailed instructions for storage and handling will be provided within a separate IMP Handling 
Manual. 
2. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
3. Only patients randomized in the study may receive study treatment and only a qualified 
ophthalmologist experienced in IVT injections should administer the injection.   
4. All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized study center staff. 
5. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for maintaining complete documentation of IMP handling up from receipt until 
destruction or return, respectively, such as study treatment accountability, reconciliation, and 
record maintenance. This documentation must be available for inspection at any time. 
6. Further guidance and information for the final disposition of unused study treatment are 
provided in the IMP Handling Manual.  
7.3 Measures to Minimize Bias: Randomization and Masking 
The randomization will occur after the written informed consent has been obtained and eligibility 
has been confirmed for participation in the study at Visit 1 (Baseline). Patients will be randomized 
1:1 to either FYB203 or Eylea. 
All patients will be centrally assigned to randomized study treatment using an IWRS. Before the 
study is initiated, the log in information and directions for the IWRS will be provided to each study 
center. 
Study treatment will be dispensed at the study visits summarized in SoA (Section 1.3).  
This is a double-masked study with limited access to the randomization code. The experimental 
product (FYB203) and comparator will be identical in physical appearance. Due to differences in 
the products presentation, the IMPs will be administered by an unmasked IVT administrator which 
will be responsible for the study injections only. The treatment each patient will receive will only 
be disclosed to the unmasked IVT administrator but not to other study center staff, patient, 
Sponsor, or study vendors. The treatment codes will be held by the IWRS vendor. 
Except for the unmasked IVT administrator, unmasking should be considered only when 
knowledge of the treatment assignment is deemed essential for the patient’s medical care by the 
Investigator or a regulatory body. Investigators are strongly discouraged from requesting the mask 
be broken for an individual patient, unless there is a patient safety issue that requires unmasking 
and would change patient management. The process for breaking the mask will be handled through 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
55 
the IWRS. Any center that breaks the mask under inappropriate circumstances may be asked to 
discontinue its participation in the study. If the mask is broken, it may be broken only for the 
patient in question. 
The Sponsor and CRO must be notified immediately if a patient and/or Investigator/site personnel 
is unmasked during the course of the study. Pertinent information regarding the circumstances of 
unmasking of a patient’s treatment code must be documented in the patient’s source documents 
and electronic case report forms (eCRFs). This includes who performed the unmasking, the 
patient(s) affected, the reason for the unmasking, the date of the unmasking and the relevant IMP 
information. 
7.4 Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any deviations 
from the intended regimen must be recorded in the respective eCRF page. 
All IMP injections will be given by the unmasked Investigator or back-up to ensure compliance. 
The exact date and time of IMP injection must be recorded in the source documentation and the 
eCRF. 
Patients who miss any scheduled dosing visit should be counseled on the importance of good 
compliance to the study dosing regimen.  
If the IMP is not given within 7 days of the scheduled dosing visit date, the IMP should be given 
at the discretion of the PI but the interval between two doses injected into one eye should be at 
least 4 weeks. If the next dose is scheduled in less than 4 weeks time, dosing should not be 
performed at the previous late visit.  
If IMP is given outside of the visit window, this will be captured as protocol deviation. Next 
scheduled dosing visit date and visit window should not be altered even if previous dosing is not 
performed on the exact scheduled dosing visit date. It is the Investigator’s responsibility to make 
every effort to return to the dosing schema summarized in SoA (Section 1.3). 
7.5 Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines) that the patient 
is receiving at the time of Screening or receives during the study must be recorded in the eCRF 
along with: 
• Reason for use; 
• Dates of administration including start and end dates; 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior 
therapy. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
56 
A list of excluded medications/therapy is provided in 
. 
7.5.1 Fellow Eye Treatment 
If during the course of the study the patient develops wet AMD in the fellow eye (non-SE) with 
an acute treatment need, the fellow eye will not be considered as an additional SE. For the fellow 
eye treatment, the patient could ONLY receive Eylea after Visit 3 and should remain in the study. 
Patients in the plasma concentration subgroup should not receive fellow eye treatment until after 
the plasma concentration blood sample collection at Visit 3a has been taken. 
Fellow eye injection will be performed by the Investigator for this study and the details about the 
injection will be documented in the eCRF. However, fellow eye visit is not part of study but should 
be timely separated by at least 14 days from study eye treatment. Ocular AEs for the fellow eye 
will be monitored and recorded after the written informed consent is obtained from the patient 
until Week 56 (Visit 9).  
7.6 Treatment After the End of the Study 
The Sponsor will not provide any additional care to patients after they leave the study because 
such care should not differ from what is normally expected for patients with the medical condition. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
57 
8 DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION/WITHDRAWAL  
8.1 Discontinuation of Study Treatment  
The patient must be discontinued from study treatment in the event of any of the following: 
• Consent withdrawal by patient: 
− If patients withdraw his/her consent, the Investigator must inquire the reasons for 
consent withdrawal as to whether it is related to the study (e.g. documented lack of 
efficacy, AE or pregnancy); however, the patient could refuse to provide such reason; 
− If the main reason for consent withdrawal is considered related to the study, the 
Investigator may select appropriate reason among the reasons listed below other than 
consent withdrawal. 
• Any newly developed or aggravated ophthalmic abnormality other than AMD in the SE which 
could interfere with evaluation of efficacy or safety of IMP including but not limited to retinal 
vascular abnormality; 
• Any AEs in the SE (e.g. intraocular inflammation, VA loss, increased IOP [> 30 mmHg], 
subretinal hemorrhage, vitreous hemorrhage, and local or systemic infection) which in the 
opinion of the Investigator and/or patient would require IMP discontinuation; 
• Protocol deviations which may adversely affect the patient’s safety and/or integrity of data as 
agreed by the masked Investigator and/or upon request from the Sponsor; 
• IMPs non-compliance (Section 7.4): 
− A patient misses any of the first 2 doses (IVT injection of IMPs at Week 0 [Day 1] and 
Week 4) after randomization. 
− A patient misses 2 consecutive doses during the study period after randomization. 
• Decision by the masked Investigator that the patient requires alternate treatment (e.g. other 
anti-VEGF agents such as bevacizumab or ranibizumab, PDT, PPV etc.) to treat wet AMD in 
the SE;  
• Decision by the Sponsor that IMP discontinuation is in the patient’s best medical interest or 
administrative decision for a reason (e.g. a suspicion of fraud, the patient enrolling in multiple 
clinical studies, lack of compliance, etc.) other than that of an AE; 
• Lost to follow-up; 
• Pregnancy; 
• Rhegmatogenous retinal detachment or full-thickness macular hole. 
Any significant change in the posterior pole (e.g. subretinal hemorrhage, macular hole, vitreous 
hemorrhage or opacity, retinal detachment, etc.) that is detected with fundus examination should 
be confirmed and documented with FP and/or FA. The masked Investigator should decide IMP 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
58 
discontinuation based on the FP and/or FA. The images taken at unscheduled visits will be sent to 
the central reading center within 72 hours. 
If a patient is prematurely discontinued from study treatment due to any of the above described 
reasons excluding death, the patient will complete the Early Termination Visit procedures (except 
for plasma concentration sampling) as described for Week 56 (Visit 9) immediately. 
If a patient agrees to continue follow-up for associated clinical outcome information until Week 56 
irrespective of IMP injection status, the patient’s clinical outcome information such as BCVA, 
AEs and concomitant medication will be collected through non-invasive chart review, if available. 
If a patient does not agree to continue follow-up of associated clinical outcome information, the 
patient will be terminated from the study accordingly. The data and blood samples collected on 
the patient up to the Early Termination Visit remains in the study database and no further data will 
be collected. 
In all cases, the reason for IMP discontinuation must be recorded in the patient’s medical records 
and in the eCRF. 
8.1.1 Temporary Investigational Medicinal Product Withhold 
• Intraocular inflammation: 
− Interrupt study treatment if intraocular inflammation (iritis, iridocyclitis, or vitritis) is 
≥ 2+ in the SE; 
− Patients with ≥ 2+ intraocular inflammation may be allowed to resume study treatment 
subsequently, as determined by Medical Monitor and Investigator. 
• Intraocular surgery in the SE (e.g. cataract operation, vitrectomy, glaucoma surgery, etc.) 
which in the opinion of the Investigator would require IMP discontinuation: 
− Interrupt study treatment after intraocular surgery in the SE; 
− Study treatment may be resumed no earlier than 28 days after an uncomplicated cataract 
surgery and no evidence of post-operational inflammation at that time. For cataract 
surgery or other intraocular surgery with complications, study treatment may be 
permitted, as determined by Medical Monitor and Investigator. 
• BCVA decrease: 
− Interrupt study treatment if there is a study treatment-related decrease of ≥ 30 letters in 
BCVA in the SE compared with the last assessment of BCVA prior to the most recent 
treatment; 
− Study treatment may be permitted subsequently, as determined by Investigator. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
59 
• Elevated IOP: 
− Interrupt study treatment if pre-treatment IOP in the SE is ≥ 30 mmHg; 
− Treatment may be permitted when IOP has been lowered to < 30 mmHg, either 
spontaneously or with treatment, as determined by Investigator. 
• Rhegmatogenous retinal break: 
− Interrupt study treatment if a retinal break is present in the SE; 
− Study treatment may be resumed no earlier than 28 days after successful laser 
retinopexy, as determined by Investigator. 
• Active infection: 
− Interrupt study treatment if active or suspected ocular or periocular infections present 
(e.g. 
infectious 
conjunctivitis, 
infectious 
keratitis, 
infectious 
scleritis, 
or 
endophthalmitis) in either eye or if the patient requires treatment for an active 
non-ocular infection; 
− Study treatment may be subsequently permitted after discussion with Medical Monitor; 
− Additional ADA sampling and evaluation will be performed in patients experiencing 
signals of unexpected ocular inflammation. 
• On-study prohibited medications: 
− See Section 8 for additional reasons for study treatment interruption or discontinuation; 
• Any other reason for treatment interruption per the discretion of the masked Investigator has 
to be discussed upfront with the medial monitor. 
8.1.2 Replacement 
Patients who are discontinued from IMP after randomization will not be replaced. 
8.2 Patient Discontinuation/Withdrawal from the Study 
• A patient may withdraw from the study at any time at his/her own request, or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
• If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
• If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the study center study records. 
• See SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
60 
8.3 Lost to Follow-up 
A patient will be considered lost to follow-up if he or she misses a study visit and subsequent visits 
despite attempts to contact the patient. The following actions must be taken if a patient fails to 
return to the clinic for a required study visit: 
• The study center must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the patient wishes to and/or should continue in the study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 contact attempts and, if necessary, 
a certified letter to the patient’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study.  
8.4 Premature Termination of the Study 
The Sponsor may terminate this study prematurely for any reasonable cause. The Independent 
Ethics Committees (IECs) / Institutional Review Boards (IRBs) and Competent Authority(ies) 
(CAs) should be informed in accordance with applicable regulations. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in the 
study, or potential study patients. 
• A decision on the part of the Sponsor to suspend or discontinue development of FYB203. If 
the study is prematurely terminated or suspended for any reason, the masked 
Investigator/institution should promptly inform the study patients and should ensure 
appropriate therapy and follow-up for the patients. The masked Investigator should also 
attempt to complete the final study assessments as outlined in the Section 6.13. Patients with 
an ongoing AE should be followed until resolution of the AE, or the masked Investigator or 
delegated staff member decides that the AE is stable and needs no further follow-up. All AEs 
should be followed up according to Section 9.3.3. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
61 
9 STUDY ASSESSMENTS 
• Study procedures and their timing are summarized in the SoA (Section 1.3).  
• Protocol waivers or exemptions are not granted. 
• Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
awareness to determine if the patient should continue or discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the SoA (Section 1.3), 
is essential and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a Screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
• Procedures conducted as part of the patient’s routine clinical management (e.g. blood count) 
and obtained before signing of the ICF may be utilized for Screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA (Section 1.3). 
• The maximum amount of blood collected from the selected subgroup of patients for the 
evaluation of systemic aflibercept concentration over the duration of the study will be 
approximately 24 mL. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples. 
9.1 Efficacy Assessments  
9.1.1 Best Corrected Visual Acuity 
Visual Acuity examiners and VA lanes at study centers must be certified to ensure consistent 
measurement of BCVA prior to start of study. 
Refraction and VA testing will be assessed by a certified masked visual acuity examiner using an 
ETDRS chart prior to any ophthalmic assessments. VA should only be performed by site 
personnel with active certification by the site certification vendor and must be a different person 
than the Investigator administering the IVT injections. Visual Acuity will be assessed with ETDRS 
charts. Please refer to the VA Specifications for full details. Patient must use the same chart 
consistently from Screening to Week 56 (Visit 9). Visual Acuity testing must be performed before 
dilation of pupils and FP/FA and OCT assessment. 
A decrease in VA of ≥ 15 letters from the last assessment of VA should be reported as AEs/Serious 
Adverse Events (SAEs) as appropriate. 
If the event meets 1 or more of the following criteria, it should be reported as SAE. 
• A decrease in VA of ≥ 30 letters from the last assessment of VA; 
• A decrease in VA to the level of light perception or worse. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
62 
9.1.2 Ophthalmological Examination 
The ophthalmological examination will consist of an external examination of the eye and adnexa 
routine screening for eyelid/pupil responsiveness (including but not limited to blepharoptosis, 
abnormal pupil shape, unequal pupils, abnormal reaction to light, and afferent pupillary defect), 
slit lamp exam, indirect ophthalmoscopy, and IOP measurements. 
Grading scales for slit lamp exam are provided in 
. 
9.1.2.1 Slit Lamp Exam 
The slit lamp exam (cornea, lens, iris, aqueous reaction [cells and flare]) will be performed on both 
eyes at Screening, Visit 7, and EOS Visit and on the SE at each other IVT administration visit until 
Week 56 (Visit 9) Visit. At the dosing visits, slit lamp exam should be performed prior to IVT 
injection by a masked Investigator. Anterior segments will be assessed with the slit lamp.  
9.1.2.2 Indirect Ophthalmoscopy 
Indirect ophthalmoscopy will be performed on both eyes at Screening, Visit 7, and EOS Visit and 
on the SE at each other IVT administration visit until Week 56 (Visit 9) prior to the IVT injection 
by a masked Investigator. The fellow eye will be followed to determine if wet AMD develops. 
The posterior segment will be examined after dilation of pupil with 2 to 3 drops of 
phenylephrine-tropicamide (or any other mydriatic drug), applied topically to the eye. 
The posterior segment assessment method can be performed using 1 of the 2 methods at the 
discretion of the PI and must remain consistent for a patient throughout the study: (1) indirect 
ophthalmoscopy at the slit lamp with a lens for indirect ophthalmoscopy (e.g. 90D) or (2) indirect 
binocular ophthalmoscopy (performed with a head mounted indirect binocular ophthalmoscope 
and a lens, e.g. 20D). 
9.1.2.3 Tonometry 
IOP will be measured on both eyes at Screening, Visit 7, and EOS Visit and on the SE at each 
other IVT administration visit until Week 56 (Visit 9) prior to the IVT injection by a masked 
Investigator and within 30 to 60 minutes after the injection either by the unmasked IVT 
administrator or the masked Investigator. 
IOP must be measured using Goldmann applanation tonometry at Screening. The Tonopen or 
Perkins Tonometer may be used at other times in each patient after Screening. The method used 
for the IOP measurement for a patient could be performed at the discretion of the PI and must 
remain consistent throughout the study. However, Goldmann applanation tonometry must be used 
to verify any IOP ≥ 30 mmHg.  

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
63 
9.1.3 Color Fundus Photography and Fluorescein Angiography 
Color FP and FA will be performed by a masked Investigator on both eyes at Screening, Visit 7 
(prior to the IVT administration), and EOS Visit and the images will be sent to the central reading 
center within 72 hours. 
Color FP and FA will also be performed on the SE prior to IVT injection of IMP at Visit 5. The 
images will be sent to the central reading center within 72 hours. Additional FA may be performed 
at any time at the discretion of the Investigator(s). 
At least 1 site staff performing FA/FP must be certified by the central reading center before study 
start at the site. 
Only FP/FA devices certified by central reading center should be used. If 1 or more FP/FA devices 
are certified in a study center, sites should use the same FP/FA device consistently from Screening 
to EOS Visit for a patient. 
All original FP/FA images will be kept at the investigational site and copies will be sent to the 
central reading center for analysis and archiving within 72 hours. A detailed protocol for FP/FA 
image acquisition and transmission will be provided in the Imaging Manual. 
If any significant change in the posterior pole (e.g. subretinal hemorrhage, macular hole, vitreous 
hemorrhage or opacity, retinal detachment, etc.) is detected with fundus examination, additional 
FP and/or FA can be performed at the Investigator’s discretion, and images will be sent to the 
central reading center within 72 hours. 
9.1.4 Spectral Domain Optical Coherence Tomography (SD-OCT) 
The SD-OCT will be performed on both eyes at Screening, Visit 7, and EOS; the SE will be 
examined at each other IVT administration visit until Week 56 (Visit 9) prior to IVT injection of 
IMP. 
At least 1 site staff who will perform SD-OCT scans in this study must be certified by the central 
reading center before study start at the site. 
The SD-OCT devices registered in a study center should meet the minimum requirements 
(including software) as defined in the Imaging Manual. The site should use the OCT devices 
registered by central reading center during the study period. The site should use the same device 
throughout the study for a patient; if there is more than 1 device approved at the site and/or the 
primary is going out of order, any of them can be used. 
All original SD-OCT images will be kept at the study center and copies will be sent to the central 
reading center for analysis and archiving within 72 hours. A detailed protocol for SD-OCT image 
acquisition and transmission will be provided in the Imaging Manual. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
64 
9.1.5 National Eye Institute Visual Function Questionnaire (NEI VFQ-25) 
Vision-related Quality of Life will be assessed by a masked Investigator using NEI VFQ-25 
 questionnaire. NEI VFQ-25 should be performed at Week 0 (Visit 1) prior to 
randomization, and at Visit 5, Visit 7, and EOS Visit. NEI VFQ-25 should be performed prior to  
any ophthalmic procedures or any other assessments. 
All questionnaires will be administered in the local language. The Investigator or delegated site 
staff will conduct a questionnaire survey with the patient. The results of the questionnaire will be 
recorded in a paper questionnaire and then entered into the eCRF. 
9.2 Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
9.2.1 Physical Assessment 
Physical assessment will be performed at Screening, at Visit 5 and Visit 7 prior to IVT injection 
of IMP and at EOS Visit by a masked Investigator. The patients will be examined before any blood 
sample collection on the same day. A safety check will be performed within 60 minutes post-IVT.  
All patients will undergo verbal health status assessments. Additionally, at any time, other physical 
assessments may be performed at the Investigators’ discretion. 
The assessment will consist of a routine interrogation of the patients’ general health. The 
assessment is divided into 9 categories: general appearance; head, eye, ear, nose, and throat 
(HEENT); chest; cardiovascular; abdominal; genitourinary; musculoskeletal; skin; and 
neurological. The findings will be recorded as either “normal” or “abnormal” for each category 
and any abnormal findings will be described. 
9.2.2 Vital Signs 
Vital signs will be assessed at Screening, at Visit 5 and Visit 7 prior to IVT injection of IMP and 
at EOS Visit. The patients will be examined before any blood sample collection on the same day. 
The Investigator should assess all vital signs and any clinically significant abnormalities should be 
reported as AE.  
The following vital signs will be assessed: 
• Body temperature, pulse rate, blood pressure. 
• Blood pressure and pulse measurements will preferably be assessed with an automated device. 
Manual techniques will be used only if an automated device is not available. 
• Vital signs will consist of 1 pulse and 3 blood pressure measurements (3 consecutive blood 
pressure readings will be recorded at intervals of at least 1 minute) in supine position after at 
least 5 minutes of rest in supine position. The average of the 3 blood pressure readings will be 
recorded in the CRF. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
65 
9.2.3 Clinical Safety Laboratory Assessments 
Blood (approximately 30 mL) and urine sampling for clinical laboratory test will be collected at 
Screening, at Visit 5 and Visit 7 prior to IVT injection of IMP and at EOS Visit. Blood and urine 
sampling for clinical laboratory test will also be collected at any time during the Visit at EOS Visit. 
Urine samples must be collected before performing FA (when applicable) to avoid false elevations 
in urine protein values. 
Blood samples will be analyzed in central laboratory and urine samples will be tested at each study 
center by using a dipstick which will be provided by the Sponsor. A detailed process for clinical 
laboratory sampling, handling, storage and shipping will be provided in the Central Laboratory 
Manual for safety laboratory testing. 
• See 
 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency.  
• The masked Investigator must review the laboratory report as soon as possible but prior to the 
next IVT administration visit, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those that 
are not associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the patient’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline values 
of Visit 1 or are no longer considered clinically significant by the Investigator or Medical 
Monitor. 
− If such values do not return to normal/baseline values of Visit 1 within a period of time 
judged reasonable by the Investigator, the etiology should be identified, and the 
Sponsor notified. 
− All protocol-required laboratory assessments, as defined in 
, must be 
conducted in accordance with the Laboratory Manual and the SoA (Section 1.3).  
− If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in patient management or are 
considered clinically significant by the Investigator (e.g. SAE, AE, or dose 
modification), then the results must be recorded in the CRF.  
9.2.4 Pregnancy and Follicle Stimulating Hormone Tests 
Serum pregnancy and FSH tests must be performed for all women at Screening. The serum samples 
taken at Screening will be analyzed in the central laboratory. 
Additional serum or urine pregnancy test can be performed at each study center during the study 
period, if necessary (at the Investigator’s discretion). 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
66 
Deleted pregnancy test result at Screening, such as handling error, lost/damaged during shipment, 
sampling error or tube breakage, should be followed by re-test. Result of re-test will be considered 
as that of an initial. 
9.2.5 3-Day Post-IVT Injection Telephone Safety Check 
The study center staff will call the patient for an AE assessment 3 days after each IVT injection to 
determine if there are any signs and symptoms of potential complications of the IVT injections 
such as but not limited to endophthalmitis, retinal detachment, etc. If a potential AE is suspected, 
the masked Investigator or delegated staff member will be responsible for further patient 
assessments and treatment, if applicable. 
9.3 Adverse Events 
The definitions of an AE or SAE can be found in 
. 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following-up AEs. 
The Investigator should follow up each AE until the event has resolved completely or to the 
baseline values of Visit 1, the event is assessed as stable by the Investigator, the patient is lost to 
follow up, or the patient withdraws consent. Every effort should be made to follow all SAEs until 
a final outcome can be reported. If after follow-up (Week 56), complete recovery, return to baseline 
status, or stabilization cannot be established, an explanation should be recorded on the AE eCRF. 
During the study period, resolution of AEs (with dates) should be documented in the patient’s 
medical records to facilitate source data verification and in the Adverse Event eCRF page. If, after 
follow-up, complete recovery, return to the baseline values of Visit 1 or stabilization cannot be 
established, an explanation should be recorded in the AE eCRF page. (Section 8).  
9.3.1 Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the signing of the ICF until Week 56 (Visit 9; EOS/Early 
Termination) Visit, at the time points specified in the SoA (Section 1.3). 
Medical occurrences that begin before ICF signature will be recorded on the Medical 
History/Current Medical Conditions section of the CRF, not in the AE section. 
All SAEs will be recorded and reported to the 
 Lifecycle Safety within 24 hours of 
awareness, as indicated in 
. The Investigator will submit any updated SAE data or 
follow-up information to the 
 Lifecycle Safety within 24 hours of it being available. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
67 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the Investigator must promptly notify the 
 Lifecycle Safety. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in 
. 
9.3.2 Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient by a masked Investigator is the preferred method to 
inquire about AE occurrences.  
9.3.3 Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section  9.3.6), will be followed until resolution, stabilization, the event is otherwise explained, or 
the patient is lost to follow-up (as defined in Section 8.3). Further information on follow-up 
procedures is given in
. 
9.3.4 Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the 
 Lifecycle Safety of an SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of patients and the safety 
of a study treatment under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor and 
 Lifecycle Safety will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor or 
 Lifecycle Safety 
policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SUSAR or other 
specific safety information (e.g. summary or listing of SUSARs) from the 
 Lifecycle 
Safety will review, document the review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
68 
9.3.5 
Pregnancy 
• Details of all pregnancies in female patients and, if indicated and a respective ICF was signed, 
female partners of male patients will be collected after the start of study treatment and until 
Week 56 (Visit 9). 
• If a pregnancy is reported, the Investigator should inform the 
 Lifecycle Safety within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
. 
• Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
9.3.6 
Adverse Events of Special Interest 
The following AEs in the SE will be classified as Adverse Events of Special Interests (AESIs) in 
this study: 
• Any case of new onset IOP of > 21 mmHg that does not respond to treatment, except the 
transient pressure rise observed within an hour after IVT injection of IMP; 
• Any case of IOP ≥ 35 mmHg, at any time, that required treatment; 
• Any case of intraocular infection such as endophthalmitis; 
• Any case of intraocular inflammation such as iritis, vitritis, and iridocyclitis; 
• Iatrogenic traumatic cataract; 
• Arterial thromboembolic events defined as nonfatal stroke, nonfatal myocardial infarction, or 
vascular death;  
• Death of unknown cause. 
9.3.7 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs 
The following disease-related events (DREs) are common in patients with wet AMD and can be 
serious: 
•  Macular hemorrhage 
•  Macular edema 
Because these events are typically associated with the disease under study, they will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may meet 
the definition of a SAE. These events will be recorded on the corresponding CRF page in the 
patient’s CRF within the appropriate time frame. These DREs will be monitored by a DMC on a 
routine basis.  
NOTE: However, if either of the following conditions applies, then the event must be recorded and 
reported as an SAE (instead of a DRE):  

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
69 
• The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual patient.  
OR 
• The Investigator considers that there is a reasonable possibility that the event was related to 
study treatment. 
9.4 Plasma Concentration  
Blood samples for plasma concentration evaluation will be collected in approximately 60 patients 
(30 patients per arm) participating in plasma concentration evaluation. 
The sites which are interested in taking part in the plasma concentration evaluation will be selected 
before the study starts. Patients screened at these sites will be asked to participate in the plasma 
concentration sub-study. If the patient consents to the blood sampling, the patient will be recruited 
in this sub-study. When the expected number of patients in the plasma concentration sub-study is 
reached, no more plasma concentration patients will be recruited. 
Blood samples of approximately 24 mL will be collected for measurement of plasma 
concentrations of systemic free and total aflibercept as specified in the SoA at Week 0 (Visit 1) 
prior to 1st IVT dose, 48 hours after 1st IVT dose (Visit 1a) close to Cmax, and at 48 hours after 
the 3rd IVT dose (Visit 3a) close to Cmax. In case of a delayed IVT dose the collection of blood for 
plasma concentration assessment should be postponed accordingly to keep the required time 
intervals (48 hours) between IVT dose and sample collection. Concentrations of free and total 
aflibercept will be measured using a validated assay by the central laboratory. Instructions for the 
collection and handling of biological samples will be provided in the Laboratory Manual. The 
actual date and time (24-hour clock time) of each sample will be recorded in the eCRF. The exact 
time and date of study treatment administration will also be recorded. 
A detailed process of plasma concentration sampling, handling, storage, and shipping will be 
provided in the Laboratory Manual. 
9.5 Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
9.6 Genetics 
Genetics parameters are not evaluated in this study. 
9.7  Immunogenicity Assessments 
Anti-drug antibodies (ADAs) to aflibercept will be evaluated in serum samples collected from all 
randomized patients according to the SoA (Section 1.3). Blood samples of approximately 26 mL 
will be collected for measurement of ADAs. To note, the plasma concentration subgroup will have 
additional ADA samples collected, (resulting in a total of 34 mL) as described in the SoA 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
70 
(Section 1.3). In case of a delayed IVT dose the collection of blood for ADA assessment should 
be postponed accordingly to keep the required time intervals between IVT dose and sample 
collection.  
Additionally, serum samples should also be collected at the Early Termination Visit from patients 
who discontinued study treatment or were withdrawn from the study. 
The exact date and time of sample collection will be recorded in the eCRF. Serum samples will be 
screened for ADA and the titer of confirmed positive samples will be reported, as well as 
assessment of neutralizing antibodies (nAbs).  
The detection and characterization of ADA will be performed using a validated assay method.  
A detailed process for immunogenicity sampling, handling, storage, and shipping will be provided 
in the Laboratory Manual. 
10 STATISTICAL CONSIDERATIONS 
10.1 Statistical Hypotheses 
The test for equivalence will be performed with respect to FYB203 versus Eylea.  
The following hypotheses will test the null hypothesis for nonequivalence against the alternative 
hypothesis of equivalence: 
𝐻𝐻0: |𝜇𝜇𝐹𝐹𝐹𝐹𝐹𝐹203 − 𝜇𝜇𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸| ≥3.5 
𝐻𝐻𝐴𝐴: |𝜇𝜇𝐹𝐹𝐹𝐹𝐹𝐹203 − 𝜇𝜇𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸| < 3.5 
where 𝜇𝜇𝐹𝐹𝐹𝐹𝐹𝐹203 is the mean change from Baseline to Week 8 in BCVA, measured in ETDRS letters, 
for patients randomized to receive FYB203 and 𝜇𝜇𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 is the mean change from Baseline to 
Week 8 in BCVA, measured in ETDRS letters, for patients randomized to receive Eylea. 
10.2 Sample Size Determination  
Originally 400 patients were planned to be randomized
. However, 
actual number of patients randomized are 434 
.  
The total sample size of approximately 400 randomized patients has been calculated on the basis 
of a 1:1 randomization ratio and a standard deviation (SD) of 9.0 ETDRS letters in BCVA. The 
calculation considers that overall, an application of a two-sided 90% CI for the US and a two-sided 
95% CI for the EU is required for assessing biosimilarity and that consistency between analyses 
based on the Full Analysis Set (FAS) and the Per Protocol Set (PPS) is required for a conclusion 
of bioequivalence of FYB203 and Eylea. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
71 
An equivalence test of means using two one-sided tests with sample sizes of 180 patients in both 
treatment groups achieves at least 90.3% power at a 2.5% significance level when there is no true 
difference between the means, the SD is 9.0, and the equivalence interval is ]-3.5; 3.5[ letters. 
Three hundred and sixty patients overall are thus an adequate sample size for the PPS analysis; if 
a difference of 10% between the FAS and the PPS is assumed, it is required to randomize 400 
patients for the FAS. 
Applying the US criterion for assessing biosimilarity, the equivalence test of means using two 
one-sided tests with sample sizes of 144 in both treatment groups (288 patients in total) achieves 
90.0% power at a 5.0% significance level when no difference between the means is assumed, the 
SD is 9.0, and the equivalence interval is ]-3.5; 3.5[ letters. Assuming a difference of 10% between 
the PPS and the FAS, 320 patients in total should be included in any US-specific analysis. 
Further, the change of FCP retinal thickness at Week 4 (Visit 2) compared to Baseline Visit 
(Visit 1), shall be evaluated as a key secondary endpoint for EU/Japan regulatory submissions. 
The sample size of 200 patients in each treatment group (400 patients in total) provides a power 
of 82.8% at a 2.5% significance level (e.g. a two-sided 95% CI) when the true difference between 
the means is 0, the SD is 135 µm and the equivalence interval is [-45.0; 45.0] µm.  
The fixed sample size described above could have been increased following the interim masked 
review of sample size after the first 200 treated patients had completed Week 8 (Visit 3) up to a 
maximal sample size of 640 patients for the US analysis and a maximum sample size of 800 
patients for the EU analysis, see Section 10.5. This interim masked review of sample size was 
performed in November 2021 and revealed that the observed variability overall does not require 
an increase in sample size to maintain the intended statistical power of 90% for the primary 
endpoint, and of 80% for the key secondary endpoint (EU/Japan only). 
The interim masked review of sample size (Section 10.5) however, may increase the type 1 error 
rate (22). Simulation results using the US criterion suggest that for true SDs of the change in BCVA 
lower than about 12 letters, an interim analysis after 200 patients, a maximal sample size of 640 
patients and a target power of 90% for the US analysis based on the PPS, a slight increase of the 
type one-error rate may occur. Therefore, an adjusted significance level of 4.8%, corresponding to 
a two-sided 90.4% confidence interval (CI) will be used in the US-specific analysis, which was 
shown to keep the overall type 1 error of the US-specific analysis below 5%. Similarly, simulation 
results using the EU/Japan criterion, when the interim analysis is performed after 200 patients, the 
maximal sample size is 800 patients and the target power is 90% for the primary endpoint based 
on the PPS and 80% for the key secondary endpoint based on the FAS, show that an alpha of 2.4% 
ensures the overall type 1 error in the EU/Japan-specific analysis to not be higher than 2.5%. 
Therefore, 2-sided 95.2% CIs for the difference between the two treatment arms will be used in 
the EU/Japan-specific analysis. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
72 
The US-and EU/Japan-specific analyses will be performed sequentially. Only if the US-specific 
analysis based on the first 320 treated patients (or the adapted sample size for the US analysis) 
shows bioequivalence using the 4.8% significance level, then EU/Japan-specific analysis based on 
the bigger sample size of all treated patients will be performed, using a 2.4% significance level. 
Bioequivalence with respect to the key secondary endpoint will only be assessed if bioequivalence 
with respect to the primary efficacy endpoint has been shown. Therefore, no inflation of the overall 
type 1 error due to multiple testing can occur. 
10.3 
Populations for Analyses 
For purposes of analysis, the analysis sets in Table 3 are defined. 
Table 3 
Analysis Sets 
Analysis Set 
Description 
FAS 
All patients randomly assigned to study treatment who receive at least 1 
injection of study treatment in the study eye. Patients will be analyzed according 
to the study treatment they have been randomized to. 
PPS 
All patients included in the FAS who have no major protocol deviations until 
Week 8 that will interfere with the interpretation of the BCVA efficacy data at 
Baseline or at Week 8 and have received treatment from the randomized 
treatment group only, and have a valid measurement of the BCVA at Baseline 
and at Week 8 available. 
Safety Analysis Set 
All patients who receive at least 1 injection of study treatment in the SE. Patients 
will be analyzed according to the treatment they actually received in the SE. 
Plasma concentration Analysis 
Set 
All patients randomly assigned to study treatment, who receive at least 1 dose 
of study treatment in the SE and who have at least 1 valid post-dose plasma 
concentration measurement. Patients will be analyzed according to the 
treatment they actually received in the SE. 
FAS = Full Analysis Set; PPS = Per Protocol Set. 
10.4 Statistical Analyses 
The SAP(s) will be developed and finalized before the first unmasked analysis is performed.  
The following analyses are planned on unmasked data: 
The final US analysis, which is intended for the US regulatory submission (Biologics License 
Application [BLA]), is planned to be performed when the first 320 treated patients have completed 
40 weeks of treatment (or discontinued the study prematurely) and all randomized and treated 
patients have completed the primary efficacy endpoint assessment at Week 8 (or discontinued the 
study prematurely).  
Due to the geopolitical situation in Ukraine in 2022, more patients than the originally planned first 
320 treated patients may be included in the US analysis. The exact number of patients will be 
determined prior to providing any access regarding treatment unmasking information to any 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
73 
personnel involved in the analysis of this data and will depend on the extent of missing treatments 
with study medication, and possibly missing information related to safety and efficacy assessments 
in affected sites and patients. Patients to be included in the US analysis will be chosen based on 
the exact sequence of the first treatment UTC date/time. Formal records on this decision will be 
kept in the blind data review meeting minutes together with time points of decision and partial 
unmasking. 
The main EU analysis intended for initial regulatory submission in EU is planned when all 
randomized and treated patients have completed 24 weeks of treatment or have discontinued the 
study prematurely.  
The final EU/Japan analysis intended for the EU and Japan regulatory submissions is planned 
when all randomized and treated patients have completed the whole study period of 56 weeks or 
discontinued the study prematurely. 
The decisions on inclusion or exclusion of any patient into any of the analysis sets and on inclusion 
into the US analysis will be finalized prior to the US analysis (i.e. the first unmasked analysis), 
and will be documented in the blind data review meeting minutes. Only patients included in the 
US analysis will be unmasked for the pre-defined group of persons and functions who will have 
access to the results of the analysis. 
Updates on protocol deviation listings and intercurrent events will be provided for EU/Japan 
analysis and report, but the allocation of each patient to the analysis sets will not change after the 
first unmasked analysis. 
Prior to the US analysis, the first unmasked analysis, a database lock will be performed on all data 
up to and including at least the Week 40 visit for all randomized and treated patients planned to be 
included in the US analysis and for all data until the individual last visit up to the cut-off date for 
all other randomized and treated patients. A second database lock will be performed for the main 
EU analysis, including all available data for all treated patients up to the cut-off date (at least up 
to and including Week 24 visit). At this second database lock, all data from visits that were already 
performed will be cleaned and locked although some data might not be included in the statistical 
analysis. The third and final database lock will be performed prior to the final EU/Japan analysis. 
The data in the EU/Japan analyses is not expected to change compared to the US analysis data and 
the data in the final EU/Japan analysis is not expected to change compared to the Week 24 EU 
analysis data. Data from visits performed after data cut-off, new concomitant medication and new 
AEs might be new; and only stop dates of any ongoing AEs and medications and final outcome of 
ongoing AE might be subject to change. 
Only a restricted number of pre-defined persons not otherwise involved in the direct conduct and 
management of the study and the study sites, will have access to any unmasking information to 
perform and review this analysis. All personnel directly involved in the management of sites, 
patients and data (i.e. Clinical Research Associate [CRA]s, Investigators, study nurses, most 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
74 
Sponsor personnel, data management) will not have access to any information with respect to the 
individual treatment group of patients or unblinded summary result; and the medical safety review 
will be performed by independent masked review personnel.  
The following conventions will be used in all planned statistical analyses: 
All collected data will be summarized using descriptive statistics by visit (when applicable) and 
treatment group for the SE and fellow eye separately, unless otherwise specified. Summary 
statistics will consist of the number of observations, mean, SD, minimum, median, quartiles and 
maximum for continuous parameters, and number and percent of patients for categorical 
parameters. 
For each eye, baseline value, for each measured parameter, will be defined as the last non-missing, 
including unscheduled assessments prior to the first injection of study drug, unless otherwise 
specified. 
Individual patient data will be presented in listings. 
Statistical analysis will be performed using Statistical Analysis Software (SAS) version 9.4 or 
higher. 
10.4.1 Efficacy Analyses 
The FAS will be used for all efficacy analyses. Sensitivity analyses based on the PPS will be 
performed for the primary and secondary efficacy endpoints (see below). For the final assessment 
of bioequivalence, it is essential that the analyses of the primary efficacy endpoint based on the 
FAS and on the PPS as well as other sensitivity analyses yield consistent results. 
10.4.1.1 Primary Estimand 
The primary estimand is the mean difference between the randomized treatment groups, FYB203 
and Eylea for the primary endpoint, i.e. change from Baseline to Week 8 in BCVA, in the SE 
regardless of treatment adherence and usage of concomitant medications and using data on all 
patients within the FAS. Also, patients randomized and treated although inclusion or exclusion 
criteria were violated will be analyzed according to the randomized treatment group. 
Any other currently unknown intercurrent events or any possible major protocol deviation in the 
time between Baseline and Week 8 will be handled in the SAP or the data review prior to database 
lock for the first unmasked analysis (final US analysis). This estimand is following a treatment 
policy strategy. 
10.4.1.2 Primary Analysis 
The primary estimand will be assessed through a mixed model for repeated measures (MMRM) 
including the BCVA at Baseline as covariate, country, visit, randomized treatment group, the 
baseline-by-visit interaction, and the treatment-by-visit interaction as fixed effects. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
75 
Within-patients’ correlations will be modeled using an unstructured variance-covariance matrix. 
Kenward-Roger degrees of freedom approximation will be used. The MMRM will use all available 
data collected until Week 24 (Visit 5) for the SE for all patients for model estimation. Missing data 
will not be explicity imputed, however if a patient has a missing data point at a specific post-
Baseline visit the model assumes that the patient’s missing value at that visit is comparable to the 
observed values of another patient having identical baseline characteristics and a comparable 
course of change from baseline until Week 24 (Visit 5). 
The difference in the treatment group least square means and the corresponding two-sided 90.4% 
and 95.2% CIs will be estimated from the MMRM to address regulatory requirements in the US 
and the EU/Japan, respectively.  
If the respective CI is completely contained in the interval ]-3.5; 3.5[ ETDRS letters, equivalence 
of FYB203 and Eylea can be concluded (rounded to the next integer, this corresponds to an 
equivalence margin of 3 ETDRS letters). 
10.4.1.3 Sensitivity Analyses and Supplemental Estimands 
Sensitivity analyses of the primary estimand may be defined in the SAP, if appropriate. 
A supplemental estimand will be the mean difference between the randomized treatment groups, 
FYB203 and Eylea in the primary endpoint for the SE, excluding patients from the FAS with major 
protocol deviations which impact the BCVA assessments until Week 8 (Visit 3).  
Another supplemental estimand will be the mean difference between the randomized treatment 
groups, FYB203 and Eylea in the primary endpoint for the SE, excluding patients from the FAS 
who discontinue treatment before Week 8 or do not have a Week 8 BCVA assessment. 
A further supplemental estimand will be a combination of the 2 estimands mentioned above and 
will be the mean difference between the randomized treatment groups, FYB203 and Eylea in the 
primary endpoint for the SE, based on the PPS. 
Other supplemental estimands, which will impute the BCVA hypothetically of those patients 
excluded from the PPS as if the intercurrent event had not happened will be considered in addition 
and finally described in the SAP.   
The supplemental estimands will be assessed using the same methods described for the primary 
analysis.  
Further supplemental estimands and sensitivity analyses of the supplemental estimands may be 
defined in the SAP, if appropriate. All supplemental estimands and sensitivity analyses will be 
performed using appropriate CIs. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
76 
10.4.1.4 Analysis of Secondary Endpoints 
The secondary endpoint of change in FCP retinal thickness from Baseline to Week 4 will be 
analyzed in a similar way as the primary endpoint using the equivalence interval from 
[- 45; 45] µm. The difference in the treatment group least square means and the corresponding 
two-sided 95.2% CI will be estimated from the MMRM using all patients in the FAS. If the 
two-sided 95.2% CI is completely contained in the equivalence interval [-45; 45] µm, equivalence 
of FYB203 and Eylea with respect to the FCP retinal thickness can be concluded. This secondary 
endpoint will be analyzed and reported as key secondary for any report intended for the EMA. 
The change from baseline in the SE over time for BCVA, FCP, and FCS retinal thickness and total 
lesion area will be analyzed using a similar MMRM model than the one used for the primary 
estimand. The absolute values and the change from baseline for each parameter will also be 
summarized descriptively by visit and treatment group for all scheduled time points for the SE. 
Data for the fellow eye will be summarized descriptively.  
NEI VFQ-25 total scores will be determined as described in the official manual. The absolute 
values and the change from baseline for each parameter will also be summarized descriptively by 
visit and treatment group for the SE and fellow eye separately.  
The proportion of patients who gain or lose ≥ 5, 10 or 15 ETDRS letters and the percentage of 
patients with fluid-free macula at each visit, based on all patients with relevant evaluations at each 
given visit, will be presented in descriptive summary tables.  
Statistical tests of secondary endpoints will be exploratory in nature and reported with nominal 
p-values. For differences or ratios between the treatment groups, two-sided 95% and possibly 90% 
CI will be provided as appropriate. 
10.4.2 Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened 
in severity after the first administration of study treatment. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
For each study treatment, numbers of ocular TEAEs and incidence rates will be tabulated by 
preferred term, system organ class, and treatment group for the SE and FE separately. Number of 
non-ocular TEAEs and incidence rates will be tabulated by preferred term, system organ class, and 
treatment group.  
Similarly, ocular and non-ocular TEAEs by maximum severity, TEAEs by relationship to study 
treatment, SAEs and TEAEs leading to discontinuation of study treatment will be tabulated for 
each treatment group.  

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
77 
All laboratory test results, vital signs measurements will be summarized using descriptive statistics 
at each visit for absolute values and change from baseline.  
10.4.3 Other Analyses  
10.4.3.1 Plasma Concentrations 
Concentrations of free and total systemic aflibercept will be listed, summarized, and presented 
graphically by treatment and time point as appropriate. No plasma concentration parameters will 
be estimated. 
Concentration summaries will be based on the plasma concentration analysis set.  
Concentrations that are below the lower limit of quantitation will be set to 0 for the computation 
of descriptive statistics.  
Further details will be provided in the SAP. 
10.4.3.2 Immunogenicity 
Immunogenicity ADA results (positive, negative, and titer, and if appropriate, nAbs result), will 
be listed by patient and sampling time.  
The number and proportion of patients with positive and negative ADA will be summarized by 
treatment group and sampling time. 
10.4.4 Subgroup Analyses 
Subgroup analyses will be defined in the SAP in all details. 
10.5 Interim Analyses  
No formal interim analyses for efficacy are planned; however, an interim masked review of sample 
size was planned after the first 200 treated patients reached the Week 8 time point. This interim 
analysis was planned to safeguard the study from a power loss due to a possible higher variability 
of more than the assumed SDs of 9.0 EDTRS letters in BCVA or of 135 µm in FCP retinal 
thickness 
Variability of the primary endpoint and of the EU-specific key secondary endpoint was estimated 
as the common covariance from the MMRM model used for the primary analysis, but with the 
treatment and treatment-by-time interaction terms excluded. This was used to calculate the 
conditional power for the study to show bioequivalence using the formula as described in Friede 
2003 (22). A target power of 90% to show bioequivalence is intended for the primary efficacy 
endpoint for the PPS and a target power of 80% for the EU-specific key secondary endpoint of 
FCP retinal thickness for the FAS. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
78 
An independent statistician who will otherwise not be involved in the planning and performance 
of the statistical analysis of the study data performed the calculations and provide 
recommendations on possible sample size adaptations. The recommendation followed the 
following rules: 
i) The total sample size shall not be lower than the currently planned 320 or 400 patients.  
ii)  If the target power is reached for US and the EU/Japan the total sample size will not be changed.  
iii) If the conditional power for the equivalence testing at the time of the interim analysis will be 
lower than the target power based on the observed results, then the statistician will recommend to 
increase the sample size for the US analysis to reach at least a power of 90% for a 4.8% significance 
level for the PPS (assuming 10% of patients will be excluded from the FAS). For the EU analysis 
at least a 90% power for a 2.4% significance level for the primary efficacy endpoint for the PPS 
and of 80% for a 4.8 significance level for the key secondary endpoint for the FAS shall be reached. 
These calculations assume that the observed overall SDs reflect the true SDs of the population and 
no difference between the two treatment groups.  
iv) If this power can only be reached by including more than 640 for the US analysis or 800 patients 
for the EU/Japan analysis overall, the recommendation will indicate this fact and the Sponsor will 
stop the study. 
This interim masked review of sample size was performed in November 2021 and revealed that 
the observed variability overall does not require an increase in sample size to maintain the intended 
statistical power of 90% for the primary endpoint, and of 80% for the key secondary endpoint 
(EU/Japan only).   
10.6 Data Monitoring Committee 
A DMC consisting of members who are independent from the Sponsor will be established. The 
DMC membership will have 5 members, including 4 specialists with expertise in Ophthalmology 
and an independent statistician, as appropriate. The DMC is responsible for reviewing and 
evaluating masked safety data collected at regularly scheduled meetings. The details of the safety 
data and time points for review will be described in the DMC Charter. The committee may also 
meet in ad hoc meetings at its discretion as needed in response to events occurring in the study. 
The DMC will be responsible for making recommendations as to whether it is scientifically and 
ethically appropriate to continue recruitment or stop the study.  
 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
79 
11 REFERENCES 
1. Kulkarni AD, Kuppermann BD. Wet age-related macular degeneration. Adv Drug Deliv Rev 
2005; 57(14): 1994-2009. 
2. Klein R, Klein BE, Cruickshanks KJ. The prevalence of age-related maculopathy by 
geographic region and ethnicity. Prog Retin Eye Res 1999; 18(3): 371–89. 
3. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. 
The Blue Mountains Eye Study. Ophthalmology 1995; 102(10): 1450–60 
4. Klaver CC, Assink JJ, van Leeuwen R, Wolfs RC, Vingerling JR, Stijnen T, et al. Incidence 
and progression rates of age-related maculopathy: the Rotterdam Study. Invest Ophthalmol 
Vis Sci 2001; 42(10): 2237–41. 
5. Kawasaki R, Yasuda M, Song SJ, Chen SJ, Jonas JB, Wang JJ, et al. The prevalence of 
age-related macular degeneration in Asians: a systematic review and meta-analysis. 
Ophthalmology 2010; 117(5): 921–27. 
6. Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, et al. The natural 
history and prognosis of neovascular age-related macular degeneration: a systematic review of 
the literature and meta-analysis. Ophthalmology 2008; 115(1): 116–26. 
7. Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, et al. 
Prevalence of age-related maculopathy in the Rotterdam trial. Ophthalmology 1995; 102(2): 
205-10. 
8. Gehrs KM, Anderson DH, Johnson LV, Hageman GS. Age-related macular degeneration: 
emerging pathogenetic and therapeutic concepts. Ann Med 2006; 38(7): 450–71. 
9. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. 
Lancet 2012; 379 (9827): 1728–38. 
10. Carneiro A, Falcao M, Pirraco A, Milheiro-Oliveira P, Falcao-Reis F, Soares R. Comparative 
effects of bevacizumab, ranibizumab and pegaptanib at intravitreal dose range on endothelial 
cells, Exp Eye Res 2009; 88: 522-527. 
11. Stewart MW. 2011. Aflibercept (VEGF-TRAP): the next anti-VEGF drug. Inflamm Allergy 
Drug Targets, 10: 497-508. 
12. Rosenfeld, PJ, Brown, DM, Heier, JS, Boyer, DS, Kaiser, PK, Chung, CY, et al.. Ranibizumab 
for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-1431. 
13. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus 
verteporfin for neo-vascular age-related macular degeneration. N Engl J Med 2006; 355(14): 
1432-44. 

CONFIDENTIAL 
Protocol FYB203-03-01- version 3.0, [15 July 2022] 
 
80 
14. EMA. 2019. European Medicines Agency, Eylea: Summary Of Product Characteristics 
(EMEA/H/C/002392 - IB/0049/G). 
15. EYLEA® Package Insert (Regeneron Pharmaceuticals, Inc) 
16. Guideline on similar biological medicinal products containing monoclonal antibodies – 
nonclinical and clinical issues. EMEA. (Dec 2012). EMA/CHMP/BMWP/403543/2010. 
Retrieved 
Dec 
29, 
2016 
from 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/  
17. Guideline 
on 
similar 
biological 
medicinal 
products. 
EMEA. 
(Oct 
2005). 
EMEA/CHMP/437/04. 
Retrieved 
Dec 
29, 
2016 
from 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ 
18. Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference 
product. U. S. Food and Drug Administration. (Apr 2015). Retrieved Dec 29, 2016 from 
http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidance
s/UCM291128.pdf 
19. Guideline on similar biological medicinal products containing biotechnology-derived proteins 
as 
active 
substance: 
quality 
issues 
(revision 
1). 
EMEA. 
(Dec 
2014). 
EMA/CHMP/BWP/247713/2012. 
Retrieved 
Dec 
29, 
2016 
from 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/ 
20. Wu EW, Schaumberg DA, Park SK. Environmental cadmium and lead exposures and 
agerelated macular degeneration in U.S. adults: the National Health and Nutrition Examination 
Survey 2005 to 2008. Environmental research. 2014;133:178-184. 
21. Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular 
degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study. 
Arch Ophthalmol. 1991;109:1242. 
22. Friede T, Kieser M. Blinded sample size reassessment in non-inferiority and equivalence trials. 
Stat Med. 2003 Mar 30;22(6):995-1007.