Conditions: Neovascular Age-related Macular Degeneration
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
Safety Assessment of Pegcetacoplan in Patients with Neovascular AMD

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Pegcetacoplan
Intervention descriptions: intervention 1: Study Drug

Protocol document:
Prot_000.pdf: 
Apellis Pharmaceuticals, Inc.
- CONFIDENTIAL -
Page 1 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
 
 
Protocol No: APL2-203
An 18-Month Phase Ib/II Multi-Center, Open Label Study to Evaluate the 
Safety of Intravitreal APL-2 Therapy in Patients with Neovascular Age-
Related Macular Degeneration (AMD)
Phase: Ib/II
Protocol Version: Version 3.0
Date: 03 August 2018
 
 
 
 
Confidentiality Statement
This document is confidential. It contains proprietary information of Apellis Pharmaceutical, Inc. Any viewing 
or disclosure of such information that is not authorized in writing by Apellis Pharmaceutical, Inc is strictly 
prohibited. Such information may be used solely for the purpose of reviewing or performing this study.


 
 
Apellis Pharmaceuticals, Inc.
- CONFIDENTIAL -
Page 2 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
INVESTIGATOR AGREEMENT  
Long Title:  
An 18-Month Phase Ib/II Multi-Center, Open Label Study to 
Evaluate the Safety of Intravitreal APL-2 Therapy in Patients with 
Neovascular Age-Related Macular Degeneration (AMD) 
Short Title:  
Furlong 
Protocol Number/Version/ 
 
APL2-203/Version 3.0/03Aug2018 
Date  
Study Phase:   
 
 
Phase Ib/II 
Sponsor Name and Address:  
 
Apellis Pharmaceuticals 
 
 
 
 
 
6400 Westwind Way, Suite A 
 
 
 
 
 
Crestwood, KY 40014 
Investigational Test Article:  
 
APL-2 
US IND#:͒124784
Indication Studied:  
Neovascular Age-Related Macular Degeneration 
Investigator Agreement:  
I have read the clinical study protocol described herein, recognize 
its confidentiality, and agree to conduct the described trial in 
compliance with Good Clinical Practices (GCP), the ethical 
principles contained within the Declaration of Helsinki, this 
protocol, and all applicable regulatory requirements.  
 
Principal Investigator:  
Name: _________________________________________  
 
Signature: ______________________________________  
 
Date: ______/______/______ (DD/MMM/YYYY)
 


 
 
Apellis Pharmaceuticals, Inc.
- CONFIDENTIAL -
Page 3 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
TABLE OF CONTENTS
TABLE OF CONTENTS...................................................................................................................................3 
LIST OF TABLES.............................................................................................................................................6 
LIST OF FIGURES...........................................................................................................................................7 
SUMMARY OF CHANGES FROM THE PREVIOUS VERSION.....................................................................8 
1. SPONSOR INFORMATION ....................................................................................................................10 
2. ABBREVIATIONS....................................................................................................................................11 
3. SYNOPSIS ..............................................................................................................................................15 
4. SCHEDULE OF EVENTS........................................................................................................................21 
5. INTRODUCTION .....................................................................................................................................24 
5.1 Background .......................................................................................................................................24 
5.1.1 
Acute Macular Degeneration Overview ...............................................................................24 
5.1.2 
APL-2 ...................................................................................................................................24 
5.2 Rationale for Treatment with APL-2..................................................................................................24 
6. NON-CLINICAL DATA.............................................................................................................................25 
6.1 Pharmacology ...................................................................................................................................25 
6.1.1 
Pharmacokinetics.................................................................................................................25 
6.2 Toxicology .........................................................................................................................................26 
7. CLINICAL DATA......................................................................................................................................27 
7.1 Purpose of the Study.........................................................................................................................28 
7.2 Dose Selection..................................................................................................................................28 
7.3 Risk/Benefit .......................................................................................................................................28 
8. STUDY OBJECTIVES AND ENDPOINTS ..............................................................................................28 
8.1 Study Objectives ...............................................................................................................................28 
8.2 Study Endpoints ................................................................................................................................29 
8.2.1 
Primary Endpoint..................................................................................................................29 
8.2.2 
Secondary Endpoints...........................................................................................................29 
8.2.3 
Pharmacokinetic Endpoint ...................................................................................................29 
8.2.4 
Exploratory Endpoint............................................................................................................29 
8.3 Study Design.....................................................................................................................................29 
9. SUBJECT SELECTION...........................................................................................................................30 
9.1 Inclusion Criteria ...............................................................................................................................30 
9.2 Approved Methods of Contraception ................................................................................................32 
10. STUDY TREATMENTS ...........................................................................................................................32 
10.1 
Identity of Investigational Product ................................................................................................32 
10.2 
Administration of Investigational Product.....................................................................................33 
10.2.1 Pre-Injection Procedure (Patient Preparation).....................................................................33 
10.2.2 Dosing ..................................................................................................................................33 
10.2.3 Investigational Product Administration.................................................................................33 
10.3 
Labelling, Packaging, Storage, and Handling..............................................................................34 


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
10.3.1 Labelling...............................................................................................................................34 
10.3.2 Packaging ............................................................................................................................34 
10.3.3 Storage.................................................................................................................................35 
10.4 
Investigational Product Accountability..........................................................................................35 
10.5 
Re-Treatment with Anti-VEGF .....................................................................................................35 
10.6 
Concomitant Medications.............................................................................................................36 
10.6.1 Prohibited Therapies............................................................................................................36 
10.6.2 Endophthalmitis Treatment..................................................................................................36 
11. STUDY PROCEDURES ..........................................................................................................................36 
11.1 
Screening Visit 1 (Day -28 ± 2 days)............................................................................................36 
11.2 
Screening Visit 2 (Day -14 ± 3) ....................................................................................................37 
11.3 
Baseline Visit (Day 1 ± 8 days): Visit 3 ........................................................................................38 
11.4 
Treatment Period (Day 30-360 ± 8 days): Visits 4-15..................................................................38 
11.5 
Follow-up (Day 450 ± 8 days): Visit 16 ........................................................................................39 
11.5.1 Exit Visit (Day 540 ± 8 days): Visit 17..................................................................................39 
11.6 
Unscheduled Follow-up Visits......................................................................................................40 
11.7 
Safety Monitoring Committee (SMC) ...........................................................................................40 
11.8 
Treatment Discontinuation and Study Withdrawal.......................................................................40 
12. ASSESSMENTS......................................................................................................................................41 
12.1 
Assessments................................................................................................................................41 
12.1.1 Medical History.....................................................................................................................41 
12.1.2 Prior and Concomitant Medications.....................................................................................41 
12.1.3 Body Height and Weight ......................................................................................................41 
12.1.4 Physical Examination...........................................................................................................41 
12.1.5 Vital Signs ............................................................................................................................42 
12.1.6 Best-Corrected Visual Acuity (BCVA)..................................................................................42 
12.1.7 Ocular Imaging.....................................................................................................................42 
12.1.8 Clinical Laboratory Tests .....................................................................................................43 
12.1.8.1 
Hematology ..........................................................................................................43 
12.1.8.2 
Serum Chemistry..................................................................................................43 
12.1.8.3 
Urinalysis..............................................................................................................43 
12.1.9 Post-Injection Assessment...................................................................................................43 
12.2 
Pharmacokinetic Assessments ....................................................................................................44 
12.2.1 Blood Sampling and Processing..........................................................................................44 
12.3 
Exploratory Assessments.............................................................................................................44 
12.4 
Anti- APL-2/PEG Antibody Assessments.....................................................................................44 
12.5 
Blood Volume for Study Assessments.........................................................................................44 
12.6 
Pregnancy Tests ..........................................................................................................................45 
13. ADVERSE EVENTS ................................................................................................................................45 
13.1 
Definition ......................................................................................................................................45 
13.2 
Adverse Event Assessment and Recording.................................................................................46 
13.2.1 Procedures For Recording Adverse Events ........................................................................46 
13.3 
Treatment and Follow-up of Adverse Events...............................................................................47 
13.4 
Reporting......................................................................................................................................47 


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
13.4.1 Relationship of Events to Study Treatment .........................................................................47 
13.4.2 Severity of Events ................................................................................................................49 
13.5 
Serious Adverse Events...............................................................................................................50 
13.6 
Unexpected Adverse Events or Unexpected Suspected Adverse Reactions..............................50 
13.7 
Treatment and Follow up of Adverse Events ...............................................................................50 
13.8 
Pregnancy ....................................................................................................................................51 
14. STATISTICS............................................................................................................................................51 
14.1 
Sample Size Justification .............................................................................................................51 
14.2 
Statistical Analysis Methodology..................................................................................................51 
14.2.1 Analysis Populations............................................................................................................52 
14.2.1.1 
Screened Population ............................................................................................52 
14.2.1.2 
Safety Population/ Intent-to-Treat (ITT) Population .............................................52 
14.2.1.3 
Pharmacokinetic (PK) Population.........................................................................52 
14.2.1.4 
Data Review for Analysis Populations .................................................................52 
14.2.2 Analyses...............................................................................................................................52 
14.2.2.1 
Primary Endpoint..................................................................................................52 
14.2.2.2 
Secondary Endpoints ...........................................................................................52 
14.2.2.3 
Pharmacokinetic Endpoints..................................................................................52 
14.2.2.4 
Exploratory Endpoints ..........................................................................................52 
14.2.3 Safety Analyses ...................................................................................................................52 
14.2.3.1 
Adverse Events ....................................................................................................53 
14.2.3.2 
Clinical Laboratory Tests......................................................................................53 
14.2.3.3 
Vital Signs.............................................................................................................53 
14.2.4 Pharmacokinetic Analyses...................................................................................................53 
14.2.5 Other Data Analyses (Treatment Group Comparability)......................................................53 
14.3 
Direct Access to Source Data/Documents...................................................................................54 
14.4 
Quality Control and Quality Assurance ........................................................................................54 
14.4.1 Monitoring ............................................................................................................................54 
14.5 
Ethics............................................................................................................................................54 
14.5.1 Ethical Conduct of the Study................................................................................................54 
14.5.2 Institutional Review Board/Ethic Committee........................................................................54 
14.5.3 Subject Information and Consent.........................................................................................55 
14.5.4 Confidentiality.......................................................................................................................55 
14.5.5 ClinicalTrials.gov..................................................................................................................55 
14.5.6 Termination of Study............................................................................................................55 
14.6 
Data Handling and Record Keeping.............................................................................................56 
14.7 
Protocol Versions .........................................................................................................................56 
14.8 
Report Format ..............................................................................................................................56 
14.9 
Finance and Insurance.................................................................................................................56 
14.9.1 Publication Policy.................................................................................................................56 
15. REFERENCES ........................................................................................................................................58 
 


 
 
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- CONFIDENTIAL -
Page 6 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
LIST OF TABLES
Table 1: Blood Volume During Study ............................................................................44 
 
 


 
 
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Page 7 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
LIST OF FIGURES
Figure 1: Study Outline .................................................................................................................. 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Apellis Pharmaceuticals, Inc.
- CONFIDENTIAL -
Page 8 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
SUMMARY OF CHANGES FROM THE PREVIOUS VERSION
Amendment 1
Amendment Number
1.0
Amendment Date
03 Jan 2018
Description of Change
Section(s) Affected by Change
Change: Collection of genotyping samples has been removed due 
to the nature of the study being conducted and given the small 
sample size.
3. Synopsis (Secondary 
Endpoints)
4. Schedule of Events
8.2.2 Secondary Endpoints
Change: Best Corrected Visual Acuity has been added as an 
assessment at screening. This was an administrative error.
4. Schedule of Events
Change: Language regarding informed consent has been updated 
to reflect a more accurate representation of the consent process 
for this study.
14.5.3 Subject Information and 
Consent
11.1 Screening Visit 1
Amendment 2
Amendment Number
2.0
Amendment Date
14 Mar 2018
Description of Change
Section(s) Affected by Change
Change: The T-cell assay has been removed from the study. 
3. Synopsis (Exploratory 
Endpoint)
4. Schedule of Events
8.2.4 Exploratory Endpoints
12.3
Treatment Period
12.3 Exploratory Assessments
12.5 Blood Volume for Study 
Assessments
14.2.2.4 Exploratory Endpoints
Change: The sample size has been increased by 10 subjects for a 
total of 20 subjects in the study.  
3. Synopsis (Number of Planned 
Subjects, Sample Size)
8.3 Study Design
9. Subject Selection
14.1 Sample Size Justification
Change: The predose vital window has been amended from 
“approximately 1 hour before dosing” to “within 90 mimutes of 
dosing”, to accommodate the large number of predose 
assessments
4. Schedule of Events
11.3 Baseline Visit
11.4 Treatment Period
12.1.5 Vital Signs
Change: The inclusion criteria for a 50% reduction in excess 
macular fluid has been amended to a clinically meaningful 
reduction in excess macular fluid
3. Synopsis
9.1 Inclusion Criteria
Change: The requirement for a patient’s IOP to be +/-5 mmHg 
from baseline after Anti-VEGF injection has been amended to <21 
mmHg for safety and consistency
8.3 Study Design
10.2.2 Dosing
10.5 Retreatment with Anti-
VEGF
11.3 Baseline Visit


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
12.1.9 Post-Injection 
Assessment
Change: The “Changes in number of Anti-VEGF injections” 
exploratory endpoint has been amended to “number of Ant-VEGF 
injections”for clarity
3. Synopsis
8.2.4 Exploratory Endpoints
14.2.2.4 Exploratory Endpoints
Amendment 3
Amendment Number
3.0
Amendment Date:
7 August 2018
Description of Change
Section(s) Affected by Change
Change in formulation of APL-2.
10.1. Identity of Investigational 
Product
10.2.3. Investigational Product 
Administration
10.3.2. Packaging
10.3.3. Storage 
It was specified that: All suspected cases of Endophthalmitis 
should be reported as a Serious Adverse Event.
10.6.2 Endophthalmitis 
Treatment
The specification that a 50% reduction in macular fluid was the 
requirement for a “clinically meaningful” reduction was removed
for consistency; this change was enacted for Amendment 2 of the 
protocol, but Section 11.2 was not updated. The error has been 
corrected in this amendment.
11.2 Screening Visit
 
 
 
 
 


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Apellis Pharmaceuticals, Inc.
- CONFIDENTIAL -
Page 11 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
2. ABBREVIATIONS
ADA 
Anti-drug Antibodies 
AE
Adverse Event
AM 
APL-2 Monthly 
AMD
Age-related Macular Degeneration 
ALT (SPGT)
Alanine Aminotransferase 
AST (SGOT)
Aspartate Aminotransferase 
AUC
Area Under the Curve 
Ba
Complement Component B, Fragment a 
BCVA
Best Corrected Visual Acuity 
BQL
Below-Quantification-Level 
BUN 
Blood urea nitrogen 
°C
Degree Centigrade 
C3
Complement component 3 
C3a
Complement Component 3, Fragment a
C3d
Complement Component 3, Fragment d
C5a
Complement Component 5, Fragment a
cc
Cubic Centimeter
CCP
Complement Control Protein
CEP 
ʘ-(2-carboxyethyl)pyrrole 
CFB
Complement Factor B
CFH
Complement Factor H
CFI
Complement Factor I
CFR
US Code of Federal Regulations
CH50
Classical Pathway of Complement Functional Test
CMV 
Cytomegalovirus 
Cmax
Maximum Observed Concentration
CNV 
Choroidal neovascularization 
CRA
Central Retinal Artery
CRC
Central Reading Center
CRF (eCRF)
Case Report Form (electronic CRF). (Used interchangeably)
CRL
Charles River Laboratory


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
CRO
Contract Research Organization
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough
Lowest Observed Concentration after a dose
DA
Disk Area
DCFP
Digital Color Fundus Photography
DSMB
Data Safety Monitoring Board
EOM
Every Other Month
ERG
Electroretinography
ETDRS
Early Treatment Diabetic Retinopathy Study
FAF
Fundus Autofluorescence
FDA 
United States Food and Drug Administration 
FFA/FA
Fundus Fluorescein Angiography or Fluorescein Angiography
FSH
Follicle-Stimulating Hormone
G
Gauge
GA
Geographic Atrophy
GCP
Good Clinical Practice
GLP 
Good Laboratory Practices 
HCG
Human Chorionic Gonadotropin
hERG 
human ether-a-go-go gene 
HIPAA
Health Insurance Portability and Accountability Act 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
ICH M3(R2)  
International Conference on Harmonization Guideline M3 (R2) 
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IOP 
Intra Ocular Pressure 
IR
Infrared Reflectance
IRB
Institutional Review Board
IV
Intravenous
IVT
Intravitreal
IWR
Interactive Web Response
kDa 
Kilodalton 


 
 
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Page 13 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
kg
Kilogram
LFT
Liver Function Test
LH
Luteinizing Hormone
LL-BCVA
Low luminance best corrected visual acuity
LLD
Low luminance deficit
MAC
Membrane Attack Complex
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MI
Myocardial Infarction
mITT
Modified Intention to Treat
mL
Milliliter
mmHg
Millimeter Of Mercury
MNV
Macular Neovascularization
MOP
Manual of Procedures
MTD
Maximum Tolerated Dose
NOAEL
No Observable Adverse Effect Level
NOEL
No Observable Effect Level
NL-BCVA
Normal Luminance Best-Corrected Visual Acuity
OCT
Optical Coherence Tomography
PD 
Pharmacodynamic 
PDT
Photodynamic Therapy
PEG
Polyethylene Glycol 
PEG40 
Polyethylene Glycol (40 kDa nominal molecular weight) 
PI 
Principal Investigator. (PI and Investigator are used interchangeably) 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QC 
Quality Control 
RBC 
Red Blood Cell 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
SC5b-9 
Soluble Terminal Complement Complex (i.e. soluble analog of MAC) 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SEOM 
Sham Every-Other-Month 
SM 
Sham Monthly 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedures 
TEAE 
Treatment Emergent Adverse Event 
TK 
Toxicokinetic 
Tmax 
Time to Maximum Measured Concentration 
TMF 
Trial Master File 
t1/2 
Terminal Elimination Half-life 
VA 
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor 
μL 
Micro liter 
WBC 
White Blood Cell 
WOCBP 
Women of Child-Bearing Potential 
WONCBP 
Women of Non Child-Bearing Potential 
YAG 
Yttrium Aluminum Garnet 


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
3. SYNOPSIS
Protocol Number:
APL2-203
Protocol Title:
An 18 Month Phase Ib/II, Multi-Center, Open Label Study to Evaluate the Safety of Intravitreal APL-
2 Therapy in Patients with Neovascular Age-Related Macular Degeneration (AMD)
Version Number:
Version 3.0
Investigational Product, Dose and Route of Administration:
x
APL-2 
x
15 mg/ 100 μL
x
Intravitreal Injection
Study Phase and Type:
Phase Ib/II study consisting of an open-label, multicenter, non-randomized group 
Number of Planned Subjects:
Open label arm, with approximately 20 patients with clinical diagnosis of neovascular AMD 
Treatment Groups:
x
Group 1: APL-2 15 mg/ 100 μL intravitreal injection 
Duration of Study Participation: 
The planned length of participation in the study for each subject is a maximum of approximately 19 
months (76 weeks), including a one-month (4-week) screening period, 12-month (48-week) 
treatment period and 6-month (24-week) follow-up period.
Study Population:
Patients, at least 60 years of age, with neovascular AMD
Rationale for the Study:
APL-2 has proven safe and tolerable in a Phase I study in patients with wet AMD (protocol POT-
CP043014; NCT02461771) and in a second Phase II study in subjects with Geographic Atrophy 
(GA) (protocol POT-CP121614; NCT02503332) associated with AMD. During the Phase II study, an 
imbalance in new exudation in subjects treated with APL-2 was discovered.PPD


 
 
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Page 16 of 58
Protocol No: APL2-203
Version 3.0: 03-Aug-2018
.  It was noted that of 
the 20 APL-2-treated subjects with new study eye exudation, 14 subjects received APL-2 Monthly
(AM) treatment and 6 subjects received Every Other Month (EOM) treatment. However, treatment 
with APL-2 was discontinued for these subjects after the onset.
Fourteen of the 21 (67%) subjects that developed new study eye exudation had a prior history of 
exudative AMD in the non-study fellow eye.  No significant imbalance in history of exudative AMD in 
the fellow eye was observed among the three arms to explain the imbalance in new exudation 
observed in study eyes. Visual acuity (VA) data did not demonstrate clear differences between 
subjects developing new study eye exudation compared with those that did not. 
Given these findings, further exploration is necessary to study the effects of APL-2 in subjects with 
neovascular AMD.  
Study Objectives and Endpoints:
Objective
The objective of this study is to establish the safety and tolerability of intravitreally injected APL-2 in 
patients with neovascular AMD. 
Endpoints
Primary Endpoint:
x
Incidence and severity of ocular and systemic Treatment- Emergent Adverse Events 
(TEAEs)
Secondary Endpoints: 
x
Changes from baseline in physical examination findings and laboratory parameters
x
Changes from baseline in central macular thickness on OCT over 12 months
Pharmacokinetic Endpoint:
x
APL-2 pharmacokinetic concentrations
Exploratory Endpoint:  
x 
Number of anti-Vascular Endothelial Growth Factor (anti-VEGF) PRN injections from Visit 4 
to the Exit Visit (Visit 17) 
 
PPD


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
Study Design:
Patients diagnosed with AMD in the study eye, who are receiving an intravitreal anti-VEGF drug, 
and who meet all other inclusion/exclusion criteria will be included in the study.  The study will 
include approximately 20 subjects across at least 3 U.S. sites.
Patients will initially be screened between Day -28 and prior to treatment on Day 1. Screening 
procedures will include laboratory tests, Best Corrected Visual Acuity (BCVA), ophthalmological 
exam, Intraocular Pressure (IOP), and Spectral Domain Optical Coherence Tomography (SD-OCT). 
Upon entry into the study (after signing the informed consent), subjects will be assigned a screening 
number. At screening visit 1 (Day -28) subjects will have an SD-OCT taken to assess for the 
presence of any subretinal, intraretinal, or sub-Retinal Pigment Epithelium (sub-RPE) fluid, followed 
by an IVT dose of an anti-VEGF drug. Subjects will return two weeks later for screening visit 2 (Day 
-14) and will have another OCT performed to confirm a decrease in excess fluid in the macula. 
Upon confirmation bu the Investigator of fluid reduction, subjects who meet all inclusion and 
exclusion criteria will be enrolled in the study and will return at Day 1 for treatment (Visit 3; Day 1). 
Treatment on Day 1 will entail a mandatory IVT dose of an anti-VEGF drug followed by an IVT 
injection of APL-2. 
All subjects will receive monthly APL-2 injections for 12 months during their scheduled monthly 
treatment visits. At each treatment visit, safety assessments will be performed including vital signs, 
labs and urinalysis, and SD-OCT. BCVA, fundus examination, dilated indirect ophthalmoscopy and 
slit lamp examination will also be performed. Subjects will be assessed at each treatment visit for 
the need for retreatment with an anti-VEGF drug based on pre-specified retreatment criteria. During 
follow-up, safety assessments will be performed for all subjects at months 15 and 18. Subjects who 
discontinue study treatment, should be encouraged to continue participation in the study and return 
to the clinical site for their scheduled study procedures. Subjects who fully withdraw from the study 
before month 12, should complete the Termination Visit.
An external, independent Safety Monitoring Committee (SMC) will assess the progress and 
cumulative safety/tolerability data of the study.
Subjects who fail the screening procedures should not be re-screened for the study unless this is 
agreed in advance and documented in writing with the sponsor.
Inclusion Criteria:
Ocular- specific inclusion criteria apply to the study eye only.
1. Age t 60 years.
2. Normal Luminance best corrected visual acuity (NL-BCVA) of 24 letters or better using Early 
Treatment Diabetic Retinopathy Study (ETDRS) charts (20/320 Snellen equivalent).
This is an 18-Month Phase Ib/II, multi-center, open label study to assess the safety and tolerability 
of monthly IVT injections of APL-2 in subjects with neovascular AMD.


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
3. Clinical diagnosis of neovascular AMD with the following criteria met: 
a. Eligible for an anti-VEGF injection with macular fluid present at Day -28. 
b. At least 6 treatments of intravitreal anti-VEGF therapy in the study eye within the last 
year with the last 2 injections occurring at intervals not greater than 8 weeks (± 7 days). 
4. A clinically meaningful reduction in excess macular fluid or macular thickness in the study 
eye at the discretion of the investigator between Screening Day -28 and Screening Day -14
as assessed by SD-OCT. 
5. Female subjects must be:
a. Women of non-child-bearing potential (WONCBP), or
b. Women of child-bearing potential (WOCBP) with a negative pregnancy test at screening 
and must agree to use protocol defined methods of contraception for the duration of the 
study and refrain from breastfeeding for the duration of the study.
6. Males with female partners of child-bearing potential must agree to use protocol defined 
methods of contraception and agree to refrain from donating sperm for the duration of the 
study.
Note: If both eyes meet the inclusion criteria, the eye with the worst VA at the screening visit will be 
designated as the study eye. If both eyes have the same VA, the Investigator and patient will 
determine the study eye.
Exclusion Criteria:
Ocular specific exclusion criteria apply to the study eye only.
1. Presence of other causes of choroidal neovascularization (CNV) including pathologic myopia 
(spherical equivalent  -6 diopters), central serous chorioretinopathy, ocular histoplasmosis 
syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis.
2. History of vitrectomy to the study eye 
3. Presence of any ophthalmologic condition that reduces the clarity of the media and that, in the 
opinion of the Investigator, interferes with ophthalmologic examination (e.g. advanced cataract 
or corneal abnormalities).
4. Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization.
5. Any history of endophthalmitis.
6. Trabeculectomy or aqueous shunt or valve in the study eye.
7. Aphakia or absence of the posterior capsule. Note: previous violation of the posterior capsule is 
also excluded unless it occurred as a result of yttrium aluminum garnet (YAG) laser posterior 
7. Willing and able to give informed consent and to comply with the study procedures and 
assessments. 


 
 
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capsulotomy in association with prior posterior chamber intraocular lens implantation and at 
least 60 days prior to baseline.
8. Any ophthalmic condition that may require surgery or medical intervention during the study 
period or, in the opinion of the Investigator, could compromise visual function during the study 
period (e.g. severe uncontrolled glaucoma, clinically significant diabetic macular edema, 
ischemic optic neuropathy, retinal vasculopathies).
9. Any contraindication to IVT injection including current ocular or periocular infection.
10. Current treatment for active systemic or localized infection.
14. Known hypersensitivity to fluorescein sodium for injection or hypersensitivity to APL-2 or any of 
the excipients in APL-2 solution.
Sample Size:
A sample size of approximately 20 subjects with neovascular AMD will be included in this study.
Statistical Methods:
Given the exploratory nature of the study, no formal statistical hypothesis testing will be performed. 
Data will be presented for the cohort by study month and nominal time postdose (if appropriate). 
Continuous variables will be summarized using descriptive statistics (e.g. median and mean) whilst 
for categorical variables the frequency and percentage in each category will be displayed. 
TEAEs will be summarized by System Organ Class and Preferred Term, according to the Medical
Dictionary for Regulatory Activities (MedDRA).  The number of patients reporting each AE preferred 
term will be tabulated for all TEAEs and separately for those considered as possibly related to study 
treatment by the Investigator.  Number of patients reporting serious adverse events (SAEs) will also 
be tabulated.
The number and percentage of patients achieving improvement in the secondary endpoints will be 
tabulated. Changes from baseline in safety endpoints will be summarized and plotted (individual 
and mean) over time.
11. Participation in any systemic experimental treatment or any other systemic investigational new 
drug within 6 weeks or 5 half-lives of the active (whichever is longer) prior to the start of study 
treatment. Note: clinical trials solely involving observation, over-the-counter vitamins, 
supplements, or diets are not exclusionary
12. Medical or psychiatric conditions that, in the opinion of the investigator, make consistent follow-
up over the 24- month treatment period unlikely, or would make the subject an unsafe study 
candidate.
13. Any baseline laboratory value (hematology, serum chemistry or urinalysis) that in the opinion of 
the Investigator is clinically significant and not suitable for study participation.


 
 
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PK parameters will be computed from the individual serum concentration-time data, using a non-
compartmental approach. PK concentrations and parameters will be summarized and concentration 
profiles over time (individual and median) will be plotted.


 
 
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4. SCHEDULE OF EVENTS
Screening
Treatment
Follow-Up
Early 
Term. A
Visit #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Day
-28
-14
1
30
60
90
120
150
180
210
240
270
300
330
360
450
540
Week
0
0
0
4
8
12
16
20
24
28
32
36
40
44
48
60
72
Month
0
0
0
1
2
3
4
5
6
7
8
9
10
11
12
15
18
Window (+ or - days)
2
3
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Informed Consent / Assign 
Screening Number 
x
Demographic Data
x
Inclusion/Exclusion Criteria B 
x
x
x
Medical/Surgical/Ophthalmic 
History C
x
Blood Draw – Safety Labs D,E
x
x
x
x
x
Urine Sample Collection D,F
x
x
x
x
x
Blood Draw - PK and Anti-APL-
2/ PEG Ab D
x
x
x
x
Vital Signs D,G
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Physical Examination H
x
x
x
Urine Pregnancy Test E,F
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
BCVA I
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Slit Lamp Examination
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


 
 
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Dilated Indirect 
Ophthalmoscopy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
IOP Measurement
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SD-OCT J
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Digital Color Fundus 
Photographs (DCFP) J
x
x
x
Fundus Fluorescein 
Angiograms (FFA) J
x
x
x
Study Eye Determination
x
Mandatory anti-VEGF injection
x
x
Anti-VEGF injection (PRN)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
APL-2 administration Injection
x
x
x
x
x
x
x
x
x
x
x
x
x
Post-Injection Assessment K
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant Medication/ 
Concomitant Ocular 
Procedures L
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x


 
 
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FOOTNOTES:
A. For patients that discontinue the study early, the early termination assessments should be performed after a minimum of 30 days 
have passed.
B. At Day -14 (Visit 2), confirm subject eligibility through reviewing the inclusion/ exclusion criteria and receive confirmation of eligibility 
from the Reading Center.
C.
Significant medical/ surgical history and tobacco use, including chronic and ongoing conditions. Significant ocular medical and
surgical history should be obtained for the previous 1 year.
D. Obtain prior to fluorescein angiograph and before study drug administration.
E.
At screening, serum pregnancy should be performed for WOCBP. If positive, subject is not eligible to continue in the study.
F.
Beginning at Day 1, perform the urine pregnancy test for WOCBP at each treatment visit. If positive, perform a serum pregnancy test. 
If serum test is positive, study drug should not be administered and an early term visit should be completed.
G. Blood pressure, respiratory rate, heart rate, and temperature; On dosing days, vital signs should be captured pre and post dosing.
Predose vitals should be captured within 90 minutes prior to dosing
H. Complete physical exam should be performed; Height and Weight should be collected at screening.
I.
Perform assessments prior to dilating the eyes.
J.
Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at a 
specific visit, study staff should make every effort to obtain images at the next scheduled visit.
K.
Post- injection assessments should be performed within 15 minutes after dosing by the investigator or study staff and should include 
a gross assessment of vision (finger-counting, hand-motion, then light perception when applicable). If subject passes gross vision 
test, the subject may leave the site. If subject fails gross vision test, IOP should be performed and if < 30 mmHg, the subject can be 
discharged. Assessments will continue every approximately 30 minutes until the subject passes gross vision test and IOP is < 30 
mmHg.
L.
Record concomitant medications (i.e. prescription and over the counter medications) used by the patient within 30 days of screening 
and throughout the subject's participation in the study. All significant concurrent ocular procedures and medications should also be 
recorded within the past 1 year and while on study.
 
 
 


 
 
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5. INTRODUCTION
5.1
Background
This study is being conducted as part of a series of studies for the clinical development of APL-2
for advanced AMD (neovascular AMD and GA).  The trial will be conducted in compliance with this 
protocol, Good Clinical Practice (GCP), and applicable regulatory requirements. The subject 
population will be comprised of adult male and female subjects with neovascular AMD. 
5.1.1
Acute Macular Degeneration Overview
AMD is the leading cause of severe vision loss in people over the age of 65 in the United States
and other Western countries.1 In the United States, about 1.75 million people have the advanced 
forms of AMD.2 The early signs of AMD (drusen and pigmentary changes) are common in 
individuals over age 65 and precede the advanced forms, which are visually devastating.  The 
Centers for Disease Control and Prevention (CDC) estimates that an additional 7-8 million U.S. 
adults have large drusen and are therefore at risk of developing AMD.  The advanced forms of 
AMD are classified into either macular neovascularization (neovascular, wet, or exudative AMD) or 
GA. Given that approximately half of the patients on anti-VEGF therapy develop retinal scars within 
two years of initiating treatment, it is clear that a substantial unmet need exists for advanced 
neovascular AMD patients alone.  
Genetic susceptibility has become increasingly recognized as a risk factor and important 
contributor to AMD. More than 19 genetic polymorphisms have been demonstrated to influence 
AMD risk, with as many as 5 of these encoded by genes that modulate the complement system. 
Inflammatory processes, especially those mediated by complement, are thought to play a key role 
in AMD.3 It is thought that these may contribute to loss of choriocapillaris, photoreceptors and RPE 
cells.
5.1.2
APL-2
APL-2 is formed by two pentadecapeptide (combining a cyclic tridecapeptide active C3-inhibiting 
moiety and a 2-amino acid linker) covalently coupled to each end of a linear 40 kDa Polyethylene 
Glycol (PEG) chain, so there are two peptide moieties per molecule of APL-2.
The peptide portion of the drug binds to complement C3 and is a broad inhibitor of the complement 
cascade, a biological process that is part of innate immunity and is involved in multiple 
inflammatory processes. The PEGylation of the molecule imparts slower elimination from 
mammalian systems following administration. 
APL-2 will be supplied in clear glass vials with thermoplastic-faced stoppers and flip-off seal-caps. 
APL-2 is being developed for the treatment of neovascular AMD and GA. 
5.2
Rationale for Treatment with APL-2
APL-2 has proven safe and tolerable in a Phase I study in patients with wet AMD (protocol POT-
CP043014; NCT02461771) and in a second Phase II study in subjects with GA associated with 


 
 
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AMD. During the Phase II study, an imbalance in new exudation in subjects treated with APL-2
was discovered.
. It was noted that of the 20 APL-2-treated subjects with new study eye 
exudation, 14 subjects received AM treatment and 6 subjects received EOM treatment. Treatment 
with APL-2 was discontinued for these subjects after the onset.
Fourteen of the 21 (67%) subjects that developed new study eye exudation had a prior history of 
exudative AMD in the non-study fellow eye.  No significant imbalance in history of exudative AMD 
in the fellow eye was observed among the three arms to explain the imbalance in new exudation 
observed in study eyes. VA data did not demonstrate clear differences between subjects 
developing new study eye exudation compared with those that did not. 
Given these findings, further exploration is necessary to study the effects of APL-2 in subjects with 
neovascular AMD.  In the current clinical study a complement C3 inhibitor, APL-2, will be 
administered to patients with neovascular AMD. The goal of the study is to assess the safety and 
tolerability of IVT APL-2 in neovascular AMD administered monthly.  Results from this study will 
guide decisions to further develop APL-2 for GA and AMD. 
6. NON-CLINICAL DATA
The nonclinical package was developed in accordance with ICH M3(R2) guidance and in 
consideration of the specific safety considerations for PEGylated products. Further details can be 
found in the APL-2 Investigator’s Brochure.  
6.1
Pharmacology
APL-2’s mechanism of action and species specificity appear to be identical to those of Ac-
compstatin.  Both the existing in vitro complement inhibitory data and the nature of identified 
compstatin binding sites are consistent in predicting that only primate species would be 
pharmacologically relevant to study APL-2-related toxicology.  All data generated in nonϣ -primate 
species using compstatin and its derivative (including APL-2) indicate a lack of significant 
bioactivity in non-primates.  The lack of C3 binding in nonϣprimates suggests that PK data 
obtained in primate species (such as cynomolgus monkeys) are the most relevant, as APLϣ2:C3 
complexes likely impact observed serum half-lives and monkey data is more representative of 
expected and observed PK in human subjects. 
The potential for APL-2 to inhibit human ether-a-go-go gene (hERG)-encoded ion channels and 
pose a risk for cardiac arrhythmias indicates that such a risk is low.  Similarly, no evidence of APL-
2-related adverse effects on myocardial conduction, cardiovascular and respiratory systems, and 
body temperature control mechanisms have been observed in monkeys.
6.1.1
Pharmacokinetics
PK and toxicokinetic (TK) assessments of APL-2 have been investigated after single and repeated 
(9-month, 10 total dose) IVT administration to cynomolgus monkeys.  
PPD


 
 
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After a single IVT administration (10mg/eye in 50 μL), APL-2 was cleared from the vitreous humor 
of monkeys into the systemic circulation following an exponential decline with a vitreal t½ of 3.2 
days. Twenty-four hours after IVT administration the mean vitreous humor APL-2 concentration 
was 2.1 mg/mL. Retinal APL-FRQFHQWUDWLRQVUDQJHGIURPWRȝJJRIWLVVXHDWWKHWLPH
of terminal necropsy (Day 30). As was the case after intravenous (IV) or subcutaneous (SC) 
administration, intravitreally administered APL-2 was cleared from the circulatory system in an 
exponential fashion with a t½ of 10.4 days. The serum half-life of intravitreally administered APL-2
LVVRPHZKDWORQJHUWKDQWKDWREVHUYHGDIWHUHLWKHU6&RU,9DGPLQLVWUDWLRQWò§GD\V
In the 9-month study in cynomolgus monkeys, serum concentrations of APL-2 were roughly dose-
proportional approximately 24 hours after the first dose.  Maximal serum concentrations were 
achieved by Test Day 6, and serum concentrations of APL-2 increased in a less-than-linear to 
approximately linear fashion with increasing dose.  There was no evidence of bioaccumulation of 
APL-2 as evidenced by the fact that serum concentrations 26 days after the final dose of APL-2
were 36 to 52% lower than those achieved 26 days after the initial dose.
Intravitreal APL-2 concentrations, like serum concentrations, appeared to increase slightly between 
the first and second IVT dose but then stabilize between the second and third dose, supporting a 
conclusion of no intraocular accumulation after the first dose.  
6.2
Toxicology 
The potential toxicity of intravitreally administered APL-2 has been investigated in 9-month and 2-
month bridging GLP (Good Laboratory Practice)-compliant studies featuring single bilateral 
injections in eyes of the animals every 4 weeks (10 total doses or 2 total doses, respectively).  
Intravitreally administered APL-2 was tolerated at all doses tested (up to and including 24.8 
mg/eye).  No local or systemic drug-related toxicity was observed in any animal.  APL-2 was found 
to be minimally immunogenic in the 9-month study as evidenced by a lack of circulating antibodies 
in the majority of monkeys studied.  A single monkey administered 12.4 mg/eye had a marginal 
titer of 1:20 APL-2 antibodies during Test Week 39 and a single monkey receiving 24.8 mg/eye 
was found to have a low 1:100 titer during Test Week 13 and a 1:500 titer during Test Week 39. No 
drug-related changes in CH50 values were observed at any of the drug treatment groups through 
Test Week 40.  The NOEL for chronic (9-month) IVT dosing was concluded to be >24.8 mg/eye.
The toxicological potential of APL-2 has also been investigated in repeat-dose toxicity studies in 
rabbits and monkeys with other routes of administration (SC, IV) under a testing strategy designed 
to facilitate differentiation between potential changes attributable to APL-2 per se and those 
attributable to the PEG40 domain of the drug molecule.  Daily subcutaneous administration of APL-
2 and PEG40 for a duration of 6 months in rabbits and 9 months in monkey were associated with 
little systemic toxicity noted in either species beyond observations in the kidney.  APL-2 and 
PEG40 were weakly to mildly immunogenic in rabbits, but not significantly immunogenic in 
monkeys.  Single- or multi-tissue (or multi-organ) macrophage vacuolation was consistently 
observed in both species, and generally comparable in incidence and severity between APL-2- and 


 
 
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PEG40-treated groups; thus, it was concluded the finding were caused by the PEG40 domain 
present within APL-2.  Renal tubular degeneration was observed with a higher incidence in the 
monkey 9-month study in APL-2-treated animals compared to the PEG40-treated ones, and was 
concluded to be APL-2-related.  The no-observed-adverse-effect-level (NOAEL) for SC-
administered APL-2 was <1 mg/kg/d in rabbits and approximately 7 mg/kg/d in monkeys after 6-
and 9-months of chronic dosing, respectively. Similarly, no adverse effects on study parameters or 
endpoints were observed for APL-2 IV arms (2 doses separated by 14 days) included in 28-day 
repeat-dose SC studies in rabbits and monkeys.
APL-2 has not demonstrated genotoxic potential in any in vitro or in vivo genotoxicity assays 
conducted, nor has it shown no effect on relevant maternal and fetal endpoints in developmental 
toxicity and teratogenicity studies conducted in rats and rabbits.
7. CLINICAL DATA
A single Phase I single ascending dose has evaluated IV dosing of APL-2 in healthy volunteers. 
The safety and tolerability of APL-2 following IVT administration in humans was tested in an open 
label, single dose escalation, Phase I clinical study in patients with wet AMD under protocol POT-
CP043014 (NCT02461771).  The study was conducted in multiple ophthalmology clinical sites in 
the US and Australia. A single dose of APL-2 was administered on Day 1 to patients with exudative 
AMD currently receiving anti-VEGF standard of care. Three escalating doses of APL-2
administered IVT were studied. Three subjects received 4 mg; 3 subjects received 10 mg, and 
7 subjects received 20 mg. No SAEs or drug-related adverse events (AEs) of concern were 
observed. It was concluded that administration of a single dose of APL-2 IVT up to 20 mg is safe 
and well-tolerated. 
A second Phase II study is also currently ongoing (Protocol POT-CP121614; NCT02503332) to 
assess the safety, tolerability and evidence of activity of multiple IVT injections in subjects with GA 
associated with AMD. The study is being conducted at multiple ophthalmology clinical sites in the 
US, Australia and New Zealand. Subjects are randomized in a 2:2:1:1 manner to either receive 
APL-2 IVT 15 mg monthly for 12 months; Sham IVT monthly for 12 months; APL-2 IVT 15 mg EOM 
for 12 months; or Sham IVT EOM for 12 months. This study demonstrated statistically significant 
slowing of disease progression at Month 12 at the pre-specified alpha of 0.1. APL-2 administered 
monthly showed a 29% (p=0.008) reduction in the rate of GA lesion growth compared to sham and 
APL-2 administered EOM showed a 20% (p=0.067) reduction. APL-2 has been generally well 
tolerated. To date, the most frequently reported AEs have been related to the procedure 
(intravitreal injection), which are common with this type of procedure. An imbalance in new 
exudation in subjects treated with APL-2 and the risk of developing new exudation may be 
increased in subjects with a prior history of exudative AMD in the fellow eye. 
Further details regarding completed studies can be found in the current APL-2 Investigator’s 
Brochure. 


 
 
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7.1
Purpose of the Study
The purpose of this study is to establish the safety and tolerability of intravitreally injected APL-2 in 
patients with neovascular AMD.
7.2
Dose Selection
A single dose of 15 mg/100 μL, administered by IVT injection monthly, for 12 months (48 weeks), 
will be tested in this study (see Section 8.3).
Physician feedback injecting a 200 mg/mL solution in the ASAP 2 Phase I trial (Study POT-
CP043014; NCT02461771) confirmed that 150 mg/mL is the highest practical concentration that 
can be routinely administered, which set the dose of the Phase II trial to 15 mg (i.e. 0.1 mL of a 
150 mg/mL solution).  While monthly and EOM dosing were well tolerated, the 15 mg dose given 
monthly was found to be the most efficacious in the Phase II trial.
7.3
Risk/Benefit
The Phase I (Study POT-CP043014; NCT02461771) and Phase II (Study POT-CP121614; 
NCT02503332) studies provided supporting evidence of a positive benefit-risk profile for the use of 
APL-2 in treating patients with AMD. Results from these studies in patients with CNV will enable to 
further study the safety and efficacy of APL-2 in patients with existing or new onset of CNV as 
monotherapy or in combination with established products. The reported safety data from these 
studies demonstrated an acceptable safety and tolerability profile with no clinically significant 
safety concerns observed. A total of 178 patients have received at least one dose (15 mg/injection) 
of APL-2 as part of these studies. Section 8.3 provides a summary of the study design and key 
results from both studies.  
The safety monitoring practices employed by this protocol (complete ophthalmologic exam, IOP 
monitoring, OCT, vital signs, hematology, serum chemistry, urinalysis, physical exam, vital signs 
and AE questioning) are adequate to protect the subjects’ safety. There are also risks associated 
with the ophthalmic procedures required for participants in this study.  However, these are all 
standard procedures that are widely performed in ophthalmology.
In the days following any IVT injection, patients are at risk of developing endophthalmitis. If the eye 
should become red, sensitive to light, painful, or develop a change in vision, the patient will be 
instructed to seek immediate care from an ophthalmologist.  Other risks of IVT injection include 
traumatic cataract, retinal detachment and hemorrhage. Transient increased IOP has also been 
identified as a risk following IVT injections.
The amount of blood (see Section 12.5) planned for collection from each subject over the 18 
months of the study does not pose an undue risk in this patient population.
8. STUDY OBJECTIVES AND ENDPOINTS
8.1
Study Objectives
Objective


 
 
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The objective of this study is to establish the safety of intravitreally injected APL-2 in patients with 
neovascular AMD. 
8.2
Study Endpoints
8.2.1
Primary Endpoint
x
Incidence and severity of ocular and systemic treatment- emergent adverse events 
(TEAEs)
8.2.2
Secondary Endpoints
x
Changes from baseline in physical examination findings and laboratory parameters
x
Changes from baseline in central macular thickness on OCT over 12 months
8.2.3
Pharmacokinetic Endpoint
x
APL-2 pharmacokinetic concentrations 
8.2.4
Exploratory Endpoint 
x
Number of anti-Vascular Endothelial Groth Factor (anti-VEGF) PRN injections from Visit 4 
to the Exit Visit (Visit 17) 
8.3
Study Design
Patients diagnosed with AMD in the study eye, who are receiving an anti-VEGF drug and who 
meet all other inclusion/exclusion criteria will be included in the study.  The study will include 
approximately 20 subjects across at least 3 U.S. sites.
Figure 1 presents the study outline. Patients will initially be screened between Day -28 and prior to 
treatment on Day 1. Screening procedures will include laboratory tests, BCVA, ophthalmological 
exam, IOP, and SD-OCT. Upon entry into the study (after signing the informed consent), subjects 
will be assigned a screening number. At screening visit 1 (Day -28) subjects will have an SD-OCT 
taken to assess for the presence of any subretinal, intraretinal, or sub-RPE fluid, followed by an 
IVT dose of anti-VEGF. Subjects will return two weeks later for screening visit 2 (Day -14) and will 
have another OCT performed to confirm a decrease in excess fluid in the macula. Upon 
confirmation of less fluid in the investigator’s opinion, patients who meet all inclusion and exclusion 
criteria will be enrolled in the study and will receive treatment with APL-2. Subjects will then return 
for treatment (Visit 3; Day 1). At this visit, subjects will be given a mandatory IVT dose of anti-
VEGF. Treatment with anti-VEGF should be given first and IOP should be taken prior to 
administration of APL-2. If IOP is <21 mmHg (prior to administration of APL-2), APL-2 may be 
administered. If not, additional measurements should be taken until IOP reaches <21 mmHg. APL-
2 should not be administered if IOP does not fall within this range.
This is an 18-Month Phase Ib/II, multi-center, open label study to assess the safety and tolerability 
of monthly IVT injections of APL-2 in subjects with neovascular AMD.


 
 
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All subjects will receive monthly APL-2 injections for 12 months (48 weeks) during their scheduled 
monthly treatment visits. At each treatment visit, safety assessments including vital signs, labs and 
urinalysis, and SD-OCT will be performed. BCVA, fundus examination, dilated indirect 
ophthalmoscopy and slit lamp examination will also be performed. Subjects will be assessed at 
each treatment visit for the need for retreatment with anti-VEGF based on pre-specific retreatment 
criteria. During follow-up, safety assessments will be performed for all subjects at months 15 and 
18. Subjects who discontinue study treatment, can continue participation in the study and return to 
the clinical site for their scheduled study procedures. Subjects who fully withdraw from the study 
before month 12, should complete the Early Termination Visit at a minimum 30 days after their last 
visit.
An external, independent SMC will assess the progress and cumulative safety/tolerability data of 
the study.
Subjects who fail the screening procedures should not be re-screened for the study unless this is 
agreed in advance and documented in writing with the sponsor.
Figure 1: Study Outline
 
9.
SUBJECT SELECTION
The study plans to enroll approximately 20 subjects with neovascular AMD in a single cohort.
9.1
Inclusion Criteria
Inclusion Criteria:
Ocular- specific inclusion criteria apply to the study eye only.
1. Age t 60 years.


 
 
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2. Normal Luminance best corrected visual acuity (NL-BCVA) of 24 letters or better using
Early Treatment Diabetic Retinopathy Study (ETDRS) charts (20/320 Snellen equivalent).
3. Clinical diagnosis of neovascular AMD with the following criteria met: 
a. Eligible for an injection of an Anti-VEGF injection with macular fluid present at Day -28. 
b. Must have been treated with anti-VEGF in study eye for at least 6 months prior to 
joining the study. 
c.
At least 6 months of intravitreal anti-VEGF therapy at intervals not greater than 8 weeks 
(± 7 days) for the past 2 injections in the eye that is selected to be the study eye.
4. A clinically meaningful reduction in excess macular fluid or macular thickness in the study 
eye at the discretion of the investigator between Screening Day -28 and Screening Day -14
as assessed by SD-OCT. 
5. Female subjects must be:
a. Women of non-child-bearing potential (WONCBP), or
b. Women of child-bearing potential (WOCBP) with a negative pregnancy test at screening 
and must agree to use protocol defined methods of contraception for the duration of the 
study and refrain from breastfeeding for the duration of the study.
6. Males with female partners of child-bearing potential must agree to use protocol defined 
methods of contraception and agree to refrain from donating sperm for the duration of the 
study.
Note: If both eyes meet the inclusion criteria, the eye with the worst VA at the screening visit will be 
designated as the study eye. If both eyes have the same VA, the Investigator and patient will 
determine the study eye.
Exclusion Criteria:
Ocular specific exclusion criteria apply to the study eye only.
1. Presence of other causes of choroidal neovascularization (CNV) including pathologic myopia 
(spherical equivalent  -6 diopters), central serous chorioretinopathy, ocular histoplasmosis 
syndrome, angioid streaks, choroidal rupture, and multifocal choroiditis.
2. History of vitrectomy to the study eye 
3. Presence of any ophthalmologic condition that reduces the clarity of the media and that, in the 
opinion of the Investigator, interferes with ophthalmologic examination (e.g. advanced cataract 
or corneal abnormalities).
4. Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization.
7. Willing and able to give informed consent and to comply with the study procedures and 
assessments. 


 
 
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5. Any history of endophthalmitis.
6. Trabeculectomy or aqueous shunt or valve in the study eye.
7. Aphakia or absence of the posterior capsule. Note: previous violation of the posterior capsule is 
also excluded unless it occurred as a result of yttrium aluminum garnet (YAG) laser posterior 
capsulotomy in association with prior posterior chamber intraocular lens implantation and at 
least 60 days prior to baseline.
8. Any ophthalmic condition that may require surgery or medical intervention during the study 
period or, in the opinion of the Investigator, could compromise visual function during the study 
period (e.g. severe uncontrolled glaucoma, clinically significant diabetic macular edema, 
ischemic optic neuropathy, retinal vasculopathies).
9. Any contraindication to IVT injection including current ocular or periocular infection.
10. Current treatment for active systemic or localized infection.
9.2
Approved Methods of Contraception
Approved methods of contraception include: abstinence, oral contraceptives, intrauterine device, 
medically acceptable barrier methods (diaphragm or condom), implantable or injectable 
contraceptives (like DepoProvera) or removable birth control device (like NuvaRing or Ortho Evra
patches); and/or surgical sterilization (at least 6 months before dosing). Subjects practicing 
abstinence and coitus interruptus (pull out method) must agree to use an approved method of 
contraception during the study.
10. STUDY TREATMENTS
10.1 Identity of Investigational Product
APL-2 will be provided in the form of either a lyophilized or liquid formulation, in glass vials with 
grey stoppers and sealed with flip-off seals. 
The lyophilized APL-2 or APL-2 for Injection is a sterile lyophilizate that needs to be reconstituted 
with 5% dextrose by investigator site staff prior to use. 
11. Participation in any systemic experimental treatment or any other systemic investigational new 
drug within 6 weeks or 5 half-lives of the active (whichever is longer) prior to the start of study 
treatment. Note: clinical trials solely involving observation, over-the-counter vitamins, 
supplements, or diets are not exclusionary
12. Medical or psychiatric conditions that, in the opinion of the investigator, make consistent follow-
up over the 24- month treatment period unlikely, or would make the subject an unsafe study 
candidate.
13. Any baseline laboratory value (hematology, serum chemistry or urinalysis) that in the opinion of 
the Investigator is clinically significant and not suitable for study participation. 
14. Known hypersensitivity to fluorescein sodium for injection or hypersensitivity to APL-2 or any of 
the excipients in APL-2 solution 


 
 
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The liquid APL-2 or APL-2 Intravitreal injection, 15 mg/0.1 mL (150 mg/mL) is a sterile presentation 
of APL-2 in an acetate buffered Trehalose solution.
Both APL-2 drug product configuration that will be injected intravitreally are sterile, clear, colorless 
to slightly yellowish solutions of APL-2 at approximately 150 mg/mL.
10.2 Administration of Investigational Product
10.2.1 Pre-Injection Procedure (Patient Preparation)
NOTE: It is recommended that the fellow eye is covered with a drape or 4x4 pad during the 
injection procedure. Study sites are to follow their standard for injection preparation and procedure. 
The procedures listed here are guidelines, please refer to the manual of procedures for more 
information. 
1. Within approximately 1 hour prior to injection: Topical 1% Mydriacyl and 2.5% 
Phenylephrine should be applied topically to achieve adequate pupillary dilation. One drop 
of the topical antibiotic should also be instilled, if applicable. It is recommended that a new 
bottle should be used daily.
2. Apply single use topical anesthetic to the study eye as needed to achieve adequate 
anesthesia for the procedure. Additional local subconjunctival anesthesia (e.g., 1% 
lidocaine hydrochloride solution) can be used at the Site Principal Investigator’s discretion.
3. Perform a local flush of povidone-iodine into the eye (enough to completely irrigate the 
fornices and caruncle and coat the eyelid margins). Do not scrub or manipulate the eyelids 
or eyelashes. Povidone- iodine bottles must not be shared between subjects.
4. A sterile drape may be used to isolate the ocular field, at the Investigator’s discretion.
5. Insert a sterile eyelid speculum (solid blade, open blade, depending upon the site’s 
standard practice). A sterile eyelid speculum must be used for all injections.
6. Place one or two drops of 5% povidone-iodine on the ocular surface at the intended 
injection site.
10.2.2 Dosing
Starting on Day 1 (Visit 3), subjects will receive monthly IVT doses of 15mg of APL-2 until the last 
dose at Month 12 (Week 48). On Day 1, anti-VEGF therapy will be administered by IVT injection, in 
addition to the APL-2 injection. The anti-VEGF therapy shall be administered first and the APL-2
injection shall occur not earlier than 30 minutes after anti-VEGF injection and only if the IOP is <21 
mmHg
10.2.3 Investigational Product Administration
1. For the IVT injection, attach a sterile 27 gauge or 29 gauge (29 gauge for liquid formulation) 
Thin Wall x 1/2 inch needle. The needle should be securely threaded onto the syringe.
2. With WKHQHHGOHHQGRIWKHV\ULQJHXSDGYDQFHWKHSOXQJHUWRWKHȝOP/PDUNWR
expel any air bubbles and obtain exactly 0.1 mL of liquid for IVT injection.


 
 
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3. Discard the syringe and needle safely into a sharps container
4. With a permanent marker, write the subject ID number and the visit number on the label of 
the vial used for the injection. All used and unused vials must be kept until the site close-out 
visit unless other advice is given by the Sponsor, or designee.
5. Note the time of the injection in the injection worksheet/source documentation.
6. The entry site for the needle for the intravitreal injection should be 3.0 to 3.5 mm from the 
limbus in pseudophakic patients, and 3.5 to 4.0 mm in phakic patients. Measure the injection 
site with sterile calipers. The globe may be stabilized with sterile forceps if necessary.
7. Saturate a cotton-tipped applicator with sterile topical anesthetic drops and push against the 
globe with the swab at the planned injection site for 15-25 seconds to soften the eye. This can 
be repeated if necessary at the physician's discretion.
8. Absorb the excess liquid and dry the periocular skin with a 4x4 pad.
10.3 Labelling, Packaging, Storage, and Handling
10.3.1 Labelling
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
All investigational product is labeled with a minimum of the following: protocol number, dosage 
form (including product name and quantity in pack), route of administration, directions for use, 
storage conditions, batch number and/or packaging reference, the statements “For clinical trial use 
only” and/or “CAUTION: New Drug – Limited by Federal (or US) Law to Investigational Use”, and 
name and address of sponsor.
Space is allocated on the label so that the site representative can record a unique subject identifier 
and date dispensed by the site to the subject.
Additional labels may, on a case-by-case basis, be applied to the investigational product in order to 
satisfy national, local or institutional requirements, but must not:
x
Contradict the clinical study label.
x
Obscure the clinical study label.
x
Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
10.3.2 Packaging
APL-2 will be supplied as either a lyophilized or liquid formulation. 
APL-2 will be supplied in clear glass vials with thermoplastic-faced stoppers and flip-off seal-caps.
Specific instructions for preparing APL-2 for the IVT injection procedure are provided in Section 
10.2.3.


 
 
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10.3.3 Storage
The lyophilized investigational product should be stored frozen at -20°C. The liquid investigational 
product should be stored refrigerated at 2-8°C.
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
A pharmacist or appropriately qualified designated person will be responsible for storing the 
investigational product appropriately . The pharmacist/nominated team member will enter the 
unique subject identifier on the investigational product bottle/carton labels as they are distributed.
Temperature monitoring is required at the investigator site (or documented storage location) to 
ensure that the investigational product is maintained within an established temperature range. The 
investigator is responsible for ensuring that the temperature in monitored throughout the duration 
of the study and that records are maintained.
10.4 Investigational Product Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out this 
protocol for the agreed number of subjects. The investigator or designee will acknowledge receipt 
of the investigational product, documenting shipment content and condition. Accurate records of all 
investigational product stored, returned or destroyed at the site must be maintained. 
At the conclusion of the study, any unused investigational product will either be destroyed at the 
investigator site or be returned to the Sponsor or designee for destruction, and destruction will be 
documented appropriately. If no supplies remain, this fact will be documented appropriately.
10.5 Re-Treatment with Anti-VEGF 
In addition to receiving the study drug, APL-2, subjects will be assessed at each of the treatment 
visits for the need for injections of intravitreal anti-VEGF treatment. Injections may be Avastin, 
Lucentis, or Eyelea; however, the treatment given at baseline should be continued throughout the 
study (where applicable). The determination to treat with anti-VEGF should be based on the 
principal investigator’s (PI’s) discretion as to whether the subject is the same, better or worse from 
the previous visit. The PI should use all available assessments in making a determination for re-
treating the subject with anti-VEGF. 
If anti-VEGF therapy is administered on the same day as an APL-2 injection, the anti-VEGF 
therapy shall be administered first and the APL-2 injection shall occur not earlier than 30 minutes 
after anti-VEGF injection and only if the IOP is <21 mmHg.
Once the subject has completed participation (either by early termination or completing all study 
visits), additional treatments with anti-VEGF can be administered according to the PIs standard 
protocol for CNV treatment but not more frequently than recommended in the label of the selected 
anti-VEGF therapy.


 
 
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10.6 Concomitant Medications
Any concomitant medications a participant is receiving at the start of the study, within 30 days prior
to screening, or that are given for any reason during the study (except for routine medications
given for ocular procedures required by the protocol, such as topical anesthetic) must be recorded
in the source document and Case Report Form (CRF) including start and stop date and time, dose,
route, and indication. In addition, all invasive intraocular procedures from the previous year must
also be recorded in the source document including start and stop dates. Surgical anesthetics,
paramedical or alternative therapies (e.g. acupuncture, massage) should also be recorded in the
source documents and CRF.
Metoclopramide or other agents to prevent nausea induced by fluorescein injection may be
administered at the discretion of the PI.
10.6.1 Prohibited Therapies
The PI should make a determination regarding patient continuation of therapies used to treat 
concomitant medical conditions. Therapies as noted in the inclusion/ exclusion criteria are 
prohibited as specified.
10.6.2 Endophthalmitis Treatment
All suspected cases of Endophthalmitis should be reported as a serious adverse event. The 
decision to treat a participant for endophthalmitis or suspected endophthalmitis will be guided by 
the clinical judgment of the PI. A culture sample should be performed prior to making a decision on 
treatment. The treatment method (pars plana vitrectomy vs. vitreous tap) and choice of 
antimicrobial agents are also at the discretion of the PI and should follow current standard practice 
patterns.  The decision to use IVT steroids (e.g. dexamethasone) for the treatment of 
endophthalmitis is also at the discretion of the PI. 
11. STUDY PROCEDURES
Please see the Schedule of Events in Section 4 for a summary of the schedule of study 
participation and procedures. The schedule of visit dates should be established, either prior to or at 
the time of screening allowing subjects an opportunity to assess whether there are likely to be 
significant conflicts with other activities or planned absences. To the extent possible, subjects will 
be expected to adhere to the visit schedule and any re-scheduling of visits must be agreed, in 
advance, with the PI and Sponsor.  
Note: All ophthalmic procedures will be for both eyes throughout the study unless otherwise noted. 
11.1 Screening Visit 1 (Day -28 ± 2 days)
After signing the informed consent, the subject will be screened to confirm that the subject 
selection criteria for the study has been met. Informed consent will be obtained at screening prior 
to any study related procedures being conducted. 
A screen failure is a subject who has given informed consent and failed to meet the study
inclusion/ exclusion criteria, and has not been randomized or administered investigational 


 
 
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product(s). Subjects should not be rescreened once they have been designated as a screen 
failure, unless this is discussed in advance and documented in writing with the sponsor. 
After confirming that the subject requires an anti-VEGF injection due to the presence of any 
subretinal, intraretinal, or sub-RPE fluid on SD-OCT, the following assessments will be performed:
x
Demographics 
x
Medical history (including Ophthalmic History) 
x
Review of inclusion/exclusion criteria 
x
Best corrected visual acuity using ETDRS at 4 meters (performed prior to dilating the eyes)
x
Study Eye Determination 
x
SD-OCT 
x
Prior and concomitant medications
x
B-HCG pregnancy test 
x
FSH, LH
x
Adverse Events evaluation/ collection 
If the subject fulfills the criteria, they will receive an anti-VEGF injection and will be asked to return 
to the clinic in 14 days to have further imaging (SD-OCT) taken to demonstrate if there is a 
response to anti-VEGF.
11.2 Screening Visit 2 (Day -14 ± 3)
Subjects that demonstrate a reduction in macular fluid (based on SD-OCT comparison from 
Screening Visit 1 to Visit 2) by this visit will complete the Day -14 procedures (Screening Visit 2) to 
ensure the rest of the study criteria are met. If all criteria are met, the subject will be scheduled to 
return for another anti-VEGF injection on Day 1.  
x
Best corrected visual acuity using ETDRS at 4 meters (performed prior to dilating the eyes)
x
SD-OCT (If the investigator determines that there is a clinically meaningful reduction in 
macular fluid, the rest of the Day -14 procedures should be performed. If the investigator 
determines that they would like to wait for reading center confirmation of the images, the 
subject can be re-scheduled for the rest of the procedures, labs should be collected and 
vital signs performed at that time.)
x
Urine Collection
x
Urine pregnancy test (if positive, serum pregnancy test should be performed) 
x
Blood draw for safety labs 
x
Vital signs
x
IOP measurement


 
 
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x
Dilated Ophthalmoscopy and Slip Lamp Assessment
x
Evaluate and record any new concomitant medication and adverse events
11.3 Baseline Visit (Day 1 ± 8 days): Visit 3
Following successful completion of the 4-week screening period (i.e. subjects that demonstrate a 
reduction of macular fluid at Screening Visit 2 and meet all study criteria), subjects will enter the 
Treatment Period to receive another anti-VEGF injection and will receive APL-2. The following 
assessments outlined in the Schedule of Events (Section 4) will be performed:
Prior to treatment with APL-2:
x
SD-OCT
x
Urine pregnancy test (if positive, serum pregnancy test should be performed) 
x
Vital signs (within 90 minutes prior to dosing)
x
IOP measurement (taken within 15 minutes prior to the APL-2 injection)
x
Dilated Ophthalmoscopy and Slip Lamp Assessment
x
Physical examination 
x
Evaluate and record any new concomitant medication and adverse events
x
Mandatory anti-VEGF injection (Note: anti-VEGF injection is performed prior to APL-2)
APL-2 administration will occur after all of the above procedures are completed (see Section 10.2.2
for more detailed procedures). If anti-VEGF therapy is administered on the same day as an APL-2
injection, the anti-VEGF therapy shall be administered first and the APL-2 injection shall occur not 
earlier than 30 minutes after anti-VEGF injection and only if the IOP is <21 mmHg.
After investigational product administration: 
x
Vital signs
x
Post Injection Assessment
11.4 Treatment Period (Day 30-360 ± 8 days): Visits 4-15
Prior to treatment:
x
Best corrected visual acuity using ETDRS at 4 meters (performed prior to dilating the eyes)
x
SD-OCT 
x
Urine pregnancy test (if positive, serum pregnancy test should be performed) 
x
Blood draw- safety labs (Visits 4,9 and 15) 
x
Blood draw- PK and anti-APL-2/ PEG (Visits 4,9, and 15)
x
Vital signs (within 90 minutes prior to dosing)


 
 
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x
IOP measurement (taken within 15 minutes prior to the APL-2 injection)
x
Dilated Ophthalmoscopy and Slip Lamp Assessment
x
FA and Color Fundus Photographs (Visit 3 and Visit 15 only)
x
Ophthalmic Exam 
x
Evaluate and record any new concomitant medication and adverse events
x
Assess need for anti-VEGF injection (Note: if anti-VEGF injection is performed, should be 
prior to APL-2 (see Section 10.5 for more detailed procedures)
After investigational product administration: 
x
Vital signs
x
Post Injection Assessment
11.5 Follow-up (Day 450 ± 8 days): Visit 16
All subjects that complete study treatment will be asked to return to the investigator site for follow-
up visits at Month 15 and Month 18, where the assessments outlined in the Schedule of Events 
(Section 4) will be performed. 
Subjects who discontinue treatment early and do not elect to continue their participation in the
study should complete a follow-up visit 6 weeks after discontinuation of treatment and also the Exit 
Visit 6 weeks thereafter. 
x
Best corrected visual acuity using ETDRS at 4 meters (performed prior to dilating the eyes)
x
SD-OCT
x
Urine pregnancy test (if positive, serum pregnancy test should be performed) 
x
Vital Signs 
x
IOP Measurement
x
Dilated Ophthalmoscopy and Slip Lamp Assessment 
x
Ophthalmic Exam
x
Physical examination
x
Evaluate and record any new concomitant medication and adverse events
x
Assess need for anti-VEGF injection
11.5.1 Exit Visit (Day 540 ± 8 days): Visit 17
All subjects will be asked to return to the clinical facility for the Exit Visit 24 weeks after the final 
dose of APL-2, at Week 72.


 
 
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Study participation for each subject will be concluded following completion of the Exit Visit. If a 
subject withdraws from the study prior to the scheduled Exit Visit, all Exit Visit evaluations should 
be performed at the subject’s final visit to the clinic.
x
Vital Signs
x
Evaluate and record any new concomitant medication and adverse events
x
Assess need for anti-VEGF injection 
11.6 Unscheduled Follow-up Visits
All subjects will be asked to return to the clinical facility for additional follow-up visits if considered 
necessary by the PI.
Unscheduled follow-up visits may include (but are not limited to) any of the procedures listed in the 
Schedule of Events in Section 4.
11.7 Safety Monitoring Committee (SMC)
A SMC will review cumulative safety/tolerability data (e.g., physical examinations, vital signs, 
clinical laboratory tests, and adverse events). The SMC will have the responsibility to conduct a 
thorough safety assessment at regular pre-defined intervals during the treatment period of the 
study.
The first SMC meeting will be scheduled four months after the first subject is dosed, and at 
intervals of every 4 months until all subjects complete the Week 48 Visit. An ad hoc SMC data 
review may be recommended by the SMC or requested by the Sponsor at any time during the 
study.
The roles, and responsibilities of the SMC will be specified in a separate SMC charter.
11.8 Treatment Discontinuation and Study Withdrawal
Subject participation in this study may be discontinued and subjects may be withdrawn from study 
for any of the following reasons:
1. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the PI that continued participation is not in the 
best interest of the subject.
2. Subject's decision to withdraw.
3. Subject’s failure to comply with protocol requirements or study-related procedures.
4. Termination of the study by the Sponsor, United States Food and Drug Administration 
(FDA), or other regulatory authorities.
The reason for treatment discontinuation and withdrawal from the study must be recorded in the 
subject’s CRF. 


 
 
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If a subject is withdrawn from the study prior to study completion, the subject will undergo all 
procedures scheduled for study completion (Exit Visit) as the situation allows. Any subject 
withdrawn due to an AE (whether serious or non-serious) or clinically significant abnormal 
laboratory test values will be evaluated by the investigator and will be treated and/or followed up 
until the symptoms or values return to normal or acceptable levels, as judged by the PI.
If consent is withdrawn, no further study evaluations are to be performed and no attempts are to be 
made to collect additional data. If the subject would like to stop taking study drug but continue 
participation in the study, they can be scheduled for all follow-up visits and complete all of the 
applicable procedures except for study drug administration. 
12. ASSESSMENTS
12.1 Assessments
Assessments to be performed during the study are described below. Every effort should be made 
to ensure that the protocol-required assessments are completed as described.
If deemed necessary, additional safety measurements will be performed at the discretion of the PI.
12.1.1 Medical History
Medical history, including surgical or ophthalmic history (including clinically significant ocular 
surgeries and procedures), will be collected at Screening Visit 1.
12.1.2 Prior and Concomitant Medications
To be eligible for entry into the study subjects will be receiving anti-VEGF therapy for at least 6 
months, and at a stable dose for at least 8 weeks prior to screening. All treatment with anti-VEGF 
during the course of the study should be recorded as a concomitant medication. 
All other prior medications administered within 12 Weeks of Screening Visit 1 will be collected. 
All medications and procedures administered to subjects from the time of informed consent 
through the End of Study Visit are regarded as concomitant and will be documented.
12.1.3 Body Height and Weight
Body height (cm) and body weight (kg) will be measured at screening visit 1 as part of the physical 
examination.
12.1.4 Physical Examination
All full physical examinations will include, at a minimum, assessment of the following: general, 
head, ears, eyes, nose and throat, dentition, thyroid (endocrine), heart, chest, lungs, abdomen, 
skin, extremities, back/neck, musculoskeletal, and lymph nodes.
The investigator (or designee) at the study site will examine each subject as outlined in the 
Schedule of Events in Section 4.


 
 
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A symptom-driven physical examination may be performed at various unscheduled time points if 
deemed necessary by the investigator.
12.1.5 Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate will be 
measured within 90 minutes of dosing and within approximately 30 minutes after dosing. Vital 
signs should be taken with the patient in a seated position after resting for 5 minutes. Vital signs 
will be measured before venipuncture
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and heart rate 
measurements will be performed with subjects in a seated position after resting for 5 minutes, 
except when they are supine or semi-reclined because of study procedures and/or AEs (e.g., 
nausea, dizziness) or if deemed necessary by the PI.
Vital signs will be measured before venipuncture, vital signs collected post-dose will be timed from 
the completion of the study drug administration.
12.1.6 Best-Corrected Visual Acuity (BCVA)
The best- corrected visual acuity will be measured at each visit as per the visit schedule by trained 
study staff. Best-corrected visual acuity testing will be assessed on ETDRS chart starting at a 
distance of 4m, performed by a certified VA examiner, and should precede any examination 
requiring administration of eye drops to dilate the eye or any examination requiring contact with the 
eye.  
A VA Specifications procedure manual and training materials will be provided to all sites. All 
examiners will require certification prior to performing this assessments as part of the study.
12.1.7 Ocular Imaging
The following ocular images will be obtained and sent to the Reading Center as outlined in the visit 
schedule. A Reading Center manual along with training materials will be provided to all sites which 
will provide information on standardized procedures for the collection, storage and transmission of 
all images. Prior to any images being taken at the site, site personnel must be properly trained and 
certified and test images and systems and software must be certified and validated by the Reading 
Center. Only trained and certified site staff delegated the responsibility of image collection should 
perform this task. Ocular images obtained as part of this study are:
x
Digital Color Fundus Photographs 
x
Fluorescein angiography 
x
Spectral Domain Optical coherence tomography angiography (Heidelberg Instrument) 
If a patient misses a visit during which ocular images should have been taken, the images should 
be collected at the next scheduled study visit. 


 
 
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12.1.8 Clinical Laboratory Tests
All tests listed below will be performed as outlined in the Schedule of Events in Section 4. In 
addition, laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the PI or recommended by the SMC. The clinical laboratory tests include (but are not 
limited to) the following:
12.1.8.1 Hematology
x
Hemoglobin
x
Hematocrit
x
Red Blood Cell count
x
Platelet count 
x
White blood cell count with differential
12.1.8.2 Serum Chemistry
x
Blood urea nitrogen (BUN)
x
Creatinine
x
Bilirubin (total and conjugated)
x
Albumin
x
Alkaline phosphatase (ALP)
x
Creatine kinase
x
Aspartate aminotransferase (AST)
x
Alanine Aminotransferase (ALT)
x
Uric acid
x
Glucose 
x
Electrolytes (Sodium, Potassium, 
Chloride, Bicarbonate)
12.1.8.3 Urinalysis
x
pH
x
Specific gravity
x
Protein
x
Glucose
x
Ketones  
x
Bilirubin
x
Blood
x
Nitrite
x
Urobilinogen
x
Leukocyte esterase 
Serum Pregnancy Test will be performed for females only. Follicle-Stimulating Hormone (FSH) and 
Luteinizing Hormone (LH) will be performed for postmenopausal females at screening Visit 1 only. 
12.1.9 Post-Injection Assessment
The study eye will be assessed before and after injection to ensure that the injection procedure 
and/or the study medication have not endangered the health of the eye. The initial post-injection 
assessments should be done within 15 minutes post-injection and include a gross assessment of 
vision (light perception). If subject does not pass the gross vision test, IOP needs to be monitored 
every 30 minutes from the previous measurement until the subject passes gross vision test and 
IOP is < 30 mmHg.  A measurement of IOP will be conducted using either Tono-pen or Goldmann 
applanation tonometer as outlined in the MOP. IOP must be monitored and recorded in all subjects 
receiving an anti-VEGF and APL-2 injection on the same day prior to and after each injection. If 
anti-VEGF therapy is administered on the same day as an APL-2 injection, the anti-VEGF therapy 
shall be administered first and the APL-2 injection shall occur not earlier than 30 minutes after anti-
VEGF injection and only if the IOP is <21 mmHg.  


 
 
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Any subject who develops a significant and sustained raise in IOP (> 30 mmHg) or a non-
adequately perfused central retinal artery (CRA) after any APL-2 injection, should be monitored 
according to the PI’s clinical judgment and may undergo additional procedures and measurements 
of IOP beyond those specified in the protocol as well as IOP lowering procedures. If any concern 
or immediate toxicity is noted, the subject will remain at the site and will be treated according to the 
PI’s clinical judgment.
12.2 Pharmacokinetic Assessments
12.2.1 Blood Sampling and Processing
Blood samples for PK assessment of APL-2 will be collected via direct venipuncture at the time 
points delineated in the Schedule of Events in Section 4. PK samples will be taken pre-dose at 
scheduled visits (Visits 4, 9, 15).
Instructions for collection, handling, processing, storage, and shipping of samples will be provided 
in a separate sample handling manual prior to study initiation.
12.3 Exploratory Assessments
Blood samples will be collected via direct venipuncture at the time points delineated in the 
Schedule of Events in Section 4.
Instructions for collection, handling, processing, storage, and shipping of samples will be provided 
in a separate Laboratory Reference Manual prior to study initiation.
12.4 Anti- APL-2/PEG Antibody Assessments 
Patients who test positive for anti-APL-2 antibodies will be followed until the antibody levels revert 
to baseline. Antibodies will be analyzed for titer, binding to cyclic pentadecapeptide (APL-1A-
EEAcK) and PEG, and neutralizing capacity.
Patients who discontinue dosing will need to have Anti-drug Antibodies (ADA) samples collected at 
Follow-up visits (Month 15 and 18). 
Patients who test positive for anti-APL-2 antibodies at any time will be followed with ADA samples 
being collected every 6 months until the antibody levels revert to baseline. Samples that test 
positive will be characterized by an assay that will determine antibody titer, binding to the cyclic 
peptide or PEG domains, and measure neutralizing capacity.
The proposed ADA sampling schedule was established to capture the ADA signal at baseline, 
along with any potential early onset and the dynamic profile (transient or persistent) of antibody 
formation while minimizing APL-2 level in the sample.
12.5 Blood Volume for Study Assessments
Table 1: Blood Volume During Study
Sample Type 
Number of Visits 
Approximate Volume 
per Visit 
Approximate Volume 
over Course of Study 


 
 
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(mL) 
(mL) 
Screening and Safety laboratory tests (including 
haematology, serum chemistry, HCG, LH, and FSH 
(for postmenopausal female patients only). 
5 
15 
75 
PK 
4 
4 
16 
Immunogenicity (Anti-APL-2/PEG antibodies) 
4 
5 
20 
Total Approximate Blood Volume for Study: 
111 
*Represents the standard collection volume planned over the duration of the study, actual volume may vary.
12.6 Pregnancy Tests
For WOCBP, a serum pregnancy test will be performed at screening (Visits 1 and 2) and during 
treatment (Visits 4, 9 and 15 if urine pregnancy test is positive). Subjects with a positive test will be 
excluded from the study. A urine pregnancy test will also be performed at each site visit (pre-dose) 
if applicable. A final urine pregnancy test will be performed at the first follow-up visit (Visit 16). Male 
subjects will be counseled to avoid donating sperm during the time between the first screening visit 
(Day -28) and the final Exit Visit.
WONCBP are not required to undergo pregnancy tests. WONCBP are defined as women meeting 
any of the following criteria:
x
Older than 45 years with amenorrhea for > 2 years or older than 60 years with amenorrhea 
for > 1 year. Both confirmed by FSH and LH levels.
x
Has undergone hysterectomy,
x
Has undergone bilateral oophorectomy,
x
Has undergone bilateral salpingectomy.
13. ADVERSE EVENTS
13.1 Definition
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign, including a clinically significant abnormal laboratory finding, symptom, or disease 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug (FDA guidance, December 2012). Any abnormal laboratory finding that is deemed not 
clinically significant is not an AE. 
Adverse events include the onset of new illness and the exacerbation of pre-existing conditions. 
Any medical condition that is present at the time that the subject is screened should be recorded 
on the medical history electronic Case Report Form (eCRF) and not reported as an AE. However, if 
that condition deteriorates or severity changes at any time during the study, it should be recorded 
as an AE. AEs should be recorded beginning at screening and ending up to 30 days after the last 
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A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. Reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the AE.
13.2 Adverse Event Assessment and Recording
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit beginning at screening and record the information in the site’s source documents and 
on the eCRF. Questions should be asked in a manner that does not lead the subject. For each AE, 
the PI should note the start and resolution dates, the severity, whether it meets the definition of an 
SAE (see Section 13.5), the relationship of the event to the study drug, the action taken regarding 
study drug, and the outcome of the event. Data should be transcribed from the source documents 
to the CRF as per the CRF instructions.
All AEs encountered during the study will be monitored and reported in detail in the source 
documents and documented on the eCRF, from signing of the Informed Consent Form (ICF) until 
the Exit Visit. AEs, especially those for which the relationship to test drug is considered by the PI to 
be possibly or probably related, should be followed up until they have returned to the baseline 
status or stabilized. If a clear explanation is established, it should be recorded on the eCRF.
Subjects will be monitored throughout the study for adverse reactions to the study formulations 
and/or procedures. Subjects will be asked how they are feeling at each Study Visit. 
AEs (whether serious or non-serious) including clinically significant abnormal laboratory test 
value(s) will be evaluated by the PI and treated and/or followed up until the symptoms or value(s) 
return to normal, or acceptable levels, as judged by the PI.
When appropriate, medical test(s) and/or examination(s) will be performed to document resolution 
of event(s). Outcome may be classified as resolved, improved, unchanged, worse, fatal or 
unknown (lost to follow-up).
13.2.1 Procedures For Recording Adverse Events  
Investigators should use their best judgment to record the correct medical terminology when 
recording adverse events on the AE CRF. Only one AE term should be recorded in the event field 
on the adverse event CRF. 
When recording events of infection and inflammation, the following terms and associated 
definitions should be used: 
Irititis: the presence of inflammatory cells in the anterior chamber 
Iridocyclitis: the presence of inflammatory cells in both the aqueous and vitreous 
Vitritis: the presence of active inflammation in the vitreous, demonstrated by the presence of 
inflammatory cells (trace or greater) 
Endophthalmitis: diffuse intraocular inflammation predominantly involving the vitreous cavity but 
also involving the anterior chamber, implying a suspected underlying infection.  
A diagnosis should be recorded, whenever known, rather than individual signs and symptoms (e.g. 
record myocardial infarction rather than chest pain). If a diagnosis cannot be made


 
 
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13.3 Treatment and Follow-up of Adverse Events
AEs (whether serious or non-serious), including clinically significant abnormal laboratory test 
values, will be evaluated by the Investigator and treated and/or followed up until the symptoms or 
value(s) return to baseline or are clinically stable. Treatment of AEs will be performed by 
appropriately trained medical personnel. When appropriate, medical tests and/or examinations will 
be performed to document resolution of the event(s). 
AEs continuing after completion of the study will be followed up by telephone or with visits per the 
discretion of the Investigator. If possible, the outcome of any AE that caused discontinuation from 
the study or was present at the end of the study should be reported, particularly if the AE was 
considered by the PI to be related to the study drug.
13.4 Reporting 
All SAE’s and pregnancies must be reported to the study Sponsor within 1 business day of 
discovery by sending the SAE reporting form to: 
Email: 
The collection of clinical information will begin after the subject’s written consent to participate in 
the study has been obtained. AEs will be collected after signing the ICF through to completion of 
the Exit Visit. Any events that occur prior to dosing on Day -28 will be categorized as pre-treatment 
events. Events occurring after dosing on Day 1 will be recorded as TEAEs. AEs may be either 
spontaneously reported or elicited during questioning and examination of a subject. 
All identified AEs, including clinically significant laboratory findings, must be recorded and
described on the appropriate AE or SAE page of the eCRF. If known, the diagnosis of the 
underlying illness or disorder should be recorded, rather than its individual symptoms. AEs will be 
coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA®) coding 
dictionary.
Subjects experiencing AEs that cause interruption or discontinuation of study drug, or those 
experiencing AEs that are present at the End of Study Visit should receive follow-up as 
appropriate. If possible, the outcome of any AE that caused permanent discontinuation or was 
present at the end of the study should be reported, particularly if the AE was considered by the PI 
to be related to the study drug.
13.4.1 Relationship of Events to Study Treatment
All AEs that occur during this study will be recorded. The PI will review each event and assess its 
relationship to study drug treatment (unrelated, possibly, probably, likely). The date and time of 
onset, time relationship to drug dosing, duration, and outcome (resolved, improved, unchanged, 
worse, fatal, or unknown/lost to follow-up) of each event will be noted. 
The following definitions should be considered when evaluating the relationship of AEs and SAEs 
to the study treatment: 
PPD


 
 
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AE Relationship to Study Drug 
Definitely 
Related
x
Event or laboratory test abnormality, with plausible time relationship to drug intake
x
Cannot be explained by disease or other drugs
x
Response to withdrawal plausible (pharmacologically, pathologically)
x
Event definitive pharmacologically or phenomenologically (i.e. an objective and specific 
medical disorder or a recognized pharmacological phenomenon)
x
Rechallenge satisfactory, if necessary
Possibly 
Related
x
Event or laboratory test abnormality, with reasonable time relationship to drug intake
x
Could also be explained by disease or other drugs
x
Information on drug withdrawal may be lacking or unclear
Unlikely 
Related
x
Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible)
x
Disease or other drugs provide plausible explanations
Not Related
x
Event or laboratory test abnormality, is plausibly related to the participant’s clinical 
state, underlying disease, or the study procedure/conditions
x
Time relationship to drug intake makes a relationship unreasonable
x
Other obvious causes for event or laboratory test abnormality exist
Unknown
x
Report suggests an adverse event, however, cannot be judged at this time because 
information is insufficient or contradictory
x
More data for proper assessment is needed, or additional data is under examination
13.4.2 Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Event Severity
Mild
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Moderate
Minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental ADL*.
Severe
Medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**.
Note: An experience may be severe but may not be serious, e.g., severe 
headache).
A semi-colon indicates ‘or’ within the description of the grade.
Note: Activities of Daily Living (ADL) 


 
 
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*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
13.5 Serious Adverse Events
If any AEs are serious, special procedures will be followed. All SAEs will be reported to the Safety 
Monitor by the PI via fax or email within one working day of becoming aware of the event, whether 
or not the serious events are deemed drug-related. SAE reporting contact information will be 
provided separately and as included in the Safety Monitoring Plan. All SAEs must be reported to 
the applicable ethics committee by the PI in accordance with their regulations. 
An SAE is any adverse event or suspected adverse reaction that in the view of either the 
investigator or sponsor, results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
Life-threatening is defined as an AE or suspected adverse reaction, which in the view of either the 
investigator or Sponsor places the patient or subject at immediate risk of death. It does not include 
an AE or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death.
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the IB or is not 
listed at the specificity or severity that has been observed; or is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current application, as 
amended.
13.6 Unexpected Adverse Events or Unexpected Suspected Adverse Reactions
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator’s Brochure (IB) or is not listed at the specificity or severity that has been observed; or 
is not consistent with the risk information described in the general investigational plan or elsewhere 
in the current application. For example, under this definition, hepatic necrosis would be unexpected
(by virtue of increased severity) if the IB referred only to elevated hepatic enzymes or hepatitis. 
The Sponsor will be responsible for reporting any serious and unexpected adverse events to the 
applicable regulatory agencies as required. 
13.7 Treatment and Follow up of Adverse Events
AEs (whether serious or non-serious), including clinically significant abnormal laboratory test 
values, will be evaluated by the Investigator and treated and/or followed up until the symptoms or 
value(s) return to baseline or are clinically stable. Treatment of AEs will be performed by 
appropriately trained medical personnel, either at the clinical site or at a nearby hospital 


 
 
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emergency room. When appropriate, medical tests and/or examinations will be performed to 
document resolution of the event(s). 
AEs continuing after completion of the study will be followed up by telephone or with visits per the 
discretion of the PI. If possible, the outcome of any AE that caused discontinuation from the study 
or was present at the end of the study should be reported, particularly if the AE was considered by 
the PI to be related to the study drug.
13.8 Pregnancy 
Although pregnancy is not considered an AE, the outcome of a pregnancy, if there is a 
spontaneous abortion, congenital anomaly or other adverse fetal outcome, may be an SAE. All 
SAEs are to be reported to the study Sponsor on the SAE Reporting Form.
WOCBP and males with female partners of child-bearing potential will be instructed to practice an 
acceptable method of birth control (as defined in Section 9.2) for the duration of the study.
If a female subject or partner of a male subject becomes pregnant during the study, the PI should 
report the pregnancy to the Safety Monitor within 24 hours of being notified. The subject or partner 
should be followed by the PI until completion of the pregnancy. At the completion of the pregnancy, 
the PI will document and report the outcome. If the outcome of the pregnancy meets the criteria for 
classification as an SAE (i.e. postpartum complication, stillbirth, neonatal death, or congenital 
anomaly) the PI should follow the procedures for reporting an SAE (see Section 13.4)
14. STATISTICS 
14.1 Sample Size Justification
Given the exploratory nature of the study no formal statistical hypothesis testing will be performed 
and so the sample sizes of both parts of the study are not based upon statistical power of the 
study.  When no untoward adverse events occurred, we can, with a 95% confidence, rule out the 
event rate of >25.9% for a sample size of n = 10 subjects, or >13.9% for n = 20 subjects.
Twenty neovascular AMD patients will be enrolled into a single cohort. 
14.2 Statistical Analysis Methodology 
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to locking the 
database. The full details of data presentations and analyses will be provided in the SAP. 
Additional statistical analyses other than those described in this section may be performed if 
deemed appropriate and included in the SAP. Any deviations from the final SAP or from what is 
outlined in the protocol will be discussed in the final study report. 
All endpoints will be summarized by treatment group and visit. Continuous data will be summarized 
using descriptive statistics (e.g. mean and standard deviation) and categorical data will be 
summarized using frequency tables (counts and percentages).


 
 
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14.2.1 Analysis Populations
14.2.1.1 Screened Population
The screened/run-in analysis set will include all patients who signed the informed consent form, 
are screened for participation, and were given initial anti-VEGF therapy in this study. This set will 
be used only for the purpose of describing patient disposition. 
14.2.1.2 Safety Population/ Intent-to-Treat (ITT) Population
The safety analysis set will include all patients who receive a dose of APL-2.
14.2.1.3 Pharmacokinetic (PK) Population
The PK population will include all subjects in the ITT population who receive APL-2 and have at 
least 1 evaluable post-dose PK measurement.
14.2.1.4 Data Review for Analysis Populations
After all the data have been verified/coded/entered into the database, a review will be performed. 
The purpose of this review will be to define the analysis populations. The review will also check the 
quality of the data, identifying outliers, and make decisions on how to deal with any data issues 
(e.g., missing values, withdrawals, protocol deviations). After the pre-analysis review, resolution of 
all issues and documentation of all decisions, the database will be locked.
14.2.2 Analyses
No formal inferential statistics will be applied to data collected in the study.
14.2.2.1 Primary Endpoint
The primary endpoint is the incidence and severity of ocular and systemic Treatment- Emergent 
Adverse Events (TEAEs).
14.2.2.2 Secondary Endpoints
Secondary endpoints for the study are:  
x
Changes from baseline in physical examination findings and laboratory parameters
x
Changes from baseline in central macular thickness on OCT over 12 months
14.2.2.3 Pharmacokinetic Endpoints
x
APL-2 pharmacokinetic concentrations.
14.2.2.4 Exploratory Endpoints
x
Number of anti-VEGF (PRN) injections from Visit 4 to the Exit Visit (Visit 17) 
14.2.3 Safety Analyses 
All safety endpoints will be evaluated and safety summaries will be presented over the 
screening/run-in period, 48 weeks of treatment and 24 weeks of follow-up, as well as the overall 
duration of the study.


 
 
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14.2.3.1 Adverse Events
Treatment emergent adverse events are defined as those AEs that develop or worsen after the first 
dose of study medication and up to 30 days beyond the last dose of study medication. The current 
version of MedDRA will be used to classify all AEs. 
Treatment-emergent adverse events will be summarized by System Organ Class and Preferred 
Term, in accordance with the MedDRA coding dictionary. The number of subjects reporting each 
AE preferred term will be tabulated for all TEAEs and separately for those considered as possibly 
related to study treatment by the Investigator. Number of subjects reporting SAEs will also be 
tabulated.
14.2.3.2 Clinical Laboratory Tests
Changes from baseline in laboratory will be summarized using descriptive statistics by treatment, 
visit and nominal time post dose. Baseline will be taken as the last measurement prior to the first 
dose of APL-2. 
Out of range values will be flagged in the data listings.
14.2.3.3 Vital Signs
Changes from baseline in vital signs will be summarized using descriptive statistics by treatment, 
visit and nominal time post dose. Baseline will be taken as the last measurement prior to the first 
dose of APL-2.
14.2.4 Pharmacokinetic Analyses 
The PK concentrations will be evaluated using the PK Population.
Concentrations will be summarized using descriptive statistics over time in the treatment period.
Individual subject concentration-time data will be plotted against actual sampling time. Median 
profiles of the concentration-time data, using nominal sampling times, will also be presented. Both 
linear-linear and linear-log plots will be presented. 
Population pharmacokinetic and exposure-response modelling of the safety and exploratory data 
will be described in an APL-2 Population Pharmacokinetic/Pharmacodynamic Analysis Plan. The 
methods will be based on the FDA Guidances for both Exposure-Response and Population 
Pharmacokinetics (FDA Guidance for Industry Population Pharmacokinetics, FDA Guidance for 
Exposure-Response Relationships). 
14.2.5 Other Data Analyses (Treatment Group Comparability)
Pharmacodynamic analyses and other exploratory analyses will be further defined in the study 
SAP. Demographic data, baseline characteristics, physical examination, concomitant medication, 
medical history data and study medication exposure will be summarized by treatment group.
World Health Organization (WHO) and MedDRA coding dictionaries will be used for the 
concomitant medications and medical histories respectively.


 
 
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14.3 Direct Access to Source Data/Documents
The PI must maintain, at all times, the primary records (i.e. source documents) of each subject’s 
data for data verification. Examples of source documents are medical records, laboratory reports, 
study drug records, and eCRFs that are used as the source.
The PI will permit study-related monitoring, audits, and inspections by the Sponsor and/or its’ 
designee, IRB/IEC, and the regulatory agencies at any time during the study. The PI will ensure 
that the auditor is allowed direct access to the source data, medical records, eCRFs, and the Site’s 
regulatory file for the study and any other pertinent information. 
14.4 Quality Control and Quality Assurance
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. The PI, Sponsor and/or its designee are responsible for 
ensuring that the study staff receive appropriate training on the protocol, study procedures and any 
other relevant information. 
Quality assurance and quality control systems are implemented and maintained using written 
Investigative site, Sponsor and/or designee Standard Operating Procedures (SOPs) to ensure that 
the study is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirement(s) national and local 
laws, rules, regulations.
Quality control (QC) checks will be applied at each stage of data handling (e.g. edit checks) to 
ensure that all data are reliable and have been processed correctly. 
14.4.1 Monitoring
On-site monitoring will be performed by the Sponsor’s designee for the duration of the study. The 
monitor will ensure that the study is conducted, recorded and reported in accordance with the 
protocol, SOPs, GCP, and the applicable regulatory requirements. The monitor will verify the 
accuracy and completeness of the eCRF entries, source documents, and other study-related 
records against each other. The PI will provide direct access to source data/documents for study-
related monitoring. It is important that the PI and the staff are available at these visits. The monitor 
will record the date of each visit together with a summary of the status and progress of the study. 
Proposed actions will be documented in writing to the PI.
14.5 Ethics
14.5.1 Ethical Conduct of the Study
This research will be carried out in accordance with the protocol, applicable regulations, the ethical 
principles set forth in the Declaration of Helsinki, and the ICH Harmonized Tripartite Guidance for 
Good Clinical Practice, E6, R2 (ICH GCP).
14.5.2 Institutional Review Board/Ethic Committee
The study protocol, any Versions to the protocol, informed consent form, the Investigator’s 
Brochure, and other study specific information will be reviewed and approved by the IRB/IEC. The 


 
 
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study will not be initiated until the IRB/IEC has approved the protocol or a modification thereof. All 
records pertaining to IRB/IEC submission and approval should be kept in the site’s regulatory files 
and Sponsor’s Trial Master File (TMF).
The IRB/IEC must be constituted and operate in accordance with the principles and requirements 
described in ICH Guidance E6 and national and local regulations as deemed appropriate.
14.5.3 Subject Information and Consent
It is the responsibility of the investigator or designee to obtain written informed consent from all 
study subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (i.e., a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time and site personnel should properly 
document the informed consent process followed. 
A copy of the IRB/EC’s written favorable opinion/approval of these documents must be provided to 
the sponsor or designee prior to the start of the study. Additionally, if the IRB/EC requires 
modification of the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
If there are any changes/Versions to the approved protocol, which may directly affect the subject’s 
decision to continue participation in the study, the ICF shall be amended to incorporate the 
changes to the protocol and the subject must re-sign the IRB/IEC approved amended ICF.
14.5.4 Confidentiality 
Confidentiality of subject’s information must be maintained in accordance with national and local 
privacy laws.
14.5.5 ClinicalTrials.gov 
This study has been listed with ClinicalTrials.gov, as required.
14.5.6 Termination of Study
The Sponsor reserves the right to suspend or discontinue this study for administrative and/or 
safety reasons at any time. The PI reserves the right to discontinue dosing subjects at any time for 
safety reasons.


 
 
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14.6 Data Handling and Record Keeping
The PI must maintain all documentation related to this study. All essential documents (as defined 
in the ICH Guideline E6) and the data generated in connection with this study, together with the 
original copy of the final report, will be retained for at least 5 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 5 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. 
It is the responsibility of the Sponsor to inform the PI/Institution as to when these documents no 
longer need to be retained.
14.7 Protocol Versions
Any Versions to the study protocol deemed necessary as the study progresses will be discussed 
between Sponsor and the PI. The PI will not implement any changes to the protocol without an 
agreement by the Sponsor and prior review and documented approval from the IRB/IEC of an 
Version, except where necessary to eliminate immediate hazards to study subject or when the 
changes involve only logistical or administrative aspects of the study (e.g., change in staff, telephone 
numbers).
Changes resulting in Versions will be made jointly between the Sponsor and the PI and must be 
confirmed in writing. Version(s) will be approved and signed off in the same way as the protocol. 
14.8
Report Format
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline (Structure and 
Content of Clinical Study Reports).
14.9
Finance and Insurance
Finance and insurance will be addressed in a Clinical Trial Agreement between the PI/Institution 
and the Sponsor.
14.9.1  Publication Policy
The data generated for this study are considered confidential information and are the property of 
the Sponsor. All study information provided to the PI and Site personnel by the Sponsor shall not 
be published or disclosed to a third party without the prior written consent of the Sponsor. 
Apellis will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Apellis adheres to external guidelines (e.g. 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Apellis. The purpose of 


 
 
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- CONFIDENTIAL -
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Apellis products or projects must undergo appropriate technical and 
intellectual property review, with Apellis agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint or 
shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty-free 
license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to include 
in any publication of study results, or necessary for other scholars to verify such study results. 
Notwithstanding the foregoing, no publication that incorporates the sponsor’s confidential 
information shall be submitted for publication without the sponsor’s prior written agreement to 
publish and shall be given to the sponsor for review at least 60 days prior to submission for 
publication. If requested in writing by Apellis, the institution and principal investigator shall withhold 
submission of such publication for up to an additional 60 days to allow for filing of a patent 
application.
If the study is part of a multicenter study, the first publication of the study results shall be made by 
the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication of the 
compiled and analyzed study results. If such a multicenter publication is not submitted to a journal 
for publication by the sponsor within an 18-month period after conclusion, abandonment, or 
termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results from 
the specific site in accordance with this section. The investigator must, however, acknowledge in 
the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which it 
is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to authorship 
of publications.


 
 
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Protocol No: APL2-203
Version 3.0: 03-Aug-2018
15.
REFERENCES
1. Rein DB, Wittenborn JS, Zhang X, et al. Forecasting age-related macular degeneration 
through the year 2050: the potential impact of new treatments. Archives of ophthalmology. 
2009;127(4):533-540.
2. Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular 
degeneration in the United States. Archives of ophthalmology. 2004;122(4):564-572.
3. Sunness JS, Bressler NM, Tian Y, Alexander J, Applegate CA. Measuring geographic 
atrophy in advanced age-related macular degeneration. Investigative ophthalmology & 
visual science. 1999;40(8):1761-1769.

SAP_001.pdf: 
Statistical Analysis Plan 
Study Title:
An 18-Month Phase Ib/II Multi-Center, Open Label Study to 
Evaluate the Safety of Intravitreal APL-2 Therapy in Patients with 
Neovascular Age-Related Macular Degeneration (AMD)
Protocol Number:
Amendment 
APL2-203
Version 3.0 / 03 Aug 2018 
Sponsor:
Apellis Pharmaceuticals, Inc.
100 5th Avenue, 3rd Floor
Waltham, MA 02451 
Sponsor Contact:
  
CRO:
DP Clinical, Inc.
9201 Corporate Boulevard, Suite 350
Rockville, MD 20850, USA
Telephone: 
Version No./Date
Version 1.0 / 03 Jul 2019
Confidential Statement: The information contained herein is proprietary and no part of this 
information may be reproduced, photocopied, stored on a retrieval system, or transmitted 
without the express written consent of Apellis Pharmaceuticals, Inc. and DP Clinical Inc. Any 
unauthorized use is prohibited. 
PPD
PPD


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Signatory Page
This Statistical Analysis Plan was reviewed and approved by: 
Author 
DP Clinical, Inc.
Date 
Reviewer 
DP Clinical, Inc.
Date 
Approval 
Apellis Pharmaceuticals, Inc.
Date
Approval 
Apellis Pharmaceuticals, Inc.
Date




PPD
PPD
PPD
PPD
PPD


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REVISION HISTORY
Version No.
Version Date
Description of Modifications
1.0
03 Jul 2019
Original Document 


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TABLE OF CONTENTS
Signatory Page.............................................................................................................................2 
1. 
List of abbreviations and acronyms.................................................................................6 
2. 
Introduction........................................................................................................................8 
3. 
Study Overview..................................................................................................................9 
3.1 
Objective.................................................................................................................9 
3.2 
Endpoints................................................................................................................9 
3.2.1 
Primary Endpoint...................................................................................9 
3.2.2 
Secondary Endpoints .............................................................................9 
3.2.3 
Exploratory Endpoint.............................................................................9 
3.3 
Study Design...........................................................................................................9 
3.3.1 
Sample Size Considerations.................................................................11 
3.3.2 
Study Assessments Schedules...............................................................11 
4. 
General Considerations...................................................................................................12 
4.1 
Definitions.............................................................................................................12 
4.1.1 
Study Day.............................................................................................12 
4.1.2 
Baseline and Change from Baseline....................................................12 
4.2 
Analysis Data Sets................................................................................................12 
4.3 
Test Hypothesis and P-Value Justification........................................................13 
4.4 
Procedures for Handling Missing Data and Dropouts.....................................13 
4.4.1 
Safety Data...........................................................................................13 
4.4.2 
Visit Windowing Based on Study Day..................................................14 
4.5 
Interim Analysis...................................................................................................14 
4.6 
Subgroup Analysis ...............................................................................................14 
4.7 
Multi-Center Studies and Pooling of Centers ...................................................14 
5. 
Statistical Analysis Methodology....................................................................................15 
5.1 
Study Subjects......................................................................................................15 
5.1.1 
Subject Disposition ..............................................................................15 
5.1.2 
Protocol Deviations .............................................................................15 
5.1.3 
Medical and Surgical History..............................................................17 
5.1.4 
Prior and Concomitant Medications ...................................................17 
5.1.5 
Exposure ..............................................................................................18 
5.2 
Safety Analysis .....................................................................................................19 
5.2.1 
Adverse Events.....................................................................................19 
Adverse Events Summary.......................................................................................20 
5.2.2 
Clinical Laboratory Tests ....................................................................21 
5.2.3 
Vital Signs............................................................................................22 
5.2.4 
Physical Examination ..........................................................................22 


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5.2.5 
Complete Ophthalmic Examination.....................................................22 
5.2.6 
Intraocular Pressure............................................................................23 
5.2.7 
Best Corrected Visual Acuity...............................................................24 
5.2.8 
Dilated Indirect Ophthalmoscopy........................................................24 
5.2.9 
Fundus Fluorescein Angiograms.........................................................25 
5.2.10 
Digital Color Fundus Photographs .....................................................26 
5.3 
Other Analyses .....................................................................................................26 
5.3.1 
Spectral Domain Optical Coherence Tomography (SD-OCT)............26 
5.3.2 
Anti-Vascular Endothelial Growth Factor (anti-VEGF) As-Needed 
Injections 27 
5.4 
Immunogenicity....................................................................................................27 
6. 
Testing/Quality Control Plan and Software/System.....................................................28 
6.1 
Programming Specifications for TLFs...............................................................28 
6.2 
Formatting Conventions......................................................................................28 
6.3 
Standard Text Conventions ................................................................................29 
6.3.1 
Header..................................................................................................29 
6.3.2 
Title ......................................................................................................29 
6.3.3 
Footnotes..............................................................................................30 
6.3.4 
Footer...................................................................................................30 
6.4 
Statistical Conventions ........................................................................................31 
6.4.1 
Statistics Reported ...............................................................................31 
6.4.2 
Tables Summarizing Categorical Data................................................31 
6.4.3 
Subject Data Listings...........................................................................32 
7. 
References.........................................................................................................................33 
8. 
Appendices........................................................................................................................34 
8.1 
Schedule of Events ...............................................................................................34 
8.2 
Planned Tables, Listings, and Figures ...............................................................36 
 
 
 


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1.
LIST OF ABBREVIATIONS AND ACRONYMS
Abbreviations and 
Acronyms
Description
ADaM
Analysis Data Model
ADDV
ADaM Data Structure for Protocol Deviation Analysis
AE
Adverse Event
AESI
Adverse Event of Special Interest
AMD
Age-related Macular Degeneration
Anti-VEGF
Anti-Vascular Endothelial Growth Factor
ATC
Anatomical Therapeutic Chemical
BCVA
Best Corrected Visual Acuity
bpm
beats per minute
BQL
Below-Quantification-Level
°C
Degrees Celsius
CFB
Change From Baseline
CNV
Choroidal Neovascularization
DCFP
Digital Color Fundus Photographs
DPC
DP Clinical Inc.
eCRF
Electronic Case Report Form
FFA/FA
Fundus Fluorescein Angiograms or Fluorescein Angiography
ICH
International Council for Harmonisation 
IOP
Intra Ocular Pressure
ITT
Intent-to-Treat
IVT
Intravitreal
LLOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
Millimeter of Mercury
OCT
Optical Coherence Tomography
ODS
Output Delivery System
QC
Quality Control
PCFB
Percent Change From Baseline


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Abbreviations and 
Acronyms
Description
PRN
Pro re nata (As Needed)
PT
Preferred Term
RPE
Retinal Pigment Epithelium
RTF
Rich Text Format
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SD-OCT
Spectral Domain Optical Coherence Tomography
SDTM
Study Data Tabulation Model
SMC
Safety Monitoring Committee
SOC
System Organ Class
SOP
Standard Operating Procedure
Sub-RPE
sub-Retinal Pigment Epithelium
TEAE
Treatment-Emergent Adverse Event
TLFs
Tables, Listings and Figures
VAS
Visual Acuity Score
VEGF
Vascular Endothelial Growth Factor
WHO
World Health Organization
WHODrug
World Health Organization Drug Dictionary
WOCBP
Woman of Child Bearing Potential


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2.
INTRODUCTION
This Statistical Analysis Plan (SAP) is prepared to provide a more technical and detailed 
elaboration of the principal statistical features stated in the protocol. The SAP will 
ensure that the tables, listings, and figures that will be produced and statistical methods 
that will be used are complete and accurate and will allow valid conclusions to be drawn.
In the development of this SAP, the following study documents were used:
1. Protocol APL2-203 Version 1.0, 20 December 2017
2. Protocol APL2-203 Version 1.1, 03 January 2018
3. Protocol APL2-203 Version 2.0, 14 March 2018
4. Protocol APL2-203 Version 3.0, 03 August 2018
5. Electronic Case Report Form (eCRF), 18 March 2019
6. Medical Coding Guidelines Version 1.0, 19 March 2018
The principles in the following guidance documents are followed in the preparation of 
this SAP:
x
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E3 (ICH 1995): Structure and Content 
of Clinical Study Reports
x
ICH E6 R2 (ICH 2016): Guideline for Good Clinical Practice - Integrated 
Addendum to ICH E6 (R1).
x
ICH E9 (ICH 1998): Statistical Principles for Clinical Trials
In the event that a discrepancy is found between the descriptions in the statistical section 
of the protocol and this document, the description in this document supersedes the 
descriptions in the statistical section of the protocol. Any deviations from the final 
analysis plan or from what is outlined in the protocol will be discussed in the final study 
report.


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3.
STUDY OVERVIEW
This is an 18-Month Phase Ib/II, multi-center, open label study to assess the safety and 
tolerability of monthly intravitreal (IVT) injections of APL-2 in subjects with 
neovascular Age-related Macular Degeneration (AMD).
3.1
Objective
The objective of this study is to establish the safety and tolerability of 
intravitreally injected APL-2 in patients with neovascular AMD.
3.2
Endpoints
3.2.1
Primary Endpoint
Incidence and severity of ocular and systemic Treatment- Emergent Adverse 
Events (TEAEs)
3.2.2
Secondary Endpoints
x
Changes from baseline in laboratory parameters
x
Changes from baseline in central macular thickness on Optical 
Coherence Tomography (OCT) over 12 months
3.2.3
Exploratory Endpoint
x
Number of anti-Vascular Endothelial Growth Factor (anti-VEGF) 
PRN injections from Visit 4 to the Exit Visit (Visit 17)
3.3
Study Design
Patients diagnosed with AMD in the study eye, who are receiving an intravitreal 
anti-VEGF drug, and who meet all other inclusion/exclusion criteria will be 
included in the study. The study will include approximately 20 subjects across 
at least 3 U.S. sites.
Patients will initially be screened between Day -28 and prior to treatment on 
Day 1. Screening procedures will include laboratory tests, Best Corrected 
Visual Acuity (BCVA), ophthalmological exam, Intraocular Pressure (IOP), and 
Spectral Domain Optical Coherence Tomography (SD-OCT). Upon entry into 


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the study (after signing the informed consent), subjects will be assigned a 
screening number. At screening visit 1 (Day -28) subjects will have an SD-OCT 
taken to assess for the presence of any subretinal, intraretinal, or sub-Retinal 
Pigment Epithelium (sub-RPE) fluid, followed by an IVT dose of an anti-VEGF 
drug. Subjects will return two weeks later for screening visit 2 (Day -14) and 
will have another OCT performed to confirm a decrease in excess fluid in the 
macula. Upon confirmation by the Investigator of fluid reduction, subjects who 
meet all inclusion and exclusion criteria will be enrolled in the study and will 
return at Day 1 for treatment (Visit 3; Day 1). Treatment on Day 1 will entail a 
mandatory IVT dose of an anti-VEGF drug followed by an IVT injection of 
APL-2.
All subjects will receive monthly APL-2 injections for 12 months during their 
scheduled monthly treatment visits. At each treatment visit, safety assessments 
will be performed including vital signs, labs and urinalysis, and SD-OCT. 
BCVA, fundus examination, dilated indirect ophthalmoscopy and slit lamp 
examination will also be performed. Subjects will be assessed at each treatment 
visit for the need for retreatment with an anti-VEGF drug based on pre-
specified retreatment criteria. During follow-up, safety assessments will be 
performed for all subjects at months 15 and 18. Subjects who discontinue study 
treatment, should be encouraged to continue participation in the study and 
return to the clinical site for their scheduled study procedures. Subjects who 
fully withdraw from the study before month 12, should complete the 
Termination Visit.
An external, independent Safety Monitoring Committee (SMC) will assess the 
progress and cumulative safety/tolerability data of the study.
Subjects who fail the screening procedures should not be re-screened for the 
study unless this is agreed in advance and documented in writing with the 
sponsor.


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Study Assessments align with those described in Section 12 of the Clinical 
Study Protocol (Version 3.0), 03 Aug 2018.
3.3.1
Sample Size Considerations
Given the exploratory nature of the study, no formal statistical 
hypothesis testing will be performed, so the sample sizes of both parts 
of the study are not based upon statistical power of the study. When no 
untoward adverse events occurred, we can, with a 95% confidence, 
rule out the event rate of >25.9% for a sample size of n = 10 subjects, 
or >13.9% for n = 20 subjects.
Twenty neovascular AMD patients will be enrolled into a single 
cohort.
3.3.2
Study Assessments Schedules  
The study assessment schedule is described in detail in Section 11 of 
the protocol (Version 3.0), and summarized in Study Flow Charts in
Appendix Section 8.1.


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4.
GENERAL CONSIDERATIONS
4.1
Definitions
4.1.1
Study Day 
Study Day 1 will be the day a subject takes the first dose of APL-2.
Study days will be calculated as:
For events that occurred on the day of or after administration of the 
first APL-2 dose:
Study Day = visit date – date of administration of first APL-2 dose + 1
For events that occurred on days before administration of the first 
APL-2 dose:
Study Day = visit date – date of administration of first APL-2 dose
4.1.2
Baseline and Change from Baseline 
In general, the baseline for this study will be taken as the pre-dose
measure on Study Day 1. If this is missing then the closest assessment 
prior to the baseline will be used, if available.
Unless indicated otherwise change from baseline (CFB) will be 
calculated as follows:
CFB = Visit Result – Baseline Result
Percent change from baseline (PCFB) will be calculated as follow:
PCFB (%) = 100*(Visit Result – Baseline Result)/Baseline Results
4.2
Analysis Data Sets
After all the data have been verified/coded/entered into the database, a review 
will be performed by DPC and the sponsor. The purpose of this review will be 
to define the analysis populations. The review will also check the quality of the 
data, identifying outliers, and making decisions on how to deal with problems in 
any data (e.g., missing values, withdrawals, protocol deviations). After the pre-


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analysis review, resolution of all issues and documentation of all decisions, the 
database will be locked.
Screened Set:
The screened/run-in analysis set will include all patients who signed the 
informed consent form, are screened for participation, and were given initial 
anti-VEGF therapy in this study. This set will be used only for the purpose of 
describing patient disposition.
Safety / Intent-to-Treat (ITT) Set:
The safety analysis set will include all patients who receive a dose of APL-2.
The ITT set will be identical to the safety analysis set for this study. 
4.3
Test Hypothesis and P-Value Justification
No formal inferential statistics will be applied to data collected in this study.
4.4
Procedures for Handling Missing Data and Dropouts
4.4.1
Safety Data
Where appropriate, screening values may be used as baseline in the 
event of missing or unusable Day 1 measurements. No imputation of 
missing data for early terminations will be performed. 
However, both partial and completely missing dates/times that are not 
related to early terminations, in addition to missing safety data (e.g., 
missing severities) will be reviewed on a case by case basis for 
potential imputations. As a general rule, a conservative approach will 
be adopted as outlined in Section 5.2.1 (e.g. partial Adverse Event 
(AE) onset dates and missing severities will be taken as the earliest ‘on 
treatment’ start date and highest severity, respectively, consistent with 
the partial information available). Moreover, the original data, without 
imputations, will be presented separately in data listings. 


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For safety lab parameters that are below or above the limit of 
quantification, the data will be presented as-is in the listings, but the 
limit of quantification will be used for the purposes of calculating
changes from baseline.
4.4.2
Visit Windowing Based on Study Day
Unless otherwise noted (See Section 5.2.9: Fundus Fluorescein 
Angiogram, Section 5.2.10: Digital Fundus Photography), unscheduled 
assessments that occur during on-study days that are within a 
scheduled visit window per the “Window (+ or - Days)” specifications 
in the schedule of assessments in Appendix 8.1 will be mapped to the 
scheduled visit name for summary tables. Subjects who complete the 
Early Termination visit within a scheduled visit window will be 
mapped to the scheduled visit for summary tables. Early Termination 
assessments that do not fall within a scheduled visit window will not 
be windowed.
Original non-windowed visit information as-collected will be 
presented in the listings. The windowed visits, where applicable, will 
be displayed alongside the visit information as-collected in the listings.
4.5
Interim Analysis
No interim analysis will be performed in this study.
4.6
Subgroup Analysis
Due to the small sample size of the study, no subgroup analyses will occur.
4.7
Multi-Center Studies and Pooling of Centers
This is a multi-center study. Due to the small number of subjects at each site, no 
adjustments will be made for study site.


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5.
STATISTICAL ANALYSIS METHODOLOGY 
In general, since there is one cohort in the study, tables will be presented for the overall
population.
Tabulations for continuous data will use a standard set of descriptive statistics: number 
of observations available (n), mean, standard deviation (SD), median, and range 
(minimum, maximum).  
Categorical or dichotomous data will be tabulated using frequencies (counts and 
percentages). The numerator and denominator for each percentage calculation will be 
specified in the footnotes of table shells.  
Data listings will present all information recorded in eCRFs for all subjects and visits.
All listings will be sorted by subject number.
5.1
Study Subjects
5.1.1
Subject Disposition
The following disposition categories will be tabulated:
x
Number of subjects screened
x
Number of screen failures with reason for screen failure
x
Number of subjects that terminated the study prior to study drug
x
Number of subjects who receive at least at least one dose of APL-2
(Safety Population/ITT Population)
x
Number of subjects who complete Treatment Phase – subjects who 
complete through Visit 15
x
Number of early termination subjects during Treatment Phase
(subjects who do not complete Visit 15) with reason for early 
termination
x
Number of subjects who complete Follow-Up through Visit 17
5.1.2
Protocol Deviations
A protocol deviation is any change, divergence, or departure from the 
study design or procedure defined in the protocol. 


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The following categories will be used to group protocol deviations:
1.
Eligibility Not Met
2.
Study Assessment Noncompliance
3.
Study Drug Noncompliance
4.
Study Schedule Noncompliance
5.
Other
The following are categorical reasons used to document why a protocol 
deviation occurred:
1.
Subject Illness
2.
Subject Unable to Comply
3.
Subject Refusal
4.
Clinical/Site Error
5.
Laboratory Error
6.
Investigator/Staff decision
7.
Other 
Subsets of the protocol deviations can be identified as major and minor 
protocol deviation as described below:
Major
Protocol Deviation:
A
protocol deviation that might 
significantly affect the completeness, accuracy, and/or reliability of the 
study data or that might significantly affect a subject’s rights, safety, or 
well-being. 
Minor Protocol Deviation: A protocol deviation that will
not
significantly affect the completeness, accuracy, and/or reliability of the 
study data and that will not significantly affect a subject’s rights, 
safety, or well-being. 
Upon soft lock of database, all documented protocol deviations in the 
study will be reviewed to identify all major and minor protocol 


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deviations by a data review team including representatives from DPC 
clinical operations, medical, data management, and statistics, and sent 
to the sponsor for approval. Final decisions will be documented and 
incorporated into the ADaM Data Structure for Protocol Deviation 
Analysis (ADDV) dataset.
Protocol deviation data will be presented for the safety population.
Protocol deviations and major protocol deviations will be summarized 
in listings. Additionally, the number of deviations and frequency of 
subjects with protocol deviations and with major protocol deviations 
will be tabulated. The number of deviations and frequency of subjects 
with each protocol deviation category will also be tabulated.
5.1.3
Medical and Surgical History
At Screening Visit 1, the general medical and surgical procedures 
history will be recorded on the eCRF, all medical/surgical history data 
and ongoing medical history will be summarized by the Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0 System 
Organ Class (SOC) and Preferred Term (PT).
5.1.4
Prior and Concomitant Medications
Prior and concomitant medications will be coded to the therapeutic 
drug classes and generic drug names using the World Health 
Organization (WHO) Drug Dictionary (WHODrug) classifications
version March 2017.
Prior medications will include any medications reported with a start 
date prior to the subject taking their first study dose and will be 
summarized by WHODrug Anatomical Therapeutic Chemical (ATC)
Class 1 Term and WHODrug
Preferred Name.
Concomitant 
medications will include any medications being taken after the subject 
starts their study medication and will also be summarized by 
WHODrug ATC Class 1 Term and WHODrug Preferred Name.


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Hence, medications ongoing at the start of dosing will be counted in 
both the prior and concomitant medication summaries.
If either the start or stop date of medication is missing, the worst or 
most conservative case will be considered when assigning medications 
to categories. So for a missing start date (where stop date is after date 
of first dose) the date will be imputed as the date of first dose; for a 
missing stop date the date will be imputed as the date of last dose or 
start date if start date is after last dose.  If a partial date is recorded, the 
following convention will be used to assign the medication:
x
If a partial date is missing a start day and the month/year is the 
same as first dose date then use first dose date, else ‘01’ will be 
used for the day; if a start date is missing a month and the year 
is the same as first dose date then use first dose date, else 
January will be used for the start month.
x
If a partial date is missing a stop day and month/year is same as 
last study date then use last study date, else last day of the 
given month will be used for the stop day; if a stop date is 
missing a month and the year is the same as last study date then 
use last study date, else December will be used for the stop 
month.
All prior medications and concomitant medications, interventions and 
procedures will be summarized in listings. The frequency of subjects 
taking prior medications and concomitant medications will be 
tabulated by WHODrug ATC Class 1 and Preferred Name.
Concomitant procedures will be summarized in a listing.
5.1.5
Exposure
All study drug exposure data will be listed based on the Study Drug 
Administration eCRF. 


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The frequency of subjects who receive a study drug injection will be 
summarized by visit for Visits 3 through 15.
5.2
Safety Analysis
The objective of the study is to establish the safety and tolerability of 
intravitreally injected APL-2 in patients with neovascular AMD. The safety 
analyses will be performed on the safety analysis set.
5.2.1
Adverse Events
Treatment emergent adverse events (TEAE) are defined as those AEs 
that develop or worsen after the first dose of study medication, up to 30 
days beyond the last dose of study medication. Version 20.0 of 
MedDRA will be used to classify all AEs.  
AEs will be considered treatment-emergent (TEAE) unless there is 
clear indication that the event occurred prior to first dose of study drug.  
AEs present prior to the first dose of study drug administration that 
increased in severity or relationship to study drug after the first dose of 
study drug and up to 30 days beyond the last dose of study drug will be 
classed as a TEAE.  Events with missing or partial dates will be 
handled such that in the absence of contradictory information an AE is 
treatment emergent.  So for a missing start date (where stop date is 
after date of first dose) the date will be imputed as the date of first 
dose; for a missing stop date the date will be imputed as the last study 
date.  If a partial date is recorded, the following convention will be 
used to assign the AE:
x
If a start date is missing the day information and month/year is the 
same as first dose date then use first dose date, else ‘01’ will be 
used for the day; if a start date is missing the month and the year is 
the same as first dose date then use first dose date, else January will 
be used for the start month.
x
If a stop date is missing the day information and month/year is 
same as last study date then use last study date, else last day of the 


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given month will be used for the stop day; if a stop date is missing 
the month and year is the same as last study date then use last study 
date, else December will be used for the stop month.
Adverse Events Summary 
A  TEAE data listing, including verbatim term, preferred term, 
treatment, severity, and relationship to treatment will be provided. 
Serious Adverse Events (SAEs), adverse events of special interest, and 
details of subjects withdrawing due to adverse events will also be 
listed. The start and stop days (relative to the first dosing day), onset 
time since last dose, and the duration of AEs will be included in 
listings. 
A topline summary for the overall time on study will present the 
number of events and the frequency of subjects with:
x any TEAE
x any TEAE considered as related to study drug (evaluated by 
the investigator as Possibly Related, Probably Related,
Definitely Related, or not reported)
x any TEAE considered as related to injection procedure 
(evaluated by the investigator as Possibly Related, Probably 
Related, Definitely Related, or not reported)
x any serious TEAE 
x Maximum intensity TEAE of none, mild, moderate, severe,
life threatening, and death; i.e. a subject with TEAEs at 
different intensities will be summarized at the most severe 
intensity
x any TEAE leading to study drug discontinuation 
x any TEAE leading to death
The table will also include the overall, total number of reported
TEAEs.  The total number of unique terms within subjects will also be 
presented, counting each TEAE only once within each subject. 


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Additionally, the following will be tabulated with the number of events 
and the frequency of subjects. Summaries will be ordered by 
descending order of event count in the overall column.
x
Non-ocular TEAEs by SOC and preferred term 
x
Ocular TEAEs by SOC and preferred term by Study Eye 
and Fellow Eye
x
TEAEs regarded as at least possibly related to study drug
by SOC and preferred term
x
TEAEs regarded as at least possibly related to injection 
procedure by SOC and preferred term
x
Non-ocular TEAE related to study drug or injection 
procedure by SOC and preferred term
The following will also be tabulated with only the frequency of 
subjects:
x
Non-ocular TEAEs and Serious AEs by SOC, preferred 
term, and maximum severity
x
Ocular TEAEs and Serious AEs by SOC, preferred term, 
and maximum severity by Study Eye and Fellow Eye
5.2.2
Clinical Laboratory Tests
Laboratory values outside the reference range will be identified in 
listings, using flags to identify whether above or below the range 
limits. Hematology, Serum Chemistry, and Urinalysis results will be 
presented separately.
Listings of all lab results and out of range lab results with their 
corresponding changes from baseline will be presented. Baseline will 
be considered as the collection on Screening Visit 2..
A table of descriptive statistics will be presented for continuous
chemistry, hematology, and urinalysis laboratory results. The number 


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and percent of subjects with low, normal, and high assessments at each 
scheduled visit will be tabulated by lab parameter.
5.2.3
Vital Signs
The listing of vital sign data will include change from baselines. 
Baseline will be considered the Study Day 1 pre-dose assessment or 
the last dose prior to Study Day 1 if missing the Study Day 1 
assessment. In the listing, data fulfilling the following criteria will be 
flagged:
Value
Parameter
Low
High
Observed
Systolic Blood Pressure 
(mmHg)


Diastolic Blood Pressure 
(mmHg)


Pulse (bpm)


Temperature (oC)

*mmHg=millimeters of mercury, bpm=beats per minute, oC=degrees Celsius
A table of descriptive statistics will be presented for each vital sign 
parameter. The number and percent of subjects with low, normal, and 
high assessments at each scheduled visit will be tabulated.
5.2.4
Physical Examination
Physical examination data will be listed.
5.2.5
Complete Ophthalmic Examination
Complete ophthalmic exams will be performed at pre-dose visits 
during the treatment period, including an examination of the eyelids 
and pupils, iris evaluation, cornea evaluation, anterior chamber 
evaluation, and lens evaluation. Results will be listed.


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The following shift tables will be produced at each visit for the study 
eye, with the Study Day 1 pre-dose assessment as baseline, or the last 
assessment before Study Day 1 if not available:
x
External Examination of Eye (Normal / Abnormal)
x
Exam of Eyelids and Pupils
o
Ptosis Present (Yes / No)
o
Abnormal Pupil Shape (Yes / No)
o
Unequal Pupils (Yes / No)
o
Abnormal Reaction to Light (Yes / No)
o
Afferent Pupillary Defect (Yes / No)
x
Iris Evaluation (Normal / Abnormal)
x
Cornea Evaluation (Normal / Abnormal)
x
Anterior Chamber Evaluation 
o
Anterior Chamber (Normal / Abnormal)
o
Cells (0 / Trace / 1+ / 2-3+ / 4+)
o
Flare (0 / Trace / 1+ / 2+ / 3+ / 4+)
x
Lens Evaluation (No Opacity / Nuclear Sclerotic Cataract / 
Posterior Subcapsular Cataract
/
Cortical Cataract / 
Pseudophakia / Aphakia)
5.2.6
Intraocular Pressure
Intraocular pressure (IOP) with change from baseline will be listed 
across Study Day 1 through Study Day 540, where baseline will be the 
Study Day 1 pre-dose assessment, or the Screening Study Day -14 
assessment if not available.
Additionally IOP will be summarized at each scheduled visit using 
descriptive statistics for pre-injection IOP and change from baseline. 
Additionally, the frequency of the following will be tabulated:
x
Subjects with pre-first-injection IOP > 21 mmHg
x
Subjects with post-injection IOP > 30 mmHg at any post-
baseline visit where an injection was received


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x
Subjects that underwent anterior chamber paracentesis 
procedure, as determined by a Concomitant Procedure term = 
“Anterior chamber paracentesis”
x
Subjects that developed AE of ocular hypertension and/or 
glaucoma, as determined by an AE with MedDRA SOC “Eye 
disorder” and one of the following preferred terms: “borderline 
glaucoma,” “glaucoma,” “normal tension glaucoma,” “ocular 
hypertension.” 
5.2.7
Best Corrected Visual Acuity
The BCVA assessments will be listed for each eye, including sphere 
sign for values not equal to 0, sphere value, cylinder sign for values not 
equal to 0, cylinder value, axis, BCVA at 1 meter (BCVA1), BCVA at 
4 meters, Total Visual Acuity Score (VAS), and Snellen equivalent. 
The Total VAS will be listed with change from baseline, where the 
Study Day 1 pre-dose assessment will be considered baseline, or the 
last assessment prior to Study Day 1 if not available.
The Total VAS will be summarized in a table using descriptive 
statistics by scheduled visit. The mean VAS score (± 2 x SD) will be 
plotted by scheduled visit. The number of subjects evaluable at each 
visit will be visible on the plot. Additionally, the frequency of the 
following will be tabulated:
x
6XEMHFWVWKDWORVWOHWWHUVFRPSDUHGWREDVHOLQH&)%-15)
at any visit
x
6XEMHFWVWKDWORVWOHWWHUVFRPSDUHGWREDVHOLQH&)%-30)
at any visit
5.2.8
Dilated Indirect Ophthalmoscopy
Dilated indirect ophthalmoscopy will be performed from Study Day 1 
(Visit 2) though the end of study (Visit 17). All results will be listed.


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The following shift tables will be produced at each visit for the study 
eye, with the Study Day 1 pre-dose assessment as baseline, or last 
assessment prior to Study Day 1 if not available.:
x
Posterior Segment Abnormalities (None / Mild / Moderate / 
Severe)
x
Posterior Vitreous Detachment (Absent / Present)
x
Retinal Hemorrhage/Detachment (Absent / Present)
x
Vitreal Hemorrhage Density (None / 1+ / 2+ / 3+ / 4+ )
x
Vitreous Cells (0 / Trace / 1 / 2 / 3 / 4 )
5.2.9
Fundus Fluorescein Angiograms
Fundus Fluorescein Angiograms (FFA) results will be listed. If the 
parameter is reported as a numeric value, the change from baseline and 
percent change from baseline will be reported in the listing.
Frequency of the following parameters in the study eye will be 
tabulated by for the pre-dose Study Day 1 assessment (Baseline) and 
for the Visit 15 or Early Termination assessment:
x
Choroidal Neovascularization (CNV) (Yes / No / Cannot 
Grade)
x
CNV Classification (Occult / Disciform Scar / Cannot Grade) –
this will be tabulated only for subjects with CNV
x
CNV Classification Detail (CNV Within Image Frame) – this 
will only be tabulated for subjects with CNV and with a 
gradable classification
Descriptive statistics will be tabulated for the following parameters 
in the study eye for the pre-dose Study Day 1 assessment (baseline)
and for the Visit 15 or Early Termination assessment:
x
Total CNV Area
x
Total Lesion Area
x
Disciform Scar Area


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For the purposes of the summary tables above, all ET visits will be 
summarized together.
5.2.10 Digital Color Fundus Photographs
Digital Color Fundus Photographs (DCFP) data will be listed. The 
frequency of responses will be tabulated for the following DCFP 
parameters in the study eye for the pre-dose Study Day 1 assessment 
(Baseline) and for the Visit 15 or Early Termination assessment:
x
Atrophy (Yes / No / Cannot Grade)
x
Atrophy Areas (Single / Multiple / Cannot Grade)
x
Intraretinal Hemorrhage (Yes / No / Cannot Grade)
x
Intraretinal Hemorrhage Location (Foveal / Macular)
x
Subretinal Fluid (Yes / No / Cannot Grade)
x
Subretinal Fluid Location (Foveal / Macular)
x
Subretinal Sub-Retinal Pigment Epithelium (RPE) Hemorrhage
(Yes / No / Cannot Grade)
x
Subretinal Sub-RPE Hemorrhage Location (Foveal / Macular)
For the purposes of the summary table above, all ET visits will be 
summarized together.
5.3
Other Analyses
The following analyses will be performed on the ITT population.
5.3.1
Spectral Domain Optical Coherence Tomography (SD-OCT)
All Spectral Domain Optical Coherence Tomography (SD-OCT)
parameters will be summarized.
If the parameter is reported as a 
numeric value, the change from baseline and percent change from 
baseline will be reported in the listing.
The Study Day 1 pre-dose assessment will be considered as baseline, 
or the last assessment before the first dose of APL-2 will be used if it is 
not available.


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Central 
subfield 
thickness, 
cube 
volume, 
pigment 
epithelial 
detachment
thickness, and subretinal fluid thickness
will be 
summarized for the study eye in tables with descriptive statistics for 
the overall intent-to-treat population at each visit. For each visit, 
change from baseline and percent change from baseline (when the 
baseline is not equal to zero) will be calculated. 
5.3.2
Anti-Vascular Endothelial Growth Factor (anti-VEGF) As-Needed 
Injections
The frequency of subjects who receive an anti-VEGF injection will be 
summarized by visit for Visits 4 through 17.
5.4
Immunogenicity
Immunogenicity data will be presented in a listing.


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6.
TESTING/QUALITY CONTROL PLAN AND SOFTWARE/SYSTEM
All statistical programs, will be written in SAS® version 9.3 or higher.  Statistical 
programs will be tested and reviewed for Quality Control (QC) by a second 
programmer/biostatistician not involved in the programming as per DPC’s standard 
operating procedure (SOP). In addition, DPC’s SOP will be followed to ensure that the 
information is complete, consistent, and accurately reflects the data stored in the 
database.  Further all TLFs will undergo a QC process by an independent 
biostatistician/programmer to ensure that the information is complete, consistent, and 
accurately reflects the data.
6.1
Programming Specifications for TLFs
Appendix 8.1 provides a list of all the TLFs that are planned to be produced.
6.2
Formatting Conventions
The following formatting conventions will be used to output TLFs: 
x
TLFs are outputted by SAS Output Delivery System (ODS) into Rich 
Text Files (RTF) format.
x
Tables and Listings will include borders around all headings and data 
cells.
x
Output will be in landscape orientation with margins of 0.5 inches on 
top, right, and left, and 1 inch for bottom.
x
The default font to be in tables/listings/figures will be Courier New.
x
Preferred and minimum font size:
Portion of Output
Preferred
Minimum
Page Header
9 pt
8 pt
Title
9 pt 
8 pt
Column header
9 pt 
8 pt
Cells
9 pt
8 pt
Footnote
9 pt 
8 pt
Page Footer
9 pt
8 pt


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x
Data will be centered within columns when the maximum length of 
the data being displayed is less than or equal to the maximum width 
of the column heading. When the maximum length of the data being 
displayed exceeds the maximum width of the column heading, the 
data will be left-justified.
x
Column headings should be in initial capital characters.  For numeric 
variables, include “unit” in the column heading when appropriate.
x
In figures, axes will be labeled appropriately.
6.3
Standard Text Conventions
6.3.1
Header
All output (table, listing, or figure) will have the following header, as 
applicable:
Apellis Pharmaceuticals, Inc.
Protocol: APL2-203
Page xx of XX
Clinical Study Report
All output will have the date and time (date and time output was 
generated) 
and 
internal 
page 
number 
in 
the 
header.
Tables/Listings/Figures should be internally paginated (i.e., page 
numbers should appear sequentially within each output).
6.3.2
Title
At least three (3) lines, in general, will be reserved for the entire title. 
x
The first line is for the table/listing/figure number;
x
The second line is for the actual title; and 
x
The third line is reserved for the analysis population descriptor.
All titles will be centered, as shown in the following example:
Table 14.3.1.1
Topline Summary of Adverse Events
Safety Population


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6.3.3
Footnotes
Unless otherwise specified, footnotes will appear on all pages within 
the tables and listings as follows:
x
Footnotes will be in the format of  “NOTE: followed by 2 spaces, 
then the footnotes”, as shown in the following example: 
NOTE:
SD = Standard Deviation.
x
Each line of a complete footnote should end with a period.
x
When an abbreviation (e.g. AE, SAE, etc.) appears first time in the 
whole set of TLFs for a study, a footnote should be provided at 
least once; and it is up to the study statistician, to decide whether 
there is a need to repeat the same footnote for the rest of TLFs.
x
A footnote serves as a brief explanation/clarification /definition 
/concept of a flag symbol or a character, an abbreviation, a 
terminology, etc., that appears in or relates directly to the displayed 
content of a table/listing/figure. 
x
All footnotes will be at the lowest line of the page immediately 
above the footer.  The footer will be directly on the line below the 
last footnote.
x
For Tables, first footnote will provide source listings and/or 
analysis datasets names for cross-referencing.
6.3.4
Footer
The following footer should appear at the very bottom of each page of 
a table, a listing, or a figure generated in SAS in the lower left corner:
Program Name: PGNAME.sas; Creation Date and Time: DDMMMYYYY HH:MM
Data Cutoff DDMMMYYYY HH:MM - ADaM Generated DDMMMYYYY          Proprietary and Confidential
where PGNAME = SAS program name.


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6.4
Statistical Conventions
6.4.1
Statistics Reported
x
Unless otherwise specified, the mean and SD will be displayed to 
one more decimal place than the original value, while minimum 
and maximum will be reported in the format of the original data, 
e.g.:  
Original: xx
Mean and SD: xx.x
Minimum and maximum: xx
x
Use of N versus n:
N = total number of subjects or subjects in the population.
n = total number of subjects or subjects in the specific category.
x
Descriptive statistics in this template include: N. Mean, Median, 
SD, Minimum, and Maximum.
x
Unless specified in the actual TLF shells for a study, all 
percentages will be rounded to 1 decimal place in all 
tables/listings/figures.  Rounding will take place
after all 
calculations have been performed.
6.4.2
Tables Summarizing Categorical Data
The following specifications apply to tables that summarize categorical 
data:
x
If the categories of a parameter are ordered, then all categories 
between the maximum possible category and the minimum 
category will be included, even if n=0 for a given category 
between the minimum and maximum level for that parameter.
x
If the categories are not ordered, then only those categories for 
which there is at least one subject represented will be included.
x
A missing category will be added to any parameter for which 
information is not available for any subjects.


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6.4.3
Subject Data Listings
In general, individual subject data listings will include the data of all 
non-screen failure subjects.  However, if a subject data listing includes 
only subjects who met a certain condition, and there were no subjects 
who met that condition, then a “message” will appear indicating that 
no subjects met the condition for inclusion in that listing. Data listings 
will provide the derived study day of an assessment or event, where 
appropriate.


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7.
REFERENCES
ICH E3 (1995): Structure and Content of Clinical Study Reports. International 
Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH).
ICH E6 R2 (2016): Integrated Addendum to ICH E6(R1). International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH).
ICH E9 (1998): Statistical Principles for Clinical Trials. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH).
MedDRA Version 20.0 (March 2017). International Federation of Pharmaceutical 
Manufacturers and Associations (IFPMA).
R: A language and environment for statistical computing (2012). R Core Team, R 
Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL 
http://www.R-project.org/.
SAS® for Windows® Version 9.3. SAS Inc. Cary, North Carolina USA.
The WHO Drug Dictionary (WHO-DD) (March 2017). World Health Organization 
(WHO) Uppsala Monitoring Center (UMC).


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8.
APPENDICES
8.1
Schedule of Events
FOOTNOTES:
A. For patients that discontinue the study early, the early termination assessments should be performed after a minimum of 
30 days have passed.
B. At Day -14 (Visit 2), confirm subject eligibility through reviewing the inclusion/ exclusion criteria and receive 
confirmation of eligibility from the Reading Center.
C. Significant medical/ surgical history and tobacco use, including chronic and ongoing conditions. Significant ocular 
medical and surgical history should be obtained for the previous 1 year.
D. Obtain prior to fluorescein angiograph and before study drug administration.


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E. At screening, serum pregnancy should be performed for Woman of Child Bearing Potential (WOCBP). If positive, subject 
is not eligible to continue in the study.
F. Beginning at Day 1, perform the urine pregnancy test for WOCBP at each treatment visit. If positive, perform a serum 
pregnancy test. If serum test is positive, study drug should not be administered and an early term visit should be completed.
G. Blood pressure, respiratory rate, heart rate, and temperature; On dosing days, vital signs should be captured pre and post 
dosing. Pre-dose vitals should be captured within 90 minutes prior to dosing
H. Complete physical exam should be performed; Height and Weight should be collected at screening.
I. Perform assessments prior to dilating the eyes.
J. Images should be captured prior to dosing on dosing days. If a subject misses a study visit or images cannot be obtained at 
a specific visit, study staff should make every effort to obtain images at the next scheduled visit.
K. Post- injection assessments should be performed within 15 minutes after dosing by the investigator or study staff and 
should include a gross assessment of vision (finger-counting, hand-motion, then light perception when applicable). If subject 
passes gross vision test, the subject may leave the site. If subject fails gross vision test, IOP should be performed and if < 30 
mmHg, the subject can be discharged. Assessments will continue every approximately 30 minutes until the subject passes 
gross vision test and IOP is < 30 mmHg.
L. Record concomitant medications (i.e. prescription and over the counter medications) used by the patient within 30 days of 
screening and throughout the subject's participation in the study. All significant concurrent ocular procedures and 
medications should also be recorded within the past 1 year and while on study.