Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH Paroxysmal Nocturnal Hemoglobinuria Complement inhibitor Anemia Hemoglobinuria Hemolysis Hematologic diseases Extravascular hemolysis (EVH) Intravascular hemolysis (IVH) C3 inhibitor
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
The objectives of the study are to assess the safety, tolerability, preliminary efficacy and PK of multiple subcutaneous (SC) doses of pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who have not received treatment with eculizumab in the past.

An exploratory objective of the study is to assess the pharmacodynamics (PD) of multiple SC doses of pegcetacoplan when administered to PNH patients.

Detailed description:
This is a Phase Ib, open-label, multiple ascending dose, pilot study in patients with PNH who have not received eculizumab (Soliris)® in the past. Two cohorts of 3 subjects are planned for evaluation.

Safety will be assessed throughout the study; serial blood and urine samples will be collected for these assessments. Blood samples will be collected for the assessment of pegcetacoplan PK. Additional samples for assessment of PD will also be collected.

The study will consist of four parts;

* Part 1: subjects will receive pegcetacoplan for 28 days.
* Part 2A: subjects may continue to receive pegcetacoplan for a further 56 days if there is evidence of perceived clinical benefit following review of available safety, PK and PD data by the investigator and sponsor
* Part 2B/Part 2C: subjects may continue to receive daily pegcetacoplan treatment for up to 364 days if there is ongoing evidence of clinical benefit following review of the available safety, PK and PD data. After completion of Part 2B, subjects could continue treatment with pegcetacoplan by transitioning to an open-label extension study or Part 2C, if enrollment into the extension study was not yet available. Subjects entering Part 2C continued their pegcetacoplan dose and regimen until enrollment in the open-label extension study was available.
* Part 3: Safety follow up Screening will take place within 30 days prior to the start of dosing on Day 1. If needed (see inclusion criteria), Neisseria menigitides types A, C, W, Y and B (administered as two separate vaccinations), Pneumococcal conjugate vaccine or Pneumococcal polysaccharide vaccine 23 (PCV13 or PPSV23, respectively), and Haemophilus influenzae Type B (Hib) vaccinations will be administered at least 14 days prior to dosing on Day 1.

Subjects will be entered into Part 1 of the study on Day 1 at a time designated by the PI. During Part 1, the first 3 daily SC doses of pegcetacoplan (Day 1 to 3) as well as doses on Day 8, 15 and 22 will be administered at the clinical site. From Day 4 to Day 28 daily doses of pegcetacoplan will be administered off-site by a trained study nurse at the subject's home, workplace, or other location convenient to the subject with the exception of those days where dosing is at the clinical site. Following ongoing review of available safety, PK and PD data by the investigator and sponsor, subjects showing evidence of perceived clinical benefit may progress to Part 2A and then to Part 2B of the study and continue to receive daily doses of pegcetacoplan until Day 84 and then until Day 364.

Cohort 2 will not be initiated until all subjects in Cohort 1 have reached the Day 29 visit and the SMC has reviewed emerging safety and efficacy data and determined that, at the initial dose, pegcetacoplan has an acceptable safety and tolerability profile.

The planned length of participation in the study for each subject in Cohort 2 is approximately 444 days (14.5 months) from Day 30 through completion of the Day 414 Exit visit procedures).

The study is planned to take place over approximately 24 months (from screening of Cohort 1 through completion of Cohort 2).

This time period may change in the event that the study is terminated early, additional cohorts are enrolled, additional time is required to review safety between cohorts, or extended safety and PK sampling is added for a cohort.

Arms:
arm 1: 180 mg pegcetacoplan/day arm 2: 270 mg pegcetacoplan/day

Interventions: intervention 1: Pegcetacoplan
Intervention descriptions: intervention 1: Complement (C3) Inhibitor

Protocol document:
Prot_000.pdf: 
 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 1 of 71 
 
 
 
 
 
 
 
Protocol No.: APL2-CP-PNH-204 
 
 
 
 
A Phase Ib, Open Label, Multiple Ascending Dose, Pilot Study to Assess the Safety, 
Preliminary Efficacy and Pharmacokinetics of Subcutaneously Administered APL-2 
in Subjects with Paroxysmal Nocturnal Hemoglobinuria (PNH). – PADDOCK – 
 
Phase: 
Ib 
Version: 
Protocol Amendment 8.0 
Date: 
25 October 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. 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 2 of 71 
1. SYNOPSIS 
Protocol Number 
APL2-CP-PNH-204 
Official Tittle 
A Phase Ib, Open Label, Multiple Ascending Dose, Pilot Study to 
Assess the Safety, Preliminary Efficacy and Pharmacokinetics of 
Subcutaneously Administered APL-2 in Subjects with Paroxysmal 
Nocturnal Hemoglobinuria (PNH). – PADDOCK – 
Protocol Version 
and Date 
Protocol Amendment 8.0 
FINAL 25 October 2018 
Compound 
APL-2 
Study Phase and 
Type 
Phase Ib. Open-label, evidence of activity, safety, tolerability, 
pharmacokinetics (PK), multiple ascending dose, pilot study. 
Study Objectives 
The objectives of the study are to assess the safety, tolerability, 
preliminary efficacy and PK of multiple subcutaneous (SC) doses 
of APL-2 in subjects with paroxysmal nocturnal hemoglobinuria 
(PNH) who have not received treatment with eculizumab in the 
past. 
An exploratory objective of the study is to assess the 
pharmacodynamics (PD) of multiple SC doses of APL-2 when 
administered 
to 
PNH 
patients. 
See 
“Pharmacodynamic 
Assessment” below. 
Study Population 
Subjects will: 
• be male and female (using contraception as specified in the 
protocol) and at least 18 years old  
• have a diagnosis of PNH 
Number of 
Subjects 
The study is planned to enrol approximately 23 subjects across 
two cohorts. Cohort 1 will include 3 subjects. Cohort 2 will 
include sufficient subjects to ensure that up to 20 subjects 
complete 28 days of dosing. Subjects may participate in more 
than one cohort. Additional cohorts may be enrolled if it is 
deemed appropriate by the Principal Investigator (PI) and the 
Sponsor to repeat a dose level or to study an additional dose 
level. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 3 of 71 
Inclusion Criteria 
At Screening (unless otherwise specified) 
• Male or female 
• At least 18 years old (inclusive) 
• Weigh >40 kg and have a body mass index (BMI) ≤38.0 kg/m2 
• Diagnosed with PNH (white blood cell (WBC) clone >10%) 
• Lactose dehydrogenase (LD) ≥2 times the upper limit of 
normal 
• Ferritin ≥ lower limit of normal (LLN) as defined by the central 
laboratory and Total Iron Binding Capacity (TIBC) < upper limit 
of normal (ULN) based on central lab reference ranges. If a 
subject is receiving iron supplements at screening, the 
investigator must ensure that his/her dose has been stable for 
8 weeks prior to enrolment and must be maintained 
throughout the study (see Section 9.4.5) 
• Last transfusion within 12 months prior to screening 
• Platelet count of >30,000/mm3 
• Absolute neutrophil count >500/µL 
• Women of child-bearing potential (WOCBP) must have a 
negative pregnancy test at screening and must agree to use 
protocol defined methods of contraception for the duration of 
the study and 90 days after their last dose of study drug 
• Males must agree to use protocol defined methods of 
contraception and agree to refrain from donating sperm for 
the duration of the study and 90 days after their last dose of 
study drug 
• Vaccination against Neisseria meningitides types A, C, W, Y 
and 
B 
(administered 
as 
two 
separate 
vaccinations), 
Pneumococcal 
conjugate 
vaccine 
or 
Pneumococcal 
polysaccharide vaccine 23 (PCV13 or PPSV23, respectively) and 
Haemophilus influenzae Type B (Hib) vaccination either within 
2 years prior to Day 1 dosing, OR 14 days after starting 
treatment with APL-2. 
• Willing and able to give informed consent 
Exclusion Criteria 
• Prior eculizumab (Soliris)® treatment 
• Active bacterial infection 
• Active infection with hepatitis B virus (HBV), hepatitis C virus 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 4 of 71 
(HCV) or human immunodeficiency virus (HIV) 
• Hereditary complement deficiency 
• History of bone marrow transplantation 
• Concurrent severe aplastic anemia (SAA), defined as currently 
receiving immunosuppressive therapy for SAA including but 
not limited to cyclosporin A, tacrolimus, mycophenolate 
mofetil or anti-thymocyte globulin. 
• Participation in any other investigational drug trial or exposure 
to another investigational agent, device or procedure within 
30 days 
• Evidence of QTcF prolongation defined as >450 ms for males 
and >470 ms for females at screening. 
• Breast-feeding women 
• History of meningococcal disease 
Endpoints 
Primary Safety Endpoint: 
The primary safety endpoints of the study are the number and 
severity of treatment emergent adverse events (TEAEs) following 
administration of multiple doses of SC APL-2. 
Primary Efficacy Endpoints: 
• Change from baseline in LD 
• Change from baseline in Haptoglobin 
• Change from baseline in Hemoglobin (Hb) 
Secondary endpoints: 
• APL-2 plasma concentrations (and pharmacokinetic (PK) 
parameters as appropriate) 
• Change from baseline in Functional Assessment of Chronic 
Illness Therapy (FACIT) Fatigue Scale score 
• Change from baseline in reticulocyte count 
• Number of red blood cell (RBC) transfusions per month 
Exploratory PD markers include: 
• Complement (e.g., CH50, AP50, and C3) levels 
• C3 deposition on RBC cells 
• Clonal distribution of PNH RBCs 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 5 of 71 
Planned Dose 
Levels 
Planned doses will be as follows: 
 
SC dose 
Cohort 1 
180 mg / day 
Cohort 2 
Starting dose 
270 mg / day 
Cohort 2 
Intra-subject escalation 
Up to 360 mg/day 
 
 
The dose for Cohort 2 was determined based on cumulative 
safety, PK, and PD data from Cohort 1. 
Dose escalation decisions will be agreed by a Safety Monitoring 
Committee (SMC), based on the safety and pharmacology results 
from the prior cohort(s). SMC review of cumulative data will 
occur approximately monthly.  
Study Design 
This is a Phase Ib, open-label, multiple ascending dose, pilot study 
in patients with PNH who have not received eculizumab (Soliris®) 
in the past. Two cohorts of subjects are planned for evaluation. 
Cohort 1 will include 3 subjects and Cohort 2 will include up to 20 
subjects who complete Part 1 (28 days of dosing). Subjects may 
participate in more than one cohort.  
Safety will be assessed throughout the study; serial blood and 
urine samples will be collected for these assessments. Blood 
samples will be collected for the assessment of APL-2 PK. 
Additional samples for assessment of PD will also be collected.  
The study will consist of four parts; 
• Part 1: subjects will receive APL-2 for 28 days.  
• Part 2A:  subjects may continue to receive APL-2 for a 
further 56 days if there is evidence of perceived clinical 
benefit following review of available safety, PK and PD 
data by the investigator and sponsor 
• Part 2B:  subjects may continue to receive daily APL-2 
treatment for up to 364 days if there is ongoing evidence 
of clinical benefit following review of the available safety, 
PK and PD data. 
• Part 3: Safety follow up (if applicable; subjects may also 
transition into an open-label extension study to continue 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 6 of 71 
treatment with APL-2 after the completion of Part 2B) 
 
Screening will take place within 30 days prior to the start of 
dosing on Day 1. 
Subjects will be entered into Part 1 of the study on Day 1 at a 
time designated by the PI. During Part 1, the first 3 daily SC doses 
of APL-2 (Day 1 to 3) as well as doses on Day 8, 15 and 22 will be 
administered at the clinical site. From Day 4 to Day 28 daily doses 
of APL-2 will be administered off-site by a trained study nurse or 
self-administered by the subject, at the subject’s home, 
workplace, or other location convenient to the subject with the 
exception of those days where dosing is at the clinical site (see 
above). Following ongoing review of available safety, PK and PD 
data by the investigator and sponsor, subjects showing evidence 
of perceived clinical benefit may progress to Part 2A and then to 
Part 2B of the study and continue to receive daily doses of APL-2 
until Day 84 and then until Day 364. Doses will be administered 
off-site by a study nurse or self-administered by the subject, at 
the subject’s home, workplace, or other location convenient to 
the subject with the exception of Days 29, 36, 43, 57, 71, 85, 113, 
141, 169, 197, 225, 253, 281, 309, and 337 where dosing is at the 
clinical site. After the conclusion of the treatment period (Day 
364), subjects will return to the clinical site for follow-up study 
procedures on Day 365, 379, and 393 and final study procedures 
at an Exit Visit on Day 414 See Study Flow Chart in Section 3. 
Cohort 2 will not be initiated until all subjects in Cohort 1 have 
reached the Day 29 visit and the SMC has reviewed emerging 
safety and efficacy data and determined that, at the initial dose, 
APL-2 has an acceptable safety and tolerability profile. 
Interim PK and PD analyses may be performed to reconsider the 
sampling time points as the study progresses. 
Subjects who complete Part 2B will be eligible to transition into 
an open-label extension study (Study APL2-307) in order to 
continue to receive treatment with APL-2. Subjects who elect to 
transition into Study APL2-307 will not complete Part 3 of this 
study.  
The planned length of participation in the study for each subject 
in Cohort 2 is a maximum of 444 days (14.5 months) from Day -30 
through completion of the Day 414 Exit visit procedures). 
The study is planned to take place over approximately 24 months 
(from screening of Cohort 1 through completion of Cohort 2). 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 7 of 71 
 
 
Some subjects who complete Part 2B and wish to transition into 
the open-label extension study may be required to dose beyond 
the planned conclusion of Part 2B (Day 364) in this study. This 
study utilizes an acetate buffered mannitol formulation of APL-2. 
The open-label extension study will utilize an alternate acetate 
buffered sorbitol formulation. Some subjects may complete 
Part 2B of this study before there is sufficient availability of the 
alternate acetate buffered sorbitol formulation to conduct Study 
APL2-307.  Subjects who complete Part 2B prior to Study APL2-
307 being open for enrollment to subjects in this study may 
continue dosing with the acetate buffered mannitol formulation 
under this protocol (Part 2C), until the extension study is open to 
them for enrollment. These subjects will continue to receive their 
current APL-2 dose and regimen and will return to the site for 
visits at bi-monthly intervals until entry into the extension study 
is possible.  Data obtained from subjects who participate in Part 
2C will not be included in endpoint assessment and will be only 
listed. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 8 of 71 
TABLE OF CONTENTS 
1. SYNOPSIS .................................................................................................................................2 
2. AMENDMENTS ....................................................................................................................... 11 
2.1 
Amendment 1 ................................................................................................................. 11 
2.2 
Amendment 2 ................................................................................................................. 12 
2.3 
Amendment 3 ................................................................................................................. 13 
2.4 
Amendment 4 ................................................................................................................. 14 
2.5 
Amendment 5 ................................................................................................................. 15 
2.6 
Amendment 6 ................................................................................................................. 17 
2.7 
Amendment 7 ................................................................................................................. 18 
2.8 
Amendment 8 ................................................................................................................. 20 
3. STUDY FLOW CHART ........................................................................................................... 22 
4. ABBREVIATIONS ................................................................................................................... 28 
5. INTRODUCTION ..................................................................................................................... 30 
5.1 
Background .................................................................................................................... 30 
5.1.1 
Paroxysmal Nocturnal Hemoglobinuria ............................................................... 30 
5.1.2 
APL-2 ................................................................................................................... 30 
5.2 
Rationale ........................................................................................................................ 35 
5.2.1 
Purpose of the Study ........................................................................................... 35 
5.2.2 
Dose Selection ..................................................................................................... 36 
5.3 
Risk/Benefit .................................................................................................................... 37 
6. STUDY OBJECTIVES AND ENDPOINTS .............................................................................. 38 
6.1 
Study Objectives ............................................................................................................ 38 
6.2 
Study Endpoints ............................................................................................................. 39 
7. STUDY DESIGN ..................................................................................................................... 39 
8. SUBJECT SELECTION .......................................................................................................... 41 
8.1 
Inclusion Criteria ............................................................................................................ 41 
8.1.1 
Approved methods of contraception .................................................................... 42 
8.2 
Exclusion Criteria ........................................................................................................... 42 
9. STUDY TREATMENTS ........................................................................................................... 42 
9.1 
Allocation to Treatment .................................................................................................. 42 
9.2 
Blinding .......................................................................................................................... 42 
9.3 
Treatments Administered ............................................................................................... 43 
9.3.1 
Drug supplies ....................................................................................................... 43 
9.3.2 
Planned Dose Levels and Dosing Schedule ....................................................... 43 
9.3.3 
Drug Administration ............................................................................................. 44 
9.3.4 
Additional Dose Levels ........................................................................................ 45 
9.4 
Concomitant Medications .............................................................................................. 45 
9.4.1 
Prophylactic antibiotics ........................................................................................ 45 
9.4.2 
Rescue antibiotics ................................................................................................ 46 
9.4.3 
Vaccinations ........................................................................................................ 46 
9.4.4 
Prophylactic antivirals .......................................................................................... 46 
9.4.5 
Iron Supplements ................................................................................................. 46 
10. STUDY PROCEDURES .......................................................................................................... 46 
10.1 Screening ....................................................................................................................... 47 
10.2 Part 1 - Treatment Period – (Days 1 to 28) ................................................................... 47 
10.2.1 On Site Administration (Day 1 to Day 3 and Days 8, 15 and 22) ........................ 47 
10.2.2 Outpatient Administration (Day 4 to Day 28) ....................................................... 47 
10.3 Part 2A - Treatment Period – (Days 29 to 84) ............................................................... 47 
10.3.1 On Site Administration (Days 29, 36, 43, 57 and 71) .......................................... 47 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 9 of 71 
10.3.2 Outpatient Administration (Day 30 to Day 84) ..................................................... 48 
10.4 Part 2B - Treatment Period – (Days 85 to 364) ............................................................. 48 
10.4.1 Outpatient Administration (Day 85 to Day 364) ................................................... 49 
10.5 Part 3 - Follow-up - (Days 365, 379, and 393, or Days 85, 99, and 113, or Days 29, 
43, and 57) .............................................................................................................. 49 
10.5.1 Exit Visit (Day 414, or Day 134, or Day 78) ......................................................... 49 
10.5.2 Unscheduled Follow-up Visits ............................................................................. 49 
10.5.3 Scheduled End of Study ...................................................................................... 50 
10.6 Dose Escalation and Periodic Safety Review ................................................................ 50 
10.6.1 Safety Monitoring Committee .............................................................................. 50 
10.7 Removal of Subjects from the Study ............................................................................. 51 
11. ASSESSMENTS ..................................................................................................................... 51 
11.1 Assessments .................................................................................................................. 51 
11.1.1 Body Height and Weight ...................................................................................... 51 
11.1.2 Physical Examination........................................................................................... 51 
11.1.3 Vital Signs ............................................................................................................ 52 
11.1.4 Electrocardiogram Monitoring .............................................................................. 52 
11.1.5 Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale ....... 52 
11.1.6 Clinical Laboratory Tests ..................................................................................... 52 
11.1.7 Injection Site Assessment ................................................................................... 54 
11.2 Pharmacokinetic Assessments ...................................................................................... 54 
11.2.1 Blood Sampling and Processing .......................................................................... 54 
11.2.2 Analytical Method ................................................................................................ 54 
11.3 Pharmacodynamic Assessments ................................................................................... 54 
11.4 Blood Volume for Study Assessments........................................................................... 55 
11.5 Pregnancy tests ............................................................................................................. 55 
12. ADVERSE EVENTS ................................................................................................................ 55 
12.1 Definitions ...................................................................................................................... 55 
12.2 Recording Adverse Events ............................................................................................ 56 
12.3 Assessment of Adverse Events ..................................................................................... 56 
12.3.1 Intensity ............................................................................................................... 56 
12.3.2 Causality .............................................................................................................. 57 
12.3.3 Serious Adverse Event ........................................................................................ 58 
12.4 Reporting Serious Adverse Event .................................................................................. 58 
12.5 Adverse Events of Special Interest ................................................................................ 59 
12.6 Unexpected Adverse Events or Unexpected Suspected Adverse Reactions ............... 59 
12.7 Treatment and Follow up of Adverse Events ................................................................. 59 
12.8 Pregnancy ...................................................................................................................... 60 
13. STATISTICS ............................................................................................................................ 60 
13.1 Sample Size Justification ............................................................................................... 60 
13.2 Statistical Analysis Methodology ................................................................................... 60 
13.2.1 Analysis Populations............................................................................................ 60 
13.2.2 Study Endpoints ................................................................................................... 61 
13.2.3 Safety Analyses ................................................................................................... 62 
13.2.4 Efficacy and Secondary Endpoint Analyses ........................................................ 62 
13.2.5 Pharmacokinetic Analyses .................................................................................. 63 
13.2.6 Pharmacodynamic Analyses ............................................................................... 63 
13.2.7 Handling of Dropouts and/or Missing Data .......................................................... 63 
13.2.8 Other Data Analyses............................................................................................ 63 
13.3 Interim Analyses ............................................................................................................ 64 
14. ADMINISTRATIVE CONSIDERATIONS................................................................................. 64 
14.1 Direct Access to Source Data/Documents .................................................................... 64 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 10 of 71 
14.2 Quality Control and Quality Assurance .......................................................................... 64 
14.2.1 Monitoring ............................................................................................................ 64 
14.3 Ethics ............................................................................................................................. 65 
14.3.1 Ethical Conduct of the Study ............................................................................... 65 
14.3.2 Institutional Review Board/Ethic Committee ....................................................... 65 
14.3.3 Subject Information and Consent ........................................................................ 65 
14.3.4 Confidentiality ...................................................................................................... 65 
14.3.5 ClinicalTrials.gov .................................................................................................. 65 
14.3.6 Termination of Study............................................................................................ 66 
14.4 Data Handling and Record Keeping .............................................................................. 66 
14.5 Protocol Amendments ................................................................................................... 66 
14.6 Report Format ................................................................................................................ 66 
14.7 Finance and Insurance .................................................................................................. 66 
14.8 Publication Policy ........................................................................................................... 66 
15. REFERENCES ........................................................................................................................ 68 
16. APPENDIX 1: PART 2C: MAINTANENCE DOSING PERIOD (IF NECESSARY TO 
MAINTAIN TREATMENT WITH APL-2 PRIOR TO EXTENSION ROLL OVER) ............. 69 
16.1 Overview and Rationale ................................................................................................. 69 
16.2 Part 2C Study Procedures ............................................................................................. 69 
16.3 Part 2C Study Flow Chart (Day 365+ as needed) ......................................................... 70 
 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 22 of 71 
3. STUDY FLOW CHART 
Study Period 
Screen 
Part 1- Treatment (Daily from Day 1 to Day 28) 
Study Week 
-4 
-2 
1 
2 
3 
4 
Study Day -30 
-14 
1 
2 
3 
4 to 7 
8 
9 to 14 
15 
16 to 21 
22 
23 to 28 
Informed Consent 
x 
Demographics 
x 
Medical, transfusion, vaccination and thrombosis history 
x 
Vaccination. A 
x 
Review entry criteria 
x 
Preventive antibiotic. B 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination. C 
x 
12-lead electrocardiogram. D 
x 
x 
x 
x 
x 
x 
APL-2 administration. E 
S 
S 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital sign measurements. G 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
x 
x 
x 
Blood. I 
x 
x 
x 
x 
x 
Pharmacokinetics. I 
x (I) 
x 
x 
x 
x 
Anti-APL-2 Ab assay 
x 
x 
Hematology and chemistry. J 
x 
x 
x 
x 
x 
x (J) 
Coagulation profile P 
x 
x 
x 
x 
x 
Complement profile (C3, CH50 and AP50) 
x 
x 
x 
x 
x 
Flow cytometry for PNH/C3 deposition 
x 
x 
x 
x 
x 
Plasma Hb 
x 
x 
x 
x 
x 
Serology (HIV, HBsAg and HCV.) K 
x 
Pregnancy (B-human chorionic gonadotropin) 
x 
Urine pregnancy test. L 
x 
x 
x 
x 
FACIT fatigue Scale 
x 
x 
Adverse events M 
x 
x 
x 
x 
x 
X 
x 
X 
x 
x 
Thrombosis record (MAVE).  
x 
x 
x 
x 
x 
X 
x 
X 
x 
x 
See notes below continuation flow chart 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 23 of 71 
Study Period 
Part 2A - Treatment (Daily from Day 29 to Day 84) 
 
Study Week 
5 
6 
7 and 8 
9 and 10 
11 and 12 
Study Day 
29 
30 to 35 
36 
37 to 42 
43 
44 to 56 
57 
58 to 70 
71 
72 to 84 
Informed Consent 
Demographics 
Medical, transfusion, and thrombosis history 
Vaccination. A 
 
 
Review entry criteria 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
X 
12-lead electrocardiogram. D 
X 
X 
X 
X 
X 
APL-2 administration. E 
S 
H 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
 
 
X 
 
 
 
X 
Anti-APL-2 Ab assay 
X 
X 
Hematology and chemistry. J 
X 
X 
X 
X 
X 
Coagulation profile P 
X 
X 
X 
X 
X 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
X 
Plasma Hb 
X 
X 
X 
X 
X 
Urine pregnancy test. L 
X 
X 
X 
X 
X 
FACIT fatigue Scale 
X 
X 
X 
Adverse events M 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes below continuation flow chart 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 24 of 71 
Study Period 
Part 2B - Treatment (Daily from Day 85 to Day 364) (N) 
Study Week 
13 to 16 
17 to 20 
21 to 24 
25 to 28 
29 to 32 
33 to 36 
Study Day 
85 
86 to 112 
113 
114 to 140 
141 
142 to 168 
169 
170 to 196 
197 
198 to 224 
225 
226 to 252 
Informed Consent 
X 
Review entry criteria 
X 
Vaccination. A 
X 
 
 
 
 
 
 
 
 
 
 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
12-lead electrocardiogram. D 
X 
X 
X 
X 
X 
X 
APL-2 administration. E 
S 
H 
S 
H 
S 
H 
S 
H 
S 
H 
S 
H 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
X 
 
X 
 
X 
 
X 
X 
Anti-APL-2 Ab assay 
X 
X 
X 
Hematology and chemistry. J 
X 
X 
X 
X 
X 
X 
Coagulation profile P 
X 
X 
X 
X 
X 
X 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
X 
X 
Plasma Hb 
X 
X 
X 
X 
X 
X 
Urine pregnancy test. L 
X 
X 
X 
X 
X 
X 
FACIT fatigue Scale 
X 
X 
X 
Adverse events M 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See footnotes below continuation flow chart 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 25 of 71 
Study Period 
Part 2B - Treatment (Daily from Day 85 to Day 364) … continued (N) (Q) 
Part 3 – Follow-up and Exit. (O)(Q) 
Study Week 
37 to 40 
41 to 44 
45 to 48 
49 to 52 
53 
55 
57 
60 
Study Day 
253 
254 to 280 
281 
282 to 308 
309 
310 to 336 
337 
338 to 364 
365 
379 
393 
414 
Informed Consent 
 
Review entry criteria 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Physical examination. C 
X 
X 
X 
 
X 
12-lead electrocardiogram. D 
X 
X 
X 
X 
X 
 
APL-2 administration. E 
S 
H 
S 
H 
S 
H 
S 
H 
 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Anti-APL-2 Ab assay 
X 
X 
X 
 
X 
Hematology and chemistry. J 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile P 
X 
X 
X 
X 
X 
X 
X 
X 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Hb 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test. L 
X 
X 
X 
X 
X 
X 
X 
FACIT fatigue Scale 
X 
X 
X 
X 
X 
Adverse events M 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See study flow chart footnotes on next page 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 26 of 71 
FOOTNOTES: 
A. At screening the vaccination history will be obtained from the subject. If required i.e. not previously vaccinated subjects will receive 
vaccinations against Neisseria meningitides types A, C, W, Y and B (administered as two vaccinations), Streptococcus pneumoniae and 
Haemophilus influenzae Type B (Hib).  If the subject’s first documented Neisseria meningitidis vaccine/s are administered at Day 15, a 
booster (for both vaccinations) should be administered at least 2 months later (Day 85). If Pneumococcal vaccination is required, a dose of 
PCV13 will be administered at Day 15 and a dose of PPSV23 will be administered at least 8 weeks later (Day 85).  
B. Preventive antibiotics will be prescribed from Day 1. Antibiotics will be taken from Day 1 until 14 days after the final dose of APL-2. 
Specifically: 
• Day 1 to Day 14: Ciprofloxacin 500 mg twice daily to commence after collection of the 2.5h post dose PK sample 
• Day 15 onwards: Penicillin V 500 mg twice daily. 
C. Full physical examination will be performed at the scheduled time points indicated. A symptom-driven physical examination may be 
performed at other times, at the PI’s discretion. 
D. If done on a dosing day, electrocardiograms (ECGs) are to be performed within 30 minutes after dosing. N.B. On Day 1 the ECG must be 
performed BEFORE administration of the first dose of Ciprofloxacin. 
E. S = Administration at clinical site. H = Administration at subject’s home, workplace, or other location convenient to the subject. 
Treatment may be stopped at any time if the investigator and sponsor conclude that there is no demonstration of clinical benefit to 
continue APL-2 administration past this point. 
F. Injection site assessment will be performed within 30 minutes after APL-2 administration. Ambulatory syringe infusion pump training will 
include instructions to report any injection site reaction to the PI. 
G. If APL-2 is administered by a study nurse or other research study staff, vital signs will be measured within 2 hours prior to dosing and 
within 30 minutes after dosing. If APL-2 is self-administered, pre- and post-dose vital signs will not be measured. 
H. Reserved – See note E. 
I. If done on a dosing day, blood samples will be taken pre-dose with the exception that on Day 1 only a pharmacokinetic sample will be 
taken pre-dose and at a minimum of 2.5 hours post-dose or immediately prior to discharge from the clinic (if subject is kept at the clinic 
longer than 2.5 hours). 
J. On Days 23 through 28, a serum chemistry sample may be obtained but LD assays only will be performed and reported. If a sufficient 
reduction in LD is observed prior to Day 22 these additional samples may not be required and this will be confirmed on an individual 
subject basis by the sponsor 
K. Absence of HIV, HBV, and HCV infection will be confirmed prior to APL-2 administration. If the HBsAg test yields a positive result, a 
negative HBV DNA test result must be obtained and prophylactic antiviral therapy must be commenced prior to APL-2 administration 
and continue until two weeks after the final dose of APL-2 to minimize the potential risk of HBV activation. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 27 of 71 
L. If done on a dosing day, urine pregnancy test should be completed for WOCBP prior to dosing.  
M. Ambulatory syringe infusion pump training will include instructions to report any adverse events to the PI. 
N. If dose is increased during Part 2B, subjects will come back to the clinical site for safety visits every other week (instead of monthly) for 
the first 6 weeks of the dose change. These visits will alternate with the monthly visits and should be recorded as unscheduled visits. 
The same procedures listed under the monthly visits will be performed. 
O. Subjects who discontinue dosing at any time during part 1, 2A or 2B, will move directly into Part 3 for safety follow up visits. 
P. The use of silica reagents in coagulation panels should be avoided in subjects treated with APL-2. 
Q.  Subjects who complete Part 2B will be eligible to transition into an open-label extension study (Study APL2-307) in order to continue to 
receive treatment with APL-2. Subjects who elect to transition into Study APL2-307 will not complete Part 3 of this study, but must 
complete the Day 365 visit procedures (the first visit of Part 3). The Day 365 visit will also be the first visit of the extension study. If 
Study APL2-307 is not open to enroll subjects from this study, subjects may continue dosing with APL-2 beyond Part 2B in Part 2C of this 
study. Details regarding procedures for dosing beyond Part 2B are provided in Appendix 1 (Section 16). 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 28 of 71 
4. ABBREVIATIONS 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CK 
Creatine kinase 
CRF 
Case report form 
CS 
Clinically significant abnormality 
ECG 
Electrocardiogram 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FDA 
Unites States Foods and Drug Administration 
g 
Gram(s) 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good laboratory practice 
Hb 
Haemoglobin 
HBV 
Hepatitis B virus 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
hERG 
Human ether-à-go-go-related gene 
Hib 
Haemophilus influenzae Type B (vaccine) 
HIV 
Human immunodeficiency virus 
HSA 
Human serum albumin 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IV 
Intravenous 
kg 
Kilogram(s) 
L 
Litre(s) 
LD 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
MAC 
Membrane attack complex 
MAVE 
Major Adverse Vascular Event 
MedDRA® 
Medical Dictionary for Regulatory Activities 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 29 of 71 
mg 
Milligram(s) 
mL 
Millilitre(s) 
MOP 
Manual of Procedures 
µM 
Micromolar; micromoles/L 
NCS 
Not clinically significant 
NOEL 
No observed effect level 
NOAEL 
No observed adverse effect level 
PCV13 
Pneumococcal conjugate vaccine 
PD 
Pharmacodynamic(s) 
PEG 
Polyethylene glycol 
PEG40 
Polyethylene glycol (40 kDa nominal molecular weight) 
PI  
Principal Investigator or designee 
PK 
Pharmacokinetic(s) 
PPSV23 
Pneumococcal polysaccharide vaccine 23   
PT 
Prothrombin time 
PNH 
Paroxysmal nocturnal hemoglobinuria 
QTc 
Corrected QT interval 
QTcB 
Bazett’s correction 
QTcF 
Fridericia’s correction 
RBC 
Red blood cell 
SAA 
Severe aplastic anaemia 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous  
SMC 
Safety Monitoring Committee 
SOP 
Standard operating procedure 
T½ 
Serum half-life 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper Limit of Normal 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Woman of Child-Bearing Potential 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 30 of 71 
5. INTRODUCTION 
5.1 
Background 
This study is being conducted as part of a series of studies for the clinical development of APL-2. The 
trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and applicable 
regulatory requirements. The subject population will be comprised of adult male and female subjects 
with paroxysmal nocturnal hemoglobinuria (PNH). 
5.1.1 Paroxysmal Nocturnal Hemoglobinuria 
PNH is an acquired, clonal, non-malignant hematological disease characterized by complement-
mediated RBC hemolysis with or without hemoglobinuria, an increased susceptibility to thrombotic 
episodes, and/or some degree of bone marrow dysfunction. The onset of PNH is often insidious. 
Although there have been reports of spontaneous remission, the course of the disease is generally 
chronic and progressive. 
It has been known for many years that PNH is caused by complement-mediated lysis of erythrocyte 
clones lacking functional CD55 and CD59 on their surface to protect them against this process. As such, 
these erythrocytes are particularly susceptible to the membrane attack complex (MAC) and have been 
shown to lyse readily in the presence of complement activation. 
Any therapy that effectively inhibits MAC formation is anticipated to be a plausible candidate-
treatment for PNH. Indeed, eculizumab is a monoclonal anti-C5 antibody that inhibits the formation of 
the MAC, and eculizumab treatment has been approved for the treatment of this serious condition. 
However, inhibition of MAC formation does not appear to be sufficient to fully control the disease, as 
many PNH patients receiving eculizumab treatment still suffer from anemia, with only roughly 13% of 
patients being classified as complete responders, i.e. achieving transfusion independence and normal 
Hb levels. Most of the patients (53%) were classified as partial responders with decreased transfusion 
needs and reduced LD, and 33% of patients were poor responders, with unchanged transfusion needs 
and persistent symptoms (DeZern, 2013). 
Recent studies have suggested that significant opsonization of PNH erythrocytes by C3 fragments is 
observed in patients receiving eculizumab treatment. This opsonization is believed to cause the 
removal of erythrocytes by the spleen and the liver, resulting in extravascular hemolysis. Extravascular 
hemolysis can be significant in a subset of eculizumab-treated PNH patients and is considered to be the 
principal contributor to the lack of complete eculizumab response in most patients. It is reasonable, 
therefore, to expect that a treatment able to inhibit both MAC formation and C3 opsonization will 
provide improved therapeutic benefit to PNH patients compared to eculizumab. 
An overview of available information regarding APL-2 follows below. Further details can be found in 
the APL-2 Investigator’s Brochure (Apellis Pharmaceuticals, 2015). 
5.1.2 APL-2 
APL-2 (PEGylated peptide) is a small 13-amino acid cyclic peptide with 12 natural amino acids and a 
single synthetic amino acid (methyltryptophan) covalently coupled via a linker to each end of a linear 
40kDa polyethylene glycol (PEG40) chain, so there are two peptide moieties per molecule of APL-2. The 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 31 of 71 
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 injection (drug product) is a solution of APL-2 in 5% dextrose or a solution of APL-2 in acetate-
buffered mannitol or a solution of APL-2 in acetate-buffered sorbitol for SC administration. APL-2 is 
being developed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). 
5.1.2.1  Nonclinical Data 
5.1.2.1.1 Pharmacology 
Primary pharmacology studies were performed with APL-2. Ex vivo studies conducted with blood from 
PNH patients revealed that APL-2 can protect PNH RBC from complement-mediated lysis and also 
prevent RBC opsonization by C3 fragments (i.e. C3 loading). The studies combined a modified Ham’s 
test with flow cytometry. Blood from PNH patients was acidified in the presence of magnesium in 
order to activate the alternative complement pathway and lyse the PNH erythrocytes. The cells were 
incubated in the presence of magnesium only (negative control), eculizumab (an anti-C5 antibody 
approved to treat PNH and used as a positive control/comparator) or APL-2. The surviving 
erythrocytes, including normal and PNH RBCs, were then labeled with anti-CD59 and anti-C3d and 
analyzed using standard flow cytometry to assess protection against hemolysis. APL-2 was as effective 
as eculizumab in protecting PNH RBCs against direct MAC-mediated hemolysis, and, unlike eculizumab, 
it was also effective in preventing massive opsonization of those cells by C3 fragments. Based upon the 
available ex vivo and clinical data, the efficacious dose for humans has been estimated to be between 
2 mg/kg/d and 4 mg/kg/d. 
During safety pharmacology studies, APL-2 produced little or no reduction in hERG current amplitude 
when tested in vitro over a concentration range of 1 µM up to 300 µM in the presence or absence of 
human serum albumin (HSA). APL-2 had no effects on body temperature nor on respiratory and 
cardiovascular parameters when administered to telemeterized Cynomolgus monkeys at doses of 28 or 
140 mg/kg. 
5.1.2.1.2 Pharmacokinetics 
Pharmacokinetics and toxicokinetics have been performed in rabbits and monkeys administered APL-2 
by intravenous (IV) or SC routes. Excellent bioavailability (approximately 85%) and t½s in the range of 6 
to 8 days were obtained with both routes of administration in Cynomolgus monkeys. T½s in rabbits 
were shorter, ranging from 2 to 3 days. 
5.1.2.1.3 Toxicology 
To date, Apellis has conducted hERG channel potassium studies; in vivo assessments of cardiovascular 
and respiratory function in monkeys; pilot 7 day studies in rabbits and monkeys; and 28-day repeat-
dose toxicity studies in rabbits and monkeys. 
A 9-month chronic dosing study in cynomolgus monkeys has recently completed its in-life phase and 
final data from the 3-month interim necropsy and draft data from the final 9-month necropsy are 
available.  A 6-month chronic dosing study in rabbits has been completed and final data are available. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 32 of 71 
In addition, in vitro and in vivo assessments of genotoxicity have been performed. In most of these 
studies, a group dosed with polyethylene glycol (PEG) with a molecular weight of 40 kDa (PEG40) was 
included to assess the differences between the PEG moiety of APL-2 and the full drug molecule, APL-2. 
APL-2 produced little or no reduction in hERG current amplitude when tested in vitro over a 
concentration range of 1 µM up to 300 µM in the presence or absence of HSA. APL-2 had no effects on 
body temperature nor on respiratory and cardiovascular parameters when administered to 
telemeterized cynomolgus monkeys at doses of 28 or 140 mg/kg. 
APL-2 did not induce genotoxicity in a bacterial reverse-mutation assay (Ames test) nor in an in vitro 
mammalian cell micronucleus test using TK6 cells (proficient p53 human lymphocytes). During in vivo 
assessments, APL-2 exhibited no clastogenic effect in the mouse micronucleus model. 
Pharmacokinetics and toxicokinetics have been performed in rabbits and monkeys administered the 
drug by IV or SC routes. Excellent SC bioavailability (approximately 85%) was obtained in cynomolgus 
monkeys. No sex-related differences were noted in either species. The long half-life of APL-2 resulted 
in a slowly increasing serum concentration over time that reached a steady state plateau after a few 
weeks of dosing. APL-2 was mildly antigenic in rabbits; however, the response was concluded to be 
caused by the PEG40 chain in both molecules and it did not affect serum concentrations of APL-2. APL-
2 and PEG40 were not immunologic in monkeys. 
In 28-day GLP rabbit and monkey studies with daily SC administration, no drug-related in-life findings 
(clinical signs, body weight, food consumption, ophthalmology) were observed at APL-2 dose levels of 
0.25, 1, 3, 7, 28 or 140 mg/kg/d. APL-2 was well tolerated, with no mortality observed. A no-
observable-effect level (NOEL) was approximated to be 3 mg/kg/d and the no-observable-adverse-
event-effect level (NOAEL) was concluded to be ≥7 mg/kg/d in both species. 
Observations were generally consistent between both species. General observations include dose-
dependent inflammatory cell infiltrates at sites of injection comprised of lymphocytes, plasma cells or 
granulocytes, as well as frequent multinucleated cells. Additionally, dose-dependent macrophage 
vacuolation was observed in multiple tissues, which is a known adaptive change attributable to the 
administration of PEG. 
Observations at the 28 and 140 mg/kg/d dose levels included a dose-dependent increase in RBC 
parameters (RBC counts, hematocrit, and Hb), reticulocyte counts, and partial activated 
thromboplastin time, and a dose-dependent decrease in WCBs, fibrinogen levels and differential 
lymphocyte counts. Some but not all of these observations resolved themselves by the end of a 4 week 
recovery phase. Observations at the two higher doses also included dose-dependent kidney tubular 
vacuolation and degeneration that were not reversible after a 4 week recovery phase. These kidney-
related findings are also a known change attributed to PEG.  
The draft data, including full histopathological assessment, from 9 months of daily SC administration in 
the cynomolgus monkey and 6 months of daily SC administration in the New Zealand white rabbit both 
concluded that the main toxicological findings are comparable to those observed after 28 days of 
dosing at the same dose. Doses of 1, 7, and 28 mg/kg/d were investigated. There were no deaths, 
injection site reactions, ocular effects, gross findings, or changes in organ weight or clinical chemistry 
parameters. Mirroring what was observed after 28 days of dosing in monkeys, multi-tissue 
macrophage vacuolation was observed at ≥7 mg/kg/d (a non-adverse observation) and kidney tubular 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 33 of 71 
degeneration was observed in animals at 28 mg/kg/d (an adverse reaction). Based on the draft data, 
7 mg/kg/d is still concluded to be a NOAEL in monkeys after considering the toxicological data from the 
9-month final necropsy in the monkey study. 
Similar to what was observed after 28 days of dosing in rabbits, multi-tissue macrophage vacuolation 
was observed at ≥7 mg/kg/d (a non-adverse observation). Based on the draft data, >28 mg/kg/d is still 
concluded to be a NOAEL in rabbits after considering the toxicological data from the 6-month necropsy 
in the chronic study. The monkey is to be considered the pivotal species from a pharmacological 
standpoint (i.e. APL-2 is only active in primates) and a toxicological observation [a kidney adverse event 
was observed at a lower dose in monkeys (28 mg/kg/d) than rabbits (140 mg/kg/d)] that establishes 
the monkeys as the most sensitive species. 
In summary, a number of findings observed in the repeated dose toxicology studies are noted to be 
associated with high doses of PEGylated proteins and their clearance from the tissues and the body. 
The primary adverse finding for both APL-2 and PEG40 was macrophage vacuolation in various tissues 
and kidney tubular degeneration. Administration of PEGylated compounds has been associated with 
macrophage vacuolation in animals and is associated with the clearance of large molecules from the 
tissues. Although noted in animal species, the macrophage vacuolation has not been associated with 
either behavioral or clinical effects in animals nor with any serious adverse events in humans at this 
time (Ivens, 2013). Furthermore, target organ toxicity in the kidneys has also been associated with 
administration of PEG in animals (Rudmann, 2013). Most of the toxicological observations noted in the 
APL-2 groups were comparable to those noted in the groups of animals receiving PEG40; thus in 
general, the peptide did not exacerbate the findings attributable to PEG40. 
Collectively there were no findings observed during any of the nonclinical studies, that would preclude 
testing daily SC administration of APL-2 in humans chronically. Results from the preclinical toxicology 
program with APL-2 provide good assurance of the safety for the proposed doses of APL-2 in humans 
by the SC route of administration. 
5.1.2.2 Clinical Data 
APL-2 SC injection has been tested in two healthy volunteer studies to assess the safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of APL-2. Both studies have been completed. The 
first is a single ascending dose study (Study APL-CP0713-1) and the second is a multiple ascending dose 
study (Study APL-CP1014). 
APL-2 SC administration is also currently being tested in two studies to assess the safety and activity of 
APL-2 in patients with PNH, including this study (APL-CP-PNH-204) and a study in patients who are 
receiving treatment with eculizumab (APL-CP0514). 
5.1.2.2.1 Single Ascending Dose Study APL-CP0713-1 
Single SC doses of APL-2 or placebo (5% dextrose solution) have been administered to 6 cohorts of 
healthy volunteers. The first cohort was initiated with a sentinel group of 2 subjects (1 active and 
1 placebo) who were dosed 24 hours before the remaining 4 subjects (3 active and 1 placebo); 
remaining cohorts included 5 subjects (4 active and 1 placebo). Available safety, PK and PD data up to 
Day 28 were reviewed for each cohort before dosing of the next cohort was initiated. Single doses of 
45, 90, 180, 360, 720 mg and 1,440 mg have been studied. 


 
 
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A total of 24 subjects received single SC doses of APL-2 and 7 subjects received placebo. Single dose 
administration of APL-2 at doses up to 1,440 mg was well tolerated and no serious AEs were reported. 
The most commonly reported treatment related AEs were headache (5/24 subjects) and redness, 
itchiness, and/or bruising at the injection site (7/24 subjects). All treatment related AEs were reported 
as either mild or moderate in severity. There was no consistent onset time of the AEs in relation to the 
timing of the administration and no apparent dose relationship with the events being reported 
sporadically across the doses studied. There were no treatment emergent, treatment related AEs 
reported in subjects who received the highest dose of 1,440 mg. All AEs resolved with no sequelae. No 
safety signals of clinical relevance were observed on review of laboratory data, vital signs, physical 
examinations or electrocardiogram results following APL-2 administration. 
Serum APL-2 concentrations generally increased linearly with dose. APL-2 was slowly absorbed into the 
systemic circulation with median Tmax values between 4.5 and 6 days across the dose groups. After 
Tmax, serum APL-2 concentration declined in a steady mono-exponential manner with the rate of decay 
similar across all dose groups. Exposure (AUC0-inf and Cmax) increased monotonically with dose, with the 
power model indicating dose proportionality. The estimated t½ was approximately between 8 and 10 
days. PK data is presented in Table 1 below.  
PD parameters (CH50, AP50 and complement C3 levels were measured for all cohorts, and intact C3 
and iC3b levels were added as additional PD parameters for Cohort 6) were assessed during the study. 
No significant change in CH50 (classical complement hemolytic activity) was measured at any dose, 
however, a significant decrease in AP50 (alternative complement hemolytic activity) was measured for 
Cohort 6. Additionally, a significant and dose-dependent increase in C3 levels was observed, suggesting 
interaction between APL-2 and its biological target, C3, as expected. Intact C3 and iC3b levels were also 
increased in the only cohort where it was measured (Cohort 6). Serum C3 level increase ranged from 
no significant changes at the lowest dose (45 mg) up to an increase of approximately 100% at a dose of 
1,440 mg when compared to levels measured in placebo subjects. Maximal levels of C3 were measured 
approximately 8 to 11 days after a single dose of APL-2, after which levels decreased back towards 
baseline. This increase in C3 was not correlated with any increase in complement activity as measured 
by either CH50 or AP50, nor with any other clinical observations. 
5.1.2.2.2 Multiple Ascending Dose Study APL-CP1014 
In this study, a daily SC dose of APL-2 or placebo (5% dextrose solution) was administered to healthy 
volunteers for 28 consecutive days. This multiple dose escalation study is completed and final data is 
available. Cohorts 1 to 4 received 30 mg/d, 90 mg/d, 180 mg/d and 270 mg/d, respectively. The safety 
monitoring committee (SMC) reviewed safety and tolerability data prior to dose escalation throughout 
the study. 
In total 16 subjects (4 in each Cohort) received SC administration of APL-2 for 28 days and 4 subjects (1 
in each Cohort) received placebo. Multiple dose administration of APL-2 at doses up to 270 mg/d for 28 
days appeared to be safe well tolerated and no serious AEs were reported. The most commonly 
reported AEs were headache and URTI. Headache was reported in 4/16 subjects administered APL-2 
and two of four subjects administered placebo. In the subjects who received APL-2, three subjects 
reported treatment-related headaches (one in 30 mg group, two in 270 mg group). In total, there were 
four reports of moderate headache reported in the study and two of these were reported in the APL-2 
270 mg group and two in the placebo group. Four of 16 subjects administered APL-2 reported URTI, 


 
 
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Multiple Ascending Dose / POC / PNH 
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Protocol Number:  APL2-CP-PNH-204
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none of which was considered to be treatment-related. Injection site reactions, reported as pain, 
pruritus, erythema, bruising and swelling, occurred in three of four subjects who received the highest 
dose (270 mg daily for 28 days) of APL-2. The injection site reactions were mild in severity and sporadic 
in nature, i.e. not reported at every injection, and none were considered, by the investigator to be 
clinically significant. One subject who received APL-2 180 mg had increased ALT and AST levels on Day 
15. The findings were considered by the investigator to be clinically significant and therefore were 
reported as AEs. Values for both parameters returned to within normal limits by Day 29 despite 
continued dosing with APL-2 between Day 15 and Day 29. No other safety signals of clinical relevance 
were observed on review of laboratory data, vital signs, physical examinations or electrocardiogram 
results following APL-2 administration. 
After first dose, APL-2 was slowly absorbed into the systemic circulation with a median Tmax of 24 hours 
across all dose groups indicating that the dose was still being absorbed into the systemic circulation at 
the time of next dose. Median serum concentration increased with each repeat dose, with 
concentrations close to steady state by Day 22. After Day 29, serum APL-2 concentration declined in a 
steady mono-exponential manner with the rate of decay similar across all dose groups. Exposure 
(AUCtau and Cmax) increased monotonically with dose at both Day 1 and Day 28, indicating dose 
proportionality. PK data is presented in Table 1 below.  
As with the single dose Phase I study APL-CP0713-1, a dose-dependent increase in C3 levels was 
observed. Additionally, a statistically significant decrease in the alternative pathway of complement 
activity (i.e. as measured by AP50 assay) was observed at doses of 30, 180 and 270 mg/d. The lowest 
AP50 values were recorded on Day 29 in the 270 mg/d group and the mean percentage reduction from 
baseline was -77%. Reductions began to resolve on cessation of dosing with APL-2. C3a, C5a, intact C3 
and iC3b were assessed in the 180 and 270 mg groups and reductions in C3a, C5a and increase in iC3b 
were observed during the dosing period at both dose levels. As a whole, these PD observations are 
consistent with a conclusion that APL-2 is interacting with complement C3 and inhibiting its activation 
through the alternative pathway. 
5.1.2.2.3 APL-2 in patients with PNH receiving eculizumab  
This study is an ongoing initial exploration of APL-2 in patients with PNH who are receiving treatment 
with eculizumab. The study is comprised of 3 cohorts with two subjects per cohort, and one cohort of 
six subjects. Cohort 1 to 3 have been completed and Cohort 4 is ongoing. To date treatment with APL-2 
270 mg/day has been well-tolerated for at least two months and has provided clinical benefit in 
subjects with PNH as an add-on to eculizumab. Based on the emerging data, dosing will continue for up 
to 364 days. 
5.2 
Rationale 
5.2.1 Purpose of the Study 
This study will be the initial exploration of APL-2 in patients with PNH that have not received treatment 
with eculizumab in the past. The assessments of safety, tolerability, preliminary efficacy, PK, and PD 
following administration of multiples doses of APL-2 will guide decisions to further develop the drug. 


 
 
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Multiple Ascending Dose / POC / PNH 
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5.2.2 Dose Selection 
APL-2 appeared to be well tolerated in a panel of standard animal toxicology studies and initial clinical 
testing in healthy volunteers. A population-based PK model was built from available single-dose and 
repeated-dose clinical data and used to predicted Cmax and AUC values for future doses. Monkey and 
human Cmax and AUC data were used to compare APL-2 exposures between species when necessary, 
although for chronic dosing, the Cmax (which is the APL-2 concentration at steady state in a daily dosing 
regimen) is the primary parameter to compare exposure (AUC becomes approximately the integration 
of Cmax in cases where dosing is much longer than the T1/2 of the drug). 
In the nonclinical toxicology studies described in the Investigator’s Brochure, the NOEL in both 
monkeys and rabbits was determined to be approximately 3 mg/kg/d in a 28 day study. A NOAEL 
between 7 mg/kg/d and 28 mg/kg/d in monkeys was established during a 9-month GLP study 
. Monkeys are considered the most relevant and pivotal species since APL-2 is only 
pharmacologically active as a complement inhibitor in primates. Additionally, compared with the PK 
parameters observed in rabbits (Cmax, t1/2, and AUCs), the PK parameters observed in monkeys 
correlate better with PK data obtained from the clinical studies APL-CP0713-1 and APL-CP1014. 
The available human PK data from the studies conducted in healthy volunteers (APL-CP0713-1 and 
APL-CP1014) were analyzed and compared to the PK data at the NOAEL in cynomolgus monkeys (see 
Table 1).  
Table 1: Comparison of PK parameters obtained from the IND-enabling toxicology study and clinical trials in healthy 
volunteers. All values reported as arithmetic means.  
 
Notes 
Dose 
(mg/kg) 
Cmax 
(μg/mL) 
Cmax  
% NOAEL 
Monkey 
NOAEL; Study 
 
7 
1087 
-- 
Human 
45 mg single dose; APL-CP0713-1 
0.6a 
7 
0.6% 
90 mg single dose; APL-CP0713-1 
1.3a 
16 
1.4% 
180 mg single dose; APL-CP0713-1 
2.6a 
29 
2.6% 
360 mg single dose; APL-CP0713-1 
5.1a 
74 
6.8% 
720 mg single dose; APL-CP0713-1 
10.3a 
139 
13% 
1440 mg single dose; APL-CP0713-1 
20.6a 
252 
23% 
30 mg/d x 28 days; APL-CP1014 
0.43a 
77 
7% 
90 mg/d x 28 days; APL-CP1014 
1.29a 
259 
24% 
180 mg/d x 28 days; APL-CP1014 
2.6a 
473 
43% 
270 mg/d x 28 days; APL-CP1014 
3.9a 
670 
62% 
360 mg/d PREDICTED 
5.14 
790 
73% 
 
The toxicological data accumulated from the animal studies were used to guide dose selection during 
the Phase I single ascending dose and multiple ascending dose studies in healthy volunteers (protocols 
CCI
CCI


 
 
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APL-CP0713-1 and APL-CP1014 respectively). In particular, the highest doses were selected based on 
exposure predicted by the PK model and compared with the exposures measured at the NOAEL in 
monkeys. 
The starting dose for this trial will not exceed the highest dose tested in the multiple ascending dose 
study in healthy volunteers, which was found to be well-tolerated. At the time of initiation of this 
study, this highest dose was 180 mg/d, which corresponds to an exposure of approximately 50% of the 
NOAEL in monkeys, but ongoing trials might provide additional safety data to support a higher starting 
dose. From a pharmacological standpoint, 180 mg/d was also the lowest dose that resulted in 
pharmacology in humans (as measured by a decrease in AP50) so a lower starting dose cannot be 
justified in this patient trial.  
The dose of the next cohort will be escalated by up to 50%. For example, if the dose of the first cohort 
is 180 mg/d, the starting dose of the following cohort will not exceed 270 mg/d. The dose selected for 
any cohort or individual subject will not exceed 360 mg/day (estimated to reach approximately 85 % of 
the Cmax of the NOAEL observed in monkeys) without a protocol amendment.  
5.3 
Risk/Benefit 
A number of safety monitoring practices are required by this protocol (i.e. physical examination, vital 
signs, 12-lead ECG, hematology, serum chemistry, urinalysis, coagulation, prompt reporting of pre-
defined AEs of special interest, and AE questioning) in order to protect the subjects’ safety. 
The volume of blood planned for collection from each subject over the course of the study (see Section 
11.4) will be limited to approximately 580 mL, in order to minimize the impact on the overall health of 
these anemic subjects. If dose is increased during part 2B, additional blood draws will be scheduled 
requiring an additional blood volume of 45 mL. 
Systemic complement inhibition might predispose individuals to infections caused by encapsulated 
organisms, including Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenza. 
Prophylactic antibiotic therapy  (ciprofloxacin 500 mg BID) will be prescribed to all subjects from Day 1 
(commencing after first administration of APL-2 and the subsequent post-dose PK sample and ECG) to 
Day 14. At Day 15 all subjects will discontinue treatment with ciprofloxacin and receive vaccinations, if 
required, against Streptococcus pneumoniae, Neisseria meningitides A, C, W, Y and B, and Haemophilus 
influenza.  Prophylactic antibiotic therapy (penicillin V 500 mg twice a day) will be prescribed to all 
subjects from Day 15 and will be taken by subjects until 14 days after the final dose of APL-2 to 
minimize potential infection risk.  Body temperature and vital signs will be monitored daily and 
relevant blood parameters monitored regularly throughout the study to assess for signs of infection. 
The principal investigator should be contacted immediately in the event of a suspected infection 
despite prophylactic antibiotic treatment for guidance and appropriate action to be taken. 
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients 
on beta-lactam antibiotic (e.g. penicillin, amoxicillin, etc.) therapy. These reactions are more likely to 
occur in individuals with a history of penicillin hypersensitivity. Before initiating therapy with penicillin 
V, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins or 
cephalosporins. Subjects with a known hypersensitivity to penicillin/amoxicillin may be prescribed 
erythromycin 500 mg twice daily as an alternative treatment at the outset (see Section 9.4 for details). 


 
 
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Protocol Number:  APL2-CP-PNH-204
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Other frequently reported adverse effects in patients taking penicillin are diarrhea/loose stools, 
nausea, skin rashes, urticaria and vomiting. Patients should, therefore, be advised that these reactions 
may occur. Treatment may be switched to erythromycin 500 mg twice daily (see Section 9.4 for details) 
if there is evidence of penicillin-related intolerability (such as nausea and diarrhea). 
There is a potential health benefit for trial participants from receipt of study drug. At the proposed 
dose levels APL-2 we observed a significant decrease in complement mediated hemolytic activity in all 
APL-2 treated subjects in our healthy volunteer study. APL-2 may, therefore, reduce complement 
mediated hemolytic activity in PNH patients. In this context, a careful evaluation of the risk/benefit 
ratio should be made. APL-2 at the proposed doses has been deemed safe for up to 9 months of 
administration in preclinical and 28 days in healthy volunteer studies. In addition, in both studies in 
subjects with PNH (See Section 5.1.2.2), ongoing treatment with APL-2 270 mg/day has been well-
tolerated for at least 28 days and up to 5 months and has provided clinical benefit to subjects either 
alone or as an add-on to eculizumab. Based on this data we propose to continue to administer APL-2 to 
PNH patients for up to 364 days (1 year). See Planned Dose Levels and Dosing Schedule in Section 
9.3.2. 
The use of silica reagents in coagulation panels should be avoided. Apellis previously conducted an 
investigation into prolonged activated partial thromboplastin time (aPTT) observed in subjects treated 
with APL-2. It was confirmed that false positive aPTT prolongation occurred when coagulation panels 
were performed using a Stago Analyzer and specifically silica reagents.  It was determined that there 
was interference between the silica reagents and PEGylated APL-2, resulting in artificially prolonged 
aPTTs. 
Details regarding the dosing regimen and administration of APL-2 are provided in Section 9.3. Subjects 
should be instructed to take their APL-2 treatment as prescribed, and to contact the investigator 
immediately for guidance in the event of any missed doses. Discontinuation with APL-2 or non-
compliance with the prescribed dose regimen may lead to the potential for an increased risk for 
serious hemolysis. The Sponsor’s medical monitor should be contacted before interrupting or 
discontinuing treatment with APL-2. 
If efficacious and safe, APL-2 is expected to continue to improve Hb levels and reduce transfusion 
dependency in these patients throughout the treatment period of 364 days. Individual patient data will 
continue to be reviewed on an ongoing basis to understand if there is a health benefit in these 
individuals during the treatment period. If the dose of APL-2 is increased to above 270 mg/day, the 
subject will be assessed by the investigator every 2 weeks (instead of every month) for the first 
6 weeks after the dose increase. APL-2 will only be continued if there is evidence of clinical benefit to 
the patient, as determined by the Investigator and the Sponsor. If a benefit is observed an extension 
study will be considered and will be submitted as a protocol amendment or as a follow-up study. 
6. STUDY OBJECTIVES AND ENDPOINTS 
6.1 
Study Objectives 
The objectives of the study are to assess safety, tolerability, preliminary efficacy and PK of multiple SC 
doses of APL-2 in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who have not received 
treatment with eculizumab (Soliris)® in the past. 


 
 
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An exploratory objective of the study is to assess the pharmacodynamics (PD) of multiple SC doses of 
APL-2 when administered to PNH patients. See “Study Endpoints” in Section 6.2. 
6.2 
Study Endpoints 
Primary Safety Endpoint: 
The primary safety endpoints of the study are the number and severity of treatment emergent adverse 
events (TEAEs) following administration of multiple doses of SC APL-2. 
Primary Efficacy Endpoints: 
• Change from baseline in LD 
• Change from baseline in Haptoglobin 
• Change from baseline in Hb 
Secondary endpoints: 
• APL-2 plasma concentrations (and PK parameters as appropriate) 
• Change from baseline in FACIT Fatigue Scale score 
• Change from baseline in reticulocyte count 
• Number of RBC transfusions per month 
Exploratory PD markers include: 
• Complement (e.g., CH50, AP50, and C3) levels 
• C3 deposition on RBC cells 
• Clonal distribution of PNH RBCs 
7. STUDY DESIGN 
This is a Phase Ib, open-label, multiple ascending dose, pilot study in patients with PNH who have not 
received eculizumab (Soliris)® in the past. The study is planned to enroll approximately 23 subjects 
across two cohorts. Cohort 1 will include 3 subjects. Cohort 2 will include up to 20 subjects. Subjects 
may participate in more than one cohort. Cohort 1 has completed.  
Safety will be assessed throughout the study; serial blood and urine samples will be collected for these 
assessments. Blood samples will be collected for the assessment of APL-2 PK. Additional samples for 
assessment of PD will also be collected.  
The study will consist of three parts; 
• Part 1: Up to 20 subjects in cohort 2 will receive APL-2 for 28 days.  
• Part 2A: Following review of available safety, PK and PD data by the investigator and sponsor, 
subjects showing evidence of perceived clinical benefit may progress to Part 2A of the study 
and continue to receive daily doses of APL 2 until Day 84.  


 
 
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• Part 2B: Following review of available safety, PK and PD data by the investigator and sponsor 
subjects showing evidence of perceived clinical benefit may progress to Part 2B of the study 
and continue to receive daily doses of APL 2 until Day 364.  
• Part 3: Safety follow up If applicable; subjects may also transition into an open-extension study 
to continue treatment with APL-2 after the completion of Part 2B, or may continue treatment 
with APL-2 in Part 2C if enrollment into the extension study is not yet available (see Appendix 1, 
Section 16). Subjects that transition to either the extension study or Part 2C must complete the 
Day 365 visit procedures for this study. For these subjects, the Day 365 visit will also be the first 
visit of the extension study or Part 2C.  
Screening will take place within 30 days prior to the start of dosing on Day 1.  
Subjects will be entered into Part 1 of the study on Day 1 at a time designated by the PI. During Part 1, 
the first 3 daily SC doses of APL-2 (Day 1 to 3) as well as doses on Day 8, 15 and 22 will be administered 
at the clinical site. From Day 4 to Day 28 daily doses of APL-2 will be administered off-site by a study 
nurse or self-administered by the subject, at the subject’s home, workplace, or other location 
convenient to the subject with the exception of those days where dosing is at the clinical site (see 
above). Following review of available safety, PK and PD data by the investigator and sponsor subjects 
demonstrating clinical benefit from the treatment may progress to Part 2A of the study and continue 
to receive daily doses of APL-2 until Day 84, and then may progress to Part 2B of the study and 
continue to receive daily doses of APL-2 until Day 364. Doses will be administered off-site by a study 
nurse or self-administered by the subject, at the subject’s home, workplace, or other location 
convenient to the subject with the exception of Days 29, 36, 43, 57, 71, 85, 113, 141, 169, 197, 225, 
253, 281, 309, and 337 where dosing is at the clinical site. If a subject has a sub-optimal clinical 
response during daily dosing with 270 mg APL-2, the dose may be increased up to 360 mg/day, and 
doses will be administered at the clinical site every 2 weeks for the first 6 weeks after commencing the 
higher dose. After the conclusion of the treatment period (Day 364), subjects will enter Part 3 of the 
study and return to the clinical site for follow-up study procedures on Day 365, 379, and 393 and final 
study procedures at an Exit Visit on Day 414. See Study Flowchart in Section 3. 
Subjects who complete Part 2B will be eligible to transition into an open-label extension study (Study 
APL2-307) in order to continue to receive treatment with APL-2. Subjects who elect to transition into 
Study APL2-307 will not complete Part 3 of this study.  
Cohort 2 will not be initiated until all subjects in Cohort 1 have reached the Day 29 visit and the SMC 
has reviewed emerging safety and efficacy data and determined that, at the initial dose, APL-2 has an 
acceptable safety and tolerability profile. 
The planned length of participation in the study for each subject is a maximum of 444 days (from Day –
30 through completion of the Day 414 Exit visit procedures). The study is planned to take place over 
approximately 24 months (from screening of Cohort 1 through completion of Cohort 2). Interim PK and 
PD analyses may be performed to reconsider the sampling time points as the study progresses.  
Some subjects who complete Part 2B and wish to transition into the open-label extension study may 
be required to dose beyond the planned conclusion of Part 2B (Day 364) in this study. This study 
utilizes an acetate buffered mannitol formulation of APL-2. The open-label extension study will utilize 
an alternate acetate buffered sorbitol formulation. Some subjects may complete Part 2B of this study 


 
 
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Multiple Ascending Dose / POC / PNH 
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Protocol Number:  APL2-CP-PNH-204
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before there is sufficient availability of the alternate acetate buffered sorbitol formulation to conduct 
Study APL2-307. Subjects who complete Part 2B prior to Study APL2-307 being open for enrollment to 
subjects in this study may continue dosing with the acetate buffered mannitol formulation under this 
protocol until the extension study is open to them for enrollment. Subjects that participate in Part 2C 
must complete the Day 365 visit procedures as outlined in the schedule of assessments, with the 
addition of APL-2 dosing and dispensation. The Day 365 visit that is the first visit of Part 3 will also be 
the first visit of Part 2C. These subjects will continue their APL-2 dose and regimen and will return to 
the site for visits at bi-monthly intervals until the extension study is open to them. Details regarding 
procedures for dosing beyond Part 2B are provided in Appendix 1 (Section 16). 
8. SUBJECT SELECTION 
The study is planned to enroll approximately 23 subjects, with 3 subjects in Cohort 1 and sufficient 
subjects in Cohort 2 for up to 20 subjects to complete at least 28 days of dosing. Additional cohorts 
may be enrolled if it is deemed appropriate by the PI (or designee) and the Sponsor in consultation 
with the SMC to repeat a dose level or to study an intermediate dose level. 
8.1 
Inclusion Criteria 
At Screening (unless otherwise specified), subjects must fulfill all of the following inclusion criteria to 
be eligible for participation in the study: 
1. Male or Female 
2. At least 18 years old (inclusive) 
3. Weigh >40 Kg and have a BMI ≤38.0 kg/m2 
4. Diagnosed with PNH (WBC clone >10%) 
5. Lactose dehydrogenase ≥2 times the upper limit of normal 
6. Ferritin ≥ lower limit of normal (LLN) as defined by the central laboratory and Total Iron Binding 
Capacity (TIBC) < upper limit of normal (ULN) based on central lab reference ranges. If a subject 
is receiving iron supplements at screening, the investigator must ensure that his/her dose has 
been stable for 8 weeks prior to enrolment and must be maintained throughout the study 
7. Last transfusion within 12 months prior to screening 
8. Platelet count of >30,000/mm3 
9. Absolute neutrophil count >500/µL 
10. Women of child-bearing potential (WOCBP) must have a negative pregnancy test at screening 
and must agree to use protocol defined methods of contraception for the duration of the study 
and 90 days after their last dose of study drug 
11. Males must agree to use protocol defined methods of contraception and agree to refrain from 
donating sperm for the duration of the study and 90 days after their last dose of study drug 
12.  Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae 
and Haemophilus influenzae Type B (Hib) either within 2 years prior to Day 1 dosing, or 14 days 
after starting treatment with APL-2. 


 
 
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13.  Willing and able to give informed consent 
8.1.1 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 Norplant or DepoProvera) or removable birth control device (like NuvaRing or 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 and 90 days after their last dose of study drug. 
8.2 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria at screening 
or check-in, as appropriate. 
1. Prior eculizumab (Soliris)® treatment  
2. Active bacterial infection 
3. Active infection with hepatitis B virus (HBV), hepatitis C virus (HCV) or human 
immunodeficiency virus (HIV) 
4. Hereditary complement deficiency 
5. History of bone marrow transplantation 
6. Concurrent SAA, defined as currently receiving immunosuppressive therapy for SAA including 
but not limited to cyclosporin A, tacrolimus, mycophenolate mofetil or anti-thymocyte globulin 
7. Participation in any other investigational drug trial or exposure to other investigational agent, 
device or procedure within 30 days 
8. Evidence of QTcF prolongation defined as >450 ms for males and >470 ms for females at 
screening 
9. Breast-feeding women 
10. History of meningococcal disease 
9. STUDY TREATMENTS 
9.1 
Allocation to Treatment 
Each subject will be assigned a unique identification number upon screening. Subjects who complete 
the study screening assessments and meet all the eligibility criteria will be scheduled to enter the study 
and dosed in the next available cohort. 
9.2 
Blinding 
None; this is an open-label study. 


 
 
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9.3 
Treatments Administered 
Sterile solutions of APL-2 up to 150 mg/mL in 5% dextrose or in acetate-buffered mannitol or in 
acetate-buffered sorbitol, administered SC. 
9.3.1 Drug supplies 
9.3.1.1 Identity of Investigational Products 
APL-2 will be supplied as a sterile solution of APL-2 in 5% dextrose or as a sterile solution of APL-2 in 
acetate-buffered mannitol or in acetate-buffered sorbitol, at concentrations of up to 150 mg/mL, 
supplied in stoppered glass vials.   
9.3.1.2 Study Supplies 
The Sponsor will supply sufficient quantities of APL-2 drug product to allow completion of this study. 
The lot numbers, manufacture dates, and expiration dates of the drugs supplied will be recorded in the 
final report. The Sponsor will also supply needles, syringes, and ambulatory syringe infusion pumps 
(e.g. Crono Super PID) as required. APL-2 in 5% dextrose solution should be stored at -20°C. APL-2 
acetate-buffered mannitol solution and APL-2 acetate-buffered sorbitol solution should be stored at 2-
8°C. 
A pharmacist or appropriately qualified designated person will be responsible for storing the APL-2 
appropriately; dispensing the vials of APL-2 to the subject, study nurse, or other study personnel, and 
for maintaining accountability records.  
9.3.1.3 Accountability 
Records will be made of the receipt and dispensing of APL-2 for administration both on and off-site.  
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. 
9.3.2 Planned Dose Levels and Dosing Schedule 
Starting on Day 1 (Visit 3), subjects will receive SC APL-2 daily for up to 364 days at the corresponding 
dose for their cohort. 
Planned doses will be as follows: 
Cohort 
Planned dosing schedule (Amendment 4) 
1 
180 mg/day from Day 1 to Day 28 
2 
270 mg/day (up to 360 mg/day) from Day 1 to Day 364* 
* The dose may be increased up to 360 mg/day if the clinical response is sub-optimal. The volume to be administered will depend on the 
final concentration provided and may be administered as either 1 or 2 bolus SC injections or as a SC infusion. 
The starting dose for Cohort 2 was determined based on safety, PK, and PD data from Cohort 1. 
Repeat of a cohort or the addition of another dose level (i.e. another cohort) will be agreed by the SMC 
based on evidence of clinical benefit and review of available safety data from prior and current 


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
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Effective: 25 October 2018
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cohort(s). Intra-subject dose escalations will be agreed by the Investigator and Sponsor and will be 
implemented on an individual subject basis and not necessarily applied across all subjects in a cohort. 
The dose selected for any cohort or individual subject will not exceed 360 mg/day (estimated to reach 
approximately 85 % of the Cmax of the NOAEL observed in monkeys) without a protocol amendment. 
The treatment period will consist of three parts as outlined in the diagram below. In Part 1, subjects 
will receive APL-2 for 28 days. LD levels will be measured weekly until Day 22 and may be measured 
daily between Day 23 and Day 28. On Day 28, subjects concluded to benefit from the treatment (as 
determined by the Investigator and sponsor after reviewing the available data) will automatically enter 
into Part 2A and continue treatment for an additional 56 days (Day 29 to 84). On Day 84, subjects 
concluded to continue to benefit from the treatment (as determined by the Investigator and sponsor 
after reviewing the available data) will automatically enter into Part 2B and will continue treatment up 
until Day 364. Following Part 2B, subjects will either transition into the open-label extension study 
APL2-307, or will complete the Part 3 safety follow up procedures. Subjects who complete Part 2B prior 
to Study APL2-307 being open for enrollment to subjects in this study may continue to receive 
treatment with APL-2 as detailed in Appendix 1 (Section 16). Subjects that transition to either the 
extension study or Part 2C must complete the Day 365 visit procedures for this study. For these 
subjects, the Day 365 visit will also be the first visit of the extension study or Part 2C. 
The first SMC meeting was scheduled once all subjects in Cohort 1 reached Day 28, and subsequent 
SMC meetings were held, and will continue to be held, at regular intervals throughout the study. 
Continuation of treatment – Decision scheme 
 
 
 
A 
Following Part 2B, subjects will either transition into the open-label extension study, APL2-307, or will complete the Part 3 safety follow up 
procedures. Subjects who complete Part 2B prior to Study APL2-307 being open for enrollment to subjects in this study may continue to receive 
treatment with APL-2 as detailed in Appendix 1 (Section 16). Subjects that transition to either the extension study or Part 2C must complete the Day 
365 visit procedures for this study. For these subjects, the Day 365 visit will also be the first visit of the extension study or Part 2C. 
9.3.3 Drug Administration 
If the dose volume is ≤3 mL, doses will be administered as 1 or 2 bolus SC injections. If the dose volume 
is >3 mL, doses will be administered as SC infusions.  
The preferred site of injection will be the abdomen; however, if a subject does not tolerate 
administration into the abdomen alternative sites may be selected e.g. thigh or upper arm. Research 
nurses or other appropriately qualified research personnel will administer bolus SC injections. Subjects 
may self-administer the SC infusions after receiving appropriate training by a research nurse or other 
A


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
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study personnel. The injections will be administered at the clinic on those days when a clinic visit 
occurs and at an off-site location convenient to the subject on all other days. 
Doses will be administered while subjects are seated. 
Dosing records will be maintained at the clinical site and available for review by the sponsor. 
Note: Discontinuation with APL-2 or noncompliance with the prescribed dose regimen may lead to the 
potential for an increased risk for serious hemolysis. Subjects should be instructed to take their APL-2 
treatment as prescribed, and to contact the investigator immediately for guidance in the event of any 
missed doses.  
9.3.4 Additional Dose Levels 
Repeat of any cohort or the addition of intermediate dose level may be added, as determined by the 
SMC, depending on the safety and efficacy results from the prior cohort(s). 
9.4 
Concomitant Medications 
9.4.1 Prophylactic antibiotics 
Prophylactic antibiotic therapy will be prescribed to all subjects to minimize potential infection risk. 
Prophylactic antibiotics will be initiated on day 1 after APL-2 dosing and continue until 2 weeks after 
the last dose. 
9.4.1.1 Primary prophylactic antibiotic Day 1-14 
• Ciprofloxacin 500 mg twice daily, initial administration on Day 1 will take place after the initial 
APL-2 dosing and after the post dose ECG has been taken  
9.4.1.2 Primary prophylactic antibiotic Day 15 – 2 weeks after last dose 
• Penicillin V 500 mg twice daily  
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients 
on beta-lactam antibiotic (e.g. penicillin, amoxicillin, etc.) therapy. These reactions are more likely to 
occur in individuals with a history of penicillin hypersensitivity. Before initiating therapy with penicillin 
V, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins or 
cephalosporins. If subjects have a known hypersensitivity to penicillin/amoxicillin they may be 
prescribed an alternative antibiotic at the outset. 
Other frequently reported adverse effects in patients taking penicillin are diarrhea/loose stools, 
nausea, skin rashes and urticaria, and vomiting. Patients should, therefore, be advised that these 
reactions may occur. 
9.4.1.3 Alternative prophylactic antibiotics 
• Erythromycin 500 mg twice daily 
• Azithromycin 500 mg 3 times per week 
Erythromycin 500 mg twice daily or azithromycin 500 mg 3 times per week may be considered as a 
suitable alternative in subjects who are unable to tolerate penicillin. 


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
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Treatment should be switched another alternative antibiotic if there is evidence of penicillin or 
erythromycin-related tolerability issue (such as nausea and diarrhea). The PI will discuss and agree to a 
suitable alternative with the sponsor’s medical monitor. The agreement will be noted in the subject’s 
medical records. 
9.4.2 Rescue antibiotics 
Body temperature and vital signs will be monitored daily and relevant blood parameters monitored 
regularly throughout the study to assess for signs of infection. The principal investigator should be 
contacted immediately in the event of a suspected infection despite prophylactic antibiotic treatment 
for guidance and appropriate action to be taken. Action to be taken may include administration of a 
broad spectrum antibiotic to cover possible resistant organisms such as resistant pneumococcus (e.g. 
levofloxacin). 
9.4.3 Vaccinations 
Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae and 
Haemophilus influenzae Type B (Hib) is required to participate in this study, either within 2 years prior 
to Day 1 dosing, or 14 days after starting treatment with APL-2. 
If required i.e. not previously vaccinated subjects will receive vaccinations against Neisseria 
meningitides types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae Type B 
(Hib).  If the subject’s first documented Neisseria meningitidis vaccine/s are administered at Day 15, a 
booster (for both vaccinations) should be administered at least 2 months later (Day 85). If 
Pneumococcal vaccination is required, a dose of PCV13 will be administered at Day 15 and a dose of 
PPSV23 will be administered at least 8 weeks later (Day 85). 
9.4.4 Prophylactic antivirals 
Prophylactic antiviral therapy will be prescribed to all HBsAg-positive subjects to minimize the potential 
risk of HBV activation. Prophylactic antivirals will be initiated at least two weeks prior to initiation of 
APL-2 dosing and continue until 2 weeks after the last dose. 
9.4.5 Iron Supplements 
For subjects receiving iron supplements at the time of APL-2 initiation, iron supplement doses must be 
maintained stable throughout the study unless iron levels (ferritin and TIBC) increase above ULN.  
10. STUDY PROCEDURES 
Please see the Study Flow Chart in Section 3 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 investigator 
and sponsor to ensure that the dosing of study medication can continue daily as required. 
If a subject’s dose is increased beyond 270 mg/day in Part 2B additional site visits will be scheduled for 
the first 6 weeks of dose increase, alternating with the monthly visits in the protocol. i.e. subjects will 


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
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return to the clinical site every two weeks for 6 weeks. These will be scheduled by the investigator and 
the same procedures as the monthly visits will be performed. These visits will be recorded as 
unscheduled visits. 
10.1 Screening 
Screening will begin within 30 days prior to dosing to confirm that subjects meet the subject selection 
criteria for the study. Informed consent will be obtained at screening (see Section 14.3.3). Subjects will 
have to meet all eligibility criteria before being enrolled into the study (see Section 8). 
The following will be recorded at screening: medical history and demographic data, including, sex, age, 
race, body weight (kg), height (cm). 
Screening procedures are listed in the Study Flow Chart in Section 3. 
10.2 Part 1 - Treatment Period – (Days 1 to 28) 
Subjects will receive daily SC doses of APL-2 on Days 1 to 28. APL-2 will be administered at the clinical 
site by study personnel or off-site at the subject’s home, workplace, or other location convenient to 
the subject by a trained study nurse or will be self-administered by the subject. 
10.2.1 On Site Administration (Day 1 to Day 3 and Days 8, 15 and 22) 
The first 3 daily SC doses of APL-2 (Day 1 to 3) as well as doses on 8, 15 and 22 will be administered at 
the clinical site. Subjects will remain in the clinic for at least 2.5 hours after receiving the first dose of 
APL-2 on Day 1. 
If required subjects will receive vaccinations on Day 15 with boosters scheduled appropriately. On day 
15, ciprofloxacin will be discontinued and penicillin V commenced. 
Blood samples for laboratory analysis, PK/PD, and antigenicity will be taken during site visits as 
outlined in the Study Flow Chart in Section 3. 
Specific procedures for each visit are listed in the Study Flow Chart.  
10.2.2 Outpatient Administration (Day 4 to Day 28) 
From Day 4 to Day 28 daily doses of APL-2 will be administered off-site by a trained nurse or self-
administered by the subject, at the subject’s home, workplace, or other location convenient to the 
subject with the exception of Days 8, 15 and 22 (see above). 
During the nurse’s visit, safety, tolerability and concomitant medication will be monitored. 
10.3 Part 2A - Treatment Period – (Days 29 to 84) 
Each subject will receive daily SC doses of APL-2 on Days 29 to 84. APL-2 will be administered at the 
clinical site by study personnel or off-site by the subject themselves or by a study nurse. If a perceived 
clinical benefit is not observed, treatment will stop on Day 28. The subject will skip Part 2A and enter 
Part 3 for safety follow up visits.  
10.3.1 On Site Administration (Days 29, 36, 43, 57 and 71) 
Daily SC doses of APL-2 on Days 29, 36, 43, 57 and 71 will be administered at the clinical site.  


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
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Blood samples for laboratory analysis, PK/PD and antigenicity will be taken during site visits as outlined 
in the Study Flow Chart in Section 3. 
Specific procedures for each visit are listed in the Study Flow Chart.  
10.3.2 Outpatient Administration (Day 30 to Day 84) 
From Day 30 to Day 84 daily doses of APL-2 will be administered off-site by a trained study nurse or 
self-administered by the subject, with the exception of Days 36, 43, 57 and 71 (see above). 
During the nurse’s visit, safety, tolerability and concomitant medication will be monitored.  
10.4 Part 2B - Treatment Period – (Days 85 to 364) 
Each subject will receive daily SC doses of APL-2 on Days 85 to 364. APL-2 will be administered at the 
site by study personnel or off-site by a study nurse or self-administered by the subject. If a clinical 
benefit is not observed, treatment will stop on Day 84. The subject will skip Part 2B and enter Part 3 for 
safety follow up visits.  
At the day 85 visit, if required, subjects will receive: 
• boosters for Neisseria meningitides types A, C, W, Y and B  
• PPSV23 vaccination 
On Site Administration (Days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337) 
Daily SC doses of APL-2 on Days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337 will be 
administered at the clinical site.  
Blood samples for laboratory analysis, PK/PD and antigenicity will be taken during site visits as outlined 
in the Study Flow Chart in Section 3. 
Specific procedures for each visit are listed in the Study Flow Chart.  
At the completion of Part 2B, subjects will be offered entry into an open-label extension study (Study 
APL2-307). Should the subjects not enter the open label extension study, they will exit the study and 
return to the site for Part 3 Follow-up, as outlined in Section 10.5. 
NOTE: Some subjects who complete Part 2B and wish to transition into the open-label extension study 
may be required to dose beyond the planned conclusion of Part 2B (Day 364) in this study. This study 
utilizes an acetate buffered mannitol formulation of APL-2. The open-label extension study will utilize 
an alternate acetate buffered sorbitol formulation. Some subjects may complete Part 2B of this study 
before there is sufficient availability of the alternate acetate buffered sorbitol formulation to conduct 
Study APL2-307. Subjects who complete Part 2B prior to Study APL2-307 being open for enrollment to 
subjects in this study may continue dosing with the acetate buffered mannitol formulation under this 
protocol until the extension study is open to them for enrollment. These subjects will continue their 
APL-2 dose and regimen and will return to the site for visits at bi-monthly intervals until the extension 
study is open to them. Details regarding procedures for dosing beyond Part 2B are provided in 
Appendix 1 (Section 16). Subjects that transition to either the extension study or Part 2C must 
complete the Day 365 visit procedures for this study. For these subjects, the Day 365 visit will also be 
the first visit of the extension study or Part 2C. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
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10.4.1 Outpatient Administration (Day 85 to Day 364) 
From Day 85 to Day 364 daily doses of APL-2 will be administered off-site by a trained study nurse or 
self-administered by the subject, with the exception of Days when the subject attends clinic visits (see 
above). 
During the nurse’s visit, safety, tolerability and concomitant medication will be monitored.  
10.5 Part 3 - Follow-up - (Days 365, 379, and 393, or Days 85, 99, and 113, or Days 29, 
43, and 57)  
All subjects who complete Part 2B, and are not transitioning to the open-label study (or Part 2C), of the 
study will be asked to return to the clinical facility in Part 3 for follow-up visits on Days 365, 379, and 
393. All subjects who complete Part 2A but do not enter Part 2B of the study will be asked to return to 
the clinical facility in Part 3 for follow-up visits on Days 85, 99 and 113. All subjects who are not eligible 
to enter Part 2A of the study will be asked to return to the clinical facility in Part 3 for follow-up visits 
on Days 29, 43 and 57. 
Subjects that transition to either the extension study or Part 2C must complete the Day 365 visit 
procedures for this study, but will not complete the remaining Part 3 visits. For these subjects, the Day 
365 visit will also be the first visit of the extension study or Part 2C. 
For subjects who skip Part 2A, the boosters for Neisseria meningitides vaccines (if needed) should be 
administered on Day 57 of Part 3. 
Specific procedures including blood collection for laboratory analysis, PK/PD and antigenicity for each 
visit are listed in the Study Flow Chart. 
10.5.1 Exit Visit (Day 414, or Day 134, or Day 78)  
All subjects will be asked to return to the clinical facility for the Exit Visit 7 weeks after the final dose of 
APL-2. 
Study participation for each subject will be concluded following completion of the Exit Visit. Subjects 
who complete Part 2B and Part 3 of the study will attend an Exit Visit on Day 414. Subjects who are not 
eligible to enter Part 2B but complete Part 2A of the study will attend an Exit Visit on Day 134. Subjects 
who are not eligible to enter Part 2A but complete Part 3 of the study will attend an Exit Visit on Day 
78. 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, including the collection of blood samples 
for PK and/or PD assessments, as well as a post-dose antigenicity sample if not yet collected. 
The Exit Visit procedures are listed in the Study Flow Chart in Section 3. 
10.5.2 Unscheduled Follow-up Visits 
Note: as part of the dose-escalation decision, the safety and PK sampling may be extended or modified 
with additional 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 or if PK/PD sampling schedule is modified or extended based on interim results. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
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Unscheduled follow-up visits may include any of the procedures listed in the Study Flow Chart in 
Section 3. 
10.5.3 Scheduled End of Study 
The end of the study is scheduled after completion of the Exit Visit evaluations in the 2 cohorts or after 
dose-limiting clinical safety endpoints have been reached to preclude further increases of dose. The 
clinical conduct of the study is intended to last approximately 24 months, including screening. 
This time period may change in the event that the study is terminated early, additional cohorts are 
enrolled, additional time is required to review safety between cohorts, extended safety and PK 
sampling is added for a cohort (e.g., extended beyond Day 414), or a decision is made to complete an 
unscheduled analysis between cohorts. 
10.6 Dose Escalation and Periodic Safety Review 
A decision to proceed to the next dose level (i.e. Cohort 2) will be made by a Safety Review Committee 
following the review of all pertinent data of Cohort 1. The review will comprise all cumulative safety, 
tolerability and efficacy data (e.g., physical examinations, ECGs, vital signs, clinical laboratory tests, and 
adverse events [AEs]) and a thorough assessment of all safety data will occur prior to initiation of 
Cohort 2. PK/PD data and predicted exposure for subsequent doses based on emerging PK data will 
also be reviewed prior to determining the proposed dose for Cohort 2. Dose escalation will not occur 
before all subjects in Cohort 1 have reached the Day 29 visit. 
The same review process will be followed if any additional cohorts are added to the study. 
10.6.1 Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will review cumulative safety/tolerability data (e.g., physical 
examinations, ECGs, vital signs, clinical laboratory tests, and adverse events [AEs]), efficacy (LD levels, 
haptoglobin levels, Hb levels, reticulocyte counts, and RBC transfusions) and PK data including 
predicted exposures for subsequent doses based on emerging PK data. The SMC will have the 
responsibility to conduct a thorough safety assessment at regular (monthly) intervals during the 
treatment phase of the study. A key responsibility of the SMC will be to decide whether to continue or 
modify the study and to allow dose escalation based on recommendations by the sponsor and upon an 
evaluation of emerging safety and efficacy data. The SMC will comprise at a minimum of the PIs, a 
sponsor representative, a PNH expert not involved in the study and an Infectious Disease Specialist. 
The SMC met approximately every 4 weeks commencing after all subjects in Cohort 1 had reached Day 
28. For the remainder of the study, regular or ad hoc SMC data reviews will be scheduled 
approximately every 8 weeks, or as recommended by the SMC or requested by the Sponsor. 
If efficacious and safe, APL-2 may reduce LD levels, improve Hb levels and reduce transfusion 
dependency in these patients. The SMC will be responsible for reviewing individual subject data to 
understand if there is a health benefit in these individuals at any time during the treatment period. If a 
benefit is observed the SMC may recommend extending the treatment beyond 364 days either 
through a protocol amendment or an extension study. 
The remit, roles, and responsibilities of the SMC will be specified in a separate SMC charter. 


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
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10.7 Removal of Subjects from the Study 
Subject participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol. 
2. 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. 
3. Subject's decision to withdraw. 
4. Subject failure to comply with protocol requirements or study-related procedures. 
5. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
The clinical report will include reason(s) for subject withdrawals as well as details relevant to the 
subject withdrawal. If a subject is withdrawn from the trial 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 PI or a monitoring physician and will be treated and/or followed up 
until the symptoms or values return to normal or acceptable levels, as judged by the PI. 
Subjects who are withdrawn may be replaced. Replacement of subjects will be discussed on a case by 
case basis. 
11. ASSESSMENTS 
11.1 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. 
11.1.1 Body Height and Weight 
Body height (cm) and body weight (kg) will be measured at screening as part of the physical 
examination.  
11.1.2 Physical Examination 
All 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. 
A licensed physician employed at the study site will examine each subject as outlined in the Study Flow 
Chart in Section 3. 
Medical history will be recorded at screening.  


 
 
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Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
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A symptom-driven physical examination may be performed at various unscheduled time points if 
deemed necessary by the PI. 
11.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate will be 
measured as outlined in the Study Flow Chart in Section 3. 
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 and ECG. 
On the days that APL-2 is administered by a study nurse or other study personnel, vital signs will be 
measured pre- and post-dose. Vital signs will be measured within 2 hours prior to dosing for the pre-
dose time point. Post-dose vital signs readings will be performed within approximately 30 minutes 
after dosing. 
11.1.4 Electrocardiogram Monitoring 
Single 12-lead ECGs will be done at the time points outlined in the Study Flow Chart in Section 3. 
If done on dosing days, ECGs will be performed within approximately 30 min after dosing. NB ECG on 
Day 1 must be taken before administration of the 1st dose of Ciprofloxacin. 
ECGs will be taken following resting in the supine position for 10 min in a quiet environment. 
ECGs will be interpreted and signed and dated by the PI. The ECGs will be classified as normal, having a 
not clinically significant (NCS) abnormality, or having a clinically significant (CS) abnormality. In 
addition, ECG parameters of ventricular rate, PQ or PR interval, QRS duration, and QT interval 
(corrected using both Bazett’s and Fridericia’s method and uncorrected) will be noted on the CRF. All 
CS findings will be recorded as AEs. 
11.1.5 Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 
Scale 
The FACIT Fatigue Scale is a 13 item Likert scaled instrument which is self-administered by the subjects 
during clinic visits on as outlined in the Study Flow Chart in Section 3. The subject is presented with 13 
statements and is asked to indicate their response as it applies to the past 7 days. The 5 possible 
responses are ‘Not at all’ (0), ‘A little bit (1), ‘Somewhat’ (2), ‘Quite a bit’ (3) and ‘Very much’ (4). With 
13 statements the total score has a range of 0 to 52. Before calculating the total score, some responses 
are reversed to ensure that the higher score corresponds to a higher quality of life. The FACIT Fatigue 
Scale and scoring guidelines are provided in the Manual of Procedures (MOP). 
11.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Flow Chart in Section 3. In addition, 
laboratory safety tests may be performed at various unscheduled time points, if deemed necessary by 


 
 
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Multiple Ascending Dose / POC / PNH 
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Protocol Number:  APL2-CP-PNH-204
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the PI or recommended by the SMC. The clinical laboratory tests include (but are not limited) the 
following: 
11.1.6.1 Hematology 
• Hb 
• Hematocrit 
• RBC count 
• Platelet count  
• WBC count with differential 
• Reticulocytes 
11.1.6.2 Coagulation 
• Prothrombin time (PT) 
• Fibrinogen 
• Activated partial thromboplastin time (aPTT) 
• D-Dimer 
NOTE: The use of silica reagents in coagulation panels should be avoided in subjects treated with 
APL-2. 
11.1.6.3 Serum Chemistry 
• Blood urea nitrogen (BUN) 
• Creatinine 
• Bilirubin (total and direct) 
• Albumin 
• Alkaline phosphatase (ALP) 
• Lactate dehydrogenase (LD) 
• Haptoglobin 
• Gamma-glutamyl transpeptidase (GGT) 
• Creatine kinase (CK) 
• Aspartate aminotransferase (AST) 
• ALT 
• Uric acid 
• Glucose  
• Sodium 
• Potassium 
• Chloride 
• Ferritin 
• B12/folate 
• Total Iron Binding Capacity (TIBC) 
11.1.6.4 Urinalysis 
• pH 
• Specific gravity 
• Protein 
• Glucose 
• Ketones 
• Bilirubin 
• Blood 
• Nitrite 
• Urobilinogen 
• Leukocyte esterase 
If an abnormality is noted for protein, blood, nitrite and/or leukocyte esterase, a 
microscopic examination will be performed. 
11.1.6.5 Serology 
• HIV 
• HBsAg 
• HBV DNA (if required) 
• HCV 


 
 
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11.1.6.6 Human Chorionic Gonadotropin (Serum Pregnancy Test) and Follicle-Stimulating 
Hormone 
Serum Pregnancy Test will be performed for females only. FSH will be performed for postmenopausal 
females at screening only. 
11.1.7 Injection Site Assessment 
On the days that APL-2 is administered by a study nurse or other study personnel, an assessment of the 
APL-2 injection site will be performed within 30 min after study drug administration. The assessment 
will be performed by a physician or other licensed health care provider (i.e. study nurse) as delegated 
by the PI. The injection site and the surrounding area will be inspected for redness, swelling, 
induration, and bruising; and the subject will be asked about the presence of pain and/or tenderness. 
The date, time, and outcome of the injection site assessment will be recorded on the source 
documents and CRFs. 
Subjects will be trained to notify the PI or other study personnel in the event that an injection site 
reaction occurs after self-administration of APL-2.  
11.2 Pharmacokinetic Assessments 
11.2.1 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 Study Flow Chart in Section 3. 
On Day 1 only, a PK sample will be taken pre-dose and at a minimum of 2.5 hours post-dose (or later 
depending on how long the subject is kept at the clinic). All PK samples on other study days will be 
collected pre-dose. 
Preliminary PK analysis may be performed to reconsider sampling time points as the study progresses. 
Instructions for collection, handling, processing, storage, and shipping of samples will be provided in a 
separate sample handling manual prior to study initiation. 
11.2.2 Analytical Method 
Serum sample analysis will be performed using GLP-compliant validated procedures and methods. The 
methods used and the results obtained will be included in the final report as an appendix. 
 
11.3 Pharmacodynamic Assessments 
Blood samples will be collected via direct venipuncture at the time points delineated in the Study Flow 
Chart in Section 3. for PD assessment of complement activation through the classical (e.g., CH50) and 
alternative (e.g., AP50) pathways, PNH clone distribution, and C3 deposition on RBCs. Blood samples 
will also be collected to measure C3 levels. Other relevant PD markers may also be assessed. 
Preliminary PD analysis may be performed to reconsider sampling time points as the study progresses 
or to guide the dose escalation decision. 


 
 
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Instructions for collection, handling, processing, storage, and shipping of samples will be provided in a 
separate Laboratory Reference Manual prior to study initiation. 
11.4 Blood Volume for Study Assessments 
Table 2: Blood Volume during Study (up to Day 85) 
Assay 
Number of Time 
Points 
Approximate 
Volume per 
Time Point * 
(mL) 
Approximate 
Sample Volume 
Over Course of 
Study (mL) 
Pharmacokinetics 
23 
2 
46 
Anti-APL-2 Ab assay 
11 
2 
22 
Hematology 
24 
3 
72 
Chemistry (Incl. screen serology and 
pregnancy) 
30 
3 
90 
Coagulation profile 
24 
4.5 
108 
Complement profile (C3, CH50 and AP50) 
24 
4 
96 
Flow cytometry for PNH and C3 deposition 
24 
2 
48 
Plasma Hb 
24 
4 
96 
Total Approximate Blood Volume for Study: 
578** 
* Represents the largest collection volume planned over the duration of the study (smaller tubes will be used whenever 
possible). 
** If dose is increased during Part 2B, additional blood draws will be scheduled requiring an additional blood volume of 45 
mL. 
11.5 Pregnancy tests 
For WOCBP, a serum pregnancy test will be performed at screening, and subjects with a positive test 
will be excluded from the study. A follow up urine pregnancy test will be performed on Day 1 pre-dose 
(a negative urine pregnancy test must be received before dosing with study drug). 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 final Exit Visit. Male subjects will be counseled to avoid donating sperm after dosing 
on Day 1 until the final Exit Visit and 90 days after their last dose of study drug. 
12. ADVERSE EVENTS 
12.1 Definitions 
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.  


 
 
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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 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. 
Any AEs that occur prior to dosing on Day 1 will be categorized as pre-treatment events. Treatment-
emergent adverse events (TEAEs) will be defined as those AEs that occur after dosing on Day 1 and up 
to 30 days after the last dose of study medication.  
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.  
12.2 Recording Adverse Events 
Subjects will be monitored for adverse events throughout the study. Adverse events may be 
volunteered spontaneously by the study subject, or discovered by the study staff during physical 
examinations, or by asking open, non-leading questions (e.g. “How have you been feeling since the last 
clinic visit?”). Subjects will be instructed to inform the investigator and/or study staff of any AEs that 
may occur at any time during the study. 
All AEs occurring from screening through the final Exit visit will be recorded in detail in the source 
documents and documented on the appropriate AE or SAE eCRF. The nature of the AE, date (and time, 
if known) of AE onset, duration, severity, and action taken will be documented, together with the PI’s 
assessment of the seriousness of the AE and relationship to study drug. All AEs should be recorded in 
the study subject’s own words (verbatim), unless in the opinion of the PI, the AE constitutes a 
recognized condition, disease, or syndrome. In that case, the condition, disease or syndrome should be 
named rather than the individual symptoms. The AEs will be coded using the current Medical 
Dictionary for Regulatory Activities (MedDRA).  
Outcome will be recorded as:  
• Ongoing  
• Resolved 
• Resolved with sequela  
• Death or  
• Unknown 
12.3 Assessment of Adverse Events 
Each AE will be assessed by the PI or physician designee with regard to the categories discussed in the 
sections below. 
12.3.1 Intensity 
The PI will determine the severity of each AE. AEs will be graded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The following definitions for rating 
severity will be used: 


 
 
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Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of Daily Living 
(ADL)*. 
Grade 3 
Severe or 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). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
A semi-colon indicates ‘or’ within the description of the grade. 
*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. 
When changes in intensity of an AE occur more frequently than once a day, the maximum intensity for 
the event should be noted for that day. Any change in severity of signs and/or symptoms over a 
number of days will be captured and recorded as a new AE, with the amended severity grade, and the 
date and time (if known) of the change. 
12.3.2 Causality 
The relationship of an AE to the study drug will be assessed using the following criteria: 
Unrelated 
• 
Does not follow a reasonable temporal sequence from the 
administration of study drug  
• 
The event or laboratory test abnormality is clearly due to extraneous 
causes (disease, other drugs, environment, etc.) 
Unlikely 
• 
Does not follow a known pattern of response to study drug 
• 
Does not follow a reasonable temporal sequence from the 
administration of study drug 
• 
Disease or other drugs provides plausible explanation 
• 
It does not reappear or worsen when study drug is re-administered 
Possibly 
• 
Follows a known pattern of response to study drug 
• 
Time sequence from administration of the study drug is reasonable 
• 
Could also be explained by disease or other drugs 
Probably 
• 
Follows a known pattern of response to study drug 
• 
Time sequence from administration of the study drug is reasonable  
• 
Response to withdrawal clinically reasonable 
• 
Cannot be reasonably explained by the known characteristics of the 
participants clinical state, environmental factors, or other therapies 


 
 
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administered to the subject 
12.3.3 Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
• Results in death; 
• Is life-threatening: this means that the subject was at risk of death at the time of the event; it 
does not mean that the event might have caused death had it occurred in a more severe form; 
• Required hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
• Is a congenital anomaly or 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. 
Medical and scientific judgment should be exercised in deciding if an AE is serious and if expedited 
reporting is appropriate. 
12.4 Reporting Serious Adverse Event 
The reporting period for adverse events begins as soon as the subject’s written consent to participate 
in the study has been obtained, and continues through the final Exit visit. The PI is responsible for 
reporting all SAEs to the Safety Monitor, whether or not the event is considered related to the study 
drug.  
If an SAE occurs, the PI should complete and sign the SAE Report Form, and fax or email it to the Safety 
Monitor at the number/address which will be provided separately to the investigator sites, within 24 
hours of becoming aware of the event:  
The initial SAE Report should include, at a minimum, the following information: 
• Study number 
• Subject number/ID 
• Gender 
• Date of birth 
• Name of PI and full clinical site address 
• Details of SAE 
• Criterion for classification as “serious” 
• Study drug name and treatment start date 
• Date of SAE onset 
• Causality assessment (if sufficient information is available to make this determination) 


 
 
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The Safety Monitor will request clarification of omitted or discrepant information from the initial 
report. The PI or designee is responsible for faxing the requested information to the Safety Monitor 
within 24 hours of the request.  
Initial reports of SAEs must be followed later with detailed descriptions, including clear copies of 
supporting documents as necessary (e.g. hospital discharge summary, laboratory reports, autopsy 
reports, etc.), with the subject’s personal identifiers removed. If a new SAE Report Form is faxed, the PI 
must sign and date the form.  
The PI must report all SAEs to the IRB/IEC according to the institutional IRB/IEC policy.  
12.5 Adverse Events of Special Interest 
An adverse event of special interest is one of scientific and medical concern specific to the Sponsor’s 
product or program where ongoing monitoring and rapid communication by the PI to the Sponsor may 
be appropriate. These adverse events may be serious or non-serious. Applicable adverse events may 
require further investigation in order to characterize and understand, and depending upon the nature 
of the event, rapid communication by the trial Sponsor to other parties may also be required. These 
adverse events of special interest must be reported promptly to the sponsor. The adverse events of 
special interest include the following: 
• Local or systemic infection of any origin 
• Thrombosis 
• Clinically significant decrease in kidney function 
• Injection site reactions 
If an adverse event of special interest occurs in a study subject, the study subject will be followed for 
resolution of the adverse event. A decision will be made by the Sponsor concerning further exposure to 
the study treatment and further participation in the study. 
12.6 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.  
12.7 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 emergency room. When 
appropriate, medical tests and/or examinations will be performed to document resolution of the 
event(s).  


 
 
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Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
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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. 
12.8 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 7.1.1) 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 (Section 11.4).  
13. STATISTICS  
13.1 Sample Size Justification 
As this is a pilot study the sample size is not based on formal statistical testing. The sample size is 
considered sufficient to obtain useful safety, tolerability, PD and PK data to assist the planning of 
future studies.  
13.2 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 therein. 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 analysis plan or from what is outlined in the protocol 
will be discussed in the final study report. 
 
13.2.1  Analysis Populations 
13.2.1.1 Screened Population 
The Screened Population will include all subjects who signed the informed consent form and are 
screened for participation in this study. This set will be used only for the purpose of describing subject 
disposition.  


 
 
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13.2.1.2 Safety Population/ Intent to Treat (ITT) Population 
The Safety Population will include all subjects eligible to receive study medication and who receive at 
least one dose of study medication. The Intent to Treat Population will be identical to the Safety 
Population for this study. All baseline characteristics, demographic and efficacy endpoint data will be 
presented using the ITT Population.  
13.2.1.3 Pharmacokinetic (PK) Population 
The PK Population will include all subjects in the Safety Population who have at least one quantifiable 
concentration of APL-2. 
13.2.1.4 Pharmacodynamic (PD) Population 
The PD Population will include all subjects in the Safety Population who have at least one quantifiable 
post dose PD parameter. 
13.2.1.5 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 making decisions on how to deal with problems in any data (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. 
13.2.2 Study Endpoints 
13.2.2.1 Safety Endpoints  
The primary safety endpoints of the study are the number and severity of TEAEs, however safety will 
also be assessed through vital signs, 12-lead ECG and laboratory safety data. Changes from baseline 
will be calculated using the last measurement prior to the start of dosing as baseline. 
13.2.2.2 Efficacy Endpoints 
Changes from baseline and percentage changes from baseline in LD, haptoglobin and Hb are the 
primary efficacy endpoints. They will be calculated for each post dose assessment, where the baseline 
will be taken as the pre-dose assessment on Day 1. 
13.2.2.3 Secondary Endpoints 
The FACIT Fatigue Scale (Version 4) is a secondary endpoint. The changes from baseline will be 
calculated for each post dose assessment, where the baseline will be taken as the pre-dose assessment 
on Day 1. 
The changes from baseline in reticulocyte count and the number of RBC transfusions per month are 
also included as secondary endpoints. 


 
 
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Amendment 8.0
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13.2.2.4 Pharmacokinetic Endpoints  
Plasma concentrations of APL-2 will be determined from multiple samples taken between Day 1 and 
the Exit Visit.  
13.2.2.5 Exploratory Pharmacodynamic Endpoints (Markers) 
Changes from baseline and percentage changes from baseline will be calculated for each of the 
complement parameters (e.g. CH50, AP50 and C3), C3 deposition on RBC cells and clonal distribution of 
PNH RBCs. Baseline will be taken as the pre-dose measurement on Day 1. 
13.2.3 Safety Analyses  
All safety endpoints will be evaluated using the Safety Population. 
13.2.3.1 Adverse Events 
Treatment emergent adverse events (TEAE) 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 Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify all AEs.  
A by-subject TEAE data listing, including verbatim term, preferred term, treatment, severity, and 
investigator judgment of relationship to treatment, will be provided. The number of subjects reporting 
each preferred term within each system organ class will be tabulated by cohort. Tabulations will be 
produced for all TEAEs and for those considered potentially treatment related (causality to study drug 
is reported as possibly or probably, or where causality is not reported). The number of TEAEs will also 
be presented; both the total number of TEAEs and the total number counting only unique terms within 
each subject.  
13.2.3.2 Clinical Laboratory Tests 
A by-subject listing will be provided including changes from baseline. Laboratory values that are 
outside the laboratory reference range will be flagged. 
13.2.3.3 Vital Signs and ECGs 
Observed and change from baseline values for vital sign and ECG parameter will be listed.  
Values of potential clinical significance (e.g. change in QTcF ≥30ms from baseline) will be flagged and 
summarized by study visit. 
13.2.4 Efficacy and Secondary Endpoint Analyses 
The efficacy endpoints will be evaluated for the ITT Population.  
Individual’s data will be listed along with changes from baseline and percentage changes from baseline 
(where appropriate) for each visit. Data will be plotted by study day with each cohort being 
identifiable. 
Absolute values and changes from baseline will be summarized over time. 


 
 
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13.2.5 Pharmacokinetic Analyses  
The PK concentrations will be evaluated using the PK Population. 
Individual concentration over time profile plots will be presented, with each cohort being identifiable. 
Median concentration over time profiles will also be plotted. Both linear-linear and linear-log plots will 
be presented. Concentrations will be summarized over time. 
Where appropriate, steady-state PK parameters for APL‐2 will be estimated from the individual serum 
concentrations-time data, using actual sample times using a non-compartmental approach. PK 
parameters will include:  
AUC0-t  
The area under the serum concentration versus time curve, from time 0 to 
 
 
the last measurable concentration (t). 
Cmax   
Maximum observed serum concentration. 
These parameters will be summarized. 
PK data will be combined with the prior data collected in earlier clinical studies and then used to 
update the APL-2 population PK model (Apellis Data on File). 
13.2.6 Pharmacodynamic Analyses  
The PD parameters will be evaluated using the PD Population. 
Individual parameter over time profile plots will be presented, with each cohort being identifiable. 
Both changes from baseline and percentage changes from baseline will be presented.  
Absolute values and changes from baseline will be summarized over time. 
13.2.7 Handling of Dropouts and/or Missing Data 
No imputation of missing data for early terminations will be performed.  
Where appropriate screen values may be used as baseline in the event of missing Day 1 
measurements. 
Missing dates/times will be reviewed on a case by case basis for potential imputations, but the original 
data will always be presented in data listings.  
PK concentration values below the limit of quantification will take the value of 0 in individual linear-
linear profile plots and the limit of quantification in linear-log profile plots. 
13.2.8 Other Data Analyses 
Demographic data, baseline characteristics, physical examination, concomitant medication and 
medical history data will be listed for each cohort. Current World Health Organization (WHO) and 
MedDRA coding dictionaries will be used for the concomitant medications and medical histories 
respectively. 


 
 
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Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
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13.3 Interim Analyses 
As mentioned in Section 9.5, a safety review committee will be formed to review safety/tolerability, PK 
and PD data between cohorts. Preliminary PK analysis may also be performed to reconsider sampling 
time points as the study progresses. 
When all subjects have completed (or discontinued) Part 2A or Part 3 if they didn’t enter Part 2A, the 
data collected up to and including these study visits will be reported. Further reports may be prepared 
with each report containing cumulative information. These reports will be performed on data that will 
have been fully checked and considered as final. Any changes to the data previously reported will be 
fully auditable and discussed in subsequent reports. 
14. ADMINISTRATIVE CONSIDERATIONS 
14.1 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 trial-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.  
14.2 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) 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.  
14.2.1 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 


 
 
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each visit together with a summary of the status and progress of the study. Proposed actions will be 
documented in writing to the PI. 
14.3 Ethics 
14.3.1 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, applicable regulations, the ethical 
princliples set forth in the Declaration of Helsinki, and the ICH Harmonized Tripartite Guidance for 
Good Clinical Practice, E6, R1 (ICH GCP). 
14.3.2 Institutional Review Board/Ethic Committee 
The study protocol, any amendments 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 
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 local regulations as deemed appropriate. 
14.3.3 Subject Information and Consent 
The PI is responsible for obtaining an informed consent. A written informed consent, in compliance 
with ICH Guidance E6, must be obtained from each subject prior to screening and enrollment or 
performing any study related procedures. 
The purpose of the study, the procedures to be carried out and the potential hazards will be described 
to the subjects in non-technical terms. The subject will be given sufficient time to consider the study’s 
implications before deciding to participate in the study. The subject and/or legal guardian will be 
required to sign and date an Informed Consent Form (ICF) and will be assured that they may withdraw 
from the study at any time without jeopardizing their medical care. The PI shall retain the original, 
signed informed consent for study participation in the subject’s medical record and shall provide the 
subject and/or legal guardian with a copy of the signed consent. 
If there are any changes/amendments 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. 
14.3.4 Confidentiality  
Confidentiality of subject’s information must be maintained in accordance with local privacy laws. 
14.3.5 ClinicalTrials.gov  
This study has been listed with ClinicalTrials.gov, as required. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 66 of 71 
14.3.6 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. 
14.4 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. 
14.5 Protocol Amendments 
Any amendments 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 
amendment, 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 amendments will be made jointly between the Sponsor and the PI and must be 
confirmed in writing. Amendment(s) will be approved and signed off in the same way as the protocol.  
14.6 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). 
14.7 Finance and Insurance 
Finance and insurance will be addressed in a Clinical Trial Agreement between the PI/Institution and 
the Sponsor. 
14.8 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.  


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 67 of 71 
After the completion of the study, the data may be reported at a scientific meeting and/or submitted 
for publication in a scientific journal with the prior written consent of the Sponsor. The Sponsor must 
be given at a minimum 30 days to review the materials to be presented at a scientific meeting and/or 
for publication in a scientific journal.  
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 68 of 71 
15. REFERENCES 
1. DeZern AE, Dorr D, and Brodsky, RA. Predictors of Hemoglobin Response to Eculizumab Therapy 
in Paroxysmal Nocturnal Hemoglobinuria, Eur J Haematol., 2013, 90(1), p.16-24 
2. Apellis Pharmaceuticals, Inc. Product: APL-2 Injection. Investigator’s Brochure. Final Version 1.0. 
12 June 2014. 
3. FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers. July 2005. Available online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
ucm078932.pdf   
4. FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. September 2007. Available online: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/Guidances/Vaccines/ucm091977.pdf 
5. FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE Studies-Small Entity Compliance Guide. December 2012. Available online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM332846.pdf 
6. Ivens, I. A., Baumann, A., McDonald, T. A., Humphries, T. J., Michaels, L. A., and Mathew, P. 
(2013). PEGylated therapeutic proteins for haemophilia treatment:  a review for haemophilia 
caregivers. Haemophilia 19:  11-20 
7. Rudmann, D.G., Alston, J.T., Hanson, J.C., and Heidel, S. (2013). High molecular weight 
polyethylene glycol cellular distribution and PEG-associated cytoplasmic vacuolation is 
molecular weight dependent and does not require conjugation to proteins. Toxicol Pathol 41:  
970-983. 
8. Walpole, S.C., Prieto-Merino, D., Edwards, P., Cleland, J., Stevens, G., and Roberts, I. (2012). The 
weight of nations: an estimation of adult human biomass. BMC Public Health 12 (1): 439. 
9. GBD 2013 Mortality and Causes of Death Collaborators (2015). Global, regional, and national 
age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a 
systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963): 117–
171. 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 69 of 71 
16.  APPENDIX 1: PART 2C: MAINTANENCE DOSING PERIOD (IF NECESSARY TO 
MAINTAIN TREATMENT WITH APL-2 PRIOR TO TRANSITION TO EXTENSION 
STUDY) 
16.1 Overview and Rationale 
Subjects who complete Part 2B and have demonstrated clinical benefit from treatment with APL-2 
are eligible to transition into a separate open-label extension study in order to continue treatment 
(Study APL2-307). While Study APL2-CP-PNH-204 utilizes an acetate buffered mannitol formulation 
of APL-2, the open-label extension study will utilize an alternate acetate buffered sorbitol 
formulation. Some subjects may complete Part 2B of this study before there is sufficient 
availability of the alternate acetate buffered sorbitol formulation to allow subjects from this study 
to transition into Study APL2-307. 
As an interim measure, an amendment to the current protocol is required to ensure that subjects 
are able to continue treatment with APL-2 with the current formulation under Study APL2-CP-
PNH-204. 
Subjects who complete Part 2B prior to Study APL2-307 being open for enrollment to subjects in 
this study may continue their APL-2 dose and regimen as Part 2C of the study, until the option 
becomes available for entry into Study APL2-307. Subjects that participate in Part 2C must 
complete the Day 365 visit procedures as outlined in the schedule of assessments, with the 
addition of APL-2 dosing and dispensation. The Day 365 visit that is the first visit of Part 3 will also 
be the first visit of Part 2C. Beginning at Day 365, these subjects will return to the site for visits at 
8-week intervals until the extension study is available. The duration of participation beyond Part 
2B will be a different for each subject, depending on the date each subject completes Part 2B. 
Study objectives will be assessed through Part 2B. Data obtained from subjects who participate in 
Part 2C will not be included in endpoint assessment and will be only listed. 
Once enrollment into the extension study is available for subjects in Study APL2-CP-PNH-204, 
the conclusion of Part 2B will be the end of the treatment period for this study. 
16.2 Part 2C Study Procedures 
Subjects will return for the Day 365 study visit and will continue their previous APL-2 dose and 
regimen. Additional Study Visits will be scheduled at 8-week intervals. Study assessments will be 
conducted as outlined in the Part 2C Study Flow Chart (Section 16.3). 
Each subject will continue to receive daily SC doses of APL-2 from Day 365 until extension study 
transition or treatment discontinuation. Subjects who discontinue dosing at any time during Part 
2C prior to enrollment into the open-label extension Study APL2-307 should conduct the Part 3 
safety follow up visits as outlined in Section 10.5. 
When enrollment into Study APL2-307 is available to subjects participating in Part 2C, subjects 
should conduct exit visit procedures as outlined in the Part 2C Study Flow Chart (Section 16.3). The 
exit visit for Part 2C will be the same day as the subject’s first visit for APL2-307. 
APL-2 will continue to be self-administered by the subject at the site on those days when a clinic 
visit occurs and at an off-site location convenient to the subject on all other days.  


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 70 of 71 
Blood samples for laboratory analysis, PK/PD and antigenicity will be taken during site visits as 
outlined in the Part 2C Study Flow Chart (Section 16.3). 
Specific procedures for each visit are listed in the Part 2C Study Flow Chart (Section 16.3).  
 
16.3 Part 2C Study Flow Chart (Day 365+ as needed) 
 
Study Period 
Part 2C - Treatment  
(Daily from Day 365 to opening of enrollment to APL2-307)A 
Study Week 
53 to 60 
61+  
Exit Visit C 
Study Day 
365 B 
366 to 420 
421+A 
56 Day 
IntervalA 
 
Visit Window (+/- Days) 
 
 
7 
 
 
Informed Consent 
X 
 
 
 
 
Preventive antibiotic D 
X 
X 
X 
X 
 
Physical examination E 
X 
X 
 
12-lead electrocardiogram F 
X 
X 
 
APL-2 administration G 
S 
H 
S 
H 
 
Injection site assessment I 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
Vital sign measurements J 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
 
Blood K 
X 
X 
 
Pharmacokinetics K 
X 
X 
 
 
Anti-APL-2 Ab assay 
X 
X 
 
Hematology and chemistry 
X 
X 
 
Coagulation profile L 
X 
X 
 
Complement profile (C3, 
CH50 and AP50) 
X 
 
X 
 
 
Flow cytometry for PNH/C3 
deposition 
X 
 
X 
 
 
Plasma Hb 
X 
X 
 
Urine pregnancy test M 
X 
X 
 
FACIT fatigue Scale 
X 
X 
 
Adverse events  N 
X 
X 
X 
X 
X 
Thrombosis record (MAVE)  
X 
X 
X 
X 
 
See study flow chart footnotes on next page 
 
 


 
 
APL-2  -  Paddock Study 
Multiple Ascending Dose / POC / PNH 
Apellis Pharmaceuticals, Inc.  
Protocol Number:  APL2-CP-PNH-204
Amendment 8.0
Effective: 25 October 2018
PROT APL2-CP-PNH-204 -  CONFIDENTIAL 
Page 71 of 71 
FOOTNOTES: 
A. Beginning at Day 365, subjects who need to continue dosing with APL-2 will schedule additional 
study visits at 8-week intervals until subjects in this study are eligible to enroll into the open-
label extension Study APL2-307. Subjects who discontinue dosing at any time during Part 2C 
prior to enrollment into the open-label extension Study APL2-307 should conduct the Part 3 
safety follow up visits. 
B. The Day 365 visit that is the first visit of Part 3 will also be the first visit for Part 2C. Procedures 
will not be duplicated. 
C. When enrollment into APL2-307 is available to subjects participating in Part 2C, subjects should 
return to the site to conduct exit visit procedures. The Part 2C exit visit will be the same day as 
the first visit for Study APL2-307. 
D. Penicillin V 500 mg twice daily. 
E. Full physical examination will be performed at the scheduled time points indicated. A symptom-
driven physical examination may be performed at other times, at the PI’s discretion. 
F. If done on a dosing day, electrocardiograms (ECGs) are to be performed within 30 minutes after 
dosing.  
G. S = Administration at clinical site. H = Administration at subject’s home, workplace, or other 
location convenient to the subject. Treatment may be stopped at any time if the investigator and 
sponsor conclude that there is no demonstration of continued clinical benefit. 
H. Reserved – See note E. 
I. Injection site assessment will be performed within 30 minutes after APL-2 administration. 
Ambulatory syringe infusion pump training will include instructions to report any injection site 
reaction to the PI. 
J. If APL-2 is administered by a study nurse or other research study staff, vital signs will be 
measured within 2 hours prior to dosing and within 30 minutes after dosing. If APL-2 is self-
administered, pre- and post-dose vital signs will not be measured. 
K. Blood samples will be taken pre-dose 
L. The use of silica reagents in coagulation panels should be avoided in subjects treated with APL-2. 
M. If done on a dosing day, urine pregnancy test should be completed for WOCBP prior to dosing.  
N. Ambulatory syringe infusion pump training will include instructions to report any adverse 
events to the PI. 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
_______________________________________________________ 
SAP Version Final v4.0  
 
Page 1 of 48 
Sponsor Name: 
Apellis Pharmaceuticals, Inc. 
Protocol Number:  
 
APL2-CP-PNH-204 
Protocol Title:  
 
A Phase Ib, Open Label, Multiple Ascending Dose, Pilot Study 
to Assess the Safety, Preliminary Efficacy and 
Pharmacokinetics of Subcutaneously 
Administered APL-2 in Subjects with Paroxysmal Nocturnal 
Hemoglobinuria (PNH). – PADDOCK – 
 
Protocol Version and 
Date: 
1.0 (16th September 2015) 
Protocol Amendment 
numbers and dates: 
Amendment 1 (12th June 2016) 
Amendment 2 (11th October 2016) 
 
Amendment 3 (17th November 2016) 
Amendment 4 (18th January 2017) 
Amendment 5 (18th April 2017) 
    - Country Specific (New Zealand) Amendment 1 (8th August 2017) 
Amendment 6 (12th December 2017)
Amendment 7 (15th March 2018) 
Amendment 8 (25th October 2018) 
 
Author(s): 
 
 
SAP Version: 
Final v4.0 
SAP Version Date: 
19th December 2019 
Notice of Confidential and Proprietary Information: 
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. 
PPD


PPD
PPD
PPD
PPD


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS .............................................................................. 6 
2. 
INTRODUCTION ..................................................................................................... 8 
2.1. 
Responsibilities ........................................................................................................................ 8 
3. 
STUDY OVERVIEW ................................................................................................. 8 
3.1. 
Study Objectives ...................................................................................................................... 8 
3.2. 
Study Design ............................................................................................................................ 8 
3.3. 
Determination of Sample Size ................................................................................................. 10 
3.4. 
Treatment Assignment and Blinding ....................................................................................... 10 
3.5. 
Administration of Study Medication ....................................................................................... 10 
3.6. 
Study Flowchart ..................................................................................................................... 12 
4. 
ENDPOINTS ......................................................................................................... 18 
4.1. 
Safety endpoints .................................................................................................................... 18 
4.2. 
Efficacy Endpoints .................................................................................................................. 18 
4.3. 
Secondary Endpoints .............................................................................................................. 18 
4.4. 
Pharmacokinetic Endpoints .................................................................................................... 18 
4.5. 
Pharmacodynamic Endpoints ................................................................................................. 19 
4.6. 
Immunogenicity Data ............................................................................................................. 19 
5. 
ANALYSIS SETS ..................................................................................................... 20 
5.1. 
Screened Set .......................................................................................................................... 20 
5.2. 
Safety Set / Intent to Treat Set ............................................................................................... 20 
5.3. 
Pharmacokinetic Set .............................................................................................................. 20 
5.4. 
Pharmacodynamic Set ............................................................................................................ 20 
5.5. 
Per Protocol Set ..................................................................................................................... 20 


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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5.6. 
Protocol Deviations ................................................................................................................ 20 
5.7. 
Data Review for Analysis Sets ................................................................................................. 21 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS .................................................... 21 
6.1. 
General Methods ................................................................................................................... 21 
6.2. 
Missing Data .......................................................................................................................... 22 
6.2.1. 
Pharmacokinetic and Pharmacodynamic Data ...................................................................... 22 
6.3. 
Visit Windows ........................................................................................................................ 23 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION .............. 24 
7.1. 
Patient Disposition and Withdrawals ...................................................................................... 24 
7.2. 
Demographic and Other Baseline Characteristics ..................................................................... 25 
7.3. 
Medical History and Concomitant Diseases ............................................................................. 25 
7.4. 
Prior and concomitant Medications ........................................................................................ 26 
8. 
EFFICACY ............................................................................................................. 27 
8.1. 
Efficacy Endpoints and Analysis .............................................................................................. 27 
8.1.1. 
Lactate Dehydrogenase, Haptoglobin and Hemoglobin ......................................................... 27 
8.2. 
Secondary Endpoints and Analysis .......................................................................................... 28 
8.2.1. 
FACIT Fatigue Scale ............................................................................................................ 28 
8.2.2. 
Reticulocyte and Total Bilirubin ........................................................................................... 28 
8.2.3. 
RBC Transfusions ................................................................................................................ 29 
9. 
PHARMACOKINETICS ........................................................................................... 29 
9.1. 
Concentration data ................................................................................................................ 29 
9.2. 
Pharamcokinetic data ............................................................................................................ 30 
10. 
PHARMACODYNAMICS .................................................................................... 30 
11. 
SAFETY ............................................................................................................ 32 
11.1. 
Extent of Exposure ................................................................................................................. 32 
11.2. 
Adverse Events ...................................................................................................................... 32 
11.3. 
Laboratory Evaluations .......................................................................................................... 34 


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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11.4. 
Immunogenicity Data ............................................................................................................. 34 
11.5. 
Vital Signs .............................................................................................................................. 34 
11.6. 
ECG ....................................................................................................................................... 35 
11.7. 
Physical Examination ............................................................................................................. 36 
12. 
INTERIM ANALYSES .......................................................................................... 36 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ........................................... 37 
14. 
INDEX OF TABLES AND FIGURES ....................................................................... 38 
15. 
INDEX OF LISTINGS ........................................................................................... 44 
16. 
APPENDIX 1 ..................................................................................................... 46 
 
 
 


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ATC 
Anatomic Therapeutic Chemical 
AUC 
Area Under the Curve 
BLQ 
Below Limit of Quantification 
CNS 
Clinical Network Services Pty Ltd 
CSR 
Clinical Study Report 
ECG 
Electrocardiograms 
FACIT 
Functional Assessment of Chronic Illness Therapy 
ITT 
Intent To Treat 
LDH  
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
QTcB 
Heart Rate Corrected QT interval, using Bazett’s formula 
QTcF 
Heart Rate Corrected QT interval, using Fridericia’s formula 
PD 
Pharmacodynamics 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PK 
Pharmacokinetics 
PRBCs 
Packed Red Blood Cells 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SE 
Standard Error 


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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Abbreviation 
Description 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures, Listings 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 
 


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables 
and figures which will be produced, and the statistical methodologies that will be used, are 
complete and appropriate to allow valid conclusions regarding the study objectives.  Any 
amendments to the SAP will be made prior to database lock. Any additional analyses not described 
in the final SAP or deviations from the final SAP will be documented in the clinical study report 
(CSR). 
2.1. 
RESPONSIBILITIES 
Clinical Network Services Pty Ltd (CNS) will perform the statistical analyses and are responsible for 
the production and quality control of all tables, figures and listings (TFLs). Pharmacokinetic (PK) 
parameters will be derived by JPharma Solutions.  
3. 
STUDY OVERVIEW 
3.1. 
STUDY OBJECTIVES 
The objectives of the study are to assess safety, tolerability, preliminary efficacy and 
pharmacokinetics (PK) of multiple subcutaneous (SC) doses of APL-2 in subjects with paroxysmal 
nocturnal hemoglobinuria (PNH) who have not received treatment with eculizumab (Soliris) in 
the past. 
An exploratory objective of the study is to assess the pharmacodynamics (PD) of multiple SC doses 
of APL-2 when administered to PNH subjects. 
3.2. 
STUDY DESIGN 
This section details the study design as documented in Protocol Amendment 8.  Additional details 
of all protocol amendments are detailed in Appendix 1. 
This is a Phase 1b, open label, multiple ascending dose pilot study in subjects with PNH who have 
not received eculizumab (Soliris) in the past. The study is planned to enrol approximately 23 
subjects across 2 cohorts.  Cohort 1 has enrolled 3 subjects who were dosed with 180 mg/day APL-
2 subcutaneously for 28 days.  Cohort 2 will include up to 20 subjects that complete 28 days of 
dosing. Subjects may participate in more than one cohort.  Additional cohorts may be enrolled if it 
is deemed appropriate by the PI and the sponsor, in consultation with the Safety Monitoring 
Committee (SMC), to repeat a dose level or to study an intermediate dose level. 
Safety will be assessed throughout the study; serial blood and urine samples will be collected for 
these assessments. Blood samples will be collected for the assessment of PD and APL-2 PK.   


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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The study will consist of the following parts: 
1. Part 1 – subjects will receive APL-2 for 28 days 
2. Part 2A – subjects may continue to receive APL-2 for a further 56 days (i.e. until Day 84) if 
there is evidence of perceived clinical benefit following review of available safety, PK and 
PD data by the investigator and sponsor 
3. Part 2B - subjects may continue to receive APL-2 for a further 280 days (i.e. until Day 364) 
if there is ongoing evidence of perceived clinical benefit following review of available safety, 
PK and PD data by the investigator and sponsor 
4. Part 2C – continuation of APL-2 treatment if enrolment into the extension study (APL2-307) 
is not open. This part was also introduced as part of a country specific amendment in New 
Zealand to allow an ongoing subject to continue to receive APL-2 treatment for up to 2 
years. 
5. Part 3 – safety follow up (if applicable; subjects may transition into an open label extension 
study to continue treatment with APL-2 after the completion of Part 2B) 
Cohort 2 was not initiated until all subjects in Cohort 1 had reached the Day 29 visit and the SMC 
had reviewed emerging safety and efficacy data and determined that, at the initial dose, APL-2 has 
an acceptable safety and tolerability profile.  No subjects in Cohort 1 progressed to Part 2A. 
If a Cohort 2 subject has a sub-optimal clinical response during daily dosing with 270 mg APL-2 in 
Part 2B, the dose may be increased up to 360 mg/day. Doses will be administered at the clinical site 
every 2 weeks for the first 6 weeks after commencing the higher dose. 
Screening will take place within 30 days prior to the start of dosing on Day 1. 
During Part 1, the first 3 daily SC doses of APL-2 (Days 1 to 3) as well as doses on Days 8, 15 and 22 
will be administered at the clinical site.  All other daily doses of APL-2 from Days 4 to 28 will be 
administered by a nurse or self-administered by the subject, at the subject’s home, workplace, or 
other location convenient to the subject.  Cohort 2 subjects progressing to Part 2A of the study will 
continue to receive daily doses of APL-2 until Day 84.  Cohort 2 subjects progressing to Part 2B of 
the study will continue to receive daily doses of APL-2 until Day 364. Doses will be administered by 
a nurse or self-administered by the subject, at the subject’s home, workplace, or other location 
convenient to the subject, with the exception of Days 29, 36, 43, 57, 71, 85, 113, 141, 169, 197, 225, 
253, 281, 309 and 337 where dosing is at the clinical site.   
Subjects who complete Part 2B will be eligible to transition into an open-label extension study in 
order to continue to receive treatment with APL-2. Subjects who elect to transition into the 
extension study will not complete Part 3 of this study. Some subjects that complete Part 2B and 
wish to transition into the extension study may be required to dose beyond the planned conclusion 
of Part 2B (Day 364) in this study until the extension study is open for enrolment. These subjects 
will continue with their current APL-2 dose and regimen and enter Part 2C of the study. During Part 
2C they will return to the site for visits at bi-monthly intervals (refer to Protocol Amendment 8 


Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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Appendix 1 for details of dosing and visit schedule and procedures).   Subjects that transition to 
either the extension study or Part 2C must complete the Day 365 visit procedures for this study. For 
these subjects, the Day 365 visit will also be the first visit of the extension study or Part 2C. 
For subjects who do not enter Part 2A treatment will be stopped on Day 28 and the subject will 
enter Part 3 for safety follow-up visits on Days 29, 43, 57 and 78 (exit visit). For subjects who do not 
enter Part 2B treatment will be stopped on Day 84 and the subject will enter Part 3 for safety follow-
up visits on Days 85, 99, 113 and 134 (exit visit). For subjects who do not enter Part 2C or the open-
label extension study, treatment will be stopped on Day 364 and the subject will enter Part 3 for 
safety follow-up visits on Days 365, 379, 393 and 414 (exit visit). 
Study objectives will be based on all data collected throughout the study however the main focus 
of the study for Cohort 2 is the period up to and including Day 365. 
3.3. 
DETERMINATION OF SAMPLE SIZE 
As this is a pilot study the sample size is not based on formal statistical testing.  The sample size is 
considered sufficient to obtain useful safety, PK and PD data to assist the planning of future clinical 
studies in patients with PNH. 
3.4. 
TREATMENT ASSIGNMENT AND BLINDING 
Each subject will be assigned a unique identification number upon entering screening.  Subjects 
who enter both cohorts will be assigned a unique number for each cohort, and a record will be kept 
to identify unique numbers for the same subject. Subjects who complete the study screening 
assessments and meet all eligibility criteria will be scheduled to enter the study and dosed in the 
next available cohort. 
The study is open label so blinding is not applicable. 
3.5. 
ADMINISTRATION OF STUDY MEDICATION 
Sterile solutions of APL-2 at 150mg/mL in 5% dextrose or in acetate-buffered mannitol (introduced 
with Amendment 4) or in acetate-buffered sorbitol (introduced with Amendment 5) will be 
administered subcutaneously. The volume of the injection will be adjusted to achieve the desired 
dose.  If the dose volume is ≤3 mL, doses will be administered as 1 or 2 bolus SC injections. If the 
dose volume is >3 mL, doses will be administered as SC infusions.  Following Amendment 4, subjects 
may self-administer the SC infusions using an ambulatory syringe pump after receiving appropriate 
training by research nurses or other study personnel. The injections will be administered at the 
clinic on those days when a clinic visit occurs and at an off-site location convenient to the subject 
on all other days. 
The planned dose for Cohort 1 was APL-2 180 mg/day and for Cohort 2 is APL-2 270 mg/day (up to 


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APL2-CP-PNH-204                                                                          
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360 mg/day). The dose of 270 mg/day for Cohort 2 was determined by the SMC based on 
cumulative safety, PK and PD data from Cohort 1.  However, subjects with a sub-optimal clinical 
response in Cohort 2 may have their dose increased to 360 mg/day. The dose will not exceed 360 
mg/day for any individual. 
 


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APL2-CP-PNH-204                                                                          
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3.6. 
STUDY FLOWCHART 
 


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Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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Apellis Pharmaceuticals, Inc. 
 
Date: 19th December 2019 
APL2-CP-PNH-204                                                                          
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Apellis Pharmaceuticals, Inc. 
 
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APL2-CP-PNH-204                                                                          
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APL2-CP-PNH-204                                                                          
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FOOTNOTES: 
A. At screening the vaccination history will be obtained from the subject. If required i.e. not previously vaccinated subjects will receive 
vaccinations against Neisseria meningitides types A, C, W, Y and B (administered as two vaccinations), Streptococcus pneumoniae and 
Haemophilus influenzae Type B (Hib).  If the subject’s first documented Neisseria meningitidis vaccine/s are administered at Day 15, a 
booster (for both vaccinations) should be administered at least 2 months later (Day 85). If Pneumococcal vaccination is required, a dose of 
PCV13 will be administered at Day 15 and a dose of PPSV23 will be administered at least 8 weeks later (Day 85).  
B. Preventive antibiotics will be prescribed from Day 1. Antibiotics will be taken from Day 1 until 14 days after the final dose of APL-2. 
Specifically: 
• 
Day 1 to Day 14: Ciprofloxacin 500 mg twice daily to commence after collection of the 2.5h post dose PK sample 
• 
Day 15 onwards: Penicillin V 500 mg twice daily. 
C. Full physical examination will be performed at the scheduled time points indicated. A symptom-driven physical examination may be 
performed at other times, at the PI’s discretion. 
D. If done on a dosing day, electrocardiograms (ECGs) are to be performed within 30 minutes after dosing. N.B. On Day 1 the ECG must be 
performed BEFORE administration of the first dose of Ciprofloxacin. 
E. S = Administration at clinical site. H = Administration at subject’s home, workplace, or other location convenient to the subject. Treatment 
may be stopped at any time if the investigator and sponsor conclude that there is no demonstration of clinical benefit to continue APL 2 
administration past this point. 
F. Injection site assessment will be performed within 30 minutes after APL-2 administration. Ambulatory syringe infusion pump training will 
include instructions to report any injection site reaction to the PI. 
G. If APL-2 is administered by a study nurse or other research study staff, vital signs will be measured within 2 hours prior to dosing and 
within 30 minutes after dosing. If APL 2 is self-administered, pre- and post-dose vital signs will not be measured. 
H. Reserved – See note E. 


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APL2-CP-PNH-204                                                                          
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I. If done on a dosing day, blood samples will be taken pre-dose with the exception that on Day 1 only a pharmacokinetic sample will be 
taken pre-dose and at a minimum of 2.5 hours post-dose or immediately prior to discharge from the clinic (if subject is kept at the clinic 
longer than 2.5 hours). 
J. On Days 23 through 28, a serum chemistry sample may be obtained but LD assays only will be performed and reported. If a sufficient 
reduction in LD is observed prior to Day 22 these additional samples may not be required and this will be confirmed on an individual subject 
basis by the sponsor 
K. Absence of HIV, HBV, and HCV infection will be confirmed prior to APL 2 administration. If the HBsAg test yields a positive result, a 
negative HBV DNA test result must be obtained and prophylactic antiviral therapy must be commenced prior to APL 2 administration and 
continue until two weeks after the final dose of APL 2 to minimize the potential risk of HBV activation. 
L. If done on a dosing day, urine pregnancy test should be completed for WOCBP prior to dosing.  
M. Ambulatory syringe infusion pump training will include instructions to report any adverse events to the PI. 
N. If dose is increased during Part 2B, subjects will come back to the clinical site for safety visits every other week (instead of monthly) for 
the first 6 weeks of the dose change. These visits will alternate with the monthly visits and should be recorded as unscheduled visits. The 
same procedures listed under the monthly visits will be performed. 
O. Subjects who discontinue dosing at any time during part 1, 2A or 2B, will move directly into Part 3 for safety follow up visits. 
P. The use of silica reagents in coagulation panels should be avoided in subjects treated with APL-2. 
Q. Subjects who complete Part 2B will be eligible to transition into an open-label extension study (Study APL2-307) in order to continue to 
receive treatment with APL-2. Subjects who elect to transition into Study APL2-307 will not complete Part 3 of this study, but must complete 
the Day 365 visit procedures (the first visit of Part 3). The Day 365 visit will also be the first visit of the extension study. If Study APL2-307 is 
not open to enroll subjects from this study, subjects may continue dosing with APL-2 beyond Part 2B in Part 2C of this study. Details 
regarding procedures for dosing beyond Part 2B are provided in Protocol Amendment 8 Appendix 1. 


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APL2-CP-PNH-204                                                                          
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4. 
ENDPOINTS 
4.1. 
SAFETY ENDPOINTS 
The primary safety endpoints for the study are the number and severity of treatment emergent 
adverse events (TEAEs).  Safety will also be assessed through vital signs, 12-lead ECG and laboratory 
safety data. Changes from baseline will be calculated taking baseline as the last measurement prior 
to the start of dosing. 
4.2. 
EFFICACY ENDPOINTS 
The primary efficacy endpoints are changes from baseline and percentage changes from baseline 
in lactase dehydrogenase (LDH), haptoglobin and hemoglobin. Changes will be calculated for each 
post dose assessment.  Baseline will be the last measurement prior to start of dosing. 
4.3. 
SECONDARY ENDPOINTS 
The secondary endpoints include changes from baseline in Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue Scale (version 4), change from baseline and percentage change from 
baseline in reticulocyte count, change from baseline and percentage change from baseline in total 
bilirubin.   
The change from baseline in FACIT fatigue scale, reticulocyte count and total bilirubin will be 
calculated for each post dose assessment 
The baseline RBC transfusions per year will be calculated for the 12 month period prior to screening 
and prior to Day 1 as the number of transfusions reported in the previous 365 days from screening 
and from Day 1 respectively. A similar calculation will be used for the baseline number of units 
transfused per year relative to screening and relative to Day 1. Only whole blood and packed RBC 
(PRBCs) transfusions will be included in the calculations. For subjects who enter both cohorts the 
baseline for both cohorts will be taken from the 12 month transfusion history prior to Cohort 1. 
4.4. 
PHARMACOKINETIC ENDPOINTS 
Serum APL-2 concentrations will be determined from multiple samples taken during the study. 
PK parameters for APL-2 will be estimated from the individual serum concentration-time data over 
the whole time period (Days 1 to 414) using a non-compartmental approach.  PK parameters will 
include: 
• 
AUCtotal   
The area under the serum concentration versus time curve, from time 0  
 
 
 (pre-dose on Day 1) to the last measurable concentration at the end of 
 
  
the study. 
• 
AUC365   
The area under the serum concentration versus time curve, from time 0  


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APL2-CP-PNH-204                                                                          
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 (pre-dose on Day 1) to the concentration recorded on Day 365. 
• 
Ctrough,max,total 
Maximum observed pre-dose serum concentration during the study. 
• 
Ctrough,max,365 
Maximum observed pre-dose serum concentration up to Day 365. 
PK parameters will be calculated using PKNCA (version 0.8.4 or higher) with R (version 3.4.3 or 
higher). 
A separate analysis will combine the PK data with prior data collected in earlier clinical studies to 
update the APL-2 population PK model. This analysis will be conducted separate to the reporting of 
this study and will be detailed in a separate population PK SAP.  
4.5. 
PHARMACODYNAMIC ENDPOINTS  
The PD endpoints include changes from baseline and percentage changes from baseline for the C3 
complement parameter, and changes from baseline and percentage of baseline value for CH50 and 
AP50. 
To reduce variability for the complement parameter AP50, all of a particular subject’s samples will 
be analysed on the same plate.  This means that only a subset of samples collected will be analysed 
for AP50.  The subset of samples includes the Screening, Days 1, 29, 85, 169 and 365 samples. Only 
if there are spurious results will other samples be analysed. 
Changes from baseline and percentage changes from baseline will also be derived for C3 deposition 
on RBC cells (percent C3d CD59 Type I, II and III), clonal distribution of PNH RBCs (percent CD59 
Type I, II and III), PNH granulocytes (percent FLAER) and PNH monocytes (percent FLAER).  
In addition the following endpoints will be derived: 
• 
Clonal distribution of PNH RBCs (percent Type II + III); this is simply the sum of the clonal 
distribution of PNH RBCs Type II and Type III. 
• 
C3d deposition on RBC cells (percent Type II + III); this is the number of events for C3d 
deposition on RBC cells (Type II) plus number of events for C3d deposition on RBC cells 
(Type III) divided by number of events for PNH CD59 Type II and III expressed as a percent. 
4.6. 
IMMUNOGENICITY DATA 
Only a subset of samples collected will be analysed. The subset includes samples collected on Days 
1, 29 and 365. For any sample confirmed positive, the remaining samples for that particular subject 
will be analysed. 
Following the Food and Drug Administration’s recommendation, any subject that tests positive for 
anti-drug antibodies will continue to be monitored until values have returned to baseline levels.  If 
necessary, this will include collecting a sample from the subject every 6 months after the 


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APL2-CP-PNH-204                                                                          
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completion of the study. Any samples collected after study completion will be reported separately. 
5. 
ANALYSIS SETS 
5.1. 
SCREENED SET 
The screened set will include all subjects who signed the informed consent form and are screened 
for participation in this study. This set will only be used for the purposes of describing the subject 
disposition. 
5.2. 
SAFETY SET / INTENT TO TREAT SET 
The safety set will include all subjects eligible to receive study medication and who receive at least 
one dose of study medication. The intent to treat (ITT) set will be identical to the safety set for this 
study.  All baseline characteristics, demography and efficacy endpoint data will be presented using 
the ITT set. 
5.3. 
PHARMACOKINETIC SET 
The PK set will include all subjects in the safety set who have at least one quantifiable concentration 
of APL-2. 
5.4. 
PHARMACODYNAMIC SET 
The PD set will include all subjects in the safety set who have at least one quantifiable post dose PD 
parameter. 
5.5. 
PER PROTOCOL SET 
The per protocol (PP) set will include all subjects in the ITT set who have not violated and inclusion 
or exclusion criteria and/or deviated from the protocol in a way that could influence their efficacy 
assessment. Decisions concerning the exclusion of subjects from this set will be made and 
documented prior to database lock. 
5.6. 
PROTOCOL DEVIATIONS 
All protocol deviations will be reviewed and documented before database lock. Protocol deviations 
will be recorded by the site staff, study monitors and medical monitor reviewers. They may also be 
identified through programmable checks of the data. 
Protocol deviations will be categorized by Apellis Pharmaceuticals, Inc. as either major (for example 
violation of inclusion or exclusion criteria) or minor prior to database lock. All protocol deviations 
will be listed. No subjects will be excluded from the screened, safety or ITT sets due to protocol 


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APL2-CP-PNH-204                                                                          
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deviations. 
5.7. 
DATA REVIEW FOR ANALYSIS SETS 
After all the data has been entered and verified into the database, a review will be performed.  The 
purpose of this review will be to define the analysis sets.  The review will also check the quality of 
the data, identify outliers and make decisions on how to deal with problems in any data (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. 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
No formal statistical testing will be performed on Cohort 1 data. Comparisons to baseline will be 
performed for Cohort 2.      
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. However, with so few subjects in Cohort 1, 
continuous data, unless specifically stated otherwise, will only be summarized for Cohort 2. 
Categorical variables will be summarized using frequencies and percentages. 
Unless otherwise specified, the estimated mean and median for a set of values should be printed 
out to 1 more decimal place than the original values, and standard deviations should be printed out 
to 2 more decimal places than the original values. The minimum and maximum should report the 
same number of decimal places as the original values. Percentages will be displayed with 1 decimal 
place; except percentages will not be presented when the count is zero and 100% will be presented 
as an integer. 
Unless stated otherwise, baseline will be taken as the pre-dose assessment on Day 1; if this is 
missing then the screening value or, if available, a pre-dose unscheduled measurement will be used 
(whichever is closer to the baseline date). For subjects who enter both cohorts the baseline for 
Cohort 2 will be taken as the pre-dose assessment associated with Cohort 2. 
In by-visit summary tables, the baseline will be summarized using all available data, but also for 
each visit using only the baseline data from subjects with available data at the visit; hence the mean 
change from baseline will equal the (mean visit value – mean baseline value). 
For summary tables that include both cohorts, data will be presented by cohort and overall, unless 
stated otherwise.  The overall summary will be based on unique subjects, so subjects who enter 
both cohorts will only be counted once.   


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APL2-CP-PNH-204                                                                          
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Where specified, summary tables will be presented by study part (1, 2A, 2B, 2C or 3). For 
assessments performed at visits e.g. vital signs, this will be based on the study part the visit is 
assigned to according to protocol. The only exception is the first visit of each part which will be 
assigned to the previous part as assessments are performed prior to administration of study drug. 
So Day 29, Day 85 and Day 365 will be assigned to Part 1, 2A and 2B respectively.  For event based 
data e.g. adverse events, the part is assigned based on the event start day (refer to Section 11.2 for 
more details). 
All data will be listed.  Data listings will be presented by cohort. Subjects who enter both cohorts 
will be identified in a footnote on the listings. Data listings will present study days in addition to 
dates, where study day is derived as (assessment date – first day of dosing+1). The first day of 
dosing will be identified as Study Day 1. For subjects who enter both cohorts the study day for 
Cohort 2 will be relative to the first day of dosing in Cohort 2.  
For Cohort 2 subjects the last dose received prior to the assessment will also be listed. This will be 
the dose received prior to the assessment on the same day or the previous day. If a subject does 
not receive study drug during this time then ‘not dosed’ will be listed. 
All statistical analyses will be performed using SAS® (Version 9.4 or higher, SAS Institute Inc., Cary, 
NC, USA). 
6.2. 
MISSING DATA 
No imputation of missing data for early termination will be performed. 
Where specified screen values or pre-dose unscheduled measurements may be used as a baseline 
value in the event of missing Day 1 measurements. 
Handling of missing dates/times for the start/stop of medications and adverse events are detailed 
in Sections 7.4 and 11.2 respectively. 
The original data will always be presented in the listings. 
6.2.1. 
Pharmacokinetic and Pharmacodynamic Data 
APL-2 concentrations reported as below the limit of quantification (BLQ) will be taken as zero for 
linear plots, and equal to the lower limit of quantification (LLOQ) for semi-logarithmic plots.  
 
If a BLQ value falls between two quantifiable concentrations the value will be set equal to the LLOQ, 
unless it’s exclusion can be justified (e.g. implausibility given the profile observed and known PK 
properties). 
If a baseline PD value is zero, then the percentage change from baseline will not be calculated. If a 


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APL2-CP-PNH-204                                                                          
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PD value is BLQ then the value will be set to the LLOQ. Similarly, for the PD plots, a BLQ value will 
be set equal to LLOQ. 
6.3. 
VISIT WINDOWS 
Data will be assigned to visits using windowing (see table below). If more than one assessment 
(including the early termination or unscheduled assessments) falls within the same defined 
window, the assessment closest to the target day with non-missing data will be considered for 
analysis. If two assessment dates are at the same distance from the target day, the first assessment 
with non-missing data will be considered for analysis. 
Part 
Visit 
Target 
Day 
Analysis Window 
Interval 
1 
Baseline 
1 
≤1* 
NA 
Day 8 
8 
5 – 11 
7 
Day 15 
15 
12 - 18 
7 
Day 22 
22 
19 – 25 
7 
2A 
Day 29 
29 
26 – 32 
7 
Day 36 
36 
33 – 39 
7 
Day 43 
43 
40 - 46 
7 
Day 57 
57 
54 - 60 
7 
Day 71 
71 
68 - 74 
7 
2B 
Day 85 
85 
78 - 92 
15 
Day 113 
113 
–106 - 120 
15 
Day 141 
141 
134 - 148 
15 
Day 169 
169 
162 - 176 
15 
Day 197 
197 
190 - 203 
15 
Day 225 
225 
218 - 232 
15 
Day 253 
253 
246 - 260 
15 
Day 281 
281 
274 - 288 
15 
Day 309 
309 
302 - 316 
15 
Day 337 
337 
330 - 344 
15 
3^ 
Day 365$ 
365 
358 - 372 
15 
Day 379 
379 
374 – 384 
11 
Day 393 
393 
388 – 398 
11 
Day 414 
414 
409 - 419 
11 
2C@ 
Day 421 
421 
410 - 432 
23 
Repeat for 
visits every 
56 days 
Previous 
target day 
+56 
(target day-11) – 
(target day+11) 
23 
* Must be prior to dosing if time of assessment is recorded. 
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APL2-CP-PNH-204                                                                          
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$ All subjects that complete Part 2B will have a Day 365 visit irrespective of whether they enter Part 2C or enter the 
extension study APL2-307. 
@Only applicable for subjects entering Part 2C while waiting to enrol in the extension study. 
A subject will only be allocated to Part 2A, 2B or 2C visits if they have agreed to enter these phases. 
Follow-up visits (Part 3), with the exception of Day 365, by design are after the last dose of study 
drug and should not be allocated to on-treatment visits. Day 365 will be performed for all subjects 
who complete Part 2B of the study irrespective of whether they are continuing APL-2 treatment. If 
a subject discontinues from the study early then they will enter the follow up Part 3 phase and the 
day will therefore not match the days above. In these cases the day will be according to the day 
post the last study dose but will be allocated to Part 3.  
Summary tables by visit will be based on the analysis visit. Data collected outside these windows 
will only be listed. All listings will include the original visit assignment as well as the analysis visit if 
it differs from the original visit. 
These visit windows will be reviewed and may be updated prior to reporting. Any assessments that 
fall outside of these windows will be reviewed on a case-by-case basis, and decisions on their 
handling will be fully documented prior to reporting.  
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
PATIENT DISPOSITION AND WITHDRAWALS 
The number of subjects screened and the number of subjects entering both cohorts will be 
presented overall.  The following will be presented by cohort: 
• 
Number of subjects starting Part 1 
• 
Number of subjects completed Part 1 
• 
Number of subjects withdrawn during Part 1 and reason for withdrawal 
• 
Number of subjects starting Part 2A 
• 
Number of subjects completed Part 2A 
• 
Number of subjects withdrawn during Part 2A and reason for withdrawal 
• 
Number of subjects starting Part 2B (Cohort 2 only) 
• 
Number of subjects completed Part 2B (Cohort 2 only) 
• 
Number of subjects withdrawn during Part 2B and reason for withdrawal (Cohort 2 only) 
• 
Number of subjects starting Part 2C (Cohort 2 only) 
• 
Number of subjects withdrawn during Part 2C and reason for withdrawal (Cohort 2 only) 
• 
Number of subjects completed Part 2C (Cohort 2 only) 
• 
Number of subjects entering extension study APL2-307 (Cohort 2 only) 
• 
Number of subjects completed Part 3 safety follow-up 


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APL2-CP-PNH-204                                                                          
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• 
Number of subjects withdrawn during Part 3  
• 
Number of subjects in each analysis set 
Disposition data will be listed. A visit listing will also be presented which will include all visits 
(scheduled and unscheduled) along with dates and study days attended and the mapped analysis 
visit if different from the scheduled visit. 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demography (gender, race, ethnicity, age [years], weight [kg], height [cm] and BMI [kg/m2]) will be 
summarized by cohort and overall for the ITT set.  Age, weight, height and BMI will be summarized 
using summary statistics for continuous variables. Gender, race and ethnicity will be summarized 
using summary statistics for categorical variables.  
Time since diagnosis of PNH (years) and the baseline measurements for complement parameters 
(CH50, AP50 and C3), clonal distribution of PNH RBCs, hemoglobin, LDH, haptoglobin,  reticulocyte, 
total bilirubin and total FACIT score will be summarized by cohort and overall using summary 
statistics for continuous variable. In addition, the number of transfusions in the 12 months prior to 
screening and in the 12 months prior to Day 1 will be summarized using summary statistics for 
continuous variables. 
Age = (informed consent date - date of birth + 1)/365.25 truncated to complete years. 
Years with PNH = (informed consent date - date of diagnosis + 1)/365.25. 
Subjects who enter both cohorts will only be counted once in the overall summary for demographic 
and baseline characteristics and only data prior to the first cohort will be used in the overall 
summary.  The summaries by cohort will use baseline data from each of the cohorts. 
7.3. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 
21.0. Summaries will be presented for the ITT set by System Organ Class (SOC) and Preferred Term 
(PT) with counts for each cohort and overall. Each subject will be counted only once in each SOC or 
SOC/PT summary. 
The number of subjects experiencing past thrombosis and the number of events will be summarized 
separately by cohort and overall.  
Subjects who enter both cohorts will only be counted once in the overall summary for medical 
history and thrombosis history and only data prior to the first cohort will be used in the overall 
summary. The summary by cohort will use baseline data from each of the cohorts. 


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APL2-CP-PNH-204                                                                          
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7.4. 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded using WHO Drug Dictionary version 2018:03. 
Medication will be presented for the safety set by Anatomic Therapeutic Chemical (ATC) level 2 
(therapeutic main group) and ATC level 5 (standardized medication name) with counts for each 
cohort and overall.  A subject who took more than one medication will be counted only once if 
these medications belong to the same extended ATC classification.   
For the prior medications summary, subjects who enter both cohorts will only be counted once in 
the overall summary and only data prior to the first cohort will be used in the overall summary. The 
summary by cohort will use baseline data from each of the cohorts.   
For the concomitant medications summary, subjects who enter both cohorts will only be counted 
once in the overall summary, all concomitant medications from both cohorts will be included in the 
overall summary. 
Prior medications will be defined as those medications started prior to the administration of APL-2 
on Day 1.  For subjects who enter both cohorts, prior medications for Cohort 2 will only consider 
those medications recorded on the eCRF for Cohort 2. Concomitant medications will be defined as 
those medications taken following the first administration of APL-2 on Day 1. Hence medications 
started before study dosing, but continuing after are considered as both prior and concomitant 
medications.  The listing of medications will identify prior and concomitant medications. 
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: 
• 
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. 
• 
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. 


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8. 
EFFICACY 
8.1. 
EFFICACY ENDPOINTS AND ANALYSIS 
8.1.1. 
Lactate Dehydrogenase, Haptoglobin and Hemoglobin 
For each parameter, absolute values will be listed together with changes from baseline and 
percentage changes from baseline for the ITT set by cohort, part of the study and study visit. Values 
that are outside the reference range will be flagged. For LDH the value related to their ULN will also 
be listed and for hemoglobin and haptoglobin the value related to their LLN will be listed. 
For Cohort 2, absolute values, changes from baseline and percentage changes from baseline will be 
summarised, using descriptive statistics, by part of the study and study visit. The associated 95% 
confidence interval and 2-sided p-value (Student’s t-test) for the changes from baseline will also be 
presented; 95% confidence intervals for the absolute values will also be presented.  The number 
and percentage of subjects ≤ ULN and ≤ 1.5*ULN for LDH will also be summarized by part of the 
study and study visit (Cohort 2 only). The number and percentage of subjects ≥ LLN for haptoglobin 
and hemoglobin will also be summarized by part of the study and study visit (Cohort 2 only). The 
summary will be generated for the ITT and PP analysis sets. 
For Cohort 2, mean absolute values with 95% confidence intervals will be plotted by study visit for 
each parameter. The number of subjects contributing to each mean value at a visit will be presented 
above the x-axis and a reference line at Day 365 will be included. The LDH and haptoglobin plots 
will shade the area between the lower and upper limits of normal. As the normal range for 
hemoglobin is dependent on gender the hemoglobin plot will be repeated for males and females 
separately and these plots will shade the area between the lower and upper limits of normal for 
the corresponding gender.  If the normal range changes during the study then the widest range 
across the study will be presented on these plots. The plots will be generated for the ITT and PP 
analysis sets. 
Absolute values, changes from baseline and percentage changes from baseline will be plotted by 
study day with each subject and cohort being identifiable. Subjects who enter both cohorts will be 
identified in a footnote. A separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 2B, 
2C and 3 combined.  A dotted line will be used to identify follow-up (Part 3).  The actual sampling 
day will be used on the x-axis. The absolute value plots will include a reference line at Day 1 and 
the change and percentage change from baseline plots will include a reference line for 0 on the y-
axis. A reference line at Day 365 will also be added for the plot covering the whole study. 
Values of LDH, reticulocytes and total bilirubin related to their ULN (i.e. value/ULN) throughout the 
study will be plotted against time for each subject in Cohort 2 individually (i.e. one plot per subject). 
Hemoglobin and haptoglobin values will also be included but related to their LLN (i.e. value/LLN). 
Each parameter will have a different symbol and a legend will identify the parameters included. A 
reference line of 1 on the y-axis will be included. On study transfusions (PRBC only) will be identified 


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APL2-CP-PNH-204                                                                          
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on the plot as a vertical line at the relevant study day. Above the profile plot a separate plot will be 
displayed which shows the APL-2 dose by study day. The study day on both plots will be aligned.  
8.2. 
SECONDARY ENDPOINTS AND ANALYSIS 
8.2.1. 
FACIT Fatigue Scale 
Absolute FACIT fatigue scores will be listed together with change from baseline for the ITT set by 
cohort, part of study and study visit.  
For Cohort 2, absolute values and changes from baseline will be summarised, using descriptive 
statistics, by part of the study and study visit. The associated 95% confidence interval and 2-sided 
p-value (Student’s t-test) for the changes from baseline will also be presented; 95% confidence 
intervals for the absolute values will also be presented. The summary will be generated for the ITT 
and PP analysis sets. 
For Cohort 2, mean absolute values with 95% confidence intervals will be plotted by study visit. The 
number of subjects contributing to each mean value at a visit will be presented above the x-axis 
and a reference line at Day 365 will be included. The plot will be generated for the ITT and PP 
analysis sets. 
Absolute values and changes from baseline will be plotted by study day with each subject and 
cohort being identifiable. Subjects who enter both cohorts will be identified in a footnote. A 
separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 2B, 2C and 3 combined.  A 
dotted line will be used to identify follow-up (Part 3).  The actual sampling day will be used on the 
x-axis. The absolute value plots will include a reference line at Day 1 and the change from baseline 
plots will include a reference line for 0 on the y-axis. A reference line at Day 365 will also be added 
for the plot covering the whole study. 
Values of FACIT fatigue scores throughout the study will be plotted against time for each subject in 
Cohort 2 individually (i.e. one plot per subject). On study transfusions (PRBC only) will be identified 
on the plot as a vertical line at the relevant study day. Above the profile plot a separate plot will be 
displayed which shows the APL-2 dose by study day. The study day on both plots will be aligned. 
8.2.2. 
Reticulocyte and Total Bilirubin 
For each parameter, absolute values will be listed together with change from baseline and 
percentage change from baseline for the ITT set by cohort, part of study and study visit. Values that 
are outside the reference range will be flagged and value related to their ULN will be listed. 
For Cohort 2, absolute values, changes from baseline and percentage changes from baseline will be 
summarised, using descriptive statistics, by part of the study and study visit. The associated 95% 
confidence interval and 2-sided p-value (Student’s t-test) for the changes from baseline will also be 


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APL2-CP-PNH-204                                                                          
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presented; 95% confidence intervals for the absolute values will also be presented.  The number 
and percentage of subjects ≤ ULN and ≤ 1.5*ULN will also be summarized by study visit for Cohort 
2 only. The summary will be generated for the ITT and PP analysis sets. 
For Cohort 2, mean absolute values with 95% confidence intervals will be plotted by study visit for 
each parameter. The number of subjects contributing to each mean value at a visit will be presented 
above the x-axis and a reference line at Day 365 will be included. The reticulocyte plot will shade 
the area between the lower and upper limits of normal. As the normal range for total bilirubin is 
dependent on gender the total bilirubin plot will be repeated for males and females separately and 
these plots will shade the area between the lower and upper limits of normal for the corresponding 
gender.  If the normal range changes during the study then the widest range across the study will 
be presented on these plots. The plots will be generated for the ITT and PP analysis sets. 
Absolute values, changes from baseline and percentage changes from baseline will be plotted by 
study day with each subject and cohort being identifiable. Subjects who enter both cohorts will be 
identified in a footnote. A separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 2B, 
2C and 3 combined.  A dotted line will be used to identify follow-up (Part 3).  The actual sampling 
day will be used on the x-axis. The absolute value plots will include a reference line at Day 1 and 
the change and percentage change from baseline plots will include a reference line for 0 on the y-
axis. A reference line at Day 365 will also be added for the plot covering the whole study. 
8.2.3. 
RBC Transfusions 
All 12 month transfusion history data and on study transfusion data will be listed by Cohort.  A 
separate listing of the baseline number of transfusions per year and baseline number of units 
transfused per year relative to screening and relative to Day 1 will also be included. 
9. 
PHARMACOKINETICS 
9.1. 
CONCENTRATION DATA 
The APL-2 concentrations will be evaluated using the PK set. For Cohort 2, APL-2 concentrations 
will be summarized by study visit and dose level (270 mg or 360 mg) using descriptive statistics (and 
standard error [SE) will also be presented). The number of subjects with a BLQ value will also be 
tabulated. 
Linear and log-linear individual concentration profile plots against time will be produced with each 
subject and cohort being identifiable. Subjects who enter both cohorts will be identified in a 
footnote. A separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 2B, 2C and 3 
combined.  A dotted line will be used to identify follow-up (Part 3).  The actual sampling day will be 
used on the x-axis. 
Linear and log-linear mean (± SE) concentration plots against study visit will be generated. The 


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APL2-CP-PNH-204                                                                          
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number of subjects contributing to each mean value at a visit will be presented above the x-axis 
and a reference line at Day 365 will be included. 
A listing of all concentration data will be presented by cohort.  The actual time and deviation from 
nominal time will also be listed. 
9.2. 
PHARAMCOKINETIC DATA  
APL-2 PK parameters, AUCtotal, AUC365 Ctrough,max,total and Ctrough,max,365, will be estimated from the 
individual serum concentration time data, using a non-compartmental approach. For Cohort 2, 
Ctrough,max and Ctrough,max,365 will be calculated for both 270mg and 360mg where subjects receive both 
doses. AUCtotal and AUC365 will be calculated using the linear-log trapezoidal method. BLQ values in 
the elimination phase will be considered missing. 
PK parameters will be listed by cohort. Additionally, for Cohort 2, PK parameters will be summarized 
using descriptive statistics. Geometric mean and CV will also be presented. 
10. 
PHARMACODYNAMICS 
The PD parameters, complement parameters (CH50, AP50 and C3), C3 deposition on RBC cells 
(percent C3d CD59 Type I, II, III and II+III) clonal distribution of PNH RBCs (percent CD59 Type I, II, 
III and II+III), PNH granulocytes (percent FLAER) and PNH monocytes (percent FLAER), will be 
evaluated using the PD set. 
Absolute PD parameter values will be listed together with changes from baseline and percentage 
changes from baseline (for CH50 and AP50 percentage of baseline will be listed instead), by cohort, 
part of the study and study visit. 
For Cohort 2, complement parameter C3, absolute values, changes from baseline and percentage 
changes from baseline will be summarised, using descriptive statistics, by part of the study and 
study visit. The associated 95% confidence interval and 2-sided p-value (Student’s t-test) for the 
changes from baseline will also be presented. A similar summary will also be produced for the 
complement parameters CH50 and AP50 however percentage of baseline values will be 
summarized instead of percentage changes from baseline. For AP50 only study visits baseline, Days 
29, 85, 169 and 365 will be summarized. 
For Cohort 2, mean absolute values with 95% confidence intervals will be plotted by study visit for 
the complement parameters (C3, CH50 and AP50). The number of subjects contributing to each 
mean value at a visit will be presented above the x-axis and a reference line at Day 365 will be 
included. 
For Cohort 2, C3 deposition on RBC cells (percent C3d CD59 Type I, II, III and II+III), clonal distribution 
of PNH RBCs (percent CD59 Type I, II, III and II+III), PNH granulocytes (percent FLAER) and PNH 


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APL2-CP-PNH-204                                                                          
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monocytes (percent FLAER), absolute values and changes from baseline will be summarised, using 
descriptive statistics, by study visit. 
For Cohort 2, mean absolute values with 95% confidence intervals will be plotted by study visit for 
C3 deposition on RBC cells (percent C3d CD59 Type II+III) and clonal distribution of PNH RBCs 
(percent CD59 Type II+III). The number of subjects contributing to each mean value at a visit will be 
presented above the x-axis and a reference line at Day 365 will be included. 
Absolute values, changes from baseline and percentage changes from baseline will be plotted for 
the complement parameter C3 by study day with each subject and cohort being identifiable. 
Subjects who enter both cohorts will be identified in a footnote. A separate plot will be presented 
for Part 1 and overall i.e. Part 1, 2A, 2B, 2C and 3 combined.   A dotted line will be used to identify 
follow-up (Part 3).  The actual sampling day will be used on the x-axis. The absolute value plots will 
include a reference line at Day 1 and the change and percentage change from baseline plots will 
include a reference line for 0 on the y-axis. A reference line at Day 365 will also be added for the 
plot covering the whole study.  
For the complement parameters CH50 and AP50 only percentage of baseline values will be plotted 
by study day with each subject and cohort being identifiable. Subjects who enter both cohorts will 
be identified in a footnote. A separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 
2B, 2C and 3 combined.   A dotted line will be used to identify follow-up (Part 3).  The actual 
sampling day will be used on the x-axis. A reference line for 100 will be presented on the y-axis and 
a reference line at Day 365 will also be added for the plot covering the whole study. 
For the complement parameter C3 values throughout the study will be plotted against time for 
each subject in Cohort 2 individually (i.e. one plot per subject). On study transfusions (PRBC only) 
will be identified on the plot as a vertical line at the relevant study day. Above the profile plot a 
separate plot will be displayed which shows the APL-2 dose by study day. The study day on both 
plots will be aligned. For the complement parameters CH50 and AP50 the same plot will be 
generated using percentage of baseline values instead. 
Absolute values in PNH granulocytes (percent FLAER) will be plotted by study day with each subject 
and cohort being identifiable. Subjects who enter both cohorts will be identified in a footnote. A 
separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 2B, 2C and 3 combined.   A 
dotted line will be used to identify follow-up (Part 3).  The actual sampling day will be used on the 
x-axis. The absolute value plot will include a reference line at Day 1. A reference line at Day 365 will 
also be added for the plots covering the whole study. These plots will be repeated for PNH 
monocytes (percent FLAER). 
Individual subject plots of the percentage distribution will be presented for the C3 deposition on 
RBC cells parameters, with all parameters included on the same subject plot, for Part 1 and overall 
i.e. Part 1, 2A, 2B, 2C and 3 combined. A dotted line will be used to identify follow-up (Part 3).  The 
actual sampling day will be used on the x-axis. The plots will include a reference line at Day 1. The 


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APL2-CP-PNH-204                                                                          
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overall plots (i.e. Part 1, 2A, 2B, 2C and 3 combined) will identify on study transfusions (PRBC only) 
as a vertical line at the relevant study day; and above the profile plot a separate plot will be 
displayed which shows the APL-2 dose by study day. The study day on both plots will be aligned. 
These plots will be repeated for clonal distribution of PNH RBCs parameters. 
Clonal distribution of PNH RBCs (percent Type II + III) over time will be plotted by cohort with each 
subject being identifiable. Subjects who enter both cohorts will be identified in a footnote. A 
separate plot will be presented for Part 1 and overall i.e. Part 1, 2A, 2B, 2C and 3 combined.   A 
dotted line will be used to identify follow-up (Part 3).  The actual sampling day will be used on the 
x-axis. The plots will include a reference line at Day 1. A reference line at Day 365 will also be added 
for the plots covering the whole study. These plots will be repeated for Clonal distribution of PNH 
RBCs (percent Type III), C3d deposition on RBC cells (percent Type II + III) and C3d deposition on 
RBC cells (percent Type III). 
11. 
SAFETY 
11.1. 
EXTENT OF EXPOSURE 
For each subject the following data will be listed: 
• 
Days of dosing in Part 1 
• 
Days of dosing in Part 2A 
• 
Days of dosing in Part 2B 
• 
Days of dosing in Part 2C 
• 
Last study day of dosing 
• 
Compliance for Part 1, 2A, 2B, 2C and overall (excluding Part 2C), based on the percentage 
of days they took study medication prior to discontinuation/completion.  
Compliance is calculated as the number of days the subject took study medication divided by the 
duration the subject was in the study. If the investigator instructed the subject to stop taking study 
medication for a period of time e.g. due to an adverse event, then this period will not be included 
in the denominator for the compliance calculation. 
If subjects in Cohort 2 have their dose escalated to 360 mg/day separate information will be 
supplied for each dose.  This will also be done if subjects change their dose for any other reason, 
with rows of the listing being in chronological order. For those subjects who use the ambulatory 
syringe pump the first day of using the pump will be listed. The date of change in formulation to 
acetate-buffered sorbitol will also be listed. 
 
11.2. 
ADVERSE EVENTS 
AEs will be coded using the MedDRA version 21.0.  


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APL2-CP-PNH-204                                                                          
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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: 
• 
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. 
• 
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 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. 
Only TEAEs will be included in the summary tables. An overall summary will present the number 
of subjects by cohort and overall with: 
• 
any TEAE 
• 
any TEAE considered as related to study drug (evaluated by the investigator as Possibly 
Related or Probably Related or not reported) 
• 
any serious TEAE  
• 
Maximum intensity TEAE of none, mild, moderate, severe ; i.e. a subject with TEAEs at 
different intensities will be summarized at the most severe intensity 
• 
any TEAE leading to study drug discontinuation  
• 
any TEAE leading to death 
The table will also include the total number of TEAEs reported in each cohort and overall.  The total 
number of unique terms within subjects will also be presented, counting each PT only once within 
each subject.  
The number of subjects with TEAEs will be presented by SOC, PT and cohort. Subjects with multiple 
TEAEs within a SOC or SOC/PT combination will be counted only once for that SOC or SOC/PT 
combination. Similar summaries will be presented for related TEAEs.  
Summaries of TEAEs by maximum intensity (Mild, Moderate, or Severe) will be presented.   
All summary tables will be presented by study part, over Parts 1 to 2B (i.e. up to and including Day 
365) and over the whole study; where AEs will be categorized by the Part in which the AE started 
i.e. an AE which began during Part 1 will be categorized under Part 1 even if it continues into Part 


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APL2-CP-PNH-204                                                                          
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2A (unless it increases in severity during Part 2A, when it will be counted in both Parts 1 and 2A).  
Summaries will be ordered by descending order of total events. 
The overall summary will be based on unique subjects, so subjects who enter both cohorts will only 
be counted once.  For subjects who enter both cohorts, AEs reported in Cohort 2 will be assessed 
for treatment emergence without taking into account AEs reported in Cohort 1. 
All TEAEs will be listed by subject and start date. Separate listings of serious TEAEs and TEAEs 
leading to discontinuation of study drug will also be generated.  The listing will also include the 
onset time since last dose, duration of AE, part of the study the AE started and the part of the study 
the AE stopped. 
11.3. 
LABORATORY EVALUATIONS 
For Cohort 2, observed and change from baseline values will be summarized for all hematology, 
chemistry and coagulation clinical laboratory parameters using descriptive statistics, by part of the 
study and study visit.   
A shift table from baseline (with marginal totals) of normal, abnormal low, abnormal high and 
missing records will also be summarised for hematology, chemistry and coagulation clinical 
laboratory parameters by cohort and study part and study visit, using frequency counts and 
percentages. 
Clinical laboratory data will be listed by cohort.  The listing will identify the study part and will 
include changes from baseline values and values that are outside the reference range will be 
flagged. Out of range laboratory results with their corresponding changes from baseline will also 
be listed. 
11.4. 
IMMUNOGENICITY DATA 
Immunogenicity data will be listed by cohort. 
11.5. 
VITAL SIGNS 
For Cohort 2, observed and change from baseline values will be summarized for all vital signs 
parameters using descriptive statistics, by part of the study and study visit.  
Absolute values and changes from baseline values will be listed by cohort. In the listing, values of 
potential clinical importance will be flagged.  These are defined as: 
• 
Systolic blood pressure ≤80mmHg or ≥165mmHg 
• 
Diastolic blood pressure ≤40mmHg or ≥95mmHg 
• 
Pulse ≤40bpm or ≥120bpm 
• 
Temperature ≥38oC 


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APL2-CP-PNH-204                                                                          
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The number of subjects satisfying each of the criteria specified below will also be summarized for 
the safety set by cohort and by  study part, over Parts 1 to 2B (i.e. up to and including the Day 365 
visit) and over the whole study. 
Systolic blood pressure: 
• 
all values within 80mmHg and 165mmHg 
• 
at least one value ≤ 80mmHg and none ≥ 165mmHg 
• 
at least one value ≥ 165mmHg and none ≤ 80mmHg 
• 
at least one value ≤ 80mmHg and at least one value ≥ 165mmHg 
Diastolic blood pressure: 
• 
all values within 40mmHg and 95mmHg 
• 
at least one value ≤  40mmHg none ≥ 95mmHg 
• 
at least one value ≥ 95mmHg none ≤  40mmHg 
• 
at least one value ≤  40mmHg and at least one value ≥ 95mmHg 
Pulse: 
• 
all values within 40bpm and 120bpm 
• 
at least one value ≤ 40bpm and none ≥ 120bpm 
• 
at least one value ≥ 120bpm and none ≤ 40bpm 
• 
at least one value ≤ 40bpm and at least one value ≥ 120bpm 
Temperature: 
• 
all values < 38 oC 
• 
at least one value ≥ 38 oC 
11.6. 
ECG 
For Cohort 2, observed and change from baseline values will be summarized for all ECG 
continuous data parameters using descriptive statistics, by part of the study and study visit.  
Observed and change from baseline values will be listed by cohort.  In the listing, values of 
potential clinical importance will be flagged.  These are defined as: 
• 
QT, QTcB, QTcF ≥450 msec 
• 
QT, QTcB, QTcF increase from baseline ≥30 msec 
• 
PR  ≤100msec or ≥240msec 
• 
QRS  ≥140msec 
• 
Heart rate ≤40bpm or ≥120bpm 
 
The number of subjects satisfying each of the criteria specified below will also be summarized for 
the safety set by cohort and by  study part, over Parts 1 to 2B (i.e. up to and including the Day 365 
visit) and over the whole study.  


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APL2-CP-PNH-204                                                                          
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QT, QTcB, QTcF: 
• 
all values < 450 msec 
• 
at least one value ≥ 450 msec and < 500 msec 
• 
at least one value ≥ 500 msec 
and 
• 
all changes from baseline < 30 msec 
• 
at least one change from baseline ≥ 30 msec and < 60 msec 
• 
at least one change from baseline ≥ 60 msec 
PR: 
• 
all values within 100msec and 240msec 
• 
at least one value ≤ 100msec and none ≥ 240msec 
• 
at least one value ≥ 240msec and none ≤ 100msec 
• 
at least one value ≤ 100msec and at least one value ≥ 240msec 
QRS: 
• 
all values < 140msec  
• 
at least one value ≥ 140msec 
Heart rate: 
• 
all values within 40bpm and 120bpm 
• 
at least one value ≤ 40bpm and none ≥ 120bpm 
• 
at least one value ≥ 120bpm and none ≤ 40bpm 
• 
at least one value ≤ 40bpm and at least one value ≥ 120bpm 
 
11.7. 
PHYSICAL EXAMINATION 
Physical examination data will be listed by cohort. 
12. 
INTERIM ANALYSES 
The SMC reviewed safety/tolerability, PK and PD data after Part 1 (Day 28) of Cohort 1 was 
completed. This data was used to decide whether to proceed to Cohort 2 and the dose level to use 
in Cohort 2.  The same review process will be followed if any additional cohorts are added to the 
study. 
In addition, the SMC are responsible for conducting regular (monthly) safety reviews during the 
treatment phase of the study. 
The remit, roles and responsibilities of the SMC are specified in a separate SMC charter. 


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APL2-CP-PNH-204                                                                          
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An interim report (Dated 18th May 2017) was prepared based on all Cohort 1 subjects and the first 
3 subjects enrolled in Cohort 2 (i.e. those recruited under protocol versions up to and including 
Amendment 4).  The interim report included data collected up to the end of Part 2A for subjects 
who completed Part 2A or to the end of Part 3 if they didn’t enter Part 2A.  Further reports may be 
prepared with each report containing cumulative information. These reports will be performed on 
data that will have been fully checked and considered as final. Any changes to the data previously 
reported will be fully auditable and discussed in the subsequent reports. 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
The changes from the analyses specified in the protocol are: 
• Total bilirubin was not included as a secondary endpoint in the protocol but has been 
included in the SAP so this endpoint can be investigated further. Similarly, PNH 
granulocytes (percent FLAER) and PNH monocytes (percent FLAER) were not included as 
PD endpoints in the protocol but have been included in the SAP. 
• No formal statistical testing is planned for this study however for Cohort 2 comparisons to 
baseline will be performed.