Clinical trial NCT02264639
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: PNH Paroxysmal Nocturnal Hemoglobinuria Complement inhibitor Anemia Hemoglobinuria hematologic diseases extravascular hemolysis (EVH) intravascular hemolysis (IVH) C3 inhibitor
Sponsor: Apellis Pharmaceuticals, Inc.
Start date: 2015-02-23; Completion date: 2018-10-22
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be the initial exploration of pegcetacoplan in patients with PNH. The assessments of the safety, tolerability, PK, and PD following administration of single and multiples doses of pegcetacoplan will guide decisions to further develop the drug.

Detailed description:

Arms: arm 1: First Dose 25mg, Repeated Dose 5 mg/day arm 2: First Dose 50 mg, Repeated Dose 30 mg/day arm 3: Repeated Dose 180 mg/day arm 4: Repeated Dose 270 mg/day
Interventions: intervention 1: Pegcetacoplan
Intervention descriptions: intervention 1: Complement (C3) Inhibitor

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Protocol No.: APL-CP0514 
 
 
 
 
An Open Label, Single and Multiple Ascending Dose Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of APL-2  
as an Add-On to Standard of Care in Subjects  
with Paroxysmal Nocturnal Hemoglobinuria (PNH). 
Phase: 
1 
Version: 
Version 4.0, Amendment 7 
Date: 
June 15, 2017 
 
 
 
 
 
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 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 2 of 72 
1. SYNOPSIS 
Protocol Number 
APL-CP0514 
Protocol Version 
and Date 
Version 4.0 Amendment 7 
June 15, 2017 
Compound 
APL-2 
Study Phase and 
Type 
Phase 1, open-label, prospective, non-randomized, single and 
multiple ascending dose, first-in-human study in patients with PNH 
Study Objectives 
The primary objectives of the study are to assess the safety, 
tolerability and pharmacokinetics of single and multiple subcutaneous 
(SC) doses of APL-2 in subjects with paroxysmal nocturnal 
hemoglobinuria (PNH) who are still anemic after treatment with 
eculizumab (Soliris®). 
An exploratory objective of the study is to assess the 
pharmacodynamics (PD) of single and multiple SC doses of APL-2 
when administered to PNH patients. See “Pharmacodynamic 
Assessment” below. 
Study Population 
Subjects will: 
x be male and female (using contraception as specified in the 
protocol) at least 18 years of age  
x have a diagnosis of PNH and still be anemic (after being 
treated with eculizumab (Soliris®) for at least 3 months prior to 
screening. 
Number of Subjects The study is planned to enroll approximately 15 subjects across 4 
Cohorts. Cohorts 1-3 will comprise 2 subjects in each cohort. Cohort 4 
will enroll sufficient subjects to ensure at least 6 subjects complete 28 
days dosing with APL-2. Subjects may participate in more than one 
cohort. Additional cohorts may be enrolled if it is deemed appropriate 
by the Sponsor in consultation with the Safety Monitoring Committee 
(SMC) to repeat a dose level or to study an interim dose level. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 3 of 72 
Inclusion Criteria 
x Male or Female 
x At least 18 years of age 
x Weigh >55 kg  
x Diagnosed with PNH 
x On treatment with eculizumab (Soliris®) for at least 3 months 
x Hb <10 g/dL at screening OR have received at least one transfusion 
within 12 months prior to screening 
x Platelet count of >30,000/mm3 
x Absolute neutrophil count >500/mm3 
x 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 
x Males must agree to use protocol defined methods of contraception and 
agree to refrain from donating sperm for the duration of the study 
x Willing and able to give informed consent 
Exclusion Criteria 
x Active bacterial infection 
x Known infection with hepatitis B, C or HIV 
x Hereditary complement deficiency 
x History of bone marrow transplantation 
x Participation in any other investigational drug trial or exposure to other 
investigational agent, device or procedure within 30 days 
x Evidence of QTcF prolongation defined as >450 ms for males and >470 
ms for females at screening 
x Creatinine clearance (CrCl) <50 mL/min (Cockcroft-Gault formula) at 
screening 
x Breast-feeding women 
x History of meningococcal disease 
x No vaccination against N. 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 within 
2 years prior to Day 1 dosing.  
Endpoints 
The primary endpoints of the study are the number and severity of TEAEs 
and pharmacokinetics parameters of APL-2 following administration of 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 4 of 72 
single and multiple SC doses. 
 
Exploratory pharmacodynamics markers include: 
x Complement (e.g., CH50, AH50, and C3) levels 
x C3 deposition on RBC cells 
x Hemoglobin 
x Reticulocytes 
x Lactate dehydrogenase (LDH) 
x Bilirubin 
x Clonal distribution of PNH vs normal bone marrow derived cells 
Planned Dose 
Levels 
Planned doses will be as follows: 
Cohort 
Planned dosing schedule (Amendment 5) 
1 
25 mg on Day 1 then 5 mg/day from Day 29 to Day 56 
2 
50 mg on Day 1 then 30 mg/day from Day 29 to Day 56 
3 
180 mg/day from Day 1 to Day 28 
4 
270 mg/day from Day 1 to Day 729* with optional 
intrasubject escalation up to 360 mg/day after Day 28** 
*Subjects may initially receive APL-2 for 28 days (Part 1) and if there is evidence of 
clinical benefit they may continue to receive APL-2 until Day 84 (Part 2A) and if 
there is ongoing evidence of clinical benefit they may continue to receive APL-2 
until Day 364 (Part 2B). If subjects continue to have clinical benefit they may receive 
APL-2 until Day 729 (Part 2C).     
** Individual patient dose escalation up to a dose of 360 mg/day may occur in 
subjects who have a sub-optimal hematological response but acceptable 
tolerability. 
Repeat of any cohort or the addition of interim dose level may be 
added, as determined by the Sponsor in consultation with the Safety 
Monitoring Committee (SMC), depending on the safety results from 
the prior cohort(s). 
Study Design 
This is a prospective, non-randomized, single and multiple ascending 
dose study. Four Cohorts are planned for evaluation. Subjects in 
Cohorts 1 and 2 will receive a single dose of APL-2 followed by a 28-
day waiting period before receiving daily doses for 28 days. Subjects 
in Cohort 3 will receive multiple doses (daily dosing) for 28 days. 
Subjects in Cohort 4 will receive multiple doses (daily dosing) for 28 
days and if, following review of available safety and PD data available 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 5 of 72 
 
 
within the first 28 days, subjects have shown evidence of clinical 
benefits, as assessed by the Investigator and Sponsor, they may 
progress to Part 2A of the study and continue to receive daily doses 
of APL 2 until Day 84 and to Part 2B of the study and continue to 
receive daily doses of APL-2 until Day 364. If subjects continue to 
have clinical benefit they may receive APL-2 until Day 729 (Part 2C).  
Subjects may participate in more than one cohort. 
Safety will be assessed throughout the study; serial blood samples 
and urine samples will be collected for these assessments. Blood 
samples will also be collected for the PK assessment of APL-2. 
Additional samples for assessment of PD will also be collected. 
Interim PK analyses may be performed to reconsider the sampling 
time points and dose escalations as the study progresses. 
For prior study design including the dosing schedule for Cohorts 1 to 
3, refer to prior versions of the protocol.  
Subjects in Cohort 4 will initially receive 270 mg SC APL-2 daily for 28 
days. Subjects will be entered into the study at Visit 2 (Day 1) at a 
time designated by the PI and will receive daily SC doses of APL-2 at 
Visits 2 to 29 (Days 1 to 28). The first 4 daily SC doses of APL-2 (Visits 
2 to 5) as well as doses at Visits 9, 16 and 23 will be administered at 
the clinical site. Subjects will remain in the clinic for at least 4 hours 
after the first dosing at Visit 2. 
Following ongoing review of available safety, PK and PD data by the 
Investigator and Sponsor, subjects showing evidence of clinical 
benefit may progress to Part 2A, then to Part 2B and then to Part 2C 
of the study and may continue to receive daily doses of APL-2 until 
Day 84, then until Day 364, and then until Day 729. Doses will be 
administered off-site at the subject’s home, workplace, or other 
location convenient to the subject, with the exception of Visits 30, 44, 
58, 72, 86, 114, 142, 170, 198, 226, 254, 282, 310, 338, 366, 367, 368, 
369, 370, and 371 (Days 29, 43, 57, 71, 85, 113, 141, 169, 197, 225, 
253, 281, 309, 337, 420, 476, 532, 616, and 729 respectively) and with 
the exception of up to 3 additional site Visits, if individual dose 
escalation occurs for subjects administered >270 mg/day SC APL-2, 
where dosing will occur at the clinical site. After conclusion of the 
Part 2C treatment period on Visit 371 (Day 729), subjects will return 
to the clinical site for final study procedures at an Exit Visit on Day 
785 See Study Flow Chart. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 6 of 72 
TABLE OF CONTENTS 
1. SYNOPSIS ................................................................................................................................. 2 
AMENDMENT 1 ............................................................................................................................... 9 
AMENDMENT 2 ............................................................................................................................. 12 
AMENDMENT 3 ............................................................................................................................. 13 
AMENDMENT 4 ............................................................................................................................. 15 
AMENDMENT 5 ............................................................................................................................. 18 
AMENDMENT 6 ............................................................................................................................. 19 
2. STUDY FLOW CHART ............................................................................................................ 22 
3. ABBREVIATIONS .................................................................................................................... 28 
4. INTRODUCTION...................................................................................................................... 30 
4.1 
Background ..................................................................................................................... 30 
4.1.1 
Paroxysmal Nocturnal Hemoglobinuria ................................................................... 30 
4.1.2 
APL-2 ....................................................................................................................... 30 
4.2 
Rationale ......................................................................................................................... 37 
4.2.1 
Purpose of the Study ............................................................................................... 37 
4.2.2 
Dose Selection ......................................................................................................... 37 
4.3 
Risk/Benefit ..................................................................................................................... 39 
5. STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 40 
5.1 
Study Objectives ............................................................................................................. 40 
5.2 
Study Endpoints.............................................................................................................. 40 
6. STUDY DESIGN ...................................................................................................................... 41 
7. SUBJECT SELECTION ........................................................................................................... 42 
7.1 
Inclusion Criteria ............................................................................................................. 42 
7.1.1 
Approved methods of contraception ........................................................................ 42 
7.2 
Exclusion Criteria ............................................................................................................ 42 
8. STUDY TREATMENTS ........................................................................................................... 43 
8.1 
Allocation to Treatment ................................................................................................... 43 
8.2 
Blinding ........................................................................................................................... 43 
8.3 
Treatments Administered ............................................................................................... 43 
8.3.1 
Drug supplies ........................................................................................................... 43 
8.3.2 
Planned Dose Levels ............................................................................................... 44 
8.3.3 
Drug Administration ................................................................................................. 45 
8.3.4 
Additional Dose Levels ............................................................................................ 45 
8.4 
Concomitant Medications ............................................................................................... 45 
8.4.1 
Vaccinations ............................................................................................................ 45 
8.4.2 
Prophylactic antibiotics ............................................................................................ 46 
9. STUDY PROCEDURES .......................................................................................................... 46 
9.1 
Screening (Visit 1) .......................................................................................................... 46 
9.2 
Treatment Period (Visits 2 to 36) .................................................................................... 47 
9.2.1 
Dosing Period (Visits 2 to 365) ................................................................................ 47 
9.2.2 
Exit Visits (Visit 372) ................................................................................................ 48 
9.2.3 
Unscheduled Follow-up Visits ................................................................................. 48 
9.2.4 
Scheduled End of Study .......................................................................................... 48 
9.3 
Dose Escalation and Periodic Safety Review ................................................................ 48 
9.3.1 
Safety Monitoring Committee .................................................................................. 49 
9.4 
Removal of Subjects from the Study .............................................................................. 50 
10. ASSESSMENTS ...................................................................................................................... 50 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 7 of 72 
10.1 
Safety Assessments ..................................................................................................... 50 
10.1.1 
Body Height and Weight ........................................................................................ 50 
10.1.2 
Physical Examination............................................................................................. 51 
10.1.3 
Vital Signs .............................................................................................................. 51 
10.1.4 
Electrocardiogram Monitoring ................................................................................ 51 
10.1.5 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale ......... 51 
10.1.6 
Clinical Laboratory Tests ....................................................................................... 52 
10.1.7 
Injection Site Assessment ..................................................................................... 53 
10.2 
Pharmacokinetic Assessments ..................................................................................... 53 
10.2.1 
Blood Sampling and Processing ............................................................................ 53 
10.2.2 
Analytical Method .................................................................................................. 54 
10.3 
Pharmacodynamic Assessments ................................................................................. 54 
10.4 
Blood Volume for Study Assessments ......................................................................... 55 
10.5 
Pregnancy tests ............................................................................................................ 55 
11. ADVERSE EVENTS ................................................................................................................ 55 
11.1 
Definitions ..................................................................................................................... 55 
11.2 
Recording Adverse Events ........................................................................................... 56 
11.3 
Assessment of Adverse Events .................................................................................... 56 
11.3.1 
Intensity ................................................................................................................. 56 
11.3.2 
Causality ................................................................................................................ 57 
11.3.3 
Serious Adverse Event .......................................................................................... 58 
11.4 
Reporting Serious Adverse Event ................................................................................ 58 
11.5 
Adverse Events of Special Interest............................................................................... 59 
11.6 
Unexpected Adverse Events or Unexpected Suspected Adverse Reactions .............. 59 
11.7 
Treatment and Follow up of Adverse Events ............................................................... 60 
11.8 
Pregnancy ..................................................................................................................... 60 
12. STATISTICS ............................................................................................................................ 60 
12.1 
Sample Size Justification .............................................................................................. 60 
12.2 
Statistical Analysis Methodology .................................................................................. 60 
12.2.1 
Study Analysis Datasets ........................................................................................ 61 
12.3 
Study Endpoints............................................................................................................ 61 
12.3.1 
Efficacy Endpoint ................................................................................................... 61 
12.3.2 
Safety Endpoints .................................................................................................... 61 
12.3.3 
Pharmacokinetic Endpoints ................................................................................... 61 
12.4 
Efficacy Analysis ........................................................................................................... 61 
12.5 
Safety Analysis ............................................................................................................. 62 
12.5.1 
Total Exposure ....................................................................................................... 62 
12.5.2 
Adverse Events ...................................................................................................... 62 
12.5.3 
Clinical Laboratory Tests ....................................................................................... 62 
12.5.4 
Vital Signs .............................................................................................................. 62 
12.5.5 
ECGs ..................................................................................................................... 63 
12.6 
Handling of Dropouts and/or Missing Data ................................................................... 63 
12.7 
Examination of Subgroups ........................................................................................... 63 
12.8 
Enumerated Data.......................................................................................................... 63 
12.9 
Pharmacokinetic Analysis ............................................................................................. 63 
12.10 Pharmacodynamic Analysis ......................................................................................... 64 
12.11 Antigenicity Analysis..................................................................................................... 64 
12.12 Interim Analysis ............................................................................................................ 64 
12.12.1 Safety (optional) ................................................................................................... 64 
13. ADMINISTRATIVE CONSIDERATIONS ................................................................................. 64 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 8 of 72 
13.1 
Direct Access to Source Data/Documents ................................................................... 64 
13.2 
Quality Control and Quality Assurance ........................................................................ 65 
13.2.1 
Monitoring .............................................................................................................. 65 
13.3 
Ethics ............................................................................................................................ 65 
13.3.1 
Ethical Conduct of the Study ................................................................................. 65 
13.3.2 
Institutional Review Board/Ethic Committee ......................................................... 65 
13.3.3 
Subject Information and Consent .......................................................................... 66 
13.3.4 
Confidentiality ........................................................................................................ 66 
13.3.5 
ClinicalTrials.gov .................................................................................................... 66 
13.3.6 
Termination of Study.............................................................................................. 66 
13.4 
Data Handling and Record Keeping ............................................................................. 66 
13.5 
Protocol Amendments .................................................................................................. 67 
13.6 
Report Format ............................................................................................................... 67 
13.7 
Finance and Insurance ................................................................................................. 67 
13.8 
Publication Policy.......................................................................................................... 67 
14. REFERENCES......................................................................................................................... 68 
15. APPENDIX 1: FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT) FATIGUE SCALE ................................................................................................ 69 
16. APPENDIX 2: ASSESSMENT OF LOCAL INJECTION SITE REACTIONS ........................... 72 
 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 9 of 72 
AMENDMENT 1 
Revision 1: Inclusion Criteria #1: The upper age limit of 65 years for inclusion will be removed. 
Rationale: Although the median age of the 1610 patients enrolled in the international PNH 
registry (as of June 30, 2012) was 42 years old; the range is 3 to 99 years old (Schrezenmeier, 
2014). This update to the inclusion criteria will allow collection of data on APL-2 across a wider 
range of the adult PNH population and better support subsequent clinical studies. 
Section updated: Section 7.1 
 
Revision 2: Inclusion Criteria #6 and #7: Hemoglobin (Hb) level and transfusion inclusion 
criteria were combined into a single criterion to allow patients with Hb <10 g/dL at screening 
OR at least one transfusion within the last 12 months. 
Rationale: The previous inclusion criteria requiring pre-transfusion Hb<10 g/dL at the last 
transfusion AND last transfusion within 12 months prior to screening is causing confusion. The 
pre-transfusion Hb value is not always available to the investigator and a value of <10 g/dL is 
implicit as the criteria for transfusion in PNH subjects is generally Hb<10 g/dL. The addition of 
Hb <10 g/dL at screening ensures that subjects are still anemic despite treatment with Soliris® 
even if they have not received a transfusion in the past year. 
Section updated: Section 7.1 
 
Revision 3:  Exclusion Criteria #7: Creatinine clearance (CrCl) (Cockcroft-Gault formula) will be 
amended from <60 mL/min to <50 mL/min. 
Rationale: Mild to moderate reduction in glomerular filtration rate (GFR) is commonly seen in 
the PNH patient population. Report from Phase III studies with Soliris® indicate that 65% of 
patients presented renal dysfunction (GFR <60 mL/min/1.73m2) at baseline with 21 % of 
patients being at the later stage of Chronic Kidney Disease (CKD) or kidney failure. Whereas 
approximately 30% of patients improve after treatment with Soliris® (mostly those with Stage 
1 or 2 CKD), close to 70% of patients do not improve and can even worsen (Hillmen, 2010). 
This is of relevance as the target population for this current trial is patients who are not fully 
responding to Soliris®. A reduction in the minimum CrCl required for inclusion will allow 
patients with moderate reduction in GFR (CKD Stage 3A) to participate in the study while 
more severe GFR reductions (CKD Stages 3B to 5) will continue to be excluded. 
Section updated: Section 7.2 
 
 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 10 of 72 
Revision 4: Multiple doses for cohort 2, 3 and 4 will be updated as follows: 
 
 
Single SC dose 
(day 1) 
Unchanged 
Multiple SC dose 
(days 29 to 56) 
Original Protocol 
Multiple SC dose 
(days 29 to 56) 
Amendment 1 
Cohort 1  
25 mg APL-2 
5 mg APL-2 / day 
5 mg APL-2 / day 
Cohort 2  
50 mg APL-2 
10 mg APL-2 / day 
30 mg APL-2 / day 
Cohort 3  
100 mg APL-2 
20 mg APL-2 / day 
90 mg APL-2 / day 
Cohort 4  
200 mg APL-2 
40 mg APL-2 / day 
180 mg APL-2 / day 
Rationale: The doses were updated based on emerging safety, pharmacokinetic and 
pharmacodynamics data from ongoing studies in healthy subjects currently conducted in 
Australia summarized in section 4.1.2.2.2. Rationale for this change is described in the 
updated Section 4.2.2 of this document.  
Sections Updated: Sections 4.1.2.2.2, 4.2.2 and 8.3.2 
 
Revision 5: Description of the investigational product has been updated to include a 
lyophilized product formulation to be used for the higher doses. 
Rationale: For reasons of stability and flexibility, the drug product is now being produced as 
lyophilized vials that are reconstituted just prior to administration. This new presentation will 
be used for the repeated dose portion of the trial at the higher doses. 
Section updated: Section 8.3.1  
 
Revision 6: Removal of pre-defined stopping rules and creation of an independent Safety 
Monitoring Committee (SMC).  
Rationale: Previously, the transition to multiple dosing and escalation to the next cohort 
would occur only after review of safety data for both subjects in the preceding cohort. This is 
problematic as both patients in a cohort would need to be scheduled to commence dosing in 
parallel on the same day, which is unfeasible given the low numbers of patients with PNH. 
Otherwise, it would result in every patient having a different window between single and 
multiple dosing and consequently being enrolled into study for different lengths of time. This 
creates a logistical challenge for the sites and makes comparison of data across patients very 
difficult.  
The new dose escalation scheme will follow the same schedule as previously stipulated (i.e. 28 
days between single and multiple dosing). However: 
The transition to multiple dosing within a subject will occur automatically once the subject has 
completed the 28-day waiting period.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 11 of 72 
Dose escalation and initiation of a subsequent cohort will only occur once both subjects in the 
preceding cohort have completed the single-dose 28-day waiting period. 
The above transitions would not occur if modification, or stopping of the study, is proposed by 
the SMC following their regular review. 
An independent SMC will be convened to include at minimum a hematologist with PHN 
experience and an infectious disease specialist. The SMC decisions will not be guided by pre-
defined stopping rules as they will have total authority to stop any dose escalation (or the 
study) at any time because of any safety concern beyond the pre-defined incidence of SAEs or 
Grade 3 toxicities. The SMC will meet every 4 weeks and review all available cumulative 
safety, PK and PD data. The SMC meeting will not always coincide with the dose escalations 
but this high frequency review of cumulative data will provide assurance of ongoing patient 
safety. 
Section Updated: Section 9.3 
 
Revision 7: Addition of an Adverse Events of special interest section. 
Rationale: This section includes AE of scientific and medical concern specific to the product or 
program where ongoing monitoring and rapid communication by the Investigator to the 
Sponsor may be appropriate. In addition, occurrence of these AEs will be presented separately 
to the SMC. 
Section Updated: Section 11.5 
 
Additional Revisions: Editorial changes have been made throughout the protocol for clarity or 
corrections. 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 12 of 72 
Amendment 2 
Revision 1: Inclusion Criteria #3: The weight and BMI criteria have been revised. 
Rationale: The weight and BMI restriction has significantly limited the number of patients 
eligible to participate in this clinical study. Preliminary pharmacokinetic (PK) data from 
ongoing studies suggests that the impact of this update will be negligible with respect to 
exposure. This update to the inclusion criteria will allow collection of data on APL-2 across a 
wider range of the adult PNH population and better support subsequent clinical studies. 
Section updated: Section 7.1 
 
Revision 2: Clarification with respect to reporting of Adverse Events (AEs) of special interest. 
Rationale: The section has been updated to include thrombosis as an AE of special interest 
and to reflect the fact that these events will be reported promptly and only within 24 hours if 
they fulfill the SAE criteria. 
Section Updated: Section 11.5 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 13 of 72 
AMENDMENT 3 
Revision 1: Protocol updated to remove single dosing period for Cohorts 3 and 4. 
Rationale:  
1. The first in human single dose study in healthy volunteers has been completed and 
doses up to and including 1440 mg have been tested providing safety and PK data to 
support moving directly into multiple dosing in this study.  
2. Recruitment of patients will be less problematic if the period of single dosing and its 
associated monitoring is removed as the study duration will be shorter 
Sections updated:  All relevant sections (including the Study Flow Chart) throughout the 
protocol (other than stated objectives) have been updated to remove the single dosing period 
for Cohorts 3 and 4. 
 
Revision 2: Multiple doses for cohorts 3 and 4 will be updated as follows: 
 
Multiple SC dose 
(days 29 to 56) 
Amendment 1 
Multiple SC dose 
(days 1 to 28) 
Amendment 3 
Cohort 1  
5 mg APL-2 / day 
N/A 
Cohort 2  
30 mg APL-2 / day 
N/A 
Cohort 3  
90 mg APL-2 / day 
180 mg APL-2 / day 
Cohort 4  
180 mg APL-2 / day 
270 mg APL-2 / day 
Rationale: The doses were updated based on emerging safety, pharmacokinetic and 
pharmacodynamics data from ongoing studies in healthy subjects currently conducted in 
Australia where multiple doses up to 270 mg/day for 28 days have been administered to 
healthy volunteers. This data is summarized in section 4.1.2.2.2. Rationale for this change is 
described in the updated Section 4.2.2 of this document.  
Sections Updated: Sections 4.1.2.2.1, 4.1.2.2.2, 4.2.2 and 8.3.2 
 
Revision 3: Prophylactic immunization requirement at screening updated to include N. 
meningitides type B (in addition to types A, C, W, Y), Pneumococcal conjugate vaccine or 
Pneumococcal polysaccharide vaccine 23 (PCV13 or PPSV23, respectively) and Haemophilus 
influenzae Type B (Hib) vaccination within 2 years prior to Day 1 dosing. Boosters for N. 
meningitides types A, C, W, Y and B (administered as two separate injections) will also be 
administered during the study. 
Rationale: This update provides broader prophylactic coverage against a range of infectious 
organisms to which subjects might be susceptible to during complement inhibition and allows 
use of Penicillin V rather than Augmentin (see revision 4 below). 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 14 of 72 
Section updated:  Sections 4.3 and 7.11 
 
Revision 4: Prophylactic antibiotics updated to include Penicillin V as first line therapy 
commencing on Day 1 of dosing. 
Rationale: The amended immunization program at screening allows the use of penicillin V 
rather than Augmentin as first line prophylaxis. Penicillin V is generally better tolerated by 
subjects for long term administration i.e. greater than 7-10 days.  
Section updated:  Sections 4.3 7.11 and 8.4 
 
Revision 5: Updates to address points that required clarification  
1. Updated to include LDH at screening as well as other time points as previously omitted 
in error 
2. Updated to include GGT as part of clinical chemistry testing as previously omitted in 
error. 
3. Blood volume table updated to show blood volumes relating to updated protocol i.e. 
removal of single dosing period  
Rationale: Editorial updates required for consistency and clarification 
Section updated:  Various throughout the document 
 
Revision 6: Drug presentation updated to reflect new doses for Cohorts 3 and 4  
Rationale: Increased doses require update to the Study Treatment sections of the protocol to 
reflect the correct presentation of APL-2 
Section updated:  Section 8 
 
Revision 7: Statistical Section Updated 
Rationale: The Statistical Section of the protocol has been updated to be consistent with the 
Statistical Analysis Plan (SAP). The SAP provides the detail around the proposed statistical 
analyses and has also been updated to reflect the protocol amendment. Information that was 
previously updated within the SAP has either been removed or updated within the body of 
the protocol to ensure consistency between documents. 
Section updated:  Section 12 
 
 


 APL-2
Ascending Dose / First in Human / PNH Add-on to SOC
Apellis Pharmaceuticals, Inc. 
Protocol Number: APL-CP0514
V4.0 Amendment 7
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 - CONFIDENTIAL
Page 15 of 72
AMENDMENT 4 
Background: 
Since the initiation of this study, emerging data from this and other clinical studies has 
become available providing additional evidence of pharmacological activity of APL-2 at doses 
≥ 180 mg/day. 
In a multiple dose healthy volunteer study (APL-CP1014) a significant decrease in complement 
mediated hemolytic activity was observed in all APL-2 treated subjects dose levels of 180 and 
270 mg/d. The inhibition of hemolytic activity observed at 180 mg/d was partial in all subjects 
but was essentially complete in 3 out of 4 subjects at 270 mg/d 
In this study (APL-CP0514) two subjects have completed cohort 3 dosing receiving a dose of 
180 mg/d for 28 days. Both subjects showed clinical improvements, consistent with related 
changes in blood biomarkers. 
 
 
 
 
 
 
 
  
In a study in PNH patients who are not receiving eculizumab (PADDOCK), two subjects have 
received APL-2 doses of 180 mg/d for 28 days. 
 
 
 
 
 
 
 
 
 
These initial data suggest that daily SC administration of APL-2 at doses of 180 mg/d or higher 
can provide sustained inhibition of hemolytic activity in PNH patients. APL-2 may, therefore, 
provide clinical benefit to subjects with PNH who have not received eculizumab treatment or 
have a suboptimal response to eculizumab treatment.  
Longer term APL-2 dosing and increased subject numbers are required to obtain additional 
safety and evidence of activity data to support the design Phase II/III studies. 
Administration of APL-2 at the proposed dose for Cohort 4 (270 mg/d) is expected to result in 
APL-2 exposure in subjects (Cmax and AUC) lower than what has been deemed safe for up to 3 
months of SC administration in monkeys. In clinical studies, the same dose has already been 
shown to be well-tolerated for 28 days in a healthy volunteer study. Based on this data we 
PPD
PPD


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 16 of 72 
propose to extend administration of APL-2 to subjects in Cohort 4 for up to 84 days (12 weeks) 
if clinical benefits of the treatment can be established within the first 28 days of dosing. 
 
Revision 1: 
Increase number of subjects in Cohort 4 to at least N=6 to complete 28 days of dosing. 
Rationale:  
To obtain additional safety data and evidence of activity at a pharmacological dose. 
Sections updated: Synopsis and Sections 6 and 7. 
 
Revision 2: 
Allow for dosing period to be extended up to 84 days, contingent on perceived benefits. 
Subjects in Cohort 4 will receive multiple doses (daily dosing) for 28 days and if, following 
review of available safety and PD data, subjects have shown evidence of clinical benefits as 
assessed by the Investigator and Sponsor, they may progress to Part 2 of the study and 
continue to receive daily doses of APL 2 until Day 84. 
Rationale:  
To obtain long term safety data and evidence of activity at a pharmacological dose. 
Sections updated: Synopsis and Sections 2, 4.3, 6, 9.2 and 9.3 
 
Revision 3: Subjects may participate in more than 1 cohort. 
Rationale: The beneficial response was seen in the two subjects who received APL-2 180 mg/d 
for 28 days may increase at the higher dose of 270 mg/d. Based on the effect observed and 
the availability of additional toxicology data to support dosing beyond 28 days, participation in 
more than 1 cohort does not pose additional undue risk and has a reasonable likelihood of 
providing additional clinical benefits to patient. 
Sections updated: Synopsis and Sections 6 and 7 
Revision 4: Inclusion Criterion #3: The Body Mass Index criterion has been removed. 
Rationale: The weight and BMI restriction has significantly limited the number of patients 
eligible to participate in this clinical study. Inclusion criterion #3 had already been revised in 
Amendment 2 (August 12, 2015) based on PK data from ongoing studies at the time. Later, 
based on the data collected in the healthy volunteer studies, a population PK model was 
developed to characterize the relationship between APL-2 serum concentrations with dose 
and time. Using the developed population PK model the possible relationships between PK 
concentration and subject characteristics such as weight, BMI and gender have been explored. 
Based on the limited ranges, the impact of weight and BMI on key PK parameters appears to 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 17 of 72 
be small. Amending the inclusion criteria to allow for subjects with higher BMI and/or weight 
to be enrolled would provide useful information to explore these covariates further. 
Sections updated: Synopsis and Section 7.1 
 
Revision 5: Prophylactic immunization requirement for Pneumococcus at screening updated 
to include a dose of PCV 13 at least 2 weeks prior to Day 1 followed by a dose of PPSV23 at 
least 8 weeks later. 
Rationale: This update follows the Center for Disease Control and Prevention’s (CDC) 
recommendations for Pneumococcal vaccine in patients with immunocompromissing 
conditions. 
Section updated:  Sections 2, 4.3 and 8.4 (new section 8.4.1) 
 
Additional Revisions: Editorial changes have been made throughout the protocol for clarity or 
corrections. 


 APL-2
Ascending Dose / First in Human / PNH Add-on to SOC
Apellis Pharmaceuticals, Inc. 
Protocol Number: APL-CP0514
V4.0 Amendment 7
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 - CONFIDENTIAL
Page 18 of 72
AMENDMENT 5 
Background: 
On September 29, 2016, the SMC met to review all available safety data and make a decision 
on extension of dosing for subjects in Cohort 4. At that time, Cohorts 1, 2, and 3 had 
completed and six subjects had been enrolled into Cohort 4 (3 subjects receiving ongoing 
treatment with APL-2 and 3 subjects scheduled to commence treatment during the month of 
October 2016). Subjects enrolled into Cohorts 3 (180 mg/day) and 4 (270 mg/day) have 
experienced clinical benefit from daily APL-2 treatment.  
As of September 29, 2016, the first three subjects in Cohort 4 (
) had 
completed Part 1 and moved into Part 2 and had received treatment with APL-2 270 mg for 
51, 30, and 38 days, respectively. There were a total of three AEs that the investigators 
assigned as possibly related to APL-2 treatment: fatigue, myalgia (30 mg APL-2) and brittle 
nails (180 mg APL-2). The SMC voted unanimously to extend the duration of APL-2 
administration beyond 84 days for subjects in Cohort 4 who experience clinical benefit as 
evidenced by reduction in LD, increase in Type III CD59 negative RBCs, reduction in blood 
transfusion requirement, reduction in reticulocytes, and/or patient’s perceived improvement 
in PNH symptoms. 
 
Revision 1:  Subjects experiencing clinical benefit during the Part 2A treatment period (Day 29 
to Day 84), may enter the Part 2B treatment period (Day 85 to Day 364).  
Rationale: If a subject experiences a measureable improvement in PNH symptoms during 
APL-2 treatment, it would be in the subject’s best interest to continue to receive APL-2 
treatment for as long as the improvement in symptoms continues. Therefore, in the event 
that the Investigator deems that a subject experienced clinical benefit during Part 2A, the 
subject will be invited to participate in Part 2B, and after providing informed consent, will 
continue to receive ongoing daily APL-2 administration for up to Day 364. In the event that the 
Investigator deems that a subject did not experience adequate clinical benefit during Part 2A 
(or at any time during Part 2B), the subject will discontinue daily APL-2 administration and will 
enter the Part 3 follow-up period. 
Sections updated: Synopsis and Sections 2, 4.1.2.1.3, added 4.1.2.2.3, 4.2.2, 4.3, 5.2, 6, 
8.3.1.2, 8.3.2, 8.3.3, 9.2, 9.2.1, 9.2.1.1, 9.2.1.2, 9.2.2, 9.2.4, 9.3, 10.1.5, 10.1.7, 10.4, 10.5, 
12.10, 12.12, 12.12.1, and removed 12.12.2. 
 
Additional Revisions: Editorial changes have been made throughout the protocol for clarity or 
corrections. 
 
 
PPD


 APL-2
Ascending Dose / First in Human / PNH Add-on to SOC
Apellis Pharmaceuticals, Inc. 
Protocol Number: APL-CP0514
V4.0 Amendment 7
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 - CONFIDENTIAL
Page 19 of 72
AMENDMENT 6 
Background: 
Cohorts 1, 2, and 3 have completed and six subjects have been enrolled into Cohort 4. All 6 
subjects have completed at least 28 days dosing with SC APL-2 270 mg/d.  
Subjects enrolled into Cohort 3 (180 mg/day) and Cohort 4 (270 mg/day) experienced clinical 
benefit from daily APL-2 treatment as evidenced by a reduction in LDH, an increase in Hb, an 
increase in Type III CD59 negative RBCs, and a reduction in reticulocytes. 
 
 
 
  
In addition, the 9-month toxicology study in cynomologous monkeys has been completed and 
final data from the 3-month interim necropsy and draft data from the final 9-month necropsy 
are available. The 6-month chronic dosing study in rabbits has also been completed and final 
data are available. The toxicological findings in the chronic studies were comparable to those 
observed in the original 28 day IND study and it was concluded that 7 mg/kg/day remains a 
NOAEL. These pre-clinical observations support chronic administration of 360 mg APL-2/day in 
humans. 
As the study has recently been extended to allow dosing with APL-2 for up to one year it is 
recognized that the requirement for research nurses to visit the subjects and administer the 
APL-2 solution using hand-held syringes is inconvenient, and that repeated SC injections may 
cause pain at the injection site. An ambulatory syringe pump (e.g. Crono Super PID), will be 
introduced to allow self administration of APL-2 by the subject. A new formulation of APL-2 
solution for SC injection in which the diluent is acetate-buffered mannitol rather than 
dextrose has been developed. This formulation allows storage at 2-8° C making it more 
suitable for use in an ambulatory setting. Relevant compatibility testing has been performed 
with the pump evaluating both the 5% dextrose and acetate-buffered mannitol formulations. 
When the infusion pump is introduced the subjects will receive thorough training by research 
nurses and/or investigator site staff. Once patients are competent and confident, they will will 
be able to self-administer APL-2 via the pump. 
Revision 1: The protocol is updated to allow intra-subject dose escalation up to 360 mg/day 
Rationale: If a subject has demonstrated acceptable tolerability but sub-optimal 
haematological responses to daily treatment with 270 mg APL-2, the investigator, in 
conjunction with the sponsor, will be able to increase the daily dose of APL-2 up to 360 mg for 
that subject in order to improve the clinical outcome. 
Revision 2: Updated to include an ambulatory syringe pump for delivery of APL-2 and the new 
formulation of APL-2 for SC injection  
Rationale: It is inconvenient for APL-2 to be administered by a research nurse on a daily basis 
and hand-held syringes may cause more injection site pain than syringe infusion pumps.  
PPD


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 20 of 72 
Sections Updated: Synopsis and Sections 2, 4.1.2, 4.1.2.1.3, 4.2.2, 4.3, 8.3.1.1, 8.3.1.2, 8.3.2,  
8.3.3, 10.4 
 
AMENDMENT 7 
Background: 
All 6 subjects in Cohort 4 continued into Part 2B of the study and 5/6 are currently receiving 
SC APL-2 270 mg/d and continue to experience clinical benefit from daily APL-2 treatment. 
Therefore, it is proposed that study treatment with APL-2 be further extended to 729 days. 
 
Revision 1:  Subjects who continue to experience clinical benefit during the Part 2B treatment 
period (Day 85 to Day 364), may enter the Part 2C treatment period (Day 365 to Day 729), 
which follows a less frequest visit schedule.  
Rationale: If a subject continues to experience improvement in PNH symptoms during APL-2 
treatment, it would be in the subject’s best interest to continue to receive APL-2 treatment 
for as long as the improvement in symptoms continues. Therefore, in the event that the 
Investigator deems that a subject experienced clinical benefit during Part 2B, the subject will 
be invited to participate in Part 2C, and after providing informed consent, will continue to 
receive ongoing daily APL-2 administration for up to Day 729. In the event that the 
Investigator deems that a subject did not experience adequate clinical benefit during Part 2B, 
the subject will discontinue daily APL-2 administration and will enter the Part 3 exit period.  
The visit schedule in Part 2C follows a less frequent schedule based on the safety experience 
and profile to date. 
Section Updated: Synopsis, Section 2, 4.3, 6, 8.3.2, 9.2.1, 9.2.1.1, 9.2.1.2, 9.2.2, 9.2.4, 9.3, 
10.1.5, 10.4, 10.5. 
 
Revision 2: Updated to include a new formulation of APL-2 for SC injection.  
Rationale: The Sponsor has developed a new formulation of APL-2 solution for SC injection in 
which the diluent is acetate-buffered sorbitol rather than dextrose. This formulations allows 
storage at 2-8° C making it more suitable for use in an ambulatory setting. Relevant 
compatibility testing has been performed with the pump evaluating both the 5% dextrose and 
acetate-buffered formulations.  
Section Updated: Section 4.1.2, 8.3.1.1, and 8.3.1.2 
 
Revision 3: Clarification with respect to reporting of Adverse Events (AEs) of special interest. 
Rationale: The section has been updated to include injection site reactions and infusion pump 
related events as an AE of special interest.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 21 of 72 
Section Updated: Section 11.5 
 
Additional Revisions: Editorial changes have been made throughout the protocol for clarity or 
corrections. 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 22 of 72 
2. STUDY FLOW CHART 
Study Period Screen 
PART 1 - Multiple Dose (Daily) 
Study Week 
 -4 
1 
2 
3 
4 
Study Day 
-30 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 
Informed Consent 
X 
 
Demographics 
X 
 
Medical, transfusion, and thrombosis history 
X 
 
Review entry criteria 
X 
 
Vaccination. A 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
S 
S 
S 
H 
H 
H 
S 
H 
H 
H 
H 
H 
H 
S 
H 
H 
H 
H 
H 
H 
S 
H 
H 
H 
H 
H 
H 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
 
Blood. I 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacokinetics. I 
X 
X 
X 
X 
X 
X 
X 
 
Anti-APL-2 Ab assay 
X 
X 
X 
X 
 
Lactate dehydrogenase 
X 
X 
X 
X 
X 
 
Hematology and chemistry.  
X 
X 
X 
X 
X 
 
Serology (HIV, HBsAg and HCV). J 
X 
 
Reticulocyte count 
X 
X 
X 
X 
 
Haptoglobin 
X 
X 
X 
X 
 
Coagulation profile 
X 
X 
 
Complement profile (C3, CH50 and AH50) 
X 
X 
X 
X 
 
Flow cytometry for PNH 
X 
X 
X 
X 
 
Flow cytometry C3 deposition 
X 
X 
X 
X 
 
Th17/Treg Analysis 
X 
 
Free hemoglobin 
X 
X 
X 
X 
 
Ferritin, vitamin B12 folate 
X 
X 
X 
X 
 
Pregnancy (B-HCG) 
X 
 
Urine pregnancy test. K 
X 
X 
X 
X 
 
FACIT fatigue Scale 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE). L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Study Flow Chart Footnotes below continuation flow chart 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 23 of 72 
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 to 42 
43 
44 to 56 
57 
58 to 70 
71 
72 to 84 
 
Study Visit 
30 
31 to 36 
37 to 43 
44 
45 to 57 
58 
59 to 71 
72 
73 to 85 
Informed Consent 
Demographics 
Medical, transfusion, and thrombosis history 
Review entry criteria 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
X 
12-lead electrocardiogram. D 
X 
X 
X 
X 
APL-2 administration. E 
S 
H 
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 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
 
X 
 
X 
 
X 
Anti-APL-2 Ab assay 
X 
X 
Lactate dehydrogenase 
X 
 
 
X 
 
X 
 
X 
 
Hematology and chemistry.  
X 
X 
X 
X 
Reticulocyte count 
X 
 
 
X 
 
X 
 
X 
 
Haptoglobin 
X 
 
 
X 
 
X 
 
X 
 
Coagulation profile 
X 
X 
X 
X 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
Th17/Treg Analysis 
X 
 
 
 
 
 
 
 
 
Free Hemoglobin 
X 
 
 
X 
 
X 
 
X 
 
Ferritin, vitamin B12 folate 
X 
 
 
X 
 
X 
 
X 
 
Urine pregnancy test. K 
X 
X 
X 
X 
FACIT fatigue Scale 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE) L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Study Flow Chart Footnotes below continuation flow chart 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 24 of 72 
Study Period 
Part 2 B- Treatment (Daily from Day 85 to Day 364) - continued… M 
 
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 
 
Study Visit 
86 
87 to 113 
114 
115 to 141 
142 
143 to 169 
170 
171 to 197 
198 
199 to 225 
226 
227 to 253 
Informed Consent 
 
 
 
Demographics 
 
 
 
Medical, transfusion, and thrombosis history 
 
 
 
Review entry criteria 
 
 
 
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 
 
 
Lactate dehydrogenase 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology and chemistry.  
X 
X 
X 
X 
X 
X 
 
Coagulation profile 
X 
X 
X 
X 
X 
X 
 
Reticulocyte count 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Haptoglobin 
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 
 
Th17/Treg Analysis 
X 
 
 
 
 
 
 
 
 
 
 
 
Free Hemoglobin 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Ferritin, vitamin B12 folate 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test. K 
X 
X 
X 
X 
X 
X 
 
FACIT fatigue Scale 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE) L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Study Flow Chart Footnotes below continuation flow chart 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 25 of 72 
Study Period 
… continued - Part 2B - Treatment (Daily from Day 85 to Day 364) M 
 
Study Week 
37 to 40 
41 to 44 
45 to 48 
49 to 52 
Study Day 
253 
254 to 280 
281 
282 to 308 
309 
310 to 336 
337 
338 to 364 
 
Study Visit 
254 
255 to 281 
282 
283 to 309 
310 
311 to 337 
338 
339 to 365 
Informed Consent 
Demographics 
Medical, transfusion, and thrombosis history 
Review entry criteria 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
12-lead electrocardiogram. D 
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 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
X 
 
X 
 
X 
Anti-APL-2 Ab assay 
X 
X 
Lactate dehydrogenase 
X 
 
X 
 
X 
 
X 
 
Hematology and chemistry.  
X 
X 
X 
X 
Coagulation profile 
X 
X 
X 
X 
Reticulocyte count 
X 
 
X 
 
X 
 
X 
 
Haptoglobin 
X 
 
X 
 
X 
 
X 
 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
Th17/Treg Analysis 
X 
 
 
 
 
 
 
 
Free Hemoglobin 
X 
 
X 
 
X 
 
X 
 
Ferritin, vitamin B12 folate 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test. K 
X 
X 
X 
X 
FACIT fatigue Scale 
X 
 
 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE) L 
X 
X 
X 
X 
X 
X 
X 
X 
See study flow chart footnotes on next page  
 
 
 
 
 
 
 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 26 of 72 
 
Study Period 
… continued - Part 2C - Treatment (Daily from Day 365 to Day 729) M 
Part 3 – Exit or ET 
(N) 
Study Week 
56 
60 
68 
80 
92 
104 
112 
 
Study Day 
365   
(+/-7 days) 
421 
(+/-7 days) 
477 
(+/-7 days) 
533 
(+/-14 days) 
617 
(+/-14 days) 
729 
(+/-14 days) 
785 
(+/-14 days) 
 
Study Visit 
366 
367 
368 
369 
370 
371 
372 
Informed Consent 
 
 
 
Demographics 
 
 
 
Medical, transfusion, and thrombosis history 
 
 
 
Review entry criteria 
 
 
 
Preventive antibiotic. B 
X 
X 
X 
X 
X 
X 
X 
Physical examination. C 
X 
 
X 
12-lead electrocardiogram. D 
X 
X 
X 
X 
X 
X 
X 
APL-2 administration. E 
S 
S 
S 
S 
S 
S 
 
Injection site assessment. F 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements. G 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Blood. I 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics. I 
X 
X 
X 
X 
X 
X 
X 
Anti-APL-2 Ab assay 
X 
X 
X 
X 
X 
X 
X 
Lactate dehydrogenase 
X 
X 
X 
X 
X 
X 
X 
Hematology and chemistry.  
X 
X 
X 
X 
X 
X 
X 
Coagulation profile 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count 
X 
X 
X 
X 
X 
X 
X 
Haptoglobin 
X 
X 
X 
X 
X 
X 
X 
Complement profile (C3, CH50 and AP50) 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry for PNH/C3 deposition 
X 
X 
X 
X 
X 
X 
X 
Th17/Treg Analysis 
X 
 
 
X 
 
X 
X 
Free Hemoglobin 
X 
X 
X 
X 
X 
X 
X 
Ferritin, vitamin B12 folate 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test. K 
X 
X 
X 
X 
X 
X 
X 
FACIT fatigue Scale 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Thrombosis record (MAVE) L 
X 
X 
X 
X 
X 
X 
X 
See study flow chart footnotes on next page  
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 27 of 72 
 
FOOTNOTES: 
A. If Neisseria meningitidis vaccine/s are administered during screening (up to Day –14), a booster (for both vaccinations) should be administered after 2 
months. If Pneumococcal vaccination is required during screening, a dose of PCV13 will be administered at least two weeks prior to Day 1 and a dose of 
PPSV23 will be administered at least 8 weeks later. 
B. Preventive antibiotics will be prescribed prior to Visit 2. Antibiotics will be taken from Visit 2 until 14 days after the last dose of APL-2. 
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. 
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 APL-2 continue administration. Subjects may self-
administer the SC infusions at home, after receiving appropriate training by a research nurse or other personnel. 
F. Injection site assessment will be performed within 30 minutes after APL-2 administration. After the subjects start to self-administer APL-2 via the pump, 
injection site reactions will no longer be evaluated by research personnel after at-home administrations. Subjects will be instructed to report any injection 
site reaction to the study coordinator. 
G. If done on a dosing day, vital signs will be measured within 2 hours prior to dosing and within 30 minutes after dosing. After the subjects start to self-
administer APL-2 via the pump, vital signs will no longer be measured before and after at-home administrations. 
H. Reserved – See note E. 
I. If done on a dosing day, blood samples will be taken pre-dose with the exception that at Visit 2 only, a pharmacokinetic sample will be taken pre-dose and 
at 4 hours post-dose. 
J. Absence of Human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), and Hepatitis C virus (HCV), will be confirmed prior to APL-2 
administration. 
K. If done on a dosing day, urine pregnancy test should be completed for WOCBP prior to dosing.  
L. MAVE = Major Adverse Vascular Event. After the subjects start to self-administer APL-2 via the pump, MAVE will no longer be evaluated by research 
personnel during home visits. Subjects will be instructed to report any events to the study coordinator. 
M. If the dose is increased to >270 mg/day, the subject will attend the clinical site for safety visits every 2 weeks (instead of every 4 weeks) for the first 
6 weeks after the dose increase i.e. up to an additional 3 clinic visits. The extra clinic visits will be recorded as Unscheduled Visits and will alternate with the 
scheduled monthly visits. 
N. Subjects that discontinue dosing at any time during part 1, 2A, 2B, or 2C will move directly into Part 3 for the exit or early termination visit. 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 28 of 72 
3. ABBREVIATIONS 
Abbreviations specific to this study are listed. Pharmacokinetic (PK) parameter abbreviations 
and definitions may be found in Section 12.9. 
 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
API 
Active pharmaceutical ingredient 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
qC 
Degrees Celsius 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CRF 
Case report form 
CS 
Clinically significant abnormality 
ECG 
Electrocardiogram 
qF 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FU 
Follow-up  
g 
Gram(s) 
GGT 
Gamma glutamyl transferase 
GCP 
Good clinical practice 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
Hem 
Hematology 
hERG 
Human ether-à-go-go-related gene 
HIV 
Human immunodeficiency virus 
HSA 
Human serum albumin 
IB 
Investigator’s brochure 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 29 of 72 
ICH 
International Conference on Harmonization 
kg 
Kilogram(s) 
L 
Liter(s) 
LDH 
Lactate dehydrogenase 
MAC 
Membrane attack complex 
MAVE 
Major Adverse Vascular Event 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mL 
Milliliter(s) 
μM 
Micromolar; micromoles/L 
NCS 
Not clinically significant 
NOEL 
No observed effect level 
NOAEL 
No observed adverse effect level 
PD 
Pharmacodynamic(s) 
PEG 
Polyethylene glycol 
PEG40 
Polyethylene glycol (40 kDa nominal molecular weight) 
PI  
Principal Investigator or designee 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
PNH 
Paroxysmal nocturnal hemoglobinuria 
QTc 
Corrected QT interval 
QTcB 
Bazett’s correction 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SC 
Subcutaneous  
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOP 
Standard operating procedure 
T½ 
Serum half-life 
TEAE 
Treatment-emergent adverse event 
UA 
Urinalysis 
US 
Unites States of America 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Woman of Child-Bearing Potential 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 30 of 72 
4. INTRODUCTION 
4.1 
Background 
This study is being conducted as the first in 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) under standard of care. 
4.1.1 Paroxysmal Nocturnal Hemoglobinuria 
PNH is an acquired, clonal, non-malignant hematological disease characterized by complement-
mediated red blood cell (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. 
The approval of eculizumab, a monoclonal anti-C5 antibody inhibiting the formation of the 
MAC, as an effective treatment for PNH, has confirmed that inhibition of the complement 
cascade is a valid therapeutic strategy for addressing this serious condition. Any therapy that 
effectively inhibits MAC formation is anticipated to be a plausible candidate treatment for PNH. 
However, inhibition of MAC formation does not appear to be sufficient to fully control the 
disease, as many PNH patients receiving eculizumab treatments still suffer from anemia, with 
only roughly 13% of patients being classified as complete responders, i.e., achieving transfusion 
independence and normal hemoglobin levels. Most of the patients (53%) were classified as 
partial responders with decreased transfusion and lactate dehydrogenase, 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. Details can be found in the 
APL-2 Investigator’s Brochure (Apellis Pharmaceuticals, 2016). 
4.1.2 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 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 31 of 72 
molecule of APL-2. The peptide portion of the drug binds to complement C3 and is a broad 
inhibitor of the complement cascade, a biological process that is part of innate immunity and is 
involved in multiple inflammatory processes. The PEGylation of the molecule imparts slower 
elimination from mammalian systems following administration.  
APL-2 injection (drug product) is a solution of APL-2 in 5% dextrose, acetate-buffered mannitol 
or acetate-buffered sorbitol for administration by subcutaneous injection (SC). APL-2 is being 
developed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). 
4.1.2.1  Nonclinical Data 
4.1.2.1.1 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 red blood cells (RBCs) from 
complement-mediated lysis and also prevents 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. The efficacious dose for humans has been estimated to be between 0.5 mg/kg/d 
and 1.5 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 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. 
4.1.2.1.2 Pharmacokinetics 
Pharmacokinetic and toxicokinetics have been performed in rabbits and monkeys administered 
the drug by 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. 
4.1.2.1.3 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 has recently completed its in life phase and final data from a 3-month interim necropsy 
and draft data from the 9-month necroscopy are available. A 6-month chronic dosing study in 
rabbits has been completed and final data are available.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 32 of 72 
In addition, in vitro and in vivo assessments of genotoxicity have been performed. In all 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. 
Pharmacokinetic 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. Serum 
concentrations were generally higher on Day 8 or Day 28 compared to Day 1; however, at 
higher doses of APL-2 serum concentrations were not linear with dose. Mean Cmax was 
2890 μg/mL on Day 28 and the AUC(0-24h) was 66250 μg•hr/mL in rabbits for the 140 mg/kg/d 
animals. In monkeys, the mean Cmax was 4175 μg/mL on Day 28 and the AUC(0-24h) was 
94400 μg•hr/mL for the 140 mg/kg/d animals. In the 28-day studies the estimated t½ was 
approximately 2.48 to 2.78 and 6.29 to 8.25 days in rabbits and monkeys, respectively.  
APL-2 and PEG40 were well tolerated when administered subcutaneously to rabbits for 7 
consecutive days at doses of 20 mg/kg/d or 16 mg/kg/d (for APL-2 and PEG40 respectively) in 
5% dextrose. There was no mortality noted and no effects on body weights, food consumption 
or injection site reactions. At termination, there were neither macro- nor microscopic changes 
attributable to administration of APL-2 or PEG40. Not surprisingly, APL-2 and PEG40 were mildly 
antigenic; however, the response did not affect serum concentrations of APL-2. Serum 
concentrations of APL-2 increased with each dose during the study period. 
APL-2 and PEG40 were well tolerated when administered subcutaneously to cynomolgus 
monkeys for 7 consecutive days at doses of 20 mg/kg/d or 16 mg/kg/d (for APL-2 and PEG40 
respectively) in 5% dextrose. A dose of 16 mg/kg/d of PEG40 was chosen as an approximation 
of the equivalent amount of PEG40 in a dose of 20 mg/kg/d of APL-2. There was no mortality 
noted and no effects on body weights, food consumption or injection site reactions. At 
termination there were neither macro- nor microscopic changes attributable to administration 
of APL-2 or PEG40. There was no evidence of an immunologic response to either molecule. 
Daily serum concentrations of APL-2 increased during the treatment period, with the maximum 
concentration noted on Day 6 or 8 for the two animals.  
In a 28-day GLP rabbit study 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 7, 
28 or 140 mg/kg/d. APL-2 was well tolerated in the rabbit, with no mortality observed. APL-2 
was shown to be weakly immunogenic at all dose levels, but PEG40 (112 mg/kg/d) was also 
moderately immunogenic, and thus the results observed in APL-2-dosed animals were 
attributed to the PEG40 portion of the APL-2 molecule and not the peptide moieties. Drug-
related dose response increases in red blood cell parameters (RBCs, hematocrit, and 
hemoglobin) and reticulocyte counts were observed at the 28 and 140 mg/kg/d dose levels, and 
some, but not all parameters were resolved by the end of the 4 week Recovery Phase of the 
study. Drug-related minimal kidney tubular degeneration was observed in 2/12 animals dosed 
with 140 mg/kg/d, and drug-related inflammatory infiltrates at the sites of injection were 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 33 of 72 
observed in the 140 mg/kg/d group. The incidence and severity of this change appeared to be 
greater in APL-2-dosed animals than in the PEG40 group, although both groups showed a 
similar inflammatory reaction. 
One histopathologic finding induced by PEG40 and not reversible by the end of the 4 week 
Recovery Phase was macrophage vacuolation in numerous tissues (epithelium of the choroid 
plexus in the brain, synovium of the femur, bone marrow (sternum and femur), cervix, ovary, 
ciliary body of the eye, adrenal gland, pituitary gland, salivary gland, kidney, spleen, liver 
sinusoids, mandibular and/or mesenteric lymph nodes, pancreas, skin (inguinal), stomach, 
thymus and/or uterus) in both PEG40-treated animals and at all APL-2 dose levels. This finding 
is a known adaptive change to PEG and was observed in a dose-response fashion. The degree 
and incidence observed at the 140 mg/kg/d APL-2 dose level was comparable to that in the 
PEG40 group. Thus, this adaptive finding was attributed to the PEG40 portion of the APL-2 
molecule and not the peptide moieties. PEG administration was associated with decreased 
WBCs and differential lymphocyte counts in the 28 and 140 mg/kg/d APL-2 groups and in the 
PEG40-treated group. These changes either resolved or showed a tendency toward reversal 
during the recovery period. PEG40 also induced increases in partial activated thromboplastin 
time and a decrease in fibrinogen levels at the 28 and 140 mg/kg/d APL-2 dose levels; both 
changes were resolved by the end of the 4-week Recovery Phase. A no-toxic-effect dose level of 
APL-2 was concluded to be 7 mg/kg/d. 
APL-2 was well tolerated by monkeys during a 28-day GLP study featuring daily SC 
administration of APL-2 (0, 7, 28 or 140 mg/kg/d) or PEG40 (112 mg/kg/d). All regimens were 
without effects on in-life parameters, which included mortality, clinical signs, body weight and 
food consumption, clinical pathology, ophthalmology, antigenicity evaluation, and 
electrocardiographic evaluations. No treatment-related findings were observed in organ 
weights or gross necropsy in PEG40-treated animals or in any APL-2 dose level. 
Histopathological changes consisting of renal tubular degeneration and tubule vacuolation 
were observed in animals administered either 28 or 140 mg/kg/d. These kidney changes did not 
resolve during the 4-week Recovery Phase. Inflammatory cell infiltrates at sites of injection 
were observed for all groups placed on study; however, high-dose animals exhibited a greater 
severity of infiltrates which were comprised of lymphocytes, plasma cells or granulocytes, as 
well as frequent multinucleated cells, which appeared to be slightly more pronounced 
compared to the PEG40 control group. 
PEG40 also induced macrophage vacuolation in the monkey similar to that seen in the rabbit, in 
similar tissues (choroid plexus of the brain (epithelium), bone marrow, adrenal gland, liver 
sinusoids, mandibular and/or mesenteric lymph nodes, ovary, pituitary, spleen (red pulp), 
stomach, and/or urinary bladder). An APL-2 dose-response relationship was observed, and the 
effects in the 140 mg/kg/d group were comparable in severity and incidence to those observed 
in the PEG40-treated animals. These changes were concluded to be related to the PEG40 
portion of the APL-2 molecule and not the peptide moieties. A no-toxic-effect dose level of APL-
2 was concluded to be 7 mg/kg/d. 
Neither APL-2 nor PEG40 induced genotoxicity under the conditions tested. Both agents were 
negative in a bacterial reverse-mutation assay (Ames test) with and without S9 metabolic 
activation, and also negative for the induction of micronuclei in both non-activated and S9-
activated test systems in the in vitro mammalian cell micronucleus test using TK6 cells 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 34 of 72 
(proficient p53 human lymphocytes). During in vivo assessments, APL-2 and PEG40 exhibited no 
clastogenic effect in the mouse micronucleus model. 
In summary, APL-2 had no effects on cardiovascular parameters or hERG channel assays and 
was not genotoxic in vitro and in vivo. In general, APL-2 was well tolerated in rabbits and 
monkeys. APL-2 was slightly to mildly antigenic in the rabbit, but had no observed immunologic 
effects in monkeys. 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. After 28 days of administration, the primary 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). The majority 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. 
The draft toxicological data, including full histopathological assessment,  after 9 months of daily 
SC administration in the cynomologous monkey and the final toxicological data after 6 months 
of daily SC administration in the New Zealand white rabbit, were 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 
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 necropsy in the chronic study. Mirroring 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 interim necropsy in the 
monkey 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, 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 35 of 72 
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 groups of animals 
that received APL-2 were comparable to those noted in the groups of animals that received 
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 chronic daily SC administration of APL-2 in humans. Results from the 
nonclinical APL-2 toxicology program provide good assurance of the safety of the proposed 
doses of APL-2 in humans by the SC route of administration. 
4.1.2.2 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 study was a single ascending dose study (Study APL-CP0713-1) and 
the second 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-CP0514) and a study in patients 
who have not received prior treatment with eculizumab (APL-CP-PNH-204). 
4.1.2.2.1 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. 
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 1440 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.  


 APL-2
Ascending Dose / First in Human / PNH Add-on to SOC
Apellis Pharmaceuticals, Inc. 
Protocol Number: APL-CP0514
V4.0 Amendment 7
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 - CONFIDENTIAL
Page 36 of 72
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. 
4.1.2.2.2 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, 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. 
 
 
 
 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 
PPD


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 37 of 72 
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. Taken 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.  
4.1.2.2.3 APL-2 in eculizumab-naïve patients with PNH 
This study is an ongoing initial exploration of APL-2 in patients with PNH who have not received 
prior treatment with eculizumab. The study is comprised of two cohorts with three subjects per 
cohort, and to date, Cohort 1 has been completed and Cohort 2 is ongoing. To date treatment 
with APL-2 270 mg/day has been well-tolerated for at least three months and has provided 
clinical benefit in subjects with PNH. Based on the emerging data, dosing will continue for up to 
364 days. 
4.2 
Rationale 
4.2.1 Purpose of the Study 
This study will be the initial exploration of APL-2 in patients with PNH. The assessments of the 
safety, tolerability, PK, and PD following administration of single and multiples doses of APL-2 
will guide decisions to further develop the drug. 
4.2.2 Dose Selection 
APL-2 appeared well tolerated in a panel of standard animal toxicology studies and initial 
clinical testing in healthy volunteers. Predicted Cmax and AUC values derived from a population-
based PK model built from available single-dose and repeated-dose clinical data. Monkey and 
human PK data were used to compare APL-2 exposures and support dose selection rather than 
the cruder method of comparing doses based on an mg/m2 basis (i.e. using a conversion factor 
of 3.1× to convert rabbit or cynomolgus monkey mg/kg doses into human-equivalent doses 
[HED]). 
In the nonclinical toxicology studies described in the IB, the no observed effect level (NOEL) in 
both monkeys and rabbits was determined to be >20 mg/kg/d in a 7 day non-GLP study (daily 
drug administration). A no observed adverse effect level (NOAEL) between 7 mg/kg/day and 
28 mg/kg/d in both species was established during a 28-day GLP study (daily drug 
administration). Monkeys are considered the most relevant and pivotal species since APL-2 is 
only pharmacologically active as a complement inhibitor in primates. Additionally, PK 
parameters observed in monkeys (Cmax, t1/2, and AUCs) correlate better with PK data obtained 
from the clinical studies APL-CP0713-1 and APL-CP1014. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 38 of 72 
The final 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 (updated to include final data from the clinical trials): Comparison of PK parameters obtained from the 
IND-enabling toxicology study and ongoing clinical trials. All values reported as arithmetic means.  
 
Notes 
Dose 
(mg/kg) 
Cmax 
(μg/mL) 
Cmax  
% NOAEL 
AUC0-29d 
(μg•h/mL) 
AUC0-29d  
% NOAEL 
AUC0-҄ 
(μg•h/mL) 
Monkey 
NOAEL; Study 13CATX-004 
7 
931 
-- 
442,950 
-- 
N/A 
Human 
45 mg single dose; APL-CP0713-1 
0.6a 
7 
1% 
 
 
3,190 
90 mg single dose; APL-CP0713-1 
1.3a 
16 
2% 
 
 
7,670 
180 mg single dose; APL-CP0713-1 
2.6a 
29 
3% 
 
 
15,500 
360 mg single dose; APL-CP0713-1 
5.1a 
74 
8% 
 
 
30,000 
720 mg single dose; APL-CP0713-1 
10.3a 
139 
15% 
 
 
59,000 
1440 mg single dose; APL-CP0713-
1 
20.6a 
252 
27% 
 
 
98,000 
30 mg/d  x 28 days; APL-CP1014 
0.43a 
77 
8% 
28,000 b 
6% 
55,900b 
90 mg/d x 28 days; APL-CP1014 
1.29a 
259 
28% 
100,900 b 
23% 
193,200 b 
180 mg/d x 28 days; APL-CP1014 
2.6a 
473 
51% 
160,000 b 
36% 
320,400 b 
270 mg/d x 28 days; APL-CP1014 
3.9a 
670 
72% 
208,500 b 
47% 
414,000 b 
360 mg/d PREDICTED 
5.14 
790 
85% 
269,400 b 
61% 
510,500 b 
 
 
a 
Assuming 70 kg subject. 
b 
AUC0-∞was not calculated. Approximate values reported from  AUC0-29 and AUC0-84 (or AUC0-
last) 
 
At the time of initiation of the study (when final data was not available), a conservative 
recommended starting dose, based on predictions from PK modelling was selected– a dose that 
was expected to result in a Cmax that is 1/50th the Cmax observed at the NOAEL dose in monkeys 
– was 5 mg/d (0.07 mg/kg/d for a 70 kg subject). This dose was expected to result in an AUC 
exposure that was approximately 90 times lower than the AUC observed at the NOAEL dose in 
monkeys. This proposed starting dose was particularly conservative because the PK model used 
was based on data derived in healthy volunteers and the PK behavior of APL-2 might be 
substantially different in PNH patients. The initial dose provided PK data to confirm the validity 
of this PK model in PNH patients.  
Following review of data from ongoing studies in healthy volunteers the doses proposed for 
Cohorts 3 and 4 were amended to 180 and 270 mg/d, respectively. A repeated dose of 
270 mg/d of APL-2 in humans resulted in a Cmax of 670 Pg/mL and a total exposure (AUC0-29d) of 
208,500 Pg•h/mL. These Cmax and AUC values are approximately 72% and 47% of those 
observed at the NOAEL dose in cynomolgus monkeys. 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). As a safety consideration, only doses that have been previously shown to be 
well tolerated in healthy volunteers will be tested in this PNH study.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 39 of 72 
The starting dose for Cohort 4 is 270 mg/d, with the option to increase the dose on an 
individual subject basis, up to 360 mg/d, which is the dose expected to reach approximately 
85% of the Cmax of the NOAEL observed in monkeys. The daily dose will not exceed 360 mg/d 
without a protocol amendment. 
4.3 
Risk/Benefit 
The safety monitoring practices employed by this protocol (i.e., physical examination, vital 
signs, 12-lead ECG, hematology, serum chemistry, urinalysis, coagulation, injection site reaction 
monitoring, and AE questioning) are adequate to protect the subjects’ safety. 
The approximate volume of blood planned for collection from each subject over the course of 
the study (see Section 0) has been limited to a maximum of approximately 896 mL over the 
course of the study, in order to minimize the impact on the overall health of these anemic 
subjects. If the dose of APL-2 is increased above 270 mg/day, up to three additional blood 
draws will be scheduled, requiring an additional blood volume of up to 45 mL (up to 687 mL in 
total). 
Systemic complement inhibition might predispose individuals to infections caused by 
encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, 
and Haemophilus influenzae. Subjects will be required to provide documented evidence of 
vaccination against Neisseria meningitides types A, C, W, Y and B (administered as two separate 
vaccinations), Streptococcus pneumoniae (Pneumococcal conjugate vaccine or Pneumococcal 
polysaccharide vaccine 23 [PCV13 or PPSV23, respectively]) and Haemophilus influenzae Type B 
(Hib) within 2 years prior to Day 1 dosing, OR willing to receive appropriate vaccinations at least 
two weeks prior to dosing on Day 1 and any required booster doses during the study (See 
Section 8.4.1 for further details). In addition to the vaccinations against these encapsulated 
organisms, prophylactic antibiotic therapy (penicillin V 500 mg twice a day) will be prescribed to 
all subjects at the initiation of dosing (Day 1) and continue until two weeks after the last dose to 
minimize potential infection risk. Body temperature and vital signs will be monitored daily 
during the dosing portion of the study 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 amoxicillin, 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 8.4.2 for details). 
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 500mg twice daily (see 
Section 8.4.2 for details) if there is evidence of penicillin-related tolerability issue (such as nausea 
and diarrhea). 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 40 of 72 
As kidneys are believed to be the key target organ for toxicity from prolonged APL-2 high level 
exposure, renal function will be closely monitored during this APL-2 repeated-dose clinical 
testing. 
There is a potential health benefit for trial participants from receipt of study drug. We propose 
to administer APL-2 to PNH patients who continue to be anemic despite treatment with 
eculizumab. If efficacious and safe, APL-2 is expected to improve Hb levels and reduce 
transfusion dependency in these patients. At the dose level of 270 mg/d of APL-2 a significant 
decrease in complement mediated hemolytic activity was observed in all APL-2 treated subjects 
in the 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. Based on this data we propose to 
administer APL-2 to subjects in Cohort 4 for up to 84 days (12 weeks) in Part 2A and then for up 
to 52 weeks (Part 2B).  If subjects continue to demonstrate benefit, APL-2 will be administered 
for up to 104 weeks (Part 2C). Subjects will be assessed by the Investigator every month for Part 
2A and Part 2B.  Subjects will be assessed by the Investigator 4 weeks, 8 weeks, and then every 
12 weeks until Day 729.  The available safety, PK and PD data will be reviewed by the 
Investigator and Sponsor on an ongoing basis. 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. 
An indirect health benefit to the patients enrolled in this trial is the free medical tests received 
at screening and during the study. 
5. STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Study Objectives 
The primary objectives of the study are to assess the safety, tolerability and pharmacokinetics 
of single and multiple subcutaneous (SC) doses of APL-2 in subjects with paroxysmal nocturnal 
hemoglobinuria (PNH) who are still anemic after treatment with eculizumab (Soliris®). 
An exploratory objective of the study is to assess the pharmacodynamics (PD) of single and 
multiple SC doses of APL-2 when administered to PNH patients. See “Study Endpoints” in 
Section 5.2. 
5.2 
Study Endpoints 
The primary endpoints of the study are the number and severity of TEAEs and PK parameters of 
APL-2 following administration of single and multiple SC doses. 
As exploratory PD endpoints, the following markers will be studied: 
x Complement (e.g., CH50, AH50, and C3) hemolytic activity and levels 
x C3 deposition on RBC cells 
x Hemoglobin 
x Reticulocytes 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 41 of 72 
x Lactate dehydrogenase (LDH) 
x Bilirubin 
x Clonal distribution of PNH vs normal bone marrow derived cells 
x Th17/Treg analysis 
x Red blood cell transfusions 
6. STUDY DESIGN 
This is a Phase 1, open-label, prospective, non-randomized, single and multiple ascending dose,  
study in patients with PNH. The study is planned to enroll approximately 15 subjects across 4 
cohorts. Cohorts 1-3 will comprise 2 subjects in each cohort. Cohort 4 will enroll sufficient 
subjects to ensure at least 6 subjects complete 28 days of dosing with APL-2. Subjects may 
participate in more than one cohort.  
Safety will be assessed throughout the study; serial blood samples and urine samples will be 
collected. Blood samples will also be collected for the PK assessment of APL-2. Additional 
samples for assessment of PD will also be collected. Interim PK analyses may be performed to 
reconsider the sampling time points as the study progresses and to guide the dose-escalation 
decision. Cumulative data will be reviewed by the Safety Monitoring Committee (SMC) on an 
regular ongoing basis and the frequency of SMC review meetings will be described in the SMC 
charter (see Section 9.3). 
The planned length of participation (from Screening [Visit 1] to completion of the Exit visit) in 
the study for each subject is approximately 140 days for Cohorts 1 and 2, 115 days for Cohort 3 
and up to 785 days for Cohort 4 . 
For prior study design including single doses and waiting period (Cohorts 1, 2, and 3), refer to 
Version 4.0, Amendment 2, 3, and 4 of the protocol.  
Subjects in Cohort 4 will initially receive 270 mg SC APL-2 daily for 28 days. Subjects will be 
entered into the study at Visit 2 (Day 1) at a time designated by the PI and will receive daily SC 
doses of APL-2 at Visits 2 to 29. The first 4 daily SC doses of APL-2 (Visits 2 to 5) as well as doses 
at Visits 9, 16 and 23 will be administered at the clinical site. Subjects will remain in the clinic 
for at least 4 hours after the first dosing at Visit 2. If a subject progresses to Part 2A, doses at 
Visits 30, 44, 58 and 72 (Days 29, 43, 57 and 71) will be administered at the clinical site, and the 
subject then progresses to Part 2B, doses at Visit 86, 114, 142, 170, 198, 226, 254, 282, 310, and 
338 (Days 85, 113, 141, 169, 197, 225, 253, 281, 309, and 337) will be administered at the 
clinical site.  If a subject progesses to Part 2C, doses at Visits 366, 367, 368, 369, 370 and 371 
(Days 365, 421, 477, 533, 617, and 729) will be administered 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. The remaining multiple doses will be 
administered by a trained nurse at the subject’s home, workplace, or other location convenient 
to the subject. After completion of dosing, subjects will enter the Part 3, and return to the 
clinical site for exit procedures at Visit 372 Exit Visit (8 weeks after the last dose). See Study 
Flow Chart in Section 2. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 42 of 72 
7. SUBJECT SELECTION 
The study is planned to enroll approximately 15 subjects across 4 Cohorts. Cohorts 1-3 will 
comprise 2 subjects in each cohort. Cohort 4 will enroll sufficient subjects to ensure at least 6 
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 Sponsor in consultation 
with the SMC to repeat a dose level or to study an interim dose level. 
7.1 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study, unless otherwise specified: 
1. Male or Female 
2. At least 18 years of age 
3. Weigh >55 kg  
4. Diagnosed with PNH 
5. On treatment with eculizumab (Soliris®) for at least 3 months 
6. Hb < 10 g/dL at screening OR have received at least one transfusion within 12 months 
prior to screening 
7. Platelet count of >30,000/mm3 
8. Absolute neutrophil count >500/mm3 
9. 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 (see below) 
10. Males with female partners of child bearing potential must agree to use protocol 
defined methods of contraception (see below) and agree to refrain from donating 
sperm for the duration of the study 
11. Willing and able to give informed consent 
7.1.1 Approved methods of contraception 
Approved methods of contraception include: abstinence, oral contraceptives, intrauterine 
device, medically acceptable double-barrier methods (diaphragm in combination with 
spermicidal jelly/foam, condom with spermicidal jelly/foam), 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 additional 
approved method of contraception during the study. 
7.2 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening or before dosing on Visit 2, as appropriate. 
1. Active bacterial infection 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 43 of 72 
2. Known infection with hepatitis B, C or HIV 
3. Hereditary complement deficiency 
4. History of bone marrow transplantation 
5. Participation in any other investigational drug trial or exposure to other investigational 
agent, device or procedure within 30 days 
6. Evidence of QTcF prolongation defined as >450 ms for males and >470 ms for females at 
screening 
7. Creatinine clearance (CrCl) <50 mL/min (Cockcroft-Gault formula) at screening 
8. Breast-feeding women 
9. History of meningococcal disease 
10. No vaccination against N. meningitidis 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 within 2 years prior to Day 1 (Visit 2) dosing. 
8. STUDY TREATMENTS 
8.1 
Allocation to Treatment 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all eligibility criteria will be scheduled to 
enter the study and dosed in the next available cohort. 
8.2 
Blinding 
None:  This is an open-label study. 
8.3 
Treatments Administered 
Sterile solutions of APL-2, up to 150 mg/mL, administered subcutaneously. 
8.3.1 Drug supplies 
8.3.1.1 Identity of Investigational Products 
APL-2 will be supplied either as: 1) sterile APL-2 solution in 5% dextrose at concentrations of 10, 
40, 100 or 150 mg/mL, supplied as 1-mL stoppered glass vials; 2) sterile APL-2 in acetate-
buffered mannitol or acetated-buffered sorbitol solution, pH 5.0, at concentrations of up to 
60 mg/mL, supplied as 10 mL stoppered glass vials; or 3) sterile vials containing lyophilized APL-
2 supplied as stoppered glass vials, to be reconstituted to a concentration of 40 - 150 mg/mL 
using the 5% dextrose diluent provided by the sponsor. The volume of injection will be adjusted 
to achieve the desired dose. A separate dosing and administration document will be provided 
to study staff, providing details of concentrations and volumes for each cohort. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 44 of 72 
8.3.1.2 Study Supplies 
The Sponsor will supply vials of APL-2 in 5% dextrose solution, APL-2 acetate-buffered mannitol 
solution, APL-2 acetate-buffered sorbitol solution or lyophilized APL-2, and 5% dextrose diluent 
to the clinical site. The Sponsor will also supply needles, syringes, infusions sets, and infusion 
pumps (e.g. Crono Super PID) as required. Drug accountability records will be maintained by a 
pharmacist or other appropriately qualified designated person at the clinical site, and will be 
made available for review by the Sponsor. 
APL-2 in 5% dextrose solution and lyophilized APL-2 should be stored at -20°C, APL-2 acetate-
buffered mannitol and acetate-buffered sorbitol solutions should be stored at 2-8°C; and 
dextrose diluent should be stored at 15-30°C. Access to the drug supplies should be restricted, 
and the Pharmacist or other appropriately qualified designated person will maintain drug 
accountability records. 
8.3.1.3 Accountability 
Records will be made of the receipt and dispensing of the drugs supplied both at the clinical site 
and by the research nurse. 
Subjects will be dispensed investigational product at 4 weekly intervals.  
At the conclusion of the study, any unused investigational product will be returned to the 
Sponsor or designee, or destroyed per Sponsor instructions or the site’s SOP. If no supplies 
remain, this fact will be documented in the pharmacy product accountability records. 
8.3.2 Planned Dose Levels 
Planned doses will be as follows: 
Cohort 
Planned dosing schedule (Amendment 7) 
1 
25 mg on Day 1 then 5 mg/day from Day 29 to Day 56 
2 
50 mg on Day 1 then 30 mg/day from Day 29 to Day 56 
3 
180 mg/day from Day 1 to Day 28 
4 
270 mg/day (up to 360 mg/day) from Day 1 to Day 729* with 
optional instrasubject escalation up to 360mg/day after Day 
28** 
*Subjects may initially receive APL-2 for 28 days (Part 1) and if there is evidence of clinical benefit they may 
continue to receive APL-2 until Day 84 (Part 2A) and if there is ongoing evidence of clinical benefit they may 
continue to receive APL-2 until Day 364 (Part 2B). If subjects continue to have clinical benefit they may receive 
APL-2 until Day 729 (Part 2C).     
** Individual patient dose escalation up to a dose of 360 mg/day may occur in subjects who have a sub-optimal 
hematological response but acceptable tolerability. 
The self-administration pump can be programmed to deliver in volumes of one mL increments, 
and no fractions of thereof. As a result, when delivering a dose of 270 mg, a nominal dose of up 
to 280 mg may be delivered dependent upon the concentration of the formulation (e.g. 
formulation 40 mg/mL administered in 7mL provides a dose of 280 mg). This difference of 
approximately 4% is considered an acceptable margin which will have minimal/no impact on 
the PK/PD or efficacy of APL-2. 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 45 of 72 
8.3.3 Drug Administration 
A pharmacist or other appropriately qualified designated person will dispense the vials of APL-2 
solution or vials of lyophilized APL-2 and diluent. The dispensing and other APL-2 accountability 
records will be maintained at the clinic and made available for review by the sponsor. 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 
administration is the abdomen; however, if a subject does not tolerate administration into the 
abdomen alternative sites may be selected e.g. thighs 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 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. 
8.3.4 Additional Dose Levels 
Repeat of any cohort or the addition of an interim dose level may be added, based on emerging 
safety, PK and PD data. Any amendments to doses will be made in consultation with and upon 
recommendation from the SMC. The Institutional Review Board (IRB) will be immediately 
notified of this revised approach. 
8.4 
Concomitant Medications 
8.4.1 Vaccinations 
Subjects will be required to provide documented evidence of having received the following 
vaccines within 2 years prior to Day 1 dosing. 
x 
Neisseria meningitides types A, C, W, Y: Menactra®, Menomune® or Menveo® 
x 
Neisseria meningitides type B: Bexsero® or Trumenba® 
x 
Streptococcus pneumoniae: Prevnar 13®(PCV13) or Pneumovax® (PPSV23) 
x 
Haemophilus influenzae type B: PedvaxHIB®, ActHIB® or Hiberix® 
If subjects are not able to provide documented evidence of having received the vaccinations 
above, they will receive the vaccinations following the CDC’s recommendations for vaccination 
in patients with immunocompromissing conditions as described below (CDC, 2016). 
x 
Neisseria meningitides types A, C, W, Y: Menactra®, Menomune® or Menveo®. First dose 
at least two weeks prior to dosing on Day 1 with a booster after 2 months. 
x 
Neisseria meningitides type B: Bexsero® or Trumenba®. First dose at least two weeks 
prior to dosing on Day 1 with a booster after 2 months. 
x 
Streptococcus pneumoniae: Prevnar 13®(PCV13) at least two weeks prior to dosing on 
Day 1 and Pneumovax® (PPSV23) after 2 months. 
x Haemophilus influenzae type B: PedvaxHIB®, ActHIB® or Hiberix® at least two weeks 
prior to dosing on Day 1. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 46 of 72 
8.4.2 Prophylactic antibiotics 
Prophylactic antibiotic therapy will be prescribed to all subjects to minimize potential infection 
risk. Prophylactic antibiotics will be initiated at Visit 2 before initiation of APL-2 dosing and 
continue until 2 weeks after the last dose of study medication. 
8.4.2.1 Primary prophylactic antibiotic 
x 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 amoxicillin, 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. 
8.4.2.2 Alternative prophylactic antibiotics 
x Erythromycin 500 mg twice daily 
Erythromycin 500 mg twice daily may be considered as a suitable alternative in subjects who 
are unable to tolerate penicillin. 
Treatment should be switched to 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. 
8.4.2.3 Rescue antibiotics 
Body temperature and vital signs will be monitored daily during the dosing portion of the study 
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/augmentin). 
9. STUDY PROCEDURES 
Please see the Study Flow Chart in Section 2 for a summary of the schedule of study 
participation and procedures. 
9.1 
Screening (Visit 1) 
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 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 47 of 72 
13.3.3). Subjects will have to meet all eligibility criteria before being enrolled into the study (see 
Section 7). 
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 2. 
9.2 
Treatment Period (Visits 2 to 36) 
For prior study design including dosing schedules for Cohort 1, 2, and 3, refer to Version 4.0, 
Amendments 2, 3, and 4 of the protocol. 
9.2.1 Dosing Period (Visits 2 to 729) 
Subjects will receive daily SC doses of APL-2 in the mornings of Visits 2 to 29. 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 Visit 85 (Day 84) , then subjects continuing to demonstrate clinical 
benefit from the treatment may progress to Part 2B of the study and continue to receive daily 
doses of APL 2 until Visit 365 (Day 364). Subjects continuing to demonstrate clinical benefit may 
progress to Part 2C of the study and continue to receive daily doses of APL-2 until Visit 371 (Day 
729). APL-2 will be administered at the site by study personnel or at the subject’s home, 
workplace, or other location convenient to the subject by a trained research nurse. Subjects 
may self-administer the SC infusions, after receiving appropriate training by a research nurse or 
other personnel. 
9.2.1.1 Clinical Site Administration (Part 1 Visits 2-5, 9, 16, & 23; Part 2A Visits 30, 44, 
58, & 72, and Part 2B Visits 86, 114, 142, 170, 198, 226, 254, 282, 310, 338; 
Part 2C Visits 366, 367, 368, 369, 370 and 371) 
Subjects will receive a daily SC dose of APL-2 starting on Visit 2. See Section 8.3.2. 
The first 4 daily SC doses of APL-2 (Visit 2 to 5) as well as doses on Visits 9, 16, 23, 30, 44, 58 and 
72 will be administered at the clinical site. Subjects will remain in the clinic at least 4 hours after 
dosing at Visit 2 only. 
Blood samples for PK/PD will be taken at the following time points during Visit 2 to Visit 86 of 
the study: 
x PK + PD: Pre-dose at Visit 2 
x PK: 4 hours post-dose at Visit 2 
x PK only: Pre-dose at Visits 3, 4 and 5 
x PK + PD: Pre-dose at Visits 9, 16, 23, 30, 44, 58 and 72. 
Blood samples for PK/PD will be then be taken pre-dose at every subsequent scheduled clinic 
visit up to and including the Exit Visit. 
 
Additional procedures for each visit are listed in the Study Flow Chart in Section 2. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 48 of 72 
9.2.1.2 Multiple-Dose Outpatient Administration (Part 1 Visits 6-8, 10-15, 17-22 and 
24-29; Part 2A Visits 31-43, 45-57, 59-71, & 73-85, Part 2B Visits 87-113, 115-
141, 143-169, 171-197, 199-225, 227-253, 255-281, 283-309, 311-337, and 
339-365, Part 2C Visits 366, 367, 368, 369, 370 and 371) 
From Visit 6 to Visit 371, with the exception of doses administered at the clinical site as 
specified above, daily doses of APL-2 will be administered by a trained research nurse, 
caregiver, or self-administered. These daily doses of APL-2 may be administered at the subject’s 
home, workplace, or other location convenient to the subject. 
If a trained research nurse completes APL-2 administration, safety, tolerability and concomitant 
medication will be monitored. If the subject (or caregiver) self-administers the SC infusions, 
after receiving appropriate training by a research nurse or other personnel, adverse events and 
concomitant medications will be reported to the clinic site. 
9.2.2  Exit Visit (Visit 372)  
All subjects will be asked to return to the clinical site for an Exit Visit 8 weeks following the last 
administration of APL-2. For any subject enrolled in the study, study participation will be 
concluded following the Exit visit evaluations (Visit 372) approximately 8 weeks after the last 
dose of APL-2 or at early termination. Should any subject withdraw or be withdrawn from the 
study, the Exit visit evaluations should be performed including the collection of blood samples 
for PK and/or PD assessments, as well as a post-dose antigenicity sample if not yet collected. 
Blood samples for PK/PD will be taken at Exit Visit. The Exit visit procedures are listed in the 
Study Flow Chart in Section 2. 
9.2.3 Unscheduled Follow-up Visits 
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 site for additional follow-up visits if considered 
necessary by the PI, the sponsor or the SMC or if PK/PD sampling schedule is modified or 
extended based on interim results. 
Unscheduled follow-up visits may include any of the procedures listed in the Study Flow Chart 
in Section 2. 
9.2.4 Scheduled End of Study 
The end of the study is scheduled after completion of the Exit visit evaluations in the 4 cohorts. 
This may change in the event that the study is terminated early if dose-limiting clinical safety 
endpoints have been reached to preclude further increases of dose, additional cohorts are 
enrolled, additional time is required to review safety data, extended safety and PK sampling is 
added for a cohort (e.g., extended beyond Visit 372), or a decision is made to complete an 
unscheduled analysis between cohorts. 
9.3 
Dose Escalation and Periodic Safety Review  
Initiation of the next dose level (i.e. next cohort) will occur as follows: 
For Cohorts 1 and 2, subjects will receive a single SC dose of APL-2 on Day 1. At least twenty-
eight days after they receive the single injection, subjects will enter the multiple-dose period 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 49 of 72 
and will receive SC APL-2 daily for 28 days at the corresponding multiple dose for their cohort. 
After both subjects in the preceding cohort have completed the single-dose 28-day waiting 
period, the next cohort will be started at the next planned single dose level. 
For Cohort 3, subjects will receive SC APL-2 daily for 28 days at the corresponding multiple dose 
for their cohort. After both subjects in the preceding cohort have completed the 28-day dosing 
period, the next cohort will be started at the next planned dose level. 
 
For Cohort 4, 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. At Visit 30 on Day 29, 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 (Days 29 to 84). At Visit 86 on Day 85, subjects continuing to benefit from the treatment 
(as determined by the Investigator and Sponsor after reviewing the available data) will 
automatically enter into Part 2B and continue treatment for an additional 309 days (Days 85 to 
364).  
 
 
9.3.1 Safety Monitoring Committee 
An external, independent Safety Monitoring Committee (SMC) will review cumulative 
safety/tolerability data (e.g., physical examinations, electrocardiograms [ECGs], vital signs, 
clinical laboratory tests, and adverse events [AEs]) and PK data including predicted exposures 
for subsequent doses based on emerging PK data and will have the responsibility to conduct a 
thorough safety assessment at regular (monthly) intervals during the dose escalation phase of 
the study. A key responsibility of this committee will be to make a recommendation whether to 
continue, modify or stop dose escalation (or the study) based upon an evaluation of emerging 
safety data, in particular Adverse Events of Special Interest as outlined in Section 11.5. The SMC 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 50 of 72 
will comprise at least of a Hematologist with PNH experience and an Infectious Disease 
Specialist. The SMC will meet regularly as defined in the SMC charter, commencing before 
initiation of Cohort 2. Dose escalations and continuation beyond 28 days (Cohort 4) will not 
always coincide with SMC meetings. Additional regular or ad-hoc safety reviews will be 
scheduled as recommended by the committee or requested by the Sponsor. 
The remit, roles, and responsibilities of the SMC will be specified in a separate SMC charter. 
9.4 
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 until the symptoms or values return to normal or 
acceptable levels, as judged by the PI. 
Subjects withdrawn will not be replaced. 
10. ASSESSMENTS 
10.1 
Safety Assessments 
This study primarily assesses the safety and tolerability of APL-2. Safety will be determined by 
evaluating physical examinations, vital signs, ECGs, clinical laboratory parameters, injection site 
reactions and AEs as outlined in the Study Flow Chart in Section 2.  
If deemed necessary, additional safety measurements will be performed at the discretion of the 
PI. 
10.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured at screening as part of 
the physical examination.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 51 of 72 
10.1.2 Physical Examination 
All physical examinations include, at a minimum, assessment of the following: general, head, 
ears, eyes, nose, 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 2. 
Medical history will be recorded at screening.  
A symptom-driven physical examination may be performed at various unscheduled time points 
if deemed necessary by the PI. 
10.1.3 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 2. 
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 dosing days, 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 will be 
performed within approximately 30 minutes after dosing. 
10.1.4 Electrocardiogram Monitoring 
Single 12-lead ECGs will be measured at the time points outlined in the Study Flow Chart in 
Section 2.  
On dosing days, 12-lead ECGs will be performed post-dose within approximately 30 minutes 
after completion of dosing.  
ECG time points will be guided by PK data and will be collected around the estimated Tmax. The 
time points may be changed depending on PK information obtained from previous cohorts. 
ECGs will be taken following resting in the supine position for 10 minutes in a quiet 
environment. 
ECGs will be interpreted, 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 Fredericia’s method and uncorrected) will be 
noted on the CRF. All CS findings will be recorded as AEs. 
10.1.5 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 Days 1 and 15 in Part 1; Days 29, 43, and 71 in Part 2A; Days 86, 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 52 of 72 
142, 198, 253, and 309 in Part 2B; Days 533 and 729 in Part 2C and during the Exit Visit on Day 
785 (see Appendix 1 for details). 
10.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Flow Chart in Section 2. In 
addition, laboratory safety tests may be performed at various unscheduled time points, if 
deemed necessary by the PI. The clinical laboratory tests include (but are not limited to) the 
following: 
10.1.6.1 Hematology 
x Hemoglobin 
x Hematocrit 
x Red blood cell (RBC) count 
x Platelet count  
x White blood cell (WBC) count with 
differential 
10.1.6.2 Coagulation 
x Prothrombin time (PT) 
x Fibrinogen 
x Activated partial thromboplastin time (aPTT) 
x D-Dimer 
10.1.6.3 Serum Chemistry 
x BUN 
x Creatinine 
x Estimated creatinine clearance 
(using Cockcroft-Gault formula) –
screening only 
x Bilirubin (total and direct) 
x Uric acid 
x Albumin 
x Alkaline phosphatase (ALP) 
x Lactate dehydrogenase (LDH) 
x Creatine kinase  
x Aspartate aminotransferase (AST) 
x Alanine aminotransferase (ALT) 
x Gamma glutamyl transpeptidase (GGT) 
x Glucose  
x Sodium 
x Potassium 
x Chloride 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 53 of 72 
10.1.6.4 Urinalysis 
x pH 
x Specific gravity 
x Protein 
x Glucose 
x Ketones 
x Bilirubin 
x Blood 
x Nitrite 
x Urobilinogen 
x Leukocyte esterase 
If an abnormality is noted for protein, blood, nitrite and/or leukocyte esterase, a 
microscopic examination will be performed. 
10.1.6.5 Serology 
x HIV 
x HBsAg 
x HCV 
10.1.6.6 Human Chorionic Gonadotropin (Serum Pregnancy Test) and Follicule-
Stimulating Hormone 
Serum Pregnancy Test will be performed for females only. FSH will be performed for 
postmenopausal females at screening only. 
10.1.7 Injection Site Assessment 
An assessment of the APL-2 injection site will be performed at each dosing day, within 30 min 
after completion of 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, or induration; and the subject 
will be queried about the presence of pain and/or tenderness (See Appendix 2 for details). The 
date, time, and outcome of the injection site assessment will be recorded on the source 
documents and CRFs. Any abnormal findings will be reported as adverse events according to 
protocol Section 11. 
10.2 
Pharmacokinetic Assessments 
10.2.1 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 2. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 54 of 72 
The allowable post-dose deviation window is as follows: 
Sample time 
Allowed deviation 
Sampling ≤72 hours after first multiple dosing 
±30 minutes 
Sampling >72 hours 
±10%  
PK samples during multiple dosing will be collected pre-dose. 
Preliminary PK analysis may be performed to reconsider sampling time points as the study 
progresses or to guide the dose escalation decision. 
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate sample handling manual prior to study initiation. 
10.2.2 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. 
10.3 
Pharmacodynamic Assessments 
Blood samples will be collected via direct venipuncture at the time points delineated in the 
Study Flow Chart in Section 2 for PD assessment of complement activation through the classical 
(e.g., CH50) and alternative (e.g., AH50) pathways, PNH clone distribution, C3 deposition on 
RBCs and Th17/Treg profile. 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. 
Instructions for collection, handling, processing, storage, and shipping of samples will be 
provided in a separate sample handling manual prior to study initiation. 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 55 of 72 
10.4 
Blood Volume for Study Assessments 
Table 2: Blood Volume during Study (up to Visit 372) 
Assay 
Number 
of Time 
Points * 
Approximate 
Volume per Time 
Point ** (mL) 
Approximate 
Sample Volume 
Over Course of 
Study (mL) 
Pharmacokinetics 
32 
2 
64 
 
Anti-APL-2 Ab assay 
20 
2 
40 
Hematology 
29 
3 
87 
Chemistry (Incl. screen serology and pregnancy) 
29 
6 
174 
Coagulation profile 
26 
4.5 
117 
Complement profile (C3, CH50 and AH50)*** 
28 
4 
112 
Flow cytometry for PNH and C3 deposition 
28 
2 
56 
Th17/Treg Analysis 
10 
19 
190 
Free hemoglobin 
28 
2 
56 
Total Blood Volume for Study 
896 mL 
* If the dose of APL-2 is increased above 270 mg/day, an additional 15 mL blood will be collected at up to three 
time-points, and the total blood volume for the study will increase to a maximum of 941 mL. 
* Represents the largest collection volume planned over the duration of the study (smaller tubes will be used 
whenever possible). 
** AH50 and AP50 both measure the hemolytic activity of alternative pathway of complement in blood samples. 
AH50 is reported in this study and AP50 has been used in other studies noted in this protocol. 
10.5 
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 at Visit 2 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. A final urine 
pregnancy test will be performed at the final Exit visit (Visit 372 or early termination). Male 
subjects will be counseled to avoid donating sperm after dosing at Visit 2 until the final Exit 
visit. 
11. ADVERSE EVENTS 
11.1 
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.  
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 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
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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 at Visit 2 will be categorized as pre-treatment events. 
Treatment-emergent adverse events (TEAEs) will be defined as those AEs that occur after 
dosing at Visit 2 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.  
11.2 
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 investigator’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 Investigator, 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:  
x Ongoing  
x Resolved 
x Resolved with sequela  
x Death or  
x Unknown 
11.3 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator or physician designee with regard to the categories 
discussed in the sections below. 
11.3.1 Intensity 
The Investigator will determine the severity of each AE. Localized injection site reactions will be 
closely monitored and will be graded according to the FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials 
(FDA, 2007). See Appendix 2 for details. 
x All other 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: 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 57 of 72 
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. 
11.3.2 Causality 
The relationship of an AE to the study drug will be assessed using the following criteria: 
Unrelated 
x 
Does not follow a reasonable temporal sequence from the 
administration of study drug  
x 
The event or laboratory test abnormality is clearly due to extraneous 
causes (disease, other drugs, environment, etc.) 
Unlikely 
x 
Does not follow a known pattern of response to study drug 
x 
Does not follow a reasonable temporal sequence from the 
administration of study drug 
x 
Disease or other drugs provides plausible explanation 
x 
It does not reappear or worsen when study drug is re-administered 
Possibly 
x 
Follows a known pattern of response to study drug 
x 
Time sequence from administration of the study drug is reasonable 
x 
Could also be explained by disease or other drugs 
Probably 
x 
Follows a known pattern of response to study drug 
x 
Time sequence from administration of the study drug is reasonable  
x 
Response to withdrawal clinically reasonable 
x 
Cannot be reasonably explained by the known characteristics of the 
participants clinical state, environmental factors, or other therapies 
administered to the subject 


 APL-2
Ascending Dose / First in Human / PNH Add-on to SOC
Apellis Pharmaceuticals, Inc. 
Protocol Number: APL-CP0514
V4.0 Amendment 7
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 - CONFIDENTIAL
Page 58 of 72
11.3.3 Serious Adverse Event 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose: 
x
Results in death; 
x
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; 
x
Required hospitalization or prolongation of existing hospitalization; 
x
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
x
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. 
11.4
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 
Investigator 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 Investigator should complete and sign the SAE Report Form, and fax it to 
the Safety Monitor at the number listed below within 24 hours of becoming aware of the event:  
Telephone No.:  
 
Telephone No.:  
 
Toll Free No.:    
 
Facsimile No.:   
 
The initial SAE Report should include, at a minimum, the following information: 
x
Study number 
x
Subject ID number 
x
Gender 
x
Date of birth 
x
Name of PI and full clinical site address 
x
Details of SAE 
x
Criterion for classification as “serious” 
x
Study drug name and treatment start date 
x
Date of SAE onset 
PPD
PPD
PPD
PPD


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 59 of 72 
x Causality assessment (if sufficient information is available to make this determination) 
The Safety Monitor will request clarification of omitted or discrepant information from the 
initial report. The Investigator 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 Investigator must sign and date the form.  
The Investigator must report all SAEs to the IRB/IEC according to the institutional IRB/IEC policy.  
11.5 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) 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 them, and depending upon the nature of the event, rapid communication by the 
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: 
x Local or systemic infection of any origin 
x Clinically significant decrease in kidney function 
x Injection site reactions 
x Thromboembolic events  
x Infusion pump related events 
If an AESI 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. 
 
11.6 
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.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 60 of 72 
11.7 
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 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. When 
appropriate, medical tests and/or examinations will be performed to document resolution of 
the event(s).  
AEs continuing after completion of the study will be followed up by telephone or with visits per 
the discretion of the Investigator. If possible, the outcome of any AE that caused 
discontinuation from the study or was present at the end of the study should be reported, 
particularly if the AE was considered by the PI to be related to the study drug. 
11.8 
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. 
Women of child-bearing potential (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 
Investigator should report the pregnancy to the Safety Monitor within 24 hours of being 
notified. The subject or partner should be followed by the Investigator until completion of the 
pregnancy. At the completion of the pregnancy, the Investigator 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 Investigator 
should follow the procedures for reporting an SAE (Section 11.4).  
12. STATISTICS  
12.1 
Sample Size Justification 
The sample size was chosen to be sufficient to address safety, tolerability and PK analyses. All 
collected data will be enumerated in listings, summary data will be tabulated, and no formal 
statistical testing is planned for the study data.  
12.2 
Statistical Analysis Methodology  
A formal Statistical Analysis Plan (SAP) will be developed and finalized prior to locking the data. 
The full details of the data presentation and analysis will be provided therein. Any deviations 
from the final analysis plan will be discussed in the final study report. Additional statistical 
analyses other than those described in this section may be performed if deemed appropriate 
and included in the SAP. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
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12.2.1 Study Analysis Datasets 
The intent-to-treat (ITT) analysis set will be the primary analysis set for the efficacy endpoint; 
safety analysis set will be used for all safety assessments.  
12.2.1.1 Intent To Treat (ITT) 
The ITT population will include all subjects enrolled and eligible to receive study medication. 
The ITT population will be analyzed only for the purpose of subject disposition.  
12.2.1.2 Safety 
The safety population will include all ITT subjects who receive at least one dose of the study 
drug. The safety population is also referenced as the modified ITT (mITT) population. The mITT 
population is the primary population for efficacy and safety evaluations. 
12.2.1.3 PK population 
The PK population will include all safety population subjects who have had at least one PK 
sample drawn.  
12.2.1.4 Data Review for Analysis Datasets 
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. 
12.3 
Study Endpoints 
12.3.1 Efficacy Endpoint 
The Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (Version 4) is an 
exploratory efficacy endpoint for exploratory purposes only and no formal analysis of efficacy 
endpoint is planned for this study (see Appendix 1).  
12.3.2 Safety Endpoints 
The primary safety endpoints of the study are the number and severity of Treatment Emergent 
Adverse Events (TEAEs).  
12.3.3 Pharmacokinetic Endpoints  
The study endpoints are the plasma concentrations of APL-2 and pharmacokinetics parameters 
of APL-2 following administration of the single SC dose in relevant cohorts (Section 12.9).  
12.4 
Efficacy Analysis 
The FACIT Fatigue Scale is a 13-item Likert scaled instrument. The FACIT instrument results in a 
score with a range of 0 to 52. The measure is collected at Visits described in the Study Flow 
Chart. The analysis of baseline score and change from baseline by cohort and time point will be 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 62 of 72 
evaluated. No imputation for any missing data will be planned. An exploratory efficacy analysis 
of the FACIT data and relevant PD markers will be presented. 
12.5 
Safety Analysis  
All safety endpoints will be evaluated using the safety population. No formal inferential 
statistics will be applied to the safety assessments. 
12.5.1 Total Exposure 
By-patient study drug exposure (date/time of injection, injection site, injection volume) will be 
presented in a listing. 
12.5.2 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.  
12.5.2.1 Adverse Events Summary 
A by-subject TEAE data listing, including verbatim term, preferred term, treatment, severity, 
and relationship to treatment will be provided. Serious adverse events (SAEs), adverse events of 
special interest (as defined in Section 11.5), and details of subjects withdrawing due to adverse 
events will also be listed.  
AEs will be tabulated as a total population and by treatment group. For Cohort 1 and Cohort 2, 
reported tables will also consider the dosing phase for the AE. The following will be tabulated: 
1. Topline summary of Adverse Events, tabulating the number of TEAEs, treatment related 
AEs, Serious AEs, AEs of special interest, injection site reactions, and adverse events 
leading to discontinuation  
2. TEAEs by SOC and preferred term  
3. TEAEs regarded as possibly/probably related to study drug by SOC and preferred term 
4. TEAEs and Serious AEs by maximum severity, and by SOC and preferred term  
5. Adverse events of special interest by maximum severity and relationship to study drug  
12.5.3 Clinical Laboratory Tests 
All laboratory endpoints will be summarized in listings. In addition, laboratory values that are 
above or below the reference range will be identified in the listings.  
12.5.4 Vital Signs 
Vital signs will be listed for each subject and time point. Any Investigator determined potential 
clinically significant findings will be identified and listed.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
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12.5.5 ECGs 
ECG results will be classified using frequency counts for normal, abnormality that is not 
clinically significant (NCS), and clinically significant abnormality (CS) by cohort and time point of 
collection. ECGs results will be listed for each subject and each time point. Any Investigator 
determined potential clinically significant changes will be identified and listed.  
12.6 
Handling of Dropouts and/or Missing Data 
No imputation of missing data for early terminations will be performed.  
12.7 
Examination of Subgroups 
Due to the potentially small sample size in any subgroup analyses performed will use 
descriptive statistics only; no tests of hypotheses will be performed. 
12.8 
Enumerated Data 
Physical Examination and changes in physical examinations findings after baseline will be 
reported in a listing. 
Concomitant medications will be listed by treatment and coded using the most current WHO 
drug dictionary. 
Medical history findings will be coded using latest MedDRA dictionary and listed by subject. 
12.9 
Pharmacokinetic Analysis 
All subjects dosed and having any measurable serum concentration of study drug will be 
included in the PK data set. 
The individual plasma concentration profiles of APL-2 after single dose phase (for Cohorts 1 and 
2) and multiple dose phase (for all cohorts) will be listed and plotted. 
Where possible, in Cohort 1 and Cohort 2, PK parameters for APL-2 will be computed from the 
individual serum concentrations-time data during the single dose phase, using actual sample 
times. PK parameters will be listed, but not summarized.  
 
AUC0-t 
The area under the serum concentration versus time curve, from time 0 
to the last measurable concentration prior to the start of multiple 
dosing, as calculated by the linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method 
when concentrations are decreasing. 
Cmax 
Maximum observed serum concentration. 
tmax 
Time of the maximum measured serum concentration. If the maximum 
value occurs at more than one time point, tmax is defined as the first 
time point with this value. 
Additional PK analyses may be performed. Any analyses or presentations will be outlined in the 
Statistical Analysis Plan. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 64 of 72 
12.10 
Pharmacodynamic Analysis 
All subjects dosed and having any measurable PD data will be included in the PD data set. 
PD parameters include Lactate Dehydrogenase (LDH), Haptoglobin, Hemoglobin, serum levels 
of CH50, AH50, and C3, and clonal distribution of PNH cells. These data will be listed by subject 
and cohort along with changes from baseline and percent changes from baseline. Individual 
changes and percent changes from baseline will be plotted against assessment. 
Red blood cell transfusion data will also be listed by subject and cohort. 
12.11 
Antigenicity Analysis 
APL-2 antigenicity will be assayed in a GLP-compliant manner using a validated direct 
ELISA-based method incorporating a mouse monoclonal antibody specific for PEG as a positive 
control that is capable of detecting extremely low amounts of anti-PEG and APL-2 antibodies, 
typically in the sub-μg/ml concentration range. This anti-PEG monoclonal antibody will be 
included as positive controls on every ELISA test plate run in these studies. 
12.12 
Interim Analysis 
As mentioned in Section 9.3, 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 the subsequent reports. 
12.12.1 Safety (optional) 
At the Sponsor’s request, safety tables, figures, and data listings may be presented to the 
sponsor’s consultants for the purposes of planning the next Phase 1 or initial Phase 2 studies 
prior to database lock. These interim analyses will be performed on data that will be edit-
checked and monitored. 
A safety programmer and a biostatistician will prepare safety tables, figures, and data listings. 
13. ADMINISTRATIVE CONSIDERATIONS 
13.1 
Direct Access to Source Data/Documents 
The Investigator 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 Investigator 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 
Investigator 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.  


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
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13.2 
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 Investigator, 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.  
13.2.1 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 Investigator will provide direct access to source 
data/documents for study-related monitoring. It is important that the Investigator and the staff 
are available at these visits. The monitor will record the date of each visit together with a 
summary of the status and progress of the study. Proposed actions will be documented in 
writing to the Investigator. 
13.3 
Ethics 
13.3.1 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996). 
13.3.2 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 the US Code of Federal Regulations (21 CFR Part 56) and/or ICH 
Guidelines, or other local regulations as deemed appropriate. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 66 of 72 
13.3.3 Subject Information and Consent 
The Investigator is responsible for obtaining an informed consent. A written informed consent, 
in compliance with the US Code of Federal Regulations (21 CFR Part 50), 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 Investigator 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. 
13.3.4 Confidentiality  
Confidentiality of subjects information must be maintained in accordance with the Health 
Insurance Portability and Accountability Act (HIPAA) Privacy Rule-Final Modification (45 CFR 
Parts 160 and 164). 
13.3.5 ClinicalTrials.gov  
This study will be listed with ClinicalTrials.gov, as required. 
13.3.6 Termination of Study 
The Sponsor reserves the right to suspend or discontinue this study for administrative and/or 
safety reasons at any time. The investigator reserves the right to discontinue dosing subjects at 
any time for safety reasons. 
13.4 
Data Handling and Record Keeping 
The Investigator 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 Investigator/Institution as to when these 
documents no longer need to be retained. 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 67 of 72 
13.5 
Protocol Amendments 
Any amendments to the study protocol deemed necessary as the study progresses will be 
discussed between Sponsor and the Investigator. The Investigator will not implement any 
changes to the protocol without an agreement by the Sponsor and prior review and documented 
approval/favorable opinion 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 
Investigator and must be confirmed in writing. Amendment(s) will be approved and signed off 
in the same way as the protocol.  
13.6 
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). 
13.7 
Finance and Insurance 
Finance and insurance will be addressed in a Clinical Trial Agreement between the 
Investigator/Institution. 
13.8 
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 Investigator and Site personnel by the 
Sponsor shall not be published or disclosed to a third party without the prior written consent of 
the Sponsor.  
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 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 68 of 72 
14. REFERENCES 
Note: A copy of the publications by DeZern (2013), Ivens (2013) and Rudmann (2013) 
referred to in this document is included in Item 10 and on the CD attached to the original 
IND submission. 
 
1. Schrezenmeier et al. Baseline characteristics and disease burden in patients in the 
International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica, 2014, 99 
(5), p. 922-929. 
2. Hillmen P, et al. Long-term effect of the complement inhibitor eculizumab on kidney 
function in patients with paroxysmal nocturnal hemoglobinuria. Am. J. Hematol., 2010,  
85, p.553–559. 
3. 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 
4. Apellis Pharmaceuticals, Inc. APL-2. Investigator’s Brochure. Version 5 April 2016. 
5. 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/Gui
dances/ucm078932.pdf   
6. 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/GuidanceComplianceRegulator
yInformation/Guidances/Vaccines/ucm091977.pdf 
7. 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/Gui
dances/UCM332846.pdf 
8. 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 
9. 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. 
10. 2016 Adult Immunization Schedule was approved by the Centers for Disease Control 
and Prevention’s (CDC). Fedruary 2016. Accessed on August 1st 2016. 
http://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-
schedule.pdf 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 69 of 72 
15. APPENDIX 1: 
FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT) FATIGUE SCALE 
 
FACIT Fatigue Scale (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
 
 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
HI7 
I feel fatigued .......................................................................................
0 
1 
2 
3 
4 
HI12 
I feel weak all over ...............................................................................
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”) ................................................................
0 
1 
2 
3 
4 
An2 
I feel tired ............................................................................................
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired ................................
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired ...............................
0 
1 
2 
3 
4 
An5 
I have energy .......................................................................................
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities .......................................................
0 
1 
2 
3 
4 
An8 
I need to sleep during the day .............................................................
0 
1 
2 
3 
4 
An12 
I am too tired to eat.............................................................................
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities ...................................................
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want to do .........
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired ............................
0 
1 
2 
3 
4 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 70 of 72 
FACIT-Fatigue Subscale Scoring Guidelines (Version 4)  
 
Instructions:* 1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, 
then divide by the number of items answered. This produces the subscale score. 
4. The higher the score, the better the QOL. 
 
Subscale 
       Item Code       Reverse item?     Item response     
 Item Score  
 
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE 
 
HI12 
 
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12  
4 
- 
________ 
 
=________ 
An14  
4 
- 
________ 
 
=________ 
An15  
4 
- 
________ 
 
=________ 
An16  
4 
- 
________ 
 
=________ 
 
Sum individual item scores: 
________ 
Multiply by 13: 
________ 
Divide by number of items 
answered: 
________ (Fatigue Subscale Score) 
Score range: 0-52 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 71 of 72 
*For guidelines on handling missing data and scoring options, please refer to the Administration 
and Scoring Guidelines in the manual or on-line at www.facit.org. 
NOTE: The FACIT and all related works are owned and copyrighted by, and the intellectual 
property of David Cella, Ph.D. Permission for use of the FACIT-FATIGUE questionnaire is 
obtained by contacting Dr. Cella at information@facit.org 
 
 


 
 
APL-2 
Ascending Dose / First in Human / PNH Add-on to SOC 
Apellis Pharmaceuticals, Inc.  
Protocol Number: APL-CP0514
V4.0 Amendment 7 
Effective: 15-JUN-2017
PROT_ APL-CP0514_Amendment 7_June 15th, 2017 -  CONFIDENTIAL 
Page 72 of 72 
16. APPENDIX 2: ASSESSMENT OF LOCAL INJECTION SITE REACTIONS 
Local injection site reactions will be rated according to the FDA Guidance for Industry: Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine 
Clinical Trials (Sep 2007)3 as follows: 
 
Local Reaction 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Pain 
Does not interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or interferes 
with activity 
Any use of narcotic pain 
reliever or prevents 
daily activity 
Tenderness 
Mild discomfort to touch Discomfort with 
movement 
Significant discomfort at 
rest 
Erythema/Redness* 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Induration/Swelling** 2.5 – 5 cm and does not 
interfere with activity 
5.1 – 10 cm or interferes 
with activity 
> 10 cm or prevents 
daily activity 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement. 
 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
Study Title:
An Open Label, Single and Multiple Ascending Dose Study to 
Assess the Safety, Tolerability, Pharmacokinetics and 
Pharmacodynamics of APL-2 as an Add-On to Standard of Care in 
Subjects with Paroxysmal Nocturnal Hemoglobinuria (PNH)
Protocol Number:
APL-CP0514
Version 4.0, Amendment 7 / 15 June 2017
Sponsor:
Apellis Pharmaceuticals
6400 Westwind Way, Suite A
Crestwood, KY  40014
Sponsor Contact:
Apellis Pharmaceuticals
200 5th Avenue
Waltham, MA 02451
CRO:
DP Clinical, Inc.
9201 Corporate Boulevard, Suite 350
Rockville, MD 20850, USA
Telephone: 
Version No.
Version 3.0
Date:
07 Jun 2018
 
 
Confidential Statement: The information contained herein is proprietary information of 
Apellis Pharmaceuticals Inc., and no part of this information may be reproduced, 
photocopied, stored on a retrieval system, or transmitted without the express written consent 
of Apellis Pharmaceuticals Inc. Any unauthorized use is prohibited. 
PPD
PPD


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Protocol: APL-CP0514  
SAP      
 
 
 
 
 
 
Version 3.0          07 Jun2018          Page 2 of 46
SIGNATORY PAGE
This Statistical Analysis Plan was reviewed and approved by: 
Author 
DP Clinical 
Date
Reviewer
DP Clinical 
Date
Approval 
Apellis Pharmaceuticals, Inc.
Date
Approval 
ParamStat Limited
Date
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
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Protocol: APL-CP0514  
SAP      
 
 
 
 
 
 
Version 3.0
07 Jun 2018
Page 3 of 46
REVISION HISTORY
Version No.
Version Date
Author
Description of Modifications
1.0
28 July 2015
Original Document
2.0
22 December 2016
Updates to account for changes 
introduced by 
Protocol 4.0 Amendment 3, 
Protocol 4.0 Amendment 4, and 
Protocol 4.0 Amendment 5
2.1
03 Feb 2017
Updates to account for changes 
introduced by Protocol 
Amendment 6; Additional 
FACIT and pharmacodynamic 
output added
3.0
07 Jun 2018
Updates to account for changes 
introduced by Protocol 
Amendment 7; added summary 
outputs of efficacy, PK, and PD 
for Cohort 4.
PPD
PPD
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PPD


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Protocol: APL-CP0514
SAP     
Version 3.0          07 Jun2018          Page 4 of 46
TABLE OF CONTENTS 
SIGNATORY PAGE ..................................................................................................................2 
REVISION HISTORY ...............................................................................................................3 
1.0 Introduction........................................................................................................................8 
2.0 Study Overview..................................................................................................................8 
2.1 
Study Objectives.....................................................................................................8 
2.2 
Study Design...........................................................................................................8 
2.3 
Study Sample Size................................................................................................10 
2.4 
Study Flow Chart.................................................................................................11 
3.0 GENERAL ANALYSIS DEFINITON...........................................................................20 
3.1 
General Considerations and Definitions of Baselines.......................................20 
3.2 
Handling of Missing Data....................................................................................21 
3.2.1 
Safety Data...........................................................................................21 
3.2.2 
PK and PD Concentration Data..........................................................21 
4.0 STUDY SUBJECTS.........................................................................................................22 
4.1 
Dispositions of Subjects.......................................................................................22 
4.2 
Protocol Deviations..............................................................................................22 
4.3 
Analysis Datasets..................................................................................................23 
4.3.1 
Screened Set.........................................................................................23 
4.3.2 
Intention to Treat (ITT) and Safety Sets...............................................23 
4.3.3 
PK and PD Sets....................................................................................23 
5.0 DEMOGRAPHIC AND BASELINE CHARACTERISTICS .....................................24 
6.0 CONCOMITANT MEDICATION ................................................................................24 
7.0 TREATMENT EXPOSURE AND TREATMENT COMPLIANCE..........................25 
8.0 EFFICACY ANALYSIS..................................................................................................25 
8.1 
Exploratory Efficacy Analysis ............................................................................25 
9.0 SAFETY ANALYSIS.......................................................................................................27 
9.1 
Adverse Events.....................................................................................................27 
9.2 
Laboratory Parameters.......................................................................................29 
9.3 
Vital Signs.............................................................................................................29 
9.4 
Electrocardiograms..............................................................................................30 
9.5 
Antigenicity Analysis ...........................................................................................30 
10.0 PHARMACOKINETIC ANALYSES............................................................................31 
11.0 PHARMACODYNAMIC ANALYSIS...........................................................................32 


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12.0 INTERIM ANALYSIS ....................................................................................................35 
13.0 SOFTWARE AND PROGRAMMING SPECIFICATIONS.......................................35 
13.1 
Statistical Software ..............................................................................................35 
13.2 
Generating Programming Specifications...........................................................35 
13.2.1 
Formatting Specifications....................................................................36 
13.2.2 
Standard Text Specifications................................................................36 
13.2.2.1 
Header ..............................................................................36 
13.2.2.2 
Title ..................................................................................36 
13.2.2.3 
Footnotes ..........................................................................37 
13.2.2.4 
Footer................................................................................38 
13.2.3 
Statistical Specifications......................................................................38 
13.2.3.1 
Statistics Reported............................................................38 
13.2.4 
SAS Procedure Output.........................................................................39 
13.2.5 
Tables Summarizing Categorical Data................................................39 
13.2.6 
Subject Data Listings...........................................................................39 
14.0 REFERENCE LIST.........................................................................................................39 
APPENDIX 1. LIST OF TABLES, FIGURES, AND LISTINGS........................................41 
 


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Protocol: APL-CP0514
SAP     
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations and 
Acronyms
Description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATC
Anatomic Therapeutic Chemical
AUC
Area Under the Curve
BLQ
Below Limit of Quantification
CS
Clinically Significant Abnormality
DMP
Data Management Plan
DPC
DP Clinical, Inc.
ECG
Electrocardiograms
eCRF
Electronic Case Report Form
FACIT
Functional Assessment of Chronic Illness Therapy
ICH
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ITT
Intent-To-Treat
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
mmHg
Millimeter(s) of Mercury 
msec
Millisecond(s)
NCS
Not Clinically Significant
ODS
Output Delivery System
OC
Oracle Clinical 
QTcB
Heart Rate Corrected QT interval, Bazett’s formula
QTcF
Heart Rate Corrected QT interval, Fridericia’s formula
PD
Pharmacodynamics
PDF
Portable Document Format
PK
Pharmacokinetics
PI
Principal Investigator
PNH
Paroxysmal Nocturnal Hemoglobinuria


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Abbreviations and 
Acronyms
Description
PRBC
Packed Red Blood Cells
PT
Preferred Term
QC
Quality Control
RBC
Red Blood Cell
RDC
Remote Data Capture 
RTF
Rich Text Format
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SMC
Safety Monitoring Committee
SOC
System Organ Class
SOP
Standard Operating Procedure
TLFs
Tables, Listings, and Figures
Th17
T-Helper 17 Cells
TEAE
Treatment Emergent Adverse Event
Treg
T-Regulatory Cells
ULN
Upper Limit of Normal
WHO
World Health Organization


Apellis Pharmaceuticals, Inc.
Protocol: APL-CP0514
SAP     
Version 3.0          07 Jun2018          Page 8 of 46
1.0 Introduction
This Statistical Analysis Plan (SAP) provides a more technical and detailed elaboration of the 
principal statistical features stated in the protocol. The SAP will ensure that the tables, 
listings, and figures (TLFs) that will be produced and statistical methods that will be used are 
complete and accurate and will allow valid conclusions regarding the study objectives. In the 
development of this SAP, the following documents were used:
1. Protocol APL-CP0514 Version 4.0, Amendment 7, 15 June 2017
2. Protocol Administrative Clarification Memorandum, 12 July 2017
3. Electronic Case Report Form (eCRF), 23 December 2015
4. Electronic Case Report Form (eCRF), 27 September 2016
5. Electronic Case Report Form (eCRF), 10 August 2017
The principles in the following guidance documents are followed in preparation of this SAP.
x
ICH E3 (1996): Structure and Content of Clinical Study Reports
x
ICH E6 (R2) (2016): Guideline for Good Clinical Practice
x
ICH E9 (1998): Statistical Principles for Clinical Trials
In the event that a discrepancy is found between the descriptions in the statistical section of 
the protocol and this document, the description in this document supersedes the descriptions 
in the statistical section of the protocol.
Any amendments to the SAP will be made prior to locking the database. Any additional 
analyses not described in the final analysis plan or deviations from the final analysis plan will 
be documented in the final clinical study report. 
2.0
Study Overview
2.1
Study Objectives
The primary objectives of the study are to assess the safety, tolerability and 
pharmacokinetics (PK) of single and multiple subcutaneous (SC) doses of APL-2 in 
subjects with paroxysmal nocturnal hemoglobinuria (PNH) who are still anemic after 
treatment with eculizumab (Soliris®).
An exploratory objective of the study is to assess the pharmacodynamics (PD) of 
single and multiple SC doses of APL-2 when administered to PNH patients.
2.2
Study Design
This is a Phase 1, open-label, prospective, non-randomized, single and multiple 
ascending dose, first-in-human study in patients with PNH. The study is planned to 
enroll approximately 15 subjects across 4 cohorts. Cohorts 1-3 will comprise 2 
subjects in each cohort. Cohort 4 will enroll sufficient subjects to ensure at least 6 
subjects complete 28 days of dosing with APL-2. Subjects may participate in more 
than one cohort on the basis of medical benefit already experienced in the study.


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Safety will be assessed throughout the study; serial blood samples and urine samples 
will be collected. Blood samples will also be collected for the PK assessment of APL-
2 and for PD assessment. Cumulative data will be reviewed by a Safety Monitoring 
Committee (SMC) on a regular basis (Section 12). Interim PK analyses may be 
performed to reconsider the sampling time points as the study progresses and to guide 
the dose-escalation decision. 
The screening period will be up to 30 days before the first dose. The planned length of 
participation (from Screening [Visit 1] to completion of the Exit visit) in the study for 
each subject is approximately 143 days for Cohorts 1 and 2 (30 day screen phase, 56 
day treatment phase and 57 day follow-up), 115 days for Cohort 3 (30 day screen 
phase, 28 day treatment phase and 57 day follow-up) and 815 days for Cohort 4 (30 
day screen phase, 729 day treatment phase and 56 day follow-up).
For Cohorts 1 and 2, subjects will receive a single SC dose of APL-2 on Study Day 1
(Visit 2). After a waiting period of at least 28 days, subjects may enter the multiple 
dose phase and receive SC APL-2 daily for 28 days at the corresponding multiple 
dose for their cohort. Dose escalation/new cohort initiation will only occur once all
subjects in the preceding cohort have completed their 28-day waiting period.
Cohorts 3 and 4 will only undergo a multiple dose phase. Subjects will receive APL-2
for 28 days in Cohort 3. For Cohort 4, the treatment period will consist of four parts
(Parts 1, 2A, 2B and 2C) - in Part 1, subjects will receive APL-2 for 28 days. On Day 
29, 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 to receive daily doses of APL-2 until Day 84. If there is 
ongoing evidence of clinical benefit on Day 84 they may enter into Part 2B of the 
study, and continue receiving daily doses of APL-2 until Day 364. If a subject
continues to demonstrate benefit, APL-2 will be administered until Day 729 (Part 2C). 
Subjects will be assessed by the Investigator every month for Part 2A and Part 2B. 
Subjects will be assessed by the Investigator at 4 weeks, 8 weeks, and then every 12 
weeks until Day 729.
In Cohort 4, 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.
For all 4 cohorts the first 4 daily SC doses of APL-2 (from the start of the multiple 
dose phase for Cohorts 1 and 2 and from Study Day 1 for Cohorts 3 and 4) and 
subsequent doses on Days 8, 15 and 22 will be administered at the clinical site.  In 
Cohort 4 doses on Days 29, 43, 57, 71, 85, 113, 141, 169, 197, 225, 253, 281, 309,
337, 365, 421, 477, 533, 617 and 729 will also be administered at the clinical site, as 
well as up to three additional site visits if individual dose escalation occurs for 
subjects administered greater than 270mg/day SC APL-2.  All other doses will be 
administered by a trained nurse at the subject’s home.
After completion of dosing, subjects will return to the clinical site for additional 
follow-up visits and the Exit visit.


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Originally subjects were not allowed to participate in more than one cohort.  
With Amendment 4 it was made possible for 
subjects to participate in more than one cohort.   
Following Protocol Amendment 6 Cohort 4 subjects will switch to using an 
ambulatory syringe pump for delivery of APL-2 and switch from a dextrose to an 
acetate-buffered mannitol formulation of APL-2 for SC injection.
2.3
Study Sample Size   
Cohorts 1-3 will comprise of 2 subjects in each cohort. Cohort 4 will enroll sufficient 
subjects to ensure at least 6 subjects complete 28 days of dosing with APL-2.  
Additional cohorts may be enrolled if it is deemed appropriate by the Sponsor in 
consultation with the Safety Monitoring Committee (SMC) to repeat a dose level or to 
study an intermediate dose level.  
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2.4
Study Flow Chart
Cohorts 1 and 2:


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Protocol: APL-CP0514
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Cohort 3:


Apellis Pharmaceuticals, Inc.
Protocol: APL-CP0514
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Cohort 4:
See Study Flow Chart Footnotes below continuation flow chart


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See Study Flow Chart Footnotes below continuation flow chart


Apellis Pharmaceuticals, Inc.
Protocol: APL-CP0514
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See Study Flow Chart Footnotes below continuation flow chart


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Apellis Pharmaceuticals, Inc.
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See Study Flow Chart Footnotes on next page


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A. If Neisseria meningitidis vaccine/s are administered during screening (up to Day –14), a booster (for both vaccinations) should be administered after 2 
months. If Pneumococcal vaccination is required during screening, a dose of PCV13 will be administered at least two weeks prior to Day 1 and a dose of 
PPSV23 will be administered at least 8 weeks later.
B. Preventive antibiotics will be prescribed prior to Visit 2. Antibiotics will be taken from Visit 2 until 14 days after the last dose of APL-2.
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.
E. S = Administration at clinical site. H = Administration at subject’s home. Treatment may be stopped at any time if the investigator and sponsor conclude 
that there is no demonstration of clinical benefit to APL-2 to continue administration. Subjects may self-administer the SC infusions at home, after 
receiving appropriate training by a research nurse or other personnel.
F.
Injection site assessment will be performed within 30 minutes after APL-2 administration. After the subjects start to self-administer APL-2 via the pump, 
injection site reactions will no longer be evaluated by research personnel after at-home administrations. Subjects will be instructed to report any injection 
site reaction to the study coordinator.
G. If done on a dosing day, vital signs will be measured within 2 hours prior to dosing and within 30 minutes after dosing. If the subjects start to self-
administer APL-2 via the pump, vital signs will no longer be measured before and after at-home administrations.
H. Reserved – See note E.
I.
If done on a dosing day, blood samples will be taken pre-dose with the exception that at Visit 2 only a pharmacokinetic sample will be taken pre-dose and 
at 4 hours post-dose.
J.
Absence of Human immunodeficiency virus, Hepatitis B surface antigen, and Hepatitis C virus, will be confirmed prior to APL-2 administration.
K. If done on a dosing day, urine pregnancy test should be completed for WOCBP prior to dosing.
L. MAVE = Major Adverse Vascular Event. After the subjects start to self-administer APL-2 via the pump, MAVE will no longer be evaluated by research 
personnel during home visits. Subjects will be instructed to report any events to the study coordinator.


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M. If the dose is increased to >270 mg/day, the subject will attend the clinical site for safety visits every 2 weeks (instead of every 4 weeks) for the first 6 
weeks after the dose increase i.e. up to an additional 3 clinic visits. The extra clinic visits will be recorded as Unscheduled Visits and will alternate with 
the scheduled monthly visits.
N. Subjects that discontinue dosing at any time during part 1, 2A, 2B or 2C, will move directly into Part 3 for the exit or early termination visit.


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3.0
GENERAL ANALYSIS DEFINITON
3.1
General Considerations and Definitions of Baselines
No formal statistical testing will be performed on data from Cohorts 1-3. Comparisons 
to baseline will be performed for Cohort 4.
Continuous variables will be summarized using the number of observations (n), mean, 
standard deviation (SD), median, minimum, and maximum. With so few subjects in 
Cohorts 1-3, continuous data, unless specifically mentioned otherwise, will only be 
summarized for Cohort 4.
Categorical data will be summarized by treatment group and over all subjects using 
frequency tables. The summary over all subjects will be based on unique subjects, so 
subjects who participate in more than one cohort will only be counted once. 
The baseline for this study will be taken as the pre-dose measure on Study Day 1 (i.e. 
prior to the first dose for all cohorts). 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).
With Cohorts 1 and 2 including a single dose phase before the multiple dose phase and 
Cohorts 3 and 4 only including a multiple dose phase, data from Cohorts 1 and 2 will 
be presented for the single dose phase separately from the multiple dose phase.
Where multiple dose phase data from Cohorts 1-4 are presented together, changes 
from baseline will use the last measurement prior to the start of multiple dosing as 
baseline.  For Cohorts 3 and 4 baseline is scheduled to be Day 1, whilst for Cohorts 1 
and 2 the multiple dose baseline may be Day 1 (ECG, complement profile, and 
cytometry data), Day 22 (FACIT and laboratory safety test data), or Day 29 (vital sign 
data).   
For Cohort 4 the treatment phase consists of four parts - Part 1 covers the first 28 days 
of dosing and Parts 2A, 2B and 2C cover the treatment period till Day 84, Day 364 and 
Day 729 respectively. To assist in the reporting of the study the treatment phases for 
Cohorts 1-3 will also be considered as Part 1, as this will cover the dosing period till 
the end of 28 days multiple dosing.
All collected data will be listed. Data listings will be presented by cohort. Subjects 
who enter more than one cohort will be identified in the listings using a unique flag, so 
it is possible to link the data across cohorts. For Cohort 4, a dose column will be added 
to all listings that contain post-dose assessments, where the last dose that was taken 
before the assessment will be listed.
Listings will include study days, which are relative to the first day of dosing (Day 1).
For subjects who participate in more than one cohort the study day for each cohort will 
be relative to the first day of dosing in that cohort.
Study days will be calculated as:
For events that occurred on the day of or after administration of the first APL-2 dose:
Study Day = visit date – date of first APL-2 dose + 1


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For events occurred on days before administration of the first APL-2 dose:
Study Day = visit date – date of administration of first APL-2 dose
Where assessments/events occur after the start of the multiple dose phase for Cohorts 1 
and 2, the listings will also include the study days relative to the first day of the 
multiple dose phase (henceforth referred to as the ‘multiple dose day’).
3.2
Handling of Missing Data
3.2.1
Safety Data
Missing safety data (e.g. partial dates and missing severities) will be dealt with on a 
case by case basis if they arise.  As a general rule, a conservative approach will be 
adopted (e.g. partial Adverse Event (AE) onset dates and missing severities will be 
taken as the earliest ‘on treatment’ start date and highest severity, respectively,
consistent with the partial information available).
Handling of missing dates/times are detailed in the appropriate sections.
In the event of a missing baseline value (e.g. vital signs) a screen measurement or pre-
dose unscheduled measurement may be used (whichever is closer to the baseline date). 
The original data will always be presented in the listings.
3.2.2
PK and PD Concentration Data
APL-2 concentrations reported from pre-dose on Day 1 to the time of the first 
quantifiable value will be taken as zero for linear plots and the calculation of PK 
parameters, and equal to the lower limit of quantification (LLOQ) for semi-
logarithmic plots.
After this time point, concentrations below the limit of quantification (BLQ) will be 
set to the following thereafter:
x
missing for the calculation of PK parameters
x
zero in linear plots 
x
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).
In the event of a missing PD baseline value a screen measurement or pre-dose 
unscheduled measurement may be used (whichever is closer to the baseline date).
If a baseline PD value is zero then the percent change from baseline will not be 
calculated. If a post baseline value is BLQ, then the value will be set to the LLOQ. 
Similarly, for PD plots, a BLQ value will be set equal to LLOQ.


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4.0
STUDY SUBJECTS
4.1
Dispositions of Subjects
The number of subjects screened and the number of subjects participating in more than 
one cohort will be presented over all subjects. 
The following numbers of subjects will be presented for each cohort:
For Cohorts 1 and 2:
x
who receive the single dose
x
who withdraw prior to Day 22 (i.e. prior to multiple dosing)
For All Cohorts (unless otherwise specified):
x
who receive at least one dose during multiple dose phase
x
who complete Part 1
x
who withdraw during multiple dose phase of Part 1 
x
who receive at least one dose during Part 2A (Cohort 4 only)
x
who complete Part 2A (Cohort 4 only)
x
who withdraw during Part 2A (Cohort 4 only)
x
who receive at least one dose during Part 2B (Cohort 4 only)
x
who complete Part 2B (Cohort 4 only)
x
who withdraw during Part 2B (Cohort 4 only)
x
who receive at least one dose during Part 2C (Cohort 4 only)
x
who complete Part 2C (Cohort 4 only)
x
who withdraw during Part 2C (Cohort 4 only)
x
who complete the study (i.e. through to end of study follow-up)
x
who withdraw during follow-up and reason for withdrawal
x
in each analysis set
x
who are still on study (interim analysis only)
Reasons for discontinuation and screen failures will also be summarized.
4.2
Protocol Deviations
A protocol deviation is any change, divergence, or departure from the study design or 
procedure defined in the protocol. A subset of the protocol deviations may be 
identified as a major protocol deviation as described below:
Important Protocol Deviation: An important protocol deviation might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject’s rights, safety, or well-being. 
The following categories will be used to group protocol deviations:


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1. Eligibility Not Met
2. Study Assessment Noncompliance
3. Study Drug Noncompliance
4. Study Schedule Noncompliance
5. Other (including details of the deviation)
The following are categorical reasons used to document why a protocol deviation 
occurred:
1. Subject illness
2. Subject unable to comply
3. Subject refusal
4. Clinical error
5. Pharmacy error
6. Laboratory error
7. Investigator/staff decision
8. Other 
Upon soft lock of the database, all documented protocol deviations in the study will be 
reviewed to identify all important protocol deviations. The data review team will 
include representatives from clinical operations, medical, data management, and 
statistics. Final decisions will be documented and databased in the SAS analysis 
datasets. 
Number 
and 
proportion 
of 
subjects 
with 
protocol 
deviations 
(Important/Other) may also be tabulated by protocol deviation category if data 
warrants.  Subjects excluded from each analysis set will be tabulated with reason for 
exclusion.
4.3
Analysis Datasets
4.3.1
Screened Set
The Screened Set will include all patients who signed the informed consent form and
were screened for participation in this study.  This set will be used only for the purpose 
of describing subject disposition.
4.3.2
Intention to Treat (ITT) and Safety Sets
The ITT and Safety Sets will include all subjects enrolled who receive at least one 
dose of the study medication.
4.3.3
PK and PD Sets
The PK set will include all subjects in the Safety Set who have at least one PK sample 
drawn with a measurable serum concentration of study drug.  The PD set will include 
all subjects in the Safety Set who have at least one PD sample drawn and a measurable
PD value.


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5.0
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
Demographic data, medical history, concomitant disease and prior medication will be 
summarized by cohort and for the overall study by means of descriptive statistics (n, 
mean, SD, median, minimum and maximum) or frequencies (counts and percentages).
Time since diagnosis of PNH (years) and the baseline measurements for complement 
parameters (CH50, AP50 and C3), clonal distribution of PNH Red Blood Cells (RBC),
hemoglobin level, LDH, haptoglobin, reticulocyte count, total bilirubin and total 
FACIT score will be summarized by cohort and overall using summary statistics for 
continuous variables. In addition, the number of transfusions in the last 12 months 
prior to randomization will be summarized using summary statistics of median, 
minimum and maximum.
Time since diagnosis = (informed consent date - date of diagnosis + 1)/365.25
Medical history, concomitant disease and prior medications will also be summarized 
for each dose group (cohort) and over all subjects by MedDRA Version 17.0 System 
Organ Class (SOC) and Preferred Term (PT). Prior medications will include any 
medications reported with a start date prior to the subject taking their first study dose
and will be summarized by WHO ATC Class 1 Term and WHO drug Preferred Term 
(March 2014).
The number of subjects experiencing past thrombosis and the number of events will be 
summarized separately by cohort and overall.
Subjects who participate in more than one cohort will only be counted once in the 
summaries over all subjects, using the data collected for their first cohort. The 
summaries by cohort will use baseline data from each of the cohorts.
6.0
CONCOMITANT MEDICATION
Concomitant medications will include any medications being taken after the subject 
starts their study medication.  Hence, medications ongoing at the start of dosing will 
be counted in both the prior and concomitant medication summaries.
Concomitant medications will be summarized for each dose group (cohort) and overall
for subjects in the Safety Set. Concomitant medications will be summarized by WHO 
ATC Class 1 Term and WHO drug Preferred Term (March 2014).
Subjects who participate in more than one cohort will only be counted once in the 
overall summary, all concomitant medications across the cohorts will be included in 
the overall summary.
A separate listing will provide information on the eculizumab dosing regimen. The 
listing will detail the subject’s periods of each dosing regimen.  Hence if the subject 
stays on the same dosing regimen during the study there will be a single entry in the 
listing with the study start and stop dates and dose. 
If either the start or stop date of medication is missing, the worst or most conservative 


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case will be considered when assigning medications to categories. So for a missing 
start date (where stop date is after date of first dose) the date will be imputed as the 
date of first dose; for a missing stop date the date will be imputed as the date of last 
dose or start date if start date is after last dose.  If a partial date is recorded, the 
following convention will be used to assign the medication:
x
If a partial date is missing a start day and the month/year is the same as first 
dose date then use first dose date, else ‘01’ will be used for the day; if a start 
date is missing a month and the year is the same as first dose date then use first 
dose date, else January will be used for the start month.
x
If a partial date is missing a stop day and month/year is same as last study date 
then use last study date, else last day of the given month will be used for the 
stop day; if a stop date is missing a month and the year is the same as last study 
date then use last study date, else December will be used for the stop month.
7.0
TREATMENT EXPOSURE AND TREATMENT COMPLIANCE
Treatment compliance will be calculated based on the drug accountability log
documented by the site staff. 
For each subject the following will be listed:
x
For Cohorts 1 and 2, the last phase of dosing (single or multiple)
x
Last study day of dosing within the last study phase (i.e. Study Day calculated 
from Day 1 if last day is in the single dose phase in Cohorts 1 and 2, or the last 
dose day relative to the start of multiple dosing)
x
Number of days during the multiple dose phase they received treatment
x
Compliance (percentage of days they took medication prior to study 
discontinuation/completion).
For Cohort 4 the number of days dosed and the compliance will be presented for Parts 
1, 2A, 2B and 2C separately as well as over the whole study.
Where subjects in Cohort 4 have their dose escalated to 360mg/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 switch to using the ambulatory syringe pump the first day of 
using the pump will be listed. The date of change in formulation will also be listed.
8.0
EFFICACY ANALYSIS
8.1
Exploratory Efficacy Analysis
RBC Transfusions


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The absolute and change in number of RBC transfusions per month and the absolute 
and change number of units transfused per month will be summarized by cohort and 
by phase of the study (Parts 1, 2A, 2B, 2C and 3) and over the whole on-treatment 
study parts (Parts 1, 2A, 2B and 2C). For Cohorts 1 and 2 the data will be split by the 
single and multiple dose phases.
Only whole blood and Packed Red Blood Cell (PRBC) transfusions will be included. 
The number of RBC transfusions per month will be calculated for each part of the 
study as number of transfusion reported during study part * 28 / number of days in that 
part of study.  The whole on-treatment study will be from first dose to last dose 
received.  A similar calculation will be used for the number of unit transfused per 
month.
The baseline number of transfusions per month will be calculated as number of 
transfusions reported on 12-month transfusion history /12.  For subjects who enter both 
cohorts the baseline for both cohorts will be taken from the 12-month transfusion 
history prior to their first cohort.
All 12 month transfusion history and on study transfusion data will be listed by 
Cohort.  A separate listing of the number of transfusions per month and number of 
units transfused per month for baseline, each part and over the whole on-treatment 
study parts will also be included.
FACIT
The Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
(Version 4) is an exploratory efficacy endpoint. The individual fatigue score will be 
calculated (see Appendix 1 of the protocol), where a higher score corresponds to a
higher quality of life.
Individual fatigue scores will be tabulated along with changes from baseline for the 
ITT population by cohort, study part and study day. 
As mentioned in Section 3.1 the multiple dose phase data from Cohorts 1-4 will be 
listed with changes from baseline using the last measurement before the start of 
multiple dosing as baseline (scheduled as Day 22 for Cohorts 1 and 2 and Day 1 for 
Cohorts 3 and 4).  Additionally, Cohort 1 and 2 data from both single and multiple 
dose phases will be listed using Study Day 1 as baseline for the changes from baseline.
In addition to the observed values and changes from baseline, the listing will also 
include the study day of assessment and the multiple dose day for assessments made 
during the multiple dose phase.
For Cohort 4, the absolute values and changes from baseline will be summarized,
using descriptive statistics, by 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.
Total score and changes from baseline in individuals’ fatigue scores will be plotted by 
multiple dose day, with each cohort (dose) and each subject being identifiable. For 
both the total score and changes from baseline, two plots will be presented. The first 
will present the Part 1 data (multiple dose data only for Cohorts 1 and 2) and the 


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follow-up data for Cohorts 1-3.  The follow-up data for Cohort 4 will also be included 
if the subject doesn’t continue dosing into Part 2A. Subjects who participate in more 
than one cohort will be identified in a footnote.
The second plot will present the Cohort 4 data over the whole study.
For all plots a dotted line will be used to identify follow-up data and the actual 
sampling day will be used on the x-axis.
The FACIT and all related works are owned and copyrighted by, and the intellectual 
property of David Cella, Ph.D.  Permission for use of the FACIT-FATIGUE 
questionnaire is obtained by contacting Dr. Cella at information@facit.org.
9.0
SAFETY ANALYSIS
9.1
Adverse Events
Treatment emergent adverse events (TEAE) are defined as those AEs that develop or 
worsen after the first dose of study medication, up to 30 days beyond the last dose of 
study medication. Version 17.0 of Medical Dictionary for Regulatory Activities 
(MedDRA) will be used to classify all AEs.  
AEs will be considered treatment-emergent (TEAE) unless there is clear indication 
that the event occurred prior to first dose of study drug.  AEs present prior to the first 
dose of study drug administration that increased in severity or relationship to study 
drug after the first dose of study drug and up to 30 days beyond the last dose of study 
drug will be classed as a TEAE.  Events with missing or partial dates will be handled 
such that in the absence of contradictory information an AE is treatment emergent.  So 
for a missing start date (where stop date is after date of first dose) the date will be 
imputed as the date of first dose; for a missing stop date the date will be imputed as the 
last study date.  If a partial date is recorded, the following convention will be used to 
assign the AE:
x
If a start date is missing the day information and month/year is the same as first 
dose date then use first dose date, else ‘01’ will be used for the day; if a start 
date is missing the month and the year is the same as first dose date then use 
first dose date, else January will be used for the start month.
x
If a stop date is missing the day information and month/year is same as last 
study date then use last study date, else last day of the given month will be used 
for the stop day; if a stop date is missing the month and year is the same as last 
study date then use last study date, else December will be used for the stop 
month.
Adverse Events Summary 
A by-subject TEAE data listing, including verbatim term, preferred term, treatment, 
severity, and relationship to treatment will be provided. Serious adverse events 
(SAEs), adverse events of special interest, and details of subjects withdrawing due to 


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adverse events will also be listed. The start and stop days (relative to the first dosing 
day), onset time since last dose, and the duration of AEs will be included in listings. 
Adverse events of special interest (AESI) include the following:
o
Local or systemic infection of any origin
o
Clinically significant decrease in kidney function
o
Thrombosis
o
Injection site reactions
o
Infusion pump related events
AESIs will be determined by a review of all AEs by the clinical and data management 
study staff. This review will allow for the inclusion of AEs of special interest arising 
during the study that are not on the above list, based on a clinical decision. It is 
expected that documentation of the AEs of special interest will be maintained outside 
the Oracle Remote Data Capture (RDC) system by the biostatistics and data 
management staff (with review by medical) and used by the programmer for analysis 
of the AEs of special interest. 
For Cohorts 1 and 2, AEs emergent during the single dose phase will be tabulated 
separately to those during the multiple dose phase, and those during the multiple dose 
phase will be presented along with Cohorts 3 and 4. For Cohort 4 TEAEs will be 
tabulated separately for Parts 1 and 2.
A topline summary will present the number of subjects by cohort (dose) and overall 
with:
x any TEAE
x any TEAE considered as related to study drug (evaluated by the investigator as 
Possibly Related or Probably Related or not reported)
x any serious TEAE 
x 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
x any TEAE of special interest
x any TEAE leading to study drug discontinuation 
x 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 TEAE only once within each subject.
Additionally, the following will be tabulated for each cohort (dose) and overall:
x
TEAEs by SOC and preferred term in descending order of total events 
x
TEAEs by preferred term in descending order of total events
x
TEAEs regarded as at least possibly related to study drug by SOC and preferred 
term
x
TEAEs and Serious AEs by maximum severity, and by SOC and preferred term
x
TE AESIs by maximum severity 


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x
TE AESIs regarded as at least possibly related to study drug by SOC and preferred 
term
All summary tables will be presented by study part 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 2A (unless 
it increases in severity).  Summaries will be ordered by descending order of event 
count in the overall column (firstly the SOCs will be ordered and then the preferred 
terms within each SOC).
If a subject is enrolled into more than one cohort, they will be counted in each cohort 
separately, but only once in the overall column for each preferred term.
9.2
Laboratory Parameters
Laboratory values outside the reference range will be identified in listings, using flags 
to identify whether above or below the range limits. Chemistry, Hematology, 
Coagulation, and Urinalysis results will be presented separately.
As mentioned in Section 3.1 the multiple dose phase data from Cohorts 1-4 will be 
listed with changes from baseline using the last measurement before the start of 
multiple dosing as baseline (scheduled as Day 22 for Cohorts 1 and 2 and Day 1 for 
Cohorts 3 and 4).  Additionally, Cohort 1 and 2 data from both single and multiple 
dose phases will be listed using Study Day 1 as baseline for the changes from baseline.
Listings of out of range lab results with their corresponding changes from baseline will 
be presented for the single dose phase (for Cohorts 1 and 2 with a baseline of Study 
Day 1) and for the multiple dose phase. For Cohort 4 the presentations will identify if 
the results were from Parts 1, 2A, 2B or 2C.
9.3
Vital Signs
The listing of vital sign data will include change from baselines. As mentioned in 
Section 3.1 the multiple dose phase data from Cohorts 1-4 will be listed with changes 
from baseline using the last measurement before the start of multiple dosing as 
baseline (scheduled as Day 29 for Cohorts 1 and 2 and Day 1 for Cohorts 3 and 4).  
Additionally Cohort 1 and 2 data from both single and multiple dose phases will be 
listed using Study Day 1 as baseline for the changes from baseline.
In the listing, data fulfilling the following criteria will be flagged:
Value
Parameter
Low
High
Observed
Systolic Blood Pressure (mmHg)


Diastolic Blood Pressure (mmHg)


Pulse (bpm)


Temperature (oC)

The number of subjects satisfying each of the above criteria will also be summarized 
for the safety population by cohort (dose) and study part. As some of the parameters 


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have both low and high criteria it is possible for a subject to meet both over the 
reporting period. Consequently, for these parameters, the number of subjects will be 
presented in the following mutually exclusive categories: 
-
All values in normal range
-
DEQRUPDOO\ORZUHDGLQJ and no abnormally high reading
-
DEQRUPDOO\KLJKUHDGLQJDQGQRDEQRUPDOO\ORZUHDGLQJ
-
DEQRUPDOO\ORZDQGDEQRUPDOO\KLJKUHDGLQJ
For Cohorts 1 and 2 the data will be split by the single and multiple dose phases.
9.4
Electrocardiograms
The listing of ECG data will include change from baselines. As mentioned in Section 
3.1 the multiple dose phase data from Cohorts 1-4 will be listed with changes from 
baseline using the last measurement before dosing as baseline (Day 1 for all cohorts).  
In the listing, data fulfilling the following criteria will be flagged:
Value
Parameter
Low
High
Observed
QT, QTcB, QTcF (msec)

PR 


QRS

Heart Rate


Increase
from 
baseline
QT, QTcB, QTcF (msec)

ECG results will be classified as normal or abnormal, with the abnormal further 
classified as either not clinically significant (NCS) or clinically significant (CS). This 
information will be included in listings.
The number of subjects satisfying each of the above criteria will also be summarized 
for the safety population by cohort (dose) and study part. For Cohorts 1 and 2 the data 
will be split by the single and multiple dose phases. As some of the parameters have 
both low and high criteria it is possible for a subject to meet both over the reporting 
period. Consequently, for these parameters, the number of subjects will be presented in 
the following mutually exclusive categories:
-
All values in normal range
-
DEQRUPDOO\ORZUHDGLQJDQGQRDEQRUPDOO\high reading
-
DEQRUPDOO\KLJKUHDGLQJDQGQRDEQRUPDOO\ORZUHDGLQJ
-
DEQRUPDOO\ORZDQGDEQRUPDOO\KLJKUHDGLQJ
9.5
Antigenicity Analysis
These data will be listed by cohort.


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10.0
PHARMACOKINETIC ANALYSES
PK Concentrations
To assess the plasma concentration profile of APL-2 after both single and multiple 
doses (steady state), concentrations will be listed and plotted. 
Presentations will include:
x
For Cohorts 1 and 2, a listing of all concentrations sorted by dose group (cohort),
subject number, study day, and nominal time post dose will be presented for the 
single dose phase. For all cohorts (1-4) a separate listing of all concentrations 
sorted by dose group (cohort), subject number, multiple dose day, and nominal 
time post dose will be presented for the multiple dose phases.  The actual time 
will also be listed, along with the deviations from nominal time in each of these 
listings.
x
For Cohort 4, APL-2 concentrations will be summarized by study visit using
descriptive statistics. The number of subjects with a value BLQ will also be 
tabulated.
x
Linear and log-linear individual concentration profile plots against actual time 
(with each cohort [dose] being identifiable). 
x
For Cohorts 1 and 2 a plot will be presented for Study Days 1 to 29 (all 
concentrations following the single dose but recorded before the first dose 
of multiple dosing).
x
For Cohorts 1-4, a plot will be presented for Multiple Dose Days 1 to 29 
(the last concentration before the start of multiple dosing through to the last 
concentration no more than 1 day after the Day 29 dose).
x
For Cohort 4, a plot will be presented over the whole study.
Subjects who participate in more than one cohort will be identified in footnotes.
For individual subject plots by time, the actual PK sampling time will be used.
PK Parameters
For Cohorts 1 and 2 only, the following PK parameters for APL-2 will be derived 
from the ’single dose’ individual serum concentrations-time data, using actual sample 
times:
AUC0-t
The area under the serum concentration versus time curve, from time 0
to the last measurable concentration prior to the start of multiple 
dosing*, as calculated using the linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method 
when concentrations are decreasing.
 
Cmax
Maximum observed serum concentration. 


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Tmax
Time of the maximum measured serum concentration. If the maximum 
value occurs at more than one time point, t max is defined as the first 
time point with this value. 
*Until the pre-dose concentration on Day 29.  If a subject starts multiple dosing after 
Day 29 then a footnote will indicate the study day of their last single dose blood 
sample. 
With too few samples taken during the terminal phase of the concentration profile to 
reliably determine the elimination rate constant t1/2, AUC0-inf, CL/F and Vz/F will be 
estimated from the population PK model.
For the multiple dose phase the APL-2 parameters AUCtotal and Ctrough,max will be 
estimated for the individual serum concentration data, using a non-compartmental 
approach. AUCtotal will be calculated using the linear-log trapezoidal method. It will be 
determined using all concentrations measured from the last dose till the last 
quantifiable concentration. For Cohort 4, Ctrough,max will be calculated for both 270mg
and 360mg where subjects receive both doses.
PK parameters will be listed by cohort. For Cohort 4, PK parameters will be 
summarized using descriptive statistics. Geometric mean and CV will also be 
presented. Additional analyses will be performed as deemed necessary upon review of 
the data. 
Population PK Modelling
In addition to the above analyses, all PK plasma concentration data will be used to 
update and further develop the population PK model which is currently based on the 
PK data collected in studies APL-CP0713-1 and APL-CP1014. The methods and 
procedures that will be used as well as the scope of the work that will be undertaken 
will be presented in a Population PK Analysis Plan.
11.0
PHARMACODYNAMIC ANALYSIS
PD parameters include the following:
1. Lactate Dehydrogenase (LDH),
2. Reticulocyte count,
3. Haptoglobin,
4. Hemoglobin level,
5. Total bilirubin, and
6. Serum levels of complement parameters (CH50, AH50, and C3)
These data will be listed by cohort, study part and subject along with changes from 
baseline and percent changes from baseline.  As mentioned in Section 3.1 the multiple 
dose phase data from Cohorts 1-4 will be listed with changes and percentage changes 
from baseline using the last measurement before the start of multiple dosing as 


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baseline (PD parameters 1-5: scheduled as Day 22 for Cohorts 1 and 2 and Day 1 for 
Cohorts 3 and 4; PD parameter 6: Day 1 for all cohorts).  Additionally, Cohort 1 and 2 
data from both single and multiple dose phases will be listed using Study Day 1 as 
baseline for the changes and percentage changes from baseline.
For Cohort 4, absolute values, changes from baseline and percentage changes from 
baseline will be summarized, using descriptive statistics, by 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.
For LDH, reticulocyte count, haptoglobin and total bilirubin the number and 
percentage of subjects  ULN and  1.5*ULN will also be summarized by study visit
for Cohort 4 only. Plots, paged by subject, will include these parameters and present 
the value related to ULN (i.e. value/ULN) against time. Each parameter will have a 
different symbol and a legend to identify the parameters will be included. A vertical 
line, labelled with the dose, will be added to the plot to identify any dose change
during the study.
For hemoglobin level the number and percentage of subjects  LLN will also be 
summarized by study visit for Cohort 4 only.
For each of the above parameters (except CH50 and AH50), individual values, 
changes from baseline, and percent changes from baseline will be plotted against 
actual study day (with each cohort and subject being identifiable) for the multiple dose 
phase. For CH50 only individual values and change from baseline will be plotted. 
AH50 will not be plotted as AH50 should be completely inhibited (i.e. BLQ) for 
subjects receiving Soliris®. For each of the individual value, changes from baseline, 
and percentage changes from baseline endpoints, three plots will be presented.
The first will present individual values, changes from baseline, and percentage
changes from baseline over the study (single and multiple dose phases) plotted against 
assessment for Cohorts 1 and 2 using the last measurement before the start of dosing 
(scheduled as Day 1) as baseline.
The second will present the Part 1 data (multiple dose data only for Cohorts 1 and 2) 
and the follow-up data for Cohorts 1-3.  The follow-up data for Cohort 4 will also be 
included if the subject doesn’t continue dosing into Part 2A. Subjects who participate 
in more than one cohort will be identified in a footnote.
The third will present the Cohort 4 data over the whole study.
For all plots a dotted line will be used to identify follow-up data and the actual 
sampling day will be used on the x-axis.
PD parameters also include the following:
x PNH granulocytes (percent FLAER), and 


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x PNH monocytes (percent FLAER)
x C3 deposition on RBCs (percent C3d CD59 Type I, II, III and II+III*)
x clonal distribution of PNH RBCs (percent CD59 Type I, II, III and II+III**)
*C3d deposition on RBC cells (percent Type II + III) 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.
** Clonal distribution of PNH RBCs (percent Type II + III) is the sum of the clonal 
distribution of PNH RBCs Type II and Type III.
For Cohort 4, absolute values and changes from baseline will be summarized, using 
descriptive statistics, by study visit. 
The individual PNH granulocytes (percent FLAER) and the change from baseline 
(Day 1 for all cohorts) will be plotted by study day with each subject and cohort and 
subject being identifiable. The first plot will present the Part 1 data (multiple dose data 
only for Cohorts 1 and 2) and the follow-up data for Cohorts 1-3.  The follow-up data 
for Cohort 4 will also be included if the subject doesn’t continue dosing into Part 2A.  
Subjects who participate in more than one cohort will be identified in a footnote. A
second plot will present the Cohort 4 data over the whole study. A dotted line will be 
used to identify follow-up (Part 3).  The actual sampling day will be used on the x-
axis. These plots will be repeated for PNH monocytes (percent FLAER) individual and 
change from baseline values.
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. The first plot will present the Part 1 data (multiple dose data only for Cohorts 1 
and 2) and the follow-up data for Cohorts 1-3.  The follow-up data for Cohort 4 will 
also be included if the subject doesn’t continue dosing into Part 2A.  Subjects who 
participate in more than one cohort will be identified in a footnote. A second plot will 
present the Cohort 4 data over the whole study. A dotted line will be used to identify 
follow-up (Part 3).  The actual sampling day will be used on the x-axis. This plot 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. Separate plots will be presented for Part 1 (all cohorts, 
multiple dose phase only for Cohorts 1 and 2) and Cohort 4 (whole study).   A dotted 
line will be used to identify follow-up (Part 3).  The actual sampling day will be used 
on the x-axis. 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).
Listings of the T-helper 17 (Th17) and T-regulatory (Treg) cell analysis will be 
prepared for the single dose phase and the multiple dose phase. The analysis will be


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performed by the Research Lab in Renal Medicine at the Icahn School of Medicine at 
Mount Sinai Medical School in New York City.  
12.0
INTERIM ANALYSIS
An external, independent Safety Monitoring Committee (SMC) will regularly review 
cumulative safety/tolerability, PK and PD data during the dose escalation phase of the 
study. The first SMC assessment will occur before the initiation of Cohort 2. 
Following this, assessments will occur approximately every four weeks. A key 
responsibility of the SMC will be to make recommendations to continue, modify, or 
stop dose escalation (or the study) based on current safety data, particularly the AEs of 
special interest listed in Section 9.1.
Additional safety reviews will be scheduled as recommended by the SMC or the 
sponsor. At the Sponsor’s request, safety tables, figures, and data listings may be 
presented to the sponsor’s consultants for the purposes of planning the next Phase 1 or 
initial Phase 2 studies prior to database lock. These interim analyses will be performed 
on data that will be edit-checked and monitored. 
Preliminary PK analysis may be performed to evaluate the sampling time points as the 
study progresses and to guide the dose escalation decision. 
When all subjects have completed (or discontinued) Part 2A in Cohort 4 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 the 
subsequent reports.
13.0
SOFTWARE AND PROGRAMMING SPECIFICATIONS
13.1
Statistical Software
All statistical programs will be written in SAS® version 9.3.  
 
 
 
 
 
 
 
 
 
 
 
PK parameters (AUC) will calculated using PKNCA (version 0.8.4 or higher) with R 
(version 3.4.3 or higher). 
13.2
Generating Programming Specifications
Appendix 1 provides a list of all the TLFs that are planned to be produced. 
CCI


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13.2.1
Formatting Specifications
The following formatting specifications will be used to output TLFs: 
x
TLFs are outputted by SAS Output Delivery System (ODS) into Rich Text Files 
(RTF) and Portable Document Format (PDF) formats.
x
Tables and Listings will include borders around all headings and data cells.
x
Output will be in landscape orientation with margins of 1.5 inches on top, and 
1 inch for right, left, and bottom.
x
The default font to be in tables/listings/figures will be Times New Roman or 
Courier New.
x
Preferred and minimum font size:
Portion of Output
Preferred
Minimum
Page Header
12 pt
8 pt
Title
12 pt bold
8 pt
Column header
12 pt bold
8 pt
Cells
9 pt
8 pt
Footnote
8 pt bold
8 pt
Page Footer
12 pt
8 pt
x
Data will be centered within columns when the maximum length of the data 
being displayed is less than or equal to the maximum width of the column 
heading. When the maximum length of the data being displayed exceeds the 
maximum width of the column heading, the data will be left-justified.
x
Column headings should be in initial capital characters.  For numeric variables, 
include “unit” in the column heading when appropriate.
x
In figures, axes will be labeled appropriately.
13.2.2
Standard Text Specifications
13.2.2.1
Header
All output (table, listing, or figure) will have the following header at the upper 
left corner:
Apellis Pharmaceuticals, Inc.
Protocol: APL-CP0514
Clinical Study Report
All output will have the date and time output was generated and internal page 
number in the footer.  Tables/Listings/Figures should be internally paginated 
(i.e., page numbers should appear sequentially within each output).
13.2.2.2
Title
At least three (3) lines, in general, will be reserved for the entire title. 


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x The first line is for the table/listing/figure number; 
x The second line is for the actual title; and 
x
The third line is reserved for the analysis population descriptor. 
All titles will be centered, as shown in the following example:
Table 14.1.1.1
Disposition of Subjects
Screened Set
13.2.2.3
Footnotes
Unless otherwise specified, footnotes will appear on all pages within the tables 
and listings.
x
Footnotes will be in the format of “Note: followed by 2 spaces, then the 
footnotes”, as shown in the following example: 
Note:  SD = Standard Deviation, Min = Minimum, Max = Maximum. 
x
Each line of a complete footnote should end with a period.
x
When an abbreviation (e.g. AE, SAE, ITT, etc.) appears in the whole 
set of TLFs for a study, a footnote should be provided. 
x
A footnote serves as a brief explanation/clarification /definition 
/concept of a flag symbol or a character, an abbreviation, a 
terminology, etc., that appears in or related directly to the displayed 
content of a table/listing/figure. 
x
Footnotes will not contain detailed/technical elaboration of, for 
example, a mathematical/statistical formula, a statistical term/test, or an 
algorithm for deriving a parameter value, which should be addressed in 
the text of the SAP.
x
All footnotes will be at the lowest line of the page immediately above 
the footer.  There will be one space between the last footnote and the 
footer.
x
For Tables, the first footnote will provide source listings and/or analysis 
datasets names for cross-referencing.
x
Any use of the FACIT score must include the footnote: 
The FACIT and all related works are owned and copyrighted by, and the intellectual 
property of David Cella, Ph.D.  Permission for use of the FACIT-FATIGUE 
questionnaire is obtained by contacting Dr. Cella at information@facit.org.
This impacts all the documents that mention the FACIT-FATIGUE 
including, but not limited to:
x
eCRFs (RDC)
x
Tables, listings and figures (including mocks)
x
eCRF/ RDC guidelines
x
Reports (including ad-hoc requested reports)
x
Data Management Plan (DMP)


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13.2.2.4
Footer
The following footer should appear at the very bottom of each page of a table, 
a listing, or a figure generated in SAS in the lower left corner:
Program: PGNAME.sas; Creation Date and Time: MMDDDYYYY HH:MM
Data Cutoff: DDMMMYY:HH:MM:SS – Listing Generated MMM DD, YYYY
and the following footer at the lower right corner:
Version
Date
Time
Page x of y (for within output pagination)
where 
PGNAME = SAS program name;
Version will be replaced by version number and “Draft” or “Final”.
13.2.3
Statistical Specifications
13.2.3.1
Statistics Reported 
x
Unless otherwise specified, the mean and standard deviation (SD) will 
be displayed to one more decimal place than the original value, while 
minimum and maximum will be reported in the format of the original 
data, e.g.:  
Original: xx
Mean and SD: xx.x
Minimum and maximum: xx
x
Unless specified in the actual TLF shells for a study, all percentages 
will be rounded to one decimal place in all tables/listings/figures.  
Rounding will take place after all calculations have been performed.
x Use of N versus n:
N = total number of subjects or subjects in the population.
n = total number of subjects or subjects in the specific category.
x P-value label formatting
Column heading 
P-value
Row heading 
P-value
Footnote – first word
P-value
Footnote – embedded word p-value
x
All p-values should be reported to using SAS pvalue6.4 format 
(displayed as ‘0.xxxx’ or ‘<0.0001’) 


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13.2.4
SAS Procedure Output
All SAS log and output will be saved to file to a secure location for final 
archive. 
13.2.5
Tables Summarizing Categorical Data
The following specifications apply to tables that summarize categorical data:
x
Percent of events should be left blank (including the parentheses) if the 
number of events is zero.
x
If the categories of a parameter are ordered, then all categories between 
the maximum possible category and the minimum category will be 
included, even if n=0 for a given category between the minimum and 
maximum level for that parameter.
x
If the categories are not ordered, then only those categories for which 
there is at least one subject represented will be included.
x
A missing category will be added to any parameter for which 
information is not available for any subjects.
13.2.6
Subject Data Listings
In general, individual subject data listings should include all subjects with data.  
However, if a subject data listing includes only subjects who met a certain 
condition, and there were no subjects who met that condition, then a “message” 
will appear indicating that no subjects met the condition for inclusion in that 
listing.
14.0
REFERENCE LIST
Denney W, Duvvuri S and Buckeridge C (2015). Simple, Automatic Noncompartmental
Analysis: The PKNCA R Package. Journal of Pharmacokinetics and Pharmacodynamics, 
42(1), pp. 11-107,S65. ISSN 1573-8744, doi: 10.1007/s10928-015-9432-2
DP Clinical SOP: SOP-ST-0601.07:  Programming for Statistical Analysis. DP Clinical, Inc., 
Rockville, MD USA.
DP Clinical SOP: SOP-ST-0601.21:  Review and Quality Control (QC) of Study Results. DP 
Clinical, Inc., Rockville, MD USA.
ICH E3 (1996): Structure and Content of Clinical Study Reports. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH).


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ICH E6 (R2) (2016): Integrated Addendum to ICH E6(R1): Guideline for Good Clinical 
Practice. International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH).
ICH E9 (1998): Statistical Principles for Clinical Trials. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH).
MedDRA Version 17.0 (March 2014). International Federation of Pharmaceutical 
Manufacturers and Associations (IFPMA).
R Core Team (2012). R: A language and environment for statistical computing. R Foundation 
for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-
project.org/.
SAS® for Windows® Version 9.3. SAS Inc. Cary, North Carolina USA.
The WHO Drug Dictionary (WHO-DD) (March 2014). World Health Organization (WHO) 
Uppsala Monitoring Center (UMC).