Clinical trial NCT04811716
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: PNH
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-07-29; Completion date: 2023-10-18
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens of pozelimab and cemdisiran combination therapy during the open-label treatment period (OLTP)

The secondary objectives of the study are:

* To evaluate the effect of the combination treatment on the following parameters of intravascular hemolysis: lactate dehydrogenase (LDH) control, breakthrough hemolysis, and inhibition of total complement hemolysis activity (CH50)
* To evaluate the effect of the combination treatment on hemoglobin levels
* To evaluate the effect of the combination treatment on red blood cell (RBC) transfusion requirements
* To evaluate the effect of the combination treatment on clinical outcome assessments (COAs) measuring fatigue and health related quality of life
* To assess the concentrations of total pozelimab in serum and total complement component (C) 5 and cemdisiran in plasma
* To assess immunogenicity to pozelimab and cemdisiran
* To evaluate the long-term safety and efficacy of pozelimab and cemdisiran in an optional open-label extension period (OLEP)
* To assess safety after treatment intensification with pozelimab and cemdisiran

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Pozelimab intervention 2: Cemdisiran
Intervention descriptions: intervention 1: Administered Sub-cutaneous (SC) per protocol intervention 2: Administered SC per protocol

Protocol documents:
Prot_000.pdf: 
EudraCT number: 2020-005005-17 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A Randomized, Open-Label, Two-Arm Study to Evaluate the Safety, 
Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran 
Combination Treatment in Patients with Paroxysmal Nocturnal 
Hemoglobinuria Who Have Received Pozelimab Monotherapy 
Compounds: 
Pozelimab (REGN3918) 
Cemdisiran (ALN-CC5) 
Clinical Phase: 
2 
Protocol Number: 
R3918-PNH-2092 
Protocol Version: 
R3918-PNH-2092 Amendment 1 
Amendment 1 Date of Issue: 
See appended electronic signature page 
Original (Admin) Date of Issue: 
12 Jan 2021 
Original Date of Issue: 
21 Dec 2020 
Medical/Study Director: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
 
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NCT04811716


Clinical Study Protocol 
 
R3918-PNH-2092 Amendment 1 
 
 
REGENERON CONFIDENTIAL 
 
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AMENDMENT HISTORY 
Overall Rationale for Amendment 1 
The main purpose of this amendment is to modify the timing of the interim analysis and to align 
endpoints with other studies in the clinical development program. 
Description of Change 
Brief Rationale 
Section # and Name 
Modified the description of the 
interim analysis to allow for an 
analysis of the data at an earlier 
timepoint (week 16) 
The interim analysis timing and 
scope is revised to allow for an 
earlier analysis and for the 
preliminary results to be shared 
externally (for example, upon 
request by regulatory authorities). 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 6.4 Planned Interim 
Analysis 
Section 11.5 Timing of Statistical 
Analysis 
Revised and clarified the following 
secondary endpoints: 
• Maintenance of adequate control 
of hemolysis, defined as lactate 
dehydrogenase (LDH) ≤1.5 x 
upper limit of normal (ULN) 
from post-baseline (on day 1) 
through week 28 and from 
week 4 through week 28, 
inclusive  
• Normalization of LDH at each 
visit, defined as LDH ≤1.0 x 
ULN from post-baseline (on 
day 1) through week 28, 
inclusive 
Corresponding changes were made 
to secondary endpoints for the 
optional open-label extension 
period (OLEP) 
The wording of the endpoint has 
been revised to be a patient-level 
metric. In addition, changes are 
made to clarify how these analyses 
will be performed and for alignment 
across the paroxysmal nocturnal 
hemoglobinuria (PNH) program: 
• A patient’s LDH is followed 
longitudinally to assess the 
maintenance of adequate control 
of hemolysis over the pre-
specified time period. 
• Normalization of LDH is 
analyzed by visit throughout the 
study.  
 
 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Secondary Endpoints 
Section 4.1.2.1 Secondary 
Endpoints for the Optional Open-
Label Extension Period 
Section 11.4.3.1 Secondary 
Efficacy Analysis 
 
Definition of treatment exposure 
was revised to reflect the duration 
of time on study drug 
This change aligns the definition of 
treatment exposure across the PNH 
program. 
Section 11.4.5.3 Treatment 
Exposure 
Added new secondary endpoint on 
the proportion of patients with 
adequate control of hemolysis at 
each visit 
This new endpoint assesses control 
of hemolysis using an additional 
methodology and is added to align 
with other studies in the program. 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Secondary Endpoints 
Section 4.1.2.1 Secondary 
Endpoints for the Optional Open-
Label Extension Period 
Section 11.4.3.1 Secondary 
Efficacy Analysis 
Revised “proportion of patient” 
endpoints to be patient-centric 
 
This change is part of a company-
wide alignment on the wording of 
endpoints to be patient-level 
metrics. 
 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.1.2 Secondary Endpoints 
Section 4.1.2.1 Secondary 
Endpoints for the Optional Open-
Label Extension Period 
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Description of Change 
Brief Rationale 
Section # and Name 
Section 4.1.3 Exploratory 
Endpoints 
Updated information about post-
trial treatment access for patients 
who complete the optional open-
label extension period 
This change provides updated 
information on post-trial access to 
study drugs for those with a 
favorable benefit-risk profile for 
continued treatment. 
Clinical Study Protocol Synopsis: 
Study Design, Study Duration 
Section 6.1 Study Description and 
Duration 
Figure 1: Study Flow Diagram 
Section 6.1.3 Optional Open-Label 
Extension Period 
Section 6.1.4 Post-Treatment Safety 
Follow-Up Period  
Section 8.9 Post-Trial Access to 
Study Treatment 
The criterion for provision of an 
additional intravenous (IV) 
pozelimab dose in the event of an 
acute complement-activating 
condition was modified.  
To allow for patients to receive an 
additional IV pozelimab dose in the 
event they have an elevated LDH 
≥2 x ULN resulting from an acute 
complement-activating condition 
even if not meeting the protocol 
definition of breakthrough 
hemolysis.   
Section 6.1.2 Open-Label 
Treatment Period (Day 1 to 
Week 28) 
Section 8.3.2 Intensified Treatment 
Removal of the requirement for 
mandatory discontinuation of study 
drug in the event of treatment for a 
meningococcal infection 
To allow investigators to use 
clinical discretion with regard to 
continuing complement inhibition 
during a serious meningococcal 
infection. Withdrawal of 
complement inhibition in the face 
of an ongoing complement 
activating condition may have 
serious clinical consequences. 
Section 8.3.3.1 Reasons for 
Permanent Discontinuation of 
Study Drug 
Removed fasting requirement for 
blood chemistry sample 
This change reduces unnecessary 
study complexity as the results of 
the assays should not be impacted 
in a meaningful way by fasting 
status. 
Section 9.2.5.2 Safety and Other 
Laboratory Assessments 
Revised footnote on bilirubin and 
added magnesium for blood 
chemistry 
This change is to include 
magnesium as part of safety 
laboratory analysis and to simplify 
the procedures for bilirubin. 
Section 9.2.5.2 Safety and Other 
Laboratory Assessments 
Included details regarding 
laboratory analyses to be performed 
for drug hypersensitivity events and 
suspected breakthrough hemolysis 
events 
This change clarifies the  sample 
collection for safety events of 
interest. 
Section 9.2.5.2 Safety and Other 
Laboratory Assessments 
Section 9.1.1.1 Table 1 Schedule of 
Events (Treatment Period), 
Footnote #18  
Revised schedule of events to have 
a separate collection for free 
hemoglobin 
 
This change reflects how the actual 
sample collection is intended to be 
performed. 
Table 3: Schedule of Events 
(Optional Open-Label Extension 
Period) 
Section 9.1.1.1 Table 1 Schedule of 
Events (Treatment Period), footnote 
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Description of Change 
Brief Rationale 
Section # and Name 
Section 9.1.1.2 Table 2 Schedule of 
Events (for Patients on Intensified 
Treatment), footnote #16  
Section 9.1.1.3 Table 3 Schedule of 
Events (for Open-Label Extension 
Period), footnote #13  
For patients requiring intensified 
treatment, clarified that samples for 
pozelimab concentration and total 
C5 will be collected on day 1r pre-
dose and post-infusion 
This change aligns with the timing 
of analysis of drug concentration in 
the phase 2 program. 
Section 9.1.1.2 Table 2 Schedule of 
Events (for Patients on Intensified 
Treatment), footnote #18  
Section 9.2.6.1 Concentrations of 
Total Pozelimab and Total C5 
Criteria for urine culture updated 
To allow urine culture to be 
performed per the Investigator 
judgment in the event of clinical 
suspicion of infection 
Section 9.2.5.2 Safety and Other 
Laboratory Assessments 
Changed baseline sample collection 
for PNH clones from day 1 to 
screening visit V1 
This change is made to facilitate 
study conduct. 
Table 1 Schedule of Events (Open-
Label Treatment Period) 
Added sample collection for 
immunoglobulin G 
This analyte is added to better 
understand potential general 
changes in protein catabolism. 
Table 1 Schedule of Events (Open-
Label Treatment Period) 
Table 2 Schedule of Events for 
Patients on Intensified Treatment in 
the OLTP 
Section 9.2.5.2 Safety and Other 
Laboratory Assessments 
Language added to allow for 
unused/leftover samples to be used 
for exploratory research. 
Exploratory research (related to 
PNH, mechanism of action of 
pozelimab, target engagement and 
possible toxicities) can be 
conducted for up to 15 years post 
study completion (pending local 
regulations) in all patients using 
leftover/unused blood samples.  
Section 9.2.8 Pharmacodynamic 
and Exploratory Biomarker 
Procedures  
Removed 30-minute observation 
period after subcutaneous injection 
on the day of treatment 
intensification. 
This is a correction; the intention 
was for patients to have 30-minute 
on-site observation only after 
intravenous pozelimab and the first 
cemdisiran and pozelimab 
subcutaneous injections. 
Section 8.3.2 Intensified Treatment 
Section 9.1.1.2 Table 2 Schedule of 
Events (for Patients on Intensified 
Treatment), Footnote #7  
Section 9.1.1.3 Table 3 Schedule of 
Events (for Open-Label Extension 
Period), Footnote #4  
Clarified that a 30-minute 
monitoring period is needed only 
after the first (but not subsequent)  
cemdisiran administration 
Because patients have been 
receiving pozelimab prior to this 
study, the 30-minute observation 
period is for reactions related to 
cemdisiran injection. 
Section 8.1.3 Dose Administration 
Section 9.1.1.1 Table 1 Schedule of 
Events (Treatment Period), footnote 
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Description of Change 
Brief Rationale 
Section # and Name 
Assessment of body weight added 
prior to any IV administration of 
pozelimab. 
Weight is added in order to assist in 
the calculation of dose to be 
administered for IV pozelimab in 
patients who require treatment 
intensification or additional 
pozelimab administration in the 
event of a complement-activating 
condition. 
Section 8.3.2 Intensified Treatment 
Included rows for daily antibiotic 
prophylaxis and review of patient 
safety card in the safety follow-up 
period in the Schedule of Events 
This is a correction. These 
procedures are intended to be 
performed throughout the study for 
risk mitigation. 
Table 4 Schedule of Events (Post-
Treatment Safety Follow-Up 
Period) 
Section 9.1.1.4 Table 4 Schedule of 
Events (Post-Treatment Safety 
Follow-Up Period) [new section], 
footnote #1 [new] and #2 [new] 
Clarified visit windows versus 
dosing windows for the different 
regimen and study periods 
This change is made to clarify the 
difference between visit windows 
and dosing windows in the study. 
Table 2 Schedule of Events for 
Patients on Intensified Treatment in 
the OLTP 
Section 9.1.1.1 Table 1 Schedule of 
Events (Treatment Period), footnote 
#11  
Section 9.1.1.2 Table 2 Schedule of 
Events (for Patients on Intensified 
Treatment), footnote #4, #5 [new] 
Section 9.1.1.3 Table 3 Schedule of 
Events (for Open-Label Extension 
Period), footnote #5  
Added language to ask that patients 
refrain from strenuous exercise 
within 24 hours prior to a blood 
draw 
This change is added to minimize 
the effect of vigorous exercise on 
blood analyses. 
Section 8.8.1  Prohibited 
Medications and Procedures 
Language on study drug 
administration in patients who 
require treatment intensification and 
the corresponding intensified 
treatment visit schedule clarified  
Clarifying language has been added 
to ensure proper understanding of 
the timing of study visits and study 
drug administration for patients 
who require treatment 
intensification.   
Section 6.1.2 Open-Label 
Treatment Period (Day 1 to 
Week 28) 
Section 6.1.3 Optional Open-Label 
Extension Period 
Renumbered days in the post-
treatment safety follow-up period 
(FUP) to days after last dose of 
study drug 
This change is made for clarity, as 
patients may enter the FUP after 
discontinuation from any period 
during the study. 
Table 4 Schedule of Events (Post-
Treatment Safety Follow-Up 
Period) 
Total number of screened patients 
revised to include all patients who 
signed the ICF 
This change is made to consider a 
patient as screened upon signing the 
main ICF even if inclusion/ 
exclusion criteria are not met. 
Section 11.4.1 Patient Disposition 
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Description of Change 
Brief Rationale 
Section # and Name 
Revised description of Functional 
Assessment of Chronic Illness 
Therapy – Fatigue (FACIT-Fatigue) 
to a 5-point Likert scale. A higher 
score indicates a higher quality of 
life 
This is a correction. 
Section 9.2.3.1 Functional 
Assessment of Chronic Illness 
Therapy‒Fatigue) 
Revised the on-treatment period 
definition to include up to 52 weeks 
after the last dose of study drug 
This reflects an update to the safety 
observation period to align with 
other studies in the program. 
Section 11.4.5.1 Adverse Events 
Updated the name of the study 
director 
This reflects an administrative 
change for the study. 
Title Page 
Updated confidentiality language 
This is an administrative change to 
the protocol template. 
Title Page 
Clarifications and corrections 
These are minor editorial changes 
for clarification and consistency, 
and also includes updated template 
language. 
Throughout document 
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Overall Rationale for R3918-PNH-2092 Original (Admin) Amendment 
The purpose of this administrative amendment is to correct visit numbering errors in the Schedule 
of Events. 
Description of Change 
Brief Rationale 
Section # and Name 
Visit numbers were corrected 
for week 24r (RV11) and 
week 28r (RV12). 
The change was made to correct 
errors in visit numbering. 
Table 2 Schedule of Events for 
Patients on Intensified 
Treatment in the OLTP 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH50 
Alternative pathway hemolytic activity assay 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
C 
Complement component (eg, C3, C5) 
CH50 
Total complement hemolysis activity assay 
CI 
Confidence interval 
COA 
Clinical outcome assessment 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSR 
Clinical study report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer: Quality-of-Life 
Questionnaire core 30 items 
EOT 
End of treatment 
ET 
Early termination 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue score 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GHS 
Global health status 
GPI 
Glycophosphatidylinositol 
IB 
Investigator’s brochure 
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ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
mAb 
Monoclonal antibody 
MAC 
Membrane-attack complex 
MAVE 
Major adverse vascular events 
MCMC 
Markov Chain Monte Carlo method 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
OLEP 
Open-label extension period (an optional period) 
OLTP 
Open-label treatment period (main study period) 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PF 
Physical function 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
Q8W 
Every 8 weeks 
QoL 
Quality of life 
QW 
Weekly 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
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SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
WOCF 
Worst observation carried forward 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................18 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Paroxysmal Nocturnal Hemoglobinuria .....................................................................24 
1.2. 
Pozelimab ...................................................................................................................25 
1.3. 
Cemdisiran ..................................................................................................................27 
1.4. 
Pozelimab + Cemdisiran: A Combination Approach .................................................27 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.2. 
Secondary Objectives .................................................................................................29 
2.3. 
Exploratory Objectives ...............................................................................................29 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................31 
3.1. 
Hypotheses ..................................................................................................................31 
3.2. 
Rationale .....................................................................................................................31 
3.2.1. 
Rationale for Study Design .........................................................................................31 
3.2.2. 
Rationale for Dose Selection ......................................................................................32 
3.3. 
Risk-Benefit ................................................................................................................33 
3.3.1. 
Potential Risk of Neisseria Infection ..........................................................................33 
3.3.2. 
Liver Function Test Abnormalities .............................................................................34 
3.3.3. 
Study Conduct in Response to Coronavirus Disease 2019 .........................................35 
4. 
ENDPOINTS ..............................................................................................................36 
4.1. 
Primary and Secondary Endpoints..............................................................................36 
4.1.1. 
Primary Endpoint ........................................................................................................36 
4.1.2. 
Secondary Endpoints ..................................................................................................36 
4.1.2.1. 
Secondary Endpoints for the Optional Open-Label Extension Period .......................37 
4.1.3. 
Exploratory Endpoints ................................................................................................38 
5. 
STUDY VARIABLES................................................................................................39 
5.1. 
Demographic and Baseline Characteristics ................................................................39 
5.2. 
Efficacy Variables ......................................................................................................39 
5.2.1. 
Laboratory Variables for the Assessment of Efficacy ................................................39 
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5.2.2. 
Transfusion Record .....................................................................................................39 
5.2.3. 
Clinical Outcome Assessments ...................................................................................39 
5.3. 
Safety and Anthropometric Variables ........................................................................40 
5.4. 
Pharmacokinetic Variables .........................................................................................40 
5.5. 
Immunogenicity Variables ..........................................................................................40 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................40 
6. 
STUDY DESIGN .......................................................................................................41 
6.1. 
Study Description and Duration .................................................................................41 
6.1.1. 
Screening (Day -8/-7 to Day -1) .................................................................................42 
6.1.2. 
Open-Label Treatment Period (Day 1 to Week 28) ....................................................43 
6.1.3. 
Optional Open-Label Extension Period ......................................................................44 
6.1.4. 
Post-Treatment Safety Follow-Up Period ..................................................................44 
6.1.5. 
End of Study Definition ..............................................................................................45 
6.2. 
Breakthrough Hemolysis ............................................................................................45 
6.3. 
Transfusion Algorithm ................................................................................................45 
6.4. 
Planned Interim Analysis ............................................................................................46 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............47 
7.1. 
Number of Patients Planned .......................................................................................47 
7.2. 
Study Population .........................................................................................................47 
7.2.1. 
Inclusion Criteria ........................................................................................................47 
7.2.2. 
Exclusion Criteria .......................................................................................................47 
7.3. 
Premature Withdrawal from the Study .......................................................................49 
7.4. 
Replacement of Patients .............................................................................................49 
8. 
STUDY TREATMENTS............................................................................................50 
8.1. 
Investigational Treatment ...........................................................................................50 
8.1.1. 
Pozelimab ...................................................................................................................50 
8.1.2. 
Cemdisiran ..................................................................................................................50 
8.1.3. 
Dose Administration ...................................................................................................50 
8.2. 
Risk Mitigation and Background Treatments .............................................................51 
8.2.1. 
Meningococcal Vaccinations ......................................................................................51 
8.2.2. 
Monitoring for Meningococcal Infection ...................................................................51 
8.2.3. 
Oral Antibiotics ..........................................................................................................51 
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8.2.4. 
Risk Management of Neisseria Gonorrhea ................................................................52 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................52 
8.3.1. 
Dose Modification ......................................................................................................52 
8.3.2. 
Intensified Treatment ..................................................................................................52 
8.3.3. 
Study Drug Discontinuation .......................................................................................53 
8.3.3.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................54 
8.3.3.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................54 
8.4. 
Management of Acute Reactions ................................................................................55 
8.4.1. 
Acute Injection Reactions ...........................................................................................55 
8.4.1.1. 
Systemic Injection Reactions ......................................................................................55 
8.4.1.2. 
Local Injection Site Reactions ....................................................................................55 
8.4.2. 
Acute Intravenous Infusion Reactions ........................................................................55 
8.4.2.1. 
Interruption of the Intravenous Infusion .....................................................................55 
8.4.2.2. 
Termination of the Intravenous Infusion ....................................................................56 
8.5. 
Method of Treatment Assignment ..............................................................................56 
8.6. 
Blinding ......................................................................................................................57 
8.7. 
Treatment Logistics and Accountability .....................................................................57 
8.7.1. 
Packaging, Labeling, and Storage ..............................................................................57 
8.7.2. 
Supply and Disposition of Treatments .......................................................................57 
8.7.3. 
Treatment Accountability ...........................................................................................57 
8.7.4. 
Treatment Compliance ................................................................................................57 
8.8. 
Concomitant Medications and Procedures .................................................................57 
8.8.1. 
Prohibited Medications and Procedures .....................................................................58 
8.8.2. 
Permitted Medications and Procedures ......................................................................58 
8.9. 
Post-Trial Access to Study Treatment ........................................................................58 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................59 
9.1. 
Schedule of Events .....................................................................................................59 
9.1.1. 
Footnotes for the Schedule of Events Tables .............................................................68 
9.1.1.1. 
Table 1 Schedule of Events (Treatment Period) .........................................................68 
9.1.1.2. 
Table 2 Schedule of Events (for Patients on Intensified Treatment) ..........................72 
9.1.1.3. 
Table 3 Schedule of Events (for Open-Label Extension Period) ...............................75 
9.1.1.4. 
Table 4 Schedule of Events (Post-Treatment Safety Follow-Up Period) ...................77 
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9.1.2. 
Early Termination Visit ..............................................................................................77 
9.1.3. 
Unscheduled Visits .....................................................................................................77 
9.2. 
Study Procedures ........................................................................................................77 
9.2.1. 
Procedures Performed Only at the Screening Visit ....................................................77 
9.2.2. 
Study Treatment ..........................................................................................................78 
9.2.3. 
Clinical Outcome Assessments ...................................................................................79 
9.2.3.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) .........79 
9.2.3.2. 
European Organization for the Research and Treatment of Cancer: Quality 
of Life of Cancer Patients Questionnaire-30 (EORTC-QLQ-C30) ............................79 
9.2.3.3. 
Treatment Satisfaction Questionnaire for Medication (TSQM) .................................79 
9.2.3.4. 
PNH Symptom-Specific Questionnaire ......................................................................80 
9.2.3.5. 
Patient Global Impression of Severity (PGIS)/Patient Global Impression of 
Change (PGIC) ...........................................................................................................80 
9.2.4. 
Safety and Anthropometric Procedures ......................................................................80 
9.2.4.1. 
Body Weight ...............................................................................................................80 
9.2.4.2. 
Vital Signs ..................................................................................................................81 
9.2.4.3. 
Physical Examination .................................................................................................81 
9.2.4.4. 
Electrocardiogram .......................................................................................................81 
9.2.4.5. 
Blood Transfusion ......................................................................................................81 
9.2.4.6. 
Safety Monitoring .......................................................................................................81 
9.2.5. 
Laboratory Testing ......................................................................................................82 
9.2.5.1. 
Laboratory Assessments of Efficacy ..........................................................................82 
9.2.5.2. 
Safety and Other Laboratory Assessments .................................................................82 
9.2.6. 
Blood Collection for Drug Concentrations .................................................................84 
9.2.6.1. 
Concentrations of Total Pozelimab and Total C5 .......................................................84 
9.2.6.2. 
Concentrations of Cemdisiran and Cemdisiran Metabolites ......................................84 
9.2.7. 
Immunogenicity Measurements and Samples ............................................................85 
9.2.8. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................85 
9.2.9. 
Future Biomedical Research (Optional) .....................................................................85 
9.2.10. 
Pharmacogenomic Analysis (Optional) ......................................................................86 
10. 
SAFETY EVALUATION AND REPORTING .........................................................87 
10.1. 
Recording and Reporting Adverse Events ..................................................................87 
10.1.1. 
General Guidelines .....................................................................................................87 
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10.1.2. 
Reporting Procedure ...................................................................................................88 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................88 
10.1.4. 
Other Adverse Events of Special Interest that do not Require Expedited 
Reporting to Sponsor ..................................................................................................89 
10.2. 
Definitions ..................................................................................................................89 
10.2.1. 
Adverse Event .............................................................................................................89 
10.2.2. 
Serious Adverse Event ................................................................................................89 
10.2.3. 
Adverse Events of Special Interest .............................................................................90 
10.2.4. 
Infusion Reactions ......................................................................................................90 
10.2.5. 
Severity .......................................................................................................................90 
10.2.6. 
Causality .....................................................................................................................91 
10.3. 
Safety Monitoring .......................................................................................................92 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................93 
11. 
STATISTICAL PLAN................................................................................................94 
11.1. 
Statistical Hypothesis ..................................................................................................94 
11.2. 
Justification of Sample Size........................................................................................94 
11.3. 
Analysis Sets ...............................................................................................................94 
11.3.1. 
Safety Analysis Sets ...................................................................................................94 
11.3.2. 
Efficacy Analysis Sets ................................................................................................94 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................94 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................94 
11.4. 
Statistical Methods ......................................................................................................95 
11.4.1. 
Patient Disposition ......................................................................................................95 
11.4.2. 
Demography and Baseline Characteristics .................................................................95 
11.4.3. 
Efficacy Analyses .......................................................................................................96 
11.4.3.1. 
Secondary Efficacy Analysis ......................................................................................96 
11.4.4. 
Control of Multiplicity ................................................................................................97 
11.4.5. 
Safety Analysis ...........................................................................................................97 
11.4.5.1. 
Adverse Events ...........................................................................................................97 
11.4.5.2. 
Other Safety ................................................................................................................98 
11.4.5.3. 
Treatment Exposure ....................................................................................................99 
11.4.5.4. 
Treatment Compliance ................................................................................................99 
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11.4.6. 
Pharmacokinetics ........................................................................................................99 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................99 
11.4.7. 
Analysis of Immunogenicity Data ............................................................................100 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ............................100 
11.5. 
Timing of Statistical Analysis ..................................................................................100 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......101 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................102 
12.1. 
Data Management and Electronic Systems ..............................................................102 
12.1.1. 
Data Management .....................................................................................................102 
12.1.2. 
Electronic Systems ....................................................................................................102 
12.2. 
Study Monitoring ......................................................................................................102 
12.2.1. 
Monitoring of Study Sites .........................................................................................102 
12.2.2. 
Source Document Requirements ..............................................................................103 
12.2.3. 
Case Report Form Requirements ..............................................................................103 
12.3. 
Audits and Inspections ..............................................................................................103 
12.4. 
Study Documentation ...............................................................................................104 
12.4.1. 
Certification of Accuracy of Data .............................................................................104 
12.4.2. 
Retention of Records ................................................................................................104 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................105 
13.1. 
Good Clinical Practice Statement .............................................................................105 
13.2. 
Informed Consent .....................................................................................................105 
13.3. 
Patients Confidentiality and Data Protection ............................................................105 
13.4. 
Institutional Review Board/Ethics Committee .........................................................106 
13.5. 
Clinical Study Data Transparency ............................................................................106 
14. 
PROTOCOL AMENDMENTS ................................................................................107 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................107 
15.1. 
Premature Termination of the Study .........................................................................107 
15.2. 
Close-out of a Site ....................................................................................................107 
16. 
CONFIDENTIALITY ..............................................................................................107 
17. 
FINANCING AND INSURANCE ...........................................................................108 
18. 
PUBLICATION POLICY ........................................................................................108 
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19. 
REFERENCES .........................................................................................................109 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................113 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................114 
 
LIST OF TABLES 
Table 1: 
Schedule of Events (Open-Label Treatment Period) ..................................................60 
Table 2: 
Schedule of Events for Patients on Intensified Treatment in the OLTP .....................63 
Table 3: 
Schedule of Events (Optional Open-Label Extension Period) ...................................65 
Table 4: 
Schedule of Events (Post-Treatment Safety Follow-Up Period) ................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................41 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Open-label, Two-arm Study to Evaluate the Safety, 
Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran 
Combination 
Treatment 
in 
Patients 
with 
Paroxysmal 
Nocturnal 
Hemoglobinuria Who Have Received Pozelimab Monotherapy  
Site Locations 
 
Principal Investigator 
Multiple centers in the European Union (EU) and Asia Pacific 
A coordinating principal investigator will be identified and documented in 
the trial master file. 
Objectives 
The primary objective of the study is to evaluate the safety and tolerability 
of 2 dosing regimens of pozelimab and cemdisiran combination therapy 
during the open-label treatment period (OLTP)  
The secondary objectives of the study are: 
• 
To evaluate the effect of the combination treatment on the 
following parameters of intravascular hemolysis: lactate 
dehydrogenase (LDH) control, breakthrough hemolysis, and 
inhibition of total complement hemolysis activity (CH50)  
• 
To evaluate the effect of the combination treatment on 
hemoglobin levels 
• 
To evaluate the effect of the combination treatment on red blood 
cell (RBC) transfusion requirements  
• 
To evaluate the effect of the combination treatment on clinical 
outcome assessments (COA) measuring fatigue and health-related 
quality of life 
• 
To assess the concentrations of total pozelimab in serum and total 
complement component 5 (C5) and cemdisiran in plasma 
• 
To assess immunogenicity to pozelimab and cemdisiran   
• 
To evaluate the long-term safety and efficacy of the combination 
treatment with pozelimab and cemdisiran in an optional open-
label extension period (OLEP)  
• 
To assess safety after treatment intensification with pozelimab 
and cemdisiran 
Study Design 
This is a randomized, open-label, 2-arm, 28-week study to evaluate the 
safety, efficacy, and pharmacodynamic (PD) effects of 2 dose regimens of 
pozelimab and cemdisiran combination treatment in patients with 
paroxysmal nocturnal hemoglobinuria (PNH) who had been receiving 
treatment with pozelimab monotherapy in a Regeneron-sponsored clinical 
study (R3918-PNH-1868). Eligible patients will be randomized 1:1 to 1 of 
2 dose regimens with the pozelimab and cemdisiran combination. The study 
consists of 4 periods: a screening period (7 to 8 days), an OLTP (28 weeks, 
but will be longer for patients who are switched to treatment intensification), 
an optional OLEP (52 weeks), and a post-treatment safety follow-up period 
(52 weeks). The fourth period begins when a patient completes or 
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permanently discontinues study treatment (eg, at the time of premature study 
drug discontinuation, at the completion of study treatment in the OLTP for 
patients who decline the optional OLEP, or at the completion of study 
treatment in the optional OLEP for patients who do not continue treatment 
in a post-trial access setting). The treatment period begins from the first dose 
of the combination treatment until the end of the dosing interval of the last 
dose to account for the treatment effect of the final dose of study drug.  
Screening (7 to 8 days) 
The screening visit should occur at a scheduled or unscheduled visit of the 
R3918-PNH-1868 study (parent study). The dose of pozelimab should be 
administered at the study site on the day of the screening visit in this study, 
which shall occur on the day of a planned administration with pozelimab 
monotherapy. Subsequently, the day 1 visit for the first combination 
treatment dosing should occur 7 to 8 days after the last dose of pozelimab 
monotherapy in the parent study.  
As part of risk mitigation for this study, patients should have documented 
vaccination 
against 
Neisseria 
meningitidis 
and 
receive 
updated 
meningococcal vaccination if needed. Daily oral antibiotic prophylaxis is 
recommended throughout the study.  Patients should be counseled regarding 
risk of infection with Neisseria gonorrhea, as applicable based on their risk 
level.  
In addition to screening procedures to determine eligibility, patients will be 
asked to complete a PNH Symptom-Specific Questionnaire daily for 
7 consecutive days prior to the day 1 visit. 
Patients may choose to participate in the optional OLEP, optional future 
biomedical research, and/or optional pharmacogenomics component of the 
study by signing the respective optional informed consent forms. 
Treatment Period (Day 1 to Week 28) 
Day 1 should be scheduled 7 to 8 days after the last dose of pozelimab 
monotherapy in the parent study. On day 1, after confirming eligibility, 
patients will be randomized in a 1:1 ratio to 1 of the 2 arms:   
Arm 1: Pozelimab 400 mg SC every 4 weeks (Q4W) and cemdisiran 
200 mg SC Q4W  
Arm 2: Pozelimab 400 mg SC every 2 weeks (Q2W) and cemdisiran 
200 mg SC Q4W  
After all baseline samples are collected and all baseline assessments are 
performed, patients will receive the first doses of the assigned combination 
treatment. 
Breakthrough hemolysis is assessed by the investigator throughout the study 
and is defined based on a pre-specified increase in LDH level along with 
clinical signs and symptoms of hemolysis. During the study, a patient 
exhibiting signs of breakthrough hemolysis plus inadequate LDH response 
may qualify for 28 weeks of intensified treatment. Pre-defined criteria for 
breakthrough hemolysis and intensified treatment is described in the 
protocol.  
Transfusions with RBCs during the study should proceed according to the 
pre-defined algorithm for transfusions described in the protocol. 
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Patients should be closely monitored for early signs and symptoms of 
meningococcal infection. Daily oral antibiotic prophylaxis is recommended. 
The last doses of study treatment are administered at week 24 for arm 1 and 
week 26 for arm 2. Patients will return for safety, efficacy, and other 
assessments at week 28. 
Optional Open-Label Extension Period 
All patients who complete the OLTP (including patients who receive 
intensified treatment) will be offered the opportunity to continue in an 
optional 52-week OLEP, whereby the transition of the combination 
treatment from the OLTP to the OLEP is planned to be uninterrupted (ie, 
day 1e visit of the OLE will correspond to the end of treatment (EOT) visit 
of the OLTP). 
Patients whose treatment was not intensified during the main study period 
will transition to the OLEP on a regimen of pozelimab 400 mg SC Q4W and 
cemdisiran 200 mg SC Q4W, regardless of their treatment assignment in the 
main treatment period. Patients whose treatment was intensified during the 
main study period will transition to the OLEP and continue on the intensified 
treatment regimen of pozelimab 400 mg SC Q2W and cemdisiran 200 mg 
SC Q4W. 
The OLEP will end 52 weeks after the first dose of study treatment in the 
OLEP, even if the patient required intensified treatment during the OLEP. 
For patients who complete the optional OLEP, post-trial access to treatment 
may be available. 
Post-Treatment Safety Follow-Up 
All patients who permanently stop study treatment will be asked to complete 
a 52-week safety follow-up period after the last dose of the study treatment.  
The safety follow-up period will begin when a patient completes or 
permanently discontinues study treatment (eg, at the time of premature study 
drug discontinuation, at the completion of study treatment in the OLTP for 
patients who decline the optional OLEP, or at the completion of study 
treatment in the optional OLEP for patients who do not continue treatment 
in a post-trial access setting). 
Study Duration 
The screening period is approximately 7 to 8 days. The duration of the 
OLTP treatment period for a patient is a minimum of approximately 
28 weeks (the duration will be longer for patients who require treatment 
intensification, which consists of a 28-week treatment regimen starting from 
the day of intensification). Patients who do not continue into the optional 
OLEP will be followed for an additional 52 weeks after the last dose of 
combination treatment. Patients opting to participate in the OLEP will 
continue open-label treatment for a 52-week period, to be followed by a 52-
week safety follow-up period after the last dose of study treatment. Patients 
who complete the optional OLEP may be able to continue study treatment 
in a post-trial access program. Patients participating in the post-trial access 
program will therefore not be followed in the safety follow-up period. 
End of Study Definition 
The end of the main study is defined as the date of the last visit of the last 
patient in the OLTP, including patients who discontinued treatment during 
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the OLTP and are being followed in the post-treatment safety follow-up 
period. 
The end of the optional OLEP is defined as the date of the last visit of the 
last patient in the optional OLEP, including patients who discontinued 
treatment during the OLEP and are being followed in the post-treatment 
safety follow-up period. 
Population 
 
 
Sample Size: 
This study will be open to all patients who have enrolled in the Regeneron 
sponsored clinical study (R3918-PNH-1868) and plans to enroll 
approximately 24 patients with PNH. 
 
Target Population: 
This study will only enroll patients with PNH who are receiving pozelimab 
monotherapy in a Regeneron-sponsored clinical study (R3918-PNH-1868) 
and are willing to switch to the combination treatment. 
Treatment 
All patients will receive treatment with the pozelimab + cemdisiran 
combination.  
 
Study Drug 
 
Dose/Route/Schedule: 
Pozelimab 
400 mg SC Q2W or 400 mg SC Q4W 
30 mg/kg IV bolus as needed may be considered for patients who 
experience breakthrough hemolysis (see protocol for details) 
 
Study Drug 
 
Dose/Route/Schedule: 
Cemdisiran 
200 mg SC Q4W 
 Intensified Treatment:  
(for patients who meet 
pre-specified criteria on 
LDH and breakthrough 
hemolysis) 
Single administration of pozelimab 30 mg/kg IV loading dose on day 1 of 
intensification (day 1r) in addition to pozelimab 400 mg SC Q2W and 
cemdisiran 200 mg SC Q4W  
Endpoints 
 
 
Primary: 
The primary endpoint is the incidence and severity of treatment-emergent 
adverse events (TEAEs) through week 28 of the OLTP 
 
Secondary: 
The secondary endpoints for the OLTP are: 
• 
Percent change of LDH from pre-treatment (defined as mean of 
LDH values at day -7 and day 1 [prior to combination dosing]) to 
end-of-treatment period (defined as mean of LDH values at week 
24 through week 28) 
• 
Maintenance of adequate control of hemolysis, defined as 
LDH ≤1.5 × upper limit of normal (ULN) from post-baseline (on 
day 1) through week 28 and from week 4 through week 28, 
inclusive  
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• 
Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) at 
each visit from post-baseline (on day 1) through week 28, 
inclusive 
• 
Normalization of LDH at each visit, defined as LDH ≤1.0 × ULN 
from post-baseline (on day 1) through week 28, inclusive  
• 
Area under the curve (AUC) of LDH over time from baseline 
through week 28 and from week 4 through week 28, inclusive 
• 
Breakthrough hemolysis (as defined in the protocol) from 
baseline to week 28  
• 
Hemoglobin stabilization (defined as patients who do not receive 
RBC transfusion and have no decrease in hemoglobin levels of 
≥2 g/dL) from baseline through week 28 
• 
Change in hemoglobin levels from baseline to week 28  
• 
Transfusion avoidance (defined as not requiring a RBC 
transfusion as per protocol algorithm) from baseline to week 28 
• 
Rate and number of units of RBCs transfused from baseline to 
week 28 
• 
Change in CH50 from baseline to week 28  
• 
Change in fatigue as measured by Functional Assessment of 
Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale from 
baseline to week 28 
• 
Change from baseline to week 28 in global health status/QOL 
scale (GHS) and physical function (PF) scores on the European 
Organization for Research and Treatment of Cancer: Quality-of-
Life Questionnaire core 30 items (EORTC QLQ-C30)  
• 
Concentrations of total pozelimab in serum and cemdisiran in 
plasma, assessed throughout the study 
• 
Change from baseline in concentration of total C5 assessed 
throughout the study 
• 
Assessment of immunogenicity to pozelimab and cemdisiran as 
determined by the incidence, titer, and clinical impact of 
treatment-emergent anti-drug antibody responses over time 
• 
Incidence and severity of TEAEs for patients who received 
treatment intensification through week 28r 
Procedures and Assessments 
Safety procedures include measurement of body weight and routine safety 
assessments (vital signs, physical examination, electrocardiogram). 
Laboratory assessments of safety include coagulation panel, chemistry, 
hematology, urinalysis, and pregnancy (if applicable). Treatment-emergent 
adverse events and concomitant medications will be monitored throughout 
the study. 
Efficacy procedures include laboratory assessments of efficacy (LDH, 
hemoglobin, and CH50), transfusion record update, and clinical outcome 
assessments (FACIT-Fatigue, EORTC QLQ-C30, Treatment Satisfaction 
Questionnaire for Medication [TSQM], Patient Global Impression of 
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Severity [PGIS], Patient Global Impression of Change [PGIC], daily PNH 
symptom-specific questionnaire). 
Other procedures include the collection of blood samples for biomarkers, 
drug concentrations, immunogenicity, and exploratory assessments. 
Statistical Plan 
No statistical hypothesis will be tested. 
Justification of Sample Size 
This study will be open to all patients who have enrolled in the Regeneron-
sponsored clinical study (R3918-PNH-1868) and plans to enroll 
approximately 24 patients with PNH.  
Data from approximately 24 patients with PNH will be used to describe and 
explore the incidence and severity of TEAEs through week 28 of the OLTP. 
Primary Analysis 
The primary endpoint is the incidence and severity of TEAEs through 
week 28 of the OLTP. Descriptive summaries will be provided by treatment 
group.  
Secondary Analysis 
Secondary endpoints on efficacy will be analyzed using analysis of 
covariance (ANCOVA). Missing data will be imputed prior to analysis 
using multiple imputation. Means and 95% confidence intervals for the 
endpoint will be reported for all patients as well as for the 2 treatment arms 
and their difference.  
Timing of Statistical Analysis 
The primary analysis will be conducted as soon as all patients have been 
randomized and all data through week 28 have been collected and validated; 
this will consist of the primary safety and secondary efficacy endpoints.  
The OLEP analysis will be conducted when all data through week 52e of 
the OLEP have been collected and validated. 
Additional safety data from the post-treatment safety follow-up period will 
be included in a subsequent analysis.  
An interim analysis may be conducted after 6 patients have completed at 
least 16 weeks of the OLTP. Additional/other interim analyses may be 
performed to support regulatory interactions. 
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1. 
INTRODUCTION 
1.1. 
Paroxysmal Nocturnal Hemoglobinuria 
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, life-threatening, and rare 
multisystem disease. It is characterized by uncontrolled complement activation on red blood cells 
(RBCs), resulting in intravascular hemolysis (Sahin, 2016), as well as on white blood cells (WBCs) 
and platelets, resulting in an increased risk of thrombosis. The estimated incidence of PNH is 
1.3 cases per million individuals per year, and the estimated prevalence is 15.9 cases per million 
individuals per year (Preis, 2014).  
Paroxysmal nocturnal hemoglobinuria originates from a multipotent, hematopoietic stem cell 
(HSC) that acquires a mutation of the phosphatidylinositol glycan anchor biosynthesis class A 
(PIGA) gene. The PIGA gene product is required for the biosynthesis of the 
glycophosphatidylinositol (GPI) anchor, a glycolipid moiety that attaches dozens of proteins to the 
plasma membrane of cells. Consequently, the PNH stem cell and all of its progeny have a reduction 
or absence of GPI-anchored proteins. The mature blood cells derived from the hematopoietic clone 
can have a complete deficiency (type III) or a partial deficiency (type II) of GPI-linked proteins 
(Hillmen, 2004). Two of the proteins that are affected by the absence of GPI anchors are 
complement regulatory proteins CD55 and CD59. The CD55 protein regulates complement 
activation by inhibiting complement component 3 (C3) convertases, whereas CD59 inhibits the 
assembly of the membrane-attack complex (MAC) C5b–C9 by interacting with C8 and C9 
(Brodsky, 2009). Their absence renders PNH erythrocytes susceptible to complement-mediated 
intravascular hemolysis. This intravascular hemolysis in patients with PNH causes anemia 
(frequently requiring blood transfusion) and hemoglobinuria. Complications of PNH include 
thrombosis, abdominal pain, dysphagia, erectile dysfunction, and pulmonary hypertension 
(Hillmen, 2006). Thromboembolism is the most common cause of mortality in patients with PNH 
and accounts for approximately 40% to 67% of attributable deaths. Potential mechanisms for 
thromboembolism include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, 
absence of other GPI-linked proteins, and endothelial dysfunction (Hill, 2013). Paroxysmal 
nocturnal hemoglobinuria frequently occurs with autoimmune aplastic anemia (Luzzatto, 2018). 
Evidence suggests that loss of PIGA provides protection for the PNH clone against HSC loss by 
removing a putative GPI-anchored autoantigen serving as a target for an autoimmune response 
against the HSC. 
The diagnosis of PNH is established using the internationally accepted definition of presence of 
increased PNH granulocyte clone size measured in peripheral blood by flow cytometry. An 
accepted definition of active disease is the presence of 1 or more of the following PNH-related 
signs or symptoms within 3 months: fatigue, hemoglobinuria, abdominal pain, shortness of breath 
(dyspnea), anemia (hemoglobin <10 g/dL), history of a major adverse vascular event (MAVE; 
including thrombosis), dysphagia, or erectile dysfunction. Alternatively, active disease can be 
established by a history of RBC transfusion due to PNH within 3 months. 
Eculizumab (Soliris®) and ravulizumab (Ultomiris®), approved for the treatment of PNH in many 
countries worldwide, including the United States (US) and European Union (EU) member states, 
are humanized monoclonal antibodies (mAbs) directed against the terminal complement protein 
C5. They block the formation of the MAC C5b-C9, thus protecting PNH RBCs from 
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complement-mediated intravascular hemolysis. Their effectiveness has been demonstrated by the 
reduction of lactate dehydrogenase (LDH) level and a reduced need for RBC transfusions. 
Eculizumab has demonstrated effectiveness over the long term by a reduced need for blood 
transfusion, reduced incidence of thrombosis, and an improvement in anemia, quality of life, and 
survival (Griffin, 2017).  Eculizumab is approved for use in complement-mediated serious ultra-
rare conditions (prevalence of 1 to 5 per million), including PNH, atypical hemolytic uremic 
syndrome (aHUS), neuromyelitis optica spectrum disorder (NMOSD), and generalized 
myasthenia gravis (gMG).  Ravulizumab is approved in PNH and aHUS.   
While eculizumab has demonstrated to be an effective therapy for these patients, not all patients 
receive optimal therapeutic benefit. For example, approximately 25% of patients still need 
recurrent, albeit less frequent, blood transfusions and half of patients achieve LDH normalization 
(Lee, 2019). Up to 27% of eculizumab-treated patients may experience breakthrough hemolysis, 
which is a recurrence of the patient’s intravascular hemolysis and associated signs and symptoms. 
Many patients experience breakthrough hemolysis due to inadequate C5 inhibition (Brodsky, 
2017). Up to 20% of patients on eculizumab therapy require significant increases in dose or dose 
frequency due to breakthrough hemolysis secondary to incomplete inhibition of C5 (Hill, 
2013)(Nakayama, 2016)(Peffault de Latour, 2015). Additionally, eculizumab is administered by 
intravenous (IV) infusion every 2 weeks (Q2W) and has been described as being burdensome for 
patients and may negatively impact quality of life (Groth, 2017). While the regulatory approval of 
ravulizumab has improved convenience with a dosing frequency of every 8 weeks (Q8W), it is not 
available in most of the world and patients still experience some hemolytic breakthrough.  
Moreover, in rare instances, eculizumab, and presumably ravulizumab, is ineffective due to 
polymorphic variation in the gene encoding C5 such that the protein is not recognized by the 
2  mAbs (Nishimura, 2014) (Sheridan, 2018). The heterogeneity in these hematological responses 
may be related to underlying aplastic anemia, C3b-mediated extravascular hemolysis, or 
incomplete pharmacologic blockade of C5, and rare polymorphisms in the gene coding for C5 (Al-
Ani, 2016).  Thus, there remains an unmet medical need for patients with PNH. 
Regeneron has developed a combination mAb therapy, pozelimab-cemdisiran, that provides 
efficacy in patients with polymorphic variant C5 protein which renders eculizumab or ravulizumab 
ineffective, and offers the significant convenience and reduced burden of subcutaneous (SC) self-
administration. 
1.2. 
Pozelimab 
Pozelimab is a human monoclonal immunoglobulin G4P (IgG4P) antibody directed against C5, 
which inhibits terminal complement activation by preventing C5 cleavage by C5 convertase into 
C5a (anaphylatoxin) and C5b, thereby blocking the formation of MAC C5b-C9, a structure 
mediating cell lysis. Pozelimab is being developed for the treatment of PNH and other diseases in 
which tissue damage is mediated by terminal complement pathway activity. Pozelimab can be 
administered by IV or SC administration. Additionally, pozelimab binds to polymorphic variations 
in C5 that are not recognized by eculizumab or ravulizumab. 
Pozelimab has been evaluated in a phase 1 randomized, placebo-controlled, double-blind study 
(R3918-HV-1659) in 56 healthy subjects 
in 
7 dose cohorts (N=8, randomized 
6:2 pozelimab:placebo for each cohort). Pozelimab was found to be generally well tolerated in 
ascending single-doses of 1, 3, 10, 30 mg/kg IV, and 300 mg and 600 mg SC. The seventh cohort, 
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a repeat-dose cohort of 4 weekly (QW) SC doses of 400 mg following a 15 mg/kg IV loading dose, 
resulted in 1 resolved serious adverse event (SAE) in the study, an episode of Salpingitis of 
undetermined microbial etiology.  Dose-dependent inhibition of C5 was demonstrated for the 
single-dose cohorts using the total complement hemolysis activity assay (CH50), an ex-vivo 
measure of complement lytic activity. The repeat-dose cohort demonstrated complete complement 
inhibition throughout the dosing period. A threshold serum concentration of approximately 
100 µg/mL of pozelimab was determined sufficient to achieve complete inhibition of CH50. To 
account for population-based variability in C5 levels and for transient increases in complement 
activity secondary to intercurrent illness, a desired minimum serum concentration of pozelimab 
greater than the threshold was used to establish a dosing regimen for pozelimab in patients with 
PNH: 30 mg/kg IV loading dose followed by 800 mg SC QW.  
Pozelimab is currently being evaluated in an ongoing phase 2 study in PNH patients with active 
signs and symptoms who are naïve to complement inhibitor therapy or have not recently received 
complement inhibitor therapy in the past 6 months (R3918-PNH-1852). In this open-label, single-
arm treatment study, patients received pozelimab as an IV loading dose of 30 mg/kg followed by 
800 mg SC QW for a period of 26 weeks. An interim analysis was performed with a total of 
17 patients enrolled, among whom 10 patients completed 26 weeks (182 days) of treatment/study 
and 7 patients received at least 10 weeks (70 days) of pozelimab treatment.  The mean baseline 
LDH is 6.1 × upper limit of normal (ULN), hemoglobin is 97.0 g/L and nearly 60% of patients had 
an RBC transfusion during the previous year.  Treatment with pozelimab led to a rapid and 
sustained reduction in LDH through study week 26. Normalization of LDH levels was observed 
at day 29 in all 17 patients, including a patient with a C5 variant known to be resistant to blockade 
by eculizumab/ravulizumab.  Reduction in LDH was sustained below 1.5 × ULN until day 183.  
Hemoglobin levels were also increased with mean (standard deviation [SD]) increase of 
8.6 (14.1 g/L) from baseline to week 26 (N=9, data from 9 patients were available and used for the 
calculation).  Following the pozelimab treatment, an improvement in the Functional Assessment 
of Chronic Illness Therapy-Fatigue score (FACIT-Fatigue, a 13-item, self-administered, clinical 
outcome assessment [COA] measure assessing an individual’s level of fatigue over the past week) 
was observed with mean change (SD) of 13.1 (13.7) from baseline to week 26 (N=9). Complement 
inhibition as measured by a CH50 was 100% and sustained post pozelimab IV infusion on day 1 
throughout day 183 (N=9). There was a total of 13 treatment-emergent adverse events (TEAEs) 
and no SAE; 2 TEAEs were assessed as severe and 6 were considered treatment-related; the most 
frequent TEAEs are headache and nausea.  
It is noted that the regimen of 800 mg SC QW represents relatively high doses for a biologic agent. 
The currently approved anti-C5 mAbs, eculizumab and ravulizumab, are similarly dosed at high 
levels (maintenance dose of 900 mg IV Q2W and 3000 mg to 3500 mg IV Q8W for eculizumab 
and ravulizumab, respectively). For PNH, doses higher than 900 mg of eculizumab are sometimes 
used in practice. The requirement for such high anti-C5 mAb doses is driven by 2 factors. First, 
C5 levels are high and there is a need for 100% inhibition which can only be achieved with 
complete target engagement (Peffault de Latour, 2015); second, in order to achieve 100% 
inhibition on a population basis, inter- and intra-patient variability of C5 concentrations and 
instances of enhanced complement activation (which may occur with intercurrent illness) must be 
considered. 
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Additional background information on pozelimab and the development program can be found in 
the Investigator’s Brochure for pozelimab. 
1.3. 
Cemdisiran 
Cemdisiran is a synthetic small interfering RNA (siRNA) targeting C5 messenger RNA (mRNA) 
that is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand. Cemdisiran is 
designed to suppress liver production of C5 protein, when administered via SC injection. C5 is 
encoded by a single gene and is expressed and secreted predominantly by hepatocytes. Through 
the RNA interference pathway, the cemdisiran siRNA leads to the degradation of C5 mRNA by 
RNases, thereby reducing C5 protein production, leading to reduced levels of circulating C5 
protein.  
Cemdisiran has been evaluated in a phase 1/2 study in healthy subjects and patients with PNH who 
are naïve to anti-C5 treatment or on a background therapy of eculizumab (ALN-CC5-001): 
32 healthy subjects were treated with single SC doses of cemdisiran ranging from 50 mg to 
900 mg, 24 healthy subjects were treated with multiple doses of cemdisiran ranging from 100 mg 
to 600 mg (dosing weekly, every other week or monthly), and 6 patients with PNH were treated 
with cemdisiran at 200 mg or 400 mg dosed weekly in an open-label manner with varying 
durations (as monotherapy in 3 eculizumab-naïve patients or in combination with eculizumab in 
3 patients who were on stable eculizumab treatment before the start of the study). Dose-dependent 
and durable reduction in C5 protein and complement activity were observed and the maximum 
reduction in C5 was between 90% and 99%. However, the maximum reduction in C5 levels 
achieved by cemdisiran monotherapy did not completely inhibit complement activity and was not 
sufficient in achieving adequate LDH reduction. Importantly, although cemdisiran monotherapy 
was insufficient in achieving adequate reduction in LDH, patients with PNH who were treated 
with cemdisiran co-administered with eculizumab were able to reduce their eculizumab dose 
and/or increase the interval between eculizumab doses while maintaining clinically meaningful 
inhibition of complement activity.  
Additional background information on cemdisiran and the development program can be found in 
the Investigator’s Brochure for cemdisiran. 
1.4. 
Pozelimab + Cemdisiran: A Combination Approach 
The benefit of blocking C5 complement activity in PNH has been clearly established by 
eculizumab (Soliris®) and ravulizumab (Ultomiris®). The pozelimab and cemdisiran combination 
offer potential additional benefits over existing standard-of-care by providing better control of 
breakthrough hemolysis and improving the dosing regimen. It is expected that cemdisiran will 
reduce C5 production, thereby reducing the level of circulating free C5. With reduced levels of 
free C5 in circulation, combination treatment may provide adequate control of hemolysis with 
either lower doses of pozelimab or a longer dosing interval. 
This study is designed to evaluate the safety, efficacy, and pharmacodynamic (PD) effects of the 
pozelimab and cemdisiran combination in patients with PNH who were previously receiving 
investigational pozelimab monotherapy. Pharmacokinetic (PK)/PD modeling of observed data 
from both pozelimab and cemdisiran first-in-human studies in healthy subjects and patients with 
PNH (naïve to anti-C5 treatment or on a background therapy of eculizumab) suggests that, by 
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combining cemdisiran and pozelimab, the desired C5 suppression may be maintained with 
significantly lower doses of both agents and a longer dosing interval for pozelimab, from once 
weekly to potentially once every 4 weeks.   
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens 
of pozelimab and cemdisiran combination therapy during the open-label treatment period (OLTP). 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the effect of the combination treatment on the following parameters of 
intravascular hemolysis: LDH control, breakthrough hemolysis, and inhibition of total 
complement hemolysis activity (CH50)   
• To evaluate the effect of the combination treatment on hemoglobin levels 
• To evaluate the effect of the combination treatment on RBC transfusion requirements  
• To evaluate the effect of the combination treatment on COAs measuring fatigue and 
health related quality of life 
• To assess the concentrations of total pozelimab in serum and total C5 and cemdisiran 
in plasma 
• To assess immunogenicity to pozelimab and cemdisiran 
• To evaluate the long-term safety and efficacy of pozelimab and cemdisiran in an 
optional open-label extension period (OLEP)  
• To assess safety after treatment intensification with pozelimab and cemdisiran 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore the effect of the combination treatment on clinical thrombosis events  
• To explore the effect of the combination treatment on renal function and renal injury 
biomarkers  
• To explore the effect of the combination treatment on complement activation and 
intravascular hemolysis relevant to PNH and other related diseases  
• To explore the effect of the combination treatment on PNH clone size  
• To evaluate the effect of the combination treatment on treatment satisfaction 
• To explore the effect of the combination treatment on a novel COA measuring 
PNH-specific symptoms  
• To study the combination treatment mechanism of action (including relationship to 
safety and efficacy), complement pathway biology, PNH and related complement-
mediated diseases  
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• To explore the effect of the combination treatment on PNH symptoms 
• To explore potential differences in genotype and gene expression that may influence 
efficacy and safety of the combination treatment for further understanding of C5, PNH, 
or other conditions associated with complement-mediated injury (for patients who 
consent to participate in a genomics sub-study) 
• To explore safety and efficacy after dose intensification with pozelimab and 
cemdisiran 
• To explore the long-term effects of the combination treatment on clinical and PD 
assessments in an optional OLEP 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
The clinical hypothesis is that pozelimab + cemdisiran combination treatment has an acceptable 
safety and tolerability profile in patients with PNH. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This trial is designed as a randomized, open-label, 28-week treatment study to assess the safety, 
efficacy, and PD effects of 2 dose regimens of pozelimab and cemdisiran combination in patients 
with PNH who have been treated with pozelimab monotherapy for at least 26 weeks. The primary 
objective of this study is to evaluate the safety and tolerability of pozelimab and cemdisiran 
combination therapy in patients with PNH. Background for the clinical development for pozelimab 
and cemdisiran is provided in Section 1 and the respective Investigator’s Brochures. 
The study does not include a placebo control, as it is considered unacceptable when there is a 
proven intervention (ie, eculizumab or ravulizumab) and patients with PNH who are not on C5 
inhibition face risks of serious or irreversible harm from sequelae of the disease.  
Patients will be randomized in 1:1 ratio to receive pozelimab 400 mg SC Q4W and cemdisiran 
200 mg SC Q4W (arm 1) or pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W (arm 2).  
The former regimen is the intended treatment for use in planned phase 3 studies, and the latter 
regimen represents a dose intensification regimen, which may be considered in the planned phase 3 
studies for patients whose hemolysis is not well controlled with the Q4W dosing regimen 
(Section 8.3.2). The data obtained from this study will be used to support the dose selections of 
treatment for the pozelimab and cemdisiran combination development program. 
In addition to safety, the study includes secondary efficacy endpoints to assess the effect of the 
combination treatment on control of intravascular hemolysis, as measured by LDH, which is 
central to the clinical monitoring of PNH (Rother, 2005), including during eculizumab therapy.  
An LDH of at least 1.5 × ULN along with related clinical symptoms is considered an indication of 
active PNH, and for treatment with eculizumab (Sahin, 2016)(Soliris®, 2019). Furthermore, 
reductions in LDH below the 1.5 × ULN threshold with eculizumab therapy have been shown to 
correlate with improvement in patient’s symptoms, quality of life measures, and transfusion 
requirements (Brodsky, 2008).   
The use of LDH as a measure of intravascular hemolysis allows for an objective and precise means 
to gauge whether the control of intravascular hemolysis with pozelimab monotherapy is sustained 
when the patients are switched to pozelimab and cemdisiran combination treatment.  The 
assessment of intravascular hemolysis is central to the clinical monitoring of PNH, as 
demonstrated in eculizumab and ravulizumab studies and accepted by US Food and Drug 
Administration (FDA) and European Medicines Agency (EMA) (Rother, 2005). Pivotal 
eculizumab studies, pivotal ravulizumab studies using eculizumab as a comparator, and the PNH 
registry have shown that the active PNH population has LDH elevated in the range of 6 to 8 × ULN 
(Röth, 2018). Upon treatment with an anti-C5 antibody, LDH levels fell rapidly and markedly in 
the patients with active PNH.  An LDH of 1.5 × ULN is a clinically meaningful threshold for 
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disease activity:  an LDH >1.5 × ULN, along with related clinical symptoms, is considered a 
marker for treatment with eculizumab (Sahin, 2016).   
The study has a treatment duration of 28 weeks in the OLTP, which is considered sufficient to 
provide an adequate understanding of the safety, efficacy, and PD effects of the combination 
treatment for continued development. Based on modeling and simulation using available PK/PD 
data from pozelimab or cemdisiran treatment in healthy subjects and patients with PNH, it is 
expected that, by week 28, pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W should 
have reached steady state and the effect on LDH will be the sole contribution of the assigned 
treatment combination regimen without impact from pozelimab 800 mg SC QW.  
The long-term safety and efficacy of the combination treatment will be assessed by providing the 
patients who complete the main OLTP on combination treatment an opportunity to participate in 
an optional long-term OLEP, in which patients shall continue to receive study treatment for an 
additional 52 weeks. Patients who opt not to participate in the OLEP (or those who stop treatment 
for any reason) will be followed for 52 weeks after the last dose of study treatment, to monitor for 
safety as the study drugs are gradually eliminated from the body. Patients who complete the OLEP 
and stop study treatment will also be followed for 52 weeks after their last dose of study treatment. 
Additional considerations on post-study treatment access are described in Section 8.9. 
3.2.2. 
Rationale for Dose Selection 
Two combination dose regimens will be evaluated in this study: 
• Pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W  
• Pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W 
Pozelimab:  
In the completed phase 1 study in healthy subjects (R3918-HV-1659), pozelimab 
was found to be generally well-tolerated at single doses up to 30 mg/kg IV and 600 mg SC, or 
4 doses of 400 mg SC QW preceded by a 15 mg/kg IV loading dose. Maximum C5 inhibition with 
complete suppression of complement activity, as measured by a CH50 assay, was observed at 
higher doses (≥3 mg/kg IV dosing). The PK of total pozelimab appears non-linear at lower 
concentrations, becoming linear as concentrations increase. This is thought to be due to a 
concentration-dependent and saturable, target-mediated elimination.  In the ongoing phase 2 study 
in patients with PNH who are naïve to anti-C5 treatment (R3918-PNH-1852), no safety signal has 
emerged after receiving a loading dose of 30 mg/kg IV of pozelimab (day 1) followed by 800 mg 
SC QW (starting on day 8).  Interim analysis showed efficacy, with normalization of LDH levels 
observed at day 29 in all 17 patients and LDH reduction sustained below 1.5 × ULN until day 183.  
More information regarding the results of the phase 1 and phase 2 studies is provided in the 
Investigator’s Brochure for pozelimab. 
Cemdisiran: Cemdisiran has been evaluated in a phase 1/2 study in healthy subjects and patients 
with PNH who are naïve to anti-C5 treatment or on a background therapy of eculizumab (ALN-
CC5-001). Cemdisiran had an acceptable safety profile in healthy subjects following a single 
injection at doses up to 900 mg SC or following repeated injections at doses up to 400 mg QW or 
600 mg Q2W. In the 6 patients with PNH included in the study, the safety of cemdisiran was 
acceptable at 200 mg QW and 400 mg QW, either administered as a single agent or on a 
background of eculizumab at standard doses. A single dose of 600 mg cemdisiran achieved a C5 
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concentration of 12.3±1.47 μg/mL by day 14 and 2.3±0.76 μg/mL by day 56. Inhibition of C5 was 
dose-dependent and durable, with >90% knockdown of C5 beginning on day 21 and persisting 
through day 238. However, the relationship between C5 concentrations and complement activity 
is asymptotic, such that, even with 90% to 99% reduction in C5 levels, there is still incomplete 
inhibition of complement activity. A maximum of 99% C5 suppression was achieved following 
200 mg weekly cemdisiran monotherapy, and little to no more suppression was achieved with 
higher dose levels (up to 600 mg bi-weekly); therefore, cemdisiran monotherapy was not sufficient 
in achieving adequate LDH reduction. More information regarding the results of the phase 1/2 
study is provided in the Investigator’s Brochure for cemdisiran. 
Combination: The goal of combining pozelimab and cemdisiran is to rapidly and continuously 
suppress concentrations of C5 to pharmacologically inactive levels. To inform the choice of the 
dosing regimen for the combination therapy in patients with PNH, a target-mediated drug 
disposition (TMDD) population PK model for pozelimab and a population PK/PD model for 
cemdisiran were developed based on respective data on healthy subjects. The models for 
pozelimab and cemdisiran were combined by introducing C5 production suppression effect of 
cemdisiran to the synthesis rate of C5 in the TMDD model for pozelimab. The unified model was 
used to perform simulations to inform dose selection of pozelimab in combination with cemdisiran. 
Based on simulations, it is expected that pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC 
Q4W (ie, the intended combination regimen in the planned phase 3 studies) is sufficient to maintain 
the suppression of C5 to biologically inactive levels. In addition, at steady-state, the simulated total 
and free pozelimab concentration-time profiles are superimposable.  This is consistent with the 
extremely low concentration of free C5 predicted by the unified population PK/PD model.  
Intensified Treatment: The intensified regimen of pozelimab 30 mg/kg IV loading dose + 
pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W in this study is included to provide 
extra C5 suppression that some patients may need to achieve adequate control of intravascular 
hemolysis and is intended to be used for patients whose hemolysis is not adequately controlled 
with the Q4W dosing regimen in the planned phase 3 studies. Both regimens will be evaluated in 
this study to support dose regimen selection in the planned phase 3 studies for the pozelimab and 
cemdisiran combination development program. 
3.3. 
Risk-Benefit 
A risk-benefit statement with respect to the overall development program is provided in the 
Investigator’s Brochure for pozelimab and the Investigator’s Brochure for cemdisiran. The 
combination treatment of pozelimab and cemdisiran is being developed in patients with PNH for 
the reasons outlined in Section 1.4. The following sections describe potential risks and strategies 
for mitigation. 
3.3.1. 
Potential Risk of Neisseria Infection 
An established risk of blocking C5 complement activity is increased susceptibility to infections, 
specifically to encapsulated organisms, the most potentially severe of which is infection with 
Neisseria meningitidis (Figueroa, 1991). The risk for meningococcal infection is largely driven by 
the degree of inhibition of C5. Two different agents acting on C5 through independent pathways 
are not expected to increase the risk for meningococcal infection above that of each of the 
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individual agents. This expectation is based on the goal of complement inhibition therapy and 
human genetic data.  The objective of pozelimab and cemdisiran combination therapy is complete 
inhibition of C5 activity. Once this is achieved, then further inhibition is not possible and the 
anticipated risk is not expected to increase further.  Human genetic data reveals that the increased 
risk of infections with Neisseria species (spp) occurs when there is homozygous loss of 
complement factor 5 (C5). Importantly, individuals who are C5 heterozygous loss of function do 
not have increased risk of infection with Neisseria spp (Platonov, 1997).  
Experience with eculizumab suggests that pretreatment with appropriate vaccinations covering 
multiple serotypes and concurrent therapy with oral antibiotics is effective at substantially 
mitigating this risk (Hillmen, 2013)(McNamara, 2017)(NHS England, 2013)(Soliris®, 2019). 
Current treatment guidelines for PNH and the eculizumab package insert recommend such 
vaccinations prior to dosing. Because vaccination does not provide 100% coverage to all strains 
and there are no proven titer levels associated with 100% protection, prophylactic oral antibiotics 
are also commonly given to patients with genetic or pharmacologic deficiency in terminal 
complement activity.  In various disease settings such as asplenia in sickle cell disease, and with 
terminal complement deficiency, use of long-term prophylactic antibiotics has been safely 
implemented for the prevention of encapsulated organisms, including N. meningitidis (Gaston, 
1986)(Wedzicha, 2008).  
In this study, vaccination prior to study treatment initiation (or at the time of administration, based 
on local practice, see Section 8.2.1) will be required to mitigate the risk of infection by 
encapsulated organisms to a level that has been considered acceptable in other anti-C5 clinical 
development programs. In addition to vaccination, monitoring for early signs and symptoms of 
infection (Section 8.2.2), providing a patient safety card that describes the signs and symptoms of 
infection and steps to follow in case of suspected infection, as well as concurrent therapy with 
recommended oral antibiotics (Section 8.2.3) will further mitigate this risk. These risk mitigation 
strategies have been acceptable and well tolerated in the precedent healthy volunteer and PNH 
patient studies for pozelimab and cemdisiran individually as well as in other anti-C5 clinical 
development programs.   
Recently, serious infections with Neisseria species (other than N. meningitidis), including 
disseminated gonococcal infections, have been reported during eculizumab treatment (Soliris®, 
2019). Therefore, patients will undergo a risk assessment and counseling regarding the potential 
risk of Neisseria gonorrhea as per the investigator’s local guidelines.  Patients will be counseled 
about N. gonorrhea prevention and regular testing will be advised for at-risk patients. A risk-factor 
assessment will be based on local practice or national guidelines to determine if the patient is at 
risk, which would lead to further management of prevention, testing, and treatment of 
N. gonorrhea (Section 8.2.4). 
3.3.2. 
Liver Function Test Abnormalities 
Liver function test abnormalities are noted as a potential risk due to the targeted delivery of 
cemdisiran to hepatocytes and were carefully followed in the cemdisiran program. No signal has 
emerged from the phase 1 and 2 clinical studies to date.  In the healthy volunteer study with 
cemdisiran, about 30% to 40% of healthy subjects had asymptomatic, transient, mild elevations in 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) that were less than 
3 × ULN in the cemdisiran dosing arms. In patients with PNH (n=6), one patient had a related 
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adverse event (AE) of increased transaminases with ALT and AST greater than 3 × ULN. The 
patient had several underlying contributing factors and the AE resolved within 120 days of onset 
in the setting of ongoing cemdisiran pharmacology. The patient was rechallenged in a 
compassionate use setting and no increase ALT or AST ≥3 × ULN has been reported. Additional 
details may be found in the Investigator’s Brochure for cemdisiran.  
In this study, patients will be closely monitored for ALT and AST abnormalities. Those with 
significant ALT or AST abnormalities, or known liver function impairment, will be excluded from 
participating in the study (Section 7.2.2). Levels of ALT and AST will be closely followed 
throughout the trial. Individual patient stopping rules will include a mandatory discontinuation of 
study treatment if specific thresholds for ALT or AST are met as per protocol (Section 8.3.3). 
These mitigation steps are considered sufficient to address this potential risk. 
3.3.3. 
Study Conduct in Response to Coronavirus Disease 2019 
Recognizing that the “Coronavirus Disease 2019” (COVID-19, caused by severe acute respiratory 
syndrome coronavirus 2 [SARS-CoV-2]) pandemic will have an impact on the conduct of clinical 
trials, the Sponsor does not intend to screen any patients in this study until the impact of the 
COVID-19 pandemic is deemed manageable and no longer interfering with the conduct of trials 
at individual sites, and patients can safely participate in this study. Until then, the Sponsor plans 
to obtain approvals from Health Authorities/Ethics Committees to enable initiation of study sites 
for this study, as allowed by local laws and regulations. 
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4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint is the incidence and severity of TEAEs through week 28 of the OLTP. 
4.1.2. 
Secondary Endpoints 
The secondary endpoints for the OLTP are: 
• Percent change of LDH from pre-treatment (defined as mean of LDH values at day -7 
and day 1 [prior to combination dosing]) to end-of-treatment period (defined as mean 
of LDH values at week 24 through week 28) 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from post-
baseline (on day 1) through week 28 and from week 4 through week 28, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN)  at each visit from post-
baseline (on day 1) through week 28, inclusive 
• Normalization of LDH at each visit, defined as LDH ≤1.0 × ULN from post-baseline 
(on day 1) through week 28, inclusive  
• Area under the curve (AUC) of LDH over time from baseline though week 28 and from 
week 4 through week 28, inclusive 
• Breakthrough hemolysis (as defined in Section 6.2) from baseline through week 28  
• Hemoglobin stabilization (defined as patients who do not receive RBC transfusion and 
have no decrease in hemoglobin levels of ≥2 g/dL) from baseline through week 28 
• Change in hemoglobin levels from baseline to week 28  
• Transfusion avoidance (defined as not requiring a RBC transfusion as per protocol 
algorithm) from baseline to week 28 
• Rate and number of units of RBCs transfused from baseline to week 28 
• Change in CH50 from baseline to week 28  
• Change in fatigue as measured by Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-Fatigue) scale from baseline to week 28 
• Change from baseline to week 28 in global health status/quality of life scale 
(GHS/QoL) and physical function (PF) scores on the European Organization for 
Research and Treatment of Cancer: Quality-of-Life Questionnaire core 30 items 
(EORTC QLQ-C30)   
• Concentrations of total pozelimab in serum and cemdisiran in plasma, assessed 
throughout the study 
• Change from baseline in concentration of total C5 assessed throughout the study 
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• Assessment of immunogenicity to pozelimab and cemdisiran as determined by the 
incidence, titer, and clinical impact of treatment-emergent anti-drug antibody (ADA) 
responses over time 
• Incidence and severity of TEAEs for patients who received treatment intensification 
through week 28r 
4.1.2.1. 
Secondary Endpoints for the Optional Open-Label Extension Period 
The secondary endpoints for the optional OLEP are: 
• Change and percent change of LDH from day 1e to week 24e and week 52e of the 
OLEP  
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from day 
1e of the OLEP through week 24e and week 52e  
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) at each visit from day 1e 
of the OLEP through week 52e 
• Normalization of LDH at each visit, defined as LDH ≤1.0 × ULN from day 1e of the 
OLEP through week 52e 
• Area under the curve (AUC) of LDH over time between day 1e of the OLEP though 
week 52e 
• Breakthrough hemolysis from day 1e of the OLEP through week 24e and week 52e 
• Hemoglobin stabilization (defined as patients who do not receive RBC transfusion and 
have no decrease in hemoglobin levels of ≥2 g/dL) from day 1e to week 24e and 
week 52e of the OLEP 
• Change in hemoglobin levels from day 1e to week 24e and week 52e of the OLEP 
• Transfusion avoidance (defined as not requiring a RBC transfusion as per protocol 
algorithm) from day 1e to week 24e and week 52e of the OLEP 
• Rate and number of units of RBCs transfused from day 1e to week 24e and week 52e 
of the OLEP 
• Change and percent change in CH50 from day 1e to week 16e, week 24e and week 52e 
of the OLEP  
• Change in fatigue as measured by FACIT-Fatigue scale from day 1e to week 52e of the 
OLEP 
• Change in global health status/quality of life scale (GHS/QoL) and physical function 
(PF) scores on the European Organization for Research and Treatment of Cancer: 
Quality-of-Life Questionnaire core 30 items (EORTC QLQ-C30) from day 1e to 
week 52e of the OLEP  
• Incidence and severity of TEAEs during the 52-week OLEP in patients treated with 
pozelimab and cemdisiran combination therapy 
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• Concentrations of total pozelimab in serum and total C5 and cemdisiran in plasma, 
assessed over time during the OLEP  
• Assessment of immunogenicity to pozelimab and cemdisiran as determined by the 
incidence, titer, and clinical impact of treatment-emergent anti-drug antibody (ADA) 
responses over time during the OLEP 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints for the OLTP are: 
• Treatment intensification throughout the study  
• Incidence of MAVE (defined in Section 10.1.4) from baseline to week 28 
• Change in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline to week 28  
• Percent change in free hemoglobin from baseline to week 28  
• Change in bilirubin from baseline to week 28  
• Change in reticulocyte count from baseline to week 28  
• Change and percent change in the alternative pathway hemolytic activity assay (AH50) 
from baseline to week 28  
• Proportion of PNH erythrocytes and granulocytes from baseline to week 28  
• Change from baseline to week 28 in functional scale scores (Role functioning, 
Emotional Functioning, Cognitive Functioning and Social Functioning) and symptom 
scale scores (Fatigue, Nausea and vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, 
Constipation, Diarrhoea) of the EORTC QLQ-C30    
• Stability in global health status, functioning and symptoms as measured by the EORTC 
QLQ-C30 from baseline to week 28  
• Comparison of treatment satisfaction (as assessed by the Treatment Satisfaction 
Questionnaire for Medication [TSQM]) at baseline vs. treatment at week 28 
• Change in Patient Global Impression of Severity (PGIS) from baseline to week 28, 
including questions on PNH symptoms, impacts and fatigue 
• Patient Global Impression of Change (PGIC) at week 28, including questions on PNH 
symptoms, impacts and fatigue 
• Change in PNH symptoms as measured by the PNH symptom-specific questionnaire 
from baseline to week 28 
Exploratory endpoints related to the analyses for those patients receiving dose intensification and 
patients participating in the OLEP will be provided in the statistical analysis plan (SAP). 
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
In accordance with local regulations, baseline characteristics will be collected and may include 
standard demographic information (eg, age, race, weight, height, etc), disease characteristics, 
medical history, and medication history for each patient. 
Note: The data will be used to describe the patient population under study and may inform whether 
there are differences in the safety or efficacy profile based on the defined patient characteristics. 
In addition, collection of data on race and ethnicity may be required by certain regulatory agencies, 
such as the FDA. 
5.2. 
Efficacy Variables 
5.2.1. 
Laboratory Variables for the Assessment of Efficacy 
Efficacy in this study is evaluated by the following laboratory assessments: 
• LDH (serum): LDH as a measure of intravascular hemolysis allows for an objective 
and precise means to gauge whether the control of intravascular hemolysis is sustained 
when the patients are switched to pozelimab and cemdisiran combination treatment.   
• Hemoglobin: Hemolytic anemia is a hallmark of PNH. 
• CH50: The CH50 assay will be used to confirm complete inhibition of complement 
activity has been achieved throughout the dosing interval in patients with PNH. 
These laboratory variables are relevant to the characterization and disease mechanisms of PNH 
(Brodsky, 2014).  
5.2.2. 
Transfusion Record 
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion 
for symptomatic management. The frequency of blood transfusion has been used in other studies 
of PNH to assess efficacy (Hillmen, 2006) (Röth, 2018).  
5.2.3. 
Clinical Outcome Assessments 
Brief descriptions of COAs are provided in Section 9.2.3 and include the following: 
• FACIT-Fatigue 
• EORTC-QLQ-C30 
• TSQM 
• PNH Symptom-Specific Questionnaire 
• PGIS 
• PGIC 
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5.3. 
Safety and Anthropometric Variables 
Safety and anthropometric variables in this study include: 
• Body weight 
• TEAEs, including breakthrough hemolysis events (defined in Section 6.2) and adverse 
events of special interest (AESIs; defined in Section 10.1.3 and Section 10.1.4) 
• Vital signs  
• Electrocardiogram (ECG) 
• Physical examination 
• Routine safety laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
testing [for women of childbearing potential or WOCBP]) 
• Concomitant medications and treatments 
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of total pozelimab, total C5 (target), cemdisiran, 
cemdisiran metabolites, and time.   
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) and nominal 
sampling time point/visit.   
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Pharmacodynamic and other biomarker variables include, but are not limited to, the following:  
• CH50 (an assay assessing the activity of the classical pathway of complement) will be 
used to measure C5 activity. This is the principle PD marker for the study and is also 
an efficacy variable in this study (Section 5.2.1) 
• Parameters of intravascular hemolysis: ie, haptoglobin, reticulocyte count, and 
bilirubin 
• Free hemoglobin 
• Alternative pathway hemolytic activity, as measured by AH50   
• Complement activation markers: ie, sC5b-C9 
• PNH clone size: ie, PNH erythrocytes and granulocytes 
The list may be altered or expanded, as it is recognized that more relevant or novel biomarkers 
may be discovered during the course of this study. The biomarkers studied will be ones believed 
to be relevant to the understanding of efficacy, pathophysiology of indication target engagement, 
mechanism of action, and possible toxicities of pozelimab and cemdisiran. 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a randomized, open-label, 2-arm, 28-week study to evaluate the safety, efficacy, and PD 
effects of 2 dose regimens of pozelimab and cemdisiran combination treatment in patients with 
PNH who had been receiving treatment with pozelimab monotherapy in a Regeneron-sponsored 
clinical study (R3918-PNH-1868). A schematic of the study design is shown in Figure 1. Eligible 
patients will be randomized 1:1 to 1 of 2 dose regimens with the pozelimab and cemdisiran 
combination. The study consists of 4 main periods: a 7- to 8-day screening period, a 28-week 
OLTP (this main study period will be longer for patients who require intensified treatment), an 
optional 52-week OLEP, and a 52-week post-treatment safety follow-up period. The fourth period 
begins when a patient completes or permanently discontinues study treatment (eg, at the time of 
premature study drug discontinuation, at the completion of study treatment in the OLTP for 
patients who decline the optional OLEP, or at the completion of study treatment in the optional 
OLEP for patients who do not continue study treatment in a post-trial access program immediately 
following the study). The treatment period begins from the first dose of the combination treatment 
until the end of the dosing interval of the last dose to account for the treatment effect of the final 
dose of study drug.  
Figure 1: 
Study Flow Diagram 
   
D, day; EOT, end of treatment period; OLEP, open-label extension period; Q2W, every 2 weeks; Q4W, every 
4 weeks; R, randomize; REGN, Regeneron; SC, subcutaneous; W, week 
a Patients will receive a one-time intensified treatment if they meet criteria of breakthrough hemolysis and LDH 
response as described in Section 8.3.2.  
b OLEP (52 weeks): Patients whose treatment was not intensified during the OLTP will transition to the OLEP on a 
regimen of pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W, regardless of their treatment assignment 
in the OLTP. Patients whose treatment was intensified during the OLTP will transition to the OLEP and continue 
with the intensified treatment regimen of pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W. 
c Safety follow-up period (52 weeks post-dose): Patients who complete or permanently discontinue study treatment 
(eg, at the time of premature study drug discontinuation, at the completion of study treatment in the OLTP for 
patients who decline the optional OLEP, or at the completion of study treatment in the optional OLEP) will be 
monitored for safety until 52 weeks after the last dose of study treatment. Patients who complete the optional 
OLEP may be able to continue study treatment in a post-trial access program. Patients participating in the post-
trial access program will therefore not be followed in the safety follow-up period. 
Safety 
Follow-Up c
Optional 
OLEP b
Screening
W28 / D197
EOT
D-8/-7 
(Day of final dose in 
prior REGN study)
Open-Label Treatment Period (28 weeks)
D1
1st combination 
dosing
Pozelimab 
800 mg SC
Arm 1: Pozelimab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W
Arm 2: Pozelimab 400 mg SC Q2W + Cemdisiran 200 mg SC Q4W
R
1:1
At any time during the study, patients who meet pre-defined criteria for LDH and 
breakthrough hemolysis will be switched to an intensified treatment regimen
a
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6.1.1. 
Screening (Day -8/-7 to Day -1) 
The screening period is 7 to 8 days. The screening visit should occur at a scheduled or unscheduled 
visit of the R3918-PNH-1868 study (parent study).The dose of pozelimab should be administered 
at the study site on the day of the screening visit in this study, which shall occur on the day of a 
planned administration with pozelimab monotherapy.  
Assessments that are common to both study protocols (R3918-PNH-1868 and R3918-PNH-2092) 
should not be duplicated during the screening visit for this study.  
During the screening visit in this study, patients will be administered their dose of 800 mg 
pozelimab SC as required in the parent study, and this should occur after all study procedures have 
been completed for both the parent study and this study. Subsequently, the day 1 visit with the 
combination treatment dosing in this study should occur 7 to 8 days after the last dose of pozelimab 
monotherapy in the parent study. 
Patients who screen fail in this study should continue with their current 800 mg pozelimab dosing 
regimen in the parent study. Patients may be rescreened up to 2 times in this study with agreement 
by the Sponsor if: 
• The day 1 visit cannot be scheduled 7 to 8 days after the screening visit 
or 
• The patient was deemed ineligible for another reason and the Investigator believes 
that the patient may be eligible upon rescreening  
Rescreening for this study should take place at a scheduled or unscheduled visit on the day of a 
planned administration with pozelimab in the parent study.  
Patients who are randomized in this study will permanently discontinue treatment in the parent 
study with the last visit assessments in the parent study being considered as end of treatment/end 
of study visit assessments.    
Patients who are randomized in this study will receive their first dose of the combination treatment 
with cemdisiran and pozelimab on day 1, as required per protocol (Section 6.1.2). 
As part of risk mitigation for this study, patients should have documented vaccination against 
Neisseria meningitidis and receive updated meningococcal vaccination if needed (Section 8.2.1). 
Daily oral antibiotic prophylaxis is recommended throughout the study (Section 8.2.3).  Patients 
should be counseled regarding risk of infection with Neisseria gonorrhea, as applicable based on 
their risk level (Section 8.2.4).  
In addition to screening procedures to determine eligibility, patients will be asked to complete a 
PNH Symptom-Specific Questionnaire daily for 7 consecutive days prior to the day 1 visit.  
Patients may choose to participate in the optional OLEP, optional future biomedical research, 
and/or optional pharmacogenomics component of the study by signing the respective optional 
informed consent forms (ICFs). 
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6.1.2. 
Open-Label Treatment Period (Day 1 to Week 28) 
Day 1 should be scheduled 7 to 8 days after the last dose of pozelimab monotherapy in the parent 
study. On day 1, after confirming eligibility, patients will be randomized in 1:1 ratio to 1 of 2 arms:   
• Arm 1: Pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W  
• Arm 2: Pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W  
Patients randomized into this study must be discontinued from the parent study. 
After all baseline samples are collected and all baseline assessments are performed, patients will 
receive the first doses of the assigned combination treatment. During the study, injection training 
may be provided for patients or caregivers who are interested in home-dosing, if this option is 
available. Upon successful completion of injection training, study treatment administration may 
be continued by the study staff, by another healthcare professional, by the patient (self-
administration), or by a designated person at the patient’s preferred location, as applicable 
(Section 8.1). In addition, study procedures, including sample collection for laboratory analysis, 
may be performed at the study clinic or at another location that is more convenient for the patient 
(including home visits), if this option is available and with agreement from the sponsor.  
Safety Considerations 
Breakthrough hemolysis is assessed by the investigator throughout the study and is defined in 
Section 6.2. During the study, a patient exhibiting an event of breakthrough hemolysis and 
inadequate LDH response may qualify for intensified treatment; patients who have an LDH 
increase ≥2 x ULN due to an acute complement-activating condition may qualify for an additional 
IV pozelimab dose. Details and requirements are described in Section 8.3.2. Study assessments for 
patients who require intensified treatment will restart from day 1r for the 28-week treatment period 
following Table 2.  
The decision to transfuse with RBCs during the study should proceed according to the predefined 
criteria in Section 6.3. 
Patients should be closely monitored for the entire study for early signs and symptoms of 
meningococcal infection (and other infections related to encapsulated organisms) and evaluated 
immediately if an infection is suspected (Section 8.2.2). Patients will be provided a patient safety 
card describing signs and symptoms of suspected meningococcal infection along with instructions 
to follow in case of a potential meningococcal infection as well as information for non-investigator 
health care provider for awareness. Daily oral antibiotic prophylaxis is recommended 
(Section 8.2.3).   
Study Procedures 
Study procedures include laboratory assessments of efficacy (LDH, hemoglobin, and CH50), 
transfusion record update, COAs, body weight, and routine safety assessments (vital signs, 
physical examination, ECG, safety laboratory testing). Treatment-emergent adverse events and 
concomitant medications will be monitored throughout the study. Patients will provide blood 
samples for biomarkers, drug concentration for potential PK/PD assessment, immunogenicity, and 
exploratory assessments. Study procedures are described in Table 1 (schedule of events for OLTP). 
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The last doses of study treatment are administered at week 24 for arm 1 and week 26 for arm 
2. Patients will return for safety, efficacy, and other assessments at the end of treatment (EOT) 
visit at week 28. For patients who restarted on intensified treatment during the study, the last doses 
of study treatment are administered at week 26r. Patients will return for safety, efficacy, and other 
assessments at the EOT visit at week 28r. 
6.1.3. 
Optional Open-Label Extension Period 
All patients who complete the OLTP treatment period (including patients who receive intensified 
treatment) will be offered the opportunity to continue in an optional 52-week OLEP, whereby the 
transition of the combination treatment from the OLTP to the OLEP is planned to be uninterrupted 
(ie, day 1e visit of the OLEP will correspond to the EOT visit of the OLTP, and any common 
assessments will be performed once for both visits). Study assessments and conduct for the OLEP 
are as described previously for the OLTP and are detailed in Table 3 (schedule of events for the 
optional OLEP).  
• Patients who are randomized to arm 1 (pozelimab 400 mg SC Q4W and cemdisiran 
200 mg SC Q4W) who have not received treatment intensification will continue the 
Q4W regimen for both pozelimab and cemdisiran starting on day 1e 
• Patients who are randomized to arm 2 (pozelimab 400 mg SC Q2W and cemdisiran 
200 mg SC Q4W) who have not received treatment intensification will switch to the 
Q4W regimen for both pozelimab and cemdisiran starting on day 1e 
• Patients who received treatment intensification during the main treatment period will 
continue with the intensified treatment regimen (pozelimab 400 mg SC Q2W and 
cemdisiran 200 mg SC Q4W) throughout the OLEP 
During the OLEP, patients who are not on intensified treatment who meet the pre-defined criteria 
for treatment intensification will follow the dosing scheme as described in Section 8.3.2 with the 
new regimen starting on the day of intensification, and will continue their visit schedule at the next 
OLEP visit. This means that starting on the day of intensification (ie, day pre-defined criteria have 
been met), the patient will receive a single administration of pozelimab 30 mg/kg IV followed by 
SC administration of pozelimab and cemdisiran the same day. Thereafter, the patients will receive 
pozelimab 400 mg Q2W and cemdisiran 200 mg Q4W starting from the day of intensification 
(±3 days). The visit schedule for the OLEP will remain unchanged. 
The OLEP will end 52 weeks after the first dose of study treatment in the OLEP, even if the patient 
required intensified treatment during the OLEP. For patients who complete the optional OLEP, 
post-trial access to treatment may be available (Section 8.9). 
6.1.4. 
Post-Treatment Safety Follow-Up Period 
Patients who permanently discontinue study treatment for any reason will be monitored in a post-
treatment safety follow up period until 52 weeks after their last dose of study treatment. The safety 
follow-up period will begin when a patient completes or permanently discontinues study treatment 
(eg, at the time of premature study drug discontinuation, at the completion of study treatment in 
the OLTP for patients who decline the optional OLEP, or at the completion of study treatment in 
the optional OLEP for patients who do not continue treatment in a post-trial access setting). 
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Follow-up visits may be conducted at the study clinic, at home, or remotely (eg, by phone, if 
applicable). Study procedures include assessment of vital signs, physical examination, blood 
collection (hematology and chemistry), and monitoring for AEs, pregnancy reporting, and 
concomitant medications. Study visits and procedures are described in Table 4 (schedule of events 
for the safety follow-up period). 
Patients who permanently discontinue study treatment should be treated in accordance with local 
standards of care. 
6.1.5. 
End of Study Definition 
The end of main study is defined as the date of the last visit of the last patient in the OLTP, 
including patients who discontinued treatment during the OLTP and are being followed in the post-
treatment safety follow-up period of the OLTP. 
The end of the optional OLEP is defined as the date of the last visit of the last patient in the optional 
OLEP, including patients who discontinued treatment during the OLEP and are being followed in 
the post-treatment safety follow-up period of the OLEP. 
6.2. 
Breakthrough Hemolysis 
Patients who experience breakthrough hemolysis may receive intensified treatment as described 
in Section 8.3.2.  
Breakthrough hemolysis is defined below as an increase in LDH with concomitant signs or 
symptoms associated with hemolysis: 
• An increase in LDH occurs when: 
− LDH ≥2 × ULN if pre-treatment LDH is ≤1.5 × ULN or 
− LDH ≥2 × ULN after initial achievement of LDH ≤1.5 × ULN if pre-treatment 
LDH is >1.5 × ULN  
• The signs or symptoms should correspond to those known to be associated with 
intravascular hemolysis due to PNH, limited to the following: new onset or worsening 
fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral icterus, erectile 
dysfunction, chest pain, confusion, dysphagia, new thrombotic event, anemia including 
hemoglobin value significantly lower (ie, ≥2 g/dL decrease) as compared to patient’s 
known baseline hemoglobin values. 
6.3. 
Transfusion Algorithm 
Transfusions with RBCs during the screening period and while the patient is receiving study 
treatment may proceed according to the following predefined criteria that will trigger a transfusion, 
as clinically indicated. The actual number of units to be transfused should be consistent with the 
practice when patients were in their parent studies, as best as possible, and at the discretion of the 
investigator: 
• Transfuse with RBCs if hemoglobin level is ≤9 g/dL with new onset or worsening signs 
or symptoms resulting from anemia that are of sufficient severity to warrant 
transfusion, or 
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• Transfuse with RBCs if hemoglobin level is ≤7 g/dL with or without signs or symptoms 
from anemia 
6.4. 
Planned Interim Analysis 
An interim analysis may be conducted after 6 patients have completed at least 16 weeks of the 
OLTP. Additional/other interim analyses may be performed to support regulatory interactions. 
 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
This study will be open to all patients who have enrolled in the Regeneron-sponsored clinical study 
R3918-PNH-1868 and plans to enroll approximately 24 patients with PNH. The study enrollment 
will be considered complete once all patients in R3918-PNH-1868 who consent to participate in 
this study are enrolled into this study.   
7.2. 
Study Population 
This study will only enroll patients with PNH who are receiving pozelimab monotherapy in a 
Regeneron-sponsored clinical study (R3918-PNH-1868) and are willing to switch to the 
combination treatment. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Patients with PNH who are receiving treatment with pozelimab monotherapy in the R3918-
PNH-1868 study 
2. Provide informed consent signed by study patient  
3. Willing and able to comply with clinic/remote visits and study-related procedures 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the criteria listed below will be excluded from the study. Patients may 
be rescreened up to 2 times after discussion between the investigator and the sponsor. 
1. Documented*, positive polymerase chain reaction (PCR) or equivalent test based on 
regional recommendations for COVID-19 or suspected SARS-CoV-2 infection and:  
a. Have not recovered from COVID-19 (ie, all COVID-19-related symptoms and major 
clinical findings which can potentially affect the safety of the patient have not been 
resolved), and  
b. Did not have 2 negative results from a nucleic acid amplification (PCR) test or 
equivalent test based on regional recommendations for COVID-19 to confirm that the 
patient is negative for SARS-CoV-2 or, if COVID-19 PCR (or equivalent) testing is 
not feasible, at least 3 months have transpired since the initial diagnosis 
* Note: Screening for COVID-19 will not be performed as part of eligibility assessments 
for this study 
2. Patients with documented history of liver cirrhosis or patients with liver disease with 
evidence of currently impaired liver function; or patients with ALT or AST (unrelated to 
PNH) >3× ULN at the screening visit (1 repeat lab is allowed during screening) 
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3. Significant protocol deviation(s) in the parent study based on the investigator’s judgment 
and to the extent that these would (if continued) impact the study objectives and/or safety 
of the patient (for example, repetitive non-compliance with dosing by the patient) 
4. Any new condition or worsening of an existing condition which, in the opinion of the 
investigator, would make the patient unsuitable for enrollment or would jeopardize the 
safety of the patient 
5. Known hypersensitivity to cemdisiran or any component of cemdisiran formulation 
6. Pregnant or breastfeeding women 
7. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the study, 
and for at least 52 weeks after the last dose.  Highly effective contraceptive measures 
include:  
a. stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening; 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS); 
c. bilateral tubal ligation; 
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure); and/or 
e. sexual abstinence†, ‡. 
*WOCBP are defined as women who are fertile following menarche until becoming 
postmenopausal, unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state. The above definitions are according to the Clinical Trial Facilitation 
Group (CTFG) guidance (CTFG, 2020). Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception.  
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Note: The use of a female or male condom is not sufficient as a contraceptive measure but 
may be considered for the safety or prevention of sexually transmitted diseases. Female 
condom and male condom should not be used together. 
7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete the early 
termination (ET) visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.3.3. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study treatment will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational Treatment 
8.1.1. 
Pozelimab 
Pozelimab drug product will be provided in a sterile, single-use glass vial for SC administration 
and/or IV administration (for intensified treatment) and will be supplied by the sponsor. 
Detailed information about the drug product and instructions on dose preparation are provided in 
the pharmacy manual. 
8.1.2. 
Cemdisiran 
Cemdisiran drug product will be provided in a sterile, single-use glass vial for SC administration 
and will be supplied by the sponsor. 
Detailed information about the drug product and instructions on dose preparation are provided in 
the pharmacy manual. 
8.1.3. 
Dose Administration 
On day 1, patients should be monitored for at least 30 minutes after receiving the first cemdisiran 
injection. A 30 minute monitoring period is not needed after the pozelimab injection. 
During the study, administrations of the combination treatment can be performed by the patient 
himself/herself or a designated person or a healthcare professional at patient’s preferred location 
(if possible) or by site personnel during the study visits, based on the preference of investigator 
and patient, local regulations as well as availability of healthcare professional.  Sufficient injection 
training with the combination dose administration will be provided.  After training, observation of 
administration by patient/designated person will be conducted by clinical site personnel and may 
be conducted in person at the patient's home or via telemedicine.  Once this observation is 
considered satisfactory, the combination dose administration can be subsequently performed by a 
patient or a designated person for the remainder of the study. 
In addition, a patient diary will be provided prior to initiation of self-administration to collect data 
on study treatment administration. The diary should be completed upon each study drug 
administration. A study drug kit will be dispensed at clinical site visit, using a direct-to-patient 
(DTP) service provider, or transported by a healthcare professional, as applicable. 
The dosing windows for the 2 dosing regimens are as follows: 
• Pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W (±7 days) 
• Pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W (±3 days) 
Note: Study procedures may have instructions pertaining to the timing relative to dosing. 
Therefore, dosing should be coordinated with the study visit windows, which are described in the 
Schedule of Events tables in Section 9.  
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8.2. 
Risk Mitigation and Background Treatments 
8.2.1. 
Meningococcal Vaccinations 
Patients will have had previous documented vaccination for meningococcus (serotypes A, C, Y, 
W and serotype B if available) from a prior Regeneron sponsored study, but may be revaccinated 
if prior vaccination is more than 5 years prior to screening. Patients should be revaccinated less 
than 5 years prior to screening if required according to current national vaccination guidelines for 
vaccination use with complement inhibitors or local practice. If vaccination precedes the initiation 
of study treatment by less than 2 weeks, then the patient must receive antibiotic prophylaxis for a 
minimum of 2 weeks from the date of vaccine administration. 
During the course of the study, the investigator should ensure the patient continues to meet the 
requirement for vaccination as stated above. Patients who require re-vaccination during the study 
should continue study treatment. Vaccinations will be sourced locally by the investigator or 
designee and reimbursed by the sponsor. 
8.2.2. 
Monitoring for Meningococcal Infection 
Patients should be closely monitored for early signs and symptoms of meningococcal infection 
and evaluated immediately if an infection is suspected.  
Patients will be provided with a patient safety card describing signs and symptoms of 
meningococcal infection, along with instructions to follow in case of a potential meningococcal 
infection, as well as information for the non-investigator healthcare provider for awareness.  
8.2.3. 
Oral Antibiotics 
It is recommended that daily oral antibiotic prophylaxis with either a penicillin or macrolide class 
antibiotic commence on the day of first dosing of study drug (or per timing of meningococcal 
vaccination, Section 8.2.1) and continue for the duration of the study, unless the risks outweigh 
the benefits or it is inconsistent with local practice. It is recommended that prophylaxis be 
continued for at least 52 weeks after last dose of pozelimab and cemdisiran combination treatment, 
including for patients who prematurely discontinue study drug. If the investigator prescribes 
antibiotic prophylaxis, then the investigator should follow the local prescribing information, 
particularly as it relates to warnings, precautions, monitoring, etc, which may necessitate 
additional monitoring, attention to drug-drug interactions, and other considerations.  
Ultimately, the decision to administer prophylaxis with oral antibiotics, the start day of 
administration, the duration of prophylaxis, and the choice and dosing regimen of antibiotics will 
be at the discretion of the investigator and should be consistent with local guidelines for use with 
complement inhibitors. Oral antibiotics will be sourced locally by the investigator or designee and 
reimbursed by the sponsor. 
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8.2.4. 
Risk Management of Neisseria Gonorrhea  
Patients should be counseled about N. gonorrhea prevention and regular testing should be advised 
for at-risk patients.  
A risk-factor assessment should be based on local practice or national guidelines. The investigator 
should make his/her own assessment of risk (and if needed, consultation with other healthcare 
provider) to determine if the patient is at risk, which would lead to further management of 
prevention, testing, and treatment of N. gonorrhea.  
Testing and treatment should be in accordance with local practice or national guidelines.  
General preventive measures include abstinence and use of a condom. Additional preventive 
measures should be considered based on local practice or national guidelines. 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed, unless the patient meets the criteria for 
intensified treatment as described in Section 8.3.2. 
8.3.2. 
Intensified Treatment 
Patients will be given intensified treatment if they meet both of the following criteria: 
• Breakthrough hemolysis that is not due to a complement activating condition (ie, 
intercurrent infection) * 
* For LDH increase ≥2 x ULN due to a complement activating condition, see 
footnote at the end of section 
• Inadequate LDH response (ie, LDH >1.5 × ULN) that is sustained (ie, on 2 consecutive 
measurements spanning at least 2 weeks) 
Patients’ treatment will be intensified depending on their assigned treatment group as outlined 
below. An assessment of the patient’s weight should be performed on the day of the IV pozelimab 
load in order to calculate the appropriate dose. 
• Patients randomized to pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W 
will receive a single administration of pozelimab 30 mg/kg IV on the day of 
intensification + an intensified pozelimab regimen of 400 mg Q2W along with 
cemdisiran 200 mg Q4W starting on the day of intensification.  The patients will be 
treated with the intensified SC dose regimen for additional 28 weeks to complete the 
study, with the last doses of the intensified treatment at week 24r (for cemdisiran) and 
week 26r (for pozelimab).   
• Patients randomized to pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W 
will receive a single administration of pozelimab 30 mg/kg IV on the day of 
intensification + a re-initiation of the assigned combination regimen of pozelimab 
400 mg SC Q2W and cemdisiran 200 mg SC Q4W starting on the day of 
intensification.  The patients will continue the same SC dose regimen for additional 28 
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weeks to complete the study, with the last doses of the intensified treatment at week 24r 
(for cemdisiran) and week 26r (for pozelimab).   
Patients who undergo treatment intensification may require unscheduled visit(s) prior to 
intensification. During the OLTP, patients whose treatment is intensified should follow Table 2 
(schedule of events for patients on intensified treatment), with the day of intensification anchored 
to day 1r (RV1).  Patients who restarted on an intensified treatment will be considered to have 
completed the OLTP once they receive 28 weeks of the intensified treatment and complete 
Week 28r assessments.  
During the OLEP, patients who are not on intensified treatment who meet criteria for treatment 
intensification will receive a single administration of pozelimab 30 mg/kg IV based on their current 
weight on the day of intensification + an intensified regimen of pozelimab 400 mg Q2W along 
with cemdisiran 200 mg Q4W starting on the day of intensification and for the remainder of the 
OLEP. Patients will continue their visit schedule at the next OLEP visit. 
Patients who experience breakthrough hemolysis that is not due to a complement activating 
condition and meet criteria for treatment intensification are eligible to receive intensification of 
pozelimab only once (whether during the main treatment period or the OLEP), beyond which no 
further intensification will be permitted. 
Note: In the event of an LDH increase ≥2 x ULN due to an acute complement activating condition 
during the OLTP or OLEP, an IV bolus of pozelimab 30 mg/kg IV may be given at the discretion 
of the investigator and in consultation with the sponsor. An assessment of the patient’s weight 
should be performed on the day of the IV pozelimab load in order to calculate the appropriate dose.  
This is not considered treatment intensification. No other changes will be made to the study 
treatment regimen (ie, the regular dose and frequency of pozelimab and cemdisiran will proceed 
unchanged). Patients will continue onto the next visit of their current visit schedule. 
Note: The IV dose should be administered first. The SC doses should be given at least 30 minutes 
after completion of the IV administration. Information related to acute reactions are provided in 
Section 8.4. 
8.3.3. 
Study Drug Discontinuation 
Patients who permanently discontinue from study treatment regardless of treatment period should 
be encouraged to remain in the study.  Those who agree and do not withdraw from the study will 
be asked to return to the clinic for all remaining study visits per the visit schedule, including the 
safety follow-up period, until 52 weeks after their last dose of study treatment. 
Patients who permanently discontinue from study treatment and who opt to withdraw from the 
study will be asked to return for an ET visit consisting of applicable assessments for the 
corresponding study period per Section 9.1.2. 
Patients who permanently discontinue study treatment should be treated in accordance with local 
standards of care. 
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8.3.3.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study treatment 
• Liver impairment as evidenced by 1 or more of the following criteria and no other 
reason can be found to explain the following lab abnormalities, such as viral hepatitis 
A, B, or C; pre-existing or acute liver disease; PNH-related complication; or another 
drug capable of causing the observed injury: 
− ALT or AST >8× ULN, or 
− ALT or AST >5× ULN for >2 weeks, or 
− ALT or AST >3× ULN and total bilirubin >2× ULN (or international normalized 
ratio [INR] >1.5)  
• Patient withdrawal of consent 
• Patient noncompliance as determined by the investigator (eg, not complying with 
protocol-required visits, assessments, and/or dosing instructions)  
• Investigator’s clinical judgment that it is in the best interest of the patient  
Note: A documented, positive PCR or equivalent test per local recommendations for COVID-19 
is not considered an automatic reason for permanent discontinuation and should be discussed with 
the medical monitor.  It may be a reason for permanent discontinuation if the benefit-risk 
assessment of continuing treatment with pozelimab and cemdisiran is deemed unfavorable. 
8.3.3.2. 
Reasons for Temporary Discontinuation of Study Drug 
Temporary discontinuation may be considered by the investigator because of suspected AEs. Study 
treatment may resume after resolution of the condition that led to temporary discontinuation of 
study treatment. Alternatively, the investigator can reinitiate study treatment under close and 
appropriate clinical and/or laboratory monitoring once the investigator has considered, according 
to his/her best medical judgment, that there is an unlikely relationship between the occurrence of 
the AE and the study treatment. 
After re-initiation of study treatment, the patient should receive any missed dose as soon as 
possible. The patient should then return to the original dosing schedule. 
Note regarding infection with SARS-CoV-2: if in the investigator’s medical judgement, it is in the 
patient’s best interest to interrupt treatment with cemdisiran/pozelimab until the patient recovers 
from SARS-CoV-2, then it is advisable that two repeat COVID-19 PCR tests, or equivalent tests 
depending on regional recommendations, be conducted to confirm the patient is negative for 
SARS-CoV-2.  If COVID-19 PCR testing is not feasible, it is advised that at least three months 
have transpired since the initial diagnosis.  The investigator may resume treatment with 
cemdisiran/pozelimab under close clinical monitoring if the Investigator feels that the benefit of 
resuming therapy outweighs the risk and the patient has no new contraindications to 
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treatment.  Input from the Sponsor regarding the permissible duration of interruption to allow 
resumption of treatment may be sought. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Injection Reactions 
8.4.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available at 
the clinical site for immediate use.  All systemic injection reactions must be reported as AEs and 
graded using the grading scales as instructed in Section 10.2.5.  
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.4.1.2. 
Local Injection Site Reactions 
Local injection site reactions (ISRs) must be reported as AEs and graded according to 
Section 10.2.5.  
In this study, ISRs related to study treatment are reported as AESIs as defined in Section 10.1.3 
and Section 10.1.4. Additional details about the event may be collected. 
8.4.2. 
Acute Intravenous Infusion Reactions 
In this study, pozelimab IV may be given in the event of a breakthrough hemolysis (Section 8.3.2). 
Patients should be observed for 30 minutes after the infusion. 
Emergency equipment and medication for the treatment of infusion reactions must be available at 
the clinical site for immediate use.  All infusion reactions must be reported as AEs (as defined in 
Section 10.2.4) and graded using the grading scales as instructed in Section 10.2.5.  
In this study, infusion reactions related to study treatment are reported as AESIs as defined in 
Section 10.1.3 and Section 10.1.4. Additional details about the event may be collected. 
8.4.2.1. 
Interruption of the Intravenous Infusion 
The infusion should be interrupted if any of the following AEs are observed: 
• Sustained/severe cough 
• Rigors/chills 
• Rash, pruritus (itching) 
• Urticaria (hives, welts, wheals) 
• Diaphoresis (sweating) 
• Hypotension 
• Dyspnea (shortness of breath) 
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• Vomiting 
• Flushing 
The reaction(s) should be treated symptomatically, and the infusion may be restarted at 50% of the 
original rate provided that the symptoms are adequately managed. 
If the investigator feels there is a medical need for treatment or discontinuation of the infusion 
other than described above, he/she should use clinical judgment to provide the appropriate 
response according to typical clinical practice. 
8.4.2.2. 
Termination of the Intravenous Infusion 
The infusion should be terminated and NOT restarted if any of the following AEs occur: 
• Anaphylaxis* 
• Laryngeal/pharyngeal edema 
• Severe bronchospasm 
• Chest pain 
• Seizure 
• Severe hypotension 
• Other neurological symptoms (confusion, loss of consciousness, paresthesia, 
paralysis, etc.) 
• Any other symptom or sign that, in the opinion of the investigator, warrants 
termination of the IV infusion 
*Consider anaphylaxis if the following is observed (Sampson, 2006):  acute onset of an illness 
(minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or ﬂushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE 
FOLLOWING:  
• Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
• Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
8.5. 
Method of Treatment Assignment 
On day 1, eligible patients will be randomized in a 1:1 ratio to receive: 
• Arm 1: Pozelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W  
• Arm 2: Pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W 
Randomization will be performed according to a central randomization scheme provided by an 
interactive web response system (IWRS) to the designated study pharmacist (or qualified 
designee). 
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8.6. 
Blinding 
This is an open-label study.  
8.7. 
Treatment Logistics and Accountability 
8.7.1. 
Packaging, Labeling, and Storage 
Open-label study drug will be packaged in cartons and will display the product lot number on the 
carton and vial label. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.7.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed / returned to the sponsor 
or designee.  
8.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
• Dispensed to each patient 
• Returned from each patient (if applicable), and 
• Disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.8. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent to the end of the post-treatment 
safety follow-up period will be considered concomitant medication.  This includes medications 
that were started before the study and are ongoing during the study. 
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8.8.1. 
Prohibited Medications and Procedures 
The following medications are prohibited, with the exception of those listed in Section 8.8.2, as 
described below: 
• Beginning on day 1 and continuing throughout the study, while the patient is 
receiving the study treatment, the patient should not take any other complement 
inhibitor therapy 
• Other investigational treatments during the course of the study 
• In addition, within 24 hours prior to each clinic visit when blood is drawn, the patient 
should not consume any alcohol and refrain from strenuous exercise if possible 
8.8.2. 
Permitted Medications and Procedures 
The following medications and procedures will be permitted, under the following conditions: 
• Any medication required to treat an AE, including systemic corticosteroids, at the 
discretion of the investigator  
• Meningococcal vaccination, as described in Section 8.2.1  
• Oral antibiotic prophylaxis as recommended, as described in Section 8.2.3  
• Oral contraceptives and hormone-replacement therapy may continue  
• Acetaminophen/paracetamol, aspirin, or ibuprofen at the recommended dose per the 
local prescribing information 
• Erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, 
anticoagulants, iron supplements, and folic acid are permitted and, if possible, should 
be kept constant throughout the study; any changes to these concomitant medications 
will be at the discretion of the investigator and consistent in the prior 26 weeks from 
enrollment. Any other medications may undergo dose adjustment or discontinuation at 
the discretion of the investigator.  
• Any other medication required for the treatment of patient’s background medical 
conditions 
8.9. 
Post-Trial Access to Study Treatment 
Post-trial access to pozelimab and cemdisiran will be provided until regulatory approval has been 
granted in the region the patient resides and consistent with sponsor guidelines. Such access to 
pozelimab and cemdisiran will be based on the request of the patient and investigator in line with 
local regulations, provided that the patient meets all post-trial access sponsor requirements. 
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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff.  Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized and deviations from planned study procedures due to COVID-19 
are to be documented as being related to COVID-19 and will remain in effect only for the duration 
of the public health emergency. 
Study assessments and procedures are presented by study period and visit. Study procedures, 
including sample collection for laboratory analysis, may be performed at the study clinic or at 
another location that is more convenient for the patient (including home visits), if this option is 
available and with sponsor approval. 
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Table 1: 
Schedule of Events (Open-Label Treatment Period) 
 
Screening 
Period 
Open-Label Treatment Period 3 
Study Procedure (Visit) 1 ,2 
Screening 
V1 
 
V24  
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
EOT5 
V13 
Week  
Up to -1 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
Day 
Up to -8 
1 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
Window (day) 
-- 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 -7/+3 -7/+3 
-7/+3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consents for OLEP, FBR, and genomics 
research (optional) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 7  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of vaccination for Neisseria 
meningitidis (or revaccination) 8  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea 9  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis 10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
x 
x 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1 only: Pozelimab 400 mg SC Q4W 11 
 
x12  
 
 
x 
 
x 
 
x 
x 
x 
x 
 
Arm 2 only: Pozelimab 400 mg SC Q2W 11 
 
x12 
 
x 
x 
x 
x 
x 
x 
x 
x 
x11 
 
Cemdisiran 200 mg SC Q4W 11 
 
x12 
 
 
x 
 
x 
 
x 
x 
x 
x 
 
Injection training/patient instructions (as needed) 13 
 
 
<---------------------------------------------x----------------------------------------> 
 
Patient diary 14  
x 15  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Antibiotics prophylaxis (recommended) 16 
<----------------------------------------------------------------x----------------------------------------------------------> 
Revaccination against meningococcal infection (if 
needed) 
<----------------------------------------------------------------x----------------------------------------------------------> 
Clinical Outcome Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue  
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
EORTC-QLQ-C30 
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
TSQM 
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH symptom-specific questionnaire (daily) 17 
<----------------------------------------------------------------x----------------------------------------------------------> 
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Screening 
Period 
Open-Label Treatment Period 3 
Study Procedure (Visit) 1 ,2 
Screening 
V1 
 
V24  
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
EOT5 
V13 
Week  
Up to -1 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
Day 
Up to -8 
1 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
Window (day) 
-- 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 -7/+3 -7/+3 
-7/+3 
PGIS 
 
x 
 
 
x 
 
 
 
x 
 
x 
 
x 
PGIC 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
Safety and Anthropometric: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
x 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
Electrocardiogram 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Breakthrough hemolysis assessment 18  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant meds/treatments 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transfusion record update 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Testing 19 : 
 
 
 
 
 
 
 
 
 
 
 
 
 
Titers to measure N. meningitidis (only if required per 
parent study) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (long panel) including LDH 20  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 21  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Immunoglobulin G 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Pregnancy test (WOCBP only): serum (S) or urine (U) 
s 
u 
 
 
u 
 
u 
 
u 
u 
u 
u 
u 
Urinalysis   
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Pharmacokinetics and Immunogenicity Sampling: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab conc. sample 22  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Cemdisiran and its metabolite conc. sample 23  
 
x 
 
 
x 
 
 
 
x  
 
 
x 
 
Pozelimab immunogenicity sample 24  
x 
 
  
 
  
 
 
 
x  
 
 
 
x 
Cemdisiran immunogenicity sample 24   
 
x 
 
 
  
 
 
 
x  
 
 
 
x 
Total C5 (plasma) 22  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free hemoglobin 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Haptoglobin 
x 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
Complement hemolytic assay (serum CH50) 25 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
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Screening 
Period 
Open-Label Treatment Period 3 
Study Procedure (Visit) 1 ,2 
Screening 
V1 
 
V24  
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
EOT5 
V13 
Week  
Up to -1 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
Day 
Up to -8 
1 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
Window (day) 
-- 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 -7/+3 -7/+3 
-7/+3 
Complement hemolytic assay (serum AH50) 25 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
sC5b-9 (plasma) 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH erythrocyte cells 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
PNH granulocyte cells 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
Optional research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and plasma for FBR (optional) 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
Whole blood sample for DNA isolation for genomics 
research (optional) 26  
 
x 
 
 
 
 
 
 
 
 
 
 
  
Whole blood RNA sample for genomics research 
(optional) 
 
x 
x 
 
 
 
 
 
 
 
 
 
x 
Footnotes for Table 1 (treatment period) are provided in Section 9.1.1.1. 
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Table 2: 
Schedule of Events for Patients on Intensified Treatment in the OLTP 
Study Procedure (Visit) 1 ,2 
Intensified Treatment Period in the OLTP 3 
RV1  
RV2 
RV3 
RV4 
RV5 
RV6 
RV7 
RV8 
RV9 
RV10 
RV11 
EOT 
RV12 
Week  
0r 
1r 
2r 
4r 
6r 
8r 
10r 
12r 
16r 5 
20r 5 
24r 5 
28r 6 
Day 
1r 
8r 
15r 
29r 
43r 
57r 
71r 
85r 
113r 
141r 
169r 
197r 
Window (day) 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Intensified Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab 30 mg/kg IV (loading dose) 4  
x7  
 
 
 
 
 
 
 
 
 
 
 
Pozelimab 400 mg SC Q2W 4 
x7 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 4 
 
Cemdisiran 200 mg SC Q4W 4 
x7 
 
 
x 
 
x 
 
x 
x 
x 
x 
 
Injection training/patient instructions (as needed) 8 
 
<---------------------------------------------------x------------------------------------------------> 
 
Patient diary 9  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Antibiotics prophylaxis (recommended) 10 
<----------------------------------------------------------------x--------------------------------------------------------> 
Revaccination against meningococcal infection (if 
needed) 
<----------------------------------------------------------------x--------------------------------------------------------> 
Clinical Outcome Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue  
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
EORTC-QLQ-C30 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
TSQM 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH symptom-specific questionnaire (daily) 11 
<----------------------------------------------------------------x--------------------------------------------------------> 
PGIS 
x 
 
 
x 
 
 
 
x 
 
x 
 
x 
PGIC 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
Safety and Anthropometric: 
 
 
 
 
 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis 12  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Body weight 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Breakthrough hemolysis assessment 13  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant meds/treatments 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transfusion record update 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Testing 14 : 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (long panel) including LDH 15  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
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Study Procedure (Visit) 1 ,2 
Intensified Treatment Period in the OLTP 3 
RV1  
RV2 
RV3 
RV4 
RV5 
RV6 
RV7 
RV8 
RV9 
RV10 
RV11 
EOT 
RV12 
Week  
0r 
1r 
2r 
4r 
6r 
8r 
10r 
12r 
16r 5 
20r 5 
24r 5 
28r 6 
Day 
1r 
8r 
15r 
29r 
43r 
57r 
71r 
85r 
113r 
141r 
169r 
197r 
Window (day) 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Hematology 16  
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Immunoglobulin G 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Pregnancy test (WOCBP only) 17  
u 
 
 
u 
 
u 
 
u 
u 
u 
u 
u 
Urinalysis   
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Pharmacokinetics and Immunogenicity Sampling: 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab drug conc. sample 18  
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Cemdisiran and its metabolite conc. sample 19  
x 
 
 
x 
 
 
 
x  
 
 
x 
 
Pozelimab immunogenicity sample 20  
x 
  
 
  
 
 
 
x  
 
 
 
x 
Cemdisiran immunogenicity sample 20 
x 
 
 
  
 
 
 
x  
 
 
 
x 
Total C5 (plasma) 18  
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
Free hemoglobin 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Haptoglobin 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
Complement hemolytic assay (serum CH50) 21 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Complement hemolytic assay (serum AH50) 21 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
sC5b-9 (plasma) 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH erythrocyte cells 
x 
 
 
 
 
x 
 
 
 
x 
 
x 
PNH granulocyte cells 
x 
 
 
 
 
x 
 
 
 
x 
 
x 
Footnotes for this table (patients on intensified treatment) can be found in Section 9.1.1.2  
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Table 3: 
Schedule of Events (Optional Open-Label Extension Period) 
Study Procedure (Visit) 1,2  
Optional Open-Label Extension Period 
OLEP-1 3  
OLEP-2 5 
OLEP-3 5 
OLEP-4 5 
OLEP-5 5 
OLEP-6 5 
OLEP-7 
Week  
0e 
8e 
16e 
24e 
32e 
40e 
52e 
Day 
1e 
57e 
113e 
169e 
225e 
281e 
365e 
Window (day) 
-- 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Treatment 4 :  
 
 
 
 
 
 
 
Pozelimab 400 mg SC Q2W or Q4W 5 
x 
x 
x 
x 
x 
x 
x 
Cemdisiran 200 mg SC Q4W 5 
x 
x 
x 
x 
x 
x 
x 
Injection training/patient instructions (as needed) 6 
<-----------------------------------------------------------x---------------------------------------------------------> 
Patient diary 7 
x 
x 
x 
x 
x 
x 
x 
Antibiotics prophylaxis (recommended) 8 
<-----------------------------------------------------------x---------------------------------------------------------> 
Revaccination against meningococcal infection (if 
needed) 
<-----------------------------------------------------------x---------------------------------------------------------> 
Clinical Outcome Assessments: 
 
 
 
 
 
 
 
FACIT-Fatigue  
x 
 
 
x 
 
 
x 
EORTC-QLQ-C30 
x 
 
 
x 
 
 
x 
PGIS 
x 
 
 
x 
 
 
x 
PGIC 
x 
 
 
x 
 
 
x 
Safety and Anthropometric: 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis 9 
x 
x 
x 
x 
x 
x 
x 
Body weight 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
x 
 
x 
 
x 
Electrocardiogram 
x 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
Breakthrough hemolysis assessment 10 
x 
x 
x 
x 
x 
x 
x 
Concomitant meds/treatments 
x 
x 
x 
x 
x 
x 
x 
Transfusion record update 
x 
x 
x 
x 
x 
x 
x 
Laboratory Testing 11 : 
 
 
 
 
 
 
 
Coagulation panel 
x 
x 
x 
x 
x 
x 
x 
Chemistry (long panel) including LDH 12 
x 
x 
x 
x 
x 
x 
x 
Hematology 13 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (WOCBP only) 14 
u 
u 
u 
u 
u 
u 
u 
Urinalysis   
x 
x 
x 
x 
x 
x 
x 
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Study Procedure (Visit) 1,2  
Optional Open-Label Extension Period 
OLEP-1 3  
OLEP-2 5 
OLEP-3 5 
OLEP-4 5 
OLEP-5 5 
OLEP-6 5 
OLEP-7 
Week  
0e 
8e 
16e 
24e 
32e 
40e 
52e 
Day 
1e 
57e 
113e 
169e 
225e 
281e 
365e 
Window (day) 
-- 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Pharmacokinetics and Immunogenicity: 
 
 
 
 
 
 
 
Pozelimab conc. sample 15 
x 
 
 
x 
 
 
x 
Cemdisiran and its metabolite conc. samples 16   
(pre-dose and 2 to 6 hours post-dose) 
x 
 
 
x 
 
 
x 
Pozelimab immunogenicity sample 17  
x 
  
 
x 
 
 
x 
Cemdisiran immunogenicity sample 17 
x 
 
 
x 
 
 
x 
Total C5 (plasma) 15 
x 
 
 
x 
 
 
x 
Biomarkers: 
 
 
 
 
 
 
 
Free hemoglobin 
x 
 
 
 
 
 
x 
Haptoglobin 
x 
 
 
 
 
 
x 
Complement hemolytic assay (serum CH50) 18  
x 
 
x 
 
x 
 
x 
Complement hemolytic assay (serum AH50) 18 
x 
 
x 
 
x 
 
x 
sC5b-9 (plasma) 
x 
 
x 
 
x 
 
x 
PNH erythrocyte cells 
x 
 
 
x 
 
 
x 
PNH granulocyte cells 
x 
 
 
x 
 
 
x 
Optional research: 
 
 
 
 
 
 
 
Serum and plasma for FBR (optional) 
x 
 
 
 
 
 
x 
Whole blood RNA sample for genomics research 
(optional) 
x 
 
 
 
 
 
x 
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Table 4: 
Schedule of Events (Post-Treatment Safety Follow-Up Period) 
 
Post-Treatment Safety Follow-Up Period 
Patients in the OLTP who discontinue study 
treatment will be asked to remain in the study 
until week 28 EOT (or week 28r for patients who 
restarted on intensified treatment) and follow the 
original schedule of events as applicable. After 
the week 28 EOT visit, their entry point into the 
safety follow-up schedule will depend on the 
number of weeks that have elapsed since their 
last dose (ie, a patient who is 20 weeks after their 
final dose of study treatment at EOT will enter 
into the safety follow-up period at visit FU-4 
[26 weeks after last dose]) 
Patients who completed 
week 28 (with last doses 
administered at week 24 or 
week 26, or week 26r) who 
choose not to continue 
treatment in the OLEP, 
patients who complete the 
OLEP, and patients who 
permanently discontinue 
treatment during the OLEP 
will start here: 
 
 
 
 
 
Study Procedure 
FU-1 
FU-2 
FU-3 
FU-4 
Phone visit  
FU-5 
Phone visit  
FU-6 
Week (after last dose of study drug) 
8 
12 
16 
26 
38 
52 
Day (after last dose of study drug) 
57 
85 
113 
183 
267 
365 
Window (day) 
±10 
±10 
±10 
±10 
±10 
±10 
Safety Assessments 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis1 
<----------------------------------------------------------------X----------------------------------------------------> 
Antibiotics prophylaxis (recommended)2 
<----------------------------------------------------------------X----------------------------------------------------> 
Vital signs 
x 
x 
x 
x 
 
 
Physical examination  
 
x 
 
x 
 
 
Concomitant meds and procedures 
x 
x 
x 
x 
x 
x 
Adverse event reporting 
x 
x 
x 
x 
x 
x 
Pregnancy reporting 
x 
x 
x 
x 
x 
x 
Laboratory Testing 
 
 
 
 
 
 
Hematology 
x 
x 
x 
x 
 
 
Blood chemistry 
x 
x 
x 
x 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events Tables 
9.1.1.1. 
Table 1 Schedule of Events (Treatment Period) 
1. Visits between week 6 and up to week 24 may be at the clinical site, or another preferred 
location, such as patient’s home. The location will be dependent on availability of home 
healthcare visiting professional as well as the preferences of the investigator and patient. 
In the event of travel restrictions due to a global pandemic, alternative mechanisms such 
as but not limited to telemedicine visits may be implemented to maintain continuity of 
study conduct. 
2. When multiple procedures are performed on the same day, the sequence of procedures is 
as follows: COAs → ECG → vital signs, physical examination, safety monitoring, lab 
collection → study treatment administration → any pre-specified post-dose sample 
collection. 
3. Patients who are restarted on an intensified treatment will undergo an adjustment to their 
scheduled visits.  Patients may require unscheduled visit(s) as needed and should be 
subsequently followed per Table 2  
4. The day 1 visit should take place 7 to 8 days after the screening visit. Patients may be 
rescreened if they cannot schedule the screening visit and the day 1 visit over a period of 
7 to 8 days. 
5. If the patient agrees to continue into the optional OLEP, the EOT visit of the OLTP will 
correspond to the day 1e visit of the OLEP (see Table 3). Any common assessments will 
be performed once for both visits.  
6. Transfusions, breakthrough hemolysis history, and laboratory parameters for measurement 
of hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) 
should be obtained for the past 52 weeks, if possible.  Prior history of thrombosis and 
Neisseria infections will be collected.  Ongoing PNH symptoms and signs will also be 
collected. Information collected from parent studies may be used whenever possible. 
7. Including pozelimab administration. 
8. Patients will have had previous documented vaccination for meningococcus (serotypes A, 
C, Y, W and serotype B if available) in the Regeneron-sponsored parent study, but may be 
revaccinated if prior vaccination is more than 5 years from screening. Alternatively, 
patients may be revaccinated in accordance with current national vaccination guidelines 
for vaccination use with complement inhibitors or local practice. Patients who require 
revaccination may be rescreened. 
9. A risk factor assessment for Neisseria gonorrhea infection is recommended, and 
counseling is advised for at-risk patients.  
10. A patient safety card will be distributed to patients at screening and risk information will 
be reviewed. Replacement cards may be given to the patient as needed. 
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11. During OLTP, the dose of cemdisiran and pozelimab SC should be given on the day of the 
corresponding study visit whenever possible. Study treatment administration should 
always be the last procedure after all blood sample collection and study assessments have 
been completed unless otherwise specified.  
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 3 days before or up to 3 days 
after the planned dosing date for Q2W dosing, provided that the combination dosing 
takes place after the corresponding study visit has been completed. For patients 
receiving pozelimab 400 mg SC Q2W + cemdisiran 200 mg SC Q4W, the dosing 
window (±3 days) is the same or narrower than the visit window (±3 days before 
week 16 or -7/+3 days on and after week 16).  
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 7 days before or 7 days after 
the planned dosing date for Q4W dosing, provided that the combination dosing takes 
place after the corresponding study visit has been completed. For patients receiving 
pozelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W, the visit window (±3 days 
before week 16 or -7/+3 days starting from week 16) is narrower than the dosing 
window (±7 days).  
Care must be taken to coordinate dosing for visits where a post-dose sample is collected to 
measure the concentration of cemdisiran and its metabolites. The final SC dosing of the 
combination (pozelimab and cemdisiran) during the OLTP is at week 24 for arm 1 and the 
final SC dosing of cemdisiran is at week 24 with pozelimab at week 26 for arm 2.  
12. Patients should be monitored for at least 30 minutes after completing the first cemdisiran 
injection. A 30 minute monitoring period is not needed after the pozelimab injection. 
13. Injection training will be provided to patients who desire self-injection or injection by a 
designated person.  Site should observe patient self-injection or injection by a designated 
person and confirm adequacy.  Patient instruction materials will be provided. SC injections 
may either be performed by the site personnel or another healthcare professional at the 
patient’s home or preferred location, or be administered by the patient or a designated 
person who has successfully completed the injection training. 
14. If study treatment is given by the patient or by a designated person, the patient will 
complete a diary for recording compliance with study treatment administration. If patient 
diary is provided to the patient, then it should be reviewed at each clinic visit and data 
collected into the case report forms (CRFs). On the final visit, the diary should be collected 
by the site. 
15. At the screening visit, patient diary should be reviewed for the R3918-PNH-1868 (parent) 
study. 
16. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting 
on the first day of dosing with study treatment and continuing until 52 weeks after 
discontinuation of study treatment.  
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17. Patient will complete daily PNH Symptom-Specific Questionnaire for 7 consecutive days 
prior to day 1 visit. Patients should try to complete the PNH Symptom-Specific 
Questionnaire at the same time each day whenever possible. 
18. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
will be collected as described for suspected breakthrough hemolysis assessment in 
Section 9.2.5.2 unless already noted in the schedule of events for that visit.  If the suspected 
event does not occur at a scheduled visit then an unscheduled visit should occur with an 
evaluation of the patient and collection of samples for suspected breakthrough hemolysis 
assessment as described in Section 9.2.5.2.  
19. Clinical lab samples will be collected prior to any study drug administration (pre-dose) 
unless otherwise specified. The same methodology will be applied across study visits for 
lab sample collection, handling and processing, as best as possible, to preserve the quality 
of samples and minimize hemolysis. The coagulation blood sample (tube) must always be 
collected first, followed by the blood chemistry sample (tube). 
20. Serum LDH, C-reactive protein (CRP), and bilirubin (total and direct) will be assessed as 
part of the blood chemistry analysis. Blood chemistry sample should be collected before 
study treatment administration (pre-dose). During lab collection, handling and processing, 
the same methodology will be applied across study visits, as best as possible, to preserve 
the quality of sample and avoid hemolysis during sample processing. If the investigator or 
sponsor suspects that the lab result is not an accurate reflection of the patient’s condition, 
the lab sample should be repeated. 
21. Hematology sample should be collected before study treatment administration (pre-dose). 
22. Blood samples for pozelimab concentration analysis and total C5 analysis will be 
obtained on the specified days prior to any study treatment administration (pre-dose).   
23. Blood samples for cemdisiran concentration analysis and concentrations of its metabolites 
will be collected on the specified days prior to any study treatment administration (pre-
dose) and 2 to 6 hours post cemdisiran administration. The post-dose sample should be 
carefully coordinated with the dosing of cemdisiran and may be collected at the clinic or 
by a visiting health care professional.  
24. Blood samples for immunogenicity will be collected on the specified days prior to any 
study treatment administration (pre-dose).  At the visits where immunogenicity samples 
are to be taken, the sample should be collected with the sample for drug concentration. In 
the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, 
additional samples for drug concentration and immunogenicity may be collected at or near 
the onset and the resolution of the event. 
25. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study 
treatment administration (pre-dose).   
26. Whole blood samples for DNA extraction (optional) should be collected on day 1 (pre-
dose) but can be collected at a later study visit. Patients who had consented to DNA testing 
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in a prior Regeneron study with pozelimab and had provided a sample for analysis do not 
need to provide separate consent/sample for this study 
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9.1.1.2. 
Table 2 Schedule of Events (for Patients on Intensified Treatment) 
1. Visits between week 6r and week 24r may be at the clinical site, or another preferred 
location, such as patient’s home. The location will be dependent on availability of home 
healthcare visiting professional as well as the preferences of the investigator and patient. 
In the event of travel restrictions due to a global pandemic, alternative mechanisms such 
as but not limited to telemedicine visits may be implemented to maintain continuity of 
study conduct. 
2. When multiple procedures are performed on the same day, the sequence of procedures is 
as follows: COAs → ECG → vital signs, physical examination, safety monitoring, lab 
collection → study drug administration → any pre-specified post-dose sample collection. 
3. The intensified treatment schedule will be anchored to the day of intensification (ie, a reset 
occurs with the day of intensification becoming the day 1r visit and subsequent visits 
following the schedule of events for intensified treatment). Patients who receive intensified 
treatment will be considered to have complete the study once they finish the 28-week 
treatment period with the intensified treatment (ie, after completing week 28r EOT 
assessments). 
4. During the intensified treatment period in the OLTP, the dose of cemdisiran and pozelimab 
SC should be given on the day of the corresponding study visit whenever possible. Study 
treatment administration should always be the last procedure after all blood sample 
collection and study assessments have been completed unless otherwise specified.  If 
pozelimab or cemdisiran cannot be administered on the day of the corresponding study 
visit, the combination may be administered up to 3 days before or up to 3 days after 
the planned dosing date provided that the dosing takes place after the corresponding study 
visit has been completed. For example, the day 29r (week 4r) visit can take place from day 
26r to day 32r given the visit window of ±3 days for the week 4r visit. The dose of 
pozelimab and cemdisiran therefore can be given from day 26r to day 32r, but only on or 
after the week 4r visit assessments have been performed. Similarly, the day 113r (week 
16r) visit can take place from day 106r to day 116r given the visit window of -7/+3 days 
for the week 16r visit. The dose of pozelimab and cemdisiran can be given from day 110r 
to day 116r, but only on or after the week 16r visit assessments have been performed. Care 
must be taken to coordinate dosing for visits where a post-dose sample is collected to 
measure concentration of cemdisiran and its metabolites. For patients on intensified 
treatment in the OLTP, the final SC dose of cemdisiran is at week 24r and the final SC 
dose of pozelimab is at week 26r.  
5. For these visits, the dosing window (±3 days) is narrower than the study visit window 
(-7/+3 days). 
6. If the patient agrees to continue into the optional OLEP, the EOT visit of the OLTP will 
correspond to the day 1e visit of the OLEP (see Table 3). Any common assessments will 
be performed once for both visits. 
7. On day 1r, pozelimab IV will be given first, with a 30-minute observation period before 
administration of SC doses. Subsequent pozelimab SC dose will be administered Q2W and 
cemdisiran SC dose will be administered Q4W. The SC injections may either be performed 
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by the site personnel or another healthcare professional at patient’s home or preferred 
location, or be administered by the patient or by a designated person who has successfully 
completed the injection training. 
8. Injection training will be provided to patients who desire self-injection or injection by a 
designated person.  Site should observe patient self-injection or injection by a designated 
person and confirm adequacy.  Patient instruction materials will be provided. 
9. If study treatment is given by the patient or by a designated person, the patient will 
complete a diary for recording compliance with study treatment administration. If patient 
diary is provided to the patient, then it should be reviewed at each clinic visit and data 
collected into the CRFs. On the final visit, the diary should be collected by the site. 
10. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended until 
52 weeks after discontinuation of study treatment. 
11. Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time 
each day whenever possible. 
12. Patient safety card: Site should review the instructions on the safety card with the patient 
at each visit. Replacement cards may be given to the patient as needed. 
13. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
for drug concentrations of pozelimab will be collected unless already noted in the schedule 
of events for that visit.  If the suspected event does not occur at a scheduled visit then an 
unscheduled visit should occur with an evaluation of the patient and collection of 
coagulation, chemistry, and drug concentrations of pozelimab. 
14. Clinical lab samples will be collected prior to any study drug administration (pre-dose) 
unless otherwise specified. During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis. The coagulation blood sample (tube) must always be 
collected first, followed by the blood chemistry sample (tube). 
15. Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood 
chemistry analysis. Blood chemistry sample should be collected before study treatment 
administration (pre-dose). During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis during sample processing. If the investigator or sponsor 
suspects that the lab result is not an accurate reflection of the patient’s condition, the lab 
sample should be repeated. 
16. Hematology sample should be collected before study treatment administration (pre-dose). 
17. Pregnancy test for WOCBP: A urine test will be done at all visits indicated. Any positive 
urine pregnancy test should be confirmed with a serum pregnancy test. 
18. On day 1r, obtain blood sample for pozelimab concentration and total C5 prior to IV 
administration of pozelimab and also within 15 minutes after the end of the IV infusion. At 
subsequent timepoints, blood samples for pozelimab drug concentration analysis and total 
C5 analysis will be obtained prior to any study treatment administration (pre-dose). 
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19. Blood samples for cemdisiran drug concentration analysis and concentrations of its 
metabolites will be collected on the specified days prior to any study treatment 
administration (pre-dose) and 2 to 6 hours post cemdisiran administration. The post-dose 
sample should be carefully coordinated with the dosing of cemdisiran and may be collected 
at the clinic or by a visiting health care professional. 
20. Blood samples for immunogenicity will be collected on the specified days prior to any 
study treatment administration (pre-dose).  At the visits where immunogenicity samples 
are to be taken, the sample should be collected with the sample for drug concentration. In 
the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, 
additional samples for drug concentration and immunogenicity may be collected at or near 
the onset and the resolution of the event. 
21. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study 
treatment administration (pre-dose). 
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9.1.1.3. 
Table 3 Schedule of Events (for Open-Label Extension Period) 
1. Visits may be at the clinical site or another preferred location, such as the patient’s home. 
The location will depend on availability of home healthcare visiting professional as well 
as the preferences of the investigator and patient. In the event of travel restrictions due to 
a global pandemic, alternative mechanisms such as but not limited to telemedicine visits 
may be implemented to maintain continuity of study conduct. 
2. When multiple procedures are performed on the same day, the sequence of procedures is 
as follows: COAs → ECG → vital signs, physical examination, safety monitoring, lab 
collection → study drug administration → any pre-specified post-dose sample collection. 
3. Day 1e of OLEP should be scheduled on the same day as week 28 (or week 28r for patients 
on intensified treatment) of the OLTP, and any common assessments will be performed 
once for both the OLTP and OLEP visits. 
4. For patients who did not receive intensified treatment during OLTP: At any time during 
the OLEP, patients who meet pre-specified criteria will receive intensified treatment 
consisting of a pozelimab 30 mg/kg IV loading dose followed 30 minutes later by the 
initiation of pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W. Patients should 
be observed for 30 minutes in the interim between the IV and SC doses. Patients will 
continue their visit schedule at the next OLEP visit. 
5. During the OLEP, the dose of cemdisiran and pozelimab SC should be given on the day of 
the corresponding study visit whenever possible. Study treatment administration should 
always be the last procedure after all blood sample collection and study assessments have 
been completed unless otherwise specified: 
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 3 days before or up to 3 days 
after the planned dosing date, provided that the combination dosing takes place after 
the corresponding study visit has been completed. For patients receiving pozelimab 
400 mg SC Q2W + cemdisiran 200 mg SC Q4W, the dosing window (±3 days) is 
narrower than the visit window (-7/+3 days).  
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 7 days before or 7 days after 
the planned dosing date, provided that the combination dosing takes place after the 
corresponding study visit has been completed. For patients receiving pozelimab 
400 mg SC Q4W + cemdisiran 200 mg SC Q4W, the visit window (-7/+3 days) is 
narrower than the dosing window (±7 days).  
Care must be taken to coordinate dosing for visits where a post-dose sample is collected to 
measure concentration of cemdisiran and its metabolites. For patients whose treatment is 
not intensified during the OLEP, the last doses of cemdisiran and pozelimab are 
administered at week 52e. For patients whose treatment was intensified during the OLEP, 
the last doses of study treatment will be determined based on the time of treatment 
intensification. 
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6. Injection training will be provided to patients who desire self-injection or injection by a 
designated person.  Site should observe patient self-injection or injection by a designated 
person and confirm adequacy.  Patient instruction materials will be provided. 
7. If study treatment is given by the patient or by a designated person, the patient will 
complete a diary for recording compliance with study treatment administration. If patient 
diary is provided to the patient, then it should be reviewed at each clinic visit and data 
collected into the CRFs. On the final visit, the diary should be collected by the site. 
8. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended until 
52 weeks after discontinuation of study treatment. 
9. Patient safety card: Site should review the instructions on the safety card with the patient 
at each visit. Replacement cards may be given to the patient as needed. 
10. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
for drug concentrations of pozelimab will be collected unless already noted in the schedule 
of events for that visit.  If the suspected event does not occur at a scheduled visit then an 
unscheduled visit should occur with an evaluation of the patient and collection of 
coagulation, chemistry, and drug concentration of pozelimab. 
11. Clinical lab samples will be collected prior to any study drug administration (pre-dose) 
unless otherwise specified. During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis. The coagulation blood sample (tube) must always be 
collected first, followed by the blood chemistry sample (tube). 
12. Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood 
chemistry analysis. Blood chemistry sample should be collected before study treatment 
administration (pre-dose). During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis during sample processing. If the investigator or sponsor 
suspects that the lab result is not an accurate reflection of the patient’s condition, the lab 
sample should be repeated. 
13. Hematology sample should be collected before study treatment administration (pre-dose). 
14. Pregnancy test for WOCBP: A urine test will be done at all visits indicated. Any positive 
urine pregnancy test should be confirmed with a serum pregnancy test. 
15. Blood samples for pozelimab concentration analysis and total C5 analysis will be 
obtained on the specified days prior to any study treatment administration (pre-dose). 
16. Blood samples for cemdisiran concentration analysis and concentrations of its metabolites 
will be collected on the specified days prior to any study treatment administration (pre-
dose) and 2 to 6 hours post cemdisiran administration. The post-dose sample should be 
carefully coordinated with the dosing of cemdisiran and may be collected at the clinic or 
by a visiting health care professional. 
17. Blood samples for immunogenicity will be collected on the specified days prior to any 
study treatment administration (pre-dose).  At the visits where immunogenicity samples 
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are to be taken, the sample should be collected with the drug concentration sample. In the 
event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, 
additional drug concentration and immunogenicity samples may be collected at or near the 
onset and the resolution of the event. 
18. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any 
study treatment administration (pre-dose). 
9.1.1.4. 
Table 4 Schedule of Events (Post-Treatment Safety Follow-Up Period) 
1. Patient safety card: Site should review the instructions on the safety card with the patient 
at each visit. Replacement cards may be given to the patient as needed. 
2. Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks 
after discontinuation of study treatment. 
9.1.2. 
Early Termination Visit 
During the OLTP (or intensified OLTP), patients who prematurely discontinue from study 
treatment who are withdrawn from the study will be asked to return to the clinic:  once for an ET 
visit consisting of week 28 EOT assessments described in Table 1. 
During the optional OLEP, patients who prematurely discontinue from study treatment who also 
withdraw from the study will be asked to return to the clinic once for an ET visit consisting of 
week 52e assessments described in Table 3. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal/uninterpretable laboratory results, for follow-up of 
AEs, to evaluate events of breakthrough hemolysis (Section 6.2), to provide intensified treatment 
(Section 8.3.2), or for any other reason, as warranted. In the event of suspected treatment-related 
SAEs, such as anaphylaxis or hypersensitivity, additional drug concentration and immunogenicity 
samples may be collected at or near the onset and the resolution of the event. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:   
• Informed consent (including optional sub-studies) 
• Medical history, including disease characteristics  
• Prior medications 
• Demographics 
• Height 
• Documentation of meningococcal vaccination or revaccination (Section 8.2.1) 
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• Patient safety card for meningococcal infection (Section 8.2.2): This card will be 
provided to the patient at baseline. At subsequent visits, risk information will be 
reviewed and replacement cards may be given to the patient as needed. 
• Sample to assess FSH (to determine postmenopausal status, if applicable; 
Section 7.2.2) 
• Risk assessment for N. gonorrhea (Section 8.2.4) 
Additionally, the following procedures may be performed for the parent study (R3918-PNH-
1868): 
• Titers to measure N. meningitidis (if required per parent study) 
• Review patient diary for the parent study 
• Other study procedures required per the parent study. Assessments that are common to 
both study protocols (R3918-PNH-1868 and R3918-PNH-2092) should not be 
duplicated during the screening visit for this study. Dosing for the parent study should 
be performed last, after all other screening and parent study visit procedures have been 
completed for both study protocols 
Additional details about the timing and conduct of the screening visit is provided in Section 6.1.1. 
At the discretion of the investigator, additional visits during the screening period may be scheduled 
as needed to complete screening procedures. Patients may be rescreened up to 2 times after 
discussion between the investigator and the sponsor. 
The day 1 dosing visit should occur 7 to 8 days after the last dose in the parent study.  
9.2.2. 
Study Treatment 
Study treatment administration is the last procedure at any visit and should be performed after all 
other study procedures for the visit have been completed, with the exception of any prespecified 
post-dose assessments or blood sample collection. Study drug supply will be managed through the 
IWRS as needed. 
Study drugs will be administered starting from day 1 based on the patient’s assigned dosing 
regimen. Details are described in Section 8.1.  
It is recommended that patients begin daily oral antibiotic prophylaxis starting from day 1 
(Section 8.2.3). 
Starting from day 1, injection training may be provided to patients or caregivers if this option is 
available (Section 8.1). A patient diary will be provided to record study drug administration for 
patients who opt to self-administer. The diary will be reviewed at each visit for treatment 
compliance. 
For patients who opt to continue study treatment in the OLEP, patients whose treatment was not 
intensified during the main study period will transition to the OLEP on a regimen of pozelimab 
400 mg SC Q4W and cemdisiran 200 mg SC Q4W, regardless of their treatment assignment in the 
main treatment period. Patients whose treatment was intensified during the main study period will 
transition to the OLEP and continue on the intensified treatment regimen of pozelimab 400 mg SC 
Q2W and cemdisiran 200 mg SC Q4W. 
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Procedures related to study treatment are described in Table 1 (OLTP), Table 2 (patients on 
intensified treatment in OLTP), and Table 3 (optional OLEP). 
9.2.3. 
Clinical Outcome Assessments 
The following COAs are self-reported and will be completed by the patient at time points 
according to in Table 1 (OLTP) and Table 2 (patients on intensified treatment in OLTP), and 
Table 3 (optional OLEP).  
9.2.3.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
The FACIT-Fatigue is a 13-item, self-administered COA assessing an individual’s level of fatigue 
during their usual daily activities over the past week. This questionnaire is part of the FACIT 
measurement system, a compilation of questions measuring health-related QoL in patients with 
cancer and other chronic illnesses. The FACIT-Fatigue assesses the level of fatigue using a 5-point 
Likert scale ranging from 0 (not at all) to 4 (very much). Scores range from 0 to 52, with higher 
scores indicating a higher quality of life. Although the FACIT-Fatigue was originally developed 
to assess fatigue in patients with cancer, it has been used in trials evaluating the efficacy of 
eculizumab (Brodsky, 2008) (Hillmen, 2006). The FACIT-Fatigue has demonstrated content 
validity among patients with PNH (Weitz, 2013). 
9.2.3.2. 
European Organization for the Research and Treatment of Cancer: Quality of 
Life of Cancer Patients Questionnaire-30 (EORTC-QLQ-C30) 
The EORTC-QLQ-C30 is a 30-item, self-administered, generic questionnaire commonly used to 
assess 
HRQoL 
in 
patients 
with 
cancer 
(Stead, 
1999) 
(Cocks, 
2007). 
The 
EORTC-QLQ-C30 assesses health-related QoL across multiple domains, including global health 
status, global QoL, functioning (physical, role, emotional, cognitive, and social functioning), 
symptom scales (fatigue, nausea and vomiting, pain, appetite loss), and single items (dyspnea, 
insomnia, constipation, diarrhea, sleep, financial impact). Although the EORTC-QLQ-30 was 
originally developed to assess health-related QoL in patients with cancer, it has been used in trials 
evaluating the efficacy of eculizumab (Brodsky, 2008) (Hillmen, 2006). The EORTC-QLQ-C30 
also has demonstrated content validity among patients with PNH (Weitz, 2013). 
9.2.3.3. 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
The TSQM is a generic measure that assesses patients’ satisfaction with their medication 
(Atkinson, 2004) (Atkinson, 2005). The TSQM is an 9-question, self-administered COA measure 
which assesses 3 domains of satisfaction: effectiveness (3 items), convenience (3 items), and 
global satisfaction (3 items). For each question, the patient rates his/her satisfaction either on a 
7-point Likert scale (ranging from extremely dissatisfied to extremely satisfied) or a 5-point Likert 
scale (ranging from extremely dissatisfied to not dissatisfied at all), with higher scores representing 
greater satisfaction. The instrument was developed using patient input and has evidence of 
psychometric validity. 
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9.2.3.4. 
PNH Symptom-Specific Questionnaire 
The PNH symptom-specific questionnaire is self-administered and will collect daily information 
on PNH symptoms including: fatigue, shortness of breath, muscle weakness, headache, abdominal 
pain, pain in back/legs, chest discomfort, difficulty sleeping, difficulty thinking clearly, and 
difficulty swallowing. The instrument was developed by conducting a literature review, consulting 
with clinical expert input, and through patient interviews assessing comprehensiveness of 
symptoms collected and the patient’s ability to read, understand, and respond to the questionnaire. 
The questionnaire was developed in accordance with regulatory guidelines (FDA, 2009) and 
scientific best practices (Patrick, 2011). 
Patients should try to complete the PNH symptom specific questionnaire at the same time each 
day whenever possible. 
9.2.3.5. 
Patient Global Impression of Severity (PGIS)/Patient Global Impression of 
Change (PGIC) 
The PGIS consists of 3 self-administered COA questions assessing the patient’s perception of the 
overall severity of the symptoms of their disease and/or of a specific symptom of their disease. At 
study visits, patients will be asked to rate the severity of their PNH symptoms on a 6-point Likert 
scale ranging from “I am not experiencing PNH symptoms” to “very severe;” the impact their 
PNH symptoms have on their ability to perform usual daily activities on a 5-point Likert scale 
ranging from “not at all impacted” to “extremely impacted;” and their overall fatigue on a 5-point 
Likert scale ranging from “not fatigued” to “extremely fatigued.” 
The PGIC consists of 3 self-administered COA questions assessing the patient’s perception of the 
change in overall severity of the symptoms of their disease and/or of a specific symptom of their 
disease compared to the start of the study. At key time points during the study, patients will be 
asked to rate the change in PNH symptoms, in their ability to perform usual daily activities, and in 
overall fatigue compared to before the start of the study on a 7-point Likert scale ranging from 
“much better” to “no change” to “much worse.” 
The PGIS and PGIC questions are developed for this trial, and allow for the interpretation of 
COA findings and the investigation of a responder definition. The answers on the PGIS and 
PGIC items serve as “anchors” to help interpret the mean change in disease-specific COA 
measures over time and to estimate responder definitions. This empirical anchor-based approach 
is the primary FDA-recommended approach for defining a responder and analyzing 
responder-based COA results. 
9.2.4. 
Safety and Anthropometric Procedures 
9.2.4.1. 
Body Weight 
Body weight will be assessed at time points specified in Table 1 (OLTP) and Table 2 (patients on 
intensified treatment in OLTP), Table 3 (optional OLEP). Patients should void (empty bladder) 
prior to weight assessment. Patients should be wearing undergarments or very light clothing and 
no shoes during weight assessments. If possible, the same type/model of scale should be used 
throughout the study. 
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9.2.4.2. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, and pulse rate, will be collected predose 
at time points according to Table 1 (OLTP), Table 2 (patients on intensified treatment in OLTP), 
Table 3 (optional OLEP), and Table 4 (safety follow-up period). 
Vital signs will be obtained after patient has been in the sitting position quietly for at least 
approximately 5 minutes.   
9.2.4.3. 
Physical Examination 
A physical examination will be performed at time points according to Table 1 (OLTP), Table 2 
(patients on intensified treatment in OLTP),Table 3 (optional OLEP), and Table 4 (safety follow-
up period).  Each physical examination will include an evaluation of the head and neck, lungs, 
heart, abdomen, extremities, and skin.  Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history. 
9.2.4.4. 
Electrocardiogram 
Electrocardiograms should be performed before blood is drawn during visits requiring blood 
draws.  A standard 12-lead ECG will be performed at time points according to Table 1 (OLTP), 
Table 2 (patients on intensified treatment in OLTP), and Table 3 (optional OLEP).  
Twelve-lead ECGs will be systematically recorded after the patient has been in the semi-recumbent 
position for at least 10 minutes.  
The ECG will be interpreted locally by the investigator. Any new and/or clinically significant 
changes in ECG parameters should be immediately rechecked for confirmation before making any 
decision for the concerned patient.  
Heart rate will be recorded from the ventricular rate, and the PR, QRS, QT intervals, and QTcF 
will be recorded. The ECG strips or reports will be retained with the source. 
9.2.4.5. 
Blood Transfusion 
Transfusions with RBCs during the study should proceed according to the predefined criteria in 
Section 6.3. Any blood transfusion will be captured in the transfusion record CRF at every visit 
according to Table 1 (OLTP), Table 2 (patients on intensified treatment in OLTP),Table 3 
(optional OLEP), and Table 4 (safety follow-up period). Hemoglobin levels pre- and 
post-transfusion will be obtained (including local values). 
9.2.4.6. 
Safety Monitoring 
At every visit, AEs will be collected and assessed as described in Section 10. Unscheduled visits 
may be scheduled to collect blood samples as part of safety monitoring (Section 9.1.3). 
In addition, at each visit during the OLTP (Table 1) or intensified treatment period in the OLTP 
(Table 3) or OLEP (Table 2), changes to concomitant medications or procedures will be recorded 
(Section 8.8).  
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During the safety follow-up period, AEs and events of pregnancy will be monitored. Other safety 
assessments for the follow-up period (eg, vital signs, physical examination, concomitant 
medications, and laboratory evaluation) are described in Table 4. 
9.2.5. 
Laboratory Testing 
9.2.5.1. 
Laboratory Assessments of Efficacy 
9.2.5.1.1. Lactate Dehydrogenase  
Samples for LDH testing are collected as part of the blood chemistry panel (Section 9.2.5.2) and 
will be collected prior to dosing of the combination at visits according to Table 1 (OLTP), Table 2 
(patients on intensified treatment in OLTP), and Table 3 (optional OLEP). 
Care must be taken with the collection of LDH as it is the primary endpoint in the study. During 
blood collection, the same methodology should be applied across all visits, as best as possible. 
Every precaution should be taken to avoid hemolysis. The coagulation blood must always be 
collected before the chemistry panel blood sample.  Detailed instructions are provided in the 
study-related documents provided to the study site and should be reviewed prior to each collection. 
9.2.5.1.2. Hemoglobin 
Samples for hemoglobin testing are collected as part of the hematology panel (Section 9.2.5.2) and 
will be collected prior to dosing of the combination at visits according to Table 1 (OLTP), Table 2 
(patients on intensified treatment in OLTP), Table 3 (optional OLEP). 
9.2.5.1.3. CH50  
Samples for CH50 testing will be collected prior to dosing of the combination at visits according 
to Table 1 (OLTP), Table 2 (patients on intensified treatment in OLTP), and Table 3 (optional 
OLEP). 
9.2.5.2. 
Safety and Other Laboratory Assessments 
Samples for laboratory testing will be collected at visits according to Table 1 (OLTP), Table 2 
(patients on intensified treatment in OLTP), Table 3 (optional OLEP), and Table 4 (safety follow-
up period). The coagulation blood sample (tube) must always be collected first, followed by the 
blood chemistry sample (tube). 
Hematology, chemistry (except total C5, CH50 and sC5b-9), and urinalysis are planned to be 
analyzed by a central laboratory. Local laboratory may be acceptable in special circumstances (eg, 
for eligibility) after discussion and agreement from the sponsor. Pregnancy testing may be 
performed at a central or a local laboratory. Other testing will be done by a central or specialized 
laboratory as outlined in the laboratory manual. Tests will include: 
Coagulation Panel 
Prothrombin time 
 
 
Activated partial thromboplastin time (APTT) 
 
 
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Blood Chemistry 
Sodium 
Total protein, serum 
Bilirubin* 
Potassium 
Creatinine** 
Uric acid 
Chloride 
Blood urea nitrogen/blood urea 
C-reactive protein (CRP) 
Carbon dioxide/bicarbonate 
Aspartate aminotransferase (AST) 
Magnesium 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
  * Obtain total, direct and indirect bilirubin 
** In addition, the estimated glomerular filtration rate will be calculated with the CKD-EPI equation (Levey, 2009) 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBC) 
 
Lymphocytes 
White blood cells (WBC) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Reticulocytes 
 
Urinalysis 
pH 
Protein 
Leukocyte esterase  
Urobilinogen 
Specific gravity 
Glucose 
Nitrite 
Ketones 
Bilirubin 
Blood 
Note: If macroscopy (urine dipstick) is abnormal, urine microscopy will be performed. A urine culture should be 
performed if there is a clinical suspicion of infection, per investigator judgment. 
Other Laboratory Tests 
Other laboratory tests include:  
• Screening samples collected for the determination of eligibility (Section 9.2.1) 
• Immunoglobulin G (IgG) will be assessed at the timepoints specified in the schedule 
of events (Section 9.1) 
• Pregnancy testing (WOCBP only): serum human chorionic gonadotrophin pregnancy 
testing, urine pregnancy testing.  Any positive urine pregnancy test will be confirmed 
with a serum test.  
Note: Postmenopausal women must be amenorrheic for at least 12 months in order 
not to be considered of childbearing potential.  Pregnancy testing and contraception 
are not required for women with documented hysterectomy or tubal ligation. 
• Unscheduled blood collection for drug hypersensitivity events including suspicion of 
an AE potentially due to large drug-target-drug (DTD) immune complexes. At 
minimum to include: complete blood count (CBC), erythrocyte sedimentation rate 
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(ESR), chemistry, complement component 3 (C3), complement component 4 (C4), 
drug concentration, ADA (against pozelimab), and urinalysis (including microscopic 
evaluation). 
• Unscheduled blood collection for suspected breakthrough hemolysis events should 
include, at a minimum, CBC, reticulocyte count, chemistry, coagulation parameters, 
D-dimer, total C5, CH50, ADA (against pozelimab), and drug concentrations of 
pozelimab, as applicable.   
• Measurements of drug concentration (Section 9.2.6)  
• Immunogenicity measurements (Section 9.2.7) 
• Pharmacodynamic and exploratory biomarkers (Section 9.2.8) 
• Optional: Future research and pharmacogenomics (Section 9.2.9 and Section 9.2.10) 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results or uninterpretable samples that occur after start of treatment 
should be repeated to confirm the nature and degree of the abnormality.  When necessary, 
appropriate ancillary investigations should be initiated.  If the abnormality fails to resolve or cannot 
be explained by events or conditions unrelated to the study medication or its administration, the 
Medical/Study Director must be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.6. 
Blood Collection for Drug Concentrations 
9.2.6.1. 
Concentrations of Total Pozelimab and Total C5 
Samples to measure the concentration of total pozelimab and total C5 will be collected prior to 
any study drug administration at time points specified in Table 1 (OLTP) and Table 2 (patients on 
intensified treatment in OLTP), and Table 3 (optional OLEP). For patients who require intensified 
treatment, samples for total pozelimab and total C5 will also be collected within 15 minutes post-
infusion on day 1r. 
Detailed instructions for blood sample collection are in the laboratory manual. 
Any unused samples may be used for exploratory research, as allowed per local regulation. 
9.2.6.2. 
Concentrations of Cemdisiran and Cemdisiran Metabolites 
Samples to measure the concentration of cemdisiran and cemdisiran metabolites will be collected 
at time points specified in Table 1 (OLTP), Table 2 (patients on intensified treatment in OLTP), 
and Table 3 (optional OLEP). At each time point, blood samples will be collected prior to any SC 
study drug administration and 2 to 6 hours after study drug administration. Detailed instructions 
for blood sample collection are in the laboratory manual. 
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Any unused samples may be used for exploratory research, as allowed per local regulation. 
9.2.7. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected separately for pozelimab and for cemdisiran at time 
points listed in Table 1 (OLTP), Table 2 (patients on intensified treatment in OLTP), and Table 3 
(optional OLEP). 
Samples that are positive in the pozelimab ADA assay may be banked for the analysis of NAb, 
until the pozelimab NAb assay is available. Samples will not be analyzed for anti-cemdisiran 
neutralizing activity. Detailed instructions for blood sample collection are in the laboratory 
manual. 
Any unused samples may be used for exploratory research, as allowed per local regulation. 
9.2.8. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Samples for biomarkers will be collected at time points specified in Table 1 (OLTP), Table 2 
(patients on intensified treatment in OLTP), and Table 3 (optional OLEP). Detailed instructions 
for blood sample collection are in the laboratory manual. Biomarker variables are described in 
Section 5.6 and include:  
• CH50 (serum) 
• Parameters of intravascular hemolysis: ie, haptoglobin, reticulocyte count, and 
bilirubin 
• Free hemoglobin 
• AH50 (serum) 
• Complement activation markers: ie, sC5b-C9 
• PNH clone size: ie, PNH erythrocytes and granulocytes 
Biomarker measurements will be performed in specified matrix to determine effects of pozelimab 
and cemdisiran on relevant physiological and pathogenic processes. The list may be altered or 
expanded, as it is recognized that more relevant or novel biomarkers may be discovered during the 
process of this study. The biomarkers studied will be ones believed to be relevant to the 
pathophysiology of PNH, target engagement, mechanism of action, and possible toxicities.  
Any unused or leftover samples, collected for any purpose from this study, may be kept for up to 
15 years after study completion (or for a shorter period of time if required per local regulations)  
for use in exploratory research related to pathophysiology of PNH and related diseases, target 
engagement, mechanism of action for pozelimab or cemdisiran, and possible toxicities.  
Biomarker results will be reported separately from the CSR, unless biomarker measurements are 
included in primary or secondary objectives. 
9.2.9. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR. Additional 
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samples will be collected for FBR at time points according to Table 1 (treatment period) and 
Table 3 (optional OLEP). Residual biomarker samples for study-related research, as well as unused 
drug concentration and immunogenicity samples, will be stored for up to 15 years after the final 
date of the database lock (or for a shorter time period if required per regional laws and regulations).  
The samples may be utilized for FBR that may or may not be directly related to the study, including 
being used as reference samples and assay development or validation.  The results of these future 
biomedical research analyses will not be presented in the CSR. 
9.2.10. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples.  Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose), but can be collected at a later study visit (note: 
patients who had consented to DNA testing in R3918-PNH-1852 or R3918-PNH-1868 and had 
provided a DNA sample for analysis do not need to provide separate consent/sample for this study, 
but consent/sample collection will be needed for the RNA analysis).  Whole blood samples for 
RNA extraction will be collected at time points according to Table 1 (treatment period) and Table 3 
(optional OLEP).  DNA and RNA samples will be collected for pharmacogenomics analyses to 
understand the genetic determinants of safety and efficacy associated with the treatments in this 
study and the molecular basis of PNH and related diseases.  These samples will be single-coded 
as defined by the International Council on Harmonisation (ICH) guideline E15.  Samples will be 
stored for up to 15 years after the final date of the database lock (or for a shorter time period if 
required per regional laws and regulations).  If there are specific site or country requirements 
involving the pharmacogenomic analyses which the sponsor is unable to comply with, samples 
will not be collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to pozelimab and/or cemdisiran, other PNH clinical outcome measures and 
possible AEs.  In addition, associations between genomic variants and prognosis or progression of 
PNH as well as related complement-mediated diseases may also be studied. These data may be 
used or combined with data collected from other studies to identify and validate genomic markers 
related to the study drug, target pathway, or PNH and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed.  The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period.  Results from the genomic analyses will not be 
reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all adverse events occurring during the study data 
collection, from the time of signing the ICF to the end of study.  Medical conditions that existed 
or were diagnosed prior to the signing of the ICF will be recorded as part of medical history.  
Abnormal laboratory values and vital signs observed at the time of ICF should also be recorded as 
medical history.  Any subsequent worsening (ie, any clinically significant change in frequency 
and/or intensity) of a pre-existing condition that is temporally associated with the use of the study 
drugs should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms.  The Investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2.  
The Investigator’s assessment must be clearly documented in the site’s source documentation with 
the Investigator’s signature.  The Investigator should follow up on SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE.   
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported 
as AEs if they are symptomatic, lead to study drug discontinuation, require corrective treatment, 
or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the ICF) procedures, treatments requiring hospitalization for pre-existing conditions that 
do not worsen in severity, and admission for palliative or social care should not be reported as 
SAEs (see Section 10.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of the study) that the Investigator 
assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.   
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10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the study drug.  For SAEs and AESIs, a detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome should be 
provided on the AE CRF.  Specific or estimated dates of event onset, treatment, and resolution 
should be included, when available.  Medical history, concomitant medications, and laboratory 
data that are relevant to the event should also be summarized in the narrative.  For fatal events, the 
narrative should state whether an autopsy was or will be performed, and include the results if 
available.  Information not available at the time of the initial report must be documented in a 
follow-up report.  Source documents (including hospital or medical records, diagnostic reports, 
etc.) will be summarized in the narrative on the AE CRF, and retained at the study center and 
available upon request.   
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Selected AESIs (serious and nonserious):  Adverse events of special interest for this 
study include the following:   
− Moderate or severe hypersensitivity reactions potentially related to study 
treatment 
− Moderate or severe infusion reactions due to study treatment administration 
− Suspected Neisseria infection  
− MAVE: Includes thrombophlebitis/deep vein thrombosis, pulmonary embolus, 
myocardial infarction, unstable angina, renal vein or artery thrombosis, acute 
peripheral vascular occlusion, hepatic vein thrombosis, portal vein thrombosis 
mesenteric/visceral vein thrombosis or infarction,  mesenteric/visceral arterial 
thrombosis 
or 
infarction, 
transient 
ischemic 
attack, 
cerebral 
arterial 
occlusion/cerebrovascular accident, cerebral venous occlusion, gangrene 
(nontraumatic; non-diabetic), amputation (nontraumatic; non-diabetic) 
− Liver transaminase elevations as evidenced by 1 or more of the following criteria: 
o ALT or AST > 8× ULN, or 
o ALT or AST >5× ULN for >2 weeks, or 
o ALT or AST >3× ULN and total bilirubin >2× ULN (or INR >1.5) 
Note: This AESI must be reported to Sponsor within 24 hours once the investigator 
confirms the abnormal laboratory value.  
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• Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of 
the investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female patient during the study or within 52 weeks of the 
last dose of study drug.  Any complication of pregnancy affecting a female study patient 
and/or fetus and/or newborn that meets the SAE criteria must be reported as an SAE.  
Outcome for all pregnancies should be reported to the sponsor. 
• Symptomatic overdose:  Accidental or intentional overdose of at least 2 times the 
intended dose of study drug within the intended therapeutic window, if associated with 
an AE. 
10.1.4. 
Other Adverse Events of Special Interest that do not Require Expedited 
Reporting to Sponsor 
Although these AESIs do not require expedited reporting to sponsor, the following events are of 
interest and will involve the collection of additional details in separate CRFs: 
• ISR due to study treatment administration 
• Mild infusion reactions due to study treatment administration 
• Mild hypersensitivity reactions due to study treatment administration 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline.  Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours.  Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event, 
or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
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• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).   
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above (eg, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate.  Such an event might warrant 
further investigation in order to characterize and understand it.   
Adverse events of special interest are defined in Section 10.1.3 (AESIs requiring expedited 
reporting) and Section 10.1.4 (other AESIs). 
10.2.4. 
Infusion Reactions 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed.  
10.2.5. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient normal functioning level.  It may 
be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms, but may be 
given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health.  Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Infusion Reactions 
The severity of infusion reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of the grade): 
Mild:  Mild transient reaction; infusion interruption not indicated; intervention not indicated. 
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Moderate:  Therapy or infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, non-steroidal anti-inflammatory drugs [NSAIDs], narcotics, IV 
fluids); prophylactic medications indicated for ≤24 hours. 
Severe:  Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for 
clinical sequelae; life-threatening consequences; urgent intervention indicated; death. 
Injection Site Reactions 
The severity of ISRs will be graded according to the following scale (semi-colon indicates “or” 
within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.6. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions.  The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
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Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
state (eg, disease under study, concurrent diseases, concomitant medications), or 
other external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Global Patient Safety; Biostatistics and Data Management).  Safety monitoring 
will be performed on an ongoing basis (eg, individual review of SAEs) and on a periodic 
cumulative aggregate basis. 
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10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the contract research organization (CRO) will inform health 
authorities, Institutional Review Board (IRB)/Ethics Committee (EC), and the participating 
investigators of any Suspected Unexpected Serious Adverse Reactions (SUSARs) occurring in 
other study centers or other studies of the active study drug (pozelimab and cemdisiran), as 
appropriate per local reporting requirements. In addition, the sponsor and/or CRO will comply 
with any additional local safety reporting requirements.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the sponsor. 
Event expectedness for study drug (pozelimab and cemdisiran) is assessed against the Reference 
Safety Information section of the IB that is effective for expedited safety reporting. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the CSR to health authorities and IRB/EC as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides a high-level description of the planned analyses and will serve as the basis 
for the SAP for the study.   
Endpoints are listed in Section 4.  Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
No statistical hypothesis will be tested. 
11.2. 
Justification of Sample Size 
This study will be open to all patients who have enrolled in the Regeneron sponsored clinical study 
(R3918-PNH-1868) and plans to enroll approximately 24 patients with PNH.  
Data  from approximately 24 patients with PNH will be used to describe and explore the incidence 
and severity of TEAEs through week 28 of the OLTP. 
11.3. 
Analysis Sets 
11.3.1. 
Safety Analysis Sets 
The safety analysis set (SAF) includes all randomized patients who received any amount of study 
drug; it is based on the treatment received (as treated).  Treatment compliance/administration and 
all clinical safety variables will be analyzed using the SAF. 
The OLEP SAF includes all patients who participated in the OLEP who received any amount of 
study drug in the OLEP. 
11.3.2. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients who received any amount of study 
drugs and have at least 1 post-baseline assessment; it is based on the treatment allocated (as 
randomized).  Efficacy endpoints will be analyzed using the FAS. 
The OLEP FAS includes all patients who participated in the OLEP who received any amount of 
study drug in the OLEP and have at least 1 post-baseline assessment in the OLEP. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis set includes all treated patients who received any amount of study drug (SAF) 
and who had a at least 1 non-missing analyte measurement following the first dose of study drug. 
The PK analysis set is based on the actual treatment received. 
The OLEP PK analysis set includes all patients who participated in the OLEP who received any 
amount of study drug in the OLEP and who had at least 1 non-missing analyte measurement 
following the first dose of study drug in the OLEP.  
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all treated patients who received any amount of study drug (SAF) 
and had at least 1 non-missing ADA result following the first study dose of study drug. The ADA 
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analysis set is based on the actual treatment received. Patients’ baseline immunogenicity status for 
pozelimab will be determined from the initial treatment study. 
The NAb analysis set includes all treated patients who received any amount of study drug and who 
are negative in the ADA assay or with at least 1 non-missing result in the NAb assay (patients who 
are ADA negative are set to negative in the NAb analysis set). 
The OLEP ADA analysis set includes all treated patients who participated in the OLEP who 
received any amount of study drug in the OLEP and had at least 1 non-missing ADA result 
following the first OLEP dose.  
The OLEP NAb analysis set includes all patients who participated in the OLEP who received any 
study drug in the OLEP and who are negative in the ADA assay or with at least 1 non-missing 
result in the NAb assay (patients who are ADA negative are set to negative in the NAb analysis 
set). 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: signed the main ICF 
• The total number of randomized patients: received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
• Total number of patients who received treatment intensification 
• Total number of patients who continued into the OLEP 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
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Baseline is defined as the last available value prior to study drug administration unless otherwise 
specified. 
11.4.3. 
Efficacy Analyses 
11.4.3.1. Secondary Efficacy Analysis 
There are no primary efficacy endpoints in this study. 
For secondary endpoints for the OLTP that are defined by the change or percent change from 
baseline to a time point in a variable, the analysis set will consist of all treated patients who have 
a non-missing baseline measurement of the variable. Means and 95% confidence intervals (CI) for 
the endpoints will be reported for both treatment arms and their difference. 
These endpoints include:  
• Percent change in LDH from pre-treatment (as defined by the mean LDH value at 
day -7 and day 1 [prior to combination dosing]) to EOT period (as defined by the 
mean value at week 24 and week 28 in the OLTP) 
• Change in CH50 levels from baseline to week 28 
• Change from baseline in concentration of total C5 assessed throughout the study  
• Change in hemoglobin levels from baseline to week 28 
• Change in FACIT-Fatigue from baseline to week 28 
• Change from baseline to Week 28 in GHS and PF scores on the EORTC QLQ-C30 
For the above secondary endpoints, the SAP will describe the multiple imputation approach. 
For binary secondary endpoints, all treated patients will be analyzed. Proportions of patients 
meeting the criteria and 95% CIs by an exact method for the endpoints will be reported for both 
treatments and their difference:  
• Proportion of patients who maintain adequate control of their hemolysis, defined as 
LDH ≤1.5 × ULN from post-baseline (on day 1) through week 28 and from week 4 
through week 28, inclusive  (A patient will be treated as not maintaining adequate 
control of hemolysis if he/she is missing >25% of scheduled LDH measurements, 
missing any 2 consecutive LDH measurements, received intensified treatment, or 
permanently discontinued treatment. Patients with breakthrough hemolysis will be 
treated as non-responders. For other patients, control of hemolysis will be assessed by 
non-missing LDH measurements.) 
• Proportion of patients with adequate control of hemolysis at each visit from post-
baseline (on day 1) through week 28, inclusive 
• Proportion of patients with normalization of LDH at each visit, defined as LDH ≤1.0 × 
ULN from post-baseline (on day 1) through week 28, inclusive  
• Proportion of patients with breakthrough hemolysis from baseline through week 28 
(Non-responder imputation will be applied for patients who receive intensified 
treatment) 
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• Proportion of patients who achieve hemoglobin stabilization (defined as patients who 
do not receive a RBC transfusion and have no decrease in hemoglobin levels of 
≥2 g/dL) from baseline through week 28  
• Proportion of patients who are transfusion-free (defined as not requiring a RBC 
transfusion as per protocol algorithm) from baseline through week 28 
For the rate and number of units of transfusion with RBCs from baseline through week 28, the 
analysis set will consist of all treated patients who never received intensified treatment. The rate 
of units of transfusion for a patient will be calculated based on the duration of treatment exposure 
of the patient.  Means and 95% CIs by a one-sample t-statistic will be reported for both treatments 
and their difference. 
For the AUC of LDH over time from baseline though week 28 and from week 4 through week 28, 
the analysis set will include all treated patients. First, missing values will be imputed using the 
multiple imputation approach described in the SAP. Then, the AUC will be computed using the 
complete set of LDH values. Mean AUC, 95% CIs, and other summary statistics will be provided 
for both treatment arms and their difference. 
Secondary efficacy analysis for the optional OLEP will be performed using the same approach as 
described for corresponding analyses in the OLTP. 
11.4.4. 
Control of Multiplicity 
Not applicable 
11.4.5. 
Safety Analysis 
The primary endpoint in this study is the incidence and severity of TEAEs through week 28 of 
the OLTP. 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of study drug for this study 
• The on-treatment period is defined as the day from first dose of study drug to either: 
− the last dose of study drug in the OLTP (or intensified OLTP) for those not 
continuing in the OLEP plus 52 weeks, or  
− the last dose in the OLEP for those continuing in the OLEP plus 52 weeks 
• The post-treatment period is defined as the time after the end of the on-treatment period  
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment period. 
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Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.5), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, sitting blood pressure, and pulse rate) will be summarized by baseline 
and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all patients 
and separately for patients in whom the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
ECG 
Electrocardiogram parameters (PR interval, QT interval, QTcF interval, QRS interval, and heart 
rate [from ventricular rate]) will be summarized by visit and change from baseline to each 
scheduled and collected assessment time. 
Listings will be provided with flags indicating PCSVs. 
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11.4.5.3. Treatment Exposure 
Treatment exposure (ie, defined as time on study drug) will be presented separately for pozelimab 
and cemdisiran. 
The duration of study drug for a study period is calculated as: 
(Date of last administration of study drug - date of the first administration of study drug 
administration for the study period) + 1 day 
Summaries (including the number of patients exposed, the duration of exposure, and the dose 
regimen to which patients were exposed) will be provided for pozelimab and for cemdisiran. 
11.4.5.4. Treatment Compliance 
Compliance with protocol-defined study drug dosing will be calculated as follows: 
Treatment compliance = (Number of study drug doses taken during treatment period) / 
(Number of study drug doses planned for the treatment period) × 100% 
Separate summaries will be provided for pozelimab and cemdisiran. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of total pozelimab, total C5, cemdisiran, and cemdisiran metabolites over time 
and selected pharmacokinetic parameters will be summarized by descriptive statistics for each of 
the treatment groups. 
No formal statistical hypothesis testing will be performed.  
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11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response, titer and NAb response observed:   
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 4-fold for anti-cemdisiran antibody 
assay or 9-fold for anti-pozelimab antibody assay over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-first dose positive ADA 
assay response when the baseline results are negative or missing 
• Treatment-boosted ADA response, defined as any post-first dose positive ADA assay 
response that is 4-fold for anti-cemdisiran antibody assay or 9-fold for anti-pozelimab 
antibody assay over baseline titer levels when baseline is positive in the ADA assay  
• Maximum ADA titer categories 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• NAb status in the anti-pozelimab NAb assay, for samples that are positive in the 
pozelimab ADA assay  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers, 
and NAb positivity presented by patient, time point, and cohort will be provided. Incidence of 
treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and percent of 
patients (%), grouped by cohort and ADA titer level. 
Plots of pozelimab drug concentrations will be examined and the influence of pozelimab ADAs 
and NAbs on individual concentration-time profiles evaluated. Assessment of impact of ADA and 
NAbs on safety and efficacy may be provided. 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Analysis of CH50 is described in Section 11.4.3.1. Analysis of other biomarker data is defined in 
the SAP. Unless specified as a secondary endpoint, the results of other biomarkers may not be 
presented in the CSR. 
11.5. 
Timing of Statistical Analysis 
A planned interim analysis may be conducted as described in Section 6.4. 
The primary analysis will be conducted as soon as all patients have been randomized and all data 
through week 28 have been collected and validated; this will consist of the primary safety and 
secondary efficacy endpoints.  
The OLEP analysis will be conducted when all data through week 52e of the OLEP have been 
collected and validated. 
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Additional safety data from the post-treatment safety follow-up period will be included in a 
subsequent analysis. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC). 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – Medidata Rave 
• SAS – statistical review and analysis 
• Pharmacovigilance safety database 
• Clinical outcomes assessments  
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners.  
RBQM strategies include: reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends. The investigator must allow study-
related monitoring activities to occur. 
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The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF. Case report forms and 
source documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on CRFs within the EDC 
system by trained site personnel.  All required CRFs must be completed for each and every patient 
enrolled in the study.  The investigator must ensure the accuracy, completeness, and timeliness of 
the data reported to the sponsor in the CRFs.  After review of the clinical data for each patient, the 
investigator must provide an electronic signature.  A copy of each patient CRF casebook is to be 
retained by the investigator as part of the study record and must be available at all times for 
inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
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Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection.  In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
CRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
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13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
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17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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studies. Blood Adv 2018; 2(17):2176-85. 
 
Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and 
extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005; 
293(13):1653-62. 
 
Sahin F, Akay OM, Ayer M, Dal MS, Ertop S, Ilhan O, et al. Pesg PNH diagnosis, follow-up and 
treatment guidelines. Am J Blood Res 2016; 6(2):19-27. 
 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. Ann Emerg Med 2006; 47(4):373-80. 
 
Sheridan D, Yu ZX, Zhang Y, Patel R, Sun F, Lasaro MA, et al. Design and preclinical 
characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS 
One 2018; 13(4):e0195909. 
 
Soliris®. 2019.  Prescribing information for eculizumab. Alexion Pharmaceuticals, Inc. 
 
Stead ML, Brown JM, Velikova G, Kaasa S, Wisloff F, Child JA, et al. Development of an EORTC 
questionnaire module to be used in health-related quality-of-life assessment for patients with 
multiple myeloma. European Organization for Research and Treatment of Cancer Study Group on 
Quality of Life. Br J Haematol 1999; 104(3):605-11. 
 
Wedzicha JA. Antibiotics at COPD exacerbations: the debate continues. Thorax 2008; 63(11):940-
2. 
 
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REGENERON CONFIDENTIAL 
 
Page 112 
 
 
Weitz I, Meyers G, Lamy T, Cahn JY, Uranga MT, Garcia Vela JA, et al. Cross-sectional 
validation study of patient-reported outcomes in patients with paroxysmal nocturnal 
haemoglobinuria. Intern Med J 2013; 43(3):298-307. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol, “A Randomized, Open-label, Two-arm Study to Evaluate the 
Safety, Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran Combination 
Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Have Received Pozelimab 
Monotherapy”, and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
A Randomized, Open-label, Two-arm Study to Evaluate the Safety, 
Efficacy, and Pharmacodynamic Effects of Pozelimab and Cemdisiran 
Combination Treatment in Patients with Paroxysmal Nocturnal 
Hemoglobinuria Who Have Received Pozelimab Monotherapy 
Protocol Number: R3918-PNH-2092 
Protocol Version:   
R3918-PNH-2092 Amendment 1 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 63 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 2.0 
Clinical Study Protocol Title: 
A Randomized, Open-Label, Two-Arm Study to Evaluate the Safety, Efficacy, 
and Pharmacodynamic Effects of Pozelimab and Cemdisiran Combination 
Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Have 
Received Pozelimab Monotherapy 
Compound: 
Pozelimab (REGN3918) 
Cemdisiran (ALN-CC5) 
Protocol Number: 
R3918-PNH-2092 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
2.0 / Dec 9, 2022 
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Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
Study Biostatistician  
 
See appended electronic signature page 
Study Clinical Pharmacology Lead 
 
See appended electronic signature page 
Study Bioanalytical Sciences 
Lead 
 
See appended electronic signature page 
Study Precision Medicine Lead 
 
See appended electronic signature page 
Study Medical Director 
 
See appended electronic signature page 
Project Biostatistician 
 
See appended electronic signature page 
Head of BDM or designee 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale for Study Design ......................................................................8 
1.2. 
Study Objectives ...........................................................................................................8 
1.2.1. 
Primary Objective .........................................................................................................8 
1.2.2. 
Secondary and Exploratory Objectives ........................................................................9 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Revision History for SAP Amendments .....................................................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design ...............................................................................................................11 
2.2. 
Sample Size Considerations .......................................................................................11 
2.3. 
Study Plan ...................................................................................................................11 
3. 
ANALYSIS POPULATIONS ....................................................................................12 
3.1. 
The Full Analysis Sets (FAS) .....................................................................................12 
3.2. 
The Safety Analysis Sets (SAF) .................................................................................12 
3.3. 
The Pharmacokinetic (PK) Analysis Sets ...................................................................12 
3.4. 
The Immunogenicity Analysis Sets ............................................................................12 
3.5. 
The Exploratory Biomarkers Endpoint Analysis Set ..................................................13 
4. 
ANALYSIS VARIABLES .........................................................................................14 
4.1. 
Demographic and Baseline Characteristics ................................................................14 
4.2. 
Medical History ..........................................................................................................14 
4.3. 
Prior/Concomitant Medication and Procedures ..........................................................15 
4.4. 
Efficacy Variables ......................................................................................................15 
4.4.1. 
Primary Efficacy Variables .........................................................................................15 
4.4.2. 
Secondary Efficacy Variables .....................................................................................15 
4.4.2.1. 
Secondary Endpoints for the Optional Open-Label Extension Period .......................16 
4.4.3. 
Exploratory Efficacy Variables ..................................................................................20 
4.5. 
Safety Variables ..........................................................................................................22 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................23 
4.5.2. 
Adverse Events of Special Interest .............................................................................24 
4.5.3. 
Laboratory Safety Variables .......................................................................................24 
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4.5.4. 
Vital Signs ..................................................................................................................24 
4.5.5. 
12-Lead Electrocardiography (ECG) ..........................................................................24 
4.6. 
Pharmacokinetic Variables .........................................................................................24 
4.7. 
Immunogenicity Variables ..........................................................................................24 
4.8. 
Pharmacodynamic Variables ......................................................................................25 
4.9. 
Clinical Outcome Assessments (COAs) .....................................................................25 
5. 
STATISTICAL METHODS .......................................................................................26 
5.1. 
Demographics and Baseline Characteristics ...............................................................26 
5.2. 
Medical History ..........................................................................................................26 
5.3. 
Prior/concomitant Medications ...................................................................................26 
5.4. 
Prohibited Medications ...............................................................................................27 
5.5. 
Patient Disposition ......................................................................................................27 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................27 
5.6.1. 
Measurement of Compliance ......................................................................................27 
5.6.2. 
Exposure to Investigational Product ...........................................................................27 
5.7. 
Analyses of Efficacy Variables ..................................................................................28 
5.7.1. 
Analysis of Continuous Secondary Efficacy Variables ..............................................29 
5.7.2. 
Analysis of Categorical Secondary Efficacy Variables ..............................................29 
5.7.3. 
Analysis of Exploratory Variables ..............................................................................30 
5.8. 
Analysis of Safety Data ..............................................................................................31 
5.8.1. 
Adverse Events ...........................................................................................................31 
5.8.2. 
Analysis of Vital Signs ...............................................................................................31 
5.8.3. 
Analysis of Laboratory Tests ......................................................................................32 
5.8.4. 
Analysis of 12-Lead ECG ...........................................................................................32 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data ...........................................32 
5.9.1. 
Analysis of Pharmacokinetic Data ..............................................................................32 
5.9.2. 
Analysis of Immunogenicity Data ..............................................................................33 
5.9.2.1. 
Analysis of ADA Data ................................................................................................33 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................34 
5.9.3.1. 
Immunogenicity and Exposure ...................................................................................34 
5.9.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................34 
5.10. 
Analysis of Pharmacodynamic and Biomarker Data ..................................................35 
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6. 
DATA CONVENTIONS ............................................................................................36 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................36 
6.2. 
Data Handling Convention for Missing Data .............................................................36 
6.2.1. 
Adverse events ............................................................................................................36 
6.2.2. 
PCSV ..........................................................................................................................38 
6.2.3. 
Date of first / last study drug administration ..............................................................38 
6.3. 
Analysis Windows ......................................................................................................38 
6.4. 
Unscheduled Assessments ..........................................................................................40 
7. 
INTERIM ANALYSIS ...............................................................................................41 
8. 
SOFTWARE ...............................................................................................................42 
9. 
REFERENCES ...........................................................................................................43 
10. 
APPENDIX.................................................................................................................44 
10.1. 
Schedule of Time and Events .....................................................................................44 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................60 
 
LIST OF TABLES 
Table 1: 
Efficacy Analysis Windows .......................................................................................39 
Table 2: 
Safety Analysis Windows ...........................................................................................40 
Table 3: 
Schedule of Events (Open-Label Treatment Period) ..................................................44 
Table 4: 
Schedule of Events for Patients on Intensified Treatment in the OLTP .....................47 
Table 5: 
Schedule of Events (Optional Open-Label Extension Period) ...................................49 
Table 6: 
Schedule of Events (Post-Treatment Safety Follow-Up Period) ................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................11 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AH50 
Alternative pathway hemolytic activity assay 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
C 
Complement component (e.g., C3, C5) 
CH50 
Total complement hemolysis activity assay 
COA 
Clinical outcome assessment 
CRF 
Case report form (electronic or paper) 
CRP 
C-reactive protein 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer: Quality-of-Life 
Questionnaire core 30 items 
EOT 
End of treatment 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue score 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
GHS 
Global health status 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MAVE 
Major adverse vascular events 
MI 
Multiple Imputation 
OLEP 
Open-label extension period (an optional period) 
OLTP 
Open-label treatment period (main study period) 
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PD 
Pharmacodynamics 
PF 
Physical function 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PT 
Preferred term 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
QoL 
Quality of life 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of study results. The 
SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for this study. 
1.1. 
Background/Rationale for Study Design 
Background information on paroxysmal nocturnal hemoglobinuria (PNH), pozelimab 
(REGN3918) and cemdisiran (ALN-CC5) may be found in the protocol. This trial is designed as 
a randomized, open-label, 28-week treatment study to assess the safety, efficacy, and PD effects 
of 2 dose regimens of pozelimab and cemdisiran combination in patients with PNH who have been 
treated with pozelimab monotherapy for at least 26 weeks.  
Patients will be randomized in 1:1 ratio to receive pozelimab 400 mg SC Q4W and cemdisiran 
200 mg SC Q4W (arm 1) or pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W (arm 2).   
In addition to safety, the study includes secondary efficacy endpoints to assess the effect of the 
combination treatment on control of intravascular hemolysis, as measured by LDH.   
The long-term safety and efficacy of the combination treatment will be assessed by providing the 
patients who complete the main 28-week open-label treatment period (OLTP) on combination 
treatment an opportunity to participate in an optional long-term open-label extension period 
(OLEP), in which patients shall continue to receive study treatment for an additional 52 weeks. 
During the OLTP, a patient meeting breakthrough hemolysis criteria and inadequate LDH response 
will qualify for intensified treatment, which consists of an initial IV loading dose of pozelimab 
and intensified pozelimab regimen to be administered Q2W along with cemdisiran at Q4W, for a 
period of 32 weeks. Patients who opt not to participate in the OLEP (or those who stop treatment 
for any reason) will be followed for 52 weeks after the last dose of study treatment, to monitor for 
safety as the study drugs are gradually eliminated from the body. Patients who complete the OLEP 
and stop study treatment will also be followed for 52 weeks after their last dose of study treatment.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens 
of pozelimab and cemdisiran combination therapy during the OLTP. 
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1.2.2. 
Secondary and Exploratory Objectives 
The secondary objectives of the study are: 
• To evaluate the effect of the combination treatment on the following parameters of 
intravascular hemolysis: LDH control, breakthrough hemolysis, and inhibition of total 
complement hemolysis activity (CH50)   
• To evaluate the effect of the combination treatment on hemoglobin levels 
• To evaluate the effect of the combination treatment on RBC transfusion requirements  
• To evaluate the effect of the combination treatment on COAs measuring fatigue and 
health related quality of life 
• To assess the concentrations of total pozelimab in serum and total C5 and cemdisiran 
in plasma 
• To assess immunogenicity to pozelimab and cemdisiran 
• To evaluate the long-term safety and efficacy of pozelimab and cemdisiran in an 
optional OLEP  
• To assess safety after treatment intensification with pozelimab and cemdisiran 
The exploratory objectives of the study are: 
• To explore the effect of the combination treatment on clinical thrombosis events  
• To explore the effect of the combination treatment on renal function and renal injury 
biomarkers  
• To explore the effect of the combination treatment on complement activation and 
intravascular hemolysis relevant to PNH and other related diseases  
• To explore the effect of the combination treatment on PNH clone size  
• To evaluate the effect of the combination treatment on treatment satisfaction 
• To explore the effect of the combination treatment on a novel COA measuring 
PNH-specific symptoms  
• To study the combination treatment mechanism of action (including relationship to 
safety and efficacy), complement pathway biology, PNH and related complement-
mediated diseases  
• To explore the effect of the combination treatment on PNH symptoms 
• To explore potential differences in genotype and gene expression that may influence 
efficacy and safety of the combination treatment for further understanding of C5, PNH, 
or other conditions associated with complement-mediated injury (for patients who 
consent to participate in a genomics sub-study) 
• To explore safety and efficacy after dose intensification with pozelimab and cemdisiran 
• To explore the long-term effects of the combination treatment on clinical and PD 
assessments in an optional OLEP 
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1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
This SAP is based on protocol amendment 1. 
1.2.4. 
Revision History for SAP Amendments 
Summary of Changes from SAP Version 1 to Version 2 Due to Protocol Amendment 1 
Changes 
Sections changed 
Updated information about post-trial treatment 
access for patients who complete the optional 
OLEP 
Figure 1 footnote 
Removed several rows from the List of 
Abbreviations, due to their not being included in 
this document 
List of Abbreviations and Definition of Terms 
Revised the descriptions of several secondary 
endpoints, to match the revisions in the protocol. 
This applies to OLTP and OLEP endpoints. 
Section 4.4.2 
Added new secondary endpoint: the proportion of 
patients with adequate control of hemolysis at each 
visit 
Section 4.4.2  
Added analysis window tables 
Section 6.4 
Updated SOE tables 
Section 10.1 
Clarifications and corrections 
Throughout the document 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design 
This is a randomized, open-label, 2-arm, 28-week study to evaluate the safety, efficacy, and PD 
effects of 2 dose regimens of pozelimab and cemdisiran combination treatment in patients with 
PNH who had been receiving treatment with pozelimab monotherapy in a Regeneron-sponsored 
clinical study (R3918-PNH-1868). A schematic of the study design is shown in Figure 1. Eligible 
patients will be randomized 1:1 to 1 of 2 combination regimens of pozelimab and cemdisiran.  
Figure 1: 
Study Flow Diagram 
 
In lieu of the safety follow-up period, patients who complete the optional OLEP may be able to continue study 
treatment in a post-trial access program. 
2.2. 
Sample Size Considerations 
This study will be open to all patients who have enrolled in the Regeneron sponsored clinical 
study (R3918-PNH-1868; n=24) and plans to enroll approximately 24 patients with PNH. 
2.3. 
Study Plan 
The study event tables are presented in Appendix 10.1. 
Safety 
Follow-Up c
Optional 
OLEP b
Screening
W28 / D197
EOT
D-8/-7 
(Day of final dose in 
prior REGN study)
Open-Label Treatment Period (28 weeks)
D1
1st combination 
dosing
Pozelimab 
800 mg SC
Arm 1: Pozelimab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W
Arm 2: Pozelimab 400 mg SC Q2W + Cemdisiran 200 mg SC Q4W
R
1:1
At any time during the study, patients who meet pre-defined criteria for LDH and 
breakthrough hemolysis will be switched to an intensified treatment regimen
a
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following populations will be used for 
statistical analysis: 
3.1. 
The Full Analysis Sets (FAS) 
The full analysis set (FAS) includes all randomized patients who received any amount of study 
drug and have at least 1 post-baseline assessment; it is based on the treatment allocated (as 
randomized).  Efficacy endpoints will be analyzed using the FAS. 
The OLEP FAS includes all patients who participated in the OLEP who received any amount of 
study drug in the OLEP and have at least 1 post-baseline efficacy assessment in the OLEP.   
3.2. 
The Safety Analysis Sets (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any amount of study 
drugs; it is based on the treatment received (as treated).  Treatment compliance/administration and 
all clinical safety variables will be analyzed using the SAF. 
The OLEP SAF includes all patients who participated in the OLEP who received any amount of 
study drug in the OLEP. 
3.3. 
The Pharmacokinetic (PK) Analysis Sets 
The PK analysis set includes all treated patients who received any amount of study drug (SAF) 
and who had at least 1 non-missing analyte measurement following the first dose of combination 
treatment. The PK analysis set is based on the actual treatment received. 
The OLEP PK analysis set includes all patients who participated in the OLEP who received any 
amount of study drug in the OLEP and who had at least 1 non-missing analyte measurement 
following the first dose of study drug in the OLEP. 
3.4. 
The Immunogenicity Analysis Sets 
The ADA analysis sets (AAS) are defined for each study drug separately and include all treated 
patients who received any amount of that study drug (SAF) and had at least 1 non-missing ADA 
result following the first on-study dose of the respective study drug. The definition of the ADA 
analysis set for each study drug is based on the actual treatment received. Patients’ baseline 
immunogenicity status for pozelimab will be determined from the initial treatment study. 
The OLEP AASs are defined for each study drug separately and include all patients who 
participated in the OLEP who received any amount of study drug in the OLEP and had at least 1 
non-missing ADA result following the first OLEP dose of respective study drug. The ADA 
analysis set for each study drug is based on the actual treatment received. Patients' baseline 
immunogenicity status for pozelimab will be determined from the initial treatment study. 
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3.5. 
The Exploratory Biomarkers Endpoint Analysis Set 
The exploratory biomarker endpoint (pharmacodynamic) analysis set includes all patients who 
received any amount of study drug and who had at least 1 non-missing analyte measurement 
following the first dose of combination treatment. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline variables will be summarized:  
• Age at screening (years) 
• Sex (Male, Female) 
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
• Ethnicity (Hispanic/Latino) 
• Baseline Weight  
• Baseline Height 
• Baseline Body mass index (BMI) calculated from weight and height 
• PNH signs and symptoms at baseline 
• Baseline hemoglobin 
• Baseline eGFR 
• Baseline creatinine 
• Baseline total C5  
• Baseline PNH clone size 
• Baseline LDH 
• Baseline total bilirubin 
• Baseline CH50 
• RBC/whole blood transfusions in last year 
• Breakthrough hemolysis in last year 
4.2. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). In 
addition, history in the previous year of RBC/whole blood transfusions and breakthrough 
hemolyses will be summarized. 
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4.3. 
Prior/Concomitant Medication and Procedures 
Medications will be recorded from the day of informed consent (ICF) until their final study visit. 
Medications will be coded using WHO Drug Dictionary (WHODD).  
Prior medications are medications taken prior to receiving any study drug following 
randomization. Concomitant medications are medications taken between the first dose of 
combination treatment and the end of the safety follow-up period. 
Prior/concomitant procedures will be recorded.  Prior procedures are procedures performed prior 
to administration of the first dose of combination treatment.  Concomitant procedures are 
procedures performed between the first dose of combination treatment and the end of the safety 
follow-up period. 
In addition, use of erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic 
agents, anticoagulants, iron supplements, and folic acid will be recorded. 
4.4. 
Efficacy Variables 
4.4.1. 
Primary Efficacy Variables 
Not Applicable 
4.4.2. 
Secondary Efficacy Variables 
The secondary efficacy endpoints for the OLTP are: 
• Percent change of LDH from pre-treatment (defined as mean of LDH values at day -7 
and day 1 [prior to combination dosing]) to end-of-treatment period (defined as mean 
of LDH values at week 24 through week 28) 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN after 
baseline through week 28, inclusive 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from 
week 4 through Week 28, inclusive 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) at each visit from 
baseline through week 28, inclusive 
• Normalization of LDH (defined as LDH ≤1.0 × ULN) at each visit from baseline 
through week 28, inclusive 
• Area under the curve (AUC) of LDH over time from baseline through week 28, 
inclusive 
• Area under the curve (AUC) of LDH over time from week 4 through week 28, inclusive 
• Breakthrough hemolysis (as defined in the protocol) from baseline through week 28  
• Hemoglobin stabilization (defined as patients who do not receive RBC transfusion and 
have no decrease in hemoglobin levels of ≥2 g/dL) from baseline through week 28 
• Change in hemoglobin levels from baseline to week 28  
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• Transfusion avoidance (defined as not requiring an RBC transfusion as per protocol 
algorithm) from baseline to week 28 
• Rate (defined as number of events per patient-years) and number of units of RBCs 
transfused from baseline to week 28 
• Change in CH50 from baseline to week 28  
• Change in fatigue as measured by Functional Assessment of Chronic Illness Therapy-
Fatigue (FACIT-Fatigue) scale from baseline to week 28 
• Change from baseline to week 28 in global health status/quality of life scale 
(GHS/QoL) and physical function (PF) scores on the European Organization for 
Research and Treatment of Cancer: Quality-of-Life Questionnaire core 30 items 
(EORTC QLQ-C30)   
• Concentrations of total pozelimab in serum and cemdisiran in plasma, assessed 
throughout the study 
• Change from baseline in concentration of total C5 assessed throughout the study 
• Assessment of immunogenicity to pozelimab and cemdisiran as determined by the 
incidence, titer, and clinical impact of treatment-emergent anti-drug antibody (ADA) 
responses over time 
4.4.2.1. 
Secondary Endpoints for the Optional Open-Label Extension Period 
The secondary endpoints for the optional OLEP are: 
• Change and percent change of LDH from day 1e to week 24e of the OLEP  
• Change and percent change of LDH from day 1e to week 52e of the OLEP 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from day 
1e of the OLEP through week 24e 
• Maintenance of adequate control of hemolysis, defined as LDH ≤1.5 × ULN from day 
1e of the OLEP through week 52e 
• Adequate control of hemolysis (defined as LDH ≤1.5 × ULN) at each visit from day 1e 
of the OLEP through week 52e 
• Normalization of LDH (defined as LDH ≤1.0 × ULN) at each visit, from day 1e of the 
OLEP through week 52e 
• Area under the curve (AUC) of LDH over time between day 1e of the OLEP through 
week 52e 
• Breakthrough hemolysis from day 1e of the OLEP through week 24e 
• Breakthrough hemolysis from day 1e of the OLEP through week 52e 
• Hemoglobin stabilization (defined as patients who do not receive RBC transfusion and 
have no decrease in hemoglobin levels of ≥2 g/dL) from day 1e to week 24e and 
week 52e of the OLEP 
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• Change in hemoglobin levels from day 1e to week 24e of the OLEP 
• Change in hemoglobin levels from day 1e to week 52e of the OLEP 
• Transfusion avoidance (defined as not requiring an RBC transfusion as per protocol 
algorithm) from day 1e to week 24e and week 52e of the OLEP 
• Rate and number of units of RBCs transfused from day 1e to week 24e of the OLEP 
• Rate and number of units of RBCs transfused from day 1e to week 52e of the OLEP 
• Change and percent change in CH50 from day 1e to week 16e of the OLEP  
• Change and percent change in CH50 from day 1e to week 24e of the OLEP 
• Change and percent change in CH50 from day 1e to week 52e of the OLEP 
• Change in fatigue as measured by FACIT-Fatigue scale from day 1e to week 52e of the 
OLEP 
• Change in global health status/quality of life scale (GHS/QoL) and physical function 
(PF) scores on the European Organization for Research and Treatment of Cancer: 
Quality-of-Life Questionnaire core 30 items (EORTC QLQ-C30) from day 1e to 
week 52e of the OLEP  
• Concentrations of total pozelimab in serum and total C5 and cemdisiran in plasma, 
assessed over time during the OLEP  
• Assessment of immunogenicity to pozelimab and cemdisiran as determined by the 
incidence, titer, and clinical impact of treatment-emergent anti-drug antibody (ADA) 
responses over time during the OLEP 
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The following table summarizes the OLTP and OLEP secondary endpoints: 
OLTP and OLEP 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
LDH 
Change 
Not Applicable 
Day 1e (BL of the 
OLEP) to week 24e 
 
Change 
Not Applicable 
Day 1e (BL of the 
OLEP) to week 52e 
LDH 
Percent change 
From pre-treatment 
(defined as mean of 
LDH values at day -7 
and day 1 [prior to 
combination dosing]) 
to EOT period (as 
defined by the mean of 
LDH values at Week 
24 through Week 28 in 
the OLTP) 
Day 1e (BL of the 
OLEP) to week 24e 
 
 
Not Applicable  
Day 1e (BL of the 
OLEP) to week 52e 
Patients who are 
transfusion-
avoidant 
Proportion 
BL through Week 28 
Day 1e through week 
24e 
 
 
Not Applicable 
Day 1e through week 
52e 
Units of RBC’s 
transfused 
Rate and Number 
BL through Week 28 
Day 1e through week 
24e 
 
 
Not Applicable 
Day 1e through week 
52e 
Breakthrough 
hemolysis 
Proportion 
BL through Week 28 
Day 1e through week 
24e 
 
 
Not Applicable 
Day 1e through week 
52e 
LDH 
Proportion of patients 
maintaining adequate control of 
hemolysis (defined as 𝐿𝐷𝐻≤
1.5 ∗𝑈𝐿𝑁 at all times at which 
LDH is measured) 
BL through Week 28 
Day 1e through week 
24e 
 
 
Week 4 through Week 
28 
Day 1e through week 
52e 
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OLTP and OLEP 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
LDH 
Proportion of patients with 
adequate control of hemolysis 
(defined as 𝐿𝐷𝐻≤1.5 ∗𝑈𝐿𝑁 
at each visit) 
BL through Week 28 
Day 1e through week 
52e 
LDH 
Proportion of patients with 
normalization of LDH (defined 
as 𝐿𝐷𝐻≤1.0 ∗𝑈𝐿𝑁 at each 
visit) 
BL through Week 28 
Day 1e through week 
52e 
 
 
Week 4 through Week 
28 
Not Applicable 
LDH 
AUC over time 
BL through Week 28 
Day 1e through week 
52e 
 
 
Week 4 through Week 
28 
Not Applicable 
Hemoglobin 
stabilization 
Proportion of patients who do 
not receive a per-protocol RBC 
transfusion and have no 
decrease in hemoglobin level of 
≥2 g/dL) 
BL through Week 28 
Day 1e through week 
24e 
 
 
Not Applicable 
Day 1e through 
week 52e 
Hemoglobin 
Change 
BL through Week 28 
Day 1e through 
week 24e 
 
 
Not Applicable 
Day 1e through 
week 52e 
Fatigue 
Change in FACIT-Fatigue 
Scale 
BL to Week 28 
Day 1e to week 52e 
Global health 
status 
Change in GHS in EORTC 
QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Physical Function 
Change in PF in EORTC QLQ-
C30 
BL to Week 28 
Day 1e to week 52e 
Total CH50 
Change 
BL to Week 28 
Day 1e to week 16e 
 
 
Not Applicable 
Day 1e to week 24e 
 
 
Not Applicable 
Day 1e to week 52e 
Total CH50 
Percent Change 
Not Applicable 
Day 1e to week 16e 
 
 
Not Applicable 
Day 1e to week 24e 
 
 
Not Applicable 
Day 1e to week 52e 
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OLTP and OLEP 
Measurement 
Metric 
Time Period in OLTP 
Time Period in OLEP 
Total Pozelimab 
in serum 
Concentrations 
Whole OLTP 
Whole OLEP 
Total Cemdisiran 
in plasma 
Concentrations 
Whole OLTP 
Whole OLEP 
Concentration of 
total C5 
Change 
Whole OLTP 
Whole OLEP 
Immunogenicity 
to pozelimab and 
cemdisiran 
Incidence, titer, and clinical 
impact of treatment-emergent 
ADA responses over time 
Whole OLTP 
Whole OLEP 
4.4.3. 
Exploratory Efficacy Variables 
The exploratory endpoints for the OLTP are: 
• Treatment intensification throughout the study  
• Incidence of MAVE (defined in Section 10.1.3 of the protocol) from baseline to week 
28 
• Change in renal function as measured by estimated glomerular filtration rate (eGFR) 
from baseline to week 28  
• Percent change in free hemoglobin from baseline to week 28  
• Change in bilirubin from baseline to week 28  
• Change in reticulocyte count from baseline to week 28  
• Change and percent change in the alternative pathway hemolytic activity assay (AH50) 
from baseline to week 28  
• Change of PNH erythrocytes and granulocytes from baseline to week 28  
• Change from baseline to week 28 in functional scale scores (Role functioning, 
Emotional Functioning, Cognitive Functioning and Social Functioning) and symptom 
scale scores (Fatigue, Nausea and vomiting, Pain, Dyspnoea, Insomnia, Appetite loss, 
Constipation, Diarrhoea) of the EORTC QLQ-C30    
• Stability in global health status, functioning and symptoms as measured by the EORTC 
QLQ-C30 from baseline to week 28  
• Change in Treatment satisfaction (as assessed by the Treatment Satisfaction 
Questionnaire for Medication [TSQM]) from baseline to week 28 
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The following table summarizes the OLTP and OLEP exploratory endpoints: 
Measurement 
Metric 
Time Period in 
OLTP 
Time Period in 
OLEP 
Treatment 
Intensification 
Proportion 
Whole OLTP 
Not applicable 
MAVE 
Incidence 
BL to Week 28 
Day 1e to week 52e 
Renal functions 
Change measured by eGFR 
BL to Week 28 
Day 1e to week 52e 
Free hemoglobin 
Percent change 
BL to Week 28 
Day 1e to week 52e 
Bilirubin 
Change 
BL to Week 28 
Day 1e to week 52e 
Reticulocyte count 
Change 
BL to Week 28 
Day 1e to week 52e 
AH50 
Change 
BL to Week 28 
Day 1e to week 52e 
 
Percent change 
BL to Week 28 
Day 1e to week 52e 
PNH erythrocytes 
Change 
BL to Week 28 
Day 1e to week 52e 
PNH granulocytes 
Change 
BL to Week 28 
Day 1e to week 52e 
Role Functioning 
Change in Functional Scale 
Scores: EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Emotional 
Functioning 
Change in Functional Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Cognitive 
Functioning 
Change in Functional Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Social Functioning 
Change in Functional Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Fatigue 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Nausea and Vomiting 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Pain 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Dyspnea 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Insomnia 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Appetite Loss 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
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Measurement 
Metric 
Time Period in 
OLTP 
Time Period in 
OLEP 
Constipation 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Diarrhea 
Change in Symptom Scale: 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Stability in global 
health status 
Proportion with stability based 
on accepted MIDs for the 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Stability in 
functioning, and 
symptoms 
Proportion with stability based 
on accepted MIDs for the 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Stability in symptoms 
Proportion with stability based 
on accepted MIDs for the 
EORTC QLQ-C30 
BL to Week 28 
Day 1e to week 52e 
Treatment satisfaction 
Comparison between two 
therapies as assessed by TSQM 
BL to Week 28 
Not applicable 
Change in PNH 
symptoms 
De novo PNH Symptom-
Specific Questionnaire 
BL to Week 28 
Not applicable 
4.5. 
Safety Variables 
The safety variables are 
• TEAEs 
• Body weight 
• Vital signs 
• Electrocardiogram (ECG) 
• Physical examination 
• Routine safety laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
testing [for WOCBP only]) 
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4.5.1. 
Adverse Events and Serious Adverse Events 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
For safety variables, there are four observation periods: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of the combination treatment 
• The OLTP on-treatment period is defined as the time of first dose of the combination 
treatment in the OLTP to: 
− For Arm 1, the last dose of study drug (Q4W) in the OLTP + 4 weeks but before 
first dose of OLEP 
− For Arm 2, the last dose of pozelimab (Q2W) in the OLTP + 2 weeks, or the last 
dose of cemdisiran (Q4W) in the OLTP + 4 weeks, whichever is later , but  before 
first dose of OLEP 
• The OLEP on-treatment period is defined as the time of first dose of the combination 
treatment in the OLEP to: 
− For Arm 1, the last dose of study drug (Q4W) in the OLEP + 4 weeks 
− For Arm 2, the last dose of pozelimab (Q2W) in the OLEP + 2 weeks, or the last 
dose of cemdisiran (Q4W) in the OLEP + 4 weeks, whichever is later 
• The post-treatment period is defined as the time after the end of the OLTP on-treatment 
period or OLEP on-treatment period, whichever is later. 
Pre-treatment AEs are defined as AEs that developed or worsened during the pre-treatment 
period.  
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened after the first 
dose of combination treatment and during treatment. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol.  
The severity of AEs and of infusion reaction AEs are graded according to the criteria given in the 
protocol.  
 Pregnancy and symptomatic overdose of study drug events require expedited reporting to the 
sponsor, and they will be described.  
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4.5.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) are AEs (serious or non-serious) required to be 
monitored, documented, and managed in a pre-specified manner as described in the protocol 
sections 10.1.3 and 10.1.4.  
4.5.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, urinalysis, and other. 
Clinical laboratory values will be grouped by function in summary tables.  Laboratory tests are 
categorized in the protocol as follows: 
• Hematology 
• Coagulation panel 
• Chemistry, including LDH 
• Urinalysis 
• Other tests 
4.5.4. 
Vital Signs 
Temperature, pulse, systolic and diastolic blood pressure will be collected. 
4.5.5. 
12-Lead Electrocardiography (ECG) 
Heart rate will be recorded from the ventricular rate, and the PR, QRS, and QT, and QTcF will 
also be recorded. 
4.6. 
Pharmacokinetic Variables  
The PK variables are the concentrations of total pozelimab, total C5 (target), cemdisiran, 
cemdisiran metabolites, and time. 
4.7. 
Immunogenicity Variables  
The immunogenicity variables include ADA status and titer at nominal sampling time/visit. Serum 
samples for ADA will be collected at the clinic visits specified in Appendix 10.1. For each study 
drug, samples positive in the ADA assay will be further characterized for ADA titers. 
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4.8. 
Pharmacodynamic Variables 
Pharmacodynamic and other biomarker variables include, but are not limited to, the following:  
• CH50 (an assay assessing the activity of the classical pathway of complement) will be 
used to measure C5 activity. This is the principle PD marker for the study and is also 
an efficacy variable in this study (Section 5.2.1 of the protocol). 
• Parameters of intravascular hemolysis: i.e., haptoglobin, reticulocyte count, and 
bilirubin 
• Free hemoglobin 
• Alternative pathway hemolytic activity, as measured by AH50   
• Complement activation markers: i.e., sC5b-9 
• PNH clone size: i.e., PNH erythrocytes and granulocytes 
The list may be altered or expanded, as it is recognized that more relevant or novel biomarkers 
may be discovered during the course of this study. 
4.9. 
Clinical Outcome Assessments (COAs) 
COAs include the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 
the EORTC-QLQ-C30, the Treatment Satisfaction Questionnaire for Medication (TSQM), and the 
PNH Symptom-Specific Questionnaire.  
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, Q1, Q3, minimum, and 
maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and for all patients combined. Baseline is defined as the last available value prior to study drug 
administration unless otherwise specified.   
5.2. 
Medical History 
Medical history will be descriptively summarized by treatment group and overall for the study in 
the safety analysis set. 
All reported patient medical history will be presented by primary SOC and PT.  The tables will be 
presented by SOC sorted alphabetically and decreasing patient frequency of PT.  In addition, all 
medical history of specific interest will be summarized by patient incidence and percentage. 
5.3. 
Prior/concomitant Medications  
All prior medications will be descriptively summarized by treatment group and overall for the 
study, for patients in the safety set. Summaries will present patient counts (and percentages) for 
all prior medications, by decreasing frequency of the overall incidence of ATC followed by 
therapeutic class.  In the case of equal frequency across anatomic or therapeutic categories, 
alphabetical order will be used. Patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication but may be counted again for a different category if the same 
medication falls under multiple categories.   
All concomitant medications will be descriptively summarized for patients in the safety set, 
separately for the OLTP and OLEP on-treatment periods, as defined in Section 4.5.1.  In the case 
of equal frequency across anatomic or therapeutic categories, alphabetical order will be used. 
Patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication, and hence may be counted again for a different category if the same medication falls 
under multiple categories. 
For the post-treatment period, medications will be listed. 
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5.4. 
Prohibited Medications  
A listing of prohibited medications will be provided for the patients in the safety analysis set for 
the treatment period. 
5.5. 
Patient Disposition 
The following displays will be provided: 
• The total number of screened patients: signed the main ICF 
• The total number of randomized patients  
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from the study treatment, and the 
reasons for discontinuation 
• A listing of patients prematurely discontinued from treatment, along with reasons 
discontinuation 
• Total number of patients who received treatment intensification 
• Total number of patients who continued into the OLEP 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Compliance with each protocol-defined investigational product will be calculated for each study 
period as follows: 
Treatment Compliance = (Number of investigational product doses taken during the study 
period)/(Number of investigational product doses prescribed to be taken during the study 
period) x 100%. 
Separate summaries will be provided for pozelimab and cemdisiran by treatment group. 
5.6.2. 
Exposure to Investigational Product 
Treatment exposure will be presented separately for pozelimab and cemdisiran by treatment group. 
The duration of study drug exposure for a study period is calculated as: 
(Date of last administration of study drug – date of the first administration of study drug 
for the study period) + 28 days (for Q4W dosing), and 
(Date of last administration of study drug – date of the first administration of study drug 
for the study period) + 14 days (for Q2W dosing) 
Summaries (including the number of patients exposed, the duration of exposure, and the dose 
regimen to which patients were exposed) will be provided for pozelimab and cemdisiran. 
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The total number of complete and incomplete study drug administrations will be summarized. 
In addition, the number of patients exposed to the investigational product will be presented by 
specific time period. The time periods of interest are as follows: 
For the OLTP: 
• ≥ Day 29 (Week 4) 
• ≥ Day 57 (Week 8) 
• ≥ Day 85 (Week 12)  
• ≥ Day 113 (Week 16)  
• ≥ Day 141 (Week 20) 
• ≥ Day 197 (Week 28) 
For OLEP: 
• ≥ Day 57 (Week 8) 
• ≥ Day 113 (Week 16) 
• ≥ Day 169 (Week 24)  
• ≥ Day 225 (Week 32)  
• ≥ Day 281 (Week 40) 
• ≥ Day 365 (Week 52) 
Few patients are expected to be in the intensified OLTP; their exposure information will be listed. 
5.7. 
Analyses of Efficacy Variables 
There are no primary efficacy variables in this study. The analysis is determined by type of efficacy 
variable (i.e., continuous or binary). Secondary efficacy analysis for the optional OLEP will be 
performed using the same approach described for corresponding analyses in the OLTP, described 
in sections 5.7.1  and 5.7.2 . Analyses will be performed on the FAS.  Levels of LDH in serum 
will be analyzed by a central laboratory. Efficacy analysis of LDH will be based on central 
laboratory data.   In an attempt to exclude hemolyzed samples, LDH values will be excluded from 
the analysis if the LDH was ≥ 2 x ULN and potassium was ≥ 6 mmol/L, in the absence of an event 
of breakthrough hemolysis. LDH values will be included in the analysis if there is an associated 
breakthrough hemolysis. 
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5.7.1. 
Analysis of Continuous Secondary Efficacy Variables 
Percent change from pre-treatment mean LDH to the mean of LDH at weeks 24 and 28 will be 
analyzed using multiple imputation (MI) with an Analysis of Covariance (ANCOVA) model based 
on the FAS. Missing data for the mean of LDH at weeks 24 and 28 will be imputed 30 times to 
generate 30 complete data sets by using the SAS procedure MI as follows:  
• Step 1: A monotone missing pattern for each treatment arm separately is induced by 
the Markov Chain Monte Carlo (MCMC) method in the MI procedure using seed 
number 39182092. 
• Step 2: The missing data at subsequent visits will be imputed using the regression 
method with seed number 39182092 adjusting for treatment group, pre-treatment mean 
LDH, and all values at preceding visits. The mean of LDH at weeks 24 and 28 will be 
calculated based on the imputed complete data. 
The percent change from pre-treatment mean LDH to the mean of LDH at weeks 24 and 28 of 
each of the 30 complete datasets will be analyzed using an Analysis of Covariance (ANCOVA) 
with treatment group and pre-baseline mean LDH included in the model, and the SAS 
MIANALYZE procedure will be used to generate valid statistical inferences by combining results 
from the 30 analyses using Rubin’s formula (Rubin 1987). As an additional analysis, the 
ANCOVA model will be fitted using only available data. 
All other secondary efficacy variables involving change or percent change from baseline to week 
28 will be analyzed using multiple imputation (MI) with an Analysis of Covariance (ANCOVA) 
model based on the FAS. Imputation and modeling will be done as described above; the same seed 
will be used. 
The AUC (based on the trapezoidal rule) of LDH over time from baseline through week 28, and 
from week 4 through week 28 will be calculated based on observed data and will be analyzed using 
an ANCOVA model comparing treatments, with baseline LDH as a covariate. 
For rate and number of units of transfusion with RBCs from baseline through week 28, the analysis 
set will consist of all treated patients up to the time they intensified treatment, if applicable. The 
rate of units of transfusion for a patient will be calculated based on the duration of treatment 
exposure of the patient and will be analyzed with negative binomial model with treatment group 
as a term.  The number of transfusions will be summarized descriptively by treatment group. 
5.7.2. 
Analysis of Categorical Secondary Efficacy Variables 
Proportions and 95% confidence intervals by the Clopper Pearson exact method for the endpoints 
will be reported by treatment group and overall. A Fisher’s exact test will be performed to assess 
the difference between groups. Patients with missing data will be considered as failures or non-
responders. 
For the secondary variable of breakthrough hemolysis through week 28, defined as the 
measurement of LDH ≥ 2 x ULN  at any time subsequent to an initial achievement of disease 
control (i.e., LDH ≤ 1.5 x ULN) concomitant with associated signs or symptoms, the proportion 
of patients achieving normalization of their intravascular hemolysis will be calculated, along with 
a 95% confidence interval by the exact Clopper Pearson method.  Signs and symptoms will be 
tabulated, as will number of breakthrough hemolyses per patient. 
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For the secondary variable of the proportion of patients achieving adequate control of their LDH 
(defined as LDH ≤ 1.5 x ULN at every scheduled time point between week 4 through week 28, 
inclusive), patients who have one or more of the following will be considered as not achieving 
adequate control of their intravascular hemolysis:  
• Have at least one measurement of LDH  > 1.5 x ULN 
• Discontinue from study treatment early 
• Have 2 consecutive missing values of the scheduled LDH measurements 
• Have 25% or more missing values of the scheduled LDH measurements 
• Having received intensified treatment 
Patients who complete study treatment, have no more than 2 consecutive missing values of the 
scheduled LDH measurements between week 4 and week 28, have fewer than 25% missing values 
of the scheduled LDH measurements between week 4 and week 28 and have no breakthrough 
hemolysis will be evaluated based on their non-missing LDH measurements.  The analysis will be 
based on scheduled central laboratory data. The proportion of patients achieving adequate control  
of their intravascular hemolysis will be calculated, along with a 95% confidence interval, by the 
exact Clopper Pearson method for each treatment group separately. In addition, proportion of 
patients with LDH ≤1.50 x ULN at each scheduled assessment timepoint will be summarized. A 
similar summary will be presented for patients with normalization of LDH. 
For the endpoints of adequate control of hemolysis at each visit and normalization of LDH at each 
visit, proportions of response will be tabulated by visit. 
For the secondary variable of the rate of transfusion of RBCs through week 28, the 28-week total 
for each patient will be used.  A mean and 95% confidence interval will be calculated for each 
treatment group and for the treatment difference, based on the assumption of a negative binomial 
distribution of the rate of transfusions with RBCs.  
5.7.3. 
Analysis of Exploratory Variables 
For the incidence of MAVE through week 28, the proportion of patients with at least one MAVE 
will be presented along with  95% confidence interval using exact Clopper-Pearson for each 
treatment group separately. A Fisher’s exact test will be performed to assess the difference between 
groups. 
For change-from-baseline exploratory variables, descriptive statistics will be presented for 
baseline, week 28 and the change from baseline, for each treatment group, along with the treatment 
difference. 
Results of exploratory endpoint analyses may be reported separately from the CSR. 
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5.8. 
Analysis of Safety Data 
The primary endpoint is the incidence and severity of TEAEs through Week 28 of the OLTP.  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Appendix 10.2. 
The summary of safety results will be presented by treatment group and overall, separately for 
OLTP and OLEP. 
For patients who enter the OLEP, safety data will be summarized in a similar manner. 
For patients who received intensified treatment, safety data after intensified treatment will be 
listed. 
5.8.1. 
Adverse Events  
Summaries that include frequencies and proportions of patients reporting AEs will include the PTs 
and the SOCs. Summaries will be presented for the OLTP on-treatment period, the OLEP on-
treatment period, and the post-treatment period.  
Summaries of all TEAEs will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity  presented by SOC and PT 
• Study drug related TEAEs presented by SOC and PT 
• Treatment-emergent AESIs (defined by experiencing a prespecified PT or prespecified 
grouping of PTs, or by being put in a grouping specified in the CRF) 
• Non-serious TEAEs by SOC and PT 
Deaths and other SAEs will be listed and summarized. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
5.8.2. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure) will be summarized by treatment group and overall 
for baseline and change from baseline to each scheduled assessment time point with descriptive 
statistics. 
Listings will be provided with flags indicating treatment-emergent PCSVs. 
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5.8.3. 
Analysis of Laboratory Tests 
Laboratory test results will be summarized by treatment group and overall for baseline and change 
from baseline to each scheduled assessment time point with descriptive statistics. 
Number and percentage of patients with a potentially clinically significant value (PCSV) at any 
post-treatment time point will be summarized for each clinical laboratory test. 
For samples with LDH ≥ 2 x ULN and potassium ≥ 6 mmol/L, the potassium, ALT, AST, 
magnesium, and phosphorous will not be used in the analysis due to hemolysis possibly caused by 
sample mishandling. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
5.8.4. 
Analysis of 12-Lead ECG 
ECG parameters (PR interval, QT interval, QTcF interval, QRS interval, and heart rate [from 
ventricular rate]) will be summarized by treatment group and overall for baseline and change from 
baseline to each scheduled and collected assessment time. Listings will be provided with flags 
indicating PCSVs. 
5.9. 
Analysis of Pharmacokinetic and Immunogenicity Data 
5.9.1. 
Analysis of Pharmacokinetic Data  
Summary of concentrations of total pozelimab, cemdisiran, cemdisiran metabolites and total C5 
will be presented by nominal time point (i.e., the time points specified in the protocol). Individual 
data will be presented by actual time. Plots of the concentrations of total pozelimab, total C5, 
cemdisiran and cemdisiran metabolites will be presented over time (linear and log scales). When 
the scale is linear, concentrations below the lower limit of quantification (LLOQ) will be set to 
zero. In the log-scaled figures, concentrations below the LLOQ will be imputed as LLOQ/2. 
Summary statistics of concentrations of total pozelimab, total C5, cemdisiran and cemdisiran 
metabolites may include, but are not limited to arithmetic mean, standard deviation, standard error 
of the mean, coefficient of variation (in %), minimum, Q1, median, Q3, and maximum. 
No formal statistical analysis will be performed. 
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5.9.2. 
Analysis of Immunogenicity Data 
5.9.2.1. 
Analysis of ADA Data 
Analyses will be performed separately for ADA against cemdisiran and ADA against pozelimab 
in all study cohorts unless otherwise specified. The immunogenicity variables described in 
Section 4.7 will be summarized using descriptive statistics.  
Immunogenicity will be characterized by ADA status, ADA category and maximum titer observed 
in patients in the ADA analysis set. 
The ADA status of each patient may be classified as one of the following: 
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as 4-fold (for anti-cemdisiran) and 9-fold (for anti-pozelimab) over the 
baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay 
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥4-fold (for anti-cemdisiran) or ≥9-fold (for anti-pozelimab) 
over the baseline titer value .  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows: 
• Treatment-emergent is further sub-categorized as: 
− Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples  
− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples  
The maximum titer category of each patient is classified as: 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
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The following listings will be provided: 
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of pre-existing patients 
• Number (n) and percent (%) of treatment-emergent ADA positive patients 
• Number (n) and percent (%) of persistent treatment-emergent ADA positive patients 
• Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
• Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.9.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.9.3.1. 
Immunogenicity and Exposure 
Association between immunogenicity and systemic exposure to pozelimab will be analyzed. Plots 
of pozelimab concentration may be provided to examine the potential impact of ADA category 
and maximum titer on these profiles.  
5.9.3.2. 
Immunogenicity and Safety and Efficacy 
Association between immunogenicity variables and safety may be explored with a primary focus 
on the following safety events during the TEAE period:  
• 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Association between immunogenicity variables and efficacy endpoints may be explored 
(e.g. scatter plot or spaghetti plot). 
The above-mentioned safety and efficacy analyses will be conducted using the following 
categories: 
• ADA Positive 
• Treatment-emergent 
• Treatment-boosted 
• Maximum post-baseline titer category 
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5.10. 
Analysis of Pharmacodynamic and Biomarker Data 
Pharmacodynamic and biomarker variable listed in Section 4.8 may be analyzed and summarized.  
For each biomarker variable, time profile and percent of change from baseline  at each time point 
will be summarized through 28 weeks. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. If the 
scheduled baseline day 1 measurements are not available, screening assessments may be used; 
when scores are used, this rule applies to scores, not individual variables. 
6.2. 
Data Handling Convention for Missing Data 
Rules for handling missing data for secondary efficacy variables are described in Section 5.7. 
For categorical variables, patients with missing data are not included in calculations of percentages 
unless otherwise specified. When relevant, the number of patients with missing data is presented. 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
6.2.1. 
Adverse events 
If the severity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
severity of TEAE. If the measurement of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date  
AE start date will be used for AE classification and analysis. If AE start date is not complete, then 
the character variable will keep the original incomplete date, the numerical date variable will be 
imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
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Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE starting date imputation, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use the last study 
visit date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 31 
December as the day and month. If this leads to a date after end of study follow up date, use the 
last study visit date instead. 
If AE end year is missing: Impute AE end date using the end of follow up date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment (described in Section 5.8) medication or 
concomitant medication or both, the missing medication start date is estimated as early as possible, 
and the missing medication end date is estimated as late as possible. If the medication start date is 
missing, the onset day will not be calculated in medication listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01 January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before informed consent date. Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, in 
order to simplify the programming flow, the imputation is proposed to align with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date -
1 instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
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Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
No imputations for missing laboratory data, ECG data, vital sign data, or physical examination 
data will be made. 
6.2.2. 
PCSV 
Patients who had post-baseline PCSV, but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.2.3. 
Date of first / last study drug administration 
Date of first study drug administration is the first non-missing start date of dosing filled in the CRF 
“Investigational Product” module. 
If a patient’s date of the last dose is totally missing or unknown, his/her last visit date will be 
substituted.  
6.3. 
Analysis Windows 
Data analyzed by visit (including efficacy, laboratory data, vital signs, ECG) will be summarized 
by the study scheduled visits described Appendix 10.1 (Schedule of Time and Events). The 
analysis visit windows will be exhaustive so that all available values obtained from unscheduled 
visits, early termination visit (ETV) and end of treatment (EOT)/end of study (EOS) have the 
potential to be summarized. No analysis visit windows will be applied to the study scheduled visits. 
The visit windows are constructed using ranges applied to the number of days in study (study days) 
when the measure is collected.  Day 1 is defined as the first date of study treatment. Analysis 
windows are given in Tables 1 and 2. 
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Table 1: 
Efficacy Analysis Windows 
Visit 
Targeted Study Day 
Analysis Windows 
Haptoglobin 
PNH Eryth, 
PNH Gran 
CH50, AH50, 
sC5b-9 
FACIT-Fatigue, 
EORTC-QLQ-
C30, TSQM 
Screening 
  
Scr 1 
Scr 1 
Scr 1 
  
Week 0 
1 
1 
  
1 
1 
Week 1 
8 
  
  
[2, 12] 
  
Week 2 
15 
  
  
[13, 25] 
[2, 25] 
Week 4 
29 
[2, 81] 
  
[26, 53] 
[26, 53] 
Week 6 
43 
  
  
  
  
Week 8 
57 
  
[2,133] 
[54, 81] 
[54, 81] 
Week 10 
71 
  
  
  
  
Week 12 
85 
[82, 189] 
  
[82, 105] 
[82, 105] 
Week 16 
113 
  
  
[106, 133] 
[106, 133] 
Week 20 
141 
  
[134, 189] 
[134, 161] 
[134, 161] 
Week 24 
169 
  
  
[162, 189] 
[162, 189] 
Week 28 
197 
[190, 204] 
[190, 204] 
[190, 204] 
[190, 204] 
OLEP-1 (Week 0e) 
1e 
1e 
1e 
1e 
1e 
OLEP-2 (Week 8e) 
57e 
  
  
  
  
OLEP-3 (Week 16e) 
113e 
  
  
[2e, 217e] 
  
OLEP-4 (Week 24e) 
169e 
  
[2e, 357e] 
  
[2e, 357e] 
OLEP-5 (Week 32e) 
225e 
  
  
[218e, 357e] 
  
OLEP-6 (Week 40e) 
281e 
  
  
  
  
OLEP-7 (Week 52e) 
365e 
[2e, 368e] 
[358e, 368e] 
[358e, 368e] 
[358e, 368e] 
 
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Table 2: 
Safety Analysis Windows 
Visit 
Targeted 
Study 
Day 
Analysis Windows 
Blood Chem (Including 
LDH), Coagulation 
Hematology 
(Including 
Hemoglobin), 
Urinalysis 
Vital Signs 
ECG 
Body 
Weight 
Screening 
  
  
  
Scr 1 
  
Scr 1 
Week 0 
1 
1 
1 
  
1 
  
Week 1 
8 
[2, 12] 
[2, 12] 
  
  
  
Week 2 
15 
[13, 25] 
[13, 25] 
[2, 25] 
  
  
Week 4 
29 
[26, 39] 
[26, 53] 
[26, 53] 
  
[2, 53] 
Week 6 
43 
[40, 53] 
  
  
  
  
Week 8 
57 
[54, 67] 
[54, 81] 
[54, 81] 
  
[54, 81] 
Week 10 
71 
[68, 81] 
  
  
  
  
Week 12 
85 
[82, 105] 
[82, 105] 
[82, 105] 
  
[82, 105] 
Week 16 
113 
[106, 133] 
[106, 133] 
[106, 133] 
  
[106, 133] 
Week 20 
141 
[134, 161] 
[134, 161] 
[134, 161] 
  
[134, 161] 
Week 24 
169 
[162, 189] 
[162, 189] 
[162, 189] 
  
[162, 217] 
Week 28 
197 
[190, 204] 
[190, 204] 
[190, 204] 
[2, 204] 
[190, 204] 
OLEP-1 (Week 0e) 
1e 
1e 
1e 
1e 
1e 
1e 
OLEP-2 (Week 8e) 
57e 
[2e, 105e] 
[2e, 105e] 
[2e, 105e] 
  
[2e, 105e] 
OLEP-3 (Week 16e) 
113e 
[106e, 161e] 
[106e, 161e] 
[106e, 161e] 
  
[106e, 161e] 
OLEP-4 (Week 24e) 
169e 
[162e, 217e] 
[162e, 217e] 
[162e, 217e] 
  
[162e, 217e] 
OLEP-5 (Week 32e) 
225e 
[218e, 273e] 
[218e, 273e] 
[218e, 273e] 
  
[218e, 273e] 
OLEP-6 (Week 40e) 
281e 
[274e, 357e] 
[274e, 357e] 
[274e, 357e] 
  
[274e, 357e] 
OLEP-7 (Week 52e) 
365e 
[358e, 368e] 
[358e, 368e] 
[358e, 368e] 
[2e, 368e] 
[358e, 368e] 
6.4. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations will 
be presented in listings. 
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7. 
INTERIM ANALYSIS 
An interim analysis may be conducted after 6 patients have completed at least 16 weeks of the 
OLTP. Additional/other interim analyses may be performed to support regulatory interactions. No 
alpha adjustment will be applied for the interim analysis since all analyses are descriptive. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher, or using R. 
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9. 
REFERENCES 
1. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
 
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10. 
APPENDIX 
10.1. 
Schedule of Time and Events 
Footnotes for Tables 3 through 6 can be found immediately after Table 6. 
Table 3: 
Schedule of Events (Open-Label Treatment Period) 
 
Screening 
Period 
Open-Label Treatment Period 3 
Study Procedure (Visit) 1 ,2 
Screening 
V1 
 
V24  
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
EOT5 
V13 
Week  
Up to -1 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
Day 
Up to -8 
1 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
Window (day) 
-- 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 -7/+3 -7/+3 
-7/+3 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consents for OLEP, FBR, and genomics 
research (optional) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 6 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 7  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of vaccination for Neisseria 
meningitidis (or revaccination) 8  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Risk assessment for Neisseria gonorrhea 9  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis 10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x  
x 
x 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Study Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 1 only: Pozelimab 400 mg SC Q4W 11 
 
x12  
 
 
x 
 
x 
 
x 
x 
x 
x 
 
Arm 2 only: Pozelimab 400 mg SC Q2W 11 
 
x12 
 
x 
x 
x 
x 
x 
x 
x 
x 
x11 
 
Cemdisiran 200 mg SC Q4W 11 
 
x12 
 
 
x 
 
x 
 
x 
x 
x 
x 
 
Injection training/patient instructions (as needed) 13 
 
 
<---------------------------------------------x----------------------------------------> 
 
Patient diary 14  
x 15  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Antibiotics prophylaxis (recommended) 16 
<----------------------------------------------------------------x----------------------------------------------------------> 
Revaccination against meningococcal infection (if 
needed) 
<----------------------------------------------------------------x----------------------------------------------------------> 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 45 of 63 
 
Screening 
Period 
Open-Label Treatment Period 3 
Study Procedure (Visit) 1 ,2 
Screening 
V1 
 
V24  
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
EOT5 
V13 
Week  
Up to -1 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
Day 
Up to -8 
1 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
Window (day) 
-- 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 -7/+3 -7/+3 
-7/+3 
Clinical Outcome Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue  
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
EORTC-QLQ-C30 
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
TSQM 
 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH symptom-specific questionnaire (daily) 17 
<----------------------------------------------------------------x----------------------------------------------------------> 
PGIS 
 
x 
 
 
x 
 
 
 
x 
 
x 
 
x 
PGIC 
 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
Safety and Anthropometric: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
x 
 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
Electrocardiogram 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Breakthrough hemolysis assessment 18  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant meds/treatments 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transfusion record update 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Testing 19 : 
 
 
 
 
 
 
 
 
 
 
 
 
 
Titers to measure N. meningitidis (only if required per 
parent study) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (long panel) including LDH 20  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 21  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Immunoglobulin G 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Pregnancy test (WOCBP only): serum (S) or urine (U) 
s 
u 
 
 
u 
 
u 
 
u 
u 
u 
u 
u 
Urinalysis   
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Pharmacokinetics and Immunogenicity Sampling: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab conc. sample 22  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Cemdisiran and its metabolite conc. sample 22  
 
x 
 
 
x 
 
 
 
x  
 
 
x 
 
Pozelimab immunogenicity sample 24  
x 
 
  
 
  
 
 
 
x  
 
 
 
x 
Cemdisiran immunogenicity sample 24   
 
x 
 
 
  
 
 
 
x  
 
 
 
x 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 46 of 63 
 
Screening 
Period 
Open-Label Treatment Period 3 
Study Procedure (Visit) 1 ,2 
Screening 
V1 
 
V24  
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
EOT5 
V13 
Week  
Up to -1 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
28 
Day 
Up to -8 
1 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
197 
Window (day) 
-- 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 -7/+3 -7/+3 
-7/+3 
Total C5 (plasma) 22  
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free hemoglobin 
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Haptoglobin 
x 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
Complement hemolytic assay (serum CH50) 25 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Complement hemolytic assay (serum AH50) 25 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
sC5b-9 (plasma) 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH erythrocyte cells 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
PNH granulocyte cells 
x 
 
 
 
 
 
x 
 
 
 
x 
 
x 
Optional research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and plasma for FBR (optional) 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
Whole blood sample for DNA isolation for genomics 
research (optional) 26  
 
x 
 
 
 
 
 
 
 
 
 
 
  
Whole blood RNA sample for genomics research 
(optional) 
 
x 
x 
 
 
 
 
 
 
 
 
 
x 
 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 47 of 63 
Table 4: 
Schedule of Events for Patients on Intensified Treatment in the OLTP 
Study Procedure (Visit) 1 ,2 
Intensified Treatment Period in the OLTP 3 
RV1  
RV2 
RV3 
RV4 
RV5 
RV6 
RV7 
RV8 
RV9 
RV10 
RV11 
EOT 
RV12 
Week  
0r 
1r 
2r 
4r 
6r 
8r 
10r 
12r 
16r 5 
20r 5 
24r 5 
28r 6  
Day 
1r 
8r 
15r 
29r 
43r 
57r 
71r 
85r 
113r 
141r 
169r 
197r 
Window (day) 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Intensified Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab 30 mg/kg IV (loading dose) 4  
x7  
 
 
 
 
 
 
 
 
 
 
 
Pozelimab 400 mg SC Q2W 4 
x7 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 4 
 
Cemdisiran 200 mg SC Q4W 4 
x7 
 
 
x 
 
x 
 
x 
x 
x 
x 
 
Injection training/patient instructions (as needed) 8 
 
<---------------------------------------------------x------------------------------------------------> 
 
Patient diary 9  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Antibiotics prophylaxis (recommended) 10 
<----------------------------------------------------------------x--------------------------------------------------------> 
Revaccination against meningococcal infection (if 
needed) 
<----------------------------------------------------------------x--------------------------------------------------------> 
Clinical Outcome Assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue  
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
EORTC-QLQ-C30 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
TSQM 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH symptom-specific questionnaire (daily) 11 
<----------------------------------------------------------------x--------------------------------------------------------> 
PGIS 
x 
 
 
x 
 
 
 
x 
 
x 
 
x 
PGIC 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
Safety and Anthropometric: 
 
 
 
 
 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis 12  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Body weight 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Vital signs 
x 
 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Breakthrough hemolysis assessment 13  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant meds/treatments 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transfusion record update 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 48 of 63 
Study Procedure (Visit) 1 ,2 
Intensified Treatment Period in the OLTP 3 
RV1  
RV2 
RV3 
RV4 
RV5 
RV6 
RV7 
RV8 
RV9 
RV10 
RV11 
EOT 
RV12 
Week  
0r 
1r 
2r 
4r 
6r 
8r 
10r 
12r 
16r 5 
20r 5 
24r 5 
28r 6  
Day 
1r 
8r 
15r 
29r 
43r 
57r 
71r 
85r 
113r 
141r 
169r 
197r 
Window (day) 
-- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Laboratory Testing 14. : 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation panel 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Chemistry (long panel) including LDH 15  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 16  
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Immunoglobulin G 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Pregnancy test (WOCBP only) 17  
u 
 
 
u 
 
u 
 
u 
u 
u 
u 
u 
Urinalysis   
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Pharmacokinetics and Immunogenicity Sampling: 
 
 
 
 
 
 
 
 
 
 
 
 
Pozelimab drug conc. sample 18  
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Cemdisiran and its metabolite conc. sample 19  
x 
 
 
x 
 
 
 
x  
 
 
x 
 
Pozelimab immunogenicity sample 20  
x 
  
 
  
 
 
 
x  
 
 
 
x 
Cemdisiran immunogenicity sample 20 
x 
 
 
  
 
 
 
x  
 
 
 
x 
Total C5 (plasma) 18  
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Biomarkers: 
 
 
 
 
 
 
 
 
 
 
 
 
Free hemoglobin 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
Haptoglobin 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
Complement hemolytic assay (serum CH50) 21 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Complement hemolytic assay (serum AH50) 21 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
sC5b-9 (plasma) 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
PNH erythrocyte cells 
x 
 
 
 
 
x 
 
 
 
x 
 
x 
PNH granulocyte cells 
x 
 
 
 
 
x 
 
 
 
x 
 
x 
 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 49 of 63 
Table 5: 
Schedule of Events (Optional Open-Label Extension Period) 
Study Procedure (Visit) 1,2  
Optional Open-Label Extension Period 
OLEP-1 3  
OLEP-2 5 
OLEP-3 5 
OLEP-4  5 
OLEP-5  5 
OLEP-6 5 
OLEP-7 
Week  
0e 
8e 
16e 
24e 
32e 
40e 
52e 
Day 
1e 
57e 
113e 
169e 
225e 
281e 
365e 
Window (day) 
-- 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Treatment  4:  
 
 
 
 
 
 
 
Pozelimab 400 mg SC Q2W or Q4W  5 
x 
x 
x 
x 
x 
x 
x 
Cemdisiran 200 mg SC Q4W  5 
x 
x 
x 
x 
x 
x 
x 
Injection training/patient instructions (as needed) 6 
<-----------------------------------------------------------x---------------------------------------------------------> 
Patient diary 7 
x 
x 
x 
x 
x 
x 
x 
Antibiotics prophylaxis (recommended) 8 
<-----------------------------------------------------------x---------------------------------------------------------> 
Revaccination against meningococcal infection (if 
needed) 
<-----------------------------------------------------------x---------------------------------------------------------> 
Clinical Outcome Assessments: 
 
 
 
 
 
 
 
FACIT-Fatigue  
x 
 
 
x 
 
 
x 
EORTC-QLQ-C30 
x 
 
 
x 
 
 
x 
PGIS 
x 
 
 
x 
 
 
x 
PGIC 
x 
 
 
x 
 
 
x 
Safety and Anthropometric: 
 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis 9 
x 
x 
x 
x 
x 
x 
x 
Body weight 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
x 
 
x 
 
x 
Electrocardiogram 
x 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
Breakthrough hemolysis assessment 10 
x 
x 
x 
x 
x 
x 
x 
Concomitant meds/treatments 
x 
x 
x 
x 
x 
x 
x 
Transfusion record update 
x 
x 
x 
x 
x 
x 
x 
Laboratory Testing 11 : 
 
 
 
 
 
 
 
Coagulation panel 
x 
x 
x 
x 
x 
x 
x 
Chemistry (long panel) including LDH 12 
x 
x 
x 
x 
x 
x 
x 
Hematology  13 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (WOCBP only) 14 
u 
u 
u 
u 
u 
u 
u 
Urinalysis   
x 
x 
x 
x 
x 
x 
x 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 50 of 63 
Study Procedure (Visit) 1,2  
Optional Open-Label Extension Period 
OLEP-1 3  
OLEP-2 5 
OLEP-3 5 
OLEP-4  5 
OLEP-5  5 
OLEP-6 5 
OLEP-7 
Week  
0e 
8e 
16e 
24e 
32e 
40e 
52e 
Day 
1e 
57e 
113e 
169e 
225e 
281e 
365e 
Window (day) 
-- 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
-7/+3 
Pharmacokinetics and Immunogenicity: 
 
 
 
 
 
 
 
Pozelimab conc. sample 15 
x 
 
 
x 
 
 
x 
Cemdisiran and its metabolite conc. samples 16 
(pre-dose and 2 to 6 hours post-dose) 
x 
 
 
x 
 
 
x 
Pozelimab immunogenicity sample 17  
x 
  
 
x 
 
 
x 
Cemdisiran immunogenicity sample 17 
x 
 
 
x 
 
 
x 
Total C5 (plasma) 15 
x 
 
 
x 
 
 
x 
Biomarkers: 
 
 
 
 
 
 
 
Free hemoglobin 
x 
 
 
 
 
 
x 
Haptoglobin 
x 
 
 
 
 
 
x 
Complement hemolytic assay (serum CH50) 18  
x 
 
x 
 
x 
 
x 
Complement hemolytic assay (serum AH50) 18 
x 
 
x 
 
x 
 
x 
sC5b-9 (plasma) 
x 
 
x 
 
x 
 
x 
PNH erythrocyte cells 
x 
 
 
x 
 
 
x 
PNH granulocyte cells 
x 
 
 
x 
 
 
x 
Optional research: 
 
 
 
 
 
 
 
Serum and plasma for FBR (optional) 
x 
 
 
 
 
 
x 
Whole blood RNA sample for genomics research 
(optional) 
x 
 
 
 
 
 
x 
 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 51 of 63 
Table 6: 
Schedule of Events (Post-Treatment Safety Follow-Up Period) 
 
Post-Treatment Safety Follow-Up Period 
Patients in the OLTP who discontinue study 
treatment will be asked to remain in the study 
until week 28 EOT (or week 28r for patients who 
restarted on intensified treatment) and follow the 
original schedule of events as applicable. After the 
week 28 EOT visit, their entry point into the 
safety follow-up schedule will depend on the 
number of weeks that have elapsed since their last 
dose (i.e., a patient who is 20 weeks after their 
final dose of study treatment at EOT will enter 
into the safety follow-up period at visit FU-4 
[26 weeks after last dose]) 
Patients who completed 
week 28 (with last doses 
administered at week 24 or 
week 26, or week 26r) who 
choose not to continue 
treatment in the OLEP, 
patients who complete the 
OLEP, and patients who 
permanently discontinue 
treatment during the OLEP 
will start here: 
 
 
 
 
 
Study Procedure 
FU-1 
FU-2 
FU-3 
FU-4 
Phone visit  
FU-5 
Phone visit  
FU-6 
Week (after last dose of study drug) 
8 
12 
16 
26 
38 
52 
Day (after last dose of study drug) 
57 
85 
113 
183 
267 
365 
Window (day) 
±10 
±10 
±10 
±10 
±10 
±10 
Safety Assessments 
 
 
 
 
 
 
Patient safety card for Neisseria meningitidis1 
<----------------------------------------------------------------X----------------------------------------------------> 
Antibiotics prophylaxis (recommended)2 
<----------------------------------------------------------------X----------------------------------------------------> 
Vital signs 
x 
x 
x 
x 
 
 
Physical examination  
 
x 
 
x 
 
 
Concomitant meds and procedures 
x 
x 
x 
x 
x 
x 
Adverse event reporting 
x 
x 
x 
x 
x 
x 
Pregnancy reporting 
x 
x 
x 
x 
x 
x 
Laboratory Testing 
 
 
 
 
 
 
Hematology 
x 
x 
x 
x 
 
 
Blood chemistry 
x 
x 
x 
x 
 
 
 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 52 of 63 
Footnotes for Table 3 Schedule of Events (Treatment Period) 
1. Visits between week 6 and up to week 24 may be at the clinical site, or another preferred 
location, such as patient’s home. The location will be dependent on availability of home 
healthcare visiting professional as well as the preferences of the investigator and patient. In 
the event of travel restrictions due to a global pandemic, alternative mechanisms such as but 
not limited to telemedicine visits may be implemented to maintain continuity of study 
conduct. 
2. When multiple procedures are performed on the same day, the sequence of procedures is as 
follows: COAs → ECG →  vital signs, physical examination, safety monitoring → lab 
collection → study treatment administration → any pre-specified post-dose sample 
collection. 
3. Patients who are restarted on an intensified treatment will undergo an adjustment to their 
scheduled visits.  Patients may require unscheduled visit(s) as needed and should be 
subsequently followed per Table 4 Schedule of Events for Patients on Intensified Treatment 
in the OLTP. 
4. The day 1 visit should take place 7 to 8 days after the screening visit. Patients may be 
rescreened if they cannot schedule the screening visit and the day 1 visit over a period of 7 
to 8 days. 
5. If the patient agrees to continue into the optional OLEP, the EOT visit of the OLTP will 
correspond to the day 1e visit of the OLEP (see Table 5 Schedule of Events (Optional Open-
Label Extension Period)). Any common assessments will be performed once for both visits.  
6. Transfusions, breakthrough hemolysis history, and laboratory parameters for measurement 
of hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) 
should be obtained for the past 52 weeks, if possible.  Prior history of thrombosis and 
Neisseria infections will be collected.  Ongoing PNH symptoms and signs will also be 
collected. Information collected from parent studies may be used whenever possible. 
7. Including pozelimab administration. 
8. Patients will have had previous documented vaccination for meningococcus (serotypes A, 
C, Y, W and serotype B if available) in the Regeneron-sponsored parent study but may be 
revaccinated if prior vaccination is more than 5 years from screening. Alternatively, patients 
may be revaccinated in accordance with current national vaccination guidelines for 
vaccination use with complement inhibitors or local practice. Patients who require 
revaccination may be rescreened. 
9. A risk factor assessment for Neisseria gonorrhea infection is recommended, and counseling 
is advised for at-risk patients.  
10. A patient safety card will be distributed to patients at screening and risk information will be 
reviewed. Replacement cards may be given to the patient as needed. 
                                        VV-RIM-00284471-1.0 Approved - 14 Dec 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 53 of 63 
11. During OLTP, the dose of cemdisiran and pozelimab SC should be given on the day of the 
corresponding study visit whenever possible. Study treatment administration should always 
be the last procedure after all blood sample collection and study assessments have been 
completed unless otherwise specified.  
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 3 days before or up to 3 days 
after the planned dosing date for Q2W dosing, provided that the combination dosing 
takes place after the corresponding study visit has been completed. For patients 
receiving pozelimab 400 mg SC Q2W + cemdisiran 200 mg SC Q4W, the dosing 
window (±3 days) is the same or narrower than the visit window (±3 days before 
week 16 or -7/+3 days on and after week 16). 
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 7 days before or 7 days after 
the planned dosing date for Q4W dosing, provided that the combination dosing takes 
place after the corresponding study visit has been completed. For patients receiving 
pozelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W, the visit window (±3 days 
before week 16 or -7/+3 days starting from week 16) is narrower than the dosing 
window (±7 days). 
Care must be taken to coordinate dosing for visits where a post-dose sample is collected to 
measure the concentration of cemdisiran and its metabolites. The final SC dosing of the 
combination (pozelimab and cemdisiran) during the OLTP is at week 24 for arm 1 and the 
final SC dosing of cemdisiran is at week 24 with pozelimab at week 26 for arm 2.  
12. Patients should be monitored for at least 30 minutes after completing the first cemdisiran 
injection. A 30 minute monitoring period is not needed after the pozelimab injection. 
13. Injection training will be provided to patients who desire self-injection or injection by a 
designated person.  Site should observe patient self-injection or injection by a designated 
person and confirm adequacy.  Patient instruction materials will be provided.  SC injections 
may either be performed by the site personnel or another healthcare professional at the 
patient’s home or preferred location or be administered by the patient or a designated person 
who has successfully completed the injection training. 
14. If study treatment is given by the patient or by a designated person, the patient will complete 
a diary for recording compliance with study treatment administration. If patient diary is 
provided to the patient, then it should be reviewed at each clinic visit and data collected into 
the case report forms (CRFs). On the final visit, the diary should be collected by the site. 
15. At the screening visit, patient diary should be reviewed for the R3918-PNH-1868 (parent) 
study. 
16. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on 
the first day of dosing with study treatment and continuing until 52 weeks after 
discontinuation of study treatment.  
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 54 of 63 
17. Patient will complete daily PNH Symptom-Specific Questionnaire for 7 consecutive days 
prior to day 1 visit. Patients should try to complete the PNH Symptom-Specific 
Questionnaire at the same time each day whenever possible. 
18. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
will be collected as described for suspected breakthrough hemolysis assessment in 
Section 9.2.5.2 in the protocol unless already noted in the schedule of events for that visit.  
If the suspected event does not occur at a scheduled visit then an unscheduled visit should 
occur with an evaluation of the patient and collection of samples for suspected breakthrough 
hemolysis assessment as described in Section 9.2.5.2 in the protocol.  
19. Clinical lab samples will be collected prior to any study drug administration (pre-dose) 
unless otherwise specified. The same methodology will be applied across study visits for lab 
sample collection, handling, and processing, as best as possible, to preserve the quality of 
samples and minimize hemolysis. The coagulation blood sample (tube) must always be 
collected first, followed by the blood chemistry sample (tube). 
20. Serum LDH, C-reactive protein (CRP), and bilirubin (total and direct) will be assessed as 
part of the blood chemistry analysis. Blood chemistry sample should be collected before 
study treatment administration (pre-dose). During lab collection, handling and processing, 
the same methodology will be applied across study visits, as best as possible, to preserve the 
quality of sample and avoid hemolysis during sample processing. If the investigator or 
sponsor suspects that the lab result is not an accurate reflection of the patient’s condition, 
the lab sample should be repeated. 
21. Hematology sample should be collected before study treatment administration (pre-dose). 
22. Blood samples for pozelimab concentration analysis and total C5 analysis will be obtained 
on the specified days prior to any study treatment administration (pre-dose). 
23. Blood samples for cemdisiran concentration analysis and concentrations of its metabolites 
will be collected on the specified days prior to any study treatment administration (pre-dose) 
and 2 to 6 hours post cemdisiran administration. The post-dose sample should be carefully 
coordinated with the dosing of cemdisiran and may be collected at the clinic or by a visiting 
health care professional. 
24. Blood samples for immunogenicity will be collected on the specified days prior to any study 
treatment administration (pre-dose).  At the visits where immunogenicity samples are to be 
taken, the sample should be collected with the sample for drug concentration. In the event of 
suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional 
samples for drug concentration and immunogenicity may be collected at or near the onset 
and the resolution of the event. 
25. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study 
treatment administration (pre-dose). 
26. Whole blood samples for DNA extraction (optional) should be collected on day 1 (pre-dose) 
but can be collected at a later study visit. Patients who had consented to DNA testing in a 
prior Regeneron study with pozelimab and had provided a sample for analysis do not need 
to provide separate consent/sample for this study.  
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 55 of 63 
Footnotes for Table 4 Schedule of Events (for Patients on Intensified Treatment) 
1. Visits between week 6r and week 24r may be at the clinical site, or another preferred 
location, such as patient’s home. The location will be dependent on availability of home 
healthcare visiting professional as well as the preferences of the investigator and patient. In 
the event of travel restrictions due to a global pandemic, alternative mechanisms such as but 
not limited to telemedicine visits may be implemented to maintain continuity of study 
conduct. 
2. When multiple procedures are performed on the same day, the sequence of procedures is as 
follows: COAs → ECG→signs, physical examination, safety monitoring → lab collection 
→ study drug administration → any pre-specified post-dose sample collection. 
3. The intensified treatment schedule will be anchored to the day of intensification (i.e., a reset 
occurs with the day of intensification becoming the day 1r visit and subsequent visits 
following the schedule of events for intensified treatment). Patients who receive intensified 
treatment will be considered to have complete the study once they finish the 28-week 
treatment period with the intensified treatment (i.e., after completing week 28r EOT 
assessments). 
4. During the intensified treatment period in the OLTP, the dose of cemdisiran and pozelimab 
SC should be given on the day of the corresponding study visit whenever possible. Study 
treatment administration should always be the last procedure after all blood sample 
collection and study assessments have been completed unless otherwise specified.  If 
pozelimab or cemdisiran cannot be administered on the day of the corresponding study visit, 
the combination may be administered up to 3 days before or up to 3 days after the planned 
dosing date provided that the dosing takes place after the corresponding study visit has been 
completed. For example, the day 29r (week 4r) visit can take place from day 26r to day 32r 
given the visit window of ±3 days for the week 4r visit. The dose of pozelimab and 
cemdisiran therefore can be given from day 26r to day 32r, but only on or after the week 4r 
visit assessments have been performed. Similarly, the day 113r (week 16r) visit can take 
place from day 106r to day 116r given the visit window of -7/+3 days for the week 16r 
visit. The dose of pozelimab and cemdisiran can be given from day 110r to day 116r, but 
only on or after the week 16r visit assessments have been performed. Care must be taken to 
coordinate dosing for visits where a post-dose sample is collected to measure concentration 
of cemdisiran and its metabolites. For patients on intensified treatment in the OLTP, the 
final SC dose of cemdisiran is at week 24r and the final SC dose of pozelimab is at 
week 26r.  
5. For these visits, the dosing window (±3 days) is narrower than the study visit window (-7/+3 
days). 
6. If the patient agrees to continue into the optional OLEP, the EOT visit of the OLTP will 
correspond to the day 1e visit of the OLEP (see Table 5: Schedule of Events (Optional 
Open-Label Extension Period)5). Any common assessments will be performed once for both 
visits. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 56 of 63 
7. On day1r, pozelimab IV will be given first, with a 30-minute observation period before 
administration of SC doses. Subsequent pozelimab SC dose will be administered Q2W and 
cemdisiran SC dose will be administered Q4W. The SC injections may either be performed 
by the site personnel or another healthcare professional at patient’s home or preferred 
location or be administered by the patient or by a designated person who has successfully 
completed the injection training. 
8. Injection training will be provided to patients who desire self-injection or injection by a 
designated person.  Site should observe patient self-injection or injection by a designated 
person and confirm adequacy.  Patient instruction materials will be provided. 
9. If study treatment is given by the patient or by a designated person, the patient will complete 
a diary for recording compliance with study treatment administration. If patient diary is 
provided to the patient, then it should be reviewed at each clinic visit and data collected into 
the CRFs. On the final visit, the diary should be collected by the site. 
10. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended until 
52 weeks after discontinuation of study treatment. 
11. Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time 
each day whenever possible. 
12. Patient safety card: Site should review the instructions on the safety card with the patient at 
each visit. Replacement cards may be given to the patient as needed. 
13. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
for drug concentrations of pozelimab will be collected unless already noted in the schedule 
of events for that visit.  If the suspected event does not occur at a scheduled visit then an 
unscheduled visit should occur with an evaluation of the patient and collection of 
coagulation, chemistry, and drug concentrations of pozelimab. 
14. Clinical lab samples will be collected prior to any study drug administration (pre-dose) 
unless otherwise specified. During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis. The coagulation blood sample (tube) must always be 
collected first, followed by the blood chemistry sample (tube). 
15. Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood 
chemistry analysis. Blood chemistry sample should be collected before study treatment 
administration (pre-dose). During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis during sample processing. If the investigator or sponsor 
suspects that the lab result is not an accurate reflection of the patient’s condition, the lab 
sample should be repeated. 
16. Hematology sample should be collected before study treatment administration (pre-dose). 
17. Pregnancy test for WOCBP: A urine test will be done at all visits indicated. Any positive 
urine pregnancy test should be confirmed with a serum pregnancy test. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 57 of 63 
18. On day 1r, obtain blood sample for pozelimab concentration and total C5 prior to IV 
administration of pozelimab and also within 15 minutes after the end of the IV infusion. At 
subsequent timepoints, blood samples for pozelimab drug concentration analysis and total 
C5 analysis will be obtained prior to any study treatment administration (pre-dose). 
19. Blood samples for cemdisiran drug concentration analysis and concentrations of its 
metabolites will be collected on the specified days prior to any study treatment 
administration (pre-dose) and 2 to 6 hours post cemdisiran administration. The post-dose 
sample should be carefully coordinated with the dosing of cemdisiran and may be collected 
at the clinic or by a visiting health care professional. 
20. Blood samples for immunogenicity will be collected on the specified days prior to any study 
treatment administration (pre-dose).  At the visits where immunogenicity samples are to be 
taken, the sample should be collected with the sample for drug concentration. In the event of 
suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional 
samples for drug concentration and immunogenicity may be collected at or near the onset 
and the resolution of the event. 
21. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study 
treatment administration (pre-dose). 
Footnotes for Table 5 Schedule of Events (for Open-Label Extension Period) 
1. Visits may be at the clinical site or another preferred location, such as the patient’s home. The 
location will depend on availability of home healthcare visiting professional as well as the 
preferences of the investigator and patient. In the event of travel restrictions due to a global 
pandemic, alternative mechanisms such as but not limited to telemedicine visits may be 
implemented to maintain continuity of study conduct. 
2. When multiple procedures are performed on the same day, the sequence of procedures is as 
follows: COAs → ECG → vital signs, physical examination, safety monitoring → lab 
collection → study drug administration → any pre-specified post-dose sample collection. 
3. Day 1e of OLEP should be scheduled on the same day as week 28 (or week 28r for patients 
on intensified treatment) of the OLTP, and any common assessments will be performed once 
for both the OLTP and OLEP visits. 
4. For patients who did not receive intensified treatment during OLTP: At any time during the 
OLEP, patients who meet pre-specified criteria will receive intensified treatment consisting 
of a pozelimab 30 mg/kg IV loading dose followed 30 minutes later by the initiation of 
pozelimab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W. Patients should be observed 
for 30 minutes in the interim between the IV and  doses. Patients will continue their visit 
schedule at the next OLEP visit. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 58 of 63 
5. During the OLEP, the dose of cemdisiran and pozelimab SC should be given on the day of 
the corresponding study visit whenever possible. Study treatment administration should 
always be the last procedure after all blood sample collection and study assessments have 
been completed unless otherwise specified: 
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 3 days before or up to 3 days 
after the planned dosing date, provided that the combination dosing takes place after 
the corresponding study visit has been completed. For patients receiving pozelimab 
400 mg SC Q2W + cemdisiran 200 mg SC Q4W, the dosing window (±3 days) is 
narrower than the visit window (-7/+3 days). 
• If pozelimab or cemdisiran cannot be administered on the day of the corresponding 
study visit, the combination may be administered up to 7 days before or 7 days after 
the planned dosing date, provided that the combination dosing takes place after the 
corresponding study visit has been completed. For patients receiving pozelimab 
400 mg SC Q4W + cemdisiran 200 mg SC Q4W, the visit window (-7/+3 days) is 
narrower than the dosing window (±7 days). 
Care must be taken to coordinate dosing for visits where a post-dose sample is collected to 
measure concentration of cemdisiran and its metabolites. For patients whose treatment is not 
intensified during the OLEP, the last doses of cemdisiran and pozelimab are administered at 
week 52e. For patients whose treatment was intensified during the OLEP, the last doses of 
study treatment will be determined based on the time of treatment intensification. 
6. Injection training will be provided to patients who desire self-injection or injection by a 
designated person.  Site should observe patient self-injection or injection by a designated 
person and confirm adequacy.  Patient instruction materials will be provided. 
7. If study treatment is given by the patient or by a designated person, the patient will complete 
a diary for recording compliance with study treatment administration. If patient diary is 
provided to the patient, then it should be reviewed at each clinic visit and data collected into 
the CRFs. On the final visit, the diary should be collected by the site. 
8. Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended until 
52 weeks after discontinuation of study treatment. 
9. Patient safety card: Site should review the instructions on the safety card with the patient at 
each visit. Replacement cards may be given to the patient as needed. 
10. Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough 
hemolysis event, then in addition to the required laboratory collection, additional samples 
for drug concentrations of pozelimab will be collected unless already noted in the schedule 
of events for that visit.  If the suspected event does not occur at a scheduled visit then an 
unscheduled visit should occur with an evaluation of the patient and collection of 
coagulation, chemistry, and drug concentration of pozelimab. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 59 of 63 
11. Clinical lab samples will be collected prior to any study drug administration (pre-dose) 
unless otherwise specified. During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis. The coagulation blood sample (tube) must always be 
collected first, followed by the blood chemistry sample (tube). 
12. Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood 
chemistry analysis. Blood chemistry sample should be collected before study treatment 
administration (pre-dose). During lab collection, handling and processing, the same 
methodology will be applied across study visits, as best as possible, to preserve the quality 
of sample and avoid hemolysis during sample processing. If the investigator or sponsor 
suspects that the lab result is not an accurate reflection of the patient’s condition, the lab 
sample should be repeated. 
13. Hematology sample should be collected before study treatment administration (pre-dose). 
14. Pregnancy test for WOCBP: A urine test will be done at all visits indicated. Any positive 
urine pregnancy test should be confirmed with a serum pregnancy test. 
15. Blood samples for pozelimab concentration analysis and total C5 analysis will be obtained 
on the specified days prior to any study treatment administration (pre-dose). 
16. Blood samples for cemdisiran concentration analysis and concentrations of its metabolites 
will be collected on the specified days prior to any study treatment administration (pre-dose) 
and 2 to 6 hours post cemdisiran administration. The post-dose sample should be carefully 
coordinated with the dosing of cemdisiran and may be collected at the clinic or by a visiting 
health care professional. 
17. Blood samples for immunogenicity will be collected on the specified days prior to any study 
treatment administration (pre-dose).  At the visits where immunogenicity samples are to be 
taken, the sample should be collected with the drug concentration sample. In the event of 
suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional drug 
concentration and immunogenicity samples may be collected at or near the onset and the 
resolution of the event. 
18. Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study 
treatment administration (pre-dose). 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 60 of 63 
Footnotes for Table 6 Schedule of Events (Post-Treatment Safety Follow-Up Period) 
1. Patient safety card: Site should review the instructions on the safety card with the patient at 
each visit. Replacement cards may be given to the patient as needed. 
2. Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks 
after discontinuation of study treatment. 
10.2. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
> 1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008 
Total Bilirubin 
> 1.5 ULN 
> 2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance Oct 2008 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Conjugated 
bilirubin 
> 35% total bilirubin (when 
total bilirubin >1.5 ULN) 
Conjugated bilirubin dosed on a case-by-case basis 
ALT and Total 
Bilirubin 
ALT > 3 ULN and Total 
Bilirubin > 2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
To be counted within the same treatment phase, whatever 
the interval between measurement 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 61 of 63 
Parameter 
PCSV 
Comments 
CPK 
> 3 ULN 
>10 ULN 
FDA Feb 2005 
Am J Cardiol April 2006 
Categories are cumulative 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Creatinine 
 150 mol/L (adults) 
   90 mol/L (6-12 year-old) 
 30% from baseline 
 100% from baseline 
Benichou C., 1994 
 
eGFR 
(Chronic Kidney 
Disease – 
Epidemiology 
Collaboration 
Equation 2009) 
< 30 ml/min (severe renal 
impairment) 
 30 - < 59 ml/min (moderate 
renal impairment) 
60 - 89 ml/min (mild renal 
impairment) 
 90 ml/min (no renal 
impairment) 
 
Uric Acid 
Hyperuricemia: 
Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Harrison- Principles of internal Medicine 17th Ed. 2008 
Sodium 
129 mmol/L 
 160 mmol/L 
 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
FDA Feb 2005 
Total Cholesterol 
 7.74 mmol/L (3 g/L) 
Threshold for therapeutic intervention 
Triglycerides 
 4.6 mmol/L (4 g/L) 
Threshold for therapeutic intervention 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 
mmol/L (unfasted) 
 
ADA May 2005 
ADA Jan 2008 
 
CRP 
> 2 ULN or 
 >10 mg/L, if ULN not 
provided 
 FDA Sept 2005 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 62 of 63 
Parameter 
PCSV 
Comments 
Hematology 
WBC 
< 3.0 Giga/L (3000/mm3) 
< 2.0 Giga/L (2000/mm3) 
(Black) 
Increase in WBC: not relevant 
To be interpreted only if no differential count available. 
Neutrophils 
< 1.5 Giga/L (1500/mm3) 
< 1.0 Giga/L (1000/mm3) 
Black 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
FDA criteria 
Eosinophils 
> 0.5 Giga/L (500/mm3) 
or > ULN if ULN  0.5 Giga/L 
Gallin 1989, Harrisson 13th Ed, 1994. 
Hemoglobin 
At least 20 g/L (1.24 mmol/L) 
decrease versus baseline 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value.  
Other categories for decrease from baseline can be used 
( 30 g/L,  40 g/L,  50 g/L) 
Platelets 
< 100 Giga/L (100 000/mm3) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Vital signs 
HR 
 40 bpm and decrease from 
baseline  20 bpm 
 100 bpm and increase from 
baseline  20 bpm 
Proposed change: To be are applied for all positions 
(including missing) except STANDING 
SBP 
 95 mmHg and decrease from 
baseline  20 mmHg 
 140 mmHg and increase from 
baseline  20 mmHg 
Proposed change: To be are applied for all positions 
(including missing) except STANDING 
DBP 
Young and elderly subjects 
 45 mmHg and decrease from 
baseline  10 mmHg 
 90 mmHg and increase from 
baseline  10 mmHg 
 
Proposed change: To be are applied for all positions 
(including missing) except STANDING 
Orthostatic 
Hypotension 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
 
Weight 
 5 % increase versus baseline 
5% decrease versus baseline 
FDA Feb 2007  
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R3918-PNH-2092 
Statistical Analysis Plan 
 
Date: 9 Dec 2022 
 
CONFIDENTIAL 
Page 63 of 63 
Parameter 
PCSV 
Comments 
ECG parameters 
CPMP 1997 guideline 
HR 
 40 bpm and decrease from 
baseline  20 bpm 
 100 bpm and increase from 
baseline  20 bpm 
 
PR 
 220 ms 
 
QRS 
 120 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
                Males           Females 
Borderline  
           431-450 ms     451-470 
ms 
Prolonged* 
           > 450 ms         > 470 ms 
QTc   ≥500 ms           ≥ 500 ms 
 
Increase versus baseline (Males 
and Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
To be applied to any kind of QT correction formula  
 
*QTc prolonged and QTc > 60 ms are the PCSA to be 
identified in individual subjects/patients listings. 
 
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