A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects With Immune-Mediated Necrotizing Myopathy
Phase: PHASE2
Conditions: Immune Mediated Necrotizing Myopathy
Sponsor: Ra Pharmaceuticals

Zilucoplan  
Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
 
 
 
RA PHARMACEUTICALS, INC. 
 
 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Tolerability, and Efficacy of Zilucoplan in Subjects 
with Immune-Mediated Necrotizing Myopathy 
 
 
 
Protocol Number:  RA101495-02.202 (UCB study IMNM01) 
Protocol Version/Date: Version 2.0/16 February 2021 
Indication Studied: Immune-Mediated Necrotizing Myopathy (IMNM) 
Developmental Phase of Study: 2 
EudraCT Number: 2019-001497-29 
Sponsor Address: Ra Pharmaceuticals, Inc. (now part of UCB) 
87 Cambridge Park Drive 
Cambridge, MA, 02140 | USA 
 
This study will be conducted by Ra Pharmaceuticals, Inc. and affiliates in compliance 
with the protocol, Good Clinical Practice, and all other applicable regulatory 
requirements, including the archiving of essential documents. 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent of Ra 
Pharmaceuticals, Inc. is strictly prohibited except to the extent required under applicable laws or regulations. Persons to whom 
the information is disclosed must be informed that the information is confidential and may not be further disclosed by them. 
 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
CONFIDENTIAL 
 
Page 2 of 72 
CENTER INVESTIGATOR SIGNATURE PAGE 
I have read this protocol and agree that it contains all necessary details for carrying out this 
study. I will conduct the study as outlined herein and will complete the study within the time 
designated. This trial will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and according to local legal and regulatory requirements 
and International Council for Harmonisation guidelines. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure they 
are fully informed regarding the drug and the conduct of the study. 
I will use only the informed consent form approved by the Sponsor or its representative and will 
fulfill all responsibilities for submitting pertinent information to the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) responsible for this study. 
I agree that the Sponsor or its representatives shall have access to any source documents from 
which case report form information may have been generated. I agree that regulatory authorities 
[Food and Drug Administration (FDA), European Medicines Agency (EMA), and other local and 
country-related agencies] can audit and review source documents. 
I further agree not to originate or use the name of Ra Pharmaceuticals, Inc. or any of its 
employees, in any publicity, news release, or other public announcement, written or oral, 
whether to the public, press, or otherwise, relating to his protocol, to any amendment hereto, or 
to the performance hereunder, without the prior written consent of Ra Pharmaceuticals, Inc. 
 
 
________________________________________________ 
_________________ 
Signature of Investigator 
 
 
 
 
 
Date 
 
________________________________________________ 
Name of Investigator (Typed or Printed) 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
CONFIDENTIAL 
 
Page 3 of 72 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Protocol Version 
Date 
Original Protocol 
1.0 
05 Apr 2019 
Protocol Amendment (United Kingdom) 
GB.1.1 
25 Jul 2019 
Protocol Amendment (France) 
FR.1.1 
20 Feb 2020 
Protocol Amendment (Global)  
2.0 
16 Feb 2021 
PROTOCOL AMENDMENT (GLOBAL) VERSION 2.0 (16 FEB 2021) 
The purpose of this protocol amendment is to make the following changes to the original 
protocol (Version 1.0 dated 05 Apr 2019): 
• Changes made in earlier United Kingdom (25 Jul 2019) and France (20 Feb 2020) 
country-specific protocol amendments have been consolidated into a single global 
protocol. 
• The objectives and endpoints were revised to reflect current UCB practices for the 
categorization and description of study objectives, estimands, and endpoints. 
• The protocol was updated to include provisions for the coronavirus disease 2019 
(COVID-19) pandemic. 
• To clarify that the snapshot will be taken after the Week 8 visit. 
• Additional administrative updates were made in the protocol. 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Updated version number and 
date; added UCB study 
number. 
Updated. 
Section 1, Synopsis, Study 
Objectives 
Notes added that the long-term 
safety, tolerability, and 
efficacy will be evaluated 
during the open-label 
Extension Portion of the study. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 1, Synopsis, Study 
Design, paragraph 8 
Text regarding safety data 
review has been updated. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol. 
Section 1, Synopsis, Study 
Design, paragraph 9  
The last sentence has been 
updated to specify Week 8 of 
the Main Portion of the study. 
 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
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Zilucoplan  
Version 2.0 
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16 February 2021 
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Page 4 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1, Synopsis, 
Duration of Study 
Participation 
The study duration for the 
Extension Portion has been 
amended from the France 
protocol amendment from 
4 months to 18 months. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol.  
Extending the duration in 
France of the open-label 
extension from 4 months to 
18 months to allow for 
enrolled patients to continue 
receiving open-label drug 
based on additional safety data 
reviewed during the updated 
Investigator's Brochure (IB). 
Section 1, Synopsis, 
Duration of Study 
Participation 
An example of zilucoplan 
access in another qualifying 
extension study has been 
added. 
To provide flexible means for 
zilucoplan access for 
participants with close medical 
supervision afforded by a 
clinical study. 
Section 1, Synopsis, 
Inclusion/Exclusion Criteria 
Added exclusion criterion 14 
(hypersensitivity to study 
drug). 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 1, Synopsis, Study 
Objectives and Endpoints 
Revised objectives and 
endpoints. 
Updated to reflect UCB 
practices for categorization 
and description of study 
objectives, estimands, and 
endpoints. 
Section 1, Synopsis, Study 
Objectives and Endpoints 
“Change from Baseline to 
Week 8 in American College of 
Rheumatology/European League 
Against Rheumatism 
(ACR/EULAR) Response 
Criteria” was updated to “At 
least minimal response based 
on ACR/EULAR Response 
Criteria Scale at Week 8”.  
Updated for clarity. 
Section 1, Synopsis, Study 
Objectives and Endpoints 
“Change in physical 
examination” has been 
removed as an other safety 
endpoint. 
Clinically significant abnormal 
physical examination findings 
will be categorized as adverse 
events (AEs).  
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Zilucoplan  
Version 2.0 
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16 February 2021 
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Page 5 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1, Synopsis, Study 
Objectives and Endpoints 
The UK protocol amendment 
included a note that the 
primary and secondary 
efficacy endpoints evaluated in 
the Main Portion of the study 
will continue to be collected 
during in the Extension 
Portion of the study to 
determine the long-term 
safety, tolerability, and 
efficacy of zilucoplan in 
subjects with IMNM. This 
change has been incorporated 
into this global protocol 
amendment by including the 
Extension Portion objective 
and endpoints in the 
Objectives and Endpoints 
table. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 1, Statistical 
Considerations, Study 
Populations 
Per protocol population 
description has been corrected. 
Typographical error has been 
corrected. 
Section 1, Statistical 
Considerations, Study 
Populations 
General considerations 
sentence has been updated to 
clarify that subject disposition 
breakdowns will include 
reasons for discontinuation. 
Updated for clarity. 
Section 1, Statistical 
Considerations, Efficacy 
Analysis  
Efficacy analysis has been 
updated from 2-sided 
Wilcoxon rank sum test to the 
2-sided stratified Wilcoxon 
rank sum test (Van Elteren 
test).  
 
A sentence has been added to 
state that the effect of 
Zilucoplan on ACR/EULAR 
minimal response will be 
investigated using a binary 
logistic regression model with 
treatment and stratification 
included as factors. 
The Van Elteren version of the 
Wilcoxon rank sum test has 
been selected to provides a 
more specific analysis. 
 
 
 
Updated for clarity. 
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Version 2.0 
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16 February 2021 
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Page 6 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2, Schedule of 
assessments, Table 1: Main 
portion time and events 
table 
Footnote “a” has been updated 
to state that if a subject 
permanently discontinues 
study drug treatment prior to 
the Week 8 visit for any 
reason, he/she will not be 
eligible for the Extension 
Portion. For subjects who 
permanently discontinue 
treatment with study drug, a 
Safety Follow-up Visit will be 
performed at 40 days after the 
last dose to collect information 
on any ongoing AEs or new 
serious AEs (SAEs) since the 
last study visit. 
Clarification of study 
procedures. 
Section 2, Schedule of 
assessments, Table 1: Main 
portion time and events 
table  
Adverse event collection 
added to the screening visit, 
and footnote “k” has been 
updated to state that only 
SAEs should be collected at 
the screening visit. 
Clarification of study 
procedures. 
Section 2, Time and Events 
Table 1: Main Portion time 
and events table 
Footnote “j” after anti-drug 
antibody has been corrected to 
“h.” 
Correction of error. 
Section 2, Time and Events, 
Table 2: Extension Portion 
time and events table  
A new footnote “b” has been 
added to the “Visits after Day 
E117” to state that for France 
only, the duration of study 
participation during the 
Extension Portion will include 
an open-label, single-arm, 
18-month Treatment Period. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol.  
Extending the duration in 
France of the open-label 
extension from 4 months to 
18 months to allow for 
enrolled patients to continue 
receiving open-label drug 
based on additional safety data 
reviewed during the updated 
IB. 
Section 5.4.2, Rationale for 
Blinding and Placebo 
Control, paragraph 3 
The last sentence has been 
updated to specify Week 8 of 
the Main Portion of the study. 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6, Study Objectives 
and Endpoints 
Revised objectives and 
endpoints. 
Updated to reflect UCB 
practices for categorization 
and description of study 
objectives, estimands, and 
endpoints. 
Section 6, Study Objectives 
and Endpoints 
“Change from Baseline to 
Week 8 in ACR/EULAR 
Response Criteria” was 
updated to “At least minimal 
response based on 
ACR/EULAR Response 
Criteria Scale at Week 8”.  
Updated for clarity. 
Section 6, Study Objectives 
and Endpoints 
“Change in physical 
examination” has been 
removed as an other safety 
endpoint. 
Clinically significant abnormal 
physical examination findings 
will be categorized as adverse 
events.  
Section 6, Study Objectives 
and Endpoints 
The UK protocol amendment 
included a note that the 
primary and secondary 
efficacy endpoints evaluated in 
the Main Portion of the study 
will continue to be collected 
during in the Extension 
Portion of the study to 
determine the long-term 
safety, tolerability, and 
efficacy of zilucoplan in 
subjects with IMNM. This 
change has been incorporated 
into this global protocol 
amendment by including the 
Extension Portion objective 
and endpoints in the 
Objectives and Endpoints 
table. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 7.1 Overview of 
Study Design, paragraph 9  
The last sentence has been 
updated to specify Week 8 of 
the Main Portion of the study. 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Section 7.2 Study Periods, 
paragraph 3 
An example of zilucoplan 
access in another qualifying 
extension study has been 
added. 
To provide flexible means for 
zilucoplan access for 
participants with close medical 
supervision afforded by a 
clinical study. 
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Zilucoplan  
Version 2.0 
Protocol RA101495-02.202 
16 February 2021 
CONFIDENTIAL 
 
Page 8 of 72 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2 Study Periods, 
paragraph 3 
The study duration for the 
Extension Portion has been 
amended from the France 
amendment from 4 months to 
18 months. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol.  
Extending the duration in 
France of the open-label 
extension from 4 months to 18 
months to allow for enrolled 
patients to continue receiving 
open-label drug based on 
additional safety data 
reviewed during the updated 
IB. 
Section 7.2.2.1 
Randomization and 
Blinding, paragraph 2  
Updated the text to specify 
Week 8 of the Main Portion of 
the study.  
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Section 7.4, Study Conduct 
During COVID-19 
Added new section. 
Update to include provisions 
for the COVID-19 pandemic. 
Section 8.2, Exclusion 
Criteria, Exclusion 
Criterion 14 
Added exclusion criterion 14 
(hypersensitivity to study 
drug). 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
Section 9.2.1.1, Alternative 
Study Treatment Supply 
due to COVID-19 
Pandemic 
Added a new section. 
Update to include provisions 
for the COVID-19 pandemic. 
Section 9.1.3 
Sentence updated to clarify 
that subjects presenting with a 
body weight outside of these 
ranges will be accommodated 
on a case-by-case basis, in 
consultation with the medical 
monitor.  
Updated for clarity. 
Section 10.2.1 Physical 
Examination 
Sentence #2 has been updated 
to state that any clinically 
significant abnormalities after 
Day 1 will be recorded as AEs 
in the eCRF.  
Updated for clarity.  
Section 10.2.4.3, Pregnancy 
Testing and Contraception 
Revised information on 
contraception. 
Consolidation of earlier 
country-specific (UK) protocol 
amendment into global 
protocol. 
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Version 2.0 
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16 February 2021 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.3.2.2 Proximal 
Manual Muscle Testing  
Manual muscle testing in 8 
muscle groups has been 
corrected to 7.  
Typographical error has been 
corrected. 
Section 11.1.1.1, 
Occurrence of COVID-19 
Added section regarding 
reporting cases of COVID-19. 
Update to include provisions 
for the COVID-19 pandemic. 
Section 11.4.1.1 Adverse 
Events  
Sentence has been updated 
that AE reporting will end 
40 days following the last dose 
of study drug. 
To comply with UCB safety 
guidance. 
Section 11.4.2.1 Safety 
Monitoring Committee, 
paragraph 2 
Text regarding safety data 
review has been updated. 
Consolidation of earlier 
country-specific (France) 
protocol amendment into 
global protocol. 
Section 12.1 Analysis 
population  
A sentence has been added to 
clarify that further details of 
additional analysis populations 
will be described in the SAP, 
which will be finalized prior to 
study unblinding.  
Updated for clarity. 
Section 12.2.1 General 
Methods, paragraph 3 
Updated the text to specify 
Week 8 of the Main Portion of 
the study. 
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Section 12.2.2 Subject 
Disposition 
Sentence has been updated to 
clarify that subject disposition 
breakdowns will include 
reasons for discontinuation 
and the disposition for the 
Main Portion as well as 
Extension Portion will be 
provided. 
Updated for clarity. 
Section 12.2.4.1 Adverse 
Events 
The last sentence has been 
updated to clarify that SAEs 
occurring before first dose of 
study drug will be listed.  
To align with the Time and 
Events Table 1. 
Section 12.2.5.1 Primary 
Efficacy Analysis 
Efficacy analysis has been 
updated from 2-sided 
Wilcoxon rank sum test to the 
2-sided stratified Wilcoxon 
rank sum test (Van Elteren 
test). 
 
Primary estimands have been 
included.  
The Van Elteren version of the 
Wilcoxon rank sum test has 
been selected to provides a 
more specific analysis. 
 
 
 
To align with the updated ICH 
E9 (R1) addendum. 
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16 February 2021 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 12.2.5.2 Secondary 
Efficacy Analysis 
Definition of the secondary 
estimands have been included. 
To align with the updated ICH 
E9 (R1) addendum. 
Section 12.2.6.1 
Pharmacokinetic and 
Pharmacodynamic Analysis 
Details of a potential 
population pharmacokinetic 
analysis and reporting have 
been added.  
To conduct, if necessary, 
additional investigation to 
support the clinical 
development of zilucoplan in 
IMNM. 
Section 12.2.7 Interim 
analysis  
Updated the text to specify 
Week 8 of the Main Portion of 
the study.  
To clarify that the snapshot 
will be taken after the Week 8 
visit. 
Sponsor Signature Page 
Moved sponsor signature page 
to end of document. 
Alignment with UCB 
document practices, including 
the use of electronic sponsor 
signatures. 
 
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Version 2.0 
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16 February 2021 
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1 
SYNOPSIS 
Protocol Title 
A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety, Tolerability, 
and Efficacy of Zilucoplan in Subjects with Immune-Mediated 
Necrotizing Myopathy 
Protocol Number 
RA101495-02.202 (UCB Study IMNM01) 
Phase of Clinical Development 
Phase 2 
Investigational Medicinal 
Product 
Zilucoplan (RA101495) administered by daily subcutaneous 
(SC) injection (0.3 mg/kg) 
Study Population 
Immune-Mediated Necrotizing Myopathy (IMNM) 
Investigative Sites 
Approximately 7 centers are planned worldwide 
Planned Number of Subjects  
Approximately 24 subjects (12 per treatment arm) 
Study Objectives 
• To evaluate the safety and tolerability of zilucoplan in subjects with IMNM 
• To evaluate the efficacy of zilucoplan in subjects with IMNM 
Please note: The long-term safety, tolerability, and efficacy will be evaluated during the open-label 
Extension Portion of the trial. 
Study Design 
This study is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and efficacy of zilucoplan in subjects with IMNM who are positive for anti-HMGCR (3-
hydroxy-3-methyl-glutaryl-coenzyme A reductase) or anti-SRP (signal recognition particle) 
autoantibodies.  
The planned enrollment is approximately 24 subjects. Subjects will be randomized in a 1:1 ratio to 
receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo. Randomization will be stratified 
based on antibody status (anti-HMGCR+ versus anti-SRP+). 
The Main Portion of the study includes a Screening Period of up to 4 weeks and an 8-week Treatment 
Period. During the Treatment Period, subjects will return to the clinic at Week 1, Week 2, Week 4, and 
Week 8 to evaluate safety, tolerability, and efficacy. Additional assessments will include biomarker 
testing, pharmacokinetics, pharmacodynamics, and optional pharmacogenomics. Safety assessments 
will include physical examinations, vital signs, electrocardiogram (ECG), clinical laboratory tests, 
adverse event (AE) monitoring, and immunogenicity. 
Randomized subjects will receive 0.3 mg/kg zilucoplan or matching placebo administered SC at the 
Day 1 visit. Following in-clinic education and training, all subjects will self-inject daily SC doses of 
blinded study drug, according to randomized treatment allocation, for the subsequent 8 weeks. Single-
use pre-filled syringes in injection devices will be provided for use during the study. 
All standard of care (SOC) therapy medications for IMNM should be kept at the same doses 
throughout the study, including corticosteroids, immunosuppressive drugs, and intravenous 
immunoglobulin (IVIG). 
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must be vaccinated 
against meningococcal infections (with a quadrivalent vaccine and, where available and in accordance 
with local SOC, serogroup B vaccine) within 3 years prior to, or at the time of, initiating study drug. 
Subjects who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine 
must receive treatment with appropriate prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, 
penicillin V) until at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be 
administered in accordance with local SOC.   
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During the Treatment Period, to mitigate the risk of infection, subjects will be counseled and reminded 
of the early signs and symptoms of Neisseria meningitidis infection. A patient safety card detailing the 
signs and symptoms of infection, with instructions to seek immediate medical attention if any such 
symptoms occur, will be provided to each subject. 
The safety of subjects will be monitored in a blinded manner on an ongoing basis. If an additional data 
review should become necessary to ensure subject safety, a supervisory committee [i.e., a Safety 
Monitoring Committee (SMC)] will convene and evaluate study data as appropriate.  
At the conclusion of the Treatment Period of the study, all subjects will have the option to receive 
zilucoplan in the Extension Portion of the study provided they meet the Extension Portion selection 
criteria. Visits during the first 8 weeks of the Extension Portion will be identical to the Main Portion 
of the study for all subjects to ensure appropriate monitoring of subjects transitioning from placebo 
to active treatment. The study will remain double-blinded until after the data from Week 8 of the 
Main Portion of the study have been reviewed, locked, and unblinded. 
If a subject permanently discontinues study drug treatment prior to the Week 8 visit for any reason, 
he/she will not be eligible for the Extension Portion. For subjects who permanently discontinue 
treatment with study drug, a Safety Follow-up Visit will be performed at 40 days after the last dose to 
collect information on any ongoing AEs or new SAEs since the last study visit. 
Duration of Study Participation 
Main Portion: The duration of study participation during the Main Portion will include a Screening 
Period of up to 4 weeks and an 8-week Treatment Period for a total of approximately 12 weeks. 
Extension Portion: The investigational medicinal product (IMP) will continue to be provided by the 
Sponsor until zilucoplan is approved and available in the territory (e.g. in another qualifying 
extension study begins) or until the Sponsor terminates development of zilucoplan for IMNM. In 
countries where zilucoplan is not approved or marketed, but in which sponsored clinical studies 
have been conducted, subjects may continue to receive zilucoplan through a compassionate use 
pathway. 
For France only: The duration of study participation during the Extension Portion of this study 
(RA101495-02.202) will include an open-label, single-arm, 18-month Treatment Period. 
Inclusion/Exclusion Criteria 
To be eligible for this study, subjects must meet ALL of the following inclusion criteria: 
1. Male or female  18 years and < 75 years. 
2. Able to provide informed consent, including signing and dating the informed consent form (ICF). 
3. Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy).  
4. Positive serology for anti-HMGCR or anti-SRP autoantibodies. 
5. Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at least one 
proximal limb muscle group. 
6. Creatinine kinase (CK) of >1000 U/L at Screening. 
7. No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur 
during the first 8-weeks on study. 
8. No changes in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or 
anticipated to occur during the first 8-weeks on study. 
9. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test within 24 hours prior to the first dose of study drug. 
10. Sexually active female subjects of childbearing potential (i.e., women who are not postmenopausal 
or who have not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and all 
male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective 
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contraception during the study. Postmenopausal women are, for the purposes of this protocol, 
defined as women who have gone 12 consecutive months without menstruation.   
Subjects who meet ANY of the following exclusion criteria must be excluded from the study: 
1. History of meningococcal disease. 
2. Current or recent systemic infection within 2 weeks prior to Screening or infection requiring 
intravenous (IV) antibiotics within 4 weeks prior to Screening. 
3. Pregnant, planning to become pregnant, or nursing female subjects. 
4. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or expected to have 
surgery requiring general anesthesia during the 8-week Treatment Period. 
5. Treatment with a complement inhibitor or an experimental drug within 30 days or 5 half-lives of 
the drug (whichever is longer) prior to Baseline. 
6. Statin use within 30 days prior to Baseline or anticipated to occur during study. 
7. Rituximab use within 90 days prior to Baseline or anticipated to occur during study. 
NOTE: In subjects who received rituximab more than 90 days but less than 6 months prior to 
Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) should be given 
upon initiation of study drug until 6 months after the last rituximab dose. 
8. Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered less than 90 
days prior to Baseline). 
9. Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-week 
Treatment Period. 
10. Active malignancy (except curatively resected squamous or basal cell carcinoma of the skin) 
requiring surgery, chemotherapy, or radiation within the prior 12 months (subjects with a history of 
malignancy who have undergone curative resection or otherwise not requiring treatment for at least 
12 months prior to Screening with no detectable recurrence are allowed). 
11. History of any significant medical, psychiatric disorder, or laboratory abnormality that in the 
opinion of the investigator would make the subject unsuitable for participation in the study. 
12. Participation in another concurrent clinical trial involving an experimental therapeutic intervention 
(participation in observational studies and/or registry studies is permitted).  
13. Unable or unwilling to comply with the requirements of the study.  
14. Subjects who have a known hypersensitivity to zilucoplan or any of its excipients. 
Study Objectives and Endpoints 
Objectives  
Estimands / Endpoints 
Primary 
Primary Objective: to evaluate the safety and 
efficacy of zilucoplan over placebo in CK 
levels in participants with IMNM 
Primary Efficacy Estimand: 
• 
Treatment: Zilucoplan administered by 
daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• 
Target Population: is defined through the 
inclusion/exclusion criteria in Section 8.1 
and Section 8.2 of the study protocol 
reflecting the targeted IMNM population. 
• 
Endpoint: Percent change from Baseline 
to Week 8 in CK levels. 
• 
Intercurrent event (ICE) handling: 
regardless of any treatment 
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discontinuation for any reason; censoring 
after prohibited medication. 
• 
Population level summary: The 
difference in ranks of the percentage 
change from baseline between treatments 
followed by the Wilcoxon-Mann-
Whitney odds (WMWodds) and Hodges–
Lehmann estimator followed by the 
corresponding 95% Confidence Intervals 
(CI). 
Primary Safety Endpoint 
• 
Incidence of treatment-emergent adverse 
events. 
Secondary 
Secondary Objective(s): to further evaluate 
the efficacy and the safety of zilucoplan over 
placebo in participants with IMNM 
Secondary Efficacy Estimands: 
• 
Treatment: Zilucoplan administered by 
daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• 
Target Population: is defined through the 
inclusion/exclusion criteria in Section 8.1 
and Section 8.2 of the study protocol 
reflecting the targeted IMNM population. 
• 
Endpoints:  
o At least minimal response based on 
the American College of 
Rheumatology/European League 
Against Rheumatism (ACR/EULAR) 
Response Criteria Scale at Week 8;  
o Change from Baseline to Week 8 in 
Triple Timed Up and Go (3TUG) 
Test (in ambulatory patients only);  
o Change from Baseline to Week 8 in 
Proximal Manual Muscle Testing 
(MMT);  
o Change from Baseline to Week 8 in 
Physician Global Activity Visual 
Analogue Scale (VAS);  
o Change from Baseline to Week 8 in 
Patient Global Activity VAS;  
o Change from Baseline to Week 8 in 
Health Assessment Questionnaire 
(HAQ);  
o Change from Baseline to Week 8 in 
myositis disease activity assessment 
tool (MDAAT) Extramuscular 
Disease Activity VAS Score;  
o Change from Baseline to Week 8 in 
Functional Assessment of Chronic 
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Illness Therapy (FACIT)-Fatigue 
Scale;  
• 
ICE handling: regardless of any treatment 
discontinuation for any reason; censoring 
after administration of prohibited 
medication. 
• 
Population level summary: 
o Odds Ratio of ACR/EULAR ≥ 20 
response proportion between 
treatment conditions;  
o Difference in continuous endpoint 
means, between treatment conditions. 
Other 
To further evaluate the safety of zilucoplan 
over placebo in participants with IMNM 
Other safety endpoints 
• 
Change in clinical laboratory tests 
• 
Change in ECG parameters  
• 
Change vital signs parameters, and  
• 
Presence of Anti-Drug Antibodies 
Exploratory 
To assess the long term efficacy of 
zilucoplan 
• 
At least minimal response based on the 
American College of 
Rheumatology/European League Against 
Rheumatism (ACR/EULAR) Response 
Criteria Scale at each visit following 
Week 8; 
• 
Change from Baseline of Timed Up and 
Go (3TUG) Test (in ambulatory patients 
only) at each visit following Week 8; 
• 
Change from Baseline of Proximal Manual 
Muscle Testing (MMT) at each visit 
following Week 8; 
• 
Change from Baseline of Physician Global 
Activity Visual Analogue Scale (VAS) at 
each visit following Week 8; 
• 
Change from Baseline of Patient Global 
Activity Visual Analogue Scale (VAS) at 
each visit following Week 8; 
• 
Change from Baseline of Health 
Assessment Questionnaire (HAQ) at each 
visit following Week 8; 
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• 
Change from Baseline of MDAAT 
Extramuscular Disease Activity VAS 
Score at each visit following Week 8;  
• Change from Baseline of FACIT-
Fatigue Scale at each visit following 
Week 8; 
To assess the pharmacokinetics (PK) of 
zilucoplan 
• 
Plasma concentrations of zilucoplan and its 
major metabolites  
To assess the pharmacodynamics (PD) of 
zilucoplan 
 
• 
Sheep red blood cell lysis assay for 
evaluation of classical complement 
pathway activation 
• 
Complement component 5 levels 
To assess the effect of zilucoplan on 
biomarkers 
• 
Mechanistic biomarkers [e.g., complement 
fixation, complement function, 
complement pathway proteins, 
autoantibody characterization (titer and 
immunoglobulin class), myocyte markers, 
and inflammatory markers].   
To assess the effect of zilucoplan on 
pharmacogenomics 
• 
Pharmacogenomic analyses (optional): 
Genomic studies [e.g., deoxyribonucleic 
acid (DNA) sequencing, including 
exploration of whether specific genomic 
features correlate with response or 
resistance to study drug] may be 
performed. 
Statistical Considerations 
Study Populations:   
The following study populations are defined: 
• 
Intention-to-Treat (ITT) Population:  All subjects randomized. 
• 
Per Protocol Population: All subjects in the ITT Population who have completed the 8-week 
Treatment Period and have no major protocol deviations.  
• 
Safety Population:  All subjects who have received at least 1 dose of study drug, with subjects to be 
analyzed based on the actual study treatment received.  
General Considerations:  A disposition of all consented subjects will be provided and will include a 
breakdown of subjects who were randomized, were treated, and discontinued treatment (including 
reasons for discontinuation). 
Continuous variables will be summarized using the number of observations, number of observations 
below the limit of quantification (if applicable), mean, standard deviation (SD), median, and range. 
Categorical variables will be summarized using frequency counts and percentages. 
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Stratification of Randomization:   
Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or 
matching placebo. Randomization will be stratified based on autoantibody status (anti-HMGCR+ 
versus anti-SRP+). 
Determination of Sample Size:   
A sample size of 12 subjects per group yields approximately 95% power to detect a difference in the 
percent reduction from baseline in creatine kinase between the active and placebo groups using a 
Wilcoxon rank sum test at the two-sided 0.05 type 1 error rate. The power calculations assume that the 
percent reduction in creatine kinase in the active dose group is approximately normally distributed with 
a mean of 80% and a standard deviation of 8%; that 4 of the placebo patients will have a percent 
reduction similar to the active dose group; and the remaining 8 placebo patients will have a percent 
reduction  that is normally distributed with a mean of 10% and a standard deviation of 8%. The 
estimation of the creatine kinase baseline levels and treatment effect are based on the data presented in 
Mammen et Tiniakou, 2015 (Mammen and Tiniakou 2015). 
Efficacy Analyses:   
The primary efficacy endpoint, percent reduction from baseline in creatine kinase at Week 8, will be 
compared between the two treatment groups using a 2-sided stratified Wilcoxon rank sum test (Van 
Elteren test). 
Treatment group differences for each of the continuous secondary efficacy change from baseline 
endpoints will be assessed using a mixed model analysis of covariance (ANCOVA) with treatment and 
baseline score as fixed effects and subject as a random effect. Additional subgroup analyses, including 
autoantibody serotype, will be prespecified in the SAP. 
The effect of Zilucoplan on ACR/EULAR minimal response will be investigated using a binary logistic 
regression model with treatment and stratification included as factors. 
Safety:   
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Incidence rates 
for treatment-emergent AEs will be summarized overall, by maximum severity, and by relationship to 
study drug for each treatment group. SAEs will also be summarized by treatment group. Quantitative 
laboratory endpoints will be summarized by treatment group at each scheduled assessment time point 
using descriptive statistics. Descriptive statistics for ECG parameters [i.e., heart rate (HR), PR interval, 
RR interval, QRS interval, and QT interval at each assessment time point will be presented by 
treatment group. Descriptive statistics for vital signs (HR, body temperature, and blood pressure) will 
be presented by treatment group. Clinically significant physical examination abnormalities will be 
reported as AEs, when appropriate. 
Pharmacokinetics:   
Individual PK results will be presented in listings and summarized using descriptive statistics. 
Pharmacodynamics:   
Pharmacodynamic endpoints will be summarized using descriptive statistics. 
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2 
SCHEDULE OF ASSESSMENTS  
Assessments to be performed during the study are shown in Table 1 and Table 2 
Table 1: MAIN PORTION Time and Events Table 
 
 
 
Week 1 
Week 2 
Week 4 
Week 8 
 
Study Procedure 
Screening 
Days -28 to -1 
Day 1 
(‘Baseline’) 
Day 8 
(± 2 days) 
Day 15 
(± 2 days) 
Day 29 
(± 2 days) 
End of Maina 
Day 57  
(± 7 days) 
Safety 
Follow-up Visita  
(last dose + 40d) 
Informed consentb 
X 
 
 
 
 
 
 
Review eligibilityb 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Medical historyc and demographics 
X 
 
 
 
 
 
 
Heightd and weight 
X 
 
 
 
X 
X 
 
Prior and concomitant medicationse 
X 
X 
X 
X 
X 
X 
X 
Safety  
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
12-Lead electrocardiogram 
X 
 
 
 
 
X 
 
Neisseria meningitidis vaccinationg 
X 
SOC 
SOC 
SOC 
SOC 
SOC 
 
Prophylactic antibioticsg (if applicable) 
 
X 
X 
X 
 
 
 
Hematology/Chemistry/CKh 
X 
X 
X 
X 
X 
X 
 
Coagulationh,i 
X 
X 
X 
X 
X 
X 
 
Urinalysish 
X 
X 
X 
X 
X 
X 
 
Pregnancy testj 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsk 
X  
X 
X 
X 
X 
X 
Xk 
Anti-drug antibodyh 
X 
 
X 
 
X  
X 
 
Efficacy 
 
 
 
 
 
 
 
3TUGl,m 
X 
X 
 
 
X 
X 
 
Proximal MMTl 
X 
X 
 
 
X 
X 
 
Physician Global Activity VASl 
X 
X 
 
 
X 
X 
 
Patient Global Activity VASl 
X 
X 
 
 
X 
X 
 
HAQl 
X 
X 
 
 
X 
X 
 
MDAATl 
X 
X 
 
 
X 
X 
 
FACIT-Fatiguel 
X 
X 
 
 
X 
X 
 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
Zilucoplan plasma PKn 
 
X 
X 
X 
X 
X 
 
Pharmacodynamic analysisn 
 
X 
X 
X 
X 
X 
 
Exploratory 
 
 
 
 
 
 
 
Autoantibodies testingo 
X 
X 
 
 
X 
X 
 
Biomarker testingp 
 
X 
X 
X 
X 
X 
 
Pharmacogenomic analysis (optional)q 
X 
 
 
 
 
 
 
Study Drug 
 
 
 
 
 
 
 
Zilucoplan or placebo administrationr 
 
X 
X 
X 
X 
X 
 
See footnotes on following page. 
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1-a. If a subject permanently discontinues study drug prior to completion of the Day 57 visit during the Main Portion, the subject should return to clinic for an End of Main Visit. 
If a subject consents to the Extension Portion, please see Table 2 for Day 57/E1 assessments. If a subject permanently discontinues study drug treatment prior to the Week 8 
visit for any reason, he/she will not be eligible for the Extension Portion. For subjects who permanently discontinue treatment with study drug, a Safety Follow-up Visit will 
be performed at 40 days after the last dose to collect information on any ongoing AEs or new SAEs since the last study visit. 
1-b. Procedures performed as SOC during the Screening Period may be used to determine eligibility. Informed consent must be obtained prior to performing any study-specific 
procedures that are not SOC.  Eligibility must be established prior to randomization on Day 1. 
1-c. Screening includes a detailed history of IMNM diagnosis information and local serology for anti-HMGCR or anti-SRP autoantibodies from a reputable laboratory. 
1-d. Height will be measured only at Screening. 
1-e. All prescriptions and over-the-counter medications taken during the 30 days prior to Baseline (i.e., Day 1) through the last study visit will be documented.  NOTE: A 
complete history of all medication taken for the treatment of IMNM will be collected. 
1-f. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
1-g. To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must be vaccinated against meningococcal infections (with a quadrivalent vaccine and, 
where available and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, or at the time of, initiating study drug. Subjects who initiate study drug 
treatment less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, 
penicillin V) until at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be administered in accordance with local SOC.  
NOTE: In subjects who received rituximab more than 90 days but less than 6 months prior to Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, 
penicillin V) should be given upon initiation of study drug until 6 months after the last rituximab dose. 
1-h. All laboratory samples should be obtained prior to administration of study drug at applicable visits.  
1-i. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
1-j. For all female subjects of childbearing potential, a negative serum pregnancy test must be documented at Screening. All other pregnancy tests will be performed via urine.  
1-k. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the 
procedures outlined in the protocol. Subjects will attend a clinic visit 40 days after their last dose to gather information on ongoing AEs and report any new SAEs since the 
last study visit. Only SAEs are collected during the screening period. 
1-l. The clinical assessments should be performed at approximately the same time of day (preferably in the morning) and should be administered in the same order by the same 
well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study.  
1-m. 3TUG will only be completed in subjects who are ambulatory. 
1-n. Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). 
1-o. Confirmatory serology testing for anti-HMGCR or anti-SRP autoantibodies will be done at a central laboratory. 
1-p. Blood samples for biomarker testing will be obtained prior to administration of study drug (within 1 hour of dosing). 
1-q. The pharmacogenomic sample may be collected at any study visit. 
1-r. Dosing on study visit days should be held until clinical assessment and blood collection has been completed.  
 
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Table 2: EXTENSION PORTION Time and Events Table 
 
Month 2 
 
 
Month 3 
Month 4 
Month 5 
Month 6 
 
Visits after Day E117b 
 
 
 
Study Procedure 
Day E1a 
(Day 57) 
Day E8 
(± 2 days) 
Day E15 
(± 2 days) 
Day E29 
(± 2 days) 
Day E57 
(± 7 days) 
Day E87 
(± 7 days) 
Day E117 
(± 7 days) 
 
Each 
Month 
(± 7 days) 
Every 3 
Months 
(± 7 days) 
 
Final 
Extension 
Visitc 
Safety 
Follow-up 
Visit  
(last dose + 40d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility and randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Safety  
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
X 
12-Lead electrocardiogram 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Neisseria meningitidis vaccinatione 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC 
SOC 
 
SOC 
SOC 
 
 
 
Hematology/Chemistry/CKf 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Coagulationf, g 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Urinalysisf 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Pregnancy testh 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Adverse eventsi 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Xh 
Anti-drug Antibodyf 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
3TUGj,k 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Proximal MMTj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Physician Global Activity VASj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Patient Global Activity VASj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
HAQj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
MDAATj 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
FACIT-Fatiguej 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Pharmacokinetic/Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zilucoplan plasma PKl 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Pharmacodynamic analysisl 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
Autoantibodies testing 
X 
 
 
X 
X 
 
X 
 
 
X 
 
X 
 
Biomarker testingm 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
Zilucoplan administrationn 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
See footnotes on following page. 
 
 
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2-a. For subjects that decide and are eligible to continue in the Extension Portion of the study, the Day 57 visit from the Main Portion will serve as the Day E1 visit and will also 
include review of eligibility to continue (see Section 8.3) and signing of an informed consent for the Extension Portion. 
2-b. For France only: The duration of study participation during the Extension Portion of this study (RA101495-02-202) will include an open-label, single-arm, 18-month 
Treatment Period. 
2-c. If a subject discontinues study drug treatment at any time during the Extension Portion, the subject should return to clinic for a Final Extension Visit. 
2-d. The vital signs assessment will include measurement of HR, body temperature, and blood pressure in the sitting position.  
2-e. During the Extension Portion of the study, all subjects should have Neisseria meningitidis booster vaccinations as indicated by SOC. Subjects should bring their patient safety 
card to every study visit. If the subject does not bring their card with them they will be given a new one. 
2-f. All laboratory samples should be obtained after clinical assessments and prior to administration of study drug at applicable visits.  
2-g. Coagulation tests should be performed only in subjects who are receiving anticoagulant therapy.  
2-h. Urine pregnancy tests will be conducted in female subjects of childbearing potential.  
2-i. All AEs and SAEs should be monitored until resolution or stabilization. SAEs that occur within 40 days after the last dose of study drug should be reported using the 
procedures outlined in the protocol. Subjects will attend a clinic visit 40 days after their last dose to gather information on ongoing AEs and report any new SAEs since the 
last study visit.  
2-j. The clinical assessments should be performed at approximately the same time of day (preferably in the morning) and should be administered in the same order by the same 
well-trained evaluator (e.g., neurologist, physical therapist, or other study staff) at each visit throughout the study.  
2-k. 3TUG will only be completed in subjects that are ambulatory. 
2-l. Blood samples for PK and PD analysis will be obtained prior to administration of study drug (within 1 hour of dosing). 
2-m. Blood samples for the exploratory tests will be obtained prior to administration of study drug (within 1 hour of dosing). 
2-n. Dosing on study visit days should be held until clinical assessment and blood collection has been completed. 
 
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3 
TABLE OF CONTENTS 
1 
SYNOPSIS ......................................................................................................11 
2 
SCHEDULE OF ASSESSMENTS ...............................................................18 
3 
TABLE OF CONTENTS ..............................................................................22 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................26 
5 
INTRODUCTION..........................................................................................27 
5.1 
OVERVIEW OF IMMUNE-MEDIATED NECROTIZING MYOPATHY ........................27 
5.2 
MECHANISM OF ACTION OF ZILUCOPLAN .........................................................28 
5.3 
CLINICAL TRIAL EXPERIENCE WITH ZILUCOPLAN .............................................29 
5.3.1 
ZILUCOPLAN PHASE 1 EXPERIENCE ..................................................................29 
5.3.2 
ZILUCOPLAN PHASE 2 EXPERIENCE ..................................................................30 
5.3.2.1 
COMPLETED PHASE 2 STUDY IN GMG ..............................................................30 
5.3.2.2 
COMPLETED PHASE 2 STUDIES IN PNH PATIENTS ............................................31 
5.4 
RATIONALE FOR THE CURRENT STUDY .............................................................32 
5.4.1 
RATIONALE FOR PRIMARY ENDPOINT ................................................................32 
5.4.2 
RATIONALE FOR BLINDING AND PLACEBO CONTROL ........................................33 
5.4.3 
DOSE SELECTION AND PRESENTATION ..............................................................33 
6 
STUDY OBJECTIVES AND ENDPOINTS ................................................34 
6.1 
OBJECTIVES ......................................................................................................34 
7 
STUDY DESIGN ............................................................................................37 
7.1 
OVERVIEW OF STUDY DESIGN ..........................................................................37 
7.2 
STUDY PERIODS ................................................................................................38 
7.2.1 
SCREENING PERIOD ...........................................................................................39 
7.2.1.1 
SCREENING AND ENROLLMENT .........................................................................39 
7.2.2 
TREATMENT PERIOD (MAIN AND EXTENSION PORTIONS) .................................40 
7.2.2.1 
RANDOMIZATION AND BLINDING ......................................................................40 
7.2.2.2 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT ......................41 
7.3 
EARLY STUDY TERMINATION ...........................................................................41 
7.4 
STUDY CONDUCT DURING COVID-19 .............................................................42 
8 
SELECTION OF STUDY POPULATION .................................................43 
8.1 
INCLUSION CRITERIA ........................................................................................43 
8.2 
EXCLUSION CRITERIA .......................................................................................43 
8.3 
SELECTION CRITERIA FOR THE EXTENSION PORTION ........................................44 
8.4 
REMOVAL OF SUBJECTS IN THE STUDY .............................................................45 
8.4.1 
WITHDRAWAL OF CONSENT ..............................................................................45 
8.4.2 
PREMATURE DISCONTINUATION .......................................................................45 
8.4.3 
REPLACEMENT OF SUBJECTS .............................................................................46 
9 
INVESTIGATIONAL MEDICINAL PRODUCT ......................................46 
9.1 
STUDY TREATMENT ADMINISTRATION .............................................................46 
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9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND MATCHING 
PLACEBO ...........................................................................................................46 
9.1.2 
DOSING SCHEDULE ...........................................................................................46 
9.1.3 
DOSE PRESENTATION ........................................................................................46 
9.1.3.1 
MISSED DOSES ..................................................................................................47 
9.2 
STUDY TREATMENT MANAGEMENT ..................................................................47 
9.2.1 
PREPARATION AND DISPENSING ........................................................................47 
9.2.1.1 
ALTERNATIVE STUDY TREATMENT SUPPLY DUE TO COVID-19 
PANDEMIC.........................................................................................................47 
9.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING ...........................................47 
9.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG ....................................47 
9.2.4 
DRUG ACCOUNTABILITY ...................................................................................48 
10 
STUDY ASSESSMENTS ..............................................................................48 
10.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS .......................................48 
10.1.1 
MEDICAL HISTORY AND DEMOGRAPHICS .........................................................48 
10.1.2 
HEIGHT AND WEIGHT .......................................................................................48 
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS ........................................................48 
10.2 
SAFETY ASSESSMENTS ......................................................................................49 
10.2.1 
PHYSICAL EXAMINATION ..................................................................................49 
10.2.2 
VITAL SIGNS .....................................................................................................49 
10.2.3 
ELECTROCARDIOGRAM .....................................................................................49 
10.2.4 
LABORATORY SAFETY ASSESSMENTS ...............................................................50 
10.2.4.1 
HEMATOLOGY, CHEMISTRY, AND COAGULATION .............................................50 
10.2.4.2 
URINALYSIS ......................................................................................................51 
10.2.4.3 
PREGNANCY TESTING AND CONTRACEPTION ....................................................51 
10.2.5 
ADVERSE EVENT RECORDING ...........................................................................52 
10.2.6 
IMMUNOGENICITY .............................................................................................52 
10.3 
EFFICACY ASSESSMENTS ..................................................................................52 
10.3.1 
PRIMARY EFFICACY ASSESSMENT ....................................................................52 
10.3.2 
SECONDARY EFFICACY ASSESSMENTS ..............................................................52 
10.3.2.1 
TRIPLE TIMED UP AND GO TEST .......................................................................52 
10.3.2.2 
PROXIMAL MANUAL MUSCLE TESTING ............................................................52 
10.3.2.3 
PHYSICIAN GLOBAL ACTIVITY VISUAL ANALOGUE SCALE ..............................53 
10.3.2.4 
PATIENT GLOBAL ACTIVITY VISUAL ANALOGUE SCALE ..................................53 
10.3.2.5 
HEALTH ASSESSMENT QUESTIONNAIRE ............................................................53 
10.3.2.6 
MYOSITIS DISEASE ACTIVITY ASSESSMENT TOOL ............................................53 
10.3.2.7 
ACR/EULAR RESPONSE CRITERIA ..................................................................54 
10.3.2.8 
FACIT-FATIGUE SCALE ...................................................................................54 
10.4 
PHARMACOKINETIC/ PHARMACODYNAMIC ASSESSMENTS ................................54 
10.5 
EXPLORATORY ASSESSMENTS ..........................................................................54 
10.5.1 
BIOMARKERS ....................................................................................................54 
10.5.2 
PHARMACOGENOMIC ASSESSMENTS .................................................................55 
11 
SAFETY REPORTING.................................................................................55 
11.1 
DEFINITIONS .....................................................................................................55 
11.1.1 
ADVERSE EVENTS .............................................................................................55 
11.1.1.1 
OCCURRENCE OF COVID-19 ............................................................................56 
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11.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................56 
11.2 
MONITORING OF INFECTION ..............................................................................56 
11.3 
EVALUATION AND CLASSIFICATIONS ................................................................57 
11.3.1 
SEVERITY ..........................................................................................................57 
11.3.2 
CAUSALITY .......................................................................................................57 
11.4 
RECORDING, REPORTING, AND MONITORING ....................................................58 
11.4.1 
RECORDING AND REPORTING ............................................................................58 
11.4.1.1 
ADVERSE EVENTS .............................................................................................58 
11.4.1.2 
SERIOUS ADVERSE EVENTS ..............................................................................59 
11.4.1.3 
DEATH ..............................................................................................................59 
11.4.1.4 
ABNORMAL LABORATORY VALUES ..................................................................59 
11.4.2 
SAFETY MONITORING .......................................................................................59 
11.4.2.1 
SAFETY MONITORING COMMITTEE ...................................................................60 
11.4.2.2 
POST-STUDY EVENTS ........................................................................................60 
11.4.2.3 
EMERGENCY UNBLINDING ................................................................................60 
11.5 
SPECIAL CIRCUMSTANCES ................................................................................61 
11.5.1 
PREGNANCY ......................................................................................................61 
11.5.2 
OTHER ..............................................................................................................61 
12 
STATISTICAL AND ANALYTICAL PLANS ...........................................61 
12.1 
ANALYSIS POPULATIONS ..................................................................................61 
12.1.1 
INTENTION-TO TREAT (ITT) POPULATION ........................................................61 
12.1.2 
PER PROTOCOL POPULATION ............................................................................61 
12.1.3 
SAFETY POPULATION ........................................................................................61 
12.2 
ANALYSIS METHODS ........................................................................................62 
12.2.1 
GENERAL METHODS .........................................................................................62 
12.2.2 
SUBJECT DISPOSITION .......................................................................................62 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS ..............................62 
12.2.4 
SAFETY ANALYSIS ............................................................................................62 
12.2.4.1 
ADVERSE EVENTS .............................................................................................62 
12.2.4.2 
CLINICAL LABORATORY EVALUATION .............................................................63 
12.2.4.3 
ELECTROCARDIOGRAMS ...................................................................................63 
12.2.4.4 
VITAL SIGNS .....................................................................................................63 
12.2.4.5 
PHYSICAL EXAMINATION ..................................................................................63 
12.2.5 
EFFICACY ANALYSIS .........................................................................................63 
12.2.5.1 
PRIMARY EFFICACY ANALYSES ........................................................................63 
12.2.5.2 
SECONDARY EFFICACY ANALYSES ...................................................................64 
12.2.6 
CLINICAL PHARMACOLOGY ANALYSIS .............................................................64 
12.2.6.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES...............................64 
12.2.7 
INTERIM ANALYSIS ...........................................................................................65 
12.3 
SAMPLE SIZE DETERMINATION .........................................................................65 
13 
ETHICAL CONSIDERATIONS ..................................................................65 
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE COMMUNICATIONS .......................................................................65 
13.1.1 
PROGRESS REPORTS ..........................................................................................65 
13.1.2 
FINAL INVESTIGATOR REPORT ..........................................................................66 
13.2 
INFORMED CONSENT OF STUDY SUBJECTS ........................................................66 
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13.3 
PROTOCOL COMPLIANCE ..................................................................................66 
13.4 
PROTECTION OF CONFIDENTIALITY ...................................................................67 
13.5 
DISCLOSURE OF STUDY RESULTS ......................................................................67 
14 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS .........67 
14.1 
QUALITY ASSURANCE .......................................................................................67 
14.1.1 
MONITORING ....................................................................................................68 
14.1.2 
AUDIT ...............................................................................................................68 
14.2 
CLINICAL RESEARCH ORGANIZATIONS .............................................................68 
14.3 
DATA MANAGEMENT ........................................................................................68 
14.3.1 
CASE REPORT FORMS .......................................................................................68 
14.3.2 
SOURCE DOCUMENTS .......................................................................................69 
14.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY .............................69 
14.5 
CLINICAL STUDY REPORT .................................................................................69 
14.6 
PUBLICATION POLICY .......................................................................................69 
15 
REFERENCES ...............................................................................................70 
 
LIST OF TABLES 
Table 1: MAIN PORTION Time and Events Table ................................... 18 
Table 2: EXTENSION PORTION Time and Events Table ....................... 20 
Table 3: Clinical Efficacy Outcomes in Study RA101495-02.201 at Week 
12 (ANCOVA) .............................................................. 31 
Table 4: Zilucoplan Dose Presentations by Weight Brackets ..................... 46 
Table 5: Chemistry, Hematology, and Coagulation Analytes .................... 50 
 
LIST OF FIGURES 
Figure 1: Mechanism of Action of Zilucoplan in the Complement System 29 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS 
 
 
3TUG Triple Timed Up and Go Test 
 
ADA anti-drug antibody 
 
AChR acetylcholine receptor 
 
ACR American College of Rheumatology 
 
AE adverse event 
 
ALP alkaline phosphatase 
 
ALT alanine aminotransferase 
 ANCOVA analysis of covariance 
 
AP alternative pathway of the complement 
cascade 
 
aPTT activated partial thromboplastin time 
 
AST aspartate aminotransferase 
 
BUN blood urea nitrogen 
 
C5 complement component 5 
 
C6 complement component 6 
 
CFB change from baseline 
 
CK creatine kinase 
 
CI confidence interval 
 COVID-19 coronavirus disease 2019 
 
CP classical pathway of the complement 
cascade 
 
CRO Clinical Research Organization 
 
CRP C-reactive protein 
 
CSR clinical study report 
 
CTCAE Common Terminology Criteria for 
Adverse Events 
 
DAP data analysis plan 
 
DNA deoxyribonucleic acid 
 
ECG electrocardiogram 
 
eCRF electronic case report form 
 
ELISA enzyme-linked immunosorbent assay 
 
EMA European Medicines Agency 
 
EMG electromyography 
 
ENMC European Neuromuscular Center 
 
EULAR European League Against Rheumatism 
 
FACIT-F Functional Assessment of Chronic 
Illness Therapy-Fatigue Scale 
 
FDA United States Food and Drug 
Administration 
 
GCP Good Clinical Practice  
 
GGT gamma-glutamyl transferase 
 
gMG generalized myasthenia gravis 
 
HAQ Health Assessment Questionnaire 
 
HCG human chorionic gonadotropin 
 
HMGCR 3-hydroxy-3-methyl-glutaryl-coenzyme 
A reductase 
 
HR heart rate 
 
IB Investigator’s Brochure 
 
ICF informed consent form 
 
IEC Independent Ethics Committee 
 
IMP investigational medicinal product 
 
IMNM immune-mediated necrotizing 
myopathy 
 
INR international normalized ratio 
 
IRB Institutional Review Board 
 
ITT Intention-to-Treat Population 
 
IV intravenous 
 
IVIG intravenous immunoglobulin 
 
IXRS interactive voice/web response system 
 
LDH lactate dehydrogenase 
 
LOCF last observation carried forward 
 
LS least squares 
 
LSLV last subject last visit 
 
MAC membrane attack complex (C5b-9) 
 
MBL Mannose-binding Lectin pathway of 
the complement cascade 
 
MCH mean corpuscular hemoglobin 
 
MCHC mean corpuscular hemoglobin 
concentration 
 
MCV mean corpuscular volume 
 
MD multiple dose 
 
MDAAT myositis disease activity assessment 
tool 
 
MedDRA Medical Dictionary for Regulatory 
Activities 
 MG-ADL MG-Activities of Daily Living Scale 
 
MGC MG Composite Scale 
MG-QOL15r MG-Quality of Life 15 (revised) 
 
MITAX myositis intention to treat activity index 
 
MMRM mixed model with repeated measures 
 
MMT manual muscle testing 
 
MRI magnetic resonance imaging 
 MYOACT myositis disease activity assessment 
visual analogue scales  
 
PD pharmacodynamic(s) 
 
PK pharmacokinetic(s) 
 
PNH paroxysmal nocturnal hemoglobinuria 
 
PT prothrombin time 
 
PTT partial thromboplastin time 
 
QMG Quantitative Myasthenia Gravis Scale 
 
RBC red blood cell 
 
SAD single ascending dose 
 
SAE serious adverse event 
 
SAP statistical analysis plan 
 
SAS Statistical Analysis System 
 
SC subcutaneous 
 
SD standard deviation 
 
se standard error 
 
SMC Safety Monitoring Committee 
 
SOC standard of care 
 
SOP standard operating procedure 
 
sRBC sheep red blood cell 
 
SRP signal recognition particle 
 
TEAE treatment-emergent adverse event 
 
TMF trial master file 
 
ULN upper limit of normal 
 
VAS visual analogue scale 
 
WBC white blood cell 
 
 
 
 
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5 
INTRODUCTION 
Ra Pharmaceuticals, Inc. is developing zilucoplan (RA101495), a SC self-administered 
15-amino acid cyclic peptide that binds to, and inhibits, the cleavage of complement 
component 5 (C5).  
Please refer to the IB for additional information on the chemistry, toxicology, 
pharmacology, and safety of zilucoplan.  
5.1 
OVERVIEW OF IMMUNE-MEDIATED NECROTIZING MYOPATHY 
Immune-mediated necrotizing myopathy (IMNM) is a rare, severe, inflammatory 
myopathy characterized by proximal limb weakness; markedly elevated serum creatine 
kinase (CK) levels; the presence of anti-SRP or anti-HMGCR auto-antibodies in serum; 
and paucicellular necrosis with prominent terminal complement deposition on muscle 
biopsy. IMNM is a relatively newly defined inflammatory myopathy, a group of diseases 
that also includes polymyositis, dermatomyositis, inclusion body myositis, and other, less 
well-defined myopathies. Previously, all patients who presented with proximal limb 
weakness and elevated CK, in the absence of skin involvement were classified as having 
polymyositis. However, many patients with the diagnostic label of ‘polymyositis’ were 
subsequently found to have distinctive findings on muscle biopsy as described above 
(Amato and Griggs 2003), leading to their separate classification as ‘necrotizing 
myopathy’. Subsequently, autoantibodies against HMGCR, a key enzyme in cholesterol 
biosynthesis, and SRP, a ubiquitous ribonucleoprotein involved in delivery of newly 
synthesized proteins to the endoplasmic reticulum, were found to be associated with this 
new entity which led to its designation as IMNM (see Pinal Fernandez 2018 for review).    
The prevalence of IMNM is estimated at approximately 16,000 patients in the US, 
Europe and Japan (Pinal-Fernandez 2018, Smoyer-Tomic 2012, Anquetil 2019). The 
disease is more common in women than in men. It does not show any clear racial 
predominance amongst Caucasians, Black or Asian populations, except for the 
association of anti-HMGCR positive IMNM with statin use, which is higher in non-Asian 
populations. The mean age at presentation is approximately 40 to 55 years old (Pinal-
Fernandez 2018). 
Clinically, IMNM presents with prominent proximal limb weakness due to the myopathy 
and can progress rapidly to disabling muscle atrophy. Although the clinicopathological 
presentation is generally similar among patients with anti-SRP and anti-HMGCR 
antibodies, there are subtle differences that have emerged since reliable and validated 
assays for these pathogenic autoantibodies have become more widely available. Patients 
with anti-SRP antibodies usually experience more severe weakness; more frequent neck 
weakness, dysphagia and respiratory insufﬁciency; and more prominent muscle atrophy. 
Moreover, clinically manifest cardiac involvement occurs in approximately 15% of 
patients with anti-SRP autoantibodies. In contrast, extra-muscular manifestations are rare 
in patients with anti-HMGCR autoantibodies (Pinal-Fernandez 2018).  
Muscle biopsy, muscle MRI and EMG are often used for narrowing of the differential 
diagnosis and further characterization of patients with IMNM. However, based on criteria 
set forth by the 224th European Neuromuscular Center (ENMC) International Workshop 
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which included experts from Europe, the US, and Japan, these additional investigations 
are not required to confirm the diagnosis of IMNM in patients with the characteristic 
clinical picture of high CK levels and positive anti-SRP or anti-HMGCR autoantibodies 
(Y. e. Allenbach 2018). If a muscle biopsy is performed, findings typically include 
myofiber necrosis and, in contrast to other inflammatory myopathies, only small numbers 
of infiltrating inflammatory cells. Moreover, with specific staining, prominent 
complement activation and diffuse deposition of the C5b-9 membrane attack complex 
(MAC) are observed, the pattern of which is distinct from other inflammatory myopathies 
(Cong 2014). MRI may demonstrate fatty replacement of muscle tissue which begins 
early after onset of IMNM (Pinal-Fernandez 2018), and EMG may confirm the presence 
of a myopathic pattern, and rules out other causes of muscle weakness. 
IMNM patients invariably exhibit the greatest elevation of serum CK levels seen among 
all forms of myositis, and serum CK levels correlate well with disease activity. Unlike in 
myopathies with less prominent tissue destruction, plasma CK levels in IMNM directly 
reflect the degree of myocyte necrosis due to ongoing release of this enzyme from injured 
skeletal muscle cells. Therefore, CK can be used for routine clinical follow-up and to 
evaluate treatment response in patients with IMNM, in addition to clinical measures such 
as standardized muscle strength testing. Specifically, CK levels may increase prior to 
manifestation or deterioration of clinical weakness, and a decline in CK levels is often the 
first sign of treatment response after treatment initiation while muscle regeneration and 
recovery of muscle strength may follow weeks to months later (Pinal-Fernandez 2018). 
Given the rapidly progressing symptoms and muscle pathology in IMNM, timely 
diagnosis and initiation of treatment are critical to help reduce long-term disability and 
improve prognosis.  While most immune mediated myopathies, to varying degrees, are 
responsive to non-specific immunosuppressive therapy, there are currently no FDA 
approved treatments for IMNM, and no randomized trials have been performed. The 
ENMC treatment recommendations identify corticosteroids as first line therapy in 
combination with, or rapidly followed by, an immunosuppressive agent such as 
methotrexate depending on disease severity. Intravenous immunoglobulin (IvIg) and 
rituximab are also increasingly used as first line therapy (Allenbach and Benveniste 
2018).  
Despite the treatments outlined above, disabling relapses and progressive muscle damage 
often continue, with particularly poor prognosis and permanent disability observed in 
younger patients and those with anti-SRP autoantibodies (Allenbach and Benveniste 
2018). Therefore, a high unmet medical need exists for additional treatment options for 
patients with IMNM.  
5.2 
MECHANISM OF ACTION OF ZILUCOPLAN 
Zilucoplan targets C5, a component of the terminal complement activation pathway. 
Zilucoplan binds to C5 with high affinity and prevents its cleavage by C5 convertases 
into the cleavage products C5a and C5b. Inhibition of C5 cleavage prevents the 
downstream assembly and cytolytic activity of the membrane attack complex (MAC). 
Using surface plasmon resonance and analysis of a high-resolution co-crystal structure, 
zilucoplan has been shown to bind to a specific site on C5 and to exhibit a strong and 
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rapid association with C5, coupled with a slow dissociation rate. Zilucoplan binds to the 
portion of C5 which corresponds to C5b. In binding to this region of C5, should any C5b 
be formed, it will be blocked from binding to C6 by zilucoplan, which further prevents 
the subsequent assembly of the MAC (C5b-9). 
Thus, zilucoplan inhibits MAC formation by a dual mechanism (Figure 1):   
1. Prevention of downstream complement activation by allosterically inhibiting C5 
cleavage  
2. Direct inhibition of the first step in MAC assembly, C5b-C6-binding. 
Figure 1: Mechanism of Action of Zilucoplan in the Complement System 
Abbreviations: 
AP: Alternative Pathway of the Complement Cascade; CP: Classical Pathway of the Complement 
Cascade; MBL: Mannose-binding Lectin pathway of the complement cascade; MAC: membrane 
attack complex; Complement components are shown using their standard abbreviations. 
The binding site of zilucoplan on the C5 protein is distinct from that of the C5 inhibitory 
monoclonal antibody, eculizumab. Nishimura and colleagues have described 11 patients 
in Japan (≈3.2% of the PNH population) who carry mutations in the C5 gene that prevent 
the binding of eculizumab to C5 and who are resistant to treatment with the antibody 
(Nishimura J 2014). Zilucoplan has been shown to effectively bind to C5 from blood 
samples from patients with this mutation, and to inhibit complement activation in vitro.  
Pharmacologically, zilucoplan has demonstrated dose-dependent inhibition of C5a and 
C5b formation following activation of classical or alternative complement pathways, as 
well as inhibition of red blood cell (RBC) lysis in the serum/plasma from various species.  
Zilucoplan is a potent complement inhibitor in humans and primates and a poor inhibitor 
in most other laboratory animal species. 
5.3 
CLINICAL TRIAL EXPERIENCE WITH ZILUCOPLAN 
Zilucoplan is currently in advanced clinical development by Ra Pharmaceuticals, Inc. for 
the treatment of patients with generalized myasthenia gravis (gMG) and paroxysmal 
nocturnal hemoglobinuria (PNH).  
5.3.1 
ZILUCOPLAN PHASE 1 EXPERIENCE 
RA101495-1001 was a randomized, double-blind, placebo-controlled, single-ascending 
dose (SAD) and multiple-dose (MD) study in healthy volunteers. The study was 
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conducted to evaluate the safety, tolerability, pharmacokinetic (PK), and 
pharmacodynamic (PD) of single-ascending doses of zilucoplan at dose levels of 0.05, 
0.10, 0.20, and 0.40 mg/kg administered by SC injection, and multiple-doses of 0.20 
mg/kg administered SC once daily for 7 days. Zilucoplan displayed a dose-proportional 
and predictable pharmacokinetic profile that was tightly correlated with the intended 
pharmacodynamic effect, suppression of the terminal complement pathway. 
Study RA101495-03.101 was an open-label, single dose Phase 1 pharmacokinetic study 
of zilucoplan in subjects with severe renal impairment (as defined by a creatinine 
clearance < 30 ml/min) and healthy controls who received a single dose of 0.3 mg/kg 
zilucoplan SC. A total of 16 subjects were enrolled into this study: 8 subjects with severe 
renal impairment and 8 healthy controls. Based on the data from this study, there is no 
significant impact of reduced creatinine clearance on the elimination of zilucoplan, and 
therefore no dose adjustment is needed for the use of zilucoplan in patients with renal 
impairment. 
Study RA101495-01.102 was a double-blind, single- and multiple-dose Phase 1 study 
evaluating safety and tolerability of zilucoplan in healthy Japanese subjects in 
comparison to healthy Caucasian subjects. A total of 36 subjects were enrolled into this 
study: 18 Japanese subjects and 18 Caucasian subjects. Based on the data from this study, 
there is no significant difference between Caucasian and Japanese subjects with respect to 
the pharmacokinetic, pharmacodynamic, and safety profiles of zilucoplan.  
A complete overview of results from these Phase 1 studies, including details of PK and 
PD measurements, is provided in the zilucoplan Investigator’s Brochure (IB). 
5.3.2 
ZILUCOPLAN PHASE 2 EXPERIENCE 
5.3.2.1 
COMPLETED PHASE 2 STUDY IN gMG 
The safety and efficacy of zilucoplan was evaluated in gMG patients in Phase 2 study 
RA101495-02.201. A total of 44 subjects were enrolled in study RA101495-02.201 and 
randomized to receive placebo, 0.1 mg/kg or 0.3 mg/kg zilucoplan SC daily for 12 weeks. 
Thereafter, subjects randomized to active zilucoplan continue dreceiving their assigned 
dose, while subjects randomized to placebo were re-randomized to receive active 
zilucoplan at either the 0.1 mg/kg or 0.3 mg/kg dose level. 
The following clinical assessments were performed in Study RA101495-02.201 to 
evaluate efficacy: The Quantitative Myasthenia Gravis (QMG) scale was the primary 
outcome measure, and the secondary outcome measures included the MG-ADL (MG-
Activities of Daily Living), the MGC (MG Composite), and the MG-QOL15r [MG-
Quality of Life 15 (revised)].  The study met its primary endpoint, showing a rapid, 
statistically significant, and clinically meaningful difference on the QMG between the 0.3 
mg/kg zilucoplan and placebo groups, favoring zilucoplan.  Additional analyses 
supported the primary analysis and showed a consistent clinical benefit of zilucoplan over 
placebo.  The results for the primary and secondary analyses are presented in Table 3. 
 
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Table 3: Clinical Efficacy Outcomes in Study RA101495-02.201 at Week 12 (ANCOVA) 
 
QMG 
MG-ADL 
MG-QOL15r 
MGC 
0.3 mg/kg zilucoplan CFB LS mean (se) 
-6.0 (1.2) 
-3.4 (0.9) 
-5.9 (1.7) 
-7.4 (1.6) 
0.1 mg/kg zilucoplan CFB LS mean (se) 
-5.5 (1.2) 
-3.3 (0.9) 
-7.4 (1.7) 
-5.3 (1.5) 
Placebo LS mean CFB (se) 
-3.2 (1.2) 
-1.1 (0.9) 
-2.1 (1.7) 
-3.3 (1.6) 
0.3 mg/kg zilucoplan CFB LS mean 
difference vs. placebo 
-2.8 (1.7) 
-2.3 (1.3) 
-3.7 (2.4) 
-4.1 (2.2) 
p- value* 
0.05 
0.04 
0.06 
0.04 
0.1 mg/kg zilucoplan CFB LS mean 
difference vs. placebo (se) 
-2.3 (1.7) 
-2.2 (1.3) 
-5.3 (2.4) 
-2.0 (2.2) 
p- value* 
0.09 
0.05 
0.02 
0.19 
* p-values are one-sided based on an ANCOVA model with baseline values as a covariate and using LOCF for subjects who received 
rescue therapy 
Abbreviations: ANCOVA = analysis of covariance; CFB = change from baseline; LOCF = last observation carried forward;  
 
LS = least squares; MG-ADL = MG-Activities of Daily Living; MG-QOL15r = MG-Quality of Life 15 (revised); 
MGC = MG Composite; QMG = quantitative myasthenia gravis; se=standard error 
Please refer to the zilucoplan IB for additional information regarding the results from 
studies RA101495-02.201. 
5.3.2.2 
COMPLETED PHASE 2 STUDIES IN PNH PATIENTS 
The global, dose-finding Phase 2 PNH program, consisted of studies RA101495-01.201 
and RA101495-01.203 as well as a long-term extension protocol RA101495-01.202.  A 
total of 32 subjects were screened in the zilucoplan Phase 2 PNH program, of which 29 
subjects were enrolled, 2 subjects did not meet eligibility criteria, and 1 subject declined 
to participate.  Studies RA101495-01.201 and RA101495-01.203 included an 8-week 
screening period and a 12-week Treatment Period. During the Treatment Period, subjects 
returned to the clinic weekly for the first 4 weeks followed by visits every 2 weeks. At 
the conclusion of the Treatment Period, subjects who completed the study and were 
demonstrating benefit had the option to enroll in the long-term extension protocol 
(RA101495-01.202). 
In treatment-naïve patients, zilucoplan achieved rapid, complete, and sustained inhibition 
of complement activity in the sheep red blood cell (sRBC) and MAC ELISA assays. 
Study RA101495-01.201 (Cohort A, n=10) met the pre-specified primary endpoint for 
LDH reduction from baseline (1174 U/L) to the mean of Week 6 to 12 (479 U/L) in 
treatment-naïve subjects, (p=0.002). The effects of zilucoplan on LDH, transfusion-
requirements, and quality of life measures in treatment-naïve patients were all similar to 
those observed with eculizumab in the pivotal TRIUMPH study (Hillmen P 2006). 
In patients switching from eculizumab to zilucoplan (Study RA101495-01.201 Cohort B 
and Study RA101495-01.203) near-complete, sustained, and uninterrupted inhibition of 
complement activity was observed in the sRBC and MAC ELISA assays during and after 
eculizumab washout. The level of complement inhibition achieved on zilucoplan 
exceeded the level of inhibition present at eculizumab trough. However, a divergent LDH 
response after switching from eculizumab to zilucoplan was observed. In switch patients 
with no evidence of pre-existing extravascular hemolysis on eculizumab (i.e., 
transfusion-independent and reticulocytes < 2 × ULN), switching was successful in all 
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cases with sustained LDH control after eculizumab washout. In switch patients with pre-
existing extravascular hemolysis on eculizumab (i.e., transfusion-dependent or 
reticulocytes > 2 × ULN), there was a high incidence of breakthrough intravascular 
hemolysis resulting in early withdrawal from the study. 
Please refer to the zilucoplan IB for additional information regarding the results from 
studies RA101495-01.201 and RA101495-01.203 as well as the long-term extension 
protocol (RA101495-01.202). 
5.4 
RATIONALE FOR THE CURRENT STUDY 
There is substantial pre-clinical and clinical evidence supporting a role for the terminal 
complement cascade in the pathogenesis of IMNM (Cong 2014) (Y. e. Allenbach 2018). 
80% of anti-SRP and 100% of anti-HMGCR autoantibodies are of the IgG1 
immunoglobulin subclass which efficiently activates the classical pathway of 
complement (Anquetil 2019). These autoantibodies bind to skeletal muscle and the 
immune complex formed by the autoantibody-antigen interaction is recognized by the 
initiating component of the classical complement pathway, the C1 complex. Binding of 
the C1 complex leads to a series of enzymatic cleavage steps culminating in the cleavage 
of C5 into C5a and C5b and deposition of MAC onto the sarcolemma, a characteristic 
finding in IMNM muscle biopsies (Y. e. Allenbach 2018).  
This uncontrolled and inappropriate activation of the classical complement cascade in 
muscle tissue is thought to lead to the characteristic histopathological findings and 
ultimately clinical weakness in patients with IMNM. Inhibition of the terminal 
complement pathway by zilucoplan is expected to prevent MAC deposition; to attenuate 
cell injury; reduce muscle cell derived creatine kinase in plasma; and potentially attenuate 
or even reverse clinical manifestations of IMNM. 
The compelling treatment effect observed with zilucoplan in patients with anti-AChR 
positive gMG (Section 5.3.2.1), a similar disease which shares with IMNM autoantibody-
driven hyperactivation of the classical complement pathway in skeletal muscle, supports 
the evaluation of zilucoplan as a potential therapy for IMNM in the present study. 
5.4.1 
RATIONALE FOR PRIMARY ENDPOINT 
IMNM patients invariably exhibit the greatest elevation of serum CK levels seen among 
all forms of myositis, and serum CK levels correlate well with disease activity. Unlike in 
myopathies with less prominent tissue destruction, plasma CK levels in IMNM directly 
reflect the degree of myocyte necrosis due to ongoing release of this enzyme from injured 
skeletal muscle cells. Therefore, CK can be used for routine clinical follow-up and to 
evaluate treatment response in patients with IMNM, in addition to clinical measures such 
as standardized muscle strength testing. Specifically, CK levels may increase prior to 
manifestation or deterioration of clinical weakness, and a decline in CK levels is often the 
first sign of treatment response after treatment initiation while muscle regeneration and 
recovery of muscle strength may follow weeks to months later (Pinal-Fernandez 2018). 
Given the reliable relationship between CK levels, disease activity and treatment 
response in IMNM, and the faster response and greater higher sensitivity of CK to 
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effective treatment interventions compared with clinical measures, CK was chosen as the 
primary endpoint for this phase 2 clinical trial. 
5.4.2 
RATIONALE FOR BLINDING AND PLACEBO CONTROL 
The secondary objective of this study is the evaluation of efficacy based on functional 
outcomes including 3TUG and components of the ACR/EULAR scale. Such clinical 
assessments are prone to placebo effects and may be influenced by knowledge of 
treatment assignment by the clinical evaluator and/or subject. Moreover, the evaluation of 
potential adverse effects may also be influenced by knowledge of treatment assignment. 
To enable rigorous efficacy and safety evaluation without the potential bias caused by 
knowledge of treatment assignment, this study was designed as a double-blind, placebo-
controlled study.  
Subjects entering the study will have stable disease and will be allowed to continue all of 
their pre-existing SOC therapies. Therefore, subjects receiving placebo will not be 
subject to increased risk due to withholding of medically necessary interventions. In 
addition, the placebo study drug contains substances that are known to be well-tolerated 
(
) and are delivered in a small volume < 1 mL; therefore, 
placebo administration by daily SC injection over the 8-week study period is expected to 
be well-tolerated. Consequently, administration of a placebo in Study RA101495-02.202 
is not anticipated to cause undue burden or risk for study subjects. 
Following the completion of the 8-week Treatment Period in the Main Portion of the 
study, all subjects will have the option to receive zilucoplan in the Extension Portion of 
the study.  Therefore, subjects originally randomized to placebo will eventually have the 
opportunity to receive active study drug. The study will remain double-blinded until after 
the data from Week 8 of the Main Portion of the study have been reviewed, locked, and 
unblinded. 
5.4.3 
DOSE SELECTION AND PRESENTATION 
The dose of 0.3 mg/kg was selected for this study based on its superior efficacy, greater 
inhibition of the terminal complement pathway, and similar safety profile as compared 
with the 0.1 mg/kg and placebo arms in the completed Phase 2 studies in patients with 
myasthenia gravis and PNH. 
In the Phase 2 Study in gMG patients (RA101495-02.201), the magnitude and speed of 
improvement on the primary (QMG) and key secondary (MG-ADL) endpoints were 
greater with the 0.3 mg/kg dose than the 0.1 mg/kg dose, and both active doses were 
superior to placebo (see Investigator’s Brochure for additional details).  
The dose response seen in the clinical outcome measures is consistent with the known 
pharmacodynamic effect of zilucoplan that resulted, as expected, in rapid, sustained and 
complete (97%) inhibition of the terminal complement pathway in all gMG patients 
receiving the 0.3 mg/kg dose while the 0.1 mg/kg group achieved only submaximal 
(88%) inhibition of the terminal complement pathway. 
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There was no apparent difference with respect to the pattern and distribution of adverse 
events or tolerability between the zilucoplan treated and the placebo groups.  No dose 
response in the safety profile was seen between the 0.1 mg/kg and 0.3 mg/kg zilucoplan 
groups.   
Similarly, in the Phase 2 studies in patients with PNH (RA101495-01.201, RA101495-
01.202, and RA101495-01.203), the starting dose of 0.1 mg/kg daily tested did not 
consistently achieve complete inhibition of complement activity in the sRBC lysis assay. 
The 0.3 mg/kg daily dose, by contrast, consistently achieved complete inhibition in the 
sRBC lysis assay (≥95% inhibition at trough) and reduced LDH to levels similar to those 
observed in patients receiving eculizumab. It is expected that the same pharmacodynamic 
response to zilucoplan as seen in patients with MG and PNH, i.e. complete complement 
inhibition, will drive the therapeutic response in patients with IMNM.  Therefore, the 
well-understood and extensively-tested dosing regimen for PNH and MG, i.e. 0.3 mg/kg 
daily dosing with three weight brackets, has again been selected for use in this study. 
Study drug will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., subjects will be provided prefilled syringes containing fixed amounts of 
zilucoplan based on their weight, and each fixed amount will cover a range of subject 
weights). This weight-bracketed dosing strategy will result in the potential for a range of 
doses to be received at each dose level (see Section 9.1.3).  
6 
STUDY OBJECTIVES AND ENDPOINTS 
6.1 
OBJECTIVES 
Objectives  
Estimands / Endpoints 
Primary 
Primary Objective: to evaluate the safety 
and efficacy of zilucoplan over placebo 
in CK levels in participants with IMNM 
Primary Efficacy Estimand: 
• Treatment: Zilucoplan administered 
by daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• Target Population: is defined through 
the inclusion/exclusion criteria in 
Section 8.1 and Section 8.2 reflecting 
the targeted IMNM population. 
• Endpoint: Percent change from 
Baseline to Week 8 in CK levels. 
• Intercurrent event (ICE) handling: 
regardless of any treatment 
discontinuation for any reason; 
censoring after prohibited medication. 
• Population level summary: The 
difference in ranks of the percentage 
change from baseline between 
treatments followed by the Wilcoxon-
Mann-Whitney odds (WMWodds) 
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and Hodges–Lehmann estimator 
followed by the corresponding 95% 
CIs. 
Primary Safety Endpoint 
• Incidence of treatment-emergent 
adverse events. 
Secondary 
Secondary Objective(s): to further 
evaluate the efficacy and the safety of 
zilucoplan over placebo in participants 
with IMNM 
Secondary Efficacy Estimands: 
• Treatment: Zilucoplan administered 
by daily SC injection (0.3 mg/kg) vs 
matching placebo. 
• Target Population: is defined through 
the inclusion/exclusion criteria at 
Sections 8.1 and 8.2 of the study 
protocol reflecting the targeted IMNM 
population. 
• Endpoints:  
o At least minimal response based 
on the American College of 
Rheumatology/European League 
Against Rheumatism 
(ACR/EULAR) Response Criteria 
Scale at Week 8;  
o Change from Baseline to Week 8 
in 3TUG Test (in ambulatory 
patients only);  
o Change from Baseline to Week 8 
in Proximal Manual Muscle 
Testing (MMT);  
o Change from Baseline to Week 8 
in Physician Global Activity 
Visual Analogue Scale (VAS);  
o Change from Baseline to Week 8 
in Patient Global Activity VAS;  
o Change from Baseline to Week 8 
in Health Assessment 
Questionnaire (HAQ);  
o Change from Baseline to Week 8 
in myositis disease activity 
assessment tool (MDAAT) 
Extramuscular Disease Activity 
VAS Score;  
o Change from Baseline to Week 8 
in Functional Assessment of 
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Chronic Illness Therapy (FACIT)-
Fatigue Scale. 
• ICE handling: regardless of any 
treatment discontinuation for any 
reason; censoring after administration 
of prohibited medication. 
• Population level summary: 
o Odds Ratio of ACR/EULAR ≥ 20 
response proportion between 
treatment conditions;  
o Difference in continuous endpoint 
means, between treatment 
conditions. 
Other 
To further evaluate the safety of 
zilucoplan over placebo in participants 
with IMNM 
Other safety endpoints 
• Change in clinical laboratory tests 
• Change in ECG parameters  
• Change vital signs parameters, and 
• Presence of Anti-Drug Antibodies 
Exploratory 
To assess the long term efficacy of 
zilucoplan 
• At least minimal response based on the 
ACR/EULAR Response Criteria Scale 
at each visit following Week 8; 
• Change from Baseline of 3TUG Test 
(in ambulatory patients only) at each 
visit following Week 8; 
• Change from Baseline of Proximal 
MMT at each visit following Week 8; 
• Change from Baseline of Physician 
Global Activity VAS at each visit 
following Week 8; 
• Change from Baseline of Patient 
Global Activity VAS at each visit 
following Week 8; 
• Change from Baseline of HAQ at each 
visit following Week 8; 
• Change from Baseline of MDAAT 
Extramuscular Disease Activity VAS 
Score at each visit following Week 8;  
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• Change from Baseline of FACIT-
Fatigue Scale at each visit following 
Week 8; 
To assess the PK of zilucoplan 
• Plasma concentrations of zilucoplan 
and its major metabolites  
To assess the PD of zilucoplan 
 
• Sheep red blood cell lysis assay for 
evaluation of classical complement 
pathway activation 
• Complement component 5 levels 
To assess the effect of zilucoplan on 
biomarkers 
• Mechanistic biomarkers [e.g., 
complement fixation, complement 
function, complement pathway 
proteins, autoantibody characterization 
(titer and immunoglobulin class), 
myocyte markers, and inflammatory 
markers].   
To assess the effect of zilucoplan on 
pharmacogenomics 
• Pharmacogenomic analyses (optional): 
Genomic studies [e.g., 
deoxyribonucleic acid (DNA) 
sequencing, including exploration of 
whether specific genomic features 
correlate with response or resistance to 
study drug] may be performed. 
7 
STUDY DESIGN 
7.1 
OVERVIEW OF STUDY DESIGN  
RA101495-02.202 is a multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the safety, tolerability, and efficacy of zilucoplan in subjects with IMNM who 
are positive for anti-HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase) or 
anti-SRP (signal recognition particle) autoantibodies. 
The planned enrollment is approximately 24 subjects. Subjects will be randomized in a 
1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or matching placebo. 
Randomization will be stratified based on antibody status (anti-HMGCR+ versus anti-
SRP+). 
The Main Portion of the study includes a Screening Period of up to 4 weeks and an 8-
week Treatment Period. During the Treatment Period, subjects will return to the clinic at 
Week 1, Week 2, Week 4, and Week 8 to evaluate safety, tolerability, and efficacy. 
Additional assessments will include biomarker testing, pharmacokinetics, 
pharmacodynamics, and optional pharmacogenomics. Safety assessments will include 
physical examinations, vital signs, electrocardiogram (ECG), clinical laboratory tests, 
adverse event (AE) monitoring, and immunogenicity. 
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Randomized subjects will receive 0.3 mg/kg zilucoplan or matching placebo 
administered SC at the Day 1 visit. Following in-clinic education and training, all 
subjects will self-inject daily SC doses of blinded study drug, according to randomized 
treatment allocation, for the subsequent 8 weeks. Single use pre-filled syringes in 
injection devices will be provided for use during the study. 
All SOC therapy medications for IMNM should be kept at the same doses throughout the 
study, including corticosteroids, immunosuppressive drugs, and IVIG. 
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must 
be vaccinated against meningococcal infections (with a quadrivalent vaccine and, where 
available and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, 
or at the time of, initiating study drug. Subjects who initiate study drug treatment less 
than 2 weeks after receiving a meningococcal vaccine must receive treatment with 
appropriate prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) until 
at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be 
administered in accordance with local SOC. (see Section 11.2). 
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled 
and reminded of the early signs and symptoms of Neisseria meningitidis infection. A 
patient safety card detailing the signs and symptoms of infection, with instructions to 
seek immediate medical attention if any such symptoms occur, will be provided to each 
subject. 
The safety of subjects will be monitored in a blinded manner on an ongoing basis. If an 
unblinded data review should become necessary to ensure subject safety, an SMC will 
convene and evaluate study data as appropriate.  
At the conclusion of the Treatment Period of the study, all subjects will have the option 
to receive zilucoplan in the Extension Portion of the study provided they meet the 
Extension Portion selection criteria. Visits during the first 8 weeks of the Extension 
Portion will be identical to the Main Portion of the study for all subjects to ensure 
appropriate monitoring of subjects transitioning from placebo to active treatment. The 
study will remain double-blinded until after the data from Week 8 of the Main Portion of 
the study have been reviewed, locked, and unblinded. 
If a subject permanently discontinues study drug treatment prior to the Week 8 visit for 
any reason, he/she will not be eligible for the Extension Portion. For subjects who 
permanently discontinue treatment with study drug, a Safety Follow-up Visit will be 
performed at 40 days after the last dose to collect information on any ongoing AEs or 
new SAEs since the last study visit. 
7.2 
STUDY PERIODS 
During the Main Portion of the study, the total duration of study participation for all 
subjects will be up to approximately 12 weeks, including a Screening Period of up to 
4 weeks and an 8-week Treatment Period. 
During the Extension Portion of the study, the investigational medicinal product (IMP) 
will continue to be provided by the sponsor until zilucoplan is approved and available in 
the territory (e.g., in another qualifying extension study) or until the sponsor terminates 
development of zilucoplan for IMNM. In countries where zilucoplan is not approved or 
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marketed, but in which sponsored clinical studies have been conducted, subjects may 
continue to receive zilucoplan through a compassionate use pathway. 
For France only: The duration of study participation during the Extension Portion of this 
study (RA101495-02.202) will include an open-label, single-arm, 18-month Treatment 
Period .  
7.2.1 
SCREENING PERIOD  
The Screening visit(s) will occur no more than 28 days (4 weeks) prior to the first dose of 
study drug on Day 1.  
Subjects that do not meet the entry criteria for the study may rescreen after 56 days 
(8 weeks). Subjects may be rescreened no more than 2 times. 
7.2.1.1 
SCREENING AND ENROLLMENT 
Procedures performed as SOC during the Screening Period may be used to determine 
eligibility. Informed consent must be obtained prior to performing any study-specific 
procedures that are not SOC. 
At the Screening visit(s), subjects will be assigned a unique subject number. The 
following assessments will be performed during Screening: 
• Informed consent 
• Review of eligibility criteria 
• Review of medical history and demographics, including collection of a detailed 
history of IMNM diagnosis information, as well as local serology for anti-HMGCR or 
anti-SRP autoantibodies. 
• Review and documentation of prior and concomitant medications 
Note: A complete history of medications taken for the treatment of IMNM will be 
collected. All medications taken during 30 days prior to Screening will be recorded. 
• Completion of the following efficacy assessments: 
o 3TUG (in ambulatory subjects only) 
o Proximal MMT 
o Physician Global VAS 
o Patient Global VAS 
o HAQ 
o MDAAT 
o FACIT-Fatigue 
• Measurement of height and weight 
• Full physical examination  
• Vital signs [heart rate (HR), body temperature, blood pressure in the sitting position] 
• 12-lead ECG  
• Neisseria meningitidis vaccination and, if applicable, prophylactic antibiotics (see 
Section 11.2) 
• Collection of blood samples for laboratory testing:  hematology, chemistry, CK, and 
coagulation (if applicable) 
• Collection of urine sample for urinalysis 
• Serum pregnancy testing for females of childbearing potential only 
• Collection of blood sample for anti-drug antibody (ADA) testing 
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• Collection of blood samples for central testing of disease specific antibody testing 
(anti-HMGCR or anti-SRP autoantibodies) 
• Collection of blood sample for pharmacogenomic analysis (optional) 
NOTE: If the pharmacogenomic analysis sample is not collected at the Screening 
visit, it may also be collected on any other visit during the study. 
• Enrollment and randomization 
7.2.2 
TREATMENT PERIOD (MAIN AND EXTENSION PORTIONS) 
Subjects will receive treatment with 0.3 mg/kg zilucoplan or placebo, according to 
randomization, from Day 1 to Day 57 during the Treatment Period of the Main Portion of 
the study. Subjects who complete the Week 8 (Day 57) visit (including those randomized 
to the placebo arm) will have the option to continue treatment with zilucoplan in the 
Extension Portion of the study. If a subject chooses not to participate in the Extension 
Portion, the subject will receive SOC treatment off-study, as recommended by the 
treating physician. 
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled 
and reminded of the early signs and symptoms of Neisseria meningitidis infection. A 
patient safety card detailing the signs and symptoms of infection, with instructions to 
seek immediate medical attention if any such symptoms occur, will be provided to each 
subject. Should a subject lose/misplace their safety instruction card they will be provided 
a new card. 
Please refer to the Time and Events Tables (Table 1 and Table 2) for details regarding 
assessments that must be completed at visits during the Treatment Period for both the 
Main and Extension Portions of the study.  
7.2.2.1 
RANDOMIZATION AND BLINDING 
Subjects who meet all entry criteria will be randomized in a 1:1 ratio to receive daily SC 
doses of 0.3 mg/kg zilucoplan or placebo. Subjects will be assigned to study arms in a 
blinded fashion using a computerized randomization algorithm. Randomization will be 
stratified based on antibody status (anti-HMGCR+ versus anti-SRP+). 
This is a double-blind study. Subjects and study staff will remain blinded to treatment 
assignments until after the data from Week 8 of the Main Portion of the study have been 
reviewed, locked, and unblinded. 
Instructions for emergency unblinding, if warranted, for safety reasons are provided in 
Section 11.4.2.3. 
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7.2.2.2 
DISCONTINUATION OF INVESTIGATIONAL MEDICINAL PRODUCT 
During the Main Portion, if a subject permanently discontinues study drug at any time 
prior to completion of Day 57 (see Section 8.4.2), the subject should return to clinic for 
an End of Main Visit. During the Extension Portion, if a subject permanently 
discontinues study drug at any time (see Section 8.4.2), the subject should return to clinic 
for a Final Extension Visit. If a subject discontinues study drug at any time, a 40 day 
follow up visit is required. 
The following procedures will be completed at the End of Main and Final Extension 
Visits:   
• Completion of the following efficacy assessments: 
o 3TUG (in ambulatory subjects only) 
o Proximal MMT 
o Physician Global VAS 
o Patient Global VAS 
o HAQ 
o MDAAT 
o FACIT-Fatigue 
• Measurement of weight 
• Review and documentation of concomitant medications 
• Physical examination  
• Vital signs (HR, body temperature, blood pressure in the sitting position) 
• 12-lead ECG 
• Collection of blood samples for laboratory testing:  hematology, chemistry, and 
coagulation (if applicable)  
• Collection of urine sample for urinalysis 
• Urine pregnancy testing for females of childbearing potential only 
• Record AEs 
• Collection of blood samples for the following assessments: 
o ADA sampling  
o PK analysis 
o PD analyses 
o Autoantibody testing 
o Biomarker analysis 
• Return of all used and unused study drug syringes to site  
All subjects who discontinue study treatment will have a Safety Follow-up Visit 40 days 
after the last dose of study drug, to collect the following information: 
• Review and documentation of concomitant medications 
• Physical examination  
• Vital signs (HR, body temperature, blood pressure in the sitting position) 
• Urine pregnancy testing for females of childbearing potential only 
• Record information on ongoing AEs or new SAEs since the last study visit.  
7.3 
EARLY STUDY TERMINATION  
The end of study, or study termination, is defined as the time at which the last subject has 
performed their last visit (LSLV). Following LSLV, all remaining data will be collected 
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in the appropriate case report forms (see Section 14.3) and the study results will be 
summarized in the clinical study report (CSR) (see Section 14.5). 
The Sponsor may terminate this study early (in its entirety, in part, or at one or more 
study sites) for reasonable cause provided that written notice is submitted in advance of 
the intended termination. The investigator may also terminate the study at the site for 
reasonable cause, after providing written notice to the Sponsor in advance of the intended 
termination. Advance notice is not required by either party if the study is stopped due to 
safety concerns. If the Sponsor terminates the study for safety reasons, the Sponsor will 
immediately notify the investigator and subsequently provide written instructions for 
study termination. 
If the Sponsor terminates or suspends the study, all applicable Competent Regulatory 
Authorities will be informed as per applicable legislation. 
7.4 
STUDY CONDUCT DURING COVID-19 
The protocol-mandated visit schedule should be followed to the extent possible, based on 
the judgment of the investigator. However, during the COVID-19 outbreak or under other 
exceptional circumstances, remote follow-up will be conducted and the subjects will be 
contacted by telephone/video contact to assess as many details as possible, according to 
the protocol scheduling, to verify that the subject is suitable for continuing study 
treatment. Some procedures may be collected by other remote means if feasible and/or 
acceptable per local guidelines. Study sites should make efforts to inform the sponsor or 
the CRO in the event that protocol procedures cannot be completed due to COVID-19. 
In those situations when the subject cannot return to the study site, the investigators will 
assess the subject’s safety by telephone/video contact. Based on information gathered 
from the telephone/video contact, investigators will confirm whether the subject could 
continue the current IMP treatment after the assessment. If the subject is suitable for 
study treatment continuation, the investigator or designee will assess if the subject agrees 
to provide name, address, telephone number, and email to the appointed courier. The 
subject will confirm his/her consent by email or verbally in order to receive IMP via 
courier. If the email option is not possible, the site must obtain consent via phone and 
document it in the medical record. 
If the shipment is agreed, the investigator or designee will clearly explain to the subject 
everything needed regarding the handling (in case of inconsistencies at delivery) and 
administration of the study drug and how to return all unused IMP to the study site at the 
next on-site visit. Only after approval by the study staff for the correct shipment will the 
subject start taking the treatment. The whole process and communication with subject 
will be documented in the subject’s medical source record. Changes in the study 
treatment supply in this situation are described in Section 9.2.1.1. 
Ad hoc subject contact may be warranted to understand the current health status of the 
subjects, to follow up on AEs, and inform them of any protective measures taken by the 
clinical site as a result of the COVID-19 pandemic (e.g., any measures that may limit 
access to the site or may require additional actions by the subject prior to entry to the 
site). 
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If a subject needs to be discontinued and cannot come into the clinic, a visit will be 
scheduled to perform final safety assessments as soon as possible. 
If a subject visits another facility for a medical issue, the investigator should request 
contact with the physician providing care to provide a detailed explanation of the 
subject’s condition and his/her participation in the clinical study. Subjects or caregivers 
shall be reminded to completely collect and keep records of this visit. 
Deviations to data collection including inability to perform some assessments, or 
alternative methods of assessment, such as phone calls, should be recorded in the source 
documentation and notated as “not done” in the eCRF. 
8 
SELECTION OF STUDY POPULATION 
8.1 
INCLUSION CRITERIA  
To be eligible for this study, subjects must meet ALL of the following inclusion criteria: 
1. Male or female  18 years and < 75 years. 
2. Able to provide informed consent, including signing and dating the informed consent 
form (ICF). 
3. Clinical diagnosis of IMNM (Immune-Mediated Necrotizing Myopathy). 
4. Positive serology for anti-HMGCR or anti-SRP autoantibodies. 
5. Clinical evidence of weakness (≤ grade 4 out of 5) on manual muscle testing in at 
least one proximal limb muscle group. 
6. CK (creatine kinase) of >1000 U/L at Screening. 
7. No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated 
to occur during the first 8-weeks on study. 
8. No changes in immunosuppressive therapy, including dose, for at least 30 days prior 
to Baseline or anticipated to occur during the first 8-weeks on study. 
9. Female subjects of childbearing potential must have a negative serum pregnancy test 
at Screening and a negative urine pregnancy test within 24 hours prior to the first 
dose of study drug. 
10. Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation) and all male subjects (who have not been surgically sterilized 
by vasectomy) must agree to use effective contraception during the study. 
Postmenopausal women are, for the purposes of this protocol, defined as women who 
have gone 12 consecutive months without menstruation. 
8.2 
EXCLUSION CRITERIA 
Subjects who meet ANY of the following exclusion criteria must be excluded from the 
study:   
1. History of meningococcal disease. 
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2. Current or recent systemic infection within 2 weeks prior to Screening or infection 
requiring intravenous (IV) antibiotics within 4 weeks prior to Screening. 
3. Pregnant, planning to become pregnant, or nursing female subjects. 
4. Recent surgery requiring general anesthesia within 2 weeks prior to Screening or 
expected to have surgery requiring general anesthesia during the 8-week Treatment 
Period. 
5. Treatment with a complement inhibitor or an experimental drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to Baseline. 
6. Statin use within 30 days prior to Baseline or anticipated to occur during study. 
7. Rituximab use within 90 days prior to Baseline or anticipated to occur during study. 
NOTE: In subjects who received rituximab more than 90 days but less than 6 months 
prior to Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, 
penicillin V) should be given upon initiation of study drug until 6 months after the 
last rituximab dose 
8. Recent initiation of intravenous immunoglobulin (IVIG) (i.e., first cycle administered 
less than 90 days prior to Baseline). 
9. Plasma exchange within 4 weeks prior to Baseline or expected to occur during the 8-
week Treatment Period. 
10. Active malignancy (except curatively resected squamous or basal cell carcinoma of 
the skin) requiring surgery, chemotherapy, or radiation within the prior 12 months 
(subjects with a history of malignancy who have undergone curative resection or 
otherwise not requiring treatment for at least 12 months prior to Screening with no 
detectable recurrence are allowed). 
11. History of any significant medical, psychiatric disorder, or laboratory abnormality 
that in the opinion of the investigator would make the subject unsuitable for 
participation in the study. 
12. Participation in another concurrent clinical trial involving an experimental therapeutic 
intervention (participation in observational studies and/or registry studies is 
permitted).  
13. Unable or unwilling to comply with the requirements of the study. 
14. Subjects who have a known hypersensitivity to zilucoplan or any of its excipients. 
8.3 
SELECTION CRITERIA FOR THE EXTENSION PORTION 
1. Completion of the Main Portion of the study. 
2. Continues to meet inclusion criteria 2, 11, and 12 from the Main Portion of the study. 
2. Able to provide informed consent, including signing and dating the ICF. 
11. Female subjects of childbearing potential must have a negative serum pregnancy test at Screening 
and a negative urine pregnancy test within 24 hours prior to the first dose of study drug. 
12. Sexually active female subjects of childbearing potential (i.e., women who are not postmenopausal 
or who have not had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) and all 
male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective 
contraception during the study. Postmenopausal women are, for the purposes of this protocol, 
defined as women who have gone 12 consecutive months without menstruation. 
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3. Did not start any disallowed medication per the exclusion criteria from the Main 
Portion of the study or alter the dose of any other concomitant medication, unless 
medically indicated. 
4. Is able and willing to comply with the requirements of the study. 
5. Does not have any new medical condition (since entry into the Main Portion) or any 
other reason that, in the opinion of the investigator or Sponsor, would disqualify the 
subject from participation in the Extension Portion of the study. 
8.4 
REMOVAL OF SUBJECTS IN THE STUDY 
8.4.1 
WITHDRAWAL OF CONSENT 
A subject may withdraw consent to participate in this study at any time without penalty 
or loss of benefits to which the subject is otherwise entitled to. When a subject wishes to 
withdraw consent, it is important to distinguish between withdrawing his/her consent for 
a particular study procedure or visit versus withdrawing his/her consent from the study 
entirely (i.e., premature discontinuation). 
When a subject withdraws consent from the study (or study procedure), the reason(s) for 
withdrawal will be recorded by the investigator or designee on the relevant page of the 
electronic case report form (eCRF). 
8.4.2 
PREMATURE DISCONTINUATION 
Every reasonable effort should be made to encourage retention of subjects in the study, 
maximize compliance with study drug, and facilitate attendance at all scheduled study 
visits/assessments.  
All subjects have the right to refuse further participation in the study at any time and for 
any reason. A subject’s participation must, therefore, be terminated immediately upon 
his/her request. 
The investigator will make every attempt to ascertain the reason(s) for discontinuation 
and to document this in detail in the source documentation and the appropriate sections of 
the eCRF. A subject must be withdrawn from the study for any of the following reasons:   
• Withdrawal by subject 
• Protocol Violation/Noncompliance (defined as refusal or inability to adhere to the 
study procedures) 
• Pregnancy while receiving study drug 
• At the request of the Sponsor, regulatory agencies, or IRB/IEC 
• Physician decision 
• Loss to follow-up 
• Death 
Subjects may be withdrawn from study treatment due to unacceptable or intolerable AEs. 
All subjects who permanently discontinue study treatment in the Main Portion of the 
study (i.e., prior to Day 57 visit) for any reason will not be eligible to participate in the 
Extension Portion of the study. 
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8.4.3 
REPLACEMENT OF SUBJECTS 
In order to obtain an adequate number of subjects that complete the study (see Section 
12.3), additional subjects may be enrolled into the study, at the discretion of the Sponsor. 
9 
INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
STUDY TREATMENT ADMINISTRATION 
9.1.1 
INVESTIGATIONAL MEDICINAL PRODUCT AND MATCHING PLACEBO 
The IMP, zilucoplan, and the placebo will be supplied as a sterile, preservative-free, 
aqueous solution prefilled into 1 mL glass syringes with a 29-gauge, ½-inch, staked 
needle placed within a self-administration device. Subjects will be instructed to self-
administer SC doses daily. Three dosage strengths of zilucoplan will be supplied as 
shown in Table 4. 
9.1.2 
DOSING SCHEDULE 
During the Main Portion of the study, all eligible subjects will be randomized 1:1 to 
receive 0.3 mg/kg zilucoplan or placebo administered SC at the Day 1 visit, which will be 
performed by the site staff at the study visit. Following in-clinic education and training, 
all subjects will self-inject daily SC doses of study drug at approximately the same time 
each day for the remainder of the Treatment Period. 
Dosing on study visit days should be held until efficacy assessments (i.e., Physician 
Global Activity VAS, Patient Global Activity VAS, Proximal MMT, HAQ, 3TUG, 
MDAAT, and FACIT-Fatigue) and PK/PD sample collection have been completed.  
Patients should be supervised while injecting to ensure adequate injection technique and 
re-instructed if and as needed. 
9.1.3 
DOSE PRESENTATION  
Investigational drug product will be provided in prefilled syringes for self-injection using 
weight bracketed dosing (i.e., subjects will be provided prefilled syringes based on their 
weight containing fixed amounts of zilucoplan, and each fixed amount will cover a range 
of subject weights). As shown in Table 4, this weight bracketed dosing strategy will 
result in the potential for a range of doses to be received, from a minimum of 0.22 mg/kg 
daily (nominal dose) to a maximum dose of 0.42 mg/kg daily. 
Matching placebo for the 0.3 mg/kg dose will be provided in 1 presentation of 0.574 mL. 
Table 4: Zilucoplan Dose Presentations by Weight Brackets 
Minimum (Nominal)  
Target Dose (mg/kg) 
Actual Dose (mg) 
Weight Range (kg) 
Dose Range (mg/kg) 
0.3 
16.6 
≥43 to <56 
0.30 to 0.39 
0.3 
23.0 
≥56 to <77 
0.30 to 0.41 
0.3 
32.4 
≥77 to 150 
0.22 to 0.42 
Subjects who present with a body weight outside of these ranges will be accommodated 
on a case-by-case basis, in consultation with the medical monitor. 
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9.1.3.1 
MISSED DOSES  
Study personnel will assess study drug compliance at every visit to record whether any 
doses were missed. If a subject misses 1 dose (i.e., 1 day) of study drug, he/she should 
take the next planned dose as scheduled and the investigator should be contacted as soon 
as possible. If a subject misses 2 or more consecutive doses, he/she must notify the 
investigator immediately and the medical monitor should be consulted. 
9.2 
STUDY TREATMENT MANAGEMENT 
9.2.1 
PREPARATION AND DISPENSING 
Prefilled syringes will be dispensed to each subject at each study visit, beginning on 
Day 1 of the Treatment Period.  
Subjects will be provided with training and detailed instructions on the administration of 
study drug using the single use pre-filled syringes in injection devices. 
9.2.1.1 
ALTERNATIVE STUDY TREATMENT SUPPLY DUE TO COVID-19 
PANDEMIC 
In circumstances where the subject is not allowed to visit the site, the IMP may be 
delivered directly to the subject via qualified courier that will act as a liaison between 
sites and subjects to deliver the drug during the outbreak. 
If the shipment of the drug directly to the subject is agreed, the investigator or designee 
will clearly explain proper handling and administration of the study drug. Subjects will be 
instructed to return all unused IMP at the next on-site visit. 
9.2.2 
STUDY DRUG SUPPLY, STORAGE, AND HANDLING 
Zilucoplan and placebo should be stored at 2°C to 8°C at the study site. Once dispensed 
to subjects, zilucoplan and placebo may be stored at room temperature [20°C to 25°C 
(68°F to 77°F)] for up to 45 days protected from sources of heat, light, and damage. 
Storage of zilucoplan and placebo outside of room temperatures should be avoided. 
Please refer to the study Pharmacy Manual for additional details. 
Subjects will be instructed to self-inject SC doses daily at approximately the same time 
each day. The subject may inject study drug into the abdomen (preferred site), thigh, or 
upper arm. 
All subjects will receive study drug kits, each of which will include 7 single-dose, 
prefilled syringes (pre-loaded into self-injection devices) containing study drug, alcohol 
wipes, and adhesive dressings, as well as a syringe disposal container. 
9.2.3 
DISPOSAL, RETURN, OR RETENTION OF UNUSED DRUG 
Subjects will receive secure containers to dispose of used syringes while at home. At 
each visit, the subject should return the container containing all used syringes to the site. 
The unused study drug (i.e., unused syringes) should be retained by the subject.  
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All unused study drug syringes and disposal containers containing used syringes must be 
returned to the site at the last study visit for each Treatment Period (i.e., Day 57/End of 
Main Visit or the Final Extension Visit). 
9.2.4 
DRUG ACCOUNTABILITY 
It is the responsibility of the pharmacist to ensure that a current record of inventory/drug 
accountability is maintained. Inventory records must be readily available for inspection 
by the study monitor and are open to inspection by regulatory authorities at any time. For 
further details, please consult the Pharmacy Manual.  
10 
STUDY ASSESSMENTS 
Please refer to Table 1 and Table 2 for the timing of study assessments. 
10.1 
SUBJECT AND BASELINE DISEASE CHARACTERISTICS 
10.1.1 
MEDICAL HISTORY AND DEMOGRAPHICS 
Relevant medical history (including surgical history) will be documented at the Screening 
visit to assess subject eligibility. The following demographic data will be collected: year 
of birth, gender, ethnicity, and race.  
The screening assessment will also include disease history with documentation of the 
diagnosis of IMNM, disease course and any IMNM-specific treatments.  Muscle biopsy 
findings (including presence or absence of C5b-9 staining) and other diagnostic tests 
(e.g., MRI, serology, and electromyography) will also be recorded.  
10.1.2 
HEIGHT AND WEIGHT  
Height (cm) will be collected at the Screening visit only. Weight (kg) will be measured at 
the study visits indicated in Table 1 and Table 2. 
10.1.3 
PRIOR AND CONCOMITANT MEDICATIONS 
Subjects are prohibited from receiving another complement inhibitor, rituximab, statins, 
or any investigational medicinal product while on study.  All other medications are 
permitted while on study. 
Subjects are expected to remain on stable doses of permitted SOC therapy for IMNM 
throughout the Main Portion of the study and through the Week 8 visit of the Extension 
Portion, including corticosteroids, immunosuppressive drugs, and IVIG. The medical 
monitor should be contacted prior to any changes throughout the duration of the study in 
IMNM specific therapy. 
All prescriptions and over-the-counter medications taken during the 30 days prior to 
Baseline (i.e., Day 1) through the last study visit will be documented. NOTE: A complete 
history of medications taken for the treatment of IMNM will be collected. 
Concomitant medications include any prescription or over-the-counter medication that is 
ongoing on Day 1 or that is initiated following the first dose of study drug on Day 1.  
Medications, including over-the-counter therapeutics, natural products, and vitamins, 
should not be changed during the Screening or Treatment Periods, unless medically 
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necessary.  All concomitant medications necessary for the health and well-being of a 
subject will be permitted. 
Medications will be recorded on the subject’s source documents and entered on the 
appropriate eCRF. Any changes to concomitant medications will be recorded in the 
eCRF. Physical therapy interventions and medical devices are considered concomitant 
interventions and will be captured in the concomitant medications eCRF.   
10.2 
SAFETY ASSESSMENTS 
10.2.1 
PHYSICAL EXAMINATION  
A physical examination will be performed on all subjects at the visits listed in the Time 
and Events tables (Table 1 and Table 2) and will include the following assessments: 
• Abdomen 
• Cardiac 
• Eyes, Ears, Nose & Throat 
• General appearance 
• Head & Neck 
• Musculoskeletal 
• Neurological 
• Respiratory 
• Skin/Mucosal 
Any clinically significant abnormalities after Day 1 found will be recorded as AEs in the 
eCRF.  
Physical examinations should also include an examination of the injection site(s). If an 
injections site reaction is observed, it should be recorded as an adverse event in the 
eCRF.  
10.2.2 
VITAL SIGNS 
Vital signs (HR, body temperature, and blood pressure) will be measured in the sitting 
position. If blood samples are scheduled at the same time, vital signs should be measured 
before the blood draw. Blood pressure may be measured manually or by automated 
device, preferably using the non-dominant arm. The same measurement technique should 
be used throughout the study for the same subjects.  
10.2.3 
ELECTROCARDIOGRAM  
12-lead ECGs will be assessed as normal or abnormal by the investigator; any abnormal 
findings will be described in the eCRF and the investigator will assess clinical 
significance. The ECG recording strip will be signed and dated by the investigator and 
stored in the medical records. 
Subjects should be in the supine position for at least 5 minutes prior to and during the 
ECG measurement. ECGs should be performed prior to blood draws when both 
assessments are required at the same visit. 
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10.2.4 
LABORATORY SAFETY ASSESSMENTS 
Safety laboratory tests for this study [chemistry, hematology, coagulation (for applicable 
subjects), and urinalysis] are to be performed by a central laboratory, and only values 
from the central laboratory are to be entered into the laboratory section of the study 
database. Values from local laboratories may be used to determine eligibility for study 
enrollment and as the basis for clinical decisions. 
10.2.4.1 
HEMATOLOGY, CHEMISTRY, AND COAGULATION 
Hematology, chemistry, and coagulation analytes that will be assessed during the study 
are identified in Table 5 and should be performed as specified in the Time and Events 
Tables (Table 1 and Table 2).  
All laboratory samples should be collected prior to the administration of study drug at 
applicable visits.  
Coagulation tests should only be performed in subjects receiving anticoagulant therapy. 
 Table 5: Chemistry, Hematology, and Coagulation Analytes 
Chemistry 
Hematology 
Alanine aminotransferase (ALT)* 
Albumin 
Alkaline phosphatase (ALP) 
Amylase 
Aspartate aminotransferase (AST)* 
Blood urea nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase (LDH)* 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total protein 
 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) 
White blood cell (WBC) count and differential: 
Basophils (% and absolute) 
Eosinophils (% and absolute) 
Lymphocytes (% and absolute) 
Monocytes (% and absolute) 
Neutrophils (% and absolute) 
Coagulation (if applicable) 
International normalized ratio (INR)/prothrombin time (PT) 
Partial thromboplastin time (PTT) or activated partial 
thromboplastin time (aPTT) 
Other 
Aldolase* 
C-reactive protein (CRP) 
Creatine Kinase (CK)* 
* The results from these labs will be blinded to site personnel in order to avoid inadvertent 
biasing of functional assessments. 
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10.2.4.2 
URINALYSIS 
A urinalysis will be performed to measure pH, specific gravity, protein (qualitative), 
glucose (qualitative), ketones (qualitative), bilirubin (qualitative), urobilinogen, occult 
blood, hemoglobin, and cells. A microscopic examination will be performed, if 
necessary.  
10.2.4.3 
PREGNANCY TESTING AND CONTRACEPTION 
A serum pregnancy test for human chorionic gonadotropin (HCG) will be performed on 
female subjects of childbearing potential at Screening.  
A urine dipstick pregnancy test (HCG) will be performed on female subjects of 
childbearing potential at all other study visits as specified in the Time and Events Tables 
(Table 1 and Table 2). 
Negative pregnancy tests must be documented for all female subjects of childbearing 
potential prior to dosing at applicable study visits.  
Sexually active female subjects of childbearing potential (i.e., women who are not 
postmenopausal or who have not had a hysterectomy, bilateral oophorectomy, or bilateral 
tubal ligation) and all male subjects (who have not been surgically sterilized by 
vasectomy) must agree to use effective contraception during the study, including the 40-
day safety follow-up visit. Postmenopausal women are, for the purposes of this protocol, 
defined as women who have gone 12 consecutive months without menstruation. Effective 
contraception is defined as: 
• Hormonal contraception (e.g., oral contraceptive, transdermal contraceptive, 
contraceptive implant, or injectable hormonal contraceptive) for at least 3 months 
prior to study drug administration, throughout the study, and for 40 days after the 
last dose of study drug. 
• Double-barrier birth control (e.g., a combination of male condom with either cap, 
diaphragm, or sponge together with spermicide) starting at the Screening visit, 
throughout the study, and for at least 40 days after the last dose of study drug. 
NOTE: Use of a male and female condom simultaneously is NOT an acceptable 
method of double-barrier birth control.  
• Intrauterine contraception/device starting at the Screening visit, throughout the 
study, and for 40 days after the last dose of study drug. 
• Total abstinence from sexual intercourse (only acceptable if it is the preferred and 
usual lifestyle of the subject) for at least 1 complete menstrual cycle prior to the 
Screening visit, throughout the study, and for 40 days after the last dose of study 
drug. 
• Maintenance of a monogamous relationship with a male partner who has been 
surgically sterilized by vasectomy. 
NOTE:  Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are 
not acceptable methods of contraception. 
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10.2.5 
ADVERSE EVENT RECORDING  
Guidance on the identification, monitoring, and reporting of AEs is provided in 
Section 11.  
10.2.6 
IMMUNOGENICITY 
Blood samples for ADA assessment will be collected as specified in the Time and Events 
Tables (Table 1 and Table 2) in all enrolled subjects. These samples will be banked and 
used to investigate and characterize any ADA response over time in the general study 
population.  
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
10.3 
EFFICACY ASSESSMENTS  
10.3.1 
PRIMARY EFFICACY ASSESSMENT 
The primary efficacy endpoint is percent change from Baseline to Week 8 in CK levels.    
CK levels will be measured by a central laboratory in accordance with the Time and 
Events Tables (Table 1 and Table 2). 
10.3.2 
SECONDARY EFFICACY ASSESSMENTS 
10.3.2.1 
TRIPLE TIMED UP AND GO TEST 
The 3TUG is a non-invasive and reproducible measure, which measures clinically 
important muscle weakness that impairs subject’s ability to walk, climb stairs, and stand 
up from a chair.  The test will only be performed in subjects who are ambulatory. 
The 3TUG test involves the subject getting up from a seated position in a chair, walking 
at their normal pace for 3 meters, turning around, walking back to the chair, and sitting 
down. This sequence is repeated 3 times without rest, and the 3TUG time is the average 
of the 3 lap times (Sanders, et al. 2018). 
3TUG evaluators must be adequately trained prior to conducting any 3TUG test. The 
3TUG test will be performed at Screening and at each study visit according to the Time 
and Events Tables (Table 1 and Table 2). The 3TUG test must be performed at 
approximately the same time of day (preferably in the morning) and administered by the 
same well-trained evaluator (e.g., neurologist, physical therapist, or other study staff 
experienced in clinical assessments) at each visit throughout the study. 
Detailed instructions regarding the administration of the 3TUG test will be provided to 
sites. 
10.3.2.2 
PROXIMAL MANUAL MUSCLE TESTING  
The proximal MMT assesses muscle strength using manual muscle testing in 7 muscle 
groups. A zero to 10-point scale based on standard MMT grades will be used (Kendall 
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and al. 1993) of 7 proximal, distal, and axial muscles performs similarly to a total of 24 
muscle groups (Rider, Koziol, et al. 2010). 
Proximal MMT evaluators must be adequately trained prior to conducting any MMT 
grading. MMT grading will be performed at Screening and at each study visit according 
to the Time and Events Tables (Table 1 and Table 2). MMT grading must be performed 
at approximately the same time of day (preferably in the morning) and administered by 
the same well-trained evaluator (e.g., neurologist, physical therapist, or other study staff 
experienced in clinical assessments) at each visit throughout the study. 
Detailed instructions regarding the administration of the proximal MMT will be provided 
to sites. 
10.3.2.3 
PHYSICIAN GLOBAL ACTIVITY VISUAL ANALOGUE SCALE 
The Physician Global Activity VAS score measures the global evaluation by the treating 
physician of the overall disease activity of the patient at the time of assessment using a 10 
cm visual analogue scale and a 5-point Likert scale (Rider, Werth, et al. 2011). 
Detailed instructions regarding the administration of the Physician Global Activity VAS 
will be provided to sites. 
10.3.2.4 
PATIENT GLOBAL ACTIVITY VISUAL ANALOGUE SCALE 
The Patient Global Activity VAS score measures the global evaluation by the patient of 
the patient's overall disease activity at the time of assessment using a 10 cm visual 
analogue scale (Rider, Werth, et al. 2011). 
Detailed instructions regarding the administration of the Patient Global Activity VAS 
will be provided to sites. 
10.3.2.5 
HEALTH ASSESSMENT QUESTIONNAIRE 
The HAQ Score is a patient related outcome measure that assesses physical function. 
There are 8 sections: dressing, arising, eating, walking, hygiene, reach, grip, and 
activities. There are 2 or 3 questions for each section. Scoring within each section is from 
0 (without any difficulty) to 3 (unable to do) (Rider, Werth, et al. 2011). 
Detailed instructions regarding the administration of the HAQ will be provided to sites. 
10.3.2.6 
MYOSITIS DISEASE ACTIVITY ASSESSMENT TOOL 
The MDAAT measures the degree of disease activity of extra-muscular organ systems 
and muscle. This is a combined tool that includes the myositis disease activity assessment 
visual analogue scales (MYOACT), which is a series of physician's assessments of 
disease activity of various organ systems modified from the Vasculitis Activity Index 
(Whiting-O'Keefe, Stone and Hellmann 1999), and the Myositis Intention to Treat 
Activity Index (MITAX).  The MITAX is scored on a 0 - 4 scale, based on worsening or 
improvement in specific clinical features and their correlation with the intention to treat.  
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Detailed instructions regarding the administration of the MDAAT will be provided to 
sites. 
10.3.2.7 
ACR/EULAR RESPONSE CRITERIA 
The ACR/EULAR scale was created to develop a response criterion for patients with 
myopathy. The scale utilizes a conjoint analysis-based continuous model using absolute 
percent change in core set measures (physician, patient, and MDAAT; muscle strength; 
Health Assessment Questionnaire; and muscle enzyme levels). A total improvement 
score (range 0-100) is determined by summing scores for each core set measure and 
comparing improvement in each respective core set measure. Thresholds for minimal, 
moderate, and major improvement are ≥20, ≥40, and ≥60 points in the total improvement 
score (Aggarwal, et al. 2017). The total improvement score will be calculated based on 
the core set measures as recorded in the eCRF and from central laboratory results. 
10.3.2.8 
FACIT-FATIGUE SCALE 
The FACIT-Fatigue Scale is a 13-item, easy to administer tool that measures an 
individual’s level of fatigue during their usual daily activities over the past week. The 
level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued, to 0 = 
very much fatigued) (Webster, Cella and Yost 2003). All subjects will be asked to 
complete the FACIT-Fatigue Scale in accordance with the Time and Events Tables 
(Table 1 and Table 2). 
10.4 
PHARMACOKINETIC/ PHARMACODYNAMIC ASSESSMENTS 
Blood samples for PK/PD assessments will be collected from all subjects and include 
measurements of: 
• Plasma concentration of zilucoplan and its major metabolites 
• sRBC lysis assay for evaluation of classical complement pathway activation 
• C5 levels 
Blood samples for PK and PD analysis will be obtained prior to administration of study 
drug (within 1 hour of dosing) at the study visits according to Table 1 and Table 2.  
All samples will be sent to an accredited laboratory for analysis. Detailed instructions 
regarding PK/PD sample collection, processing, and shipping will be provided to sites. 
10.5 
EXPLORATORY ASSESSMENTS  
10.5.1 
BIOMARKERS 
Blood samples for biomarker testing will be obtained prior to administration of study 
drug (within 1 hour of dosing) at study visits according to Table 1 and Table 2.  
The analysis of biomarkers pertaining to the pathophysiology of IMNM [e.g., 
complement fixation, complement function, complement pathway proteins, autoantibody 
characterization (titer and immunoglobulin class), myocyte markers, and inflammatory 
markers] may provide further insight into the clinical efficacy and safety of zilucoplan in 
subjects with IMNM. Complement protein levels and complement activity will be tested 
to evaluate response to zilucoplan and to understand subject characteristics related to 
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variations in response to drug. Markers of inflammation may be tested to assess 
correlation with complement function and clinical response to zilucoplan. A list of 
analytes will be created through review of the literature, ongoing clinical studies, and 
ongoing exploratory work and may be finalized after completion of the study.  
The completion of these investigations may be conditional based on the results of this or 
other clinical studies, and samples may be selected for analysis on the basis of clinical 
outcome. The results of the biomarker investigations may be reported separately from the 
main CSR. 
Detailed instructions regarding sample collection, processing, and shipping will be 
provided to sites. 
10.5.2 
PHARMACOGENOMIC ASSESSMENTS 
Participation in the pharmacogenomic assessment is optional, and subjects must provide 
additional consent for the pharmacogenomic analysis. 
For subjects who choose to participate in pharmacogenomic studies, a blood sample can 
be obtained at any study visit. All genomic analyses will be performed at an accredited 
laboratory. Detailed instructions regarding sample collection, processing, and shipping 
will be provided to sites. 
Genomic studies [e.g., DNA sequencing, including exploration of whether specific 
genomic features correlate with response or resistance to study drug], may be performed. 
The completion of these investigations may be conditional based on the results of this or 
other clinical studies, and samples may be selected for analysis on the basis of clinical 
outcome. The results of the genomic investigations may be reported separately from the 
main CSR. 
11 
SAFETY REPORTING 
11.1 
DEFINITIONS 
11.1.1 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with study treatment. 
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The following are not considered to be AEs despite requiring hospitalization: 
• Pre-existing conditions that, in the opinion of the investigator, did not worsen or 
progress during study participation 
• Routinely scheduled procedures or treatment 
• Elective procedures that were scheduled prior to study participation (i.e., signing of 
the ICF) 
All AEs should be appropriately recorded according to the instructions in Section 11.4. 
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11.1.1.1 
OCCURRENCE OF COVID-19 
Occurrence of COVID-19 in subjects should be reported as either “suspected 
COVID-19” or “confirmed COVID-19” along with all available relevant data, including 
diagnostic and laboratory data. For subjects where COVID-19 is still suspected despite a 
negative viral test, please report as “suspected COVID-19” and provide relevant data to 
support the diagnosis as well as the test results. 
11.1.2 
SERIOUS ADVERSE EVENTS 
An SAE is any AE that: 
• Results in death 
• Is life-threatening (note that this refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe) 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
An SAE may also be any other important medical event that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or 
require intervention to prevent one of the other outcomes listed in the definition above. 
Examples of such events include intensive treatment in an emergency room or at home 
for bronchospasm, hyperkalemia, or convulsions that do not result in a formal 
hospitalization. 
Elective hospitalizations that were scheduled prior to study participation (i.e., signing of 
the ICF) are not considered to be SAEs and should not be reported.  
11.2 
MONITORING OF INFECTION 
All subjects will be monitored at every study visit for signs and symptoms of Neisseria 
meningitidis infection.  
To reduce the risk of meningococcal infection (Neisseria meningitidis), all subjects must 
be vaccinated against meningococcal infections (with a quadrivalent vaccine and, where 
available and in accordance with local SOC, serogroup B vaccine) within 3 years prior to, 
or at the time of, initiating study drug. Subjects who initiate study drug treatment less 
than 2 weeks after receiving a meningococcal vaccine must receive treatment with 
appropriate prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) until 
at least 2 weeks after initial dose of vaccine(s). Booster vaccinations should be 
administered in accordance with local SOC.  In subjects who have received rituximab 
less than 6 months prior to Day 1, prophylactic antibiotics should be given until at least 6 
months after the last rituximab dose (e.g., ciprofloxacin, erythromycin, penicillin V). 
NOTE: In subjects who received rituximab more than 90 days but less than 6 months 
prior to Baseline, prophylactic antibiotics (e.g., ciprofloxacin, erythromycin, penicillin V) 
should be given upon initiation of study drug until 6 months after the last rituximab dose. 
During the Treatment Period, to mitigate the risk of infection, subjects will be counseled 
and reminded of the early signs and symptoms of Neisseria meningitidis infection. A 
patient safety card detailing the signs and symptoms of infection, with instructions to 
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seek immediate medical attention if any such symptoms occur, will be provided to each 
subject. Should a subject lose/misplace their safety instruction card they will be provided 
a new card. 
11.3 
EVALUATION AND CLASSIFICATIONS 
11.3.1 
SEVERITY 
The investigator should determine the severity of the reported AE by using the CTCAE 
(Version 5.0 or higher).  
For any reported AE not described in the CTCAE, the following guidelines must be 
considered for severity evaluation: 
Adverse Event Severity 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s). 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
11.3.2 
CAUSALITY 
The causal relationship of the AE to study drug will be assessed by both the investigator 
and the Sponsor. The assessment of causal relationship to study drug should be evidence-
based, and not based on the premise that all AEs are causally related to study drug until 
proven otherwise. Default categorization of ‘related’ without supportive evidence for a 
causal relationship to study drug is generally uninformative and does not contribute to 
understanding of the safety profile of the drug with respect to the intended population. 
Examples of evidence that would suggest a causal relationship between the study drug 
and the AE include the occurrence of an AE that is known to be strongly associated with 
drug exposure (e.g., injection site reactions) or an AE that is otherwise uncommon in the 
study population. Lack of efficacy of study drug, in isolation, leading to unmasking of 
underlying symptoms and signs of disease, should NOT be considered evidence of 
relatedness. 
The causal relationship of each AE is assessed using a binary system, with all AEs 
classified as either ‘related’ or ‘not related’. 
Related:  There is ‘reasonable possibility’ that the study drug caused the AE. The AE 
follows a reasonable temporal association from the time of study drug administration. 
There is supportive evidence to suggest a possible causal relationship, irrespective of the 
degree of certainty, between the observed AE and the study drug. There is no alternative 
more likely explanation for the AE. Lack of study drug efficacy is not considered, by 
itself, to be evidence of relatedness.  
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Not Related:  Lack of a reasonable temporal or causal association from the 
administration of the study drug and the occurrence of the AE. There is evidence of an 
alternative explanation that is more likely the cause of the AE. 
11.4 
RECORDING, REPORTING, AND MONITORING 
11.4.1 
RECORDING AND REPORTING 
The investigator must make every effort to properly evaluate all information relevant to 
the reported AE in such a way that a diagnosis can be confidently made and reported. For 
example, it is preferable to report ‘pneumonia’ as the AE rather than its symptoms (e.g., 
‘rales’ or ‘fever’) as separate AEs. 
When recording and/or reporting AEs or SAEs, the following elements must be included: 
• The fulfilled criteria for seriousness as presented in Section 0 
• The severity of the event as defined in Section 11.3.1 
• The relationship of the event to study treatment as defined in Section 11.3.2 
Actions taken in relation to the AE will be recorded as drug discontinued, drug 
interrupted, concomitant medication, other action (e.g., diagnostic testing), or no action. 
Any medication given to treat the AE will be recorded separately in the concomitant 
medication list of the eCRF. 
The outcome of the AE will be recorded as date ended, ongoing, or resulting in death 
with date of death. 
11.4.1.1 
ADVERSE EVENTS 
Pre-existing conditions that are detected prior to administration of the first dose of study 
drug will be recorded as part of the medical history. For all subjects, the AE reporting 
period will start with the first administration of study drug on Day 1 (for SAE reporting 
period, see Section 11.4.1.2) and will end 40 days following the last dose of study drug 
(i.e., the End of Main Visit, Day 57 Visit, or Final Extension Visit), after which no new 
non-serious AEs are to be reported. The subjects will be monitored throughout the study 
for any AEs, including clinically significant findings at vital signs measurements, 
spontaneous reports by study subjects, and observations by the study personnel. 
When possible, ongoing AEs assessed as related to the study drug will be followed until 
resolved or stabilized. Subjects visit the clinic 40 days after their last dose to gather 
information on ongoing AEs and report any new SAEs since the last study visit (see 
Section 11.4.1.2 for SAE reporting instructions).  
All AEs will be recorded in the eCRF. The investigator will assess and record any AE in 
detail including the date and time of onset, event diagnosis (if known) or sign/symptom, 
severity, time course (end date or ongoing), relationship of the AE to study drug, and 
action(s) taken. All AEs should be reported separately (i.e., 1 record per event). 
Reporting of AEs is event-based (i.e., an ongoing event will not be closed until resolved 
or at the end of study). For the AE description, a diagnosis is preferred over symptoms. If 
no diagnosis can be made, each symptom will be reported as a separate AE. 
Abbreviations should be avoided. Descriptive words should be used for ongoing 
conditions as applicable (e.g., 
).  
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AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA; 
Version 20.0 or higher) after the eCRFs have been monitored and signed by the 
investigator. 
11.4.1.2 
SERIOUS ADVERSE EVENTS 
Any SAE experienced by the subject from signing the ICF through to 40 days after the 
last dose of study drug, regardless of severity or causality, must be recorded on the eCRF 
and SAE forms. Subjects visit the clinic 40 days after their last dose to gather information 
on ongoing AEs and report any new SAEs since the last study visit. 
The study site must formally notify the Sponsor (or delegate) of the SAE within 24 hours 
from the time the study site becomes aware of the SAE. A formal notification must be 
submitted to the Sponsor regardless of the following: 
• Severity 
• Causality 
• Whether or not the subject received study treatment or underwent study related 
procedures  
The IRB/IEC will be notified as required by local regulations. The investigator will be 
responsible for submitting the required safety information to the appropriate IRB/IEC, 
including any safety reports received from the Sponsor as well as any SAEs occurring at 
his/her site.  
The Sponsor, or designee, will prepare any required safety reports for Competent 
Regulatory Authorities and all active investigators. These reports will be provided as 
addenda to the IB, and the investigator will place these with the IB. All Competent 
Regulatory Authorities will be informed as per applicable legislation.  
11.4.1.3 
DEATH 
Any event with an outcome of death should be appropriately recorded in the eCRF. All 
identified causes of death, including an assessment of the possible relationship of each to 
study treatment, must be reported as SAEs as outlined in Section 11.4.1.2. Any autopsy 
or other postmortem findings (including a coroner’s report) should be provided if 
available. 
11.4.1.4 
ABNORMAL LABORATORY VALUES 
All central laboratory data generated during the study will be included in standard 
Statistical Analysis System (SAS) datasets. Throughout this study, subjects will have 
samples sent to local laboratories and to the central laboratory. Only the values from the 
central laboratory will be captured in the database and used for the safety analysis. 
Investigators may report AEs based upon local laboratory values, if clinically relevant. In 
this event, the actual value and the normal range for the local laboratory should be 
recorded on the AE eCRF. 
11.4.2 
SAFETY MONITORING 
All AEs should be monitored by the investigator until resolution or stabilization.  
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11.4.2.1 
SAFETY MONITORING COMMITTEE 
The safety of study subjects will be monitored throughout the study on an ongoing basis. 
Given the double blind, placebo-controlled design of Study RA101495-02.202, this 
standard safety data review will be performed while blinded to treatment assignment. 
If an additional data review should become necessary to ensure subject safety, a separate 
supervisory committee (i.e., an SMC) will convene and evaluate study data as 
appropriate. To ensure the scientific integrity of the study, members of the SMC will not 
be directly involved in management of the study. 
11.4.2.2 
POST-STUDY EVENTS 
Any SAE that was continuing at the time of subject discontinuation or study completion 
should be monitored by the investigator until resolution or stabilization. 
SAEs that occur within 40 days after the subject discontinues from or completes the study 
should be reported using the same procedures outlined in Section 11.4.1.2. These SAEs 
should be recorded in the eCRF. Subjects will visit the clinic 40 days after their last dose 
of study drug to gather information on ongoing AEs and report any new SAEs since the 
last study visit (see Section 11.4.1.2 for SAE reporting instructions).  All SAEs will be 
followed to resolution or stabilization. 
11.4.2.3 
EMERGENCY UNBLINDING 
The study drug treatment assignment may be unblinded only in emergency situations 
when knowledge of the treatment assignment is considered absolutely necessary for 
medical management of the subject or for clinical decision-making (i.e., when knowledge 
of the treatment assignment would impact a treatment decision). The investigator will 
have unrestricted and immediate access to unblind the treatment code in the interactive 
voice/web response system (IXRS). The instructions for unblinding a subject in the IXRS 
can be found in the IXRS User Guide. 
In the event unblinding is necessary, the investigator is strongly encouraged, but not 
required, to contact the appropriate medical monitor to discuss the situation and the 
subject’s medical status prior to unblinding. 
When a subject’s treatment assignment is unblinded, a comprehensive source note must 
be completed by the unblinding investigator that includes the date and time and the 
reason(s) the subject’s treatment code was unblinded. In the event the investigator 
chooses to discuss the unblinding with the medical monitor, the source note must also 
include a record of the discussion.  
It is mandatory that all personnel who are involved in the unblinding and who have 
access to the unblinded treatment assignment information maintain the confidentiality of 
the information by not divulging the treatment assignment. 
Following emergency unblinding, the subject’s further participation in the study should 
be discussed with the medical monitor. 
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11.5 
SPECIAL CIRCUMSTANCES 
11.5.1 
PREGNANCY 
Subjects and their partners should avoid pregnancy throughout the course of the study. 
Pregnancy in a study subject or partner must be reported to the Sponsor within 24 hours 
of the study site becoming aware of the pregnancy. Subjects with a positive pregnancy 
test before study drug dosing must not be dosed. 
Information regarding a pregnancy occurrence in a study subject or partner and the 
outcome of the pregnancy will be collected. 
Pregnancy in a study subject or partner is not, in itself, considered an AE. However, the 
medical outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly 
is considered an SAE and must be reported to the Sponsor within 24 hours of the site 
becoming aware of the event. The procedure of elective abortion should not be reported 
as an AE.  
11.5.2 
OTHER 
Certain safety events, called ‘Special Situations’, that occur in association with study 
drug(s) may require reporting. These Special Situations include, but are not limited to, the 
following: 
• Overdose of the medicinal product, where ‘overdose’ is defined as a subject receiving 
≥ 2 times the intended dose for any given SC injection 
• Suspected abuse/misuse of the medicinal product 
• Inadvertent or accidental exposure to the medicinal product 
• Medication error involving study drug (with or without subject exposure to the 
Sponsor’s medicinal product, e.g., name confusion) 
Special situations should be reported whether they result in an AE/SAE or not. 
12 
STATISTICAL AND ANALYTICAL PLANS 
12.1 
ANALYSIS POPULATIONS 
Further details of additional analysis populations will be described in the SAP, which will 
be finalized prior to study unblinding.  
12.1.1 
INTENTION-TO TREAT (ITT) POPULATION 
The Intention-to-Treat (ITT) Population will include all randomized subjects. 
12.1.2 
PER PROTOCOL POPULATION 
The Per Protocol Population will include all subjects in the ITT Population who have 
completed the 8-week Treatment Period and have no major protocol deviations. 
12.1.3 
SAFETY POPULATION 
The Safety Population will include all subjects who have received at least 1 dose of study 
drug, with subjects to be analyzed based on the actual treatment received. 
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12.2 
ANALYSIS METHODS 
12.2.1 
GENERAL METHODS 
Details of the statistical analysis methodology will be provided in a statistical analysis 
plan (SAP), which will be finalized prior to study unblinding.  
Continuous variables will be summarized using the number of observations, number of 
observations above the limit of quantification (if applicable), mean, standard deviation 
(SD) median, and range. Categorical variables will be summarized using frequency 
counts and percentages. 
Once all patients have completed Week 8 of the Main Portion of the study, the study 
database will be locked, unblinded, and efficacy analyses for the Main Portion will be 
performed.  
12.2.2 
SUBJECT DISPOSITION 
A disposition of all consented subjects will be provided and will include a breakdown of 
subjects who were randomized, were treated, and discontinued treatment (including 
reasons for discontinuation) at the Main Portion. A disposition of all consented subjects 
entered the Extension Portion will be also provided. Additionally, a summary of subjects 
included in the analysis populations defined in Section 12.1 will be provided. 
12.2.3 
DEMOGRAPHY AND BASELINE DISEASE CHARACTERISTICS 
Demographic and baseline disease characteristics will be summarized by treatment group 
and overall. 
12.2.4 
SAFETY ANALYSIS 
Safety analyses will be performed on the Safety Population. 
12.2.4.1 
ADVERSE EVENTS 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
Version 20.0 or higher). Incidence rates for treatment-emergent AEs will be summarized 
overall, by maximum severity, and by relationship to study drug for each treatment 
group. SAEs will also be summarized by treatment group. 
Incidence rates for TEAEs and SAEs will be summarized overall, by maximum severity, 
and by relationship to study drug. A TEAE is defined as: 
• An AE that occurs after study treatment start that was not present at the time of 
treatment start. 
• An AE that increases in severity after treatment start if the event was present at the 
time of treatment start. 
The SAEs occurring before the first dose of study drug will be listed. 
12.2.4.1.1 
INFECTION 
AEs related to infection with Neisseria meningitidis will be summarized by system organ 
class and preferred term. 
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12.2.4.2 
CLINICAL LABORATORY EVALUATION 
Quantitative laboratory endpoints will be summarized by treatment group at each 
scheduled assessment time point using descriptive statistics. 
12.2.4.3 
ELECTROCARDIOGRAMS 
Descriptive statistics for ECG parameters [i.e., HR, PR interval, RR interval, QRS 
interval, QT interval, QT interval] at each assessment time point will be presented by 
treatment group. 
12.2.4.4 
VITAL SIGNS 
Descriptive statistics for vital signs (i.e., HR, body temperature, and blood pressure) will 
be presented by treatment group. 
12.2.4.5 
PHYSICAL EXAMINATION 
Clinically significant physical examination abnormalities will be included and 
summarized as AEs, when appropriate. 
12.2.5 
EFFICACY ANALYSIS 
Details of analyses beyond what is specified in this protocol will be discussed in detail in 
the SAP. 
12.2.5.1 
PRIMARY EFFICACY ANALYSES 
The primary efficacy endpoint, percent reduction from baseline in creatine kinase at 
Week 8, will be compared between the two treatment groups using a 2-sided stratified 
Wilcoxon rank sum test (Van Elteren test). Magnitude of treatment effect will be shown 
by the WMWOdds and the Hodges-Lehman estimator followed by the corresponding 
95% Confidence Intervals (CIs). 
Definition of primary estimand: 
• Treatment: zilucoplan administered by daily SC injection (0.3 mg/kg) vs matching 
placebo. 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 8.1 
and 8.2 of the study protocol reflecting the targeted IMNM population. 
• Endpoint: percentage change from Baseline to Week 8 in CK levels while on non-
prohibited medication. 
• Intercurrent event: regardless of any treatment discontinuation for any reason; 
censoring after prohibited medication 
• Population level summary: difference in ranks of the percentage change from baseline 
between treatments followed by the WMWodds and Hodges–Lehmann estimator 
followed by the corresponding 95% CIs.  
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12.2.5.2 
SECONDARY EFFICACY ANALYSES 
Secondary Estimands are defined below: 
• Treatment: Zilucoplan administered by daily subcutaneous (SC) injection (0.3 
mg/kg) vs matching placebo. 
• Target Population: is defined through the inclusion/exclusion criteria at Sections 
8.1 and 8.2 of the current document, reflecting the targeted IMNM population. 
• Endpoints:  
o At least minimal response based on the ACR/EULAR minimal Response 
Criteria at Week 8 
o Change from Baseline to Week 8 in 3TUG Test (in ambulatory patients 
only);  
o from Baseline to Week 8 in Proximal MMT;  
o Change from Baseline to Week 8 in Physician Global Activity VAS;  
o Change from Baseline to Week 8 in Patient Global Activity VAS;  
o Change from Baseline to Week 8 in HAQ;  
o Change from Baseline to Week 8 in MDAAT Extramuscular Disease 
Activity VAS Score; 
o Change from Baseline to Week 8 in FACIT-Fatigue Scale; 
o  ICE handling: regardless of any treatment discontinuation for any reason; 
censoring after administration of prohibited medication; 
o Population level summary: 
▪ Odds ratio of ACR/EULAR of ACR/EULAR ≥ 20 response 
proportion between treatment conditions; 
▪ Difference in the continuous endpoint means between treatment 
conditions; 
The analysis to determine the odds ratio and the corresponding 95%CI for the 
ACR/EULAR response will be performed via logistic regression. Treatment group 
differences for each of the continuous secondary efficacy change from baseline endpoints 
will be assessed using a linear mixed effects model using the change from baseline to 
Week 8 as response variable; treatment, and baseline score (i.e., the baseline score for the 
secondary efficacy endpoint being analyzed) will be fitted as fixed effects and subject as 
a random effect. 
Secondary efficacy endpoint analyses will be performed on the ITT Population. 
12.2.6 
CLINICAL PHARMACOLOGY ANALYSIS 
12.2.6.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
For the PK analysis, concentrations of zilucoplan and metabolites were presented in 
listings and summarized using descriptive statistics. 
Plasma concentration data of zilucoplan may be subjected to population PK analysis to 
derive population estimates of PK parameters and test the effect of various covariates 
such as anti-drug antibodies, age, weight, and gender. Details of the analysis will be 
described in a separate Data Analysis Plan (DAP). This analysis may be performed by 
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combining the data from the current study with data from other zilucoplan studies if 
deemed appropriate. The results of the population PK analysis will not be reported in the 
CSR but in a separate modeling report. 
Pharmacodynamic endpoints will be summarized using descriptive statistics by treatment 
and time point. 
Population PD or population PK/PD analyses may be conducted for the PD variables of 
interest. Details of such PD or PK/PD analyses will be described in a separate DAP. The 
results of the analyses will not be reported in the CSR but in a separate report. 
12.2.7 
INTERIM ANALYSIS 
No interim analysis is planned for the Main Portion of the study.  
Interim analyses of the Extension Portion of the study, after Week 8 of the Main Portion 
of the study has been locked and unblinded, may be performed. 
12.3 
SAMPLE SIZE DETERMINATION 
A sample size of 12 subjects per group yields approximately 95% power to detect a 
difference in the percent reduction from baseline in creatine kinase between the active 
and placebo groups using a Wilcoxon rank sum test at the two-sided 0.05 type 1 error 
rate. The power calculations assume that the percent reduction in creatine kinase in the 
active dose group is approximately normally distributed with a mean of 80% and a 
standard deviation of 8%; that 4 of the placebo patients will have a percent reduction 
similar to the active dose group; and the remaining 8 placebo patients will have a percent 
reduction  that is normally distributed with a mean of 10% and a standard deviation of 
8% (Mammen and Tiniakou 2015). 
13 
ETHICAL CONSIDERATIONS 
This study shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice 
(GCP) and applicable regulatory requirement(s).  
13.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
COMMUNICATIONS 
Prior to study initiation, the investigator/institution should have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol, written ICF, consent 
form updates, subject recruitment procedures (e.g., advertisements), and any other written 
information to be provided to subjects. A current copy of the IB must be provided to the 
IRB/IEC as part of the written application. During the study, the investigator/institution 
should provide to the IRB/IEC all documents subject for review. 
13.1.1 
PROGRESS REPORTS 
The investigator should submit written summaries of the study status to the IRB/IEC 
annually, or more frequently, if requested by the IRB/IEC. 
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13.1.2 
FINAL INVESTIGATOR REPORT 
Upon completion of the study, the investigator/institution should provide a summary of 
the study’s outcome to the IRB/IEC and the regulatory authorities with any required 
reports. 
13.2 
INFORMED CONSENT OF STUDY SUBJECTS 
In obtaining and documenting informed consent, the investigator must comply with the 
applicable regulatory requirement(s) and adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  
The written ICF and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised written ICF and written information should receive the 
IRB/IEC’s approval/favorable opinion in advance of use. The subject or the subject’s 
legally acceptable representative will be informed in a timely manner if new information 
becomes available that may be relevant to the subject’s willingness to continue 
participation in the study. The communication of this information should be documented. 
The investigator will fully inform the subject or the subject’s legally acceptable 
representative of all pertinent aspects of the study, including the written information and 
the approval/favorable opinion by the IRB/IEC. Before informed consent may be 
obtained, the investigator should provide the subject or the subject’s legally acceptable 
representative ample time and opportunity to inquire about details of the study and to 
decide whether or not to participate in the study. All questions about the study should be 
answered to the satisfaction of the subject or the subject’s legally acceptable 
representative.  
Prior to a subject’s participation in the study, the written ICF must be signed and 
personally dated by the subject or by the subject’s legally acceptable representative and 
by the person who conducted the informed consent discussion. If a subject is unable to 
read or if a legally acceptable representative is unable to read, an impartial witness will 
be present during the entire informed consent discussion. 
Prior to participation in the study, the subject or the subject’s legally acceptable 
representative will receive a copy of the signed and dated written ICF and any other 
written information provided to the subjects. During a subject’s participation in the study, 
the subject or the subject’s legally acceptable representative will receive a copy of the 
signed and dated consent form updates and a copy of any amendments to the written 
information provided to subjects. 
Subjects will provide additional consent to participate in optional pharmacogenomic 
testing. 
13.3 
PROTOCOL COMPLIANCE 
The investigator/institution will conduct the study in compliance with the protocol agreed 
to by the Sponsor and regulatory authorities (if required) and which was given 
approval/favorable opinion by the IRB/IEC. The investigator/institution and the Sponsor 
should sign the protocol, or an alternative contract, to confirm agreement. 
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The investigator should not implement any deviation from, or changes to, the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate 
immediate hazard(s) to study subjects or when the change involves only logistical or 
administrative aspects of the study (e.g., change in monitor, change of telephone 
number). When an important deviation from the protocol is deemed necessary for an 
individual subject, the investigator must contact the medical monitor for the study. 
Such contact must be made as soon as possible to permit a review by the Sponsor to 
determine the impact of the deviation on the subject’s participation and/or the assessment 
of safety or efficacy in the study. Any significant protocol deviations affecting subject 
eligibility and/or safety must be reviewed and/or approved by the IRB/IEC and regulatory 
authorities, as applicable, prior to implementation. 
The investigator should document and explain any deviation from the approved protocol.  
13.4 
PROTECTION OF CONFIDENTIALITY 
Prior to study participation, the investigator shall inform the subject or the subject’s 
legally acceptable representative that the monitor(s), auditor(s), IRB/IEC, and the 
regulatory authorities will be granted direct access to the subject’s original medical 
records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations and that, by signing a written ICF, the subject or the subject’s legally 
acceptable representative is authorizing such access.  
In addition, prior to study participation, the subject must be informed that the records 
identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available; if the results of 
the study are published, the subject’s identity will remain confidential. 
13.5 
DISCLOSURE OF STUDY RESULTS 
The Sponsor will post the results of the study in a publicly accessible database in 
accordance with the applicable laws and regulations. 
14 
REGULATORY AND ADMINISTRATIVE CONSIDERATIONS 
14.1 
QUALITY ASSURANCE 
Quality assurance and quality control systems shall be implemented and maintained with 
written standard operating procedures (SOPs) to ensure that the study is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, 
GCP, and the applicable regulatory requirement(s). Quality control shall be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly. 
An agreement must be secured from all involved parties to ensure direct access to all 
study related sites, source documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and of inspection by regulatory authorities. 
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14.1.1 
MONITORING 
On-site monitoring visits will be conducted before, at regular intervals during, and after 
the study, as appropriate, by Sponsor-approved monitors. At a minimum, the accuracy 
and completeness of the eCRF entries, source documents, and other study-related records 
will be checked against one another during these visits. After each monitoring visit, a 
report of any significant findings/facts, deviations, and deficiencies will be 
communicated to the investigator. The actions taken to address the findings and secure 
compliance should be documented.  
14.1.2 
AUDIT 
An audit may be performed independently of, and separately from, routine monitoring to 
evaluate clinical study conduct and compliance with the protocol, SOPs, GCP, and the 
applicable regulatory requirements.  
14.2 
CLINICAL RESEARCH ORGANIZATIONS  
A Clinical Research Organization (CRO) will be utilized to assist in the conduct of this 
study. Accredited central laboratories will be used for the analysis of all clinical samples.  
14.3 
DATA MANAGEMENT 
14.3.1 
CASE REPORT FORMS 
The data for this study will be collected with an eCRF.  eCRFs must be completed for 
each subject enrolled in this study. These forms will be used to transmit information 
collected during the study to the Sponsor and regulatory authorities, as applicable.  The 
documentation related to the validation of the eCRFs will be maintained in the Trial 
Master File (TMF). The TMF will be maintained by the CRO and the Sponsor. 
The investigator will document subject data in his/her own subject files. These subject 
files will serve as source data for the study. All eCRF data required by this protocol will 
be recorded by investigative site personnel. All data entered into the eCRF will be 
supported by source documentation. 
The investigator or an authorized member of the investigator’s staff will make any 
necessary corrections to the eCRF. All change information, including the date and person 
performing the corrections, will be available via the audit trail, which will be part of the 
electronic data capture system. For any correction, a reason for the alteration will be 
provided. The eCRFs will be reviewed periodically for completeness and acceptability by 
Sponsor personnel (or their representatives). The Sponsor (or their representatives) will 
also be allowed access to all source documents pertinent to the study in order to verify 
eCRF entries. The investigator will review the eCRFs for completeness and accuracy and 
provide his or her electronic signature and date to eCRFs as evidence thereof. 
Access to the electronic data capture system will be password-protected and will be 
removed from the study site at the end of the site’s participation in the study. Data from 
the eCRF will be archived on appropriate data media and provided to the investigator at 
that time as a durable record of the site’s eCRF data. It will be possible for the 
investigator to make paper printouts from that media. 
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14.3.2 
SOURCE DOCUMENTS 
Source documents are defined as original documents, data, and records. These may 
include hospital records, clinical and office charts, laboratory data/information, subjects’ 
diaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, ECGs, X-rays, ultrasounds, angiograms, venograms, computed tomography scans, 
and/or magnetic resonance imaging scans. Data collected during this study must be 
recorded on the appropriate source documents. 
The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspection(s), providing direct access to source data documents. 
14.4 
PREMATURE TERMINATION OR SUSPENSION OF THE STUDY 
If the Sponsor terminates or suspends the study, the investigator/institution should 
promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of 
the termination or suspension. If the IRB/IEC terminates or suspends its 
approval/favorable opinion of the study, the investigator/institution should promptly 
notify the Sponsor and provide the Sponsor with a detailed written explanation of the 
termination or suspension. 
14.5 
CLINICAL STUDY REPORT 
Whether the study is completed or prematurely terminated, the clinical study report will 
be prepared and provided to the regulatory agencies as required by the applicable 
regulatory requirement(s). 
14.6 
PUBLICATION POLICY 
The publication policy is outlined in the Clinical Trial Agreement. The data generated in 
this clinical trial are the exclusive property of Ra Pharmaceuticals, Inc. and are 
confidential. Written approval from Ra Pharmaceuticals, Inc.is required prior to 
disclosing any information related to this clinical trial. 
 
 
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15 
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dermatomyositis, polymyositis, and inclusion body myositis: Physician and 
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SPONSOR SIGNATURE PAGE 
Protocol Number: 
RA101495-02.202 
Protocol Title:   
A Phase 2, Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the Safety, Tolerability, and 
Efficacy of Zilucoplan in Subjects with Immune-Mediated 
Necrotizing Myopathy 
Protocol Version:   Version 2.0/16 February 2021 
 
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Approval Signatures
Name:
imnm01-protocol-amend-v2.0
Version:
1. 0
Document Number:
CLIN-000168746
Title:
IMNM01 (RA101495-02.202) Study Protocol v2.0
Approved Date:
17 Feb 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Feb-2021 16:05:26 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 16-Feb-2021 18:08:29 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 17-Feb-2021 12:14:44 GMT+0000
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