HEALEY ALS Platform Trial - Regimen A Zilucoplan
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Merit E. Cudkowicz, MD

HEALEY ALS Platform Trial - Regimen A Zilucoplan 
NCT04436497 
Document Date: 15 Jul 2021 

REGIMEN-SPECIFIC APPENDIX A 
 
FOR ZILUCOPLAN 
 
 
Regimen-Specific Appendix Date:  15 July 2021 
Version Number:  5.0 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 2 of 62 
TABLE OF CONTENTS 
 
SIGNATURE PAGE .................................................................................................................................... 5 
LIST OF ABBREVIATIONS .................................................................................................................... 6 
Regimen-Specific Appendix SUMMARY ................................................................................................. 7 
SCHEDULE OF ACTIVITIES ................................................................................................................. 9 
1 
INTRODUCTION ............................................................................................................................ 13 
1.1 
Zilucoplan Background Information ...................................................................................... 13 
1.1.1 
Clinical Trial Experience with Zilucoplan .......................................................................... 14 
1.2 
Zilucoplan- US FDA IND Background ................................................................................... 14 
2 
OBJECTIVES .................................................................................................................................. 15 
2.1 Study Objectives and Endpoints ................................................................................................... 15 
3 RSA DESIGN ......................................................................................................................................... 17 
3.1 
Scientific Rationale for RSA Design ........................................................................................ 17 
3.2 
 End of Participation Definition ............................................................................................... 23 
3.3 
End of Regimen Definition ....................................................................................................... 24 
4 RSA Enrollment ..................................................................................................................................... 25 
4.1 
Number of Study Participants ................................................................................................. 25 
4.2 
Inclusion and Exclusion Criteria ............................................................................................. 25 
4.2.1    RSA Inclusion Criteria ........................................................................................................... 25 
4.2.2    RSA Exclusion Criteria .......................................................................................................... 25 
5 
INVESTIGATIONAL PRODUCT ................................................................................................. 26 
5.1 
Investigational Product Manufacturer ................................................................................... 26 
5.2 
Acquisition, Storage, and Preparation .................................................................................... 27 
5.3      Study Medication/Intervention, Administration, Escalation, and Duration ........................ 28 
5.4 
Drug Returns and Destruction................................................................................................. 28 
5.5      Justification for Dosage ............................................................................................................. 29 
5.5.1   Additional Scientific Justification for Dose Selection ............................................................ 30 
5.6 
Dosage Changes ......................................................................................................................... 32 
5.7      Participant Compliance............................................................................................................. 32 
5.8      Overdose ..................................................................................................................................... 33 
5.9      Prohibited Medications ............................................................................................................. 33 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 3 of 62 
5.10 
Zilucoplan Known Potential Risks and Benefits .................................................................... 33 
5.10.1 
Known Potential Risks ........................................................................................................ 33 
5.10.2 
Known Potential Benefits ................................................................................................... 34 
5.11  Treatment Assignment Procedures ......................................................................................... 34 
6  REGIMEN SCHEDULE ...................................................................................................................... 35 
6.1 
Placebo-Controlled Period ....................................................................................................... 35 
6.1.1 
Regimen-Specific Screening Visit ...................................................................................... 36 
6.1.2  
Baseline Visit ...................................................................................................................... 37 
6.1.3 
Week 2 Telephone Visit ...................................................................................................... 37 
6.1.4 
Week 4 Visit ....................................................................................................................... 37 
6.1.5 
Week 8 Visit ....................................................................................................................... 38 
6.1.6 
Week 12 Telephone Visit .................................................................................................... 38 
6.1.7 
Week 16 Visit ..................................................................................................................... 38 
6.1.8 
Week 20 Telephone Visit .................................................................................................... 39 
6.1.9 
Week 24 Visit or Early Termination Visit .......................................................................... 39 
6.1.10    Follow-Up Safety Call ......................................................................................................... 40 
6.1.11    Process for Early Terminations ............................................................................................ 40 
6.2 
Open Label Extension ............................................................................................................... 41 
6.2.1 
Week 2 OLE Telephone Visit ............................................................................................. 41 
6.2.2 
Week 4 OLE Visit ............................................................................................................... 41 
6.2.3 
Week 8 OLE Visit ............................................................................................................... 42 
6.2.4  Week 12 OLE Telephone Visit ................................................................................................ 42 
6.2.5  Week 16 OLE Visit .................................................................................................................. 43 
6.2.6  Week 20 OLE Telephone Visit ................................................................................................ 43 
6.2.7  Week 24 OLE Telephone Visit ................................................................................................ 44 
6.2.8  Week 28 and Q12 Weeks OLE Visits ...................................................................................... 44 
7 CLINICAL ASSESSMENTS AND OUTCOME MEASURES ..................................................... 46 
7.1  
Voice Analysis ............................................................................................................................ 46 
7.2     ALSAQ-40 ................................................................................................................................... 46 
7.3    Center for Neurologic Study Bulbar Function Scale ................................................................ 46 
7.4 Home Spirometry ........................................................................................................................... 47 
8  
BIOFLUID COLLECTION ..................................................................................................... 48 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 4 of 62 
8.1  
Anti-drug Antibody Sampling ................................................................................................. 48 
8.2  
Zilucoplan Plasma PK Analysis ............................................................................................... 48 
8.3  
Zilucoplan Pharmacodynamic Analysis .................................................................................. 48 
8.4  
Zilucoplan Peripheral Blood Biomarker Samples ................................................................. 48 
9  
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS ............................................ 49 
9.1  Deviations from the Default Master Protocol Trial Design ....................................................... 49 
9.2 
Regimen Specific Operating Characteristics .......................................................................... 49 
9.3  Sharing of Controls from other Regimens .................................................................................. 49 
Appendix I: The ALSAQ-40 .................................................................................................................... 50 
Appendix II: The Bulbar Function Scale (CNS-BFS) ........................................................................... 59 
REFERENCES ..................................................................................................................................... 61 
List of Figures and Tables 
Figure 1: Mechanism of Action of Zilucoplan in the Complement System ........................................ 13 
Figure 2: Terminal complement activation products in the serum and CSF of healthy controls 
versus ALS patients. Data represents individual patients with mean + standard deviation. Data on 
record at Ra Pharma. ............................................................................................................................ 18 
Figure 3: Mechanism of Action of Zilucoplan in the Complement System ........................................ 20 
Figure 4: PK/PD Relationship for Zilucoplan in Cynomolgus Monkeys and Translation to the Clinic
 
22 
Figure 5: Complement C5 concentrations in healthy donors (n=14), age range 40–77yrs and ALS 
patients (n=17 of which n=15 sporadic ALS and n=2 familial ALS), age range 40-81yrs. ................ 30 
Figure 6: Functional potency of zilucoplan in healthy donors (n=13) and ALS patients (n=16) 
plasma. ................................................................................................................................................... 31 
Figure 7: Pharmacokinetic / Pharmacodynamic relationship of zilucoplan in Phase 2, dose ranging 
study in generalized myasthenia gravis (IND 134340). ........................................................................ 32 
 
Table 1: Pharmacological potency of zilucoplan (IC50) in species tested .......................................... 21 
Table 2: Rodent Quantitative Whole-Body Radiography of [14C]-zilucoplan .................................... 23 
Table 3: Zilucoplan Dose Presentations by Weight Brackets .............................................................. 27 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 5 of 62 
SIGNATURE PAGE 
I have read the attached Regimen-Specific Appendix (RSA) entitled, “Regimen A: Zilucoplan,” 
dated July 15, 2021 (Version 5.0) and agree to abide by all described RSA procedures.  I agree to 
comply with the International Conference on Harmonisation Tripartite Guideline on Good Clinical 
Practice, applicable FDA regulations and guidelines identified in 21 CFR Parts 11, 50, 54, and 
312, central Institutional Review Board (IRB) guidelines and policies, and the Health Insurance 
Portability and Accountability Act (HIPAA). 
 
By signing the RSA, I agree to keep all information provided in strict confidence and to request 
the same from my staff. Study documents will be stored appropriately to ensure their 
confidentiality. I will not disclose such information to others without authorization, except to the 
extent necessary to conduct the study.  
 
 
 
 
Site Name: 
 
 
 
 
Site Investigator: 
 
 
 
 
Signed: 
 
 
 
 
 
Date: 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 6 of 62 
LIST OF ABBREVIATIONS 
 
ALS 
 
Amyotrophic Lateral Sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 
C5 
 
Complement component 5 
CNS-BFS  
Center for Neurologic Study Bulbar Function Scale 
Covid-19 
Coronavirus Disease 2019 
FVC  
Forced Vital Capacity 
gMG  
Generalized Myasthenia Gravis 
IMNM  
Immune-mediated Necrotizing Myopathy 
IP 
 
Investigational product 
ITT 
 
Intent-to-Treat 
IV 
 
Intravenous 
OLE 
 
Open Label Extension 
PD 
 
Pharmacodynamic 
PK 
 
Pharmacokinetic 
RBC 
 
Red blood cells 
RSA 
 
Regimen-Specific Appendix 
SOC 
 
Standard of care 
SVC 
 
Slow Vital Capacity 
VC 
 
Vital Capacity 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 7 of 62 
REGIMEN-SPECIFIC APPENDIX SUMMARY 
Regimen-Specific Appendix A 
For 0.3mg/kg SC zilucoplan administered once daily and placebo 
 
Allocation to Treatment Regimens 
Participants must first be screened under the Master Protocol and before they are randomized to 
an RSA.  
 
As soon as pre-defined criteria for futility for the RSA are met, or the target number of 
randomized participants has been reached, enrollment will stop in the RSA.   
 
Number of Planned Participants and Treatment Groups 
The number of planned participants for this regimen is approximately 160.   
 
There are 2 treatment groups for this regimen, active and placebo. Participants will be 
randomized in a 3:1 ratio to active treatment or placebo (i.e., 120 active: 40 placebo).   
 
Planned Number of Sites 
Research participants will be enrolled from approximately 60 centers in the US.   
 
Treatment Duration  
The maximum duration of the placebo-controlled portion is 24 weeks.  
 
Follow-up Duration 
At the conclusion of the 24-week placebo-controlled period of the study, all participants will 
either schedule a 40-day follow up safety phone call and end their participation in the regimen or 
have the option to receive zilucoplan in the Open Label Extension phase of the study.  
 
In the Open Label Extension, zilucoplan will be provided by Ra Pharmaceuticals, Inc. until 
zilucoplan is approved and available in the United States, or Ra Pharmaceuticals, Inc. terminates 
development of zilucoplan for ALS.  
 
Total Planned Trial Duration 
For participants completing the placebo-controlled treatment period of the study, the planned 
amount of time in the trial is up to 36 weeks, or about 9 months.  This duration assumes a 6-week 
screening window, a 24-week placebo-controlled treatment period, and a 40-day safety follow-
up period for those participants who do not enter the Open Label Extension.  
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 8 of 62 
If participants opt into the subsequent Open Label Extension, their participation in the trial will 
have no set endpoint. The Open Label Extension will continue until zilucoplan is approved and 
available in the territory, or Ra Pharmaceuticals, Inc. terminates development of zilucoplan for 
ALS.  For participants continuing into the OLE, their total planned participation in the trial will 
include the 6-week screening window, 24-week placebo-controlled period, and the open-ended 
Open Label Extension.  
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 9 of 62 
SCHEDULE OF ACTIVITIES  
As per the Schedule of Activities (SOA) below, visits must occur every 4 weeks and will be alternatively clinic-, phone-, or telemedicine-based, as 
applicable.  There is a maximum 24-week duration of placebo-controlled treatment for a Regimen. 
 
Screening 
 
 
 
 
 
 
 
 
 
Open Label Extension (Optional) 
Activity (page 1 of 3) 
(Master Protocol or 
Regimen-Specific) 
 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baselin
e 
Week 
2 
Week 
423 
Week 
822, 23 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit16, 
22 
Follow
-Up 
Safety 
Call15, 
16 
Week 
2 
Week 
423 
Week 
823 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 
Week 
28 and 
Q12 
Wks22, 
23 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
-42 to -1 
Days 
-41 to -14 
Days 
Day 0 
Day 
14 ±3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 ±7 
40d ±3 
after 
last 
dose 
Day 
14 
±3 
Day 
28 ±7 
Day 
56 
±7 
Day 84 
±3 
Day 
112 
±7 
Day 
140  ±3 
Day 
168  ±3 
q12w 
±14d 
Written 
Informed 
Consent -
Placebo-
Controlled 
Period2 
Master 
X 
X25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written 
Informed 
Consent -OLE 
Regimen 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Review 
Master 
X 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALS & Medical 
History 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Exam 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs4 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Slow Vital 
Capacity 
Master 
X24 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Home 
Spirometry 
Regimen 
X24 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Muscle 
Strength 
Assessment  
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
ALSFRS-R 
Master 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-40 
Regimen 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X20 
CNS Bulbar 
Function Scale 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X21 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 10 of 62 
 
Screening 
 
 
 
 
 
 
 
 
 
Open Label Extension (Optional) 
Activity (page 1 of 3) 
(Master Protocol or 
Regimen-Specific) 
 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baselin
e 
Week 
2 
Week 
423 
Week 
822, 23 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit16, 
22 
Follow
-Up 
Safety 
Call15, 
16 
Week 
2 
Week 
423 
Week 
823 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 
Week 
28 and 
Q12 
Wks22, 
23 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
-42 to -1 
Days 
-41 to -14 
Days 
Day 0 
Day 
14 ±3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 ±7 
40d ±3 
after 
last 
dose 
Day 
14 
±3 
Day 
28 ±7 
Day 
56 
±7 
Day 84 
±3 
Day 
112 
±7 
Day 
140  ±3 
Day 
168  ±3 
q12w 
±14d 
12-Lead ECG 
Master 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Clinical Safety 
Labs5 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Anti-drug 
Antibody 
Sampling 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X18 
Zilucoplan PK 
Analysis11 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Zilucoplan PD 
Analysis12 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Zilucoplan 
Biomarker 
Samples13 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Biomarker 
Blood 
Collection13 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Biomarker 
Urine 
Collection13 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
DNA 
Collection7 
(optional) 
Master 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF Collection 
(optional) 
Master 
 
 
X 
 
 
 
 
X19 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
Review 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Review6 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-
Suicide 
Severity Rating 
Scale 
Master 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Install 
Smartphone 
App26 
Regimen 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Voice 
Recording8 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 11 of 62 
 
Screening 
 
 
 
 
 
 
 
 
 
Open Label Extension (Optional) 
Activity (page 1 of 3) 
(Master Protocol or 
Regimen-Specific) 
 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baselin
e 
Week 
2 
Week 
423 
Week 
822, 23 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit16, 
22 
Follow
-Up 
Safety 
Call15, 
16 
Week 
2 
Week 
423 
Week 
823 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 
Week 
28 and 
Q12 
Wks22, 
23 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
-42 to -1 
Days 
-41 to -14 
Days 
Day 0 
Day 
14 ±3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 ±7 
40d ±3 
after 
last 
dose 
Day 
14 
±3 
Day 
28 ±7 
Day 
56 
±7 
Day 84 
±3 
Day 
112 
±7 
Day 
140  ±3 
Day 
168  ±3 
q12w 
±14d 
Uninstall 
Smartphone 
App 
Regimen 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Assignment to 
the Regimen 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
within the 
Regimen 
Master 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer/ 
Dispense  
Investigational 
Product (IP) 
Regimen 
 
 
X9 
 
X 
X 
 
X 
 
X14 
 
 
X 
X 
 
X 
 
 
 
 
X27 
IP 
Accountability/
Compliance 
Master 
 
 
 
X28 
X 
X 
X28 
X 
X28 
X 
 
X28 
X 
X 
X28 
X 
X28 
 
X28 
X 
Exit 
Questionnaire 
Master 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
N. meningitidis 
Vaccination10 
Regimen 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X10 
 
 
 
Vital Status 
Determination17 
Master 
 
 
 
 
 
 
 
 
 
X17 
 
 
 
 
 
 
 
 
 
1. 
Master Protocol Screening procedures must be completed within 42 days to 1 day prior to Baseline Visit.  
2. 
During the Master Protocol Screening Visit, participants will be consented via the Master Protocol informed consent form (ICF). After a participant is randomized to a regimen, participants will be 
consented a second time via the regimen-specific ICF.  
3. 
At the Regimen Specific Screening Visit, participants will have regimen-specific inclusion and exclusion criteria assessed.   
4. 
Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature.  Height measured at Master Protocol Screening Visit only. 
5. 
Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function and urinalysis. Serum pregnancy testing will occur in women of child-bearing potential at the 
Master Protocol Screening Visit and as necessary during the study. Pregnancy testing is only repeated as applicable if there is a concern for pregnancy. 
6. 
Adverse events that occur after signing master protocol consent form will be recorded.  
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 12 of 62 
7. 
The DNA sample can be collected after Baseline Visit if a baseline sample is not obtained or the sample is not usable. 
8. 
In addition to study visits outlined in the SOA, participants will be asked to complete twice weekly voice recordings at home. During weeks when a participant is doing a voice recording in-clinic, 
he or she would only do one other voice recording at home that week. 
9. 
Administer first dose of investigational product (IP) only after Baseline Visit procedures are completed 
10. To reduce the risk of meningococcal infection (Neisseria meningitidis), all participants must be vaccinated against meningococcal infections (with a quadrivalent vaccine and serogroup B vaccine) 
prior to initiating study drug. Booster vaccinations should be administered in accordance with the vaccination and booster guidance document for this regimen and may occur at different study 
visits in the OLE based on the vaccine brand.  To mitigate the risk of infection, participants 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 participant. 
11. Blood samples for PK analysis (zilucoplan and metabolites) should be obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
12. Blood samples for PD analysis (sheep RBC hemolysis assay, Wieslab alternative pathway assay, C5 levels) should be obtained prior to administration of study drug at each clinic visit (i.e., pre-
dose). 
13. Blood samples for biomarker analysis should be obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
14. Drug will only be dispensed at this visit if the participant continues in the OLE. 
15. Participants will only have a Follow-Up Safety Call at this time if they do not continue into the OLE.   
16. Participants who continue into the OLE and then early terminate will be asked to complete an Early Termination Visit and Follow-Up Safety Call as described in the body of this RSA. 
17. Vital status, defined as a determination of date of death or death equivalent or date last known alive, will be determined for each randomized participant at the end of the placebo-controlled portion 
of their follow-up (generally the Week 24 Visit, as indicated). If at that time the participant is alive, his or her vital status should be determined again at the time of the last participant’s last visit 
(LPLV) of the placebo-controlled portion of a given regimen. We may also ascertain vital status at later time points by using publicly available data sources as described in section 8.15 of the 
Master Protocol. 
18. During the OLE, Master Biomarker Blood Collection, Master Biomarker Urine Collection, and all regimen-specific samples will occur at OLE Weeks 16, 28, and 52 only. 
19. If the CSF collection is unable to be performed for logistical reasons, such as scheduling, at the Week 16 Visit, it may be performed at the Week 24 Visit 
20. The ALSAQ-40 is done only at Week 28 and Week 52 during OLE 
21. The CNS Bulbar Function Scale is done only at Weeks 8, 16, 28, 40 and 52 during OLE. 
22. Participants should be instructed to hold the morning dose of study drug on the day of the study visit. Study drug should not be taken until after study visit procedures are complete. 
23. Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to protect the safety of the participant due to a pandemic, or other reason. During the 
OLE, the Week 4, 8, 16, 28, and 40 Visits may be done remotely.  The Week 52 Visit should still be done in clinic. 
24. If required due to pandemic-related restrictions, Forced Vital Capacity (FVC) performed by a Pulmonary Function Laboratory evaluator or with a study-approved home spirometer, or sustained 
phonation using a study approved method may be used for eligibility (Master Protocol Screening ONLY).    
25. If a participant chooses to obtain the vaccination from their local provider, Regimen A informed consent may be completed remotely to allow a participant to consent to the regimen prior to 
obtaining the vaccination so that the participant does not need to attend an in-person screening visit to obtain the vaccination. The process for obtaining remote consent is detailed in section 6.1.1.  
26. Two smartphone apps should be installed on the participant’s phone, once to collect the voice recordings and one to collect home spirometry. 
27. Investigational product is not administered at the participant’s final in-clinic visit at the completion of the OLE.   
28. Drug accountability will not be done at phone visits. A drug compliance check-in should be held during phone visits to ensure participant is taking drug per dose regimen and to note any report of 
missed doses.  
  

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 13 of 62 
1 INTRODUCTION 
 
Regimen 1: Zilucoplan 
 
1.1 
Zilucoplan Background Information 
 
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 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 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 (4): 
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 complement 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 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 14 of 62 
(Nishimura et al. 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.  
 
1.1.1 Clinical Trial Experience with Zilucoplan 
 
The experience in clinical trials with zilucoplan can be referenced in the most current version of 
the Investigator’s Brochure (IB). 
 
1.2 
Zilucoplan- US FDA IND Background 
 
Zilucoplan has ongoing clinical trials to assess the safety and efficacy for the treatment of 
patients with PNH (Paroxysmal Nocturnal Hemoglobinuria), gMG (generalized Myasthenia 
Gravis), and IMNM (Immune Mediated Necrotizing Myopathy), Coronavirus Disease 2019 
(COVID-19)-associated respiratory syndrome, amyotrophic lateral sclerosis (ALS), and 
potentially for other complement-mediated diseases.  Clinical trials in the US are being 
conducted under the US FDA IND oversight process.  To support clinical studies in multiple 
diseases, zilucoplan has undergone extensive preclinical characterization to understand the 
pharmacology, pharmacokinetics, safety pharmacology, and toxicology of the drug.  The 
preclinical data package has been extensively reviewed by the FDA’s Division of Neurology 
Products, Office of Hematology and Oncology Product, as well as the FDA DPARP (Division of 
Pulmonary, Allergy, Rheumatology Products). Additionally, clinical safety data generated from 
completed clinical trials has been reviewed by the FDA as part of the IND review process. The 
FDA has determined the benefit/risk to be suitable for clinical investigations of zilucoplan for the 
treatment of multiple neurodegenerative diseases. 
 
The Regimen A protocol was designed with input from the US FDA as well as designed to be 
consistent with FDA’s Guidance for Industry for ALS. This includes overall study design, 
appropriate ALS clinical study endpoints, as well as long-term safety follow-up.   
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 15 of 62 
2 OBJECTIVES 
 
2.1 Study Objectives and Endpoints  
 
Primary Efficacy Objective: 
To evaluate the efficacy of zilucoplan as compared to placebo on ALS disease progression.  
 
Secondary Efficacy Objective: 
• To evaluate the effect of zilucoplan on selected secondary measures of disease 
progression, including survival. 
 
Safety Objective: 
• To evaluate the safety of zilucoplan for ALS. 
 
Exploratory Efficacy Objective: 
• To evaluate the effect of zilucoplan on selected biomarkers and endpoints. 
 
Primary Efficacy Endpoint: 
Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-
R) total score using a Bayesian repeated measures model that accounts for loss to follow-up due 
to mortality.  
 
Secondary Efficacy Endpoints: 
• Change in respiratory function as assessed by slow vital capacity (SVC). 
• Change in muscle strength as measured isometrically using hand-held dynamometry 
(HHD) and grip strength. 
• Survival. 
 
Safety Endpoints: 
• Treatment-emergent adverse and serious adverse events. 
• Changes in laboratory values and treatment-emergent and clinically significant laboratory 
abnormalities. 
• Changes in ECG parameters and treatment-emergent and clinically significant ECG 
abnormalities. 
• Treatment-emergent suicidal ideation and suicidal behavior. 
 
Exploratory Efficacy Endpoints: 
• Changes in quantitative voice characteristics. 
• Changes in biofluid biomarkers of neurodegeneration. 
• Changes in patient reported outcomes.  
• Change in respiratory function as assessed by home spirometry. 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 16 of 62 
• Change in circulating complement pathway biomarker levels (e.g. sC5b-9) 
• Optional CSF sampling for complement pathway biomarkers in CNS (e.g. sC5b-9) 
• Optional CSF sampling for pharmacokinetics of zilucoplan in CNS 
• Optional CSF sampling for pharmacodynamics of zilucoplan in CNS 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 17 of 62 
3. RSA DESIGN 
3.1 
Scientific Rationale for RSA Design 
 
This RSA is designed to correspond with the design of the Master Protocol and the goals of the 
Platform Trial. 
 
Rationale for Complement Inhibition in ALS 
 
The complement cascade is one of the most potent effector mechanisms in the immune system 
which, through the formation of the terminal membrane attack complex (C5b-9 or MAC) and the 
recruitment of inflammatory cells via the potent anaphylatoxin C5a, has great potential to cause 
tissue injury. All components of the complement cascade can be locally synthesized in the CNS, 
specifically by neurons, astrocytes, oligodendrocytes and microglia (Barnum, 1995; Gasque et 
al., 1997; O'Barr et al., 2001). Hyperactivation of the complement system has been shown to 
participate in several neurodegenerative diseases including Alzheimer's disease, Parkinson's 
disease, Huntington's disease and ALS (Kjaeldgaard et al., 2018; Loeffler et al., 2006; Morgan, 
2018; Singhrao et al., 1999). At the time of study design, no complement inhibitor had been 
investigated in a clinical trial of ALS, although substantial preclinical and clinical data provide 
rationale to do so. 
 
The predominant pathway involved in ALS pathophysiology is the classical complement 
pathway. This is primarily activated by the recognition molecule C1q, which binds to antigen 
antibody complexes and endogenous pattern recognition molecules. Elevations in biomarkers of 
classical pathway activation such as C1q and C4 have been shown to be associated with ALS in 
serum, cerebrospinal fluid, CNS parenchyma (motor cortex and spinal cord) and skeletal muscle 
tissue (Bahia El Idrissi et al., 2016a; Sta et al., 2011; Trbojevic- Cepe et al., 1998). In house data 
has also identified marked elevations in serum and cerebrospinal fluid markers of terminal 
complement pathway activation (C5a and C5b-9) in patients with ALS as compared with healthy 
controls (Figure ). 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 18 of 62 
Figure 2: Terminal complement activation products in the serum and CSF of healthy controls 
versus ALS patients. Data represents individual patients with mean + standard deviation. Data on 
record at Ra Pharma. 
Healthy
ALS
0
10
20
30
40
C5a (ng/mL)
C5a in Serum samples
          p=0.0001***
Healthy
ALS
0
1000
2000
3000
4000
5000
SC5b-9 [ng/mL]
sC5b-9 in Serum samples
          p<0.0001 ****
 
Healthy
ALS
0.0
0.5
1.0
1.5
2.0
C5a (ng/mL)
C5a in CSF samples
          p=0.0087**
Healthy
ALS
0
20
40
60
80
100
SC5b-9 [ng/mL]
sC5b-9 in CSF samples
          p=0.0006 ***
 
 
Peripheral nervous involvement of the classical complement pathway has also been documented, 
suggesting that pharmacological inhibition of the complement cascade outside the CNS may also 
deliver therapeutic benefit in ALS. In a study by Bahia El Idrissi et al., 2016 on post-mortem 
intercostal muscle from ALS patients and control donors, increased levels of C1q on the axons 
innervating the motor end plates of ALS patients were identified but C1q was undetectable in 
control (p=0.001). Additionally, C1q was deposited on innervated motor endplates prior to 
denervation, suggesting that classical pathway activation may play an early role in the 
degradation of the neuromuscular junction, the so-called “dying-back” mechanism (Chou and 
Norris 1993), suggesting that effective complement inhibition at the neuromuscular junction (as 
achieved by zilucoplan in Ra Pharma’s gMG Phase 2 trial: RA101495-02.201) could salvage 
early motor junction deterioration in ALS and prevent further loss. 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 19 of 62 
With regard to investigation into the role of complement C5 in animal models of ALS this has 
been limited. The contribution of C5a and C5b have been investigated separately and support the 
concept that broader inhibition of complement C5 could be effective in ALS. SOD1G93A rats 
and mice were treated with the specific C5aR1 antagonist, PMX205.  Chronic administration of 
PMX205 in SOD1G93A rats markedly delayed the onset of motor symptoms and increased 
survival (Woodruff et al., 2008). PMX205 treatment in SOD1G93A mice also extended survival, 
improved motor function (i.e. hind-limb grip strength) and slowed disease progression (Lee et 
al., 2017). Furthermore, deletion of the C5a receptor 1 (CD88) in SOD1G93A mice resulted in a 
significant extension in survival compared to control SOD1G93A mice in both sexes, also 
supporting a pathogenic role for C5a in this model of ALS (Woodruff et al., 2014). With respect 
to the MAC forming C5b product this has been implicated by antisense inhibition of C6 (another 
MAC pore-forming protein) which also resulted in delayed disease progression and extended 
survival in SOD1G93A mice (Bahia El-Idrissi et al., 2016b).  
 
These data have been supported by broader description of classical complement pathway 
activation in several animal models of ALS at the transcript level. In SOD1G93A mice, up-
regulation of C1qA and C1qB mRNA transcripts was observed in the spinal cord at later stages 
of disease (Olsen et al., 2001) and was subsequently confirmed by RT-PCR in isolated lumbar 
motor neurons from other SOD1 models: SOD1G93A, SOD1G37R and SOD1G85R mice 
(Ferraiuolo et al., 2007; Lobsiger et al., 2007; Perrin et al., 2005). Similarly, in non-SOD1 
models increases in C1qB and C4 mRNA levels in the lumbar spinal cord of TDP43Q331K 
transgenic mice have also been identified (Lee et al., 2018). Downstream of C1q an upregulation 
of C3 mRNA and protein expression is observed in SOD1G93A and TDP43Q331K rodents' 
spinal cord (Heurich et al., 2011; Lee et al., 2013, 2018; Woodruff et al., 2008). C3b, the 
activated fragment of C3, is found localized with activated glia and dying motor neurons, 
consistent with its role as an opsonin. 
 
Analysis of peripheral changes in classical complement proteins using SOD1G93A and 
TDP43Q331K mice has demonstrated upregulated mRNA expression of C1qB and C4 in the 
tibialis anterior at the mid-stage and end stages of disease (Lee et al., 2018; Wang et al., 2017) 
and at the motor end-plates of SOD1G93A mice, (Bahia El Idrissi et al., 2016a; Heurich et al., 
2011). Increases in downstream markers such as C3, C5, C5b9 (MAC) deposition at the motor 
end plates and nerve terminals, starting at the pre-symptomatic stage, have been observed in 
SOD1G93A mice, as well as TDP43 models. 
 
In summary, there are numerous studies documenting activation of the complement cascade in 
both the peripheral and central pathophysiology of ALS. In the periphery, studies suggest that 
activation of complement may temporally precede motor end plate degeneration and therefore 
complement inhibition could be disease modifying. In the CNS, complement activation is closely 
associated with the ongoing neuroinflammatory process. More broadly, complement activation 
has been documented in association with a diverse set of other neurodegenerative disorders 
including trauma, MS, Alzheimer's disease, Parkinson's disease and Huntington's disease. In all 
cases, the presence of terminal complement components C5a and C5b, potent inflammatory and 
membrane attack moieties, respectively, suggests that inhibition of C5 activation could 
contribute to the treatment of ALS and other neurodegenerative diseases. 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 20 of 62 
Zilucoplan and the Complement Cascade 
 
Zilucoplan has undergone extensive preclinical characterization to understand the pharmacology, 
pharmacokinetics, safety pharmacology and toxicology of the drug. The preclinical data package 
has been reviewed by all major regulatory agencies including the FDA’s Division of Neurology 
Products. 
  
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 MAC (Figure ). 
 
Figure 3: 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. 
 
Zilucoplan shows species selectivity for non-human primate and human complement C5 only. 
The primary pharmacology of zilucoplan was established in vitro using direct binding and 
functional inhibition of complement assays, as well as enzyme-linked immunosorbent assays 
(ELISAs). 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 
rapid association with C5, as well as a slow dissociation rate. The binding site is distinct from 
that of the complement C5 inhibitor monoclonal antibody eculizumab and therefore is not 
affected by mutations in complement C5 known to prevent binding of eculizumab in patients of 
Asian and Han-Chinese descent (Nishimura et al. 2014). Target (C5) binding was confirmed 
using a competitive ELISA employing biotinylated zilucoplan to capture C5. Additionally, 
zilucoplan demonstrated dose-dependent inhibition of C5a and C5b formation following 
activation of classical or alternative pathways, as well as inhibition of RBC lysis in 
serum/plasma. Zilucoplan is a potent complement inhibitor in primates and humans and a 
weak/poor inhibitor in all other animal species tested (see below).  

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 21 of 62 
 
Species 
IC50 (nM) 
Human 
6.6 
Non-human primate 
 
Baboon 
 
Chimpanzee 
 
Cynomolgus 
 
Rhesus 
 
5.2 
11.7 
3.5 
17.6 
Dog 
> 4,700 
Rabbit 
> 67,000 
Porcine 
 
Mini-pig 
 
Pig 
 
51.9 
118.6 
Rodents 
 
Mouse 
 
Rat 
 
Guinea Pig 
 
> 36,000 
591.2 
> 100,000 
 
Table 1: Pharmacological potency of zilucoplan (IC50) in species tested 
 
Zilucoplan is slowly absorbed in preclinical species after single SC administration, with mean 
Tmax ranging from approximately 5 to 8 hours post-dose. The mean elimination half-life in 
plasma is 7 days in monkeys and humans. The slow elimination kinetics are largely driven by 
high affinity interaction with the target protein C5 and a much lower affinity interaction with 
albumin and other plasma proteins. Metabolism of zilucoplan is well-characterized and studies 
have identified two primary metabolites that occur in similar ratios in both monkeys and humans. 
Excretion of parent and major metabolites is predominantly hepatobiliary. 
 
The PK/PD relationship of zilucoplan has been extensively investigated in cynomolgus monkeys. 
An EC90 of 2500 ng/mL was determined in monkeys which translated nearly precisely to the 
clinical experience in generalized myasthenia gravis trials (Figure ). 
 
 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 22 of 62 
Figure 4: PK/PD Relationship for Zilucoplan in Cynomolgus Monkeys and Translation to the 
Clinic 
 
A) Zilucoplan PK/PD in Cynomolgus Monkeys   
B) Zilucoplan PK/PD in Phase 2 gMG trial 
 
 
Quantitative whole-body autoradiography studies in rats have been conducted using [14C]-
zilucoplan to determine the in vivo biodistribution of zilucoplan. Importantly, zilucoplan 
biodistribution to ALS disease compartments such as muscle, spinal cord and brain are enhanced 
when compared to literature data of therapeutic monoclonal antibodies (see below). Furthermore, 
as this rodent study was carried out in “normal” animals, the blood brain barrier would be intact, 
potentially analogous to current understanding of ALS blood brain barrier integrity. Ra Pharma 
believes that this biodistribution advantage is conferred by smaller molecular size of a 
macrocyclic peptide (3.5 kDa) versus a monoclonal antibody (approx. 140 kDa). Therefore, 
zilucoplan may be ideally suited to test the hypothesis of both peripheral and CNS involvement 
of complement in ALS.  
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 23 of 62 
 
 
Table 2: Rodent Quantitative Whole-Body Radiography of [14C]-zilucoplan:  
Improved biodistribution into tissue vs. literature values of typical mAb taken from Shah DK, 
Betts AM (2013). Ra data represent tissue AUC0-24 as a percentage of plasma. 
 
In summary, preclinical studies have extensively characterized the pharmacokinetics, 
pharmacology, safety, and toxicology of zilucoplan. The biodistribution advantages of zilucoplan 
when compared to monoclonal antibodies particularly with respect to access to the muscle and 
brain/spinal cord compartments may be an important determinant of success in treating ALS. 
Literature data support a strong activation of complement in the peripheral and central nervous 
system in both patients and animal models of ALS.  
  
3.2 
 End of Participation Definition 
 
 
A participant is considered to have ended his or her participation in the placebo-controlled period 
of the Regimen if they: 
• Complete planned placebo-controlled period visits, as described in the SOA, including 
participants on or off study drug 
• Early terminate from the study and complete the Early Termination Visit and Follow-Up 
Phone call as described in Section 6.1.11 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 24 of 62 
• Withdraw consent to continue participation in the study, or are lost to follow up 
If a participant initiates open-label study drug in the OLE period, he or she is considered to have 
completed his or her participation in the OLE period of the Regimen if they choose to withdraw 
or all planned OLE period visits, including the last visit or the last scheduled procedure shown in 
the SOA, have been completed.  
3.3    End of Regimen Definition 
 
The end of the placebo-controlled period in a Regimen occurs when all randomized participants 
have completed their participation in the placebo-controlled period as defined in section 3.2. 
The end of the OLE period in a Regimen occurs when all participants who initiated open-label 
study drug in the OLE period have completed their participation in the OLE period as defined in 
Section 3.2. 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 25 of 62 
4. RSA ENROLLMENT 
4.1 
Number of Study Participants 
 
Approximately 160 participants will be randomized for this Regimen.   
 
4.2 
Inclusion and Exclusion Criteria 
 
To be randomized to an RSA, participants must meet the Master Protocol eligibility criteria.  In 
addition, participants meeting all the following inclusion and exclusion criteria will be allowed to 
enroll in this Regimen:  
 
4.2.1    RSA Inclusion Criteria 
 
 
1. Vaccination with a quadrivalent meningococcal vaccine and meningococcal serotype B 
vaccine at least 14 days prior to the first dose of study drug at the Baseline (Day 0) visit. 
Meningococcal vaccines (including boosters) should be administered in accordance with 
the study’s vaccination worksheet. 
 
4.2.2    RSA Exclusion Criteria  
 
1. History of meningococcal disease. 
2. Prior treatment with a complement inhibitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 26 of 62 
 
5 INVESTIGATIONAL PRODUCT 
 
5.1     Investigational Product Manufacturer 
 
Zilucoplan injection is manufactured in accordance with current Good Manufacturing Practices. 
 
Drug Substance 
RA101495 sodium drug substance is comprised of all L-α-amino acids.  There are 15 L-α-amino 
acids in the main chain and an additional L-glutamic acid in the side-chain group on lysine15.  
This side-chain group on lysine15 contains a palmitic acid, a γ-linked L-glutamic acid, and then 
an amino-ethylene-glycol-acid spacer (EG24) attached to the ε-group of lysine15.  Using IUPAC 
naming convention for peptides and writing the EG24 as a polyoxygenated long-chain fatty acid, 
the name of RA101495 sodium is:   
Acetyl‐[L-lysyl1-L-valyl2-L-glutamyl3-L-arginyl4-L-phenylalanyl5-L-aspartyl6] -N-
methyl-L-aspartyl7-L-tert-leucyl8-L-tyrosyl9-L-7-azatryptophyl10-L-glutamyl11-L-tyrosyl12-
L-prolyl13-L-cyclohexylglycyl14-[L-lysyl15, Nε-palmitoyl-γ-L-glutamyl-(1-amino-
3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54, 57,60,63,66,69,72-
tetracosaoxapentaheptacontan-75-oyl)], cyclic (Lactam 1-6), tetra sodium 
 
Excipients 
The excipients used in the manufacture of zilucoplan injection are commonly used excipients in 
the pharmaceutical industry for parenteral dosage forms.  All excipients comply with the 
requirements of the relevant monographs in the United States Pharmacopeia (USP)/National 
Formulary (NF), European Pharmacopoeia (Ph. Eur.), the British Pharmacopoeia (BP) and the 
Japanese Pharmacopoeia (JP).  The purpose of the formulation components are as follows: 
phosphate buffer to maintain product pH (6.5 to 7.5) and saline to maintain an isotonic product 
(270 to 330 mOsm/kg). 
 
The excipients used in the manufacture of zilucoplan placebo drug product for injection are the 
same as those used to produce 40 mg/mL zilucoplan drug product, however the molar quantities 
of the formulation ingredients differ in order to account for absence of active zilucoplan drug 
substance and to produce an isotonic solution within specified pH range.  All excipients comply 
with the requirements of their respective monographs in the USP/NF and Pharm. Eur., as well as 
the Japanese Pharmacopoeia (JP), as applicable. 
 
Drug Product / Investigational Product (IP) 
Zilucoplan for injection is packaged into a Beckton Dickinson (BD) 1 mL long glass syringe 
with a 29-gauge ½” long staked in needle.  The glass syringe is closed with a West 4423/50 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 27 of 62 
Bromobutyl rubber B2/40 coated, Teflon-faced stopper. The zilucoplan injection syringes are 
then placed into the secondary packaging BD UltraSafe Plus. The Becton Dickinson UltraSafe 
Plus device is a non-sterile, non-measuring, single use needle safety shield system.  The device 
does not perform, interfere with or in any way impact the delivery of the drug, which is 
accomplished by the prefilled syringe.   
 
Drug product will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., participants will be provided prefilled syringes based on their weight containing 
fixed amounts of zilucoplan, and each fixed amount will cover a range of participant weights). 
As shown in Table 3, 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 to a maximum dose of 0.42 mg/kg 
daily. 
 
Placebo will be provided in 1 presentation of 0.574 mL. 
 
Nominal Target Dose 
(mg/kg) 
Actual Dose 
(mg) 
Injection Volume 
(mL) 
Weight Range 
(kg) 
Dose Range 
(mg/kg) 
0.3 
16.6 
0.416 
≥43 to <56 
0.30 to 0.39 
0.3 
23.0 
0.574 
≥56 to <77 
0.30 to 0.41 
0.3 
32.4 
0.810 
≥77 to 150 
0.22 to 0.42 
Table 3: Zilucoplan Dose Presentations by Weight Brackets 
 
Participants who present with a lower body weight (<43 kg) or a higher body weight (≥150 kg) 
will be accommodated on a case-by-case basis, in consultation with the medical monitor. 
 
5.2     Acquisition, Storage, and Preparation 
 
Zilucoplan and placebo should be stored at 2°C to 8°C at the study site. Once dispensed to 
participants, zilucoplan and placebo may be stored at room temperature. Storage of zilucoplan 
and placebo outside of room temperatures should be avoided, eg, it should not be refrigerated 
once it has been removed to room temperature. Please refer to the Regimen specific pharmacy 
manual for additional details. 
 
Participants will receive secure containers to dispose of used syringes while at home. At each 
visit, the participant should return the disposal container containing all used syringes to the site. 
The participant should also bring any unused study drug (i.e., unused syringes) back to the site at 
each in-person study visit.  
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 28 of 62 
All unused study drug syringes and disposal containers containing used syringes must be 
returned to the site at the end of the participant’s participation in the Regimen.  For participants 
not continuing on in the OLE, this would be the Week 24 Visit or earlier if study participation is 
terminated early. Participants who enter the OLE and end their participation in the OLE early 
should also return all unused study drug syringes and disposal containers containing used 
syringes to the site once their participation in the OLE ends. 
 
5.3      Study Medication/Intervention, Administration, Escalation, and Duration 
 
The drug product, 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. Participants will be instructed to self-administer SC 
doses daily; when necessary the SC injections may be administered by a caregiver. Three dosage 
strengths of zilucoplan will be supplied as shown in 6. 
 
All eligible participants will be randomized 3:1 to receive 0.3 mg/kg zilucoplan or placebo 
administered SC at the Baseline (Day 0) visit, which will be performed by the site staff at the 
study visit. Following in-clinic education and training, all participants and/or caregivers will 
inject daily SC doses of study drug at approximately the same time each day for the remainder of 
the 24-week Treatment Period. 
  
Dosing on study visit days as outlined in the SOA should be held until all assessments have been 
completed. At each clinic study visit, dosing should be supervised to ensure the correct injection 
technique is being followed by participants and/or caregivers. 
 
Participants and caregivers will be instructed to inject SC doses daily at approximately the same 
time each day. The participant/caregiver will subcutaneously inject study drug into the abdomen 
only. 
 
All participants 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. 
 
5.4 Drug Returns and Destruction 
At each in person visit the steps outlined in the Manual of Procedures must be followed for study 
drug accountability and compliance, as well as study drug return and destruction.  
 
Prior to study drug destruction, all partial and empty kits require a second accountability 
verification to be completed by a different study team member, and both verifications should be 
documented on the study destruction logs. No study drug may be destroyed on-site until written 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 29 of 62 
approval is provided by the study monitoring team. Sites should comply with their local drug 
destruction policies. 
 
5.5      Justification for Dosage 
 
 
The dosage of 0.3 mg/kg daily is selected for this study based on its well-understood safety and 
efficacy profile from prior clinical trial experience in neurology.  In Ra Pharma’s Phase 2 gMG 
study (RA101495-02.201), the 0.3mg/kg dose demonstrated superior efficacy, greater inhibition 
of the terminal complement pathway, with a similar safety and tolerability profile as compared 
with the 0.1 mg/kg and placebo arms.  The magnitude and speed of improvement on the primary 
(Quantitative Myasthenia Gravis Score, QMG) and key secondary (MG Activities of Daily 
Living, 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. The superior efficacy of the 0.3 mg/kg dose was 
further demonstrated by participants’ complete freedom from the need for rescue therapy with 
IVIG or PLEX in the 0.3mg/kg arm, as compared with a 7% rescue rate in the 0.1mg/kg arm, and 
a 20% rescue rate in the placebo arm. A higher proportion of participants achieved minimal 
symptom expression (Vissing 2018), defined as an MG-ADL of 0 or 1, in the 0.3mg/kg arm 
(35.7%) as compared with the 0.1mg/kg arm (26.7%) and placebo (13.3%). 
 
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 participants 
receiving the 0.3 mg/kg dose while the 0.1 mg/kg group achieved only submaximal (88%) 
inhibition of the terminal complement pathway.  
 
The once daily dosing interval used in study RA101495-02.201 will be retained in this study 
because pharmacokinetic simulations indicate that longer dosing intervals cannot achieve 
adequate exposures and fail to maintain the depth of complement inhibition needed for 
maximum therapeutic benefit.  For example, once every other day dosing is estimated to reduce 
the zilucoplan trough concentration by approximately 50%, resulting in inadequate 
pharmacodynamic effect. 
 
The same weight brackets as used in study RA101495-02.201 have been selected for use in this 
study. Study drug will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., participants will be provided prefilled syringes containing fixed amounts of 
zilucoplan based on their weight, and each fixed amount will cover a range of participant 
weights).  
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 30 of 62 
5.5.1   Additional Scientific Justification for Dose Selection 
 
Although activation of the complement system has been shown to participate in several 
neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's 
disease and ALS (Kjaeldgaard et al., 2018; Loeffler et al., 2006; Morgan, 2018; Singhrao et al., 
1999), basal levels of unactivated complement C5 are unchanged in ALS when compared to 
healthy controls. It is therefore apparent that ALS pathophysiology is driven, in part, by 
hyperactivation of complement system rather than over expression / elevated levels of the 
individual fluid phase proteins. This is exemplified by the below figure (Error! Reference 
source not found.) whereby complement C5 levels in plasma and CSF in ALS patients remain 
in the physiological range and comparable to healthy volunteer samples. 
 
Figure 5: Complement C5 concentrations in healthy donors (n=14), age range 40–77yrs and ALS 
patients (n=17 of which n=15 sporadic ALS and n=2 familial ALS), age range 40-81yrs. 
 
*Statistical difference assessed using unpaired, non-parametric, 2-tailed Mann-Whitney test in Prism 
(also called Wilcoxon rank sum test. Data is shown as mean ± Standard Deviation) 
 
With respect to dose selection for this trial, as drug levels (complement C5) are within the 
normal range and comparable with healthy volunteers (see above) and myasthenia gravis patients 
(not shown) no special dose adjustment for the ALS population is necessary. Furthermore, the 
sponsor assessed the apparent functional potency of zilucoplan in ALS plasma using a bioassay 
of pharmacodynamic activity (Error! Reference source not found.). The potency of zilucoplan 
to inhibit complement activation is unchanged relative to potency observed in healthy volunteer 
plasma samples.  
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 31 of 62 
Figure 6: Functional potency of zilucoplan in healthy donors (n=13) and ALS patients (n=16) 
plasma.  
 
 
 
 
 
 
 
 
 
Donor plasma (1% v/v) was incubated with antibody sensitized sheep erythrocytes. Hemolysis 
was assessed using OD412nm absorbance of the supernatant. A 10-pt dose-response curve with 
zilucoplan was generated for each sample to assess the IC50 and IC90 values. Samples are from 
the same patients and healthy volunteers as described in Error! Reference source not found.. 
 
Based on similar target:drug stoichiometry across patient populations studied in the clinical 
development program of zilucoplan and unchanged functional potency of zilucoplan in ALS 
biomatrices, a daily dose of 0.3mg/kg/day will provide complete inhibition of complement C5 
activity. The PK/PD relationship for zilucoplan in the phase 2, dose ranging study in a 
comparable neuromuscular disorder generalized myasthenia gravis is shown in Error! 
Reference source not found.. 
Samples 
IC50 (nM) 
Mean ± SD 
IC90 (nM) 
Mean ± SD 
Healthy (n=13)  5.7 ± 1.3 
13.4 ± 3.5 
ALS (n=16) 
5.4 ± 1.3 
12.4 ± 2.5 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 32 of 62 
Figure 7: Pharmacokinetic / Pharmacodynamic relationship of zilucoplan in Phase 2, dose ranging 
study in generalized myasthenia gravis (IND 134340).  
 
 
Finally, data supports the blood-brain barrier permeability of zilucoplan in preclinical species 
(rats and non-human primates). Quantitative whole-body autoradiography studies in rats have 
been conducted using [14C]-zilucoplan to determine the in vivo biodistribution of zilucoplan). In 
rats with a fully intact blood brain barrier approximately 1% (AUC0-24 as a percentage of 
plasma) of dosed compound was detected in the CNS compartment. Microdialysis studies in 
non-human primates also with an intact blood brain barrier have also been conducted and support 
these findings. 
 
In summary 0.3mg/kg/day in the current study, should provide complete inhibition of circulating 
complement C5 in ALS patients. Furthermore, irrespective of blood brain barrier status 
(compromised vs intact) zilucoplan is expected to enter the CNS and engage complement C5. 
Pharmacodynamic biomarkers and pharmacokinetic analysis will be employed in this trial in 
both peripheral and CNS compartments to support interpretation of clinical data. 
 
5.6      Dosage Changes 
 
Not applicable. 
 
5.7      Participant Compliance 
 
Study personnel will assess study drug compliance at every in-person visit to record whether any 
doses were missed. During phone visits, drug compliance check-in will be discussed to ensure 
participant is taking drug per dose regimen and to note any report of missed doses. If a 
participant misses 1 dose (i.e., 1 day) of study drug, he/she should take the next planned dose as 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 33 of 62 
scheduled and the investigator should be contacted as soon as possible. If a participant misses 2 
or more doses, he/she must notify the investigator immediately and the medical monitor should 
be consulted.  
 
If a participant misses 10 or more consecutive doses, he/she must notify the investigator 
immediately, the medical monitor should be consulted, and this will be considered a major 
protocol deviation. 
 
5.8      Overdose  
 
Certain safety events that occur in association with study drug may require reporting. These 
safety events include, but are not limited to, the following: 
• Overdose of the study drug, where ‘overdose’ is defined as a participant receiving ≥ 2 times 
the intended dose for any given SC injection 
• Suspected abuse/misuse of the study drug 
• Inadvertent or accidental exposure to the study drug 
• Medication error involving study drug (with or without participant exposure to the study 
drug, e.g., name confusion) 
These safety events should be reported to the Coordination Center whether they result in an 
AE/SAE or not. Safety events associated with an AE/SAE should also be reported in the EDC. 
 
In the event of overdose, study staff should monitor the participant and provide supportive care 
as needed. The SI should also contact the Medical Monitor within 24 hours of the SI’s 
awareness.  
 
5.9      Prohibited Medications 
 
Participants are prohibited from receiving another complement inhibitor and/or any other 
investigational products while on study.  All other medications are permitted while on study. 
Participants are expected to remain on stable doses of permitted SOC therapy for ALS 
throughout the Treatment Period of the study.  
 
5.10 
      Zilucoplan Known Potential Risks and Benefits 
 
5.10.1 Known Potential Risks 
 
There are potential benefits and risks with the administration of any new investigational medicine 
as the effects are not fully known. To date, zilucoplan has shown good tolerability and a favorable 
safety profile across studies as described in the current version of the IB.  
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 34 of 62 
 
It is well established that inhibition of C5 and the terminal complement pathway increases the 
susceptibility to infection with encapsulated bacteria, in particular N. meningitidis. This risk is 
also described in the prescribing information for eculizumab (Soliris® USPI 2017). Given the 
increased risk for N. meningitidis with C5 inhibition or deficit, patients who participate in 
zilucoplan clinical trials will be required to have documentation of N. meningitidis vaccination 
(and booster if appropriate) prior to study entry. In addition, while on treatment with zilucoplan, 
participants will be monitored closely for signs and symptoms of N. meningitidis infection. More 
information on the safety profile of zilucoplan can be found in the IB.  
 
5.10.2 Known Potential Benefits 
 
The potential benefits of zilucoplan comprise improved control of complement-mediated disease 
processes (e.g., such effects have already demonstrated on muscle weakness due to impaired 
neuromuscular signaling in patients with gMG).  In ALS we hypothesize that zilucoplan can inhibit 
complement-mediated tissue damage in the CNS and the neuromuscular junction, and that this 
may translate into improved neurological function as assessed by ALSFRS-R. 
 
5.11  Treatment Assignment Procedures 
 
Each participant who meets all eligibility criteria for the RSA will be randomized to receive 
either 0.3 mg/kg zilucoplan daily or placebo for approximately 24 weeks of placebo-controlled 
treatment (with the option of an Open Label Extension).   
 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 35 of 62 
6  REGIMEN SCHEDULE  
6.1 
Placebo-Controlled Period  
 
In addition to procedures in the Master protocol, the following regimen specific procedures will 
be conducted during the study: 
 
• Home Spirometry 
o Note: Home spirometry should be collected within the visit window but will occur 
while the participant is not in the clinic (at home or other remote location).  
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Smartphone installation and removal 
• Voice recording 
• Dispense investigational product to participant 
• Neisseria Meningitidis Vaccination 
o Note: Booster vaccinations should be administered in accordance with SOC.  
Please refer to SOC and vaccination worksheet for details about timing. 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
 
Participants may be required to reconsent to the regimen if new procedures or information is 
added in the future. Should a participant need to reconsent, this should occur during the 
participant’s next in-person visit. If the participant’s next in-clinic visit is conducted remotely, 
reconsent may also be completed remotely using the following procedures: 
 
1. The site staff sends a copy of the informed consent form to the participant. 
2. The participant reads through the consent form but does not sign.  
3. The Site Investigator, or other study staff member approved and delegated to obtain informed 
consent, contacts the participant and reviews the informed consent form with the participant.  
4. The participant signs the informed consent form and returns the original signed consent form 
back to the site. 
5. Once received at the site, the individual who consented the participant signs the informed 
consent form. 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 36 of 62 
 
Modifications to Regimen Schedule  
Designated visits in the Schedule of Activities (i.e., Week 4, Week 8, and Week 16) may be 
conducted via telemedicine (or phone if telemedicine is not available) with remote services 
instead of in-person if needed to protect the safety of the participant due to a pandemic or other 
reason. If a planned in-clinic visit is conducted via telemedicine (or phone if telemedicine is not 
available) with remote services, only selected procedures will be performed. Instructions on how 
to document missed procedures are included in the MOP.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry (Week 8 and 16 only) 
• Voice Recording 
• CNS Bulbar Function Scale (Week 8 and 16 only)  
• Neisseria Meningitidis Vaccination booster shots 
 
Details on collection of the CNS Bulbar Function Scale, dispensing IP during remote visits, and 
documenting participants’ willingness to participate in OLE are described in the MOP. 
Blood samples for anti-drug antibody sampling, PK and PD analyses, and peripheral blood 
biomarker samples are not collected during the remote visits by the home health agency and this 
should be recorded as such in the applicable source documentation and EDC.  
 
6.1.1 Regimen-Specific Screening Visit  
 
This visit will take place in-person after the Master Protocol randomization to a regimen. The 
visit must occur at least 14 days prior to the Baseline Visit. This is because the 
meningococcal vaccine needs 14 days to take effect.  Participants must not start study drug 
until the 14-day period has elapsed.   The following procedures will be performed: 
 
• Neisseria Meningitidis Vaccination 
 
The regimen-specific screening may occur remotely if the participant would like to obtain the 
vaccination from their local provider, rather than traveling to the study site to obtain the 
vaccination during the screening visit. If the regimen-specific screening visit occurs remotely, 
then informed consent must be obtained remotely. The site should follow the steps below for 
obtaining remote consent from the participant prior to when the participant receives the 
vaccination: 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 37 of 62 
• 
The site staff sends the informed consent form to the participant. 
• 
The participant reads through the consent form but does not sign.  
• 
The Site Investigator, or other study staff member approved and delegated to obtain informed 
consent, contacts the participant and reviews the informed consent form with the participant. 
• 
The participant signs the informed consent form and returns the original signed consent form 
back to the site. 
• 
Once received at the site, the individual who consented the participant signs the informed 
consent form. 
 
6.1.2  Baseline Visit 
 
This visit will take place in-person at least 14 days after the Regimen-Specific Screening Visit. 
The following procedures will be performed: 
 
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Install Smartphone Apps 
• Home Spirometry 
• Voice Recording 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Dispense investigational product to participant 
• Administer investigational product to participant once all other Baseline procedures are 
complete 
• Remind participant to bring investigational product to the next visit 
 
6.1.3 Week 2 Telephone Visit 
 
This visit will take place 14 ± 3 days after the Baseline Visit via telephone.  No regimen-specific 
procedures will be performed at this visit. 
 
 
6.1.4 Week 4 Visit 
 
This visit will take place in-person 28 ± 7 days after the Baseline Visit The following procedures 
will be performed: 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 38 of 62 
 
• Voice Recording 
• Dispense investigational product to participant 
• Remind participant to bring investigational product to the next visit 
 
6.1.5 Week 8 Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 56 ± 7 days after the Baseline Visit.  The following 
procedures will be performed: 
 
• Home Spirometry  
• CNS Bulbar Function Scale 
• Voice Recording 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Dispense investigational product to participant 
• Remind participant to bring investigational product to the next visit 
 
6.1.6 Week 12 Telephone Visit 
 
This visit will take place 84 ± 3 days after the Baseline Visit via telephone.  No regimen-specific 
procedures will be performed at this visit. 
 
6.1.7 Week 16 Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 112 ± 7 days after the Baseline Visit. The following 
procedures will be performed: 
 
• Home Spirometry 
• CNS Bulbar Function Scale 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 39 of 62 
• Voice Recording 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Document participant’s willingness to participate in the OLE 
o If OLE consent is not obtained at Week 16, it may be obtained at Week 24. 
• Dispense investigational product to participant 
• Remind participant to bring investigational product to the next visit 
 
6.1.8 Week 20 Telephone Visit 
 
This visit will take place 140 ± 3 days after the Baseline Visit via telephone. No regimen-specific 
procedures will be performed at this visit. 
 
6.1.9 Week 24 Visit or Early Termination Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
The Week 24 Visit will take place in-person 168 ± 7 days after the Baseline Visit.  The following 
procedures will be performed at either the Week 24 Visit or the Early Termination Visit: 
 
• Home Spirometry  
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Voice Recording 
• Uninstall Smartphone App 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Dispense investigational product to participant [See note below.] 
• Remind participant to bring investigational product to the next visit (only if continuing in 
OLE) 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 40 of 62 
Note: Drug is only dispensed at this visit if the participant is continuing in the Open Label 
Extension. Participants should be instructed to continue using effective contraception for at 
least 40 days after their last dose of study drug.  
 
6.1.10    Follow-Up Safety Call 
 
Participants will have a Follow-Up Safety Call about 40 days after their last dose of study drug.  
Only those participants NOT continuing on in the Open Label Extension will have the Follow-
Up Safety Call following the end of their participation in the placebo-controlled portion of the 
trial.  The following procedures will be performed: 
 
• Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
 
6.1.11    Process for Early Terminations 
 
Participants who early terminate from the study and do not complete the protocol will be asked 
to be seen for an in-person Early Termination Visit and complete a Follow-Up Safety Call. If a 
participant is not able to be seen in-person, safety assessments and others that can be conducted 
remotely should be performed. 
 
The in-person Early Termination Visit should be scheduled as soon as possible after a participant 
early terminates. If the participant early terminates during the placebo-controlled portion of the 
Regimen, all assessments that are collected at the Week 24 in-clinic visit should be conducted. If 
the participant early terminates during the OLE phase, all assessments that are collected at the 
OLE Week 52 in-clinic visit should be conducted. The Follow-Up Safety Call should be 
completed approximately 40 days after the last dose of study drug.   
 
If the Early Termination Visit occurs approximately 40±3 days after the last dose of study drug, 
the information from the Follow-Up Safety Call can be collected during the Early Termination 
Visit, and a separate Follow-Up Safety Call does not need to be completed. If the in-person Early 
Termination Visit does not occur within 40±3 days of the last dose of study drug, the Follow-Up 
Safety Call should occur approximately 40±3 days after the last dose of study drug and the Early 
Termination Visit will be completed after the Follow-Up Safety Call.      
 
Note: Participants should be instructed to continue using effective contraception for at least 
40 days after their last dose of study drug.  
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 41 of 62 
6.2 
Open Label Extension  
 
Participants who have completed the placebo-controlled portion of the trial on drug, will be 
eligible to continue on in the Open Label Extension.  The Open Label Extension of the study will 
continue until zilucoplan is approved and available in the territory, or the Sponsor terminates 
development of zilucoplan for ALS. 
 
Modifications to OLE Schedule  
Designated visits in the Schedule of Activities for the OLE (i.e. Week 4, Week 8, Week 16, 
Week 28, and Week 40) may be conducted via telemedicine (or phone if telemedicine is not 
available) with remote services instead of in-person if needed to protect the safety of the 
participant due to a pandemic or other reason. If a planned in-clinic visit is conducted via 
telemedicine (or phone if telemedicine is not available) with remote services, only selected 
procedures will be performed. Instructions on how to document missed procedures are included 
in the MOP.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry  
• CNS Bulbar Function Scale (Not done at OLE Week 4).  
• Neisseria Meningitidis Vaccination booster shot 
 
Blood samples for anti-drug antibody sampling, PK and PD analyses, and peripheral blood 
biomarker samples are not collected during the remote visits by the home health agency and this 
should be recorded as such in the applicable source documentation and EDC.  
 
6.2.1 Week 2 OLE Telephone Visit 
 
This visit will take place via telephone 14 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.2 Week 4 OLE Visit 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 42 of 62 
This visit will take place in-person 28 ± 7 days after the Week 24 Visit of the placebo-controlled 
portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Dispense investigational product to participant 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.3 Week 8 OLE Visit 
 
This visit will take place in-person at 56 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Dispense investigational product to participant 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.4  Week 12 OLE Telephone Visit 
 
This visit will take place via telephone at 84 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 43 of 62 
 
• 
Administer ALSFRS-R questionnaire 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.5  Week 16 OLE Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person at 112 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Collect urine sample biomarker analyses 
• 
Collect blood sample for biomarker analyses 
• 
Anti-drug Antibody Sampling 
• 
Zilucoplan Plasma PK Analysis 
• 
Zilucoplan Pharmacodynamic Analysis 
• 
Zilucoplan Peripheral Blood Biomarker Samples 
• 
Dispense investigational product to participant 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.6  Week 20 OLE Telephone Visit 
 
This visit will take place via telephone at 140 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 44 of 62 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.7  Week 24 OLE Telephone Visit 
 
This visit will take place via telephone at 168 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.8  Week 28 and Q12 Weeks OLE Visits 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
The Week 28 OLE Visit will take place in-person 196 ± 14 days after the Week 24 Visit of the 
placebo-controlled portion of the trial.  Following the Week 28 OLE Visit, visits will occur every 
12 weeks ± 14 days.  The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
ALSAQ-40 [Only done at OLE Weeks 28 and 52 Visits] 
• 
CNS Bulbar Function Scale [Only done at OLE Weeks 28, 40, and 52 Visits] 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Collect urine sample biomarker analyses [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Collect blood sample for biomarker analyses [Only done at OLE Weeks 16, 28, and 52 
Visits] 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 45 of 62 
• 
Anti-drug Antibody Sampling [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Zilucoplan Plasma PK Analysis [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Zilucoplan Pharmacodynamic Analysis [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Zilucoplan Peripheral Blood Biomarker Samples [Only done at OLE Weeks 16, 28, and 52 
Visits] 
• 
Dispense investigational product to participant 
• 
Remind participant to bring in investigational product to the next visit 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 46 of 62 
7. CLINICAL ASSESSMENTS AND OUTCOME MEASURES 
For all assessments listed below, please refer to the Manual of Procedures for detailed 
instructions. 
7.1  
Voice Analysis 
Voice samples will be collected twice per week, using an app installed on either an android or 
iOS based smartphone.  The app characterizes ambient noise, then asks patients to perform a set 
of speaking tasks: reading sentences -- 5 fixed and 5 chosen at random from a large sentence 
bank-- repeating a consonant-vowel sequence, producing a sustained phonation, and counting on 
a single breath. Voice signals are uploaded to a HIPAA-compliant web server, where an AI-
based analysis identifies relevant vocal attributes. Quality control (QC) of individual samples 
will occur by evaluation of voice records by trained personnel. 
 
The voice analysis app is only available in English, therefore participants who do not speak 
English should not complete the voice recording. Caregivers cannot provide language assistance 
when the participant is completing the voice recording. 
 
7.2     ALSAQ-40 
 
The Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) is a patient self-
report health status patient-reported outcome. The ALSAQ-40 consists of forty questions that are 
specifically used to measure the subjective well-being of patients with ALS and motor neuron 
disease. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
7.3    Center for Neurologic Study Bulbar Function Scale 
 
The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) is a patient self-report scale 
that has been developed for use as an endpoint in clinical trials and as a clinical measure for 
evaluating and following ALS patients. The CNS-BFS consists of three domains (swallowing, 
speech, and salivation), which are assessed with a 21-question, self-report questionnaire. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
Instructions on administering the questionnaire during a phone or telemedicine visit will be 
included in the MOP. 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 47 of 62 
 
7.4 Home Spirometry 
Home-based forced vital capacity will be conducted via telemedicine (or phone if telemedicine is 
not available) and will be measured with the MIR Spirobank Smart spirometer. Instructions for 
use will be provided to the participant.  The participant will perform the vital capacity maneuver 
with real time video coaching (or phone coaching, if video is not available) by the evaluator.  
Three to five vital capacity maneuvers will be performed, consistent with the manner vital 
capacity is obtained in clinic.   
   
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 48 of 62 
8.  
BIOFLUID COLLECTION 
8.1  
Anti-drug Antibody Sampling 
 
All participants will provide blood samples for anti-drug antibody sampling. 
 
8.2  
Zilucoplan Plasma PK Analysis 
 
All participants will provide blood samples for PK analysis (zilucoplan and metabolites).  These 
blood samples should be obtained prior to administration of study drug at each clinic visit (i.e., 
pre-dose). 
 
8.3  
Zilucoplan Pharmacodynamic Analysis 
 
All participants will provide blood samples for pharmacodynamic analysis (e.g., sheep RBC 
hemolysis assay, Wieslab alternative pathway assay, C5 levels). Blood samples should be 
obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
 
8.4  
Zilucoplan Peripheral Blood Biomarker Samples 
 
All participants will provide blood samples for biomarker analysis.  Blood samples should be 
obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 49 of 62 
 
9.  
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS 
9.1  Deviations from the Default Master Protocol Trial Design 
The statistical design for this regimen will be in accordance with the default statistical design 
described in Appendix I of the Master Protocol with only one deviation. This regimen will not 
include interim analyses for early success.  
 
9.2  Regimen Specific Operating Characteristics  
Clinical trial simulation is used to quantify operating characteristics for this regimen (refer to the 
regimen SAP for further details).   
 
9.3  Sharing of Controls from other Regimens 
 
The primary analysis of this regimen will include sharing of all controls from the other 
regimens.  This is justified by the minor differences in inclusion/exclusion criteria of the RSA, 
such that there are no expected systematic differences in the primary endpoint between the 
controls across regimens.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 50 of 62 
APPENDIX I: THE ALSAQ-40 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 51 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 52 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 53 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 54 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 55 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 56 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 57 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 58 of 62 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 59 of 62 
APPENDIX II: THE BULBAR FUNCTION SCALE (CNS-BFS)  
BULBAR FUNCTION SCALE (CNS-BFS) 
SIALORRHEA 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
 
1. Excessive saliva is a concern to 
me. 
 
 
 
 
 
2. I take medication to control 
drooling. 
 
 
 
 
 
3. Saliva causes me to gag or 
choke. 
 
 
 
 
 
4. Drooling causes me to be 
frustrated or embarrassed. 
 
 
 
 
 
5. In the morning I notice saliva on 
my pillow. 
 
 
 
 
 
6. My mouth needs to be dabbed to 
prevent drooling. 
 
 
 
 
 
7. My secretions are not 
manageable. 
 
 
 
 
 
  
TOTAL Sialorrhea Score: _____ 
SPEECH 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
Unable to 
Communicate 
by Speaking 
(6) 
1. My speech is difficult to 
understand. 
 
 
 
 
 
 
2. To be understood I repeat myself. 
 
 
 
 
 
 
3. People who understand me tell 
other people what I said.  
 
 
 
 
 
 
4. To communicate I write things 
down or use devices such as a 
computer. 
 
 
 
 
 
 
5. I am talking less because it takes 
so much effort to speak. 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 60 of 62 
6. My speech is slower than usual. 
 
 
 
 
 
 
7. It is hard for people to hear me. 
 
 
 
 
 
 
  
TOTAL Speech Score: _____ 
SWALLOWING 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
  
    Feeding tube is in place 
1. Swallowing is a problem. 
 
 
 
 
 
2. Cutting my food makes it easier 
to chew and swallow. 
 
 
 
 
 
3. To get food down I have 
switched to a soft diet. 
 
 
 
 
 
4. After swallowing I gag or choke. 
 
 
 
 
 
5. It takes longer to eat. 
 
 
 
 
 
6. My weight is dropping because I 
can't eat normally. 
 
 
 
 
 
7. Food gets stuck in my throat. 
 
 
 
 
 
  
TOTAL Swallowing Score: _____ 
OVERALL SCORE: _____ 
 
 
 
 
 
 
 
 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 61 of 62 
REFERENCES 
Bahia El Idrissi, N., et al., 2016a. Complement activation at the motor end-plates in 
amyotrophic lateral sclerosis. J. Neuroinflammation 13, 72. 
Bahia El Idrissi, N., et al., 2016b. Complement component C6 inhibition decreases 
neurological disability in female transgenic SOD1G93A mouse model of amyotrophic 
lateral sclerosis. Ann Neurodegener Dis. 1, 1015. 
Barnum, S.R., 1995. Complement biosynthesis in the central nervous system. Crit. Rev. 
Oral Biol. Med. 6, 132–146. 
Chou SM, Norris FH, 1993. Amyotrophic lateral sclerosis: lower motor neuron disease 
spreading to upper motor neurons. Muscle & Nerve;16:864–9. 
Ferraiuolo, L., et al., 2007. Microarray analysis of the cellular pathways involved in the 
adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of 
familial ALS. J. Neurosci. 27, 9201–9219. 
Gasque, P., et al., 1997. Expression of the receptor for complement C5a (CD88) is 
upregulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human 
central nervous system. Am. J. Pathol. 150, 31–41. 
Heurich, B., et al., 2011. Complement upregulation and activation on motor neurons and 
neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral 
sclerosis. J. Neuroimmunol. 235, 104–109. 
Kjaeldgaard, A.L., et al., 2018. Amyotrophic lateral sclerosis: the complement and 
inflammatory hypothesis. Mol. Immunol. 102, 14–25. 
Lee, J.D., et al., 2013. Dysregulation of the complement cascade in the hSOD1G93A 
transgenic mouse model of amyotrophic lateral sclerosis. J. Neuroinflammation 10,119. 
Lee, J.D., et al., 2017. Pharmacological inhibition of complement C5a-C5a1 receptor 
signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic 
lateral sclerosis. Br. J. Pharmacol. 174, 689–699. 
Lee, J.D., et al., 2018. Complement components are upregulated and correlate with disease 
progression in the TDP-43(Q331K) mouse model of amyotrophic lateral sclerosis. J. 
Neuroinflammation 15, 171. 
 
Lobsiger, C.S., et al., 2007. Toxicity from different SOD1 mutants dysregulates the 
complement system and the neuronal regenerative response in ALS motor neurons. Proc. 
Natl. Acad. Sci. U. S. A. 104, 7319–7326. 

 
HEALEY ALS Platform Trial  
Regimen-Specific Appendix A, Zilucoplan 
 
Version 5.0, 15-July-2021 
CONFIDENTIAL 
Page 62 of 62 
Loeffler, D.A., et al., 2006. Complement activation in the Parkinson's disease substantia 
nigra: an immunocytochemical study. J. Neuroinflammation 3, 29. 
Morgan, B.P., 2018. Complement in the pathogenesis of Alzheimer's disease. Semin. 
Immunopathol. 40, 113–124 
Nishimura, J. et al., 2014 Genetic Variants in C5 and Poor Response to Eculizumab N Engl 
J Med. 370:632-639 
O'Barr, S.A., et al., 2001. Neuronal expression of a functional receptor for the C5a 
complement activation fragment. J. Immunol. 166, 4154–4162. 
Perrin, F.E., et al., 2005. No widespread induction of cell death genes occurs in pure 
motoneurons in an amyotrophic lateral sclerosis mouse model. Hum. Mol. Genet. 14,3309–
3320. 
Shah DK, Betts AM, 2013. Antibody biodistribution coefficients: inferring tissue 
concentrations of monoclonal antibodies based on the plasma concentrations in several 
preclinical species and human. mAbs 5:297-305  
Singhrao, S.K., et al., 1999. Increased complement biosynthesis by microglia and 
complement activation on neurons in Huntington's disease. Exp. Neurol. 159, 362–376 
Sta, M., et al., 2011. Innate and adaptive immunity in amyotrophic lateral sclerosis: 
evidence of complement activation. Neurobiol. Dis. 42, 211–220. 
Trbojevic-Cepe, M., et al., 1998. Cerebrospinal fluid complement activation in neurological 
diseases. J. Neurol. Sci. 154, 173–181. 
Vissing J, O'Brien F, Wang JJ, Howard JF., 2018. Correlation between myasthenia gravis-
activities of daily living (MG-ADL) and quantitative myasthenia gravis (QMG) assessments 
of anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis in 
the phase 3 regain study. Muscle Nerve;58(2): E21-E22 
Wang, H.A., et al., 2017. Complement C5a-C5aR1 signaling drives skeletal muscle 
macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. 
Skelet. Muscle 7, 10. 
Woodruff, T.M., et al., 2008. The complement factor C5a contributes to pathology in a rat 
model of amyotrophic lateral sclerosis. J. Immunol. 181, 8727–8734. 
Woodruff, T.M., et al., 2010. The role of the complement system and the activation 
fragment C5a in the central nervous system. NeuroMolecular Med. 12, 179–192. 
Woodruff, T.M., et al., 2014. Role for terminal complement activation in amyotrophic 
lateral sclerosis disease progression. Proc. Natl. Acad. Sci. U. S. A. 111, E3–E4.