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

HEALEY ALS Platform Trial - Regimen B Verdiperstat 
NCT04436510 
Document Date: 02 Dec 2021 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
CONFIDENTIAL 
 
Page 1 of 65 
REGIMEN-SPECIFIC APPENDIX [B] 
 
FOR VERDIPERSTAT (BHV-3241) 
 
 
Regimen-Specific Appendix Date: 02 December 2021 
Version Number: 
6.0 
 
 
 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
CONFIDENTIAL 
 
Page 2 of 65 
TABLE OF CONTENTS 
 
SIGNATURE PAGE..................................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................................... 6 
REGIMEN-SPECIFIC APPENDIX (RSA) SUMMARY ......................................................... 9 
SCHEDULE OF ACTIVITIES – 24-WEEK PLACEBO-
CONTROLLED PHASE ............................................................................................................ 11 
SCHEDULE OF ACTIVITIES – REGIMEN-SPECIFIC 
OPEN-LABEL EXTENSION PHASE (OPTIONAL) ............................................................. 15 
1 
INTRODUCTION REGIMEN B: VERDIPERSTAT 
(BHV-3241) ................................................................................................................................. 17 
1.1 
Verdiperstat Background Information ................................................................ 17 
1.1.1 
Primary Pharmacodynamics............................................................................. 17 
1.1.2 
Secondary Pharmacodynamics ....................................................................... 18 
1.1.3 
Safety Pharmacology......................................................................................... 18 
1.2 
Verdiperstat Rationale ............................................................................................ 19 
1.2.1 
Dosage Selection and Justification ................................................................. 20 
2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 21 
3 
RSA DESIGN ...................................................................................................................... 22 
3.1 
Scientific Rationale for RSA Design ................................................................... 22 
3.3 
End of Regimen Definition ......................................................................................... 23 
4 
RSA ENROLLMENT ......................................................................................................... 24 
4.1 
Number of Study Participants .............................................................................. 24 
4.2 
Additional RSA Inclusion and Exclusion Criteria ........................................... 24 
4.2.1 
RSA Inclusion Criteria ....................................................................................... 24 
4.2.2 
RSA Exclusion Criteria ...................................................................................... 24 
4.3 
Treatment Assignment Procedures .................................................................... 24 
5 
INVESTIGATIONAL PRODUCT ..................................................................................... 25 
5.1 
Investigational Product Manufacturer ................................................................ 25 
5.2 
Labeling, Packaging, and Resupply ................................................................... 25 
5.2.1 
Labeling ............................................................................................................... 25 
5.2.2 
Acquisition and Preparation .............................................................................. 25 

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Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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5.2.3 
Drug Returns and Destruction .......................................................................... 26 
5.3 
Study Medication/Intervention, Administration and Duration, and Titration
 
26 
5.3.1 
Administration and Duration ............................................................................. 26 
5.3.2 
Dosage Modification .......................................................................................... 27 
5.4 
Drug Holiday .............................................................................................................. 28 
5.5 
Participant Compliance .......................................................................................... 28 
5.6 
Justification for Dosage ......................................................................................... 28 
5.7 
Overdose .................................................................................................................... 28 
5.8 
Drug-Drug interactions and Prohibited Medications ..................................... 29 
5.8.1 
Effect of other drugs on verdiperstat metabolism ......................................... 29 
5.8.2 
Effect of verdiperstat on the metabolism of other drugs: ............................. 29 
5.9 
Verdiperstat Known Potential Risks and Benefits .......................................... 30 
5.9.1 
Known Potential Risks ....................................................................................... 30 
5.9.2 
Known Potential Benefits .................................................................................. 33 
6 
REGIMEN SCHEDULE ..................................................................................................... 34 
6.1 
Placebo-Controlled Period .................................................................................... 35 
6.1.1 
Verdiperstat Regimen Specific Screening Visit ............................................. 35 
6.1.2 
Baseline Visit....................................................................................................... 35 
6.1.3 
Week 2 Telephone Visit .................................................................................... 36 
6.1.4 
Week 4 Visit ........................................................................................................ 36 
6.1.5 
Week 8 Visit ........................................................................................................ 36 
6.1.6 
Week 12 Telephone Visit .................................................................................. 37 
6.1.7 
Week 16 Visit ...................................................................................................... 37 
6.1.8 
Week 20 Telephone Visit .................................................................................. 37 
6.1.9 
Week 24 Visit or Early Termination Visit ........................................................ 38 
6.1.10 
Follow-Up Safety Call ........................................................................................ 39 
6.1.11 
Process for Early Terminations ........................................................................ 39 
6.1.12 
Criteria for Participant Termination .................................................................. 39 
6.2 
Open Label Extension (OLE)................................................................................. 40 
6.2.1 
Week 2 Telephone Visit - OLE ......................................................................... 41 
6.2.2 
Week 4 Visit – OLE ............................................................................................ 41 
6.2.3 
Week 8 Visit - OLE ............................................................................................. 41 
6.2.4 
Week 12 Telephone Visit – OLE ...................................................................... 41 
6.2.5 
Week 16 Visit – OLE .......................................................................................... 41 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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6.2.6 
Week 20 Telephone Visit – OLE ...................................................................... 42 
6.2.7 
Week 24 Telephone Visit – OLE ...................................................................... 42 
6.2.8 
Week 28 Visit and Q12 Weeks – OLE ............................................................ 42 
7 
OUTCOME MEASURES AND ASSESSMENTS ......................................................... 43 
7.1 Voice Analysis ................................................................................................................ 43 
7.2 ALSAQ-40 ........................................................................................................................ 43 
7.3 Center for Neurologic Study Bulbar Function Scale ........................................... 43 
8 
BIOFLUID COLLECTION................................................................................................. 44 
8.2 Pharmacokinetic Assessments ................................................................................. 44 
8.3 Pharmacodynamic Biomarker Assessments ........................................................ 44 
9 
SAFETY AND ADVERSE EVENTS ............................................................................... 45 
9.1 
Adverse Events of Special Interest – Thyroid Function ................................ 45 
10 
REGIMEN-SPECIFIC STATISTICAL 
CONSIDERATIONS .................................................................................................................. 46 
10.1 
Deviations from the Default Master Protocol Trial Design ........................... 46 
10.2 
Regimen Specific Operating Characteristics ................................................... 46 
10.3 
Sharing of Controls from Other Regimens ....................................................... 50 
11 
REFERENCES ............................................................................................................... 51 
Appendix I: The Bulbar Function Scale (CNS-BFS) .................................................... 53 
Appendix II: The ALSAQ-40............................................................................................... 56 
 
List of Figures 
Figure 1. 
Regimen Specific Appendix Schematic ........................................................... 22 
 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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SIGNATURE PAGE 
I have read the Regimen-Specific Appendix (RSA) entitled, Verdiperstat (BHV-3241) in 
Participants with Amyotrophic Lateral Sclerosis (ALS) 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 B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALS 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire 
Anti-TPO  
Anti-Thyroid Peroxidase 
AUC 
Area Under the Curve 
BHV-3241 
Verdiperstat 
BID 
Twice daily 
°C 
Degrees Celsius 
CBC 
Complete blood count 
Cmax 
Maximum Plasma Concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
Cytochrome P450 
DNA 
ECG 
eCRF 
ER 
°F 
FVC 
GRAS 
HDPE 
HHD 
HIPAA 
HR 
Deoxyribonucleic Acid 
Electrocardiogram 
Electronic Case Report Form 
Extended Release 
Degrees Fahrenheit 
Forced Vital Capacity 
Generally recognized as safe 
High-density polyethylene  
Hand Held Dynamometry 
Health Insurance Portability and Accountability Act 
Hazard Ratio 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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IB 
ICF/IC 
ICH 
IP 
IRB 
IWRS 
LPLV 
MAD 
mg 
MPO 
MSA 
NADPH 
NfL 
NOEL 
NOX 
NRF2 
OLE 
PD 
PET 
P-gp 
PK 
PMA 
PP 
QD 
QTcF 
ROS 
RNS 
RSA 
SAD 
SAE 
Investigator Brochure 
Informed Consent Form 
International Council on Harmonization  
Investigational Product 
Institutional Review Board 
Interactive Web-Based Response System 
Last participant last visit 
Modification of Diet in Renal Disease 
Milligram 
Myeloperoxidase 
Multiple System Atrophy 
Nicotinamide adenine dinucleotide phosphate 
Neurofilament Light Chain 
No-Observed-Effect-Level 
NADPH oxidase 
Nuclear factor erythroid 2–related factor 2 
Open-Label Extension 
Pharmacodynamic 
Positron emission tomography 
P-glycoprotein 
Pharmacokinetic 
Phorbol-12-myristate-13-acetate 
Polypropylene 
Once Daily 
Corrected QT Interval by Fridericia 
Reactive oxygen species 
Reactive nitrogen species 
Regimen-specific appendix 
Single Ascending Dose 
Serious Adverse Event 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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SI 
SOA 
SOD 
SVC 
T3 
T4 
TSPO 
TPO 
TSH 
TSPO 
USB 
USP 
VC 
WOCBP 
Site Investigator 
Schedule of Activities 
Superoxide dismutase 
Slow Vital Capacity 
Triiodothyronine 
Thyroxine 
Translocator Protein 
Thyroid Peroxidase 
Thyroid Stimulating Hormone 
Translocator Protein 
Universal Serial Bus 
US Pharmacopoeia 
Vital Capacity 
Women of Childbearing Potential 
 
 
 

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Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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REGIMEN-SPECIFIC APPENDIX (RSA) SUMMARY 
Regimen-Specific Appendix [B] 
For verdiperstat (also known as BHV-3241). 
Rationale and RSA Design 
The proposed study is based on cumulative preclinical and clinical studies that implicate 
myeloperoxidase (MPO) activity in the onset and progression of neurodegenerative diseases and 
suggest treatment with verdiperstat at a dosage of 600 mg twice daily (BID) has the potential to 
slow neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). 
Allocation to Treatment Regimens 
Participants must first be screened under the Master Protocol 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 for the RSA 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 28-day follow up phone call and end their participation in the regimen or have 
the option to receive verdiperstat in the open-label extension (OLE) phase of the study.  
The OLE portion of the study will continue until verdiperstat is approved and available in the 
United States, or Biohaven Pharmaceuticals terminates development of verdiperstat for ALS. At 
the completion of the OLE, a Follow-up Safety Call should be conducted approximately 28 days 
after the last dose of study drug. 
For participants who early terminate from the placebo-controlled phase, an in-person Early 
Termination Visit and a Follow-up Safety Call should be conducted. At the Early Termination 
Visit the same procedures as described for the Week 24 visit should be conducted. At the 
Follow-up Safety Call, information on clinical status should be collected.  

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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For participants who early terminate from the OLE, an in-person Early Termination Visit and a 
Follow-up Safety Call should be conducted. At the Early Termination Visit the same procedures 
as described for the Final visit should be conducted. At the Follow-up Safety Call, information 
on clinical status should be collected. 
Total Planned Trial Duration 
For participants completing only the placebo-controlled Treatment Period of the study, the 
planned amount of time for participation in the trial is 34 weeks, or about 8 months. This 
duration assumes a 6-week screening window, a 24-week placebo-controlled treatment period, 
and a 28-day safety follow-up period for those participants who do not enter the OLE. 
Participants will complete approximately 10 study visits during the placebo-controlled period of 
the study.

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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SCHEDULE OF ACTIVITIES – 24-WEEK PLACEBO-CONTROLLED PHASE 
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. 
 
Activity  
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit3, 
18 
Follow-
up 
Safety 
Call3,4 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Days 
Day 0 
Day 
14 +3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 
±7 
28±7 
days 
after 
last 
dose 
Written Informed Consent – 
Placebo-controlled Period5 
Master 
X 
X 
 
 
 
 
 
 
 
 
 
Written Informed Consent - 
OLE 
Regimen 
 
 
 
 
 
 
 
X 
 
 
 
Inclusion/Exclusion Review 
Master 
X 
X6 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
Master 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs7 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slow Vital Capacity 
Master 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Home Spirometry 
Regimen 
X20 
 
X 
 
 
X 
 
X 
 
X 
 
Muscle Strength Assessment 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
ALSFRS-R 
Master 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
Regimen 
 
 
X 
 
 
 
 
 
 
X 
 
CNS bulbar Function Scale 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
Regimen 
X 
 
 
 
 
X 
 
 
 
X 
 

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Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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Activity  
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit3, 
18 
Follow-
up 
Safety 
Call3,4 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Days 
Day 0 
Day 
14 +3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 
±7 
28±7 
days 
after 
last 
dose 
Clinical Safety Labs8 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Verdiperstat (BHV-
3241specific PD 
biomarkers10 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
PK Blood Collection10 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Biomarker Blood Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
Biomarker Urine Collection 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
DNA Collection11(optional) 
Master 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
Master 
 
 
X 
 
 
 
 
X17 
 
 
 
Concomitant Medication 
Review 
Master 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant Medication 
Review 
Regimen 
 
 
 
X 
 
 
 
 
 
 
 
Adverse Event Review9 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale 
Master 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Install Smartphone App21 
Regimen 
 
 
X 
 
 
 
 
 
 
 
 
Voice Recording12 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
Master 
 
 
 
 
 
 
 
 
 
X 
 
Assignment to the Regimen  
Master 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within the 
Regimen 
Master 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense 
Investigational product 
Regimen 
 
 
X13 
 
X 
X 
 
X 
 
X14 
 

HEALEY ALS Platform Trial 
Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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Activity  
Master 
Protocol 
or 
Regimen-
Specific 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baseline 
Week 
22 
Week 
418,19 
Week 
818,19 
Week 
12 
Week 
1618,19 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit3, 
18 
Follow-
up 
Safety 
Call3,4 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
-42 to -1 
Days 
-41 to 0 
Days 
Day 0 
Day 
14 +3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 
±7 
28±7 
days 
after 
last 
dose 
Study Drug 
Accountability/Compliance 
Master 
 
 
 
X2,22 
X 
X 
X22 
X 
X22 
X 
 
Dose Escalation 
Regimen 
 
 
X15 
X15 
 
 
 
 
 
 
 
Exit Questionnaire 
Master 
 
 
 
 
 
 
 
 
 
X 
 
Vital Status Determination 
Master 
 
 
 
 
 
 
 
 
 
X16 
 
1 Master Protocol Screening procedures must be completed within 42 days to 1 day prior to the Baseline Visit. The Regimen-Specific Screening Visit and 
Baseline Visit should be combined if possible.  
2 At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule will be conducted. The assessment will be conducted by phone. 
If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the titration schedule may be modified (see Section 5.3.2). 
3  Participants will only have a Follow-Up Safety Call at this time if they do not continue into the OLE or if they discontinue prior to Week 24. Participants who 
continue into OLE will have a Follow-Up Safety Call after their last dose of study drug during the OLE phase.   
4 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.  
5 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 RSA ICF.  
6At the Regimen Specific Screening Visit, participants will have regimen-specific inclusion and exclusion criteria assessed, if applicable.  
7 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature. Height is measured at Master Protocol Screening Visit 
only. 
 8 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function (TSH) 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.  
9 Adverse events that occur after signing the master protocol consent form will be recorded.  
10 Myeloperoxidase protein and activity, and plasma concentrations of verdiperstat will be measured. For each sample, the time of the last verdiperstat or 
matching placebo dose prior to sample collection, time of the last meal prior to sampling and time of the PD/PK sample collection should be reported on the 
CRF. 

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Regimen-Specific Appendix B, Verdiperstat 
 
Version 6.0 , 02-December-2021  
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11 The DNA sample can be collected after baseline if a baseline sample is not obtained or the sample is not usable. 
12 In addition to study visits outlined in the SOA, participants may 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.  
13 Administer first dose of investigational product (IP) only after Baseline Visit procedures are completed. Participants should take the first dose of IP while in the 
office/clinic on the day of the Baseline visit and stay at the clinic for approximately 30 minutes post-dose for observation. 
14 Investigational product will only be dispensed at this visit if the participant continues in the OLE.  
15 From start to end of Week 1, participants will ingest either 300 mg QD of verdiperstat or matching placebo QD. From start to end of Week 2, participants will 
ingest either 300 mg BID of verdiperstat or matching placebo BID. Starting with Week 3 and continuing to Week 24, participants will ingest either 600 mg BID 
of verdiperstat or matching placebo BID. 
16 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. 
17  If the CSF collection cannot happen at the Week 16 Visit for logistical reasons such as scheduling, it can happen at the Week 24 Visit. 
18 Participants should be instructed to skip 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. 
19 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.  
20 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).    
21 Two smartphone apps should be installed on the participant’s phone, one to collect the voice recordings and one to collect home spirometry. 
22 Drug accountability will not be done at phone visits. A drug compliance check in must be held during phone visits to ensure participant is taking drug per dose regimen and to 
note any report of missed doses.  

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Version 6.0 , 02-December-2021  
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SCHEDULE OF ACTIVITIES – REGIMEN-SPECIFIC OPEN-LABEL EXTENSION PHASE (OPTIONAL) 
Open Label Extension (Optional) 
Activity 
Week 
24 
Visit  
Week 
21 
Week 
411 
Week 
811 
Week 
12 
Week 1610,11 
Week 
20 
Week 
24 
Week 2810,11 
and Q12 
weeks 
Follow-up 
Safety Call3,4 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Day 0 
Day 
14 +3 
Day 28 
+7 
Day 
56 
±7 
Day 
84 +3 
112 +7 days 
140+3 
days 
168+3 
days 
Q12 weeks 
+14 days 
28±7 days after 
last dose 
Vital Signs5 
X 
 
X 
X 
 
X 
 
 
X 
 
Slow Vital Capacity 
X 
 
X 
X 
 
X 
 
 
X 
 
Home Spirometry 
 
 
X 
X 
 
X 
 
 
X 
 
Muscle Strength Assessment 
X 
 
 
 
 
 
 
 
 
 
ALSFRS-R 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
X 
 
 
 
 
 
 
 
X14 
 
CNS bulbar Function Scale 
X 
 
 
X 
 
X 
 
 
X 
 
12-Lead ECG 
X 
 
X 
 
 
 
 
 
X13 
 
Clinical Safety Labs6 
X 
 
X 
X 
 
X 
 
 
X 
 
Biomarker Blood Collection 
X 
 
 
 
 
X 
 
 
X12 
 
Verdiperstat (BHV-3241specific 
PD biomarkers7 
X 
 
 
 
 
X 
 
 
X12 
 
PK Blood Collection7 
X 
 
 
 
 
X 
 
 
X12 
 
Biomarker Blood Collection 
X 
 
 
 
 
X 
 
 
X12 
 
Biomarker Urine Collection 
X 
 
 
 
 
X 
 
 
X12 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale 
X 
 
X 
X 
 
X 
 
 
X 
 
Administer/Dispense 
Investigational product 
X8 
 
X 
X 
 
X 
 
 
X15 
 
Drug 
Accountability/Compliance 
X 
X16 
X 
X 
X16 
X 
X16 
X16 
X 
 
Dose Escalation 
 
X9 
 
 
 
 
 
 
 
 

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Version 6.0 , 02-December-2021  
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1 At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule will be conducted. The assessment will be conducted by phone. 
If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the titration schedule may be modified (see Section 5.3.2). 
2 The last visit for the open-label extension will be at Week 52. Participants who withdraw consent or terminate early (prior to Week 52) from the study will be 
asked to be seen for an in-person Early Termination Visit and should have the same procedures as the Week 52 visit.  
3 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.  
4  Participants will have a Follow-up Safety Call approximately 28 days after the last dose of study drug. At this call, information on clinical status should be 
collected.  
5 Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature. 
6 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, liver function tests, thyroid function (TSH) 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. 
7 Myeloperoxidase protein and activity, and plasma concentrations of verdiperstat will be measured. For each sample, the time of the last verdiperstat dose prior 
to sample collection, time of the last meal prior to sampling, and time of the PD/PK sample collection should be reported on the CRF. 
8 Administer first dose of investigational product (IP) only after Week 24 procedures are completed. Participants should take the first dose of IP while in the 
office/clinic on the day of the Week 24 visit and stay at the clinic for approximately 30 minutes post-dose for observation. 
9 From start to end of Week 1, participants will ingest 300 mg QD of verdiperstat QD. From start to end of Week 2, participants will ingest 300 mg BID of 
verdiperstat BID. Starting with Week 3 and continuing to Week 52, participants will ingest 600 mg BID of verdiperstat BID.  
10 Participants should be instructed to skip the morning dose of study drug on the day of the study visit – at OLE Weeks 16, 28 and 52. Study drug should not be 
taken until after study visit procedures are complete. 
11 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.  
12 Biomarker Blood Collection, Biomaker Urine Collection and all regimen-specific samples will occur at OLE Weeks 16, 28 and 52 only. 
13 12-Lead ECG is performed at OLE Weeks 4 and 52 only 
14 The ALSAQ-40 is performed at OLE Weeks 28 and 52 only 
15 Investigational product is not administered at the participant’s final in-clinic visit at the completion of the OLE. 
16 Drug accountability will not be performed at phone visits.  A drug compliance check-in must be held during phone visits to ensure participant is taking drug 
per dose regimen and to note any report of missed doses. 
 

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CONFIDENTIAL 
1 
   INTRODUCTION REGIMEN B: VERDIPERSTAT (BHV-3241)  
1.1 
Verdiperstat Background Information 
Biohaven Pharmaceuticals, Inc [Biohaven] is developing a new drug, verdiperstat (also known as 
BHV-3241), for the treatment of neurodegenerative diseases, including amyotrophic lateral 
sclerosis (ALS). 
Verdiperstat is a first-in-class, potent, selective, brain-permeable, irreversible myeloperoxidase 
(MPO) enzyme. MPO is one of the most abundant enzymes in activated myeloid cells, including 
microglia [1]. It is a lysosomal enzyme that plays essential roles in immune surveillance and host 
defense. In disease, innate immune system activation leads to MPO-induced pathological 
oxidative stress and further inflammation that contribute to cellular injury [1]. Increasing 
evidence suggests MPO is involved several neurodegenerative diseases [1],[2]. 
The proposed study is based on cumulative nonclinical, clinical, and neuroimaging studies that 
implicate MPO activity in the onset and progression of neurodegenerative diseases and suggest 
treatment with verdiperstat has the potential to slow neurodegeneration. The high unmet need for 
an effective treatment, together with the available data, provide a compelling rationale for the 
development of verdiperstat as a treatment for ALS. 
Summaries of relevant findings from nonclinical and clinical studies conducted with verdiperstat 
are provided. Please refer to the Investigator Brochure [3] for additional information.  
1.1.1 Primary Pharmacodynamics  
1.1.1.1 In Vitro Pharmacology  
Verdiperstat inhibitory potency was characterized in biochemical and cellular assays. In the 
biochemical assay, which was based on the physiological enzymatic activity of MPO (using 
chloride and hydrogen peroxide as substrates and hypochlorous acid as product), verdiperstat 
inhibited human MPO with an IC50 of 630 nmol/L. In cellular assays, MPO is not active in 
cellular systems unless the cells expressing the enzyme are activated, which can be accomplished 
by using phorbol-12-myristate-13-acetate (PMA), which promotes both an oxidative burst and 
extracellular release of MPO. Using PMA-activated neutrophils from human donors, verdiperstat 
was measured to have IC50 of 88 nmol/L; and using PMA-activated rat peritoneal leukocytes 
(primarily neutrophils), it had similar potency with an IC50 of 100 nmol/L.  
1.1.1.2 In Vivo Pharmacology  
• Verdiperstat efficiently inhibited MPO activity in vivo during acute rat peritonitis. 
• Verdiperstat shows the ability to reduce neurodegeneration and microglial activation in MSA 
animal models, suggesting a potential therapeutic effect in other neurodegenerative patients.  

 
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1.1.2 Secondary Pharmacodynamics  
• Verdiperstat is 14 times more potent at human MPO than at human thyroid peroxidase 
(TPO).  
• No significant interactions were observed for any other of the over 150 targets tested, 
resulting in a selectivity of more than 15- to 150-fold.  
1.1.3 Safety Pharmacology  
A battery of safety pharmacology studies was performed with verdiperstat to examine potential 
effects on the cardiovascular, nervous, respiratory, renal, and gastrointestinal functions in 
accordance with the International Conference on Harmonization (ICH) S7A and ICH S7B 
guidelines for safety pharmacology studies. Please refer to the Investigator’s Brochure (IB) for 
additional information. 
• Verdiperstat had no significant effects on central nervous system, gastrointestinal, or 
respiratory function in rats.  
• Verdiperstat had no effects on arterial blood pressure or electrocardiograms (ECGs) in 
telemetry studies in rats and dogs. Verdiperstat increased heart rate by 46% compared to 
baseline 15 minutes after administration of 600 μmol/kg (152 mg/kg) in rats.  
• In the dog cardiovascular telemetry study, verdiperstat affected only heart rate, which was 
increased by a maximum of 52% at the mid dose and by a maximum of 84% at the high dose 
at 1-2 hours. The no-observed-effect level (NOEL) for cardiovascular effects was therefore 
90 μmol/kg, giving a Cplasma of 49.8 µmol/L.  
• Hemodynamic effects of verdiperstat were evaluated in telemetered dogs following acute 
administration of 3.5, 8, 18, and 45 mg/kg. At the three lower doses, there were no major 
effects compared to vehicle on mean arterial pressure, heart rate, myo-cardiac contractility, 
cardiac output, or total peripheral resistance. At 178 μmol/kg, with a Cplasma of 100 μmol/L, 
verdiperstat increased heart rate. In addition, aortic blood flow was slightly increased and 
total peripheral resistance and stroke volume were slightly decreased. The cardiovascular 
response evoked by a rapid orthostatic tilt following oral administration of verdiperstat at 5, 
18, and 45 mg/kg was evaluated. Administration of 45 mg/kg verdiperstat caused a 
significant increase in heart rate at pre-tilt for up to 2 hours post-dosing, whereas no relevant 
variations were observed on arterial blood pressure. No incidents of orthostatic hypotension 
were observed following administration of verdiperstat at any of the doses tested. 

 
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1.2 
Verdiperstat Rationale 
Oxidative stress 
Based on extensive supportive evidence from human ALS and animal models, oxidative stress is 
thought to promote neurodegeneration in ALS and other disorders [4]. MPO catalyzes generation 
cytotoxic oxidizing and nitrosylating compounds, e.g., hypochlorous acid and peroxynitrite [5] 
[6] which are strongly implicated in the pathophysiology of ALS. This is because biological 
macromolecules undergo oxidative damage by reactive oxygen and nitrogen species 
(ROS/RNS), which leads to organelle dysfunction and neuronal death. Free radical scavengers 
and other antioxidants are obvious treatment approaches but have had disappointing effects in 
clinical trials. Advances in ROS/RNS biology explain the failure of such antioxidants and 
suggest more mechanistic strategies for reducing oxidative stress. ROS/RNS are not merely toxic 
metabolic waste products. Rather, they are part of complex cellular signaling networks that 
include ROS/RNS producing enzymes (MPO, NADPH oxidase [NOX], xanthine oxidase), ROS 
targets (NF-κB mediated inflammatory pathways, inflammasomes), and ROS-metabolizing 
enzymes (SOD and NRF2-regulated antioxidant pathways). Deregulation of ROS/RNS pathways 
contributes to other known neurodegenerative disease mechanisms, i.e., microglial activation and 
neuroinflammation. Thus, it may be advantageous to inhibit ROS/RNS producing enzymes, such 
as MPO, thereby reducing oxidative stress and inflammation in a physiologic manner. The 
general relevance of this strategy is supported by preliminary data that suggest inhibiting NOX 
reduces microglial activation and may have other benefits in an ALS model [7].  
Neuroinflammation 
Based on extensive supportive evidence from human ALS and animal models, 
neuroinflammation is also thought to be an important mediator of neurodegeneration in ALS and 
other disorders [8], [9]. Microglia, the primary innate immune cells of the brain, are central 
players that drive neuroinflammation. In disease, resting microglia are activated or transformed 
into a pathological “M1” phenotype that is characterized by secretion of pro-inflammatory 
cytokines and ROS/RNS as well as an ameboid morphology and phagocytic properties similar to 
peripheral macrophages. Modulating microglial activation is a promising and common 
therapeutic strategy for neurodegenerative diseases, including ALS. However, it is unclear how 
to determine the optimal molecular target for intervention in this dynamic, in vivo process from 
studies in disease models.  
Positron emission tomography (PET) imaging of translocator protein (TSPO) is a state-of-the-art 
method for assessing pathological neuroinflammation in human disease states Because TSPO is 
highly expressed in activated microglia, signal from TSPO-specific radioligands, such as [11C]-
PBR28, is interpreted as a measure of microglial activation. [11C]-PBR28 PET signal is dynamic, 
responsive to treatment, and potentially predictive of benefit on clinical outcome measures. 
Thus, [11C]-PBR28 PET is a valuable pharmacodynamic biomarker for anti-inflammatory 
therapies that can demonstrate central target engagement and provide proof of mechanism of 
action in human neurodegenerative disorders [10]. Cross-sectional and longitudinal [11C]-PBR28 
PET studies in participants with ALS show that [11C]-PBR28 signal is increased in ALS but 

 
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stable over at least 6 months of disease progression. Corresponding sample size and power 
calculations suggest [11C]-PBR28 PET is a sensitive biomarker allowing for efficient signal 
detection in smaller, early phase studies. Several such studies are ongoing to assess 
investigational treatments in ALS, however none of these treatments has yet demonstrated the 
ability to decrease [11C]-PBR28 uptake. By contrast, MPO inhibition is the only approach that 
has demonstrated the ability to decrease [11C]-PBR28 uptake in human neurodegenerative 
disease, highlighting the therapeutic relevance of this target for ALS. 
Additional 
MPO may also play a role in increasingly recognized disease mechanisms mediated by 
peripheral myeloid cells, including those that migrate into the brain as well as those that remain 
in the periphery [8], suggesting relevance of MPO as a therapeutic target at both sites. For 
example, circulating immune cell numbers (particularly neutrophils) appear to correlate with 
ALS disease progression measured by ALSFRS-R. And, MPO+ neutrophils seem to contribute to 
distal motor axon and muscular pathology in human ALS autopsy tissue and in an ALS animal 
model. 
1.2.1 Dosage Selection and Justification 
The dosage of verdiperstat selected for evaluation in this study is 600 mg BID. This dosage was 
selected based on cumulative experience, including nonclinical toxicology and 
safety/tolerability, pharmacokinetic, pharmacodynamic, and preliminary efficacy data from 
phase 1 and phase 2 studies.  
Nonclinical toxicology: The program for verdiperstat is comprehensive and supports oral 
administration in the clinic for chronic treatment. The following studies were included in the 
toxicology program: single and repeat-dose toxicity in rats and dogs, genotoxicity, reproductive 
toxicity, phototoxicity, and safety pharmacology. The verdiperstat 600 mg BID dosage is 
anticipated to produce pharmacokinetic exposures below limits set based on nonclinical 
toxicology data. 
Clinical studies: As of January 2021, approximately 490subjects have received verdiperstat in 
completed and ongoing studies. In the phase 1 studies (5 completed studies) in healthy subjects, 
treatment with multiple dosages of up to 900 mg BID was generally safe and well tolerated. In 
the completed phase 2 studies in participants with Parkinson’s disease and Multiple System 
Atrophy (MSA), treatment at dosages of up to 600 mg BID for 8-12 weeks was generally safe 
and well tolerated. In the phase 2 studies, the 600 mg BID dosage decreased MPO activity in 
plasma, providing evidence of peripheral target engagement; reduced TSPO binding on brain 
PET imaging, providing evidence of central target engagement and proof of mechanism 
(decreased microglial activation/neuroinflammation); and demonstrated favorable, dose-
dependent trends on clinical efficacy measures at 12 weeks in subjects with MSA. 
A phase 3 study in patients with MSA is ongoing and currently is still blinded.  In this study, 
approximately 336 subjects have received verdiperstat or placebo.  Subjects are randomized 1:1 

 
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to receive verdiperstat or placebo, 600 mg BID, for 48 weeks with the option to continue in the 
study for an additional 48 weeks of open-label treatment with verdiperstat.  Please refer to the 
Investigator’s Brochure [3] for additional information. 
2 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Efficacy Objective: 
To evaluate the efficacy of verdiperstat as compared to placebo on ALS disease progression.  
 
Secondary Efficacy Objective: 
• To test the effect of verdiperstat on selected secondary measures of disease progression, 
including survival.  
 
Safety Objective: 
• To evaluate the safety of verdiperstat for ALS.  
 
Exploratory Efficacy Objective: 
• To test the effect of verdiperstat on selected biomarkers and endpoints. 
• To explore verdiperstat pharmacokinetics (PK) and pharmacodynamic (PD) effects. 
 
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. 

 
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• Changes in patient reported outcomes. 
• 
Changes in verdiperstat PK and PD biomarkers.  
• Change in respiratory function as assessed by home spirometry. 
 
3 
RSA DESIGN 
This study is a multicenter, randomized, double-blind, 2-arm placebo-controlled parallel-group 
study designed to evaluate the efficacy and safety of verdiperstat in a population of participants 
with ALS. The study is planned to consist of a Screening phase lasting a maximum of 
approximately 6 weeks (42 days) and a randomized double-blind treatment phase of 
approximately 24 weeks (see Figure 1). It is anticipated that the Randomization phase will 
include a dose titration period of approximately 2 weeks followed by a full dosage period of 
approximately 22 weeks. Participants completing 24 weeks of treatment with verdiperstat or 
placebo will be eligible to continue to an Open-label Extension Phase (OLE) which will include 
an additional 52 weeks of dosing. Approximately 160 participants in total are planned to be 
randomized in a 3:1 ratio to receive either verdiperstat 600 mg BID, or matching placebo BID. 
The assessments for each visit are outlined in the Schedule of Activities (SoA).  
  
Figure 1. 
Regimen Specific Appendix Schematic 
 
3.1 
Scientific Rationale for RSA Design 
This RSA is designed to correspond with the design of the Master Protocol and the goals of that 
study. 
Verdiperstat (BHV-3241) 
600 mg BID 
Placebo BID 
Master/RSA 
Screening 
Phase 
6 weeks 
(maximum) 
Randomized Double Blind 
Phase 
24 weeks 
R
Open-label 
Extension Phase 
52 weeks  
Verdiperstat 

 
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3.2 End of Partipation 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 
• 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 
discontinue participation or if 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. 
 
 

 
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4 
RSA ENROLLMENT  
4.1 
Number of Study Participants 
Approximately 160 participants will be randomized into this Regimen. 
4.2 
Additional RSA 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 
There are no additional RSA Inclusion Criteria from those described in the Master Protocol. 
4.2.2 RSA Exclusion Criteria  
• Participants who are taking strong inhibitors of CYP1A2 (i.e., ciprofloxacin, enoxacin, 
fluvoxamine, zafirlukast) for chronic/long-term use defined as more than two weeks.  
• Participants who are taking strong inhibitors of CYP3A4 (i.e., conivaptan, itraconazole, 
ketoconazole, posaconazole, troleandomycin, voriconazole, clarithromycin, diltiazem, 
idelalisib, nefazodone, and certain antiviral agents [cobicistat, danoprevir, ritonavir, 
elvitegravir, indinavir, lopinavir, paritaprevir, ombitasavir, dasabuvir, saquinavir, tipranavir, 
nelfinavir]) for chronic/long-term use defined as more than two weeks. Note: Topical 
antifungal use is not exclusionary. Participants should not consume large quantities of 
grapefruit juice (more than 8oz per day) on a regular basis.  
There are RSA-specific requirements that apply to Master Protocol exclusion criteria #6. For 
further details of contraceptive requirements for this RSA, please refer to Section 5.8.2. 
Guidance regarding CYP1A2 and CYP3A4 has been updated in Protocol Section 5.8 Drug-Drug 
Interactions and Prohibited Medications, however this exclusion criteria has not been modified 
as all participants have been enrolled. 
4.3 
Treatment Assignment Procedures 
Each participant who meets all eligibility criteria for the RSA will be randomized to receive 
either verdiperstat or matching placebo for approximately 24 weeks of treatment. Participants 
who complete the 24-week blinded Treatment Period will be eligible to continue treatment with 
open-label verdiperstat for an additional 52 weeks. 

 
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5 
INVESTIGATIONAL PRODUCT 
The Investigational Product (IP) should be stored in a secure area according to local regulations. 
It is the responsibility of the Site Investigator (SI) to ensure that the IP is only dispensed to study 
participants. The IP must be dispensed only from official study sites by authorized personnel 
according to local regulations.  
In this protocol, the IP is verdiperstat 300 mg extended release (ER) tablets and matching 
placebo tablets. 
5.1 
Investigational Product Manufacturer 
Biohaven Pharmaceuticals, Inc. is the manufacturer of verdiperstat. 
5.2 
   Labeling, Packaging, and Resupply 
5.2.1 Labeling 
Container(s) of investigational product will bear a label containing (at a minimum) the name of 
the study drug, lot and/or batch number and appropriate storage conditions (15°-25°C [59°-77°F] 
[see USP controlled room temperature] in a tightly closed container, protected from light).  
The drug product is presented as verdiperstat Extended Release (ER) Tablets that are reddish-
beige, film coated and oval (300 mg strength). The tablets each consist of 300 mg of verdiperstat 
drug substance as free base, and generally recognized as safe (GRAS) excipients for oral dosage 
forms including hydroxypropyl methyl cellulose, microcrystalline cellulose, hydroxypropyl 
cellulose, sodium stearyl fumarate and orange color. Matching placebo tablets contain 
microcrystalline cellulose and sodium stearyl fumarate and are film-coated with OPADRY® 
(mixture of hypromellose, polyethylene glycol and titanium dioxide) and iron oxide to give 
reddish-beige color. The tablets are packed in high-density polyethylene (HDPE) bottles. The 
bottles are induction sealed and closed with child resistant polypropylene (PP) screw caps. 
All investigational products should be kept in a secure area with limited access under appropriate 
storage conditions: 15°-25°C (59°-77°F) (see USP controlled room temperature) in a tightly 
closed container, protected from light.  
Excursions outside this storage temperature range should be reported as per the Pharmacy 
Manual Instructions.  
5.2.2    Acquisition and Preparation 
Initially, after informed consent is obtained at the Screening Visit, the SI or designee will enter 
the participant into the study and obtain a participant number assignment. After completion of 
Screening evaluations, all eligible participants will be randomized, in a 3:1 ratio to receive either 
verdiperstat (600 mg BID) or matching placebo, using an EDC.  

 
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5.2.3 Drug Returns and Destruction 
At each in person visit the steps outlined in 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 used and unused IP requires 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 
approval is provided by the study monitoring team. Sites should follow their local drug 
destruction policies. 
 
5.3 
Study Medication/Intervention, Administration and Duration, and Titration 
All participants will be randomized to receive verdiperstat 600 mg BID or matching placebo 
BID. Participants should take the study drug twice a day; dosing in the morning and evening 
approximately 12 hours apart. 
The tablets should be swallowed whole with a drink of water (or other liquid) or swallowed 
with substances of other consistencies as appropriate (e.g., apple sauce). The tablets should 
not be split, chewed, or crushed.  
Study medication can be taken without regard to meals. 
5.3.1 Administration and Duration 
Day 1/first dose: 
Participants should be administered the Day 1/first dose of study medication (300 mg QD or 
matching placebo QD) while in the office/clinic on the day of the Regimen-Specific Baseline 
visit after all visit assessments are complete. Participants should stay at the office/clinic for 
monitoring for approximately 30 minutes post-dose. 
Dose titration period: 
From the beginning to the end of Week 1 participants should ingest either 300 mg QD of 
verdiperstat or matching placebo QD. From the beginning to the end of Week 2, participants 
should ingest either 300 mg BID of verdiperstat or matching placebo BID.  
At the end of Week 2, an assessment of compliance and tolerance to this dose titration schedule 
will be conducted. The assessment will be conducted by phone. If tolerability issues are 
experienced with 300 mg QD or 300 mg BID dosing, the titration schedule may be modified (see 
5.3.2). 

 
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Full dose period: 
Starting with the beginning of Week 3 and throughout the remainder of the study, participants 
should ingest either 600 mg BID of verdiperstat or matching placebo BID. 
At the Weeks 4, 8, 16, and 24 study visits, the morning dose of study medication should be held 
on the day of the study visit and administered in the clinic/office during the study visit, to collect 
one pre-dose (trough) PK and PD blood sample (see Section 8). 
5.3.2 Dosage Modification 
Participants will be instructed on the dosing regimen. If tolerability issues are experienced during 
the dosage titration period with the 300 mg QD and/or 300 mg BID doses (or matching placebo), 
the titration schedule may be extended (e.g., up titration to the next dosage level delayed by an 
additional week). Potential tolerability issues may include sudden, clinically significant changes 
from baseline in symptoms of presyncope, syncope, orthostatic hypotension, or falls that are not 
otherwise explained. The SI must consult with the Medical Monitor if he or she believes that a 
change to the dosage titration schedule is warranted; and, the SI must document any such 
changes to the dosage titration schedule.  
During the full dose period of the study, it is anticipated that all participants will receive either 
verdiperstat 600 mg BID or matching placebo BID. If participants have difficulty tolerating 
verdiperstat 600 mg BID or matching placebo BID dosing, the SI may permit the participants to 
switch to verdiperstat 300 mg BID or matching placebo BID dosing (and document this change 
in the participant’s records). Potential tolerability issues may include those listed above as well 
as clinically significant laboratory abnormalities (i.e., thyroid and renal function) that are not 
otherwise explained. Down titration to verdiperstat 300 mg BID or matching placebo BID will 
only be allowed to address tolerability issues and only with Medical Monitor approval. If a 
participant is down titrated to the 300 mg BID dose, they may be allowed to retry the 600 mg 
BID dose (re-challenge), if deemed appropriate by the SI and Medical Monitor. Only two re-
challenges are allowed. Any such changes must be documented. If a switch to verdiperstat 300 
mg BID or matching placebo BID dosing does not result in acceptable tolerability, then dosing 
should be discontinued.  
Dosage modification should be considered if a participant experiences one of the following:  
a. Clinically significant changes in frequency and/or severity from baseline in symptoms of 
presyncope, syncope, orthostatic hypotension, and/or falls that are not explained by disease 
progression or intercurrent illness and not able to be adequately treated with symptomatic 
pharmacological and non-pharmacological treatments, based on the judgement of the SI. 
b. Development of Grade 3 or Grade 4 hypothyroidism. Re-challenge may be attempted, if 
warranted, when improved to less than or equal to Grade 2 (inclusive of treatment with 
thyroxine replacement therapy, see Section 9.1). 

 
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c. Development of a greater than or equal to Grade 3 toxicity or an intolerable side effect 
attributed to verdiperstat based on the judgement of the SI. Re-challenge may be attempted, if 
warranted, when symptoms improve to less than or equal to Grade 1.  
 
5.4 
Drug Holiday 
Other dosage reductions or holidays may be determined by the SI who should consult with the 
Medical Monitor. If a participant experiences an AE for which the SI believes a dose reduction 
or holiday is warranted, then the SI may temporarily suspend dosing (dose holiday) until such 
time as he/she feels it is safe for the participant to return to the assigned dose. Any such 
modifications to the dosage regimen should be noted in the eCRF. If greater than seven days, 
then a discussion with the Medical Monitor must take place and is required. If a participant is off 
study drug for more than 14 consecutive days, the participant should re-escalate using the 
titration paradigm described in section 5.3.1.  
5.5 
Participant Compliance 
Responsible study personnel will dispense the study drug. Participants will be requested to return 
any unused IP including empty packaging and used bottles at each study visit. Treatment 
compliance will be assessed at in clinic study visits through bottle counts and will be 
documented and summarized by a drug-dispensing log for each participant. During phone visits, 
drug compliance check-in will be held to ensure participant is taking drug per dose regimen and 
to note any report of missed doses. Participants will be counseled on the importance of taking the 
study drug as directed at all study visits. If poor compliance continues, (i.e., multiple missed 
doses resulting in less than 80% overall compliance), discontinuation of the participant from the 
trial should be considered and discussed with the Medical Monitor.  
If the participant loses the ability to swallow while enrolled in Regimen B, the participant will no 
longer be able to take the study drug as directed. If this occurs the participant will discontinue 
study drug and will be asked to complete the 6-month study under ITT.  
 
5.6 
Justification for Dosage 
The dosage of verdiperstat proposed for evaluation in this ALS platform trial regimen is 600 mg 
BID. This dosage selection was based on cumulative clinical and nonclinical experience with 
verdiperstat, including nonclinical toxicology, safety and efficacy data in multiple system 
atrophy and Parkinson’s disease patients. Please refer to the Investigator’s Brochure [3] for 
additional information. 
5.7 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of the product 
that is considered both excessive and medically important. All occurrences of overdose as 
defined above (suspected or confirmed and irrespective of whether or not it involved 

 
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verdiperstat) must be communicated to the Healey Center and Biohaven Pharmaceutical or a 
specified designee within 24 hours of the SI becoming aware of the updated information and be 
fully documented as an SAE. An SAE is reported for overdose when the SI feels the overdose 
was excessive and medically important. Details of any signs or symptoms and their management 
should be recorded including details of any antidote(s) administered. 
5.8 
Drug-Drug interactions and Prohibited Medications 
5.8.1 Effect of other drugs on verdiperstat metabolism 
Verdiperstat drug-drug interactions have been evaluated in clinical DDI studies. One recently 
conducted study evaluated the effect of fluvoxamine (a strong CYP1A2 inhibitor) on 
concomitantly administered verdiperstat [11]. Fluvoxamine increased the AUC of verdiperstat 
2.2-fold and the Cmax by 68%, indicating that verdiperstat is a moderately sensitive CYP1A2 
substrate. Therefore, interactions are expected to occur when verdiperstat is given concurrently 
with agents that affect CYP1A2. In order to minimize any potential safety risks:  
: 
• Strong inhibitors of CYP1A2 (i.e., ciprofloxacin, enoxacin, fluvoxamine) could potentially 
increase verdiperstat levels and should be excluded for both chronic/long-term and 
acute/short-term use.  
• Moderate inhibitors of CYP1A2 (i.e., methoxsalen, mexiletine) could potentially increase 
verdiperstat levels and should be used with caution for chronic/long-term (>2 weeks) use, 
based on the clinical judgement of the SI. 
• Moderate inducers of CYP1A2 (i.e., phenytoin, rifampin, ritonavir, and teriflunomide) could 
reduce verdiperstat levels and should be used with caution for chronic/long-term (>2 weeks) 
use, based on the clinical judgement of the SI. 
An additional clinical DDI study, which was recently conducted, tested the effect of itraconazole 
(a strong CYP3A4 inhibitor) on concomitantly administered verdiperstat [12]. Itraconazole did 
not have a clinically significant impact on verdiperstat exposure, indicating that verdiperstat is 
not a sensitive CYP3A4 substrate in vivo. Therefore, there are no recommended DDI-based 
restrictions to concomitant administration of CYP3A4 inhibitors or inducers with verdiperstat. 
5.8.2 Effect of verdiperstat on the metabolism of other drugs:  
A clinical DDI study was recently conducted to evaluate the effect of verdiperstat on 
concomitantly administered midazolam (a sensitive CYP3A4 substrate) [13]. Verdiperstat 
moderately reduced the exposure of midazolam and a ~2.5-fold increase of hydroxy-
Metabolite/Parent ratio confirmed metabolic induction as the mechanism for midazolam 
exposure decrease. These results support the conclusion that verdiperstat is a moderate CYP3A4 

 
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inducer. Therefore, interactions are expected to occur when verdiperstat is given concurrently 
with agents that are principally metabolized by CYP3A4. 
Drugs principally metabolized by CYP3A4 (i.e., atorvastatin, buspirone,, ethinylestradiol 
[hormonal contraceptives], quetiapine, telithromycin, quinidine, verapamil, warfarin, zileuton) 
should be used with caution, based on the clinical judgement of the SI. Note: The effectiveness 
of certain estrogen-containing oral hormonal contraceptives may potentially be reduced. Women 
of childbearing potential (WOCBP) who use estrogen-containing oral hormonal contraceptives 
must use alternative and/or additional barrier methods of birth control while participating in this 
RSA. Procedures for documenting alternative and/or additional methods of birth control will be 
detailed in the Manual of Procedures. 
 In vitro, verdiperstat markedly induced human CYP2B6 at 50 μmol/L, but not at 1 mol/L [14]. 
The verdiperstat dosage of 600 mg BID measured in previous studies generated a steady state, 
geometric mean Cmax level of 4.15 μmol/L [CV: 41.6%]). Thus, verdiperstat is unlikely to cause 
significant enhancements in the clearance of coadministered drugs through CYP2B6 inductive 
processes at therapeutic verdiperstat concentrations. 
Nonetheless, interactions may theoretically occur when verdiperstat is given concurrently with 
agents that are principally metabolized by CYP2B6. Verdiperstat induction of CYP2B6 may 
reduce exposures of CYP2B6 substrates, leading to potential loss of efficacy.  Therefore, in order 
to minimize any potential safety risks: 
• Drugs principally metabolized by CYP2B6 (i.e., bupropion, cyclophosphamide, efavirenz, 
ifosfamide, methadone) should be used with caution, based on the clinical judgement of the 
SI.  
5.9 
Verdiperstat Known Potential Risks and Benefits 
ALS is an adult-onset, fatal neurodegenerative disease. No disease modifying treatment currently 
exists, only symptomatic and palliative approaches are available. Verdiperstat is an irreversible 
inhibitor of the MPO enzyme that promotes oxidative stress and neuroinflammation. The high 
unmet need for an effective treatment for ALS, together with the available preclinical and 
clinical data with verdiperstat, provide a compelling and favorable overall benefit-risk 
assessment for the development of verdiperstat at the 600 mg BID dosage as a treatment for 
ALS. The safety monitoring in the planned clinical study will minimize the potential risks to 
study participants. 
5.9.1 Known Potential Risks 
Preclinical and clinical studies have demonstrated an acceptable safety and tolerability profile for 
verdiperstat but do suggest specific potential risks. The present study includes general and 
specific safety procedures anticipated to minimize any potential risks. 
General procedures will include frequent safety assessments by SIs, thorough evaluations and 
review of AEs and SAEs on an ongoing basis to monitor for any safety signals or trends by the 

 
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Sponsor and Medical Monitor, and Data Safety Monitoring Board review of the benefit-risk of 
the study for participants. 
5.9.1.1 Thyroid 
In preclinical studies, reversible histopathological changes in the thyroid gland and reversible 
thyroid hormone changes were observed. In clinical studies, verdiperstat has been associated 
with laboratory changes indicative of decreased thyroid function. Specifically, there have been 
increases over time in mean TSH levels and some decreases over time in mean free T4 and mean 
free T3 levels relative to placebo. Most participants did not have thyroid function test values 
outside the normal range, and the abnormalities that occurred were mild. Changes in thyroid 
function tests associated with verdiperstat returned toward baseline levels during the period of 
observation following discontinuation of verdiperstat. 
In aggregate, clinically significant thyroid function abnormalities were rare or infrequent with 
verdiperstat. The present study will involve monitoring of thyroid function. Thyroid function test 
abnormalities indicating clinically significant thyroid hormone deficiency are readily treatable 
with thyroid hormone replacement (see Section 9.1).  
5.9.1.2 Renal 
Reversible renal findings were observed in the 1-month preclinical studies in female rats at high 
doses, and no renal changes were noted in the 6-month study. In clinical studies, verdiperstat has 
been associated with decreases in mean uric acid levels over time relative to placebo. A variable 
proportion of participants receiving verdiperstat have had plasma uric acid levels below the 
lower limit of normal. Decreases in uric acid levels associated with verdiperstat have tended to 
return toward baseline following the discontinuation of dosing. Indices of renal function have not 
shown any abnormalities associated with verdiperstat. The mechanism of the changes in uric acid 
levels is unclear but could include decreased uric acid production or decreased renal tubular 
reabsorption. Hypouricemia is thought to be a biochemically defined disorder with no known 
clinical significance.  
In aggregate, clinically significant renal events associated with decreases in uric acid levels have 
not been observed with verdiperstat. The present study will continue to monitor for indices of 
renal function. 
5.9.1.3 Cardiovascular 
Increases in heart rate were observed in dogs during the preclinical studies. However, 
verdiperstat had no effect on blood pressure or on ECG parameters at any dose. Two studies 
evaluating cardiovascular response to orthostatic tilt in dogs were also performed; no incidences 
of orthostatic hypotension were observed following administration of verdiperstat. 
The first SAD clinical study [15] was discontinued on the basis of AEs that included syncope 
associated with brief sinus pauses detected on cardiac telemetry. Two of the cases of syncope 
were associated with orthostatic testing. There was not a relationship between these events and 

 
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verdiperstat concentrations. There was no evidence of direct proarrhythmic or other cardiotoxic 
effects. It was considered that events of syncope may have represented an exaggerated 
physiological response to study procedures, involving syncope of neurocardiogenic origin. 
However, an effect of verdiperstat could not be ruled out. A second SAD study [16] was 
conducted with 2 modifications designed to reduce the risk of syncope: (1) the exclusion of 
participants with a history of recurrent presyncope and/or syncope in connection with orthostatic 
challenge, and (2) fractionated dosing. In this second SAD study, there were no episodes of 
presyncope or syncope, and no clinically relevant findings involving vital signs or ECG 
parameters. Subsequent clinical studies have used ER formulations and there have been no cases 
of syncope in participants receiving verdiperstat. There have been some AEs potentially related 
to syncope (e.g., dizziness, orthostatic hypotension). Overall, there have been no clinically 
relevant findings involving vital signs or ECGs, with the exception of some decreases in the 
mean RR interval observed in the verdiperstat 600-mg BID group in the safety/tolerability study 
conducted in participants with Parkinson’s disease [17].  
In the clinically concluded Phase 1 study (BHV3241-101), the effect of verdiperstat on ECG 
parameters was evaluated in 14 healthy volunteers.  Preliminary analyses of continuous ECG 
recordings (Holter monitors) demonstrated that verdiperstat may have had an effect on heart rate, 
but no clinically relevant effects on the QTcF, PR, or QRS intervals.  
In the ongoing, blinded Phase 3 study in subjects with MSA (BHV3241-301) and Phase 2/3 
study in subjects with ALS, cardiovascular events have been reported. Independent Data 
Monitoring Committees are responsible for reviewing unblinded study data from each study on a 
regular basis in order to safeguard the interests of the enrolled study subjects and for monitoring 
the benefit-risk profile of the blinded clinical study. 
 
In aggregate, the clinical data do not show clear evidence of significant cardiovascular 
abnormalities associated with administration of verdiperstat ER formulations. However, an effect 
of verdiperstat cannot be ruled out, and cardiovascular TEAEs and parameters, including vital 
signs and ECGs, will continue to be monitored in this study. 
 
5.9.1.4 Liver 
Minimally non-adverse, increased alanine aminotransferase and slight (adaptive) 
histopathological effects in the liver were observed in rats during the preclinical studies; these 
are likely related to enzyme induction (e.g., CYP2B1 induction). In the MAD study [18], several 
participants, including those receiving verdiperstat and placebo, had increases in hepatic 
transaminases.  
In the ongoing, blinded Phase 3 study in subjects with MSA (BHV3241-301), preliminary data 
indicate that 4 subjects (1.2%) discontinued the study due to elevations in liver enzymes.  Of 
these, 3 subjects had elevations 5x upper limit of normal.  All 4 subjects were asymptomatic, and 
the elevations in liver enzymes were isolated without increased bilirubin levels.  Elevated levels 
returned to normal in a few weeks. 

 
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In aggregate, the clinical data show a possible association of asymptomatic and reversible liver 
enzyme increases with verdiperstat. The present study will involve monitoring of liver function 
tests. 
5.9.2 Known Potential Benefits 
The rationale for the proposed study is based on cumulative preclinical and clinical studies that 
implicate MPO activity in the onset and progression of neurodegenerative diseases and suggest 
treatment with verdiperstat has the potential to reduce oxidative stress and neuroinflammation 
(microglial activation). 
 
 
 
 
 
 

 
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6 
REGIMEN SCHEDULE  
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 
• Blood samples for PK and PD analyses  
• Smartphone installation and removal 
• Voice recording 
 
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).  
 
Details on collection of the CNS Bulbar Function Scale, dispensing IP during remote visits, and 
documenting subjects’ willingness to participate in OLE are described in the MOP. 
 
Blood samples for PK and PD analyses and the Week 8 ECG (Week 8 only) 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.  
 

 
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6.1 
Placebo-Controlled Period 
6.1.1  Verdiperstat Regimen Specific Screening Visit 
This visit will take place in-person after the Master Protocol randomization to a regimen. There 
are no additional procedures specific for the verdiperstat RSA other than what is being done at 
the Master Protocol. 
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 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. 
 
 
6.1.2 Baseline Visit 
This visit will take place in-person after the Regimen-Specific Screening Visit. The following 
procedures will be performed for the regimen schedule: 
 
• ALSAQ-40 
• CNS Bulbar Function Scale  
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Install Smartphone App 
• Home Spirometry 
• Voice Recording 
• Dispense IP 
• Remind participant to bring IP to the next visit 
 
After all Baseline procedures are completed, administer a single 300 mg tablet of verdiperstat or 
placebo. Participants should stay at the clinic for approximately 30 minutes for observation. 

 
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Participants should be instructed: 
• To ingest either 300 mg QD of BHV-3241 or matching placebo QD for the rest of Week 1. 
• To ingest either 300 mg BID of BHV-3241 or matching placebo BID starting at the 
beginning of Week 2.  
• Participants should take the study drug twice a day; dosing in the morning and evening 
approximately 12 hours apart.  
6.1.3 Week 2 Telephone Visit  
This visit (via telephone) will take place 14 ± 3 days after the baseline Visit. The following 
procedures will be performed for the regimen schedule: 
• Collection of concomitant medication information. 
• An assessment of compliance (i.e. whether participant has stopped taking study drug) and 
tolerance to this dose titration schedule. 
• If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the titration 
schedule may be modified (see Section 5.3.2). 
• Participants should be instructed: 
• Starting at the beginning of Week 3, to ingest either 600 mg BID of verdiperstat or 
matching placebo BID and continue taking this dosage through the remainder of the 24-
week Treatment Period. 
 
6.1.4 Week 4 Visit 
Participants should be instructed to skip 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. 
 
This visit will take place in-person 28 ± 7 days after the Baseline Visit. The following 
procedures will be performed for the regimen schedule: 
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice Recording 
• Dispense IP 
• Remind participant to bring study drug to the next visit 
 
6.1.5 Week 8 Visit  
Participants should be instructed to skip 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. 
 

 
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This visit will take place in-person 56 ± 7 days after the Baseline Visit.  The following 
procedures will be performed for the regimen schedule: 
• Home Spirometry 
• CNS Bulbar Function Scale  
• 12-Lead ECG 
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice recording  
• Dispense IP 
• Remind participant to bring IP 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.  
6.1.7 Week 16 Visit  
Participants should be instructed to skip 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. 
 
This visit will take place in-person 112 ± 7 days after the Baseline Visit. The following 
procedures will be performed: 
 
• 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. 
• Home Spirometry  
• CNS Bulbar Function Scale 
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice Recording 
• Dispense IP 
• Remind participant to bring IP 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. 

 
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6.1.9 Week 24 Visit or Early Termination Visit 
Participants should be instructed to skip 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. 
 
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 for the 
regimen schedule: 
 
• Home Spirometry 
• ALSAQ-40 
• CNS Bulbar Function Scale  
• Collection of plasma samples for verdiperstat PD biomarkers (MPO protein and activity) and 
a plasma PK sample 
• Voice Recording 
• Uninstall Smartphone App 
• Dispense IP (only if continuing in OLE) 
• Remind participant to bring IP to the next visit  
 
For participants rolling into the OLE, all participants should be instructed to follow the dose 
escalation scheme. 
• After all Week 24 procedures are completed, administer a single 300 mg tablet of 
verdiperstat. Participants should stay at the clinic for approximately 30 minutes for 
observation. 
• Dispense study drug to last for the next 4 weeks. 
• Participants should be instructed: 
• To ingest 300 mg QD of BHV-3241 for the rest of Week 1. 
• To ingest 300 mg BID of BHV-3241 starting at the beginning of Week 2. Participants 
should take the study drug twice a day; dosing in the morning and evening approximately 
12 hours apart. 
• If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the 
titration schedule may be modified (see Section 5.3.2). 
• To ingest 600 mg BID of BHV-3241 starting at the beginning of Week 3 and through the 
remainder of the 52-week OLE. Participants should take the study drug twice a day; 
dosing in the morning and evening approximately 12 hours apart. 
 
For participants NOT rolling into the OLE: 
A Follow-up Safety Call should be scheduled approximately 28 days after last dose of study drug 
to collect clinical status information. 

 
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6.1.10 Follow-Up Safety Call 
Participants will have a Follow-Up Safety Call 28+7 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 per ITT 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. 
The Follow-Up Safety Call should be completed approximately 28±7 days after the last dose of 
study drug.  If the participant terminates early during the OLE period, all assessments that are 
intended for collection at the OLE Week 24 in-clinic visit should be conducted. The Follow-Up 
Safety Call should be completed approximately 28±7 days after the last dose of IP. 
 
If the Early Termination Visit occurs approximately 28±7 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 28±7 days of the last dose of study drug, the Follow-Up 
Safety Call should occur approximately 28±7 days after the last dose of study drug and the Early 
Termination Visit will be completed after the Follow-Up Safety Call.   
6.1.12 Criteria for Participant Termination 
Participants MUST discontinue the IP (and non-investigational product at the discretion of the 
SI) for any of the following reasons: 
•  Withdrawal of informed consent (participant’s decision to withdraw for any reason) 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the SI or sponsor, indicates that continued participation in the study is not in the 
best interest of the participant 

 
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• Disease progression, which, in the opinion of the SI or sponsor, indicates that continued 
participation in the study is not in the best interest of the participant 
• Pregnancy 
• Termination of the study by the Sponsor 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
All participants who discontinue study treatment earlier than Week 24 should comply with 
protocol specified Early Termination procedures as appropriate, outlined in the Schedule of 
Activities.  
An exception to the requirement for End of Treatment procedures is when a participant 
withdraws consent for all study procedures or loses the ability to consent freely (i.e., is 
imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or physical 
illness).  
6.2 
Open Label Extension (OLE) 
Participants who have completed the placebo-controlled portion of the trial on drug, will be 
eligible to continue in the Open Label Extension.  The OLE of the study will continue until 
verdiperstat is approved and available in the United States, or Biohaven Pharmaceuticals 
terminates development of verdiperstat 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 Manaul of Procedures.  
 
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 (Week 8 and 16 only).  
 

 
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Blood samples for Week 16  PK and PD analysis and the Week 4 and 28 ECGs 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 Telephone Visit - OLE 
This visit (via telephone) will take place 14 ± 3 days after the Week 24 visit. The procedures 
listed in the SoA should be performed including: 
• Assess and document AEs and concomitant medications, including Key Study Events 
(see section 10.3 of Master Protocol) 
• Assess compliance and tolerance to this dose titration schedule  
• If tolerability issues are experienced with 300 mg QD or 300 mg BID dosing, the 
titration schedule may be modified (see Section 5.3.2). 
• Instruct participants on appropriate dosing  
• Starting at the beginning of Week 3, to ingest 600 mg BID of verdiperstat and 
continue taking this dose through the remainder of the 52-week OLE 
• Remind participant to bring in IP to the next visit  
6.2.2 Week 4 Visit – OLE 
This visit will take place in-person 28 ± 10 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 4 weeks of drug and instructions for dosing.  
6.2.3 Week 8 Visit - OLE 
This visit will take place in-person 56 ± 7 days after the Week 24 Visit of the placebo-controlled 
portion of the trial. The procedures listed in the SoA should be performed and participants should 
be provided with 8 weeks of drug and instructions for dosing.  
6.2.4 Week 12 Telephone Visit – OLE 
This visit will take place 84 ± 3 days after the Week 24 Visit of the placebo-controlled portion of 
the trial via telephone. The procedures listed in the SoA should be performed. 
 
6.2.5 Week 16 Visit – OLE 
Participants should be instructed to skip 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. 
 

 
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This visit will take place in-person 112 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 12 weeks of drug and instructions for dosing.  
 
6.2.6 Week 20 Telephone Visit – OLE 
This visit will take place in-person 140 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed. 
 
6.2.7 Week 24 Telephone Visit – OLE 
This visit will take place 196 ± 3 days after the Week 24 Visit of the placebo-controlled portion 
of the trial via telephone. The procedures listed in the SoA should be performed. 
 
6.2.8 Week 28 Visit and Q12 Weeks – OLE 
Participants should be instructed to skip 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. 
 
This visit will take place in-person 196 ± 14 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The procedures listed in the SoA should be performed and 
participants should be provided with 8 weeks of drug and instructions for dosing. Following the 
Week 28 OLE Visit, visit will occur every 12 weeks ± 14 days. 
 
 
 

 
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7 
OUTCOME MEASURES AND ASSESSMENTS 
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 participants 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. 
 

 
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Instructions on administering the questionnaire during a phone or telemedicine visit will be 
included in the MOP. 
 
7.4 Home Spirometry 
Remote/home-based forced vital capacity 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 at home 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.   
 
8 
BIOFLUID COLLECTION 
8.2 Pharmacokinetic Assessments  
Blood samples for PK analysis should be collected at Baseline and Weeks 4, 8, 16, and 24 in the 
Treatment Phase, and at Weeks 16, 28, and 52 for participants who are in the OLE. Participants 
who discontinue early from study medication are not required to have PK samples collected at 
the early discontinuation visit. 
A PK sample should be collected pre-dose at the Baseline visit. 
At Weeks 4, 8, 16, and 24 in the Treatment Phase, and at Weeks 4, 16, 28, 40, and 52 in the 
OLE, the morning dose of study drug should be held and administered in the clinic/office during 
the study visit, so that one pre-dose (trough) PK sample can be collected. For each sample, the 
time of the last dose of study drug prior to sample collection, time of the last meal, and time of 
collection of the PK samples should be reported on the CRF.  
8.3 Pharmacodynamic Biomarker Assessments   
Blood samples for PD biomarker analysis and verdiperstat-specific PD analysis should be 
collected at Baseline and Weeks 4, 8, 16, and 24 in the Treatment Phase, and at Weeks 16, 28 
and 52 for participants who are in the OLE. Participants who discontinue early from study 
medication are not required to have PD samples collected at the early discontinuation visit.  
PD biomarkers should be collected along with the PK samples, so that one pre-dose PD sample 
is collected at each specified visit. For each sample, the time of the last dose of study drug prior 
to sample collection and time of the PD sample collection should be reported on the CRF. The 
verdiperstat-specific PD biomarkers that will be analyzed are MPO protein and MPO activity. 
Uric Acid will be collected and results remain blinded throughout the duration of the trial 
 
 

 
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9 
SAFETY AND ADVERSE EVENTS 
9.1 
Adverse Events of Special Interest – Thyroid Function 
Reversible changes in thyroid function tests were observed during the preclinical studies and 
clinical studies with verdiperstat. Based on prior trials, a small percentage of participants may be 
expected to develop mild (subclinical) hypothyroidism generally with serum TSH < 10 mIU/L. 
Laboratory monitoring of thyroid function will be performed and documented throughout this 
study. Site Investigators should review TSH levels and note the trend over time. The Central 
Laboratory will flag any TSH > ULN, and T3 and free T4 analysis should be performed.  
Any significant abnormal findings should be discussed with the study Medical Monitor and may 
be followed up as per local practice (e.g., investigations and consultation with endocrinologist). 
In cases of suspected hypothyroidism, repeat thyroid function tests should be measured and 
levothyroxine replacement therapy should be considered. Initiation of treatment is at the 
discretion of the SI.  
Potential initiation of levothyroxine (T4) replacement therapy may be considered according to 
the following guidelines: 
• For a serum TSH between 5 and 10, levothyroxine 0.05 mg daily (50 mcg) is a 
reasonable dose to prescribe. 
• For a serum TSH between 10 and 20, levothyroxine 0.075 mg daily (75 mcg) is a 
reasonable dose to prescribe. 
• For a serum TSH greater than 20, many physicians would feel more comfortable having 
an endocrinologist treat such participants.  
 
If signs/symptoms of hypothyroidism (i.e. adverse event, initiation of levothyroxine) and/or 
significant changes in thyroid function develop, collection of follow up clinical chemistry 
samples and/or unscheduled study visits may be warranted. It is recommended to wait for 5 or 6 
half-lives (5 – 6 weeks) to retest thyroid function. Serum T3, free T4 and TSH should be 
monitored in such participants, and the serum TSH assesses whether therapy is adequate. 
If there are clinically significant issues with tolerability that are not able to be treated adequately 
with levothyroxine replacement therapy, the SI may consider modifications to the dosage 
regimen. Consultation with the Medical Monitor is required. Modifications may include reducing 
the dose of verdiperstat /matching placebo to 300 mg BID or taking a dose holiday. Any such 
modifications to the dosage regimen should be noted in the CRF. 

 
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10 REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS 
10.1 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. As such, unless this regimen is stopped early for 
futility, it will enroll to the maximum sample size. At the final analysis, the treatment will be 
considered success relative to the shared control group if the posterior probability of superiority 
is greater than 98.0%. This value was selected by simulation to control the overall one-sided 
Type I error rate across the null scenarios to less than 2.5%. Results are based on 5000 
simulations per scenario. 
10.2 Regimen Specific Operating Characteristics 
Clinical trial simulation is used to quantify operating characteristics for this regimen given the 
difference from the default design. The simulation of virtual participants and the simulation 
scenarios are as described in Appendix I to the master protocol. We present here the operating 
characteristics for the regimen, according to the default design but with no opportunity to stop 
early for success. Futility is considered non-binding and as such, Table 10.2.1 shows null 
hypothesis scenarios and resulting Type I error with no futility stopping. We show null and 
alternative hypothesis scenarios inclusive of futility stopping in Tables 10.2.2 and 10.2.3. Table 
10.2.2 shows operating characteristics under the base case assumptions and Table 10.2.3 shows 
operating characteristics for the various sensitivity scenarios.  
This regimen will be one of the first three regimens to be enrolled in the platform and so there 
are no participants in the shared control from regimens already complete. The comparison to 
control will rely entirely upon concurrently randomized controls.  Concurrently randomized 
controls will be defined according to Appendix I to the master protocol. 
Table 10.2.1: Null Hypothesis Scenarios with No Early Futility Stopping 
Sensitivity 
Scenario 
Mean 
Duration 
(Months) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Null Treatment Effect (0% Slowing; Mort HR = 1.0) 
Base 
15 
160 
0.000 
0.020 
0.000 
1.007 
Slower Accrual 
27 
160 
0.000 
0.023 
0.000 
1.007 
Faster Accrual 
11 
160 
0.000 
0.023 
0.000 
1.008 
Less Dropout 
15 
160 
0.000 
0.021 
0.000 
1.006 
More Dropout 
15 
160 
0.000 
0.023 
0.000 
1.007 
Reg. Start Same 
Time 
18 
160 
0.000 
0.025 
0.000 
1.005 

 
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Table 10.2.1: Null Hypothesis Scenarios with No Early Futility Stopping 
Sensitivity 
Scenario 
Mean 
Duration 
(Months) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Reg. Start 3 
Months Apart 
11 
160 
0.000 
0.025 
0.000 
1.017 
ALSFRS-R 
Slower Less 
Var. Progress 
15 
160 
0.000 
0.022 
0.000 
1.006 
ALSFRS-R 
Faster More Var. 
Progress 
15 
160 
0.000 
0.022 
0.000 
1.007 
ALSFRS-R 
Lower Resid. 
Error 
15 
160 
0.000 
0.024 
0.000 
1.006 
ALSFRS-R 
Higher Resid. 
Error 
15 
160 
0.000 
0.022 
0.000 
1.007 
10% Mortality 
Rate 
15 
160 
0.000 
0.025 
0.000 
1.005 
20% Mortality 
Rate 
15 
160 
0.000 
0.023 
0.000 
1.006 
  
Table 10.2.2: Base Scenarios Operating Characteristics. Null and Alternative Hypotheses 
With Futility Stopping 
Scenario 
(% Slowing 
ALSFRS-R) 
HR 
Mort. 
Mean 
Duration 
(Months
) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. 
Total 
Success 
Prob. 
Early 
Futility 
Mean 
DRR 
0% 
1 
14 
155 
0.000 
0.020 
0.290 
1.049 
25% 
.75 
15 
160 
0.000 
0.615 
0.008 
0.747 
30% 
.7 
15 
160 
0.000 
0.776 
0.002 
0.694 
35% 
.65 
15 
160 
0.000 
0.888 
0.001 
0.642 
30% 
1 
15 
160 
0.000 
0.731 
0.003 
0.708 
30% 
1.3 
15 
160 
0.000 
0.683 
0.004 
0.722 
 
 

 
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Table 10.2.3: Base and Sensitivity Scenarios with Early Futility Stopping.  
Sensitivity 
Scenario 
Mean 
Duration 
(Months
) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Null Treatment Effect (0% Slowing; Mort HR = 1.0) 
Base 
14 
155 
0.000 
0.020 
0.290 
1.049 
Slower 
Accrual 
23 
143 
0.000 
0.023 
0.347 
1.063 
Faster Accrual 
11 
160 
0.000 
0.023 
0.257 
1.034 
Less Dropout 
14 
155 
0.000 
0.021 
0.280 
1.047 
More Dropout 
14 
155 
0.000 
0.023 
0.271 
1.047 
Reg. Start 
Same Time 
16 
154 
0.000 
0.025 
0.281 
1.035 
Reg. Start 3 
Months Apart 
10 
160 
0.000 
0.025 
0.219 
1.043 
ALSFRS-R 
Slower Less 
Var. Progress 
14 
155 
0.000 
0.022 
0.283 
1.049 
ALSFRS-R 
Faster More 
Var. Progress 
14 
155 
0.000 
0.022 
0.300 
1.047 
ALSFRS-R 
Lower Resid. 
Error 
14 
155 
0.000 
0.024 
0.295 
1.046 
ALSFRS-R 
Higher Resid. 
Error 
14 
155 
0.000 
0.022 
0.284 
1.050 
10% Mortality 
Rate 
14 
155 
0.000 
0.025 
0.286 
1.046 
20% Mortality 
Rate 
14 
155 
0.000 
0.023 
0.294 
1.046 
Alternative Common Treatment Effect (30% Slowing; Mort HR = .70) 
Base 
15 
160 
0.000 
0.776 
0.002 
0.694 
Slower 
Accrual 
27 
160 
0.000 
0.771 
0.005 
0.695 
Faster Accrual 
11 
160 
0.000 
0.762 
0.002 
0.694 
Less Dropout 
15 
160 
0.000 
0.745 
0.003 
0.694 
More Dropout 
15 
160 
0.000 
0.722 
0.003 
0.694 
Reg. Start 
Same Time 
18 
160 
0.000 
0.782 
0.002 
0.691 

 
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Table 10.2.3: Base and Sensitivity Scenarios with Early Futility Stopping.  
Sensitivity 
Scenario 
Mean 
Duration 
(Months
) 
Mean 
N 
  
Prob.  
Early 
Success 
Prob. Total 
Success 
Prob. 
Early 
Futility 
Mean DRR 
Reg. Start 3 
Months Apart 
11 
160 
0.000 
0.681 
0.003 
0.700 
ALSFRS-R 
Slower 
Progress 
15 
160 
0.000 
0.754 
0.003 
0.693 
ALSFRS-R 
Faster 
Progress 
15 
160 
0.000 
0.791 
0.002 
0.694 
ALSFRS-R 
Lower Resid. 
Error 
15 
160 
0.000 
0.793 
0.003 
0.692 
ALSFRS-R 
Higher Resid. 
Error 
15 
160 
0.000 
0.758 
0.003 
0.694 
10% Mortality 
Rate 
15 
160 
0.000 
0.782 
0.003 
0.693 
20% Mortality 
Rate 
15 
160 
0.000 
0.799 
0.003 
0.695 
Alternative Treatment Effect No Mort. Benefit (30% Slowing; Mort HR = 1.0) 
Base (5% 
Mort. Rate) 
15 
160 
0.000 
0.731 
0.003 
0.708 
10% Mort. 
Rate 
15 
160 
0.000 
0.695 
0.004 
0.721 
20% Mort. 
Rate 
15 
160 
0.000 
0.602 
0.007 
0.749 
Alternative Treatment Effect Worse Mort. (30% Slowing; Mort HR = 1.3) 
Base (5% 
Mort. Rate) 
15 
160 
0.000 
0.683 
0.004 
0.722 
10% Mort. 
Rate 
15 
160 
0.000 
0.592 
0.008 
0.750 
20% Mort. 
Rate 
15 
160 
0.000 
0.411 
0.015 
0.803 
  

 
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10.3  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.   
 

 
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11 REFERENCES 
1. Lefkowitz, D.L., and Lefkowitz, S.S. (2008). Microglia and myeloperoxidase: a deadly 
partnership in neurodegenerative disease. Free Radic Biol Med 45, 726-731. 
2. Pravalika, K., Sarmah, D., Kaur, H., Wanve, M., Saraf, J., Kalia, K., Borah, A., Yavagal, 
D.R., Dave, K.R., and Bhattacharya, P. (2018). Myeloperoxidase and Neurological Disorder: 
A Crosstalk. ACS Chem Neurosci 9, 421-430. 
3. Biohaven Pharmaeuticals Inc. Investigator Brochure Verdiperstat, Edition 3.0, March 2021. 
4. Singh, A., Kukreti, R., Saso, L., and Kukreti, S. (2019). Oxidative Stress: A Key Modulator 
in Neurodegenerative Diseases. Molecules 24. 
5. Casas, A.I., Dao, V.T., Daiber, A., Maghzal, G.J., Di Lisa, F., Kaludercic, N., Leach, S., 
Cuadrado, A., Jaquet, V., Seredenina, T., et al. (2015). Reactive Oxygen-Related Diseases: 
Therapeutic Targets and Emerging Clinical Indications. Antioxidants & redox signaling 23, 
1171-1185. 
6. van der Vliet, A., Eiserich, J.P., Halliwell, B., and Cross, C.E. (1997). Formation of reactive 
nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional 
mechanism of nitric oxide-dependent toxicity. The Journal of biological chemistry 272, 
7617-7625. 
7. Seredenina, T., Nayernia, Z., Sorce, S., Maghzal, G.J., Filippova, A., Ling, S.C., Basset, O., 
Plastre, O., Daali, Y., Rushing, E.J., et al. (2016). Evaluation of NADPH oxidases as drug 
targets in a mouse model of familial amyotrophic lateral sclerosis. Free Radic Biol Med 97, 
95-108. 
8. Beers, D.R., and Appel, S.H. (2019). Immune dysregulation in amyotrophic lateral sclerosis: 
mechanisms and emerging therapies. Lancet Neurol 18, 211-220. 
9. Hammond, T.R., Marsh, S.E., and Stevens, B. (2019). Immune Signaling in 
Neurodegeneration. Immunity 50, 955-9. 
10. Chew, S., and Atassi, N. (2019). Positron Emission Tomography Molecular Imaging 
Biomarkers for Amyotrophic Lateral Sclerosis. Front Neurol 10, 135. 
11. BHV3241-103. BHV3500-103. A Phase1, Open-Label, Drug Interaction Study to Evaluate 
the Effect of Fluvoxamine on the Pharmacokineticsof Single-Dose 
VerdiperstatAdministeredas anExtended Release Tablet in Healthy Adult Subjects: Biohaven 
Pharmaceuticals, Inc.; in reporting. 
12. BHV3241-107. A Phase1, Open-Label,Drug Interaction Study to Evaluate the Effect of 
Itraconazoleon the Pharmacokineticsof Single-Dose Verdiperstat Administered as an 
Extended Release Tablet in Healthy Adult Subjects: Biohaven Pharmaceuticals, Inc.; in 
reporting. 
13. BHV3241-106. A Phase 1, Open-Label, Drug Interaction Study to Evaluate the Effect of 
Multiple-Dose Verdiperstat Administeredas an Extended Release Tablet on the 
Pharmacokinetics of Midazolam, a Sensitive CYP3A4 Substrate, in Healthy Adult Subjects: 
Biohaven Pharmaceuticals, Inc.; in reporting. 
14. Study 3210-1088-1800. AZD3241: In Vitro Assessment of the Induction Potential of 
AZD3241 in Primary Human Hepatocyte Cultures: AstraZeneca; 2009. 
15. D0490C00001. A First Time in Man, Single-Centre, Placebo Controlled, Randomized, 
Double-blind (within dose panel) Study in Healthy Volunteers to Evaluate Safety, 

 
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Tolerability and Pharmacokinetics after Oral Single Ascending Doses of AZD3241: 
AstraZeneca; 2007. 
16. D0490C00012. A Single-Centre, Placebo-Controlled, Randomised, Double-Blind Study to 
Evaluate the Safety, Tolerability and Pharmacokinetics of AZD3241 following 
Administration of Single Ascending (Part A) and Fractionated Ascending (Part B) Oral 
Doses to Young Healthy Volunteers: AstraZeneca; 2009. 
17. D0490C00005. A Phase IIa, 12 Week, Multicentre, Double-Blind, Randomized, Placebo 
Controlled, Parallel-Group Study to Assess the Safety and Tolerability of Oral AZD3241 in 
Patients with Parkinson’s Disease: AstraZeneca; 2014. 
18. D0490C00002. A Phase I, Single Centre, Double-blind, Randomised, Placebo-controlled, 
Parallel-group Study to Assess the Safety, Tolerability and Pharmacokinetics of Extended 
Release Tablets of AZD3241 after Administration of Multiple Ascending Doses in Healthy 
Male and Female Volunteers including the Effect of Food: AstraZeneca; 2010. 
 
 
 

 
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Appendix I: 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. 
 
 
 
 
 
 

 
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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. 
 
 
 
 
 
 
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. 
 
 
 
 
 

 
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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: _____ 
 
 
 
 
 
 
 

 
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Appendix II: The ALSAQ-40  
 

 
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