A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH)
Phase: PHASE3
Conditions: Facioscapulohumeral Muscular Dystrophy (FSHD)
Sponsor: Fulcrum Therapeutics

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CLINICAL STUDY PROTOCOL 
IND: 138739 
EUDRACT: 2022-000389-16 
A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled, 48-Week, 
Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating 
Patients with Facioscapulohumeral Muscular Dystrophy (REACH) 
PROTOCOL 1821-FSH-301 
Sponsor: 
Fulcrum Therapeutics 
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Sponsor Contact: 
, MD 
Vice President, Clinical Development, Neuromuscular 
Fulcrum Therapeutics 
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Telephone: 617-678-4980 
Version of Protocol:  
Version 5.1  
Date of Protocol:  
21 December 2023 
Compound Name: 
Losmapimod  
Study Phase: 
Phase 3 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Fulcrum Therapeutics. The 
concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without the express written consent of Fulcrum 
Therapeutics. The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R2): Good Clinical Practice. 

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PROTOCOL APPROVAL – SPONSOR SIGNATORY 
Study Title 
A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled, 
48-Week, Parallel-Group Study of the Efficacy and Safety of 
Losmapimod in Treating Patients with Facioscapulohumeral Muscular 
Dystrophy (FSHD) (REACH) 
Protocol Number and 
Version 
1821-FSH-301, Version 5.1 
Protocol Date  
21 December 2023  
Protocol accepted and approved by: 
Name and Title 
Signature 
Date 
, PhD 
Vice President, Biometrics 
Fulcrum Therapeutics, Inc. 
 
 
, MD 
Vice President, Clinical 
Development, 
Neuromuscular 
Fulcrum Therapeutics, Inc. 
 
 
, MD 
Executive Medical Director, 
Drug Safety and PV Medical 
Sciences 
Fulcrum Therapeutics, Inc. 
 
 
 
 
12/21/2023
12/21/2023
12/21/2023

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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol entitled “A Phase 3 Global, Randomized, 
Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of 
Losmapimod in Treating Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) 
(REACH)” and the current losmapimod Investigator’s Brochure. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 5.1, dated 21 December 2023, the International 
Council for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice and 
all applicable government regulations. I will not make changes to the protocol before consulting 
with Fulcrum Therapeutics or implement protocol changes without independent ethics committee 
approval except to eliminate an immediate risk to subjects. I agree to administer study treatment 
only to subjects under my personal supervision or the supervision of a subinvestigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Subject identity will not be disclosed to third parties or appear 
in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Fulcrum Therapeutics. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 

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SUMMARY OF CHANGES TO THE PROTOCOL 
The previous version of this protocol (Version 4.0, 01 March 2023) was amended to create the 
current version (Version 5.1, 21 December 2023). The protocol history is below: 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 17 February 2022 
Original version 
Version 2.0, 03 March 2022 
Global amendment 
Version 3.0, 08 August 2022 
Global amendment 
Version 4.0, 01 March 2023 
Global amendment  
Version 5.1, 21 December 2023 
Global amendment 
 
Country/region-specific differences are defined in Appendix 2 and cross-referenced throughout. 
Key changes made in the current version of the protocol are summarized below.   
Typographical and administrative changes were also made to improve the clarity of the 
document. 
Change and Rationale 
Affected Sections  
Study objectives and endpoints for Part A were updated; primary 
endpoint will assess RSA as the average of both arms instead of 
dominant arm only and an exploratory endpoint was added to 
assess RSA in dominant or non-dominant arms separately. This 
change was made to provide a more robust assessment of 
shoulder mobility. Shoulder strength assessed by hand-held 
quantitative dynamometry was changed from an exploratory to a 
secondary endpoint. Statistical analyses were updated as 
appropriate.  
Synopsis, Section 2.1, Section 
9.1 
Oral CYP3A4, OAT3, and MATE substrates are no longer 
systematically prohibited as concomitant medications. This 
change is based on the results of the recently completed drug-
drug interaction study (1821-CLP-102). Only those concomitant 
medications that are substrates of OAT1/OAT3 and have a 
narrow therapeutic index may need to have their blood levels 
monitored when coadministered with losmapimod.  
The following changes were made:  
• 
Background sections were updated (Section 1.3.4) 
• 
Exclusion criteria were updated for Part A (EC #3 and 
#4) and for Part B (EC #2) (Section 4.1) 
• 
Concomitant medications were updated (Section 5.8) 
• 
Contraception guidelines were updated; oral combined 
Section 1.3.4, Section 4.1, 
Section 5.5, Section 5.5.1, 
Section 5.8, Appendix 4 

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Change and Rationale 
Affected Sections  
hormonal methods are now allowed (Section 5.5.1).  
• 
List of CYP3A4, OAT1, and OAT3 substrates in 
Appendix 3 was deleted and a list of OAT1/OAT3 
substrates with narrow therapeutic index (NTI) was 
added as a new Appendix 4. 
• 
Lifestyle restrictions were updated; subjects no longer 
have to avoid nutrients known to modulate CYP enzyme 
activity (Section 5.5).  
Clarified the study duration of Part B (OLE). The OLE will last 
for approximately 2 years, according to the visits defined in the 
OLE schedule of assessments (Table 8). Any plans to extend the 
study duration will be executed in a future amendment. The 
phrase “until after commercial drug is available post regulatory 
approval” was also deleted. 
Synopsis, Section 3.1, Section 
3.1.2, Appendix 1 
Added clarification for safety follow-up visits for clarity; only 
subjects that do not continue to the OLE will complete the safety 
follow-up visits in Part A. 
Synopsis, Section 3.1.1, 
Appendix 1 
Background sections were updated to align with most recent 
version of the losmapimod Investigator’s Brochure. 
Section 1.2.3, Section 1.2.4, 
Section 1.3.2 
Clarified guidance on use of statins as concomitant medications 
Section 5.8, Appendix 3 
Added clarification for direct bilirubin testing per Protocol 
Clarification Letter dated 01 Sep 2023 
Section 6.1.5 
Clarified procedures for clinically significant abnormal 
laboratory test results.  
Section 6.1.5 
Deleted incorrect statement referring to a central reader for 
electrocardiograms; a central reader is not being utilized for this 
study.  
Section 6.1.9 
Updated safety reporting information to account for a vendor 
change. 
Section 7.3.2 
Clarified adverse event follow-up procedures by removing 
redundant language   
Section 7.4 
Clarified safety procedures in the case of an overdose. 
Section 7.8.1 
Updated pregnancy testing to follow local regulations; this 
change eliminates the need for a UK-specific protocol version to 
allow for more frequent pregnancy testing. 
Section 6.1.5, Appendix 1 
Added new appendix to define any country/region-specific 
differences and allow for a harmonized protocol  
Appendix 2 

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TABLE OF CONTENTS 
PROTOCOL APPROVAL – SPONSOR SIGNATORY.............................................................. 2 
DECLARATION OF INVESTIGATOR ..................................................................................... 3 
SUMMARY OF CHANGES TO THE PROTOCOL ................................................................... 4 
TABLE OF CONTENTS ............................................................................................................ 6 
LIST OF ABBREVIATIONS.................................................................................................... 13 
PROTOCOL SYNOPSIS .......................................................................................................... 16 
1. 
BACKGROUND .................................................................................................... 22 
1.1. 
Nonclinical Studies ................................................................................................. 23 
1.2. 
Clinical Studies ....................................................................................................... 24 
1.2.1. 
Pharmacokinetics .................................................................................................... 24 
1.2.2. 
Pharmacodynamics ................................................................................................. 25 
1.2.3. 
Safety ..................................................................................................................... 26 
1.2.4. 
Efficacy .................................................................................................................. 26 
1.3. 
Benefit Risk ............................................................................................................ 28 
1.3.1. 
Identified Risks ....................................................................................................... 28 
1.3.2. 
Potential Risks ........................................................................................................ 28 
1.3.2.1. 
Hepatotoxicity ........................................................................................................ 28 
1.3.2.2. 
Immune Function .................................................................................................... 29 
1.3.3. 
Contraindications .................................................................................................... 30 
1.3.4. 
Interactions ............................................................................................................. 30 
1.3.4.1. 
Drug Interactions .................................................................................................... 30 
1.3.4.2. 
Food Interactions .................................................................................................... 31 
1.3.5. 
Other Clinically Relevant Information .................................................................... 31 
1.3.5.1. 
Effects on Serum Creatinine .................................................................................... 32 
1.3.5.2. 
Thorough QT Study ................................................................................................ 32 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 33 
2.1. 
Part A: Placebo-Controlled Treatment Period .......................................................... 33 
2.1.1. 
Primary Objective and Endpoint ............................................................................. 33 
2.1.2. 
Secondary Objectives and Endpoints ....................................................................... 33 

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2.1.3. 
Exploratory Objectives and Endpoints .................................................................... 34 
2.2. 
Part B: Open-Label Extension ................................................................................. 35 
2.2.1. 
Primary Objectives and Endpoints .......................................................................... 35 
2.2.2. 
Secondary Objectives and Endpoints ....................................................................... 35 
2.2.3. 
Exploratory Objectives and Endpoints .................................................................... 35 
3. 
INVESTIGATIONAL PLAN ................................................................................. 36 
3.1. 
Study Design .......................................................................................................... 36 
3.1.1. 
Part A: Placebo-Controlled Treatment Period .......................................................... 36 
3.1.2. 
Part B: Open-Label Extension ................................................................................. 37 
3.2. 
Rationale of Study Design ....................................................................................... 38 
3.2.1. 
Rationale of Dose Selection .................................................................................... 38 
3.2.2. 
Rationale of Study Design ....................................................................................... 38 
4. 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA......................... 41 
4.1. 
Selection of Study Participants ................................................................................ 41 
4.1.1. 
Part A: Placebo-Controlled Treatment Period .......................................................... 41 
4.1.1.1. 
Inclusion Criteria .................................................................................................... 41 
4.1.1.2. 
Exclusion Criteria ................................................................................................... 42 
4.1.2. 
Part B: Open-Label Extension ................................................................................. 44 
4.1.2.1. 
Inclusion Criteria .................................................................................................... 44 
4.1.2.2. 
Exclusion Criteria ................................................................................................... 44 
4.2. 
Rescreening of Study Participants ........................................................................... 44 
4.3. 
Withdrawal of Patients from Study Treatment and/or the Study .............................. 45 
4.3.1. 
Reasons for Withdrawal/Discontinuation ................................................................ 45 
4.3.2. 
Handling of Withdrawals ........................................................................................ 46 
4.3.3. 
Replacements .......................................................................................................... 46 
5. 
STUDY TREATMENTS ........................................................................................ 47 
5.1. 
Part A: Placebo-Controlled Treatment Period .......................................................... 47 
5.1.1. 
Method of Assigning Participants to Treatment Groups........................................... 47 
5.1.2. 
Treatments Administered ........................................................................................ 47 
5.2. 
Part B: Open-Label Extension ................................................................................. 47 

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5.2.1. 
Treatments Administered ........................................................................................ 47 
5.3. 
Identity of Investigational Product .......................................................................... 48 
5.4. 
Management of Clinical Supplies ............................................................................ 48 
5.4.1. 
Study Drug Packaging and Storage ......................................................................... 48 
5.4.2. 
Study Drug Accountability ...................................................................................... 48 
5.5. 
Lifestyle Restrictions .............................................................................................. 49 
5.5.1. 
Contraception Requirements ................................................................................... 49 
5.5.1.1. 
Highly Effective Methods for Avoiding Pregnancy in Females of Childbearing 
Potential ................................................................................................................. 49 
5.6. 
Blinding .................................................................................................................. 50 
5.6.1. 
Part A: Placebo-Controlled Treatment Period .......................................................... 50 
5.6.2. 
Part B: Open-Label Extension ................................................................................. 51 
5.7. 
Treatment Compliance ............................................................................................ 51 
5.8. 
Prior and Concomitant Therapy............................................................................... 51 
6. 
STUDY ASSESSMENTS AND PROCEDURES.................................................... 52 
6.1. 
Efficacy and Safety Assessments ............................................................................ 52 
6.1.1. 
Reachable Workspace ............................................................................................. 52 
6.1.2. 
Skeletal Muscle Magnetic Resonance Imaging ........................................................ 53 
6.1.3. 
Hand-Held Dynamometry ....................................................................................... 53 
6.1.4. 
Eliciting and Documenting Adverse Events ............................................................ 53 
6.1.5. 
Laboratory Analyses ............................................................................................... 54 
6.1.6. 
Medical History ...................................................................................................... 55 
6.1.7. 
Vital Signs .............................................................................................................. 55 
6.1.8. 
Physical Examinations ............................................................................................ 56 
6.1.9. 
Twelve-Lead Electrocardiograms ............................................................................ 56 
6.2. 
Other Assessments .................................................................................................. 56 
6.2.1. 
Genetic Confirmation of FSHD ............................................................................... 56 
6.2.5. 
Patient Global Impression of Change ...................................................................... 58 

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6.2.8. 
Neuro-QoL Upper Extremity Patient Reported Outcome ......................................... 58 
6.2.12. 
Qualitative Exit Interview ....................................................................................... 59 
6.2.14. 
Sample Collections ................................................................................................. 60 
7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................. 61 
7.1. 
Definitions .............................................................................................................. 61 
7.1.1. 
Definition of Adverse Event .................................................................................... 61 
7.1.2. 
Definition of Treatment-Emergent Adverse Event ................................................... 61 
7.1.3. 
Definition of Serious Adverse Event ....................................................................... 61 
7.1.3.1. 
Definition of Terms................................................................................................. 62 
7.1.4. 
Definition of Suspected Unexpected Serious Adverse Reaction ............................... 62 
7.1.5. 
Reference Safety Information .................................................................................. 62 
7.2. 
Classification of Adverse Events ............................................................................. 63 
7.2.1. 
Assessment of Intensity/Severity ............................................................................. 63 
7.2.2. 
Assessment of Causality ......................................................................................... 63 
7.2.3. 
Outcome ................................................................................................................. 64 
7.2.4. 
Action Taken .......................................................................................................... 64 
7.3. 
Reporting Guidelines .............................................................................................. 64 
7.3.1. 
Reporting Adverse Events ....................................................................................... 64 
7.3.2. 
Reporting Serious Adverse Events .......................................................................... 65 
7.3.3. 
Expectedness of an Adverse Event .......................................................................... 65 
7.3.4. 
Reporting Suspected Unexpected Serious Adverse Reactions .................................. 65 
7.4. 
Adverse Event Follow-up ........................................................................................ 66 
7.5. 
Adverse Events of Special Interest .......................................................................... 66 
7.6. 
Adverse Events of Significance ............................................................................... 66 

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7.7. 
Clinical Laboratory Changes ................................................................................... 67 
7.8. 
Special Situations .................................................................................................... 67 
7.8.1. 
Overdose................................................................................................................. 67 
7.8.2. 
Death ...................................................................................................................... 67 
7.8.3. 
Pregnancy ............................................................................................................... 67 
7.8.4. 
Medication Error ..................................................................................................... 68 
7.8.5. 
Unblinding Due to Medical Emergency .................................................................. 68 
8. 
INVESTIGATIONAL PRODUCT COMPLAINTS ................................................ 69 
8.1. 
Definition of Investigational Product Complaints .................................................... 69 
8.2. 
Reporting of Investigational Product Complaints .................................................... 69 
9. 
STATISTICAL CONSIDERATIONS ..................................................................... 70 
9.1. 
Part A: Placebo-Controlled Treatment Period .......................................................... 70 
9.1.1. 
Estimands and Intercurrent Events .......................................................................... 70 
9.1.2. 
Statistical Hypothesis .............................................................................................. 70 
9.1.3. 
Sample Size Determination ..................................................................................... 71 
9.1.4. 
Analysis Sets .......................................................................................................... 71 
9.1.5. 
Description of Subgroups to Be Analyzed ............................................................... 71 
9.1.6. 
Statistical Analysis Methodology ............................................................................ 71 
9.1.6.1. 
General Considerations ........................................................................................... 71 
9.1.6.2. 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity Analyses72 
9.1.6.3. 
Analysis of Primary Endpoint ................................................................................. 72 
9.1.6.4. 
Analysis of Secondary Efficacy Endpoints .............................................................. 72 
 
 
9.1.6.6. 
Pharmacokinetic Analyses ...................................................................................... 73 
9.1.6.7. 
Safety Analyses ...................................................................................................... 73 
9.1.6.8. 
Other Analyses ....................................................................................................... 73 
9.1.6.9. 
Handling of Missing Data ....................................................................................... 74 
9.1.6.10. 
Independent Data Monitoring Committee................................................................ 74 
9.2. 
Part B: Open-Label Extension ................................................................................. 74 
9.2.1. 
Statistical Hypotheses ............................................................................................. 74 

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9.2.2. 
Sample Size Determination ..................................................................................... 74 
9.2.3. 
Analysis Sets .......................................................................................................... 74 
9.2.4. 
Description of Subgroups to be Analyzed................................................................ 74 
9.2.5. 
Statistical Analysis Methodology ............................................................................ 75 
9.2.5.1. 
General Considerations ........................................................................................... 75 
9.2.5.2. 
Safety Analyses ...................................................................................................... 75 
9.2.5.3. 
Other Analyses ....................................................................................................... 75 
9.2.6. 
Handing of Missing Data ........................................................................................ 75 
9.3. 
Interim Analyses ..................................................................................................... 76 
10. 
DATA QUALITY ASSURANCE ........................................................................... 77 
10.1. 
Data Management ................................................................................................... 77 
11. 
ETHICS .................................................................................................................. 78 
11.1. 
Independent Ethics Committee or Institutional Review Board ................................. 78 
11.2. 
Ethical Conduct of the Study ................................................................................... 78 
11.3. 
Patient Information and Consent ............................................................................. 78 
12. 
INVESTIGATOR’S OBLIGATIONS ..................................................................... 80 
12.1. 
Confidentiality ........................................................................................................ 80 
12.2. 
Financial Disclosure and Obligations ...................................................................... 80 
12.3. 
Investigator Documentation .................................................................................... 80 
12.4. 
Study Conduct ........................................................................................................ 81 
12.5. 
Adherence to Protocol ............................................................................................. 81 
12.6. 
Adverse Events and Study Report Requirements ..................................................... 81 
12.7. 
Investigator’s Final Report ...................................................................................... 81 
12.8. 
Records Retention ................................................................................................... 82 
12.9. 
Publications ............................................................................................................ 82 
13. 
STUDY MANAGEMENT ...................................................................................... 83 
13.1. 
Monitoring .............................................................................................................. 83 
13.1.1. 
Sponsor Safety Review ........................................................................................... 83 
13.1.2. 
Monitoring of the Study .......................................................................................... 83 
13.1.3. 
Inspection of Records.............................................................................................. 83 

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13.2. 
Management of Protocol Amendments and Deviations............................................ 83 
13.2.1. 
Modification of the Protocol ................................................................................... 83 
13.2.2. 
Protocol Deviations ................................................................................................. 84 
13.3. 
Study Termination .................................................................................................. 84 
13.4. 
Final Report ............................................................................................................ 85 
14. 
REFERENCES ....................................................................................................... 86 
APPENDIX 1. SCHEDULES OF ASSESSMENTS ............................................................... 90 
APPENDIX 2. COUNTRY/REGION-SPECIFIC DIFFERENCES ......................................... 96 
APPENDIX 3. DRUGS POTENTIALLY AFFECTING MUSCLE FUNCTION .................... 97 
APPENDIX 4. LIST OF OAT1/OAT3 SUBSTRATES WITH A NARROW THERAPEUTIC 
INDEX ................................................................................................................... 98 
 
LIST OF TABLES 
Table 1: 
Primary Objective and Endpoint (Part A) ................................................................ 33 
Table 2: 
Secondary Objectives and Endpoints (Part A) ......................................................... 33 
Table 3: 
Exploratory Objectives and Endpoints (Part A) ....................................................... 34 
Table 4: 
Primary Objectives and Endpoints (Part B) ............................................................. 35 
Table 5: 
Exploratory Objectives and Endpoints (Part B) ....................................................... 35 
Table 6: 
Protocol-Required Laboratory Tests ....................................................................... 54 
Table 7: 
Part A: Placebo-Controlled Treatment Period Schedule of Assessments.................. 90 
Table 8: 
Part B: Open-Label Extension Schedule of Assessments ......................................... 94 
LIST OF FIGURES 
Figure 1: 
Study Schematic ..................................................................................................... 36 
 
 
 
 

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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
3D 
3-dimensional 
ACS 
acute coronary syndrome 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
Cmax 
maximum plasma concentration 
COA 
clinical outcome assessments 
CYP 
cytochrome P450 
DILI 
drug-induced liver injury 
DUX4 
double homeobox 4 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMEA 
Europe, Middle East, and Africa 
 
 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSHD 
facioscapulohumeral muscular dystrophy 
FSHD1 
facioscapulohumeral muscular dystrophy type 1 
FSHD2 
facioscapulohumeral muscular dystrophy type 2 
GCP 
Good Clinical Practice 
HSP27 
heat shock protein 27 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 

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Abbreviation 
Definition 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IPC 
investigational product complaint 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
KLH 
keyhole limpet hemocyanin 
LME 
linear mixed-effects model 
LMV 
lean muscle volume 
LS 
least squares 
MAPK 
mitogen-activated protein kinase 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFF 
muscle fat fraction 
MFI 
muscle fat infiltration 
MMRM 
mixed-effects model for repeated measures 
MRI 
magnetic resonance imaging 
Neuro-QoL 
Quality of Life in Neurologic Disorders 
 
 
OAT 
organic anion transporter 
OLE 
open-label extension 
OLS 
open-label study 
PD 
pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change 
 
 
pHSP27 
phosphorylated heat shock protein 27 
PI 
Principle Investigator 
PK 
pharmacokinetic(s) 
PO 
orally 
PRO 
patient-reported outcome 
PVG 
pharmacovigilance 
Q 
quintant/quadrant 

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Abbreviation 
Definition 
QTc 
QT interval corrected  
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
RSA 
relative surface area 
RWS 
reachable workspace 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMCHD1 
structural maintenance of chromosomes flexible hinge domain 1 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TDAR 
T–cell-dependent antibody response 
TEAE 
treatment-emergent adverse event 
UE 
upper extremity 
ULN 
upper limit of normal 
WB 
whole-body 

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PROTOCOL SYNOPSIS 
Protocol Number: 
1821-FSH-301 
Title: 
A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled, 48-Week, 
Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating 
Patients with Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH) 
Sponsor: 
Fulcrum Therapeutics, Inc. 
26 Landsdowne Street, 5th Floor  
Cambridge, MA 02139 USA 
Study Phase: 
3 
Study Sites: 
Approximately 36 sites in North America and Europe 
Indication: 
FSHD 
Rationale: 
Treatment of FSHD with losmapimod has demonstrated evidence of slowing of 
disease progression and/or improvement on clinical outcome assessments in 
people living with FSHD. Nonclinical studies have shown that losmapimod 
reduces the aberrant expression of double homeobox 4 (DUX4); the underlying 
cause of FSHD. Two Phase 2 clinical studies, a 48-week randomized controlled 
study (ReDUX4, FIS-002-2019) and a 52-week open-label study (OLS, FIS-001-
2019) demonstrate evidence of benefit of treatment with losmapimod on 
structural and FSHD-relevant clinical endpoints that is recognized by patients, 
and a favorable safety and tolerability profile supporting continued development. 
Objectives: 
Part A: Placebo-Controlled Treatment Period 
Primary Objective: 
• 
To evaluate the efficacy of losmapimod for the treatment of FSHD on 
disease progression assessed by reachable workspace quantification of 
total relative surface area (RSA) Q1-Q5 with 500 g wrist weight, 
averaged over both arms  
Secondary Objectives: 
• 
To evaluate Patient Global Impression of Change (PGIC) relative to 
placebo 
• 
To evaluate efficacy of losmapimod to slow accumulation of fat in 
muscle-by-muscle fat infiltration (MFI) with whole-body (WB) 
musculoskeletal (MSK) magnetic resonance imaging (MRI) relative to 
placebo 
• 
To evaluate relative change from baseline in shoulder strength by hand-
held quantitative dynamometry relative to placebo 
• 
To evaluate the change in Quality of Life in Neurological Disorders: 
Upper Extremities (Neuro-QoL UE) relative to placebo  

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• 
To assess safety and tolerability of losmapimod in patients with FSHD  
Exploratory Objectives: 
• 
To evaluate relative change from baseline in muscle strength by 
handheld quantitative dynamometry, relative to placebo 
Part B: Open-Label Extension 
Primary Objective: 
• 
To assess the long-term safety and tolerability of losmapimod in patients 
with FSHD   
Exploratory Objectives: 
Endpoints: 
Part A: Placebo-Controlled Treatment Period 
Primary Endpoints: 
• 
Change from baseline in average total RSA Q1--Q5 with 500 g wrist 
weight at Week 48, where average is applied over both arms  
Secondary Endpoints: 
• 
PGIC at Week 48 
• 
Change from baseline in WB longitudinal composite MFI of B muscles 

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at Week 48 
• 
Relative change from baseline in average shoulder abductor strength by 
hand-held quantitative dynamometry at Week 48  
• 
Change from baseline in Neuro-QoL UE at Week 48 
• 
Safety and tolerability, based on the assessment of adverse events (AEs), 
clinical laboratory tests, electrocardiograms (ECGs), vital signs, and 
physical examinations 
Exploratory Endpoints: 
• 
Change from baseline in WB longitudinal composite MFF at Week 48 
• 
Relative change from baseline in muscle strength by hand-held 
quantitative dynamometry at Week 48 
Part B: Open-Label Extension 
Primary Endpoint: 
• 
Safety and tolerability of long-term treatment with losmapimod, based 
on the assessment of AEs, clinical laboratory tests, ECGs, vital signs, 
and physical examinations   
Exploratory Endpoints: 

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• 
Study Population: 
Part A: Males and females between the ages of 18 to 65 years, inclusive, with a 
diagnosis of FSHD1 or FSHD2 verified by genetic testing and a Clinical 
Severity Score of 2 to 4 (Ricci score; range 0 to 5), with no contraindications to 
MRI. 
Part B: Patients who have completed Part A of this study. 
Study Design: 
Part A of Study 1821-FSH-301 is a global, randomized, double-blind, placebo-
controlled, parallel-group, multicenter study. Efficacy and safety of losmapimod 
will be evaluated in patients with FSHD over a 48-week treatment period. A total 
of approximately 230 patients with FSHD will be randomized 1:1 to receive 
losmapimod or placebo.  
Upon completion of Part A, patients will have the option to rollover into Part B, 
the open-label extension. The long-term safety, tolerability, and efficacy of 
losmapimod will be evaluated in patients.  
Duration of 
Treatment: 
Part A: Placebo-Controlled Treatment Period 
Patients will participate in the randomized, controlled treatment period, 
including the following: 
• 
• 
A 48-week placebo-controlled treatment period. 
• 
Safety follow-up visits 
 days and 
 days after last dose (only for 
patients who discontinue from treatment early or who do not rollover 
into Part B). 
− 
For patients who rollover into Part B, the Week 48 visit will be 
the end of study visit for Part A.  
• 
Patients will have the opportunity to rollover into Part B (open-label 
extension) after completing Part A. Approval from the Medical Monitor 
will be required if patients do not rollover without interruption after 
completing the Week 48 assessments. If a patient rolls over more than 7 
days after the last dose in Part A, they may be required to repeat selected 
Week 48 assessments at the discretion of the Medical Monitor. 
Part B: Open-Label Extension 
• 
Patients may participate in the open-label extension after completing 
Part A.  
• 
All patients in Part B will be eligible to receive losmapimod 15 mg 
orally twice daily (BID) from the time they complete Part A of this study 
and for the duration of the study as specified in the Schedule of 
Assessments for Part B or until the study is discontinued by the sponsor.  
• 
Patients will have safety follow-up visits 
 and 
 days after the 
last dose. 
Details of Applicable 
Monitoring 
In Part A only, an Independent Data Monitoring Committee (IDMC) will 
conduct periodic planned safety reviews of study data, as outlined in the IDMC 

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Committee: 
charter. 
Investigational 
Product, Dosage, 
and Route of 
Administration: 
Part A: Placebo-Controlled Treatment Period 
Losmapimod 15 mg will be administered orally BID with food. 
Placebo tablets (Part A only) will be identical in appearance to losmapimod 
tablets and will have the same excipients as the active tablets. 
Part B: Open-Label Extension 
Losmapimod 15 mg will be administered orally BID with food for the duration 
of the study as specified in the Schedule of Assessments for Part B or until the 
study is discontinued by the sponsor. 
Sample Size: 
Part A: Placebo-Controlled Treatment Period 
Approximately 210 patients with genetically confirmed FSHD1 and 20 patients 
with genetically confirmed FSHD2 will be enrolled. All previous FSHD studies 
of losmapimod have been conducted in patients with FSHD1; therefore, sample 
size calculations are based on patients with FSHD1 genotype. Additional 
patients with FSHD2 genotype will be enrolled to explore safety and efficacy in 
this subgroup. 
Assuming the within-group SD of change is 0.08 and that 10% of the study 
population has missing Week 48 data, a sample size of 210 patients with FSHD1 
(105 patients per group) will be needed to provide  at least 95% power with a 2-
sided test at 0.05 significance level to detect a difference of 0.05 between 
losmapimod and placebo in change from baseline in average total RSA Q1-Q5 
with 500 g wrist weight at Week 48. An additional approximately 20 patients 
with FSHD2 will be recruited. 
Part B: Open-Label Extension 
Patients who complete Part A will be given the opportunity to participate in Part 
B. The sample size is not based on any formal statistical assumptions. Up to 230 
patients may be enrolled in Part B.  
Statistical Methods: 
Part A: Placebo-Controlled Treatment Period 
The primary endpoint of absolute change from baseline in average total RSA 
Q1-Q5 with 500 g wrist weight at Week 48 will be formally tested only during 
the final analysis, when all patients complete Part A participation. 
The full analysis set (FAS) will be used for the primary analysis in the placebo-
controlled treatment period. The FAS will consist of all patients with FSHD1 
and FSHD2 who are randomized and receive at least 1 dose of study drug in the 
placebo-controlled treatment period. 
The analysis of the absolute change from baseline in average total RSA will be 
based on a mixed-effects model for repeated measures with the absolute change 
from baseline at post-baseline visits up to Week 48 as the dependent variable. 
The model will include terms for treatment group, visit, treatment group by visit 
interaction, baseline value, baseline value by visit interaction, region, and FSHD 
repeat number category, where appropriate. An unstructured covariance matrix 
will be used to model the correlations between repeated measurements within 
each patient. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. 
Part B: Open-Label Extension 
The open-label analysis set will be used for all analyses, unless otherwise 

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specified, for Part B. It will consist of all patients who receive at least 1 dose of 
losmapimod in the open-label extension portion. All statistical analyses will be 
descriptive. The statistical methods are described in Section 9.2.5 and in the 
Statistical Analysis Plan. 
Version and Date of 
Protocol 
Version 5.1, 21 December 2023 

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1. 
BACKGROUND 
Fulcrum Therapeutics Inc. (Fulcrum) is developing losmapimod for the treatment of 
facioscapulohumeral muscular dystrophy (FSHD). Losmapimod is an orally bioavailable small 
molecule inhibitor of the p38α/β mitogen-activated protein kinase (MAPK) that specifically 
reduces double homeobox 4 (DUX4) protein expression and its downstream transcriptional 
targets. Losmapimod is not authorized for marketing in any country worldwide at this time.  
FSHD is a serious, rare, progressive and debilitating neuromuscular disease, with a prevalence of 
approximately 16,000 to 38,000 diagnosed individuals in the United States (Deenen et al. 2014; 
Preston, Tawil, and Wang 2020). Symptoms of FSHD typically appear in the second decade of 
life but can begin at any age (Tawil et al. 2015); however, earlier onset typically manifests in 
more severe progression (Chen, Wu, and Tseng 2020; Goselink et al. 2019). About two-thirds of 
cases are familial-inherited in an autosomal dominant fashion, and one-third of cases are 
sporadic. During a June 2020 FSHD Externally Led Patient-Focused Drug Development virtual 
meeting with the US Food and Drug Administration (FDA), patients, caregivers, and others, a 
number of testimonials conveyed a message of suffering, stress, and despair (Arjomand et al. 
2020). 
FSHD is characterized by muscle weakness and eventual loss of function. It is a relentlessly 
progressive disease, with accumulation of weakness rostral to caudal, characteristically starting 
with facial and scapular weakness, followed by lower extremities and trunk. The progression of 
the disease significantly impacts activities of daily living (ADLs), independence, self-esteem, 
and mental status, with some experiencing pain and lost ability to function or work. The most 
prevalent functional motor limitations include difficulty getting up from lying down in bed and 
difficulty using arms for ADLs (Statland and Tawil 2014). FSHD significantly impacts all 
quality-of-life domains on the 36-Item Short Form Health Survey, and over half of patients with 
FSHD report at least mild to moderate pain (Moris et al. 2018; Padua et al. 2009). 
The natural history of FSHD disease progression has been captured in a longitudinal assessment 
of reachable workspace (RWS). Total relative surface area (RSA) quadrants (Q1-Q4) 
demonstrates an annualized 1.63% RSA decline over 5 years across patients with FSHD assessed 
without weights and a significant 1.82% RSA decline in total RWS with weights (Hatch, Kim, et 
al. 2019). Moderately impaired individuals with baseline RSA values between 0.20 and 0.70 (out 
of 1.0, for quadrants Q1-Q4) were more likely to show predictable declines over time with an 
annualized total RSA loss of 2.74% (P=0.047) (Hatch, Kim, et al. 2019). 
Muscle strength, measured by quantitative muscle testing, decreases at a rate of approximately 
1% to 4% per year (Statland and Tawil 2014; Stübgen and Stipp 2010), and a 6-year risk of    
wheelchair use is 24% (Statland, Shah, et al. 2015). Asymmetry of muscle involvement is 
common. In the most severe cases, there can be extramuscular manifestations, including retinal 
vascular changes and hearing loss (Statland and Tawil 2014); cardiac and respiratory muscles are 
usually spared.  

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FSHD is caused by aberrant expression of the DUX4 gene, a homeobox transcription factor. 
DUX4 pathological expression in skeletal muscle in both FSHD type 1 (FSHD1) and FSHD type 
2 (FSHD2) leads to the activation of genes usually not expressed in skeletal muscle and almost 
exclusively found in the early embryo (Bosnakovski et al. 2014; Homma et al. 2015; 
Jagannathan et al. 2016; Yao et al. 2014). This aberrant DUX4-driven gene expression activates 
complex pathological cell processes including expression of cytokines (Statland, Odrzywolski, et 
al. 2015), cellular stress, and programmed cell death (apoptosis) with no single process currently 
defined as driving the pathology (Wang et al. 2019; Wong et al. 2020). The result is myofiber 
death with skeletal muscle tissue loss, as well as muscle fat infiltration and eventual replacement 
by fat. This loss of muscle tissue and replacement by fat is responsible for the clinical 
manifestation of the disease, including progressive loss of muscle strength and strength (muscle 
weakness), loss of function, and slow accumulation of physical disability. 
The primary treatment goal for patients living with FSHD is slowing or stopping disease 
progression (Arjomand et al. 2020). There are currently no approved disease-modifying 
treatments for FSHD. Low-intensity aerobic exercise tailored to the patient’s distribution of 
weakness may provide limited beneficial effect (Janssen et al. 2016). Limited range of motion in 
the shoulder girdle stems from periscapular muscle weakness; in such cases, surgical scapular 
fixation (scapulodesis) can result in some functional improvement for select patients (Tawil et al. 
2015). No therapy has been proven to reduce disease severity or delay the progression of the 
disease; therefore, there is a high unmet need for an effective therapy for FSHD.  
1.1. 
NONCLINICAL STUDIES 
In vitro studies, including absorption, distribution, metabolism, and excretion assessments, have 
demonstrated that losmapimod is a highly selective p38α/β MAPK inhibitor with a limited risk 
of significant interaction with most other kinases, transporters, or cytochrome P450 enzymes at 
pharmacologically relevant concentrations. Further in vitro characterization of the effects of 
losmapimod in FSHD patient-derived immortalized myotubes showed potent and selective 
inhibition of the p38α pathway, DUX4 mRNA and protein production, and DUX4-regulated 
gene expression program, as well as profound inhibition of muscle cell death and prevention of 
death of the FSHD myotubes.  
In vivo muscle pharmacokinetic (PK)/pharmacodynamic (PD) studies in non-fasted mice and 
rats demonstrated that a single dose of losmapimod (0.3 mg/kg orally [PO]) resulted in clinically 
relevant plasma exposure, significant muscle exposure, and significant p38α/β MAPK pathway 
inhibition in skeletal muscles. Muscle PK experiments in mice and rats demonstrated that 
losmapimod rapidly distributes to the target tissue and achieves a muscle:plasma ratio of ≥0.6. 
The muscle exposures achieved are predicted to result in a >50% reduction in DUX4-dependent 
targets in FSHD patient skeletal muscle based on the in vitro data obtained using FSHD patient 
myotubes. Additionally, the PK/PD analysis indicated that significant p38α/β MAPK pathway 
inhibition would be expected in muscle with the proposed clinical dose of 15 mg PO twice daily 
(BID) (Barbour et al. 2013; Lomas et al. 2012). Fulcrum and others have demonstrated that the 

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treatment effect of losmapimod on the root cause of FSHD occurs regardless of the genotype of 
the patient-derived muscle cell models used (Oliva et al. 2019; Rojas et al. 2020).  
Metabolism occurs primarily via hydrolysis of the cyclopropylamide group by carboxylesterase-
1 to form a pharmacologically inactive primary metabolite, referred to as FTX-5508 (Barbour et 
al. 2013; Barbour et al. 2015). The ratio of metabolite to parent is approximately 0.03 to 0.25 in 
nonclinical species, but it is higher (2-fold) in humans. The major metabolite, FTX-5508, is 
unlikely to interact with most other kinases, transporters, or cytochrome P450 enzymes. 
Losmapimod produced no concerning effects either in vitro in human ether-a-go-go related gene 
assays or in vivo on neurobehavioral function (rats), respiratory function (rats), or cardiovascular 
function, including electrocardiogram (ECG) and QT interval corrected (QTc) monitoring 
(monkeys) at multiple exposures and concentrations well above the clinical exposure levels. Data 
from genotoxicity assessments indicate that losmapimod does not present a genotoxic hazard to 
humans. The totality of the nonclinical package indicated that there were no findings in chronic 
toxicology (rodent and non-rodent), safety pharmacology, or genetic toxicity studies that would 
preclude the oral administration of losmapimod to humans. There were no concerns in 
carcinogenicity studies. 
1.2. 
CLINICAL STUDIES 
Fulcrum is evaluating losmapimod for the treatment of patients with FSHD. Previously, 
losmapimod was evaluated for the treatment of 10 different indications other than FSHD or other 
muscle disorders; however, losmapimod did not show the desired efficacy in those indications 
and thus is no longer under investigation for those conditions. Losmapimod was generally well 
tolerated in those studies. As part of these development programs, safety data are available from 
>3500 healthy volunteers or patients who have been treated with oral losmapimod. 
Fulcrum has completed 3 Phase 1 studies (FIS-001-2018, 1821-CLP-101, and 1821-CLP-102); 
2 Phase 1 studies (1821-CLP-103 and 1821-CLP-104) and 2 Phase 2 studies (FIS-001-2019 
[open-label study (OLS)] and FIS-002-2019 [ReDUX4]) are currently ongoing. The main parts 
of the Phase 2 studies have been completed while the open-label extensions portions of these 
studies are ongoing. 
For additional details regarding the clinical studies refer to the current version of the losmapimod 
Investigator’s Brochure.  
1.2.1. 
Pharmacokinetics 
Elimination of losmapimod is almost exclusively by metabolism with only 2% of the 
administered dose recovered as unchanged drug in urine and feces. The predominant route of 
elimination of losmapimod (mostly as the FTX-5508 metabolite) is via urine (approximately 
65% of the dose) with approximately 29% of the dose eliminated via feces. The formation of 
FTX-5508 was shown to be catalyzed by carboxylesterase-1. The absolute oral bioavailability of 
the tablet formulation is 62%.  

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Following a single intravenous dose of losmapimod, the volume of distribution at steady state 
indicated extensive tissue distribution (Mellion et al. 2021). Food was found to increase the oral 
absorption of losmapimod for both milled and micronized formulations of losmapimod with up 
to 60 mg tablets (Studies FIS-001-2018 and 1821-CLP-101).  
The PK of losmapimod tablets was evaluated in healthy volunteers and patients with FSHD in 
Fulcrum’s completed Phase 1 study FIS -001-2018 (Barbour et al. 2013; Cheriyan et al. 2011). 
Single-dose plasma PK profiles of losmapimod in patients with FSHD1 were similar to the PK 
profiles in healthy patients and multiple-dose plasma PK profiles in patients with FSHD1 were 
similar to that in published literature (Barbour et al. 2013; Cheriyan et al. 2011). Exposures 
increased approximately dose proportionally from 7.5 to 15 mg and were generally non-
significantly higher than losmapimod exposures described in the literature, which may be due to 
formulation differences, PK sampling duration differences, and/or food effects.  
Exposure at target tissue level, in the muscle, was confirmed by detection of losmapimod in 
biopsied muscle at levels ranging from 42.10 to 97.16 ng/g after 14 days of 15 mg PO BID 
dosing; these concentrations exceed the half-maximal inhibitory concentration as determined in 
blood by Barbour et al (Barbour et al. 2013) of 37.4 ng/mL as well as preclinical concentrations 
(approximately 30 ng/mL) that resulted in a reduction of aberrant DUX4-driven gene expression 
and muscle cell death. Approximately dose-proportional levels of losmapimod were observed in 
muscle in patients with FSHD. 
For additional details regarding PK, refer to the current version of the losmapimod Investigator’s 
Brochure.  
1.2.2. 
Pharmacodynamics 
Losmapimod is highly selective for p38α and p38β MAPKs, and phosphorylation of heat shock 
protein 27 (HSP27) is directly related to the activation of p38α (MAPK14) through a 
downstream kinase, MK2. Therefore, phosphorylated HSP27 (pHSP27) is a relevant surrogate to 
measure the degree of p38α MAPK inhibition as it is activated by induction of the p38α MAPK 
signaling pathway, downstream from p38α MAPK itself. Data have shown that the ratio 
pHSP27/HSP27 is more responsive to single- and multiple-dose treatment compared to pHSP27 
or total HSP27 separately.  
In Phase 1 and Phase 2 studies conducted by Fulcrum, target engagement was confirmed in 
blood and muscle based on a decrease in the pHSP27/HSP27 ratio. Levels of pHSP27/total 
HSP27 in blood after sorbitol stimulation ex vivo showed a percent reduction from baseline of 
approximately 35% to 65% at maximum plasma concentration (Cmax; 4 hours postdose) in the 
losmapimod group, demonstrating target engagement in the Phase 2 ReDUX4 study. 
Additionally, target engagement was similar for the one 15-mg tablet dose and the two 7.5-mg 
tablet dose whether it was administered with or without food. 
For additional details regarding pharmacodynamics, refer to the current version of the 
losmapimod Investigator’s Brochure.  

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1.2.3. 
Safety  
Fulcrum has conducted Phase 1 Studies FIS-001-2018 (Part A), 1821-CLP-101, and 1821-CLP-
102 in healthy volunteers and evaluated the safety of losmapimod. Also, Fulcrum has evaluated 
the safety of losmapimod in patients with FSHD in the Phase 1 Study FIS-001-2018 (Parts B and 
C) and is currently conducting 2 Phase 1 studies (1821-CLP-103 and 1821-CLP-104), 2 Phase 2 
studies (FIS-001-2019 and FIS-002-2019 [ReDUX4]), and 1 Phase 3 study (1821-FSH-301 
[REACH]).  
Additionally, the safety profile of losmapimod has been evaluated previously in >3500 subjects 
across multiple clinical studies and indications, none of which were FSHD or muscle disorders.  
The safety of losmapimod tablets was evaluated in healthy volunteers and in patients with FSHD 
aged 18 years and above in Fulcrum’s completed Phase 1 studies and 2 ongoing Phase 2 studies.  
As of 09 January 2022, a total of 208 subjects have received losmapimod in a Fulcrum-
sponsored clinical study: 66 healthy volunteers, approximately 120 patients with FSHD, and 22 
patients with COVID-19. To date, there were no drug-related serious adverse events (SAEs) or 
deaths reported. One subject discontinued from the study due to an adverse event (AE) of 
dizziness considered unrelated to the study drug by the investigator; the patient decided to 
discontinue treatment and withdrew consent.  
Evaluation of treatment-emergent adverse events (TEAEs), vital signs, physical findings, 
electrocardiograms (ECGs), and safety hematology and chemistry results showed no safety 
concerns or findings of losmapimod given in tablet formulation to healthy volunteers in single 
doses of 7.5 and 15 mg and to patients with FSHD receiving 15 mg doses BID for up to 
48 weeks. There were no reported deaths, SAEs, or severe AEs throughout the studies. There 
was no specific pattern of TEAEs discernable across treatments (losmapimod 7.5 mg, 
losmapimod 15 mg, or placebo). There was no identifiable causal relationship between the use of 
losmapimod and the occurrence of infections, bleeding events, congestive heart failure AEs, 
stroke AEs, or skin-related AEs. Despite the pharmacology of p38 MAPK inhibition, there is no 
clear evidence to suggest clinically relevant immune compromise in subjects taking losmapimod. 
In summary, review of studies in healthy volunteers and patient populations did not identify 
differences in the type, frequency, or severity of AEs or SAEs between losmapimod and placebo. 
No definitive safety signals have been identified. The potential benefit of losmapimod continues 
to outweigh the risk following exposure in more than 3500 subjects in GSK and Fulcrum clinical 
studies. 
For additional details regarding safety, refer to the current version of the losmapimod 
Investigator’s Brochure.  
1.2.4. 
Efficacy 
Fulcrum is evaluating the efficacy of losmapimod for the treatment of patients with FSHD aged 
18 years and above in 2 Phase 2 studies (FIS-001-2019 and FIS-002-2019). The main parts of the 
studies have been completed, and the open-label extensions are ongoing. 

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Losmapimod demonstrated disease-modifying properties as evidenced by efficacy on structural, 
functional, and patient-reported measures of FSHD disease progression in the main parts of the 
2 Phase 2 studies. Both studies have ongoing extensions in which all participants are taking 
losmapimod.  
These studies show that treatment with losmapimod resulted in:  
• Dose-dependent exposure in plasma and muscle at concentrations predicted by 
nonclinical models to provide efficacy by reducing DUX4 activity 
• Superiority over placebo in maintaining or improving muscle function as assessed by 
total RWS (a quantitative measure of upper arm mobility and strength), and, importantly, 
range of motion above the shoulder and behind the back 
• Stability or improved muscle strength on hand-held quantitative dynamometry and 
quantitative muscle testing  
• Improvements in ankle dorsiflexion strength supportive of the trends of faster timed up-
and-go (TUG)  
• Reduction in the progression of muscle fat infiltration (MFI) and muscle fat fraction 
(MFF) in A and B muscles, suggesting losmapimod has an impact on fat accumulation in 
muscles that have not yet reached end-stage which has been previously reported to have 
little remaining functional capacity; muscles were categorized based on MFI and MFF as 
normal appearing (Category A; MFI <0.10, MFF, <0.50), intermediate (Category B; MFI 
≥0.10, MFF <0.05), or late-stage (Category C; MFF ≥0.50)  
• Moderate and strong correlations in functional correlation composites of muscles 
involved in functional assessments of interest (TUG and RWS) with MFI, MFF, and lean 
muscle volume (LMV)  
Importantly, the effect of treatment with losmapimod is recognized by patients (clinically 
meaningful difference of -0.58 on the Patients’ Global Impression of Change [PGIC] scale 
between losmapimod and placebo groups) in ReDUX4. Of subjects reporting at Week 48 (29 and 
31 subjects for the losmapimod and placebo groups, respectively), 27.6% of losmapimod patients 
and 6.5% of placebo patients reported improvement by PGIC, and 72.4% of losmapimod patients 
and 93.5% of placebo patients reported not improved.   
Even though there is downstream evidence of benefits of reduction in DUX4-driven gene 
expression, the prespecified population and subgroup analyses (including subgroups by DUX4 
repeat category, clinical severity score, sex, fat fraction on muscle MRI, baseline DUX4 score on 
muscle biopsy, completion of classical or FSHD TUG with use of assisted device) did not show 
differences in DUX4-driven gene expression in muscle biopsies, between or within groups in 
either study, due to the variability of DUX4-driven gene expression, which spanned over 1000-
fold among patients at baseline. Multiple factors contributed to this large variability, including 
the stochastic nature of DUX4-driven gene expression, the very transient duration of and relative 
scarcity of DUX4 expression among myonuclei (which has been shown to be approximately 
1/1000 to 1/3000), the heterogeneity in composition of FSHD muscles, and the variability in the 
muscle biopsy procedure performed across multiple clinical sites.  

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Additionally, an interim analysis of the ongoing OLE data from Study FIS-002-2019 (ReDUX4) 
shows stability in annualized total (Q1-5) RSA in the dominant arm with weights in the 
participants continuing to receive losmapimod (LOS/LOS) during the second year of dosing 
compared to the first (0.31%/year vs -0.62%/year, respectively) and improvement in placebo 
participants who converted to losmapimod after the first year of the study (PBO/LOS) (0.98% in 
the OLE vs -7.49% in the placebo-controlled portion).  
For additional details regarding efficacy, refer to the current version of the losmapimod 
Investigator’s Brochure. 
1.3. 
BENEFIT RISK 
1.3.1. 
Identified Risks 
Currently, there are no important identified risks for losmapimod.  
1.3.2. 
Potential Risks 
This section summarizes the important potential risks that have been recognized during the 
conduct of the losmapimod clinical development program. For more details, refer to the current 
version of the losmapimod Investigator’s Brochure. 
1.3.2.1. 
Hepatotoxicity 
Evidence of hepatotoxicity typified by increased concentrations of transaminases, with or 
without hyperbilirubinemia, has been noted after repeat dose administration of some other p38 
MAPK inhibitors. The mechanism of liver injury for these compounds is not known. Patients 
receiving losmapimod have not demonstrated clinically apparent hepatotoxicity in studies to 
date. Reasons for this apparent difference may include different selectivity, a lower total daily 
dose, less than complete inhibition of p38 MAPK (as demonstrated by pHSP27 inhibition), and 
the absence of active metabolites.  
Based on consolidated data from 11 repeat-dose clinical studies across patient populations 
conducted by GSK, the proportion of subjects who experienced alanine aminotransferase (ALT) 
≥3×ULN was 0.9% in those receiving losmapimod and 0.5% in those receiving placebo. ALT 
elevations were generally reversible following drug discontinuation, although follow-up is not 
available in all cases. There was a slightly higher incidence of ALT elevation in the non-ST-
segment elevation myocardial infarction (NSTEMI) study (Study PM1111810), in which ALT 
≥3×ULN occurred in 8/391 (2%) of those receiving losmapimod and 1/135 (0.7%) of those 
receiving placebo. In the acute coronary syndrome (ACS) Phase 3 study (Study PM1116197), 
5/1724 subjects in the losmapimod group and 4/1752 subjects in the placebo group experienced 
simultaneous ALT ≥3× ULN and total bilirubin ≥2×ULN. 
Factors that likely contributed to the rise in ALT and bilirubin in these cases included the 
underlying ACS event, concomitant high dose statin administration, cholecystitis, and/or a 
history of autoimmune hepatitis. 

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In studies in patients with FSHD, the following was observed in terms of liver function 
evaluations: 
In the open-label Study FIS-001-2019, 5/14 (35.7%) patients had an AE of ALT increased 
(defined as ALT values > ULN) and 3/14 (25.4%) patients had an AE of aspartate 
aminotransferase (AST) increased (defined as AST values >ULN). All cases of ALT increased, 
and AST increased resolved with continued dosing, and all cases were considered mild in 
severity. The mean change (SD) from baseline at Week 52 of treatment was 6.8 (7.20) U/L for 
ALT and 6.1 (4.25) U/L for AST. 
In the randomized, placebo-controlled portion of Study FIS-002-2019 (ReDUX4), 2/40 patients 
randomized to losmapimod experienced AEs of increased ALT levels (defined as ALT values 
>ULN); all events were considered mild in severity and resolved with continued dosing. None of 
the 40 subjects randomized to placebo experienced increased ALT levels during the placebo-
controlled period. No other patients experienced clinically notable liver-related laboratory values 
or drug-induced liver injury (DILI).  
Cumulatively, there have been no reported SAEs or adverse events of special interest in 
Fulcrum-sponsored FSHD clinical studies, in relation to the potential risk of hepatotoxicity. 
The liver effects in patients with FSHD are consistent with the safety profile of losmapimod in 
patients with other clinical conditions.  
The liver safety data available to date support the enrollment of patients with stable liver disease 
in clinical trials, provided there is no evidence of clinically relevant active liver dysfunction.  
1.3.2.2. 
Immune Function 
Based on the pharmacology of p38 MAPK inhibition, losmapimod theoretically may have an 
impact on immunity and be associated with an increased risk of infection. To date, there is no 
evidence to suggest an increased risk of infection based on exposure to losmapimod. However, 
this drug class has demonstrated a modest but broad influence on various cytokines. It should 
also be noted that at a clinical dose of 15 mg orally, losmapimod only partially inhibits the p38 
MAPK pathway (approximately 60% at Cmax), as estimated by inhibition of HSP27 
phosphorylation (Study PM1113022). In addition, losmapimod does not inhibit neutrophil 
response to a variety of stimuli. Further, clinical studies to date have not demonstrated an 
increase in the incidence, type, or severity of infections in patients who have received 
losmapimod when compared to those who received placebo. Thus, the degree of impact of 
losmapimod will continue to be monitored. 
Of note, additional nonclinical investigation has shown marked reductions in immunoglobulin 
(Ig)M and IgG responses to keyhole limpet hemocyanin (KLH) at maximal inhibitory doses 
(300 mg/kg/day) in the rat T–cell-dependent antibody response (TDAR) model. These findings 
were reversible after a 4-week recovery period. No clear dose- or sex-dependent reductions in 
IgM or IgG responses to KLH were noted at lower doses (≤3 mg/kg/day). The reduction in 
TDAR response is consistent with the known pharmacology of p38 kinase inhibition (Khiem et 
al. 2008) when using doses that produce maximal inhibition.  

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In considering the totality of nonclinical and clinical data for losmapimod to date, there may be 
clinical circumstances under which the theoretical risk of administration of losmapimod 
outweighs the benefit, particularly due to limited or no prior experience in certain populations. 
This includes the co-administration of losmapimod and cytotoxic chemotherapy for cancer, as 
data in this population are not available. In addition, administration of losmapimod during active 
opportunistic infection and tuberculosis, as well as other active, life-threatening infections, may 
carry theoretical risks. The rat immunotoxicology study showed that reductions in T–cell-
dependent antigen response (with large safety margins) were reversible once losmapimod 
administration was stopped. 
It is theoretically possible that losmapimod could diminish the efficacy of immunizations if 
given during the same period of time. Attenuated live vaccines should not be administered 
shortly prior to, during, or shortly after dosing with losmapimod.  
1.3.3. 
Contraindications 
There are no specific disease-related contraindications to the administration of losmapimod. 
Losmapimod should not be administered to: 
• Pregnant or nursing mothers 
• Women of childbearing potential who are not employing adequate contraceptive 
measures 
Teratogenicity and effects on embryo fetal survival were noted in rat and rabbit reproductive 
toxicity studies with losmapimod. The use of losmapimod is currently limited to females of 
nonchildbearing potential or to females of childbearing potential who are utilizing adequate 
contraceptive methods. 
Losmapimod is contraindicated in patients who are known to have previously experienced 
hypersensitivity to losmapimod and patients with known hypersensitivity to any of the excipients 
 
 
 used in its 
formulations. 
1.3.4. 
Interactions 
1.3.4.1. 
Drug Interactions 
Losmapimod has low potential to cause clinically significant drug interactions with most 
metabolizing enzymes and transporters studied. Losmapimod is a potent in vitro inhibitor of 
breast cancer resistance protein (BCRP), but in a clinical study, losmapimod (at 7.5 mg PO BID) 
did not significantly increase the exposure of rosuvastatin (a substrate of BCRP). However, 
caution is advised if losmapimod is co-administered with orally administered BCRP substrates 
with a narrow therapeutic index as high intestinal concentrations of losmapimod may enhance 
their absorption.  

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An in vitro study investigating the effect of losmapimod on kidney transporters revealed that 
losmapimod is an in vitro inhibitor of the multidrug and toxin extrusion (MATE)-1, or MATE2-
K, renal transporter. A Phase 1, drug-drug interaction study (1821-CLP-102) was conducted to 
evaluate the effect of multiple oral doses of losmapimod on the PK profile of midazolam (a 
known cytochrome P450 [CYP] 3A4 substrate) and separately on the PK profiles of furosemide 
(a known organic anion transporter [OAT] 1 and OAT3 transporter substrate) and metformin (a 
known organic cation transporter [OCT] 2, multidrug and toxin extrusion [MATE]-1, and 
MATE2-K transporter substrate). The results of this study demonstrate that there is no clinically 
meaningful drug-drug interaction potential of losmapimod or the FTX-5508 metabolite with 
CYP3A4, MATE, or OAT substrates, with the exception of substrates of OAT1/OAT3 with a 
narrow therapeutic index; subjects taking such concomitant medications may require monitoring 
of blood concentrations of these substrates when coadministered with losmapimod (see guidance 
in Section 5.8).  
FTX-5508 does not meet the current drug-drug interaction thresholds of safety concern stipulated 
in the regulatory guidance (European Medicines Agency guidance, CPMP/EWP/560/95/Rev. 1 
Corr. 2 and FDA draft guidance, 2020) for interactions with carboxylesterase [CES]-1, P-
glycoprotein, BCRP, organic anion transporting polypeptides (OATP) 1B1/1B3, OAT1/2/4, 
OCT 2, MATE-1, or MATE2-K and consequently has low potential to cause clinically 
significant drug interactions via these enzymes or transporters. The major metabolite (FTX-
5508) is a potent in vitro inhibitor of OAT3 (see above guidance). FTX-5508 does not inhibit nor 
induce major CYPs at clinical doses. 
Losmapimod and FTX-5508 are unlikely to be victims of inhibitors or inducers of the enzymes 
and transporters studied.  
Patients should be instructed as to the risk of drug-drug interaction and to report any change in 
medication prescription or usage to the study Investigator. 
1.3.4.2. 
Food Interactions 
The food effect on the oral absorption of losmapimod has been investigated. A high-fat meal 
increased 
 
 of losmapimod (wet granulation formulation) compared to the fasted state 
at the 15 mg dose. This increase in exposure is not considered clinically significant and, as a 
result, losmapimod may be taken without regard to meals unless otherwise stated in individual 
protocols. In this study, losmapimod will be taken with food to reduce PK variability and 
enhance exposure. 
1.3.5. 
Other Clinically Relevant Information 
This section documents safety observations or events that may be potentially relevant in the 
clinical management of patients receiving losmapimod. A reasonable possibility of a causal 
association with losmapimod and the potentially medically important observations or events 
listed below has not been established, and at this time none of these are considered expected for 

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the purpose of expedited reporting. Further characterization is ongoing. Additional details may 
be found elsewhere in the losmapimod Investigator’s Brochure. 
1.3.5.1. 
Effects on Serum Creatinine 
A small increase in (model-adjusted geometric mean) serum creatinine in the combined 
losmapimod group compared to placebo at Week 12 was noted in Study PM1111810 (ratio 1.07 
[95% CI: 1.02, 1.11]). Retrospective statistical analyses for creatinine levels in three other 
Phase 2 studies demonstrated similar trends (model-adjusted geometric mean ratio: 1.01 to 1.07 
at Week 12). This increase appeared to attenuate with continued therapy (to Week 24 in chronic 
obstructive pulmonary disease) as well as with discontinuation (2 weeks post-treatment in acute 
coronary syndrome). There was no increase in the incidence of renal insufficiency or related 
adverse events.  
There were no clinically relevant changes in serum creatinine or changes in estimated glomerular 
filtration rate observed in Fulcrum losmapimod clinical studies.  
1.3.5.2. 
Thorough QT Study 
A thorough QT study (PM1116628) was conducted with losmapimod at 7.5 mg BID or 20 mg 
once daily or placebo administered for 5 days in healthy volunteers. Moxifloxacin (single 400 
mg dose) was included as a positive control. The primary PD analysis showed that, at the 20 mg 
dose of losmapimod, the upper bound of the 90% CI of ΔΔQTcF (change from baseline in QT 
interval corrected for heart rate by Fridericia’s formula [QTcF] compared to that for placebo) 
exceeded the 10 msec threshold at the 24-hour post-dose time point. For the 7.5 mg dose, the 
upper bound of the 90% CI of ΔΔQTcF exceeded the 10 msec threshold at multiple time points. 
No subjects experienced QTcF values >480 msec or QTcF changes from baseline ≥60 msec at 
any time in the study. PK/PD modeling, using the raw QTcF and plasma concentration data, 
showed that at plasma losmapimod concentrations 4 times the 7.5 mg BID exposure, ie, at 
exposures approximately 2-fold higher than 15 mg BID, the predicted upper bound of the 90% 
CI of ΔΔQTcF did not exceed 10 msec and the predicted median ΔΔQTcF was less than 5 msec. 
In summary, although the upper bound of the 90% CI exceeded the 10 msec regulatory threshold 
of concern in the primary PD analysis, it is unlikely that there will be a clinically relevant effect 
on the QT interval data, as there was no clinically relevant concentration QTc effect using 
standard placebo/baseline subtracted measured QTc data. Additional information on the QTc 
interval and its behavior as demonstrated in the large cohort of patients treated with losmapimod 
obtained from Study PM1116197 supports the lack of a QT effect. 
Across the completed and ongoing Fulcrum losmapimod studies, there were no notable or 
clinically meaningful changes or trends noted in changes from baseline in ECG parameters; this 
was confirmed by ECG interpretation by visit. 
 

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
PART A: PLACEBO-CONTROLLED TREATMENT PERIOD 
2.1.1. 
Primary Objective and Endpoint 
The primary objective and endpoint are presented in Table 1. 
Table 1: 
Primary Objective and Endpoint (Part A) 
Objectives 
Endpoint 
• 
To evaluate the efficacy of losmapimod for 
the treatment of FSHD on disease 
progression assessed by RWS 
quantification of total RSA Q1-Q5 with 
500 g wrist weight, averaged over both 
arms 
• 
Change from baseline in average total RSA 
Q1-Q5 with 500 g wrist weight at Week 
48, where average is applied over both 
arms   
Abbreviations: FSHD = facioscapulohumeral muscular dystrophy; Q = quintant/quadrant; RSA = relative surface 
area; RWS = reachable workspace. 
2.1.2. 
Secondary Objectives and Endpoints 
Secondary objectives and endpoints are presented in Table 2. 
Table 2: 
Secondary Objectives and Endpoints (Part A) 
Objectives 
Endpoints 
• 
To evaluate PGIC relative to placebo 
• 
To evaluate efficacy of losmapimod to 
slow accumulation of fat in muscle by MFI 
with WB MSK MRI relative to placebo 
• 
To evaluate relative change from baseline 
in shoulder strength by hand-held 
quantitative dynamometry relative to 
placebo 
• 
To evaluate the change in Neuro-QoL UE 
relative to placebo  
• 
To assess safety and tolerability of 
losmapimod in patients with FSHD  
• 
PGIC at Week 48 
• 
Change from baseline in WB longitudinal 
composite MFI of B muscles at Week 48  
• 
Relative change from baseline in average 
shoulder abductor strength by hand-held 
quantitative dynamometry at Week 48  
• 
Change from baseline in Neuro-QoL UE at 
Week 48  
• 
Safety and tolerability, based on the 
assessment of AEs, clinical laboratory 
tests, ECGs, vital signs, and physical 
examinations   
Abbreviations: AE = adverse event; ECG = electrocardiogram; FSHD = facioscapulohumeral muscular dystrophy; 
MFI = muscle fat infiltration; MRI = magnetic resonance imaging; MSK = musculoskeletal; Neuro-
QoL-UE = Quality of Life in Neurologic Disorders-upper extremity; PGIC = Patient Global Impression of 
Change; WB = whole-body. 

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2.1.3. 
Exploratory Objectives and Endpoints 
Exploratory objectives and endpoints are presented in Table 3. 
Table 3: 
Exploratory Objectives and Endpoints (Part A) 
Objectives 
Endpoints 
• 
To evaluate relative change from 
baseline in muscle strength by hand-held 
quantitative dynamometry, relative to 
placebo 
 
• 
Relative change from baseline in muscle 
strength by hand-held quantitative 
dynamometry at Week 48 
Abbreviations: 
; FSHD = facioscapulohumeral muscular dystrophy; 
 
 MSK = musculoskeletal; NPRS = numeric pain rating scale; 
 
; PRO = patient-reported outcomes; Q = quadrant/quintant; RSA = 
relative surface area; WB = whole-body. 
 
 
 

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2.2. 
PART B: OPEN-LABEL EXTENSION 
2.2.1. 
Primary Objectives and Endpoints 
The primary objectives and endpoints are presented in Table 4. 
Table 4: 
Primary Objectives and Endpoints (Part B) 
Objectives 
Endpoint 
• 
To assess the long-term safety and 
tolerability of losmapimod in patients with 
FSHD   
• 
Safety and tolerability of long-term 
treatment with losmapimod, based on the 
assessment of AEs, clinical laboratory 
tests, ECGs, vital signs, and physical 
examinations   
Abbreviations: AE = adverse event; ECG = electrocardiogram; FSHD = facioscapulohumeral muscular dystrophy. 
2.2.2. 
Secondary Objectives and Endpoints  
There are no secondary objectives and endpoints in Part B. 
2.2.3. 
Exploratory Objectives and Endpoints 
Exploratory objectives and endpoints are presented in Table 5. 
Table 5: 
Exploratory Objectives and Endpoints (Part B) 
Objectives 
Endpoints 
Abbreviations: 
 FSHD = facioscapulohumeral muscular dystrophy; 
; RSA = relative surface area; RWS = Reachable Workspace. 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
STUDY DESIGN 
Figure 1: 
Study Schematic 
 
Patients will have the opportunity to rollover into Part B after completing Part A. Approval from the Medical 
Monitor will be required if patients do not rollover without interruption after completing the Week 48 assessments. 
If a patient rolls over more than 7 days after the last dose in Part A, they may be required to repeat selected Week 
48 assessments at the discretion of the Medical Monitor. Losmapimod will be administered continuously for the 
duration of the study as specified in the Schedule of Assessments for Part B or until the study is discontinued by the 
sponsor.  
3.1.1. 
Part A: Placebo-Controlled Treatment Period  
Part A of Study 1821-FSH-301 is a global, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study with a 
 screening period, a 48-week treatment period, 
and safety follow-up visits 
 days and 
 days after last dose (for patients who discontinue 
from treatment early or who do not rollover into Part B).  
During the placebo-controlled treatment period, a total of approximately 230 patients with FSHD 
will be randomized 1:1 to receive 15 mg PO of losmapimod (n=115) or placebo (n=115) tablets 
BID with food for 48 weeks (Figure 1).  
Patients will complete a 
 screening period followed by a 48-week placebo-controlled 
treatment period. After Week 48 patients will have the option to participate in Part B: Open-
Label Extension (Section 3.1.2).  
• Patients will have the opportunity to rollover into Part B after completing Part A. 
Approval from the Medical Monitor will be required if patients do not rollover without 
interruption after completing the Week 48 assessments. If a patient rolls over more than 7 
days after the last dose in Part A, they may be required to repeat selected Week 48 
assessments at the discretion of the Medical Monitor. 
• For patients who rollover into Part B, the Week 48 visit will be the end of study visit for 
Part A. 
• All patients who discontinue from treatment early or who do not rollover into Part B will 
return for a complete safety follow-up visit 
 days after the last dose of study drug and 
will complete a safety follow-up phone screen 
 days after the last dose of study drug. 
During the treatment period, patients will be asked to attend the study clinic at each scheduled 
visit (Table 7).  

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Safety and tolerability will be evaluated based on the assessment of AEs, AEs of special interest 
(AESIs), SAEs, laboratory tests, ECGs, vital signs, and physical examinations. The full schedule 
of assessments for the placebo-controlled treatment period is provided in Table 7. Scheduled 
visits may be split over 2 days, if required, and must be completed within the protocol-defined 
visit windows (Table 7). Unscheduled visits may be performed if clinically indicated.  
3.1.2. 
Part B: Open-Label Extension 
Upon completion of Part A at Week 48, patients will have the option to rollover into Part B, the 
open-label extension (Figure 1). Patients should be prepared to rollover into Part B as soon as 
possible after the last dose of study drug in Part A (Week 48 visit). Approval from the Medical 
Monitor will be required if patients do not rollover without interruption after completing the 
Week 48 assessments. If a patient does not rollover within 7 days of the last dose of study drug 
in Part A, they may be required to repeat selected Week 48 assessments (at the discretion of the 
Medical Monitor) to establish baseline for Part B. Study drug will not be administered in Part B 
until all assessments for Part A have been completed. 
As outlined in Table 8, the Day 1 visit of Part B (baseline) may occur on the same day as the 
Week 48 visit of Part A. If the patient rolls over within 7 days of the Week 48 visit, the Week 48 
assessments will not be repeated at the beginning of Part B. Patients will provide informed 
consent before any Part B–specific assessments are performed.  
Patients will remain blinded to their Part A treatment assignment (losmapimod or placebo) 
through completion of Part B. During Part B, all patients will receive 15 mg PO losmapimod 
tablets BID with food. Patients may continue to receive study drug in Part B for the duration of 
the study as specified in the visit schedule (Table 8) or until the study is discontinued by the 
sponsor. Any planned treatment interruptions (e.g., scheduled surgery) during Part B may be 
permitted on a case-by-case basis with approval from the Medical Monitor.  
Part B will consist of in-person clinic visits at baseline (Week 48) and at Weeks 
 
. After the 
 visit and for the remainder of the study, in-
person clinic visits will occur 
 
. All patients who complete or discontinue 
from treatment will return for a complete safety follow-up visit 
 days after the last dose of 
study drug and will complete a safety follow-up phone call 
 days after the last dose of study 
drug. 
Safety and tolerability of long-term treatment with losmapimod will be evaluated based on the 
assessment of AEs, clinical laboratory tests, ECGs, vital signs, and physical examinations. Long-
term efficacy 
 
) will be evaluated as exploratory endpoints. The full 
schedule of assessments is provided in Table 8. Unscheduled visits may be performed if 
clinically indicated.  

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3.2. 
RATIONALE OF STUDY DESIGN 
3.2.1. 
Rationale of Dose Selection 
Losmapimod is a small molecule inhibitor of the p38α/β MAPK that specifically reduces DUX4 
protein expression and its downstream transcriptional targets. Based on clinical PK/PD studies 
(Barbour et al. 2013), it is predicted that the proposed human dose of losmapimod for FSHD 
clinical trials at 15 mg PO BID would provide drug concentrations in skeletal muscles sufficient 
to significantly inhibit p38α/β and reduce aberrant expression of DUX4 and DUX4-driven gene 
expression.  
HSP27 is a phosphorylated substrate of p38α/β MAPK that has been demonstrated to be a 
relevant target engagement marker of p38 inhibition. There is a clear relationship between 
losmapimod plasma concentrations and target engagement for p38α/β MAPK, as measured by 
pHSP27.  
PK/PD modeling indicates that losmapimod dosed at 15 mg PO BID should result in 40% to 
70% pHSP27 reduction (Barbour et al. 2013; Cheriyan et al. 2011; Mellion et al. 2021). Target 
engagement in the Phase 1 and Phase 2 studies confirm that there is a 40% to 70% reduction in 
pHSP27:total HSP27. 
Fulcrum has shown that a 15 mg PO BID with food dosing regimen, as proposed, results in mean 
steady-state Cmin and Cmax values of approximately 30 ng/mL and 75 ng/mL, respectively. The 
15 mg PO BID regimen maintains steady state losmapimod plasma concentrations above the 
minimal level of 30 ng/mL needed for robust target engagement. Importantly, at the proposed 
dose level of 15 mg PO BID, exposures in FSHD patients does not exceed those previously 
demonstrated to be safe in humans in multiple previous studies in healthy volunteers and various 
patient populations (Barbour et al. 2013; Cheriyan et al. 2011; Kools et al. 2021; Mellion et al. 
2021; Pascoe et al. 2017; Tawil et al. 2021; Watz et al. 2014). 
In Part A: Placebo-Controlled Treatment Period and in Part B: Open-Label Extension, 
losmapimod will be administered 15 mg PO BID with food.   
3.2.2. 
Rationale of Study Design 
Part A: Placebo-Controlled Treatment Period 
This study is designed to demonstrate that treatment with losmapimod will slow the progression 
of disease and/or improve function in patients with FSHD. The study will evaluate the efficacy, 
safety, and tolerability of losmapimod. The placebo-controlled treatment period is a randomized 
design that includes an active treatment group and a placebo group (Section 3.1.1). The inclusion 
of a placebo group is necessary because there is clinical equipoise. The use of a placebo group 
will ensure that any potential for bias is minimized. Additionally, the use of matching placebo 
tablets to the losmapimod tablets will help maintain blinding of the patients to study treatment.  
The selection of study objectives and endpoints was informed by the Phase 2 study results. The 
primary objective of this study is to evaluate the efficacy of losmapimod for the treatment of 

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FSHD on disease progression assessed by RWS quantification of total relative surface area 
(RSA) Q1-Q5 with 500 g wrist weight, averaged over both arms relative to placebo. RWS is a 
sensitive and quantitative evaluation of function and is a relevant and suitable outcome measure 
to assess clinical efficacy. RWS can distinguish between healthy volunteers and people living 
with FSHD and can identify those patients more likely to decline over time. It is sensitive to 
change and quantitatively tracks progressive change in upper extremity (UE) function. 
Importantly, assessment of RWS (by measuring RSA) provides a functional clinical outcome 
that can track disability accumulation throughout a patient’s lifespan. It is a reliable and sensitive 
clinical outcome assessment (COA) that characterizes not just the presence, but also the extent, 
of dysfunction, which strongly correlates with and predicts impact on important quality of life 
measures by providing not only an assessment of absolute change, but also a quantification of the 
change in the slope of disease progression over time. 
RWS is a clinical outcome assessment that is sensitive to disease progression and responsive to 
treatment. This primary endpoint provides a robust representation of the effect of losmapimod on 
slowing of disease progression in FSHD. Selection of RWS is supported by findings from the 
ReDUX4 and OLS studies. For further details regarding RWS in clinical studies, refer to the 
current losmapimod Investigator’s Brochure. 
The secondary objectives were selected to inform interpretation and support clinical 
meaningfulness of the RWS as well as provide additional support for the efficacy of losmapimod 
to slow disease progression in FSHD. The patient reported outcome Quality of Life in 
Neurologic Disorders (Neuro-QoL) item bank “Upper Extremity function - fine motor, ADL” 
(Neuro-QoL UE) is a validated assessment that evaluates one’s ability to carry out various 
activities involving digital, manual, and reach-related functions, ranging from fine motor to self-
care (ADL). A prior study showed that there are moderate to strong correlations between the 
total score with an even slightly higher correlation with the 5 proximal- and shoulder-related 
items. Additionally, this study identified cut-off values for risk of dependence. Individuals with 
total RSA (Q1-Q4) values of less than 0.7 are more likely to be dependent in all 5 proximal and 
shoulder Neuro-QoL questions. An RSA value of 0.7 has a positive predictive value of 83% and 
negative predictive value of 100% (Hatch et al. 2020). 
In Study FIS-001-2019, we observed that the RWS assessment was able to quantify meaningful 
change captured by PGIC. Looking across the scale, as the PGIC score increases we observe 
there was a directional and measurable association between change in PGIC and percent change 
in RSA. This demonstrates that PGIC-recognized improvement, stability or worsening was also 
captured in RWS assessments over this same time period. 
The secondary endpoint to support efficacy includes assessment of change from baseline in the 
whole-body longitudinal composite MFI. The magnetic resonance imaging (MRI) technique to 
be used in this protocol is a standardized, objective, quantitative technique with automatic 
skeletal muscle segmentation for the 3-dimensional (3D) 
 volumes and 
 
analyses via robust algorithms using Dixon imaging to measure the extent of skeletal muscle 
tissue replacement by fat in FSHD patients. MFI provides an assessment of fatty changes in 
functional muscle tissue, the most proximal target of pathology (Dahlqvist et al. 2020). MFI is 

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the fat fraction calculated within voxels with less than 50% fat (West et al. 2018). This 
measurement is a representation of the fat content in parts of the muscle that are not fat-replaced 
and is analogous to the use of magnetic resonance spectroscopy (Aisen and Chenevert 1989) to 
measure 
. In ReDUX4, losmapimod preserved muscle 
structure, assessed by MFI, relative to placebo, which demonstrated increased MFI, over the 
course of 48 weeks; this assessment also showed moderate to strong cross-sectional correlations 
with RWS. For further details regarding the secondary endpoints, refer to the current 
losmapimod Investigator’s Brochure.  
The Sponsor will continue to expand and contribute to the understanding and evaluation of 
FSHD through selected exploratory endpoints and additional pre-specified analyses. 
Additionally, a patient advisory board reviewed and provided feedback on the design of this 
study. 
Part B: Open-Label Extension 
The Part B open-label extension (Section 3.1.2) will allow patients to continue to receive 
losmapimod and will provide long-term safety and tolerability data. 

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4. 
PARTICIPANT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
SELECTION OF STUDY PARTICIPANTS 
Approximately 210 patients with genetically confirmed FSHD1 and 20 patients with genetically 
confirmed FSHD2 will be enrolled at approximately 36 sites in North America and Europe. 
Eligibility will be reviewed and documented by an appropriately qualified member of the 
Investigator’s team before patients are enrolled. Patients will be assigned to study treatment only 
if they meet all the inclusion criteria and none of the exclusion criteria. 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or patient safety. 
Therefore, adherence to the eligibility criteria as specified in the protocol is essential. 
4.1.1. 
Part A: Placebo-Controlled Treatment Period 
4.1.1.1. 
Inclusion Criteria 
1. Patient will sign and date an informed consent form (ICF).  
2. Patients will have a diagnosis of FSHD1 or FSHD2 verified by genetic testing (see 
Section 6.2.1). 
− Randomization will be stratified for FSHD1 to ensure that treatment allocation is 
balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 4 to 9 
repeats). 
− Randomization will be stratified for FSHD2 to ensure that an equal number of 
patients will be allocated to treatment and placebo.  
3. Patients will have a Clinical Severity Score of 2 to 4 (Ricci score; range 0 to 5) at 
screening. Patients who are wheelchair-dependent or dependent on walker or wheelchair 
for activities are not permitted to enroll in the study.  
4. Patients with screening total RSA (Q1-Q4) without weight in the dominant UE assessed 
by RWS ≥ 0.2 and ≤ 0.7. 
5. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
6. No contraindications to MRI.  
7. Patients (male and female) will be between the ages of 18 and 65 years at the time of 
consent, inclusive.  
− A female patient is eligible to participate if she is of non-childbearing potential, 
defined as pre-menopausal females with a documented hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy; if she is postmenopausal, defined as no 
menses for 12 months without an alternative medical cause; OR 

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− If of child-bearing potential, she is using a highly effective method for avoidance 
of pregnancy for the duration of dosing and until 90 days after the last dose. For 
details regarding contraception requirements, refer to Section 5.5.1.1.  
− Male patients must agree to use one of the contraception methods listed in 
Section 5.5.1. This criterion must be followed from the time of the first dose of 
study medication and until 90 days after the last dose of study drug. 
4.1.1.2. 
Exclusion Criteria 
1. History of any illness or any clinical condition that, in the opinion of the Investigator, 
might confound the results of the study or pose an additional risk in administering study 
drug to the patient. This may include, but is not limited to, history of relevant drug or 
food allergies; history of cardiovascular or central nervous system disease; history or 
presence of clinically significant pathology; clinically significant history of mental 
disease. 
2. Previously diagnosed cancer that has not been in complete remission for at least 5 years. 
Localized carcinomas of the skin and carcinoma in situ of the cervix that have been 
resected or ablated for cure are not exclusionary. 
3. For patients who are on drug(s) or supplements that may affect muscle function, as 
determined by the Investigator, or that are included in the list of drugs presented in 
Appendix 3: patients must be on a stable dose of that drug(s) or supplement for at least 3 
months prior to the first dose of study drug and remain on that stable dose for the 
duration of the study. Changes to the dose or treatment discontinuation during the study 
can only be done for strict medical reasons by the treating physician with clear 
documentation and notification to the Sponsor.   
4. History of febrile illness within 5 days before the first study drug dose. Patients who were 
healthy during screening but develop febrile illness in the 5 days before randomization 
need to have the baseline visit postponed until the febrile illness is fully resolved (fever-
free without the use of antipyretic agents for 24 hours). Once the febrile illness is fully 
resolved, the patient’s baseline visit can be scheduled. The duration of the screening 
period in such cases can be extended to up to 35 days. 
5. Known active opportunistic or life-threatening infections including HIV and hepatitis B 
or C. 
6. Known active or inactive tuberculosis infection.  
7. Current acute liver disease or chronic liver disease as defined by any of the following:  
• Current ALT ≥ 2 × upper limit of normal (ULN) or total bilirubin > 1.5 × ULN 
(unless participant has Gilbert’s syndrome characterized by the combination of total 
bilirubin < 3 × ULN, direct bilirubin within the normal range and normal ALT and 
AST, or the presence of mutations in the UDP-glucuronosyltransferase 1 gene, 
indicative of Gilbert’s syndrome). 
• Positive for hepatitis B surface antigen. 

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• Positive for hepatitis C antibody unless additional testing for hepatitis C viral RNA is 
negative, ALT is < 2 × ULN and total bilirubin is ≤ 1.5 × ULN, indicating 
inactive/resolved hepatitis C infection. 
8. Known severe renal impairment (defined as a glomerular filtration rate of 
< 30 mL/min/1.73 m2). 
9. Standard 12-lead ECG demonstrating QTcF >450 msec for male patients and 
QTcF >470 msec for female patients at screening. If QTcF exceeds 450 msec for males 
or 470 msec for females, the ECG will be repeated 2 more times, and the average of the 
3 QTcF values will be used to determine the patient’s eligibility. 
10. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or 
evidence of abnormal ECGs that, in the opinion of the Investigator or Medical Monitor, 
would preclude the patient’s participation in the study. 
11. Male patients with a female partner who is planning to become pregnant during the study 
or within 90 days after the last study drug dose. 
12. Concomitant use of cytotoxic chemotherapy for cancer or known ongoing or anticipated 
use of chronic severe immunosuppressive agents. 
13. Positive pregnancy test, known to be pregnant or lactating, or planning to become 
pregnant during study drug administration and until 90 days after last dose. 
14. Any current mental condition (psychiatric disorder, senility or dementia) that may affect 
study compliance or prevent understanding of the aims, investigational procedures, or 
possible consequences of the study. 
15. Patient has any condition possibly affecting drug absorption (eg, gastrectomy, 
cholecystectomy, or other gastrointestinal tract surgery, except appendectomy). 
16. History of alcohol, analgesic/opioid, and/or illicit drug abuse, as defined by the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American 
Psychiatric Association, 2013), in the last 6 months before screening or a positive test for 
drugs of abuse at screening. Use of CBD/THC is permitted.  
17. Use of another investigational product within 30 days or 5 half-lives (whichever is 
longer) or according to local regulations, or currently participating in a study of an 
investigational device.  
18. Current or anticipated participation in a natural history study. Previous participation is 
allowed but patients cannot continue after enrollment in Study 1821-FSH-301.  
19. Known hypersensitivity or intolerance to losmapimod or any of its excipients.  
20. Previous participation in a Fulcrum-sponsored FSHD losmapimod study (FIS-001-2019 
or FIS-002-2019).  
21. Anticipated inability to comply with any study procedures, including participation in 
study visits according to the visit schedule through 48 weeks. 
22. Abnormal laboratory results indicative of any significant medical disease that, in the 
opinion of the Investigator, would preclude the patient's participation in the study. 

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23. Patient, or close relative of the patient, is the Investigator or a subinvestigator, research 
assistant, pharmacist, study coordinator, or other staff directly involved with the conduct 
of the study at that site. 
24. Patient is vulnerable (i.e., deprived of freedom), including inmates of psychiatric wards 
and prison or state institutions, patients with commitments to an institution, or a patient 
who is detained or committed to an institution by a law court or by legal authorities. 
25. For Italy only: Vaccination with a live attenuated vaccine within 6 weeks prior to 
randomization until the safety follow-up visit (see Appendix 2 for all country-specific 
differences) 
4.1.2. 
Part B: Open-Label Extension 
4.1.2.1. 
Inclusion Criteria 
1. Patient completed 48 weeks of treatment during Part A. 
2. Patient will sign and date an ICF.  
3. Patient is willing and able to comply with scheduled visits, treatment plan, study 
restrictions, laboratory tests, contraceptive guidelines, and other study procedures. 
4. Patient agrees to the following methods of contraception:  
− Female patients of childbearing potential agree to continue using a highly 
effective method for avoidance of pregnancy for the duration of dosing and until 
90 days after the last dose. For details regarding contraception requirements, refer 
to Section 5.5.1.  
− Male patients must agree to use one of the contraception methods listed in 
Section 5.5.1. This criterion must be followed from the time of the first dose of 
study medication and until 90 days after the last dose of study drug. 
4.1.2.2. 
Exclusion Criteria 
1. Any clinical condition that, in the opinion of the Investigator, might confound the results 
of the study or pose an additional risk in administering study drug to the patient. 
2. Male patients with a female partner who is planning to become pregnant during the study 
or within 90 days after the last study drug dose. 
3. Anticipated inability to comply with any study procedures, including participation in 
study visits. 
4.2. 
RESCREENING OF STUDY PARTICIPANTS 
Participants who are not enrolled within the screening period will be considered screen failures. 
Rescreening of participants for Part A is permitted with approval of the Medical Monitor. 
Participants can only be rescreened once and must be reconsented at the time of rescreening. 
Rescreened participants will be assigned the same screening number assigned at initial screening.  

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Rescreening of participants is not permitted if the reason for screen failure includes any of the 
following: 
• Did not have a Clinical Severity Score of 2 to 4 (Ricci score; range 0 to 5) at screening 
(failure to meet inclusion criterion 3) 
• Did not have a screening total RSA (Q1-Q4) without weight in the dominant UE assessed 
by RWS ≥ 0.2 and ≤ 0.7 (failure to meet inclusion criterion 4)  
• Meets any of the exclusion criteria  
Participants who are rescreened may not be required to repeat the MRI imaging if performed less 
than 60 days prior to study treatment administration.  
Rescreening is not applicable for the Open-Label Extension (Part B).  
4.3. 
WITHDRAWAL OF PATIENTS FROM STUDY TREATMENT AND/OR THE 
STUDY 
4.3.1. 
Reasons for Withdrawal/Discontinuation 
Patients may withdraw from the study at any time and for any reason without prejudice to their 
future medical care by the Investigator or at the study site. Every effort should be made to keep 
patients in the study, including if a patient decides to prematurely discontinue study treatment 
(see Section 4.3.2). The reasons for a patient not completing the study will be recorded. A patient 
may be withdrawn from the study drug for any of the following reasons: 
1. The patient does not meet the protocol inclusion or exclusion criteria. 
2. The patient is noncompliant with the protocol. 
3. The patient has laboratory safety results that reveal clinically significant hematological or 
biochemical changes from the baseline values. 
4. The patient has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
5. The patient is lost to follow-up. 
6. Other reasons (eg, development of contraindications of use of study drug). 
A patient must be withdrawn from the study drug for any of the following reasons: 
1. The patient has a serious or intolerable AE(s) that, in the Investigator’s opinion, requires 
withdrawal from the study.  
2. The patient withdraws consent, or the Investigator or Sponsor decides to discontinue the 
patient’s participation in the study. 
3. The patient becomes pregnant.  
The Investigator will also withdraw a patient if Fulcrum terminates the study. Upon occurrence 
of a serious or intolerable AE, the Investigator will confer with the Sponsor. If a patient is 

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discontinued because of an AE, the event must continue to be followed to satisfactory resolution 
as described in Section 7.4. Any patient may withdraw his or her consent at any time. 
4.3.2. 
Handling of Withdrawals 
Patients are free to withdraw from the study or study treatment at any time upon request. Patient 
participation in the study may be stopped at any time at the discretion of the Investigator or at the 
request of the Sponsor. 
Patients who discontinue study treatment or active participation in the study will no longer 
receive study drug. When a patient withdraws from the study treatment or active participation in 
the study, the reason(s) for withdrawal shall be recorded by the Investigator on the relevant page 
of the electronic case report form (eCRF).  
If a patient prematurely discontinues study treatment, they will be encouraged to remain in the 
study and continue with all other aspects of the study. If appropriate, patients can restart study 
drug at the Investigator’s discretion (depending on the reason for discontinuation of study 
treatment), after approval from the Sponsor. 
If a patient decides to prematurely discontinue study treatment and not continue with all other 
aspects of the study, they will be considered to have withdrawn from the study. If a patient 
withdraws from the study, they will be asked to complete the early termination (ET) visit as soon 
as possible after the decision to terminate study participation and to complete the safety follow-
up visit 
 days and a safety phone screen 
 days after their last dose of study drug. If 
the ET visit will be scheduled more than 7 days after the last dose of study drug, the safety 
follow-up and ET visits may be combined, with no duplication of assessments required. 
Patients who fail to return for final assessments will be contacted by the site in an attempt to 
have them comply with the protocol. In the case of patients being lost to follow-up, at least 
3 documented attempts to contact the patient must be made.  
It is vital to obtain follow-up data on any patient withdrawn because of an AE or SAE. In every 
case, efforts must be made to undertake protocol-specified safety follow-up procedures. 
4.3.3. 
Replacements 
Patients who withdraw or discontinue will not be replaced. 

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5. 
STUDY TREATMENTS 
5.1. 
PART A: PLACEBO-CONTROLLED TREATMENT PERIOD 
5.1.1. 
Method of Assigning Participants to Treatment Groups 
Patients will be randomly assigned at the baseline visit (Day 1) to receive losmapimod (active 
drug) or placebo using a 1:1 allocation ratio. Randomization will be stratified to ensure that 
treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 
4 to 9 repeats) and by FSHD Type (FSHD1 versus FSHD2). 
An Interactive Response Technology (IRT) system will be used to administer the randomization 
schedule. A designated unblinded statistician separate from the study team will generate the 
randomization schedule using the latest version of SAS software (SAS Institute, Cary, NC) for 
IRT, which will link sequential patient randomization numbers to treatment codes. The 
randomization will use an appropriate block size, which will not be revealed.  
Patients can be randomized only once. 
5.1.2. 
Treatments Administered 
Study drug tablets (losmapimod or placebo) will be dispensed to patients at the visits detailed in 
Table 7. 
During the 48-week placebo-controlled treatment period, patients will receive 15 mg 
losmapimod PO BID or placebo BID with food.  
If a patient misses a dose and it is more than 6 hours until the next planned dose, the patient will 
be instructed to take the missed dose and resume study drug dosing as normal. If it is less than 6 
hours until the next planned dose, the patient will be instructed to skip the missed dose and then 
resume study drug dosing as normal. 
On visit days during which blood collection will occur for PK assessment (see Table 7), patients 
should wait to take their dose in the clinic.   
5.2. 
PART B: OPEN-LABEL EXTENSION 
5.2.1. 
Treatments Administered 
Losmapimod will be dispensed to patients at the visits detailed in Table 8. Patients are not to 
receive study drug until all assessments for Part A have been completed. 
While on study, patients will receive 15 mg losmapimod tablets PO BID with food.  
If a patient misses a dose and it is more than 6 hours until the next planned dose, the patient will 
be instructed to take the missed dose and resume study drug dosing as normal. If it is less than 6 
hours until the next planned dose, the patient will be instructed to skip the missed dose and then 
resume study drug dosing as normal. 

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Any planned treatment interruptions (e.g., scheduled surgery) during Part B may be permitted on 
a case-by-case basis with approval from the Medical Monitor. 
5.3. 
IDENTITY OF INVESTIGATIONAL PRODUCT 
Losmapimod tablets for oral administration are available as 
 
 tablets containing 15 mg of losmapimod as the 
 free base. Losmapimod 
tablets also contain the inactive excipients 
 
 
Placebo tablets (Part A only) are identical in appearance to losmapimod and are manufactured 
using commonly used and recognized tablet excipients that are also used in the active tablets. 
An IRT system will be used to ensure that the study site is provided with adequate supplies of 
blinded losmapimod and placebo (Part A only) or losmapimod (Part B only) and that no expired 
tablets will be dispensed to study patients. 
5.4. 
MANAGEMENT OF CLINICAL SUPPLIES 
5.4.1. 
Study Drug Packaging and Storage 
All tablets are packed in white high-density polyethylene bottles with a child-resistant closure 
and include an induction sealed liner. 
Each dispensation will contain a blinded (Part A only) or labeled (Part B only) dosage for 
1 patient with a sufficient quantity to cover until the next scheduled visit plus additional tablets 
to cover the visit window. If needed, patients may be provided additional study drug via a courier 
service, as applicable. Study drug will be packaged and labeled in accordance with regulatory 
requirements. In Part A only, study drug will be packaged and labeled in a manner to retain the 
study blind.  
Further details of study drug packaging, labeling, and distribution of the study medication will be 
provided in the Pharmacy Manual. For information on proper storage of the study drug, refer to 
the current losmapimod Investigator’s Brochure or Pharmacy Manual.  
5.4.2. 
Study Drug Accountability 
During the study, each patient will be provided a sufficient quantity of study drug to allow for 
dosing until their next scheduled visit plus additional tablets to cover the visit window. If needed, 
patients may be provided additional study drug via a courier service, as applicable. At the next 
scheduled clinic visit, patients must return their bottles of study drug for accountability.  
The Investigator will maintain accurate records of receipt of all study drug, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study drug is 
dispensed and used by each patient in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy regulatory 

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requirements regarding drug accountability, all study drug will be reconciled and retained or 
destroyed according to applicable regulations. 
5.5. 
LIFESTYLE RESTRICTIONS 
Strenuous physical activity (eg, heavy lifting, weight or fitness training) should be avoided for 48 
hours prior to each study visit. Routine ambulatory and other activities (eg, walking at normal 
pace) will be permitted, with the level of activities kept as similar as possible on all days of the 
study.  
For the screening visit in Part A and the baseline visit in Part B, patients will be required to fast 
for at least 4 hours prior to laboratory blood samples being taken.  
5.5.1. 
Contraception Requirements 
A female patient of childbearing potential is eligible to participate if she is using or willing to use 
a highly effective method for avoidance of pregnancy for the duration of dosing and until 
 
 after the last dose of study drug.  
Women of childbearing potential and male patients with female partners of childbearing 
potential must agree to use one of the contraception methods listed in Section 5.5.1.1. This 
criterion must be followed from the time of the first dose of study medication until 
 after 
the last dose of study drug. 
5.5.1.1. 
Highly Effective Methods for Avoiding Pregnancy in Females of Childbearing 
Potential 
The following is the all-inclusive list of highly effective methods for avoiding pregnancy (ie, 
have a failure rate of less than 1% per year when used consistently and correctly and, when 
applicable, in accordance with the product label) (Hatcher 2007):  
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation:  
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 

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• Vasectomized partner, provided that the partner is the sole sexual partner of the WOCBP 
trial patient and that the vasectomized partner has received medical assessment of the 
surgical success 
• Sexual abstinence (Sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient.) 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Progestogen-only oral hormonal contraception (where inhibition of 
ovulation is not the primary mode of action), male or female condom with or without spermicide, 
and cap, diaphragm or sponge with spermicide are not considered as highly effective. A 
combination of male condom with either cap, diaphragm, or sponge with spermicide (double 
barrier methods) are not considered highly effective, birth control methods. 
5.6. 
BLINDING 
5.6.1. 
Part A: Placebo-Controlled Treatment Period 
The placebo-controlled treatment period will be performed in a double-blind fashion. The 
Investigator, study staff, patients, and monitor will remain blinded to patient-level treatment 
assignment until study closure. The Sponsor and/or its designee will remain blinded to the 
treatment until after all patients have completed Part A of the study and the database has been 
locked for statistical analyses, after which time they will be unblinded.  
The study drug and its matching placebo are indistinguishable and will be packaged in the same 
way. There are no tolerability issues that could unblind drug versus placebo. 
A patient’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the patient depends on knowing the study treatment the patient received. In the 
event that the blind needs to be broken because of a medical emergency, the Investigator may 
unblind an individual patient’s treatment allocation without the Sponsor's prior agreement. As 
soon as possible, the Investigator should contact the Medical Monitor to discuss the medical 
emergency and the reason for revealing the actual treatment received by that patient. 
For medical emergencies, the treatment assignment will be unblinded through the IRT. Reasons 
for treatment unblinding must be clearly explained and justified in the eCRF. The date on which 
the code was broken together with the identity of the person responsible must also be 
documented. 
Patients who continue to Part B will remain blinded to their Part A treatment condition through 
completion of Part B. 

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5.6.2. 
Part B: Open-Label Extension 
Neither patients nor study staff will be unblinded to Part A treatment condition. Patients will not 
be blinded in Part B. 
5.7. 
TREATMENT COMPLIANCE  
Patient compliance will be monitored by tablet counts in the clinic. In addition, patient diaries 
may be used to record the date and time of each dose taken. This information may also be used to 
calculate compliance. Site staff should encourage the proper use of study drug for those patients 
who are not compliant. 
5.8. 
PRIOR AND CONCOMITANT THERAPY 
Use of all concomitant medications taken within 28 days before screening through the safety 
follow-up visits will be recorded in the patient’s eCRF. The minimum requirement is that drug 
name and the dates of administration are to be recorded. This will include all prescription drugs, 
herbal products, vitamins, minerals, and over-the-counter medications. Any changes in 
concomitant medications also will be recorded in the patient’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the Investigator. However, it is the responsibility of the 
Investigator to ensure that details regarding the medication are recorded in full in the eCRF. 
The use of the following medications is restricted or prohibited in this study: 
• Vaccination with a live attenuated vaccine from 6 weeks prior to randomization until the 
safety follow-up visits. 
• Patients who are on drug(s) or supplements that may affect muscle function, as 
determined by the Investigator, or that are included in the list of drugs presented in 
Appendix 3 must be on a stable dose of that drug(s) or supplement for at least 3 months 
prior to the first dose of study drug and remain on that stable dose for the duration of the 
study. Changes to the dose or treatment discontinuation during the study can only be 
done for strict medical reasons by the treating physician with clear documentation and 
notification to the Sponsor. Treatment with a statin can be initiated during the study if it 
is medically required. In this case, preference should be given to hydrophilic statins (e.g., 
pravastatin, rosuvastatin, fluvastatin) over lipophilic statins (e.g., simvastatin, 
atorvastatin, lovastatin.) Particular attention should be paid to creatine phosphokinase 
(already part of the laboratory safety monitoring) in patients who start treatment with a 
statin during the study.  
Subjects who take concomitant medications that are OAT1/OAT3 substrates and have a narrow 
therapeutic index may need to have their blood levels monitored for levels of the OAT1/OAT3 
substrates after losmapimod dosing (see Appendix 4). 
 

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6. 
STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study procedures, all potential patients will sign an ICF. Patients will 
have the opportunity to have any questions answered before signing the ICF. The Investigator 
must address all questions raised by the patient. The Investigator or designee will also sign the 
ICF. 
Patients continuing to Part B will sign and date an ICF before performing any study procedures 
for Part B of this protocol. Patient numbers will be maintained from Part A. 
Study visits and the timing of assessments for the screening period or the treatment and follow-
up periods are detailed in the schedules of assessments (Table 7 and Table 8). 
6.1. 
EFFICACY AND SAFETY ASSESSMENTS 
Efficacy assessments will be performed during Part A and select efficacy assessments will also 
be performed during Part B 
 Select safety 
assessments (Eliciting and Documenting Adverse Events, Laboratory Analyses, Vital Signs, 
Physical Examinations, Twelve-Lead Electrocardiograms) will also be performed during Part B. 
6.1.1. 
Reachable Workspace 
The RWS Microsoft Kinect-based movement sensor system will be used at the visits noted in 
Table 7 and Table 8 to determine the patient’s RWS. 
The RWS is a 3D sensor-based system (using a single depth-ranging sensor) that can 
unobtrusively detect an individual’s RWS and reflects individual global UE function, including 
shoulder and proximal arm. Previous and ongoing evaluation of the hardware and software 
system using a commercially available and cost-effective single sensor platform (Microsoft 
Kinect sensor) has demonstrated its high reliability, repeatability, face validity, feasibility, 
sensitivity to change, and promise as a COA for FSHD and other neuromuscular disorders (Han 
et al. 2015). Moderately impaired individuals with baseline RSA values between 0.20 and 0.70 
(out of 1.0, for quadrants Q1-Q4) were more likely to show predictable declines over time with 
an annualized total RSA loss of 2.74% (P=0.047) (Hatch, Chan, et al. 2019). This study includes 
an inclusion criteria of screening total RSA (Q1-4) without weight between 0.20 and 0.70 to 
enrich for a population that is likely to change over a 1-year period.  
During the evaluation, patients will be seated in front of the Microsoft Kinect sensor and will 
undergo a standardized upper extremity movement protocol under the supervision of a study 
clinical evaluator while looking at a video monitor. The evaluation will be performed with and 
without weights and on both the dominant and non-dominant arms. The Kinect sensor will track 
the 3D upper limb trajectory and transform the movements into a body-centric coordinate 
system. Each individual’s RWS envelope will be reconstructed in a graphical output. Each body 
side’s RWS envelope will be divided into 5 quintants, with the shoulder joint serving as the 
origin. The absolute total RWS surface envelope area (m2) as well as areas for each of the 

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quadrants will be calculated. Scaling of the data by each person’s arm length will allow 
normalization for comparison between patients (Han et al. 2015).  
Instructions for equipment assembly, setup, testing, and site certification; a manual of operation; 
and a quick reference guide will be described in an RWS manual. A central reader will be 
responsible for training, quality control, data analysis, and standardization of the RWS across all 
sites in the study. 
6.1.2. 
Skeletal Muscle Magnetic Resonance Imaging 
Whole-body Dixon MRI for MFF, LMV, and MFI will be performed at the visits noted in 
Table 7. Patients will be screened for any contraindications to MRI as per clinic standard 
practice. Patients can travel for MRI if needed, but the use of a study-approved MRI scanner 
should be consistent during the trial. 
Details will be described in the study MRI manual. The study MRI manual will also describe in 
detail the steps involved in the acquisition, transmission, quality evaluation, and analysis of MRI 
images between the study site and the central reader. 
6.1.3. 
Hand-Held Dynamometry 
Dynamometry will be performed at the visits noted in Table 7 and Table 8. Quantitative 
isometric dynamometry (hand-held dynamometer) will be used to assess the skeletal muscle 
strength. Isometric dynamometry measures the static muscle strength without any movement.  
Further details of the assessment will be provided in a study reference manual. All sites will use 
the same equipment and standardized testing procedure. 
6.1.4. 
Eliciting and Documenting Adverse Events 
AEs and SAEs will be assessed from the time the patient signs the ICF (for Part A and Part B) up 
to the last study visit, or up to 30 days after the patient has stopped study treatment, whichever is 
later, and SAEs must be reported to the Sponsor (or designee) by the Investigator without undue 
delay, but not later than 24 hours of obtaining knowledge of its occurrence (as described in 
Section 7.3.2). Any SAEs experienced after this period should be reported to the Sponsor (or 
designee) only if the Investigator suspects a causal relationship to the study drug. 
At every study visit, patients will be asked a standard nonleading question to elicit any medically 
related changes in their well-being. They will also be asked if they have been hospitalized, had 
any accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and over-the-counter medications). 
In addition to patient observations, AEs identified from any study data (eg, clinically significant 
laboratory values, physical examination findings, ECG changes) or identified from review of 
other documents that are relevant to patient safety will be documented on the AE page in the 
eCRF. 

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AEs that occur during Part A will continue to be monitored until they are resolved or the patient 
is lost to follow-up. For those patients who rollover to Part B, ongoing AEs will continue to be 
monitored during Part B.  
6.1.5. 
Laboratory Analyses 
Samples for serum chemistry, hematology, and urinalysis will be collected at the time points 
specified in Table 7 and Table 8. Processing, storage, and shipping procedures for all clinical 
laboratory samples are provided in a laboratory manual. Sample collection details are presented 
in Section 6.2.14. For the screening visit in Part A and the baseline visit in Part B, patients will 
be required to fast for at least 4 hours prior to laboratory blood samples being taken. 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, radiological scans, vital sign measurements), including those that 
worsen from baseline (ie, prior to first dose) and are felt to be clinically significant in the medical 
and scientific judgment of the Investigator, are to be recorded as AEs or SAEs. However, any 
clinically significant safety assessments that are associated with the underlying disease, unless 
judged by the Investigator to be more severe than expected for the patient’s condition, are not to 
be reported as AEs or SAEs. Clinically significant abnormal laboratory test results will be 
reviewed by the Investigator and recorded as AEs or SAEs on the appropriate page in the eCRF.  
If the laboratory reports are not transferred electronically, the values must be filed with the 
source information (including reference ranges). In most cases, clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the patient’s condition. 
All laboratory tests with clinically significantly abnormal results during participation in the study 
or within 7 days after the last dose of investigational product should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the Investigator. 
All protocol-required laboratory assessments (Table 6) must be conducted in accordance with the 
laboratory manual and the Schedules of Assessments. If laboratory values from 
non-protocol-specified laboratory assessments performed at the institution’s local laboratory 
require a change in patient management or are considered clinically significant by the 
Investigator (eg, SAE, AE, or dose modification), then the results must be recorded in the eCRF. 
Blood and other biological samples will be collected for the clinical laboratory tests in Table 6. 
Table 6: 
Protocol-Required Laboratory Tests   
Serum chemistry 
Glucose, sodium, potassium, calcium, inorganic phosphate, total protein, 
albumin, blood urea nitrogen, creatinine, total bilirubin, direct bilirubin*, 
alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 
gamma-glutamyltransferase, creatine phosphokinase 
*Direct bilirubin will only be tested in instances where total bilirubin is 
elevated. Direct bilirubin will be measured automatically by the central lab on 
the sample where total bilirubin is elevated. An additional sample is not 
required to be collected.  

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Hematology 
Hemoglobin (including mean corpuscular volume), mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red blood 
cell count, total white blood cell count, platelet count 
Differential blood counts, including basophils, eosinophils, neutrophils, 
lymphocytes, and monocytes 
Urinalysis 
Leukocytes, blood, nitrite, protein, urobilinogen, bilirubin, pH, specific gravity, 
ketones, glucose 
If there is a clinically significant positive result, urine will be sent for 
microscopy and/or culture. 
Pregnancy 
Serum beta human chorionic gonadotropin (all female patients of child-bearing 
potential), serum follicle-stimulating hormone (suspected postmenopausal 
female patients only [defined in Section 5.5.1]), urine pregnancy test (as 
required by local regulations) 
Serology testing 
Hepatitis B surface antigen, hepatitis C virus antibody, HIV-1/HIV-2 
antibodies; tuberculosis will also be tested locally by QuantiFERON-TB Gold 
at Italian sites only (Appendix 2). 
Patients with a known history of hepatitis infection must be tested to confirm 
active infection. All patients will be tested for hepatitis B surface antigen and, if 
positive, will not be allowed to enroll in the study. All patients will also be 
tested for hepatitis C antibody and, if positive, should be tested for viral RNA. 
If the viral RNA test is negative, indicating inactive/resolved hepatitis C 
infection, then the patient can enroll in the study as long as their liver panel is 
within range of the inclusion and exclusion criteria (Section 4.1). If the viral 
RNA test is positive, indicating active viral hepatitis C, the patient will not be 
allowed to enroll in the study.  
Urine drug screen 
Cocaine, amphetamines, opiates (morphine), benzodiazepines, and 
cannabinoids 
Use of CBD/THC is permitted. 
6.1.6. 
Medical History 
Medical history will be recorded at screening and will be reviewed at baseline to ensure no 
changes have occurred since the screening visit. Clinically relevant findings that are present prior 
to study drug initiation must be recorded on the Medical History page in the eCRF. Clinically 
relevant findings found after study drug initiation and meeting the definition of an AE (new AE 
or worsening of previously existing condition) must be recorded on the AE page in the eCRF. 
FSHD-specific history will be recorded at screening.  
6.1.7. 
Vital Signs 
Vital sign (pulse rate, respiration rate, blood pressure, and temperature) assessments will be 
performed at the time points specified in Table 7 and Table 8. Assessments will be taken after 
the patient has been seated or recumbent for at least 5 minutes and before any 12-lead ECG 
assessment or blood sampling is performed. 

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6.1.8. 
Physical Examinations 
Physical examinations will be performed at the time points specified in Table 7 and Table 8.  
Physical examinations at screening and safety follow-up will include an evaluation of body 
systems, including but not limited to the following: skin; head, eyes, ears, nose, and throat; 
respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological 
system; and musculoskeletal system.  
Symptom-directed physical examinations can occur at any time during the study if triggered by 
AEs or if deemed necessary by the Investigator.  
Weight (kg) will be recorded at screening and throughout the study at the time points specified in 
Table 7 and Table 8.  
Height (cm) will be recorded and body mass index (BMI) calculated at screening: BMI (kg/m2) = 
weight (kg) / (height [cm] / 100)2. Weight and height will be measured with shoes off and 
preferably with the same balance at each visit. 
6.1.9. 
Twelve-Lead Electrocardiograms 
Single 12-lead ECGs will be performed at the time points specified in Table 7 and Table 8. The 
primary ECG tracings will be locally read by the Investigator.  
Twelve-lead ECGs will be performed after patients have been recumbent for at least 5 minutes. 
The ECGs should be performed after the measurement of vital signs and before any procedures 
that may affect heart rate (eg, blood sampling). 
At the screening visit, if QTcF exceeds 450 msec for males or 470 msec for females, the ECG 
will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine 
the patient’s eligibility for the study.  
Any clinically significant changes from baseline should be reported as AEs or SAEs, if 
applicable. 
6.2. 
OTHER ASSESSMENTS 
Assessments, described below, will be performed in Part A. 
 
 will also be performed in Part 
B. 
6.2.1. 
Genetic Confirmation of FSHD 
Genetic testing for FSHD is highly sensitive and specific. The finding of a D4Z4 contraction on 
chromosome 4q35 likely has a sensitivity of 93% and a specificity of 98% for the diagnosis of 
clinically defined FSHD. Healthy individuals possess at least 11 D4Z4 repeats, yielding a DNA 
fragment >38 kb on standard genetic testing. Affected individuals possess between 1 and 10 
repeats, yielding DNA fragments ranging from 10 to 38 kb in size. Measurement of the size of 
the residual D4Z4 sequence on 4q35 forms the basis for genetic testing in FSHD (Tawil et al. 

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2015). For this study, only patients with 1 to 9 repeats will be enrolled. The number of repeats 
will be calculated by a diagnostic laboratory using the size of the D4Z4 bands on Southern blot 
testing. The site will enter the number of repeats into the IRT system. Patients with >9 repeats 
will be excluded from the study because such individuals tend to have slower progression and 
are more variable due to the presence of genetic modifiers. 
FSHD2 (5% of FSHD) is also the result of hypomethylation of the D4Z4 region of chromosome 
4q35. However, in this case, hypomethylation is not associated with a D4Z4 contraction. About 
80% of patients with FSHD2 have a separate mutation in SMCHD1 (structural maintenance of 
chromosomes flexible hinge domain 1), a hypermethylating enzyme with a normal role in X 
chromosome inactivation. Mutations in SMCHD1 (and presumably other yet-to-be-defined loci) 
result in hypomethylation of the D4Z4 region, which leads to DUX4 transcript expression. 
Genetic confirmation must be obtained before the patient is randomized. Genetic confirmation 
can come from previous testing, if verified with appropriate documentation from an accredited 
laboratory. If genetic testing is necessary, the 
 screening window and activities will not 
start until the results are obtained and verified by the Principal Investigator (PI).  
Due to the stable transmission of repeat sizes within families, patients with a clinical diagnosis of 
FSHD who have a first-degree relative with a genetically confirmed diagnosis of FSHD may be 
entered into the study for screening assessments including MRI. During screening, a 
confirmatory genetic diagnosis will be conducted. If genetic testing during screening is 
necessary, the 
 screening window will not start until the results are obtained and verified 
by the PI. 
Further detailed handling, processing, storage, and shipping procedures for genetic testing 
samples are described in a laboratory manual. 

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6.2.5. 
Patient Global Impression of Change 
The PGIC will be performed at the visits noted in Table 7 to obtain the patients’ rating of overall 
improvement. Patients will be asked to rate their overall status at the start of the study on a scale 
from 1 (very much improved) to 7 (very much worse). The PGIC scale has been validated in 
several other indications and is recommended by the FDA for use as a meaningful measure of 
within-patient change (Gautschi et al. 2016; Chan et al. 2020). 
6.2.8. 
Neuro-QoL Upper Extremity Patient Reported Outcome 
The Neuro-QoL UE function measure will be performed at the visits noted in Table 7 to obtain 
the patients’ self-reported rating of quality of life related to upper extremity function (Cella et al. 
2012). The Neuro-QoL UE measures ability across fine motor and activities of daily living 
involving digital, manual and reach-related function and self-care. Responses are divided into 5 
ordinal levels (1 = unable to do, 2 = with much difficulty, 3 = with some difficulty, 4 = with a 
little difficulty, 5 = without any difficulty). 

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6.2.12. 
Qualitative Exit Interview 
A qualitative exit interview will be conducted in a subset of the patient population at Week 48 as 
noted in Table 7 to assess the patient’s experience during the study. 
The purpose of the qualitative exit interview is to capture study participants’ subjective 
experience with treatment, with study participation, and to gather insights to inform 
interpretation and clinical meaningfulness of the primary endpoint, RWS. Interview topics will 
include their experience with the disease, associated symptoms, symptom impact/burden and 
interference on the patient’s life, patient perceptions of meaningful changes during the double-
blind treatment period, and to explore patient experience with treatment.  
The interview will consist of a 1-time telephone interview, lasting approximately 60 minutes. 
Interviews will be conducted by trained interviewers using a semi-structured interview guide and 
will be conducted within 7 days of completing the Week 48 visit. Neither failure to complete the 
interview nor completion outside of the targeted 7-day window will constitute a protocol 
deviation. All patients enrolling in the study will be invited to participate in the qualitative 
interview until the targeted subsample of at least 60 patients has been filled. This sample is large 
enough to accomplish objectives and reasonable for achieving a mix of patients from each 
treatment arm as well as inclusion of a small number of the patients who will be enrolled with 
FSHD2. If more study participants are consented than required, the larger pool of interview 
candidates will be used to select a more diverse sample across countries and/or regions. 
Patients will be invited to participate in the qualitative interview substudy as part of the main 
consenting process at the beginning of the study. Patients already enrolled and randomized at the 
time of this amendment can be invited later in their treatment period and can re-sign the amended 
consent form to document their willingness to participate in the substudy. Patients who agree to 

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participate in the qualitative exit interviews will also be asked to complete a contact information 
transfer form during the consent process, which gives the clinic site staff permission to provide 
their contact information to the interview team and allows the interviewers in each country to 
contact the patients directly to schedule their interview at a convenient date and time. 
Additionally, the clinic site staff will obtain verbal consent no later than the Week 48 visit (Visit 
6) to confirm that the patients are still willing to participate in the exit interview sub-study. 
Fulcrum has engaged Evidera Patient Centered Research to support the study by providing 
skilled interview services. Before conducting the interview, Evidera will confirm with the site 
that the study participant has completed the necessary study procedures for the Week 48 visit to 
ensure compliance with the exit interview protocol procedures. Evidera personnel are not 
authorized to contact patients after they complete their exit interview.  
Any unfavorable changes or AEs reported by the patients during the conduct of the exit 
interviews will be communicated to the Investigator or designee by the interviewer within 
24 hours (or 1 business day). The Investigator will be responsible for reporting all AEs and SAEs 
based upon appropriate medical judgement in accordance with this protocol.      
6.2.14. 
Sample Collections 
Processing, storage, and shipping procedures for all clinical laboratory samples are provided in 
the laboratory manual. 

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7. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The Investigator is responsible for reporting all AEs that are observed or reported during the 
study regardless of their relationship to study drug or their clinical significance. All AEs from the 
time of Part A informed consent and assent, if applicable, through the last follow-up visit in Part 
A or Part B (if applicable) will be recorded in each enrolled patient’s eCRF.   
7.1. 
DEFINITIONS 
7.1.1. 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product (International Council for Harmonisation [ICH]-E2A). Conditions that were 
already present at the time of informed consent should be recorded on the Medical History page 
of the eCRF. Adverse event monitoring should be continued for at least 30 days after the last 
dose of study drug. 
Disease progression should not be regarded or reported as an AE itself, unless it is associated 
with a separate AE. 
Patients will be instructed to contact the Investigator at any time after randomization if any 
symptoms develop. 
7.1.2. 
Definition of Treatment-Emergent Adverse Event 
A TEAE is defined as any event that was not present before exposure to the study drug or any 
event already present that worsens in either intensity or frequency after exposure to the study 
drug. 
7.1.3. 
Definition of Serious Adverse Event 
An SAE is defined as any event that meets 1 of the following criteria: 
• results in death 
• is immediately life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly or birth defect  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, they 

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may jeopardize the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
7.1.3.1. 
Definition of Terms 
Life-threatening: Life-threatening means that the patient was at immediate risk of death from the 
event as it occurred; ie, it does not include a reaction that if it had occurred in a more serious 
form might have caused death. For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though drug induced 
hepatitis can be fatal. 
Hospitalization: AEs requiring in-patient hospitalization or prolongation of an existing 
hospitalization should be considered SAEs. Hospitalization for elective surgery or routine 
clinical procedures that are not the result of AE (eg, elective surgery for a pre-existing condition 
that has not worsened) need not be considered AEs or SAEs. If anything untoward is reported 
during the procedure, that occurrence must be reported as an AE, either “serious” or “non-
serious” according to the usual criteria. 
In general, hospitalization signifies that the patient has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician's office or outpatient setting. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the patient's ability to carry out normal life functions. 
7.1.4. 
Definition of Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an untoward and 
unintended response to a study drug, which is not listed in the applicable product information, 
and meets one of the following serious criteria: results in death, is life-threatening, requires 
hospitalization or prolongation of an existing hospitalization, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect.  
7.1.5. 
Reference Safety Information 
No serious adverse reactions are considered expected by the Sponsor for the purpose of 
expedited reporting of SUSARs and identification of SUSARs in the “Cumulative summary 
tabulations of serious adverse reactions” section of the current Investigator’s Brochure for the 
investigational medical product.  

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7.2. 
CLASSIFICATION OF ADVERSE EVENTS 
Each AE, whether non-serious or serious, will be classified by the Investigator according to the 
following rules and definitions.  
7.2.1. 
Assessment of Intensity/Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s daily 
activities. The intensity of the AE will be rated as mild, moderate, or severe using the following 
criteria: 
Mild: 
An event that is usually transient in nature and generally does not interfere with 
normal activities. 
Moderate: 
An AE that is sufficiently discomforting to interfere with normal activities. 
Severe: 
An AE that is incapacitating and prevents normal activities. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed. Adverse events characterized as 
intermittent do not require documentation of the onset and duration of each episode. 
NOTE: Severity is not the same as “seriousness.” The Investigator will assess the severity of all 
AEs according to the appropriate categories.  
7.2.2. 
Assessment of Causality 
For each AE, the Investigator will determine whether there is a reasonable likelihood that the AE 
may have been caused by study drug according to the categories below. The Investigator’s 
assessment of an AE’s relationship to study drug is part of the documentation process, but it is 
not a factor in determining what is or is not reported in the study. If there is any doubt as to 
whether a clinical observation is an AE, the event should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Not related: 
This relationship suggests that there is no association between the study drug 
and the reported event. 
Unlikely: 
This relationship suggests that the event is most likely produced by other 
factors such as the patient’s clinical condition, intercurrent illness, or 
concomitant drugs administered to the patient, and does not follow a known 
response pattern to the study drug, or the temporal relationship of the event 
to study drug administration makes a causal relationship unlikely. 
Possible: 
This relationship suggests that treatment with the study drug caused or 
contributed to the AE, ie, the event follows a reasonable temporal sequence 
from the time of drug administration or follows a known response pattern to 
the study drug but could also have been produced by other factors. 

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Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with drug administration exists, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the 
drug or class of drugs, or judgment based on the Investigator’s clinical 
experience, the association of the event with the study drug seems likely. 
The event disappears or decreases on cessation or reduction of the dose of 
study drug. 
Definite: 
This relationship suggests that a definite causal relationship exists between 
drug administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) 
do not appear to explain the event. The event reappears or worsens if the 
study drug is re-administered. 
7.2.3. 
Outcome 
The Investigator will provide information regarding the patient outcome of each AE. Outcome 
categories are as follows: Recovered, Recovered with Sequela, Not Recovered, Fatal, and 
Unknown.  
7.2.4. 
Action Taken 
The Investigator will provide information regarding the action taken with respect to the study 
treatment in response to the AE. Categories for action taken include: 
• Drug withdrawn 
• Dose not changed 
• Unknown 
• Not applicable  
7.3. 
REPORTING GUIDELINES 
7.3.1. 
Reporting Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes the following: 
• Drug treatment 
• Dose 
• Event term 
• Time of onset 
• Investigator-specified assessment of severity and relationship to study drug 
• Time of resolution of the event 
• Seriousness 

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• Any required treatment or evaluations 
• Outcome 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications, or progression of disease states (if unexpected worsening beyond normal 
disease progression based on the Investigator’s assessment) must also be reported. All AEs must 
continue to be followed to satisfactory resolution. The latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the patient is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
Reporting for AESIs is described in Section 7.5. 
7.3.2. 
Reporting Serious Adverse Events 
The Investigator (or designee) must report the SAE to the Sponsor or designee without undue 
delay but no later than 24 hours of obtaining knowledge via the paper SAE Intake Form. 
This form should be completed, scanned, and emailed as a PDF attachment to 
clinicalsafety@propharmagroup.com within 24 hours of SAE awareness. Alternately, the report 
may be faxed to +1 (866) 681-1063.  
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of an investigational product under clinical investigation. 
The Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), and Investigators. 
An Investigator who receives an investigator safety report describing an SAE or other specific 
safety information from the Sponsor will review and then file it as appropriate and will notify the 
IRB/IEC, if appropriate according to local requirements. 
7.3.3. 
Expectedness of an Adverse Event 
The expectedness of all AEs will be determined according to the current version of the 
losmapimod Investigator’s Brochure. 
7.3.4. 
Reporting Suspected Unexpected Serious Adverse Reactions  
Suspected unexpected serious adverse reactions will be handled by the Sponsor or designee and 
the Investigator and reported within the required timelines in an unblinded fashion to Regulatory 
Authorities and the IRB/IEC per the requirements of the concerned Regulatory Authorities. 
SUSARs will also be reported in a blinded fashion to study investigators. Investigators may 
request that SUSARs be unblinded. 

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7.4. 
ADVERSE EVENT FOLLOW-UP 
All AEs will be followed until the resolution of AE, completion of the patient’s study 
participation, or study termination, whichever occurs first.  
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs. 
7.5. 
ADVERSE EVENTS OF SPECIAL INTEREST 
An AESI (serious or non-serious) is one of scientific and medical concern for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor is appropriate. If an AE 
or the abnormality is an AESI, the event should be reported on an SAE form, regardless of 
seriousness, and captured in the safety database. Non-serious AESIs will not be reported to the 
Regulatory Authorities unless required.  
Adverse events of special interest for this study include liver tests that meet the criteria for 
potential drug-induced liver injury, in accordance with the US FDA “Guidance for Industry-
Drug-Induced Liver Injury: Premarketing Clinical Evaluation.” 
Liver Tests and Stopping Criteria 
The following 3 laboratory value criteria must be met for potential DILI, or “Hy’s Law”: 
• An elevated ALT or aspartate aminotransferase laboratory value that is ≥3 × ULN 
• An elevated total bilirubin laboratory value that is ≥2 × ULN 
• An alkaline phosphatase laboratory value that is <2 × ULN 
Study drug should be discontinued for patients who meet the laboratory criteria for potential 
DILI as a result of within-protocol specific testing or unscheduled testing. This AESI must be 
reported to the Sponsor within 24 hours of awareness. Further safety steps should be taken to 
closely observe and follow the event until resolution. These steps include, but are not limited to: 
• Making every reasonable attempt to have the patient return to the clinic within 24 hours 
for repeat liver enzyme tests. 
• Obtaining a more detailed history of symptoms and prior or concurrent disease, 
concomitant medication use, alcohol use, recreational drug use, and special diets. 
• Repeating liver enzyme and serum bilirubin tests twice weekly. Frequency of retesting 
can decrease to once a week or less if abnormalities stabilize and the patient is 
asymptomatic. 
• Obtaining viral hepatitis serology. 
• Considering liver imaging and/or hepatology consultation. 
7.6. 
ADVERSE EVENTS OF SIGNIFICANCE 
If an AE of significance occurs (eg, dose-limiting toxicity AE), the event should be reported on 
an SAE form, regardless of seriousness, and captured in the safety database. Non-serious AEs of 
significance will not be reported to the Regulatory Authorities.  

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7.7. 
CLINICAL LABORATORY CHANGES 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, vital sign measurements), including those that worsen from 
baseline (i.e., prior to first dose) and are felt to be clinically significant in the medical and 
scientific judgment of the Investigator are to be recorded as AEs or SAEs. Clinically significant 
abnormal laboratory test results will be reviewed by the Investigator and recorded as AEs or 
SAEs on the appropriate page in the eCRF. 
7.8. 
SPECIAL SITUATIONS 
7.8.1. 
Overdose 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it involved 
losmapimod) that meets SAE criteria (defined in Section 7.1.3) must be communicated to the 
Sponsor or a specified designee within 24 hours. Overdose with or without associated signs or 
symptoms must be reported in the AE eCRF. Any signs or symptoms associated with an 
overdose must also be reported as AEs. Details of any signs or symptoms and their management 
should be recorded including details of any antidote(s) administered. No specific antidote for 
losmapimod is known. In case of overdose, patients should be observed and be provided with a 
supportive standard of care. 
7.8.2. 
Death 
Events that result in death should be recorded and reported on the appropriate eCRF. All causes 
of death must be reported as SAEs. The Investigator should make every effort to obtain and send 
death certificates and autopsy reports to Sponsor or designee’s Pharmacovigilance. 
7.8.3. 
Pregnancy 
Pregnancies occurring in patients enrolled in a study or in a female partner of a male patient must 
be reported and followed to outcome. If a female patient inadvertently becomes pregnant while 
on study treatment, the patient will immediately be removed from the study.  
The Investigator should complete the Pregnancy Report Form and forward it to the Sponsor (or 
designee) within 24 hours of knowledge of the pregnancy. If there is an associated serious 
outcome, then both the Pregnancy Report Form and SAE report form should be completed.  
The site will follow-up with the patient until the pregnancy has been completed or terminated. 
The Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. The Pregnancy 
Outcome report form should be completed and submitted to the Sponsor within 24 hours after 
the Investigator becomes aware of the pregnancy outcome. If an SAE occurred, then the SAE 
form must be completed and submitted as well. 
In the event the pregnancy outcome occurs following the end of the study and database lock, the 
Investigator will report the pregnancy outcome to the Sponsor (or designee) within 24 hours after 

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the outcome of the pregnancy is known to the Investigator in accordance with the procedure for 
reporting SAEs (per SAE reporting guidelines). 
Pregnancy alone is not regarded as an AE unless there is a possibility that the study drug may 
have interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be considered AEs unless they were therapeutic abortions, but should 
be reported to the Sponsor. Hospitalization for normal delivery of a healthy newborn should not 
be considered an SAE. Pregnancy is not considered an SAE unless there is an associated serious 
outcome. Spontaneous abortions should always be reported as SAEs. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (e.g., maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs. 
7.8.4. 
Medication Error 
In case of medication errors, patients should be observed and be provided with a supportive 
standard of care.  
Medication errors should be documented as protocol deviations. A brief description should be 
provided in the deviation, including whether the patient was symptomatic (list of symptoms) or 
asymptomatic and the event accidental or intentional. 
Dosing detail should be captured on the dosing CRF. If the patient takes a dose of study drug that 
exceeds protocol specifications and the patient is symptomatic, then the symptom(s) should be 
documented as an AE(s) and be reported per Section 7.3.1.  
7.8.5. 
Unblinding Due to Medical Emergency 
Any unblinding in Part A should be done only in an emergency that requires the investigational 
drug be identified for the welfare of the patient. Fulcrum will be notified immediately, and a full, 
written description explanation will be provided if the blind is broken. Before the investigational 
drug is unblinded, every attempt should be made to discuss the case with the Investigator. 
Breaking the code at the study site/center will immediately disqualify the patient from further 
participation in the study. 
For IRT Unblinding: 
In an emergency, the PI can obtain the treatment assignment of any patient at his or her study 
site/center through the IRT. In an emergency, the PI will access the IRT to break the blind. 

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8. 
INVESTIGATIONAL PRODUCT COMPLAINTS 
8.1. 
DEFINITION OF INVESTIGATIONAL PRODUCT COMPLAINTS 
An Investigational Product Complaint (IPC) means any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a drug after distribution for investigational use. 
Examples of possible IPCs can be reviewed in the associated Pharmacy Manual. 
All product complaints associated with the material packaged, labeled, and released by the 
Sponsor or its designee will be reported. 
The Investigator or his/her designee is responsible for reporting a complete description of the 
product complaint and any AEs associated via the reporting form or other written 
communication to Fulcrum. 
8.2. 
REPORTING OF INVESTIGATIONAL PRODUCT COMPLAINTS 
IPCs must be reported within 24 hours and details fully documented on the reporting form 
provided within the Study 1821-FSH-301 Pharmacy Manual. The reporting process is detailed 
within the Study 1821-FSH-301 Pharmacy Manual. 

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9. 
STATISTICAL CONSIDERATIONS 
Details regarding the statistical methods and definitions will be provided in statistical analysis 
plans (SAPs). Separate SAPs will be prepared for Part A and Part B. Any deviations from the 
SAPs are to be justified in the clinical study report. Statistical analysis will be performed using 
the latest version of SAS software (SAS Institute, Cary, NC) or other validated software. 
9.1. 
 PART A: PLACEBO-CONTROLLED TREATMENT PERIOD 
Primary Part A analysis will be conducted when the last patient has completed the 
 safety 
follow-up phone call or 48 weeks of treatment (for those who rollover into Part B). For details of 
the interim analyses, see Section 9.3. 
9.1.1. 
Estimands and Intercurrent Events 
The estimand of the primary analysis is the mean difference of the change from baseline in 
average total RSA Q1-Q5 with 500 g wrist weight at Week 48 between treatment groups in the 
full analysis set (FAS) (as per the ICH E9 (R1)). The FAS will consist of all patients with 
FSHD1 and FSHD2 who are randomized and receive at least one dose of study drug in the 
placebo-controlled treatment period. All observed data will be included in the primary analysis, 
including data collected after intercurrent events (as described in ICH E9 (R1) Addendum 2017), 
i.e., treatment discontinuation or a change in concomitant use of FSHD symptomatic medication. 
The change from baseline in average total RSA Q1-Q5 with 500 g wrist weight will be 
summarized by treatment group at each post-baseline visit. A mixed-effects model for repeated 
measures (MMRM) will be used as the primary analysis to analyze change from baseline in 
average total RSA Q1-Q5 with 500 g wrist weight, with terms for treatment group, visit, 
treatment group by visit interaction, baseline value, baseline value by visit interaction, region, 
and FSHD repeat number category, where appropriate. An unstructured covariance matrix will 
be used to model the correlations between repeated measurements within each patient. If the 
unstructured covariance matrix results in a lack of convergence, the first-order autoregressive 
covariance structure followed by the compound symmetric covariance structure will be used. 
The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. In the primary analysis, missing data are assumed to be missing at random (Rubin 
1976). 
9.1.2. 
Statistical Hypothesis 
The primary endpoint is the absolute change from baseline in average total RSA Q1-Q5 with 
500 g wrist weight at Week 48.  
The null hypothesis for the primary endpoint is that the mean change from baseline in average 
total RSA Q1-Q5 with 500 g wrist weight at Week 48 is the same for the 2 treatment groups.  

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The alternative hypothesis for the primary endpoint is that the mean changes from baseline in 
average total RSA Q1-Q5 with 500 g wrist weight at Week 48 are different between the 2 
treatment groups. 
9.1.3. 
Sample Size Determination 
The target population for this clinical trial is patients with FSHD1 and FSHD2. The clinical trial 
will reflect the current epidemiologic information about FSHD, with patients with FSHD1 
making up approximately 95% of the study population and the other 5% being people living with 
FSHD2. However, all studies thus far have been conducted with FSHD1 patients; therefore, this 
calculation was based on that population. Additional FSHD2 patients will be enrolled to explore 
safety and efficacy in this subgroup.  
Assuming the within-group SD of change is 0.08 and that 10% of the study population has 
missing Week 48 data, a sample size of 210 patients with FSHD1 (105 patients per group) will be 
needed to provide at least 95% power with a 2-sided test at 0.05 significance level to detect a 
difference of 0.05 between losmapimod and placebo in change from baseline in average total 
RSA Q1-Q5 with 500 g wrist weight at Week 48. An additional approximately 20 patients with 
FSHD2 will be recruited. The primary analysis will include patients with FSHD1 and FSHD2. 
9.1.4. 
Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
Full analysis set: The FAS will consist of all patients with FSHD1 and FSHD2 who are 
randomized and receive at least 1 dose of study drug in the placebo-controlled treatment period. 
All analyses using the FAS will group patients according to randomized treatment.  
Safety analysis set: The safety analysis set will consist of all patients who receive any study drug 
in the placebo-controlled treatment period. All analyses using the safety analysis set will group 
patients according to treatment actually received. 
Pharmacokinetic analysis set: The PK analysis set will consist of all patients who receive at least 
1 dose of losmapimod and have evaluable PK data for losmapimod. 
9.1.5. 
Description of Subgroups to Be Analyzed 
Any planned subgroup analyses will be described in the SAP for Part A. Subgroups will include 
a subgroup of patients with FSHD2 and subgroups of region, sex, and age. 
9.1.6. 
Statistical Analysis Methodology 
Details of the statistical analyses, methods, and data conventions will be described in the SAP for 
Part A. 
9.1.6.1. 
General Considerations 
Continuous variables will be summarized using the mean, standard deviation, standard error, 
median, first quartile, third quartile, minimum value, and maximum value. Categorical variables 

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will be summarized using frequency counts and percentages. Data will be presented in data 
listings. 
All statistical tests will be 2-sided and performed using a 0.05 significance level, unless 
otherwise specified. 
9.1.6.2. 
Overview of Statistical Methods: Estimation of Estimands and Sensitivity 
Analyses 
See Section 9.1.1 for the estimand of the primary endpoint. Sensitivity analysis of the primary 
and selected secondary endpoints will be described in the SAP for Part A. 
9.1.6.3. 
Analysis of Primary Endpoint 
The primary endpoint of the placebo-controlled treatment period is the change from baseline in 
average total RSA Q1-Q5 with 500 g wrist weight at Week 48. An MMRM will be used to 
analyze the primary endpoint, with the change from baseline in average total RSA Q1-Q5 with 
500 g wrist weight at each post-baseline visit as the dependent variable. The model will include 
terms for treatment group, visit, treatment group by visit interaction, baseline value, baseline 
value by visit interaction, region, and FSHD repeat number category, where appropriate. An 
unstructured covariance matrix will be used to model the correlations between repeated 
measurements within each patient. If the unstructured covariance matrix results in a lack of 
convergence, the first-order autoregressive covariance structure followed by the compound 
symmetric covariance structure will be used. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. Least squares (LS) mean, standard error, and 95% 
CI will be provided for each treatment group. The difference in LS means between treatment 
groups and the 95% CI of the difference will also be calculated. The primary endpoint of 
absolute change from baseline in average total RSA Q1-Q5 with 500 g wrist weight at Week 48 
will be formally tested only during the final analysis when all patients complete Part A study 
participation. All available data will be used.  
The FAS will be used for the primary analysis in the placebo-controlled treatment period. 
In addition, a linear mixed-effects model (LME) will be used to analyze data on average total 
RSA Q1-Q5 with 500 g wrist weight over the placebo-controlled treatment period to estimate the 
slope of trend line and % change/year for each treatment group, and differences of estimated 
slopes and % changes/year between treatment groups. 
9.1.6.4. 
Analysis of Secondary Efficacy Endpoints 
Secondary endpoints (detailed in Section 2.1.2) will be summarized using descriptive statistics. 
Continuous endpoints with multiple post-baseline assessments will be analyzed using an MMRM 
model analogous to the one used for the primary analysis of the primary endpoint based on the 
FAS. They will also be analyzed using an LME model analogous to the linear trend analysis in 
Section 9.1.6.3 based on the FAS, where appropriate. Relative changes from baseline will be 
analyzed using the Wilcoxon rank-sum test, stratified by the FSHD repeat number category. The 
Hodges-Lehmann estimate of the associated treatment difference and asymptotic nonparametric 

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95% confidence interval will be computed. For all patients, changes in measurements will be 
calculated relative to measurements obtained at baseline. 
Further details of these endpoints and analyses are presented in Section 2.1.2 and the SAP for 
Part A. 
9.1.6.6. 
Pharmacokinetic Analyses 
Plasma PK concentrations at each time point for losmapimod will be presented in listings and 
summarized in tables. The summary tables will display the following descriptive statistics: n, 
mean, standard deviation, coefficient of variation, median, minimum, and maximum. 
The individual and mean plasma concentrations will be presented by nominal collection time in 
figures on linear and semi-log scales. 
Population PK models may be developed to address program objectives that require an 
integrative interpretation of these study results. These may include investigations of the nature of 
the PK/PD relationship and the use of these study results as part of a larger model-based data 
analysis. If population PK and PK/PD analyses are performed, those results will be reported 
separately from the results of this study. 
9.1.6.7. 
Safety Analyses 
Safety data in the placebo-controlled treatment period will be analyzed using the safety analysis 
set and summarized by treatment group and visit (if applicable) using descriptive statistics.  
Treatment-emergent AEs will be summarized by MedDRA system organ class and preferred 
term; separate summaries will be produced for treatment-related AEs, AESIs, SAEs, and 
discontinuations due to AEs. Laboratory tests, vital signs, findings from physical examinations, 
and ECGs will be summarized for changes over time during treatment using descriptive 
statistics. 
9.1.6.8. 
Other Analyses 
Descriptive statistics will be provided for demographics, medical history, physical examinations, 
and baseline characteristics. 
Medical history will be coded using MedDRA and summarized by treatment group. 

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9.1.6.9. 
Handling of Missing Data 
For the primary analysis of the primary endpoint, with a mixed-effects model based on restricted 
maximum likelihood estimation and assuming that, conditional on fixed and random effects, data 
are missing at random, no imputation of missing data will be performed. 
Sensitivity analysis will be described in the SAP for Part A. 
9.1.6.10. 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be formed before study initiation, and 
it will be set up according to EMEA/CHMP/EWP/5872/03 Corr. The IDMC is an independent 
and external multidisciplinary group consisting of at least 2 physicians (one of which will serve 
as Chair) and a statistician that, collectively, have experience in the management of relevant 
patients and in the conduct and monitoring of clinical trials. IDMC membership is to be for the 
duration of the trial. If any member would leave the IDMC during the trial, the Sponsor may 
promptly appoint their replacement.  
The IDMC is responsible for periodically reviewing selected data for the purpose of ensuring 
patient safety and maintaining the overall integrity of the trial. The IDMC has the responsibility 
to ensure that any safety and/or efficacy issues and/or recommendations regarding the ongoing 
conduct of the study realized from its review are fairly and expeditiously reported to the Sponsor.  
Full details will be described in a separate IDMC Charter, which will be finalized before the first 
patient is screened in the study.  
9.2. 
PART B: OPEN-LABEL EXTENSION 
9.2.1. 
Statistical Hypotheses 
9.2.2. 
Sample Size Determination 
Patients from Part A who meet the entry criteria may participate in Part B. The sample size is not 
based on any formal statistical assumptions. Up to 230 patients will be enrolled in Part B.  
9.2.3. 
Analysis Sets 
The open-label analysis set will consist of all patients who received at least 1 dose of 
losmapimod in Part B. The open-label analysis set will be used for all analyses, unless otherwise 
specified. 
9.2.4. 
Description of Subgroups to be Analyzed 
Any planned subgroup analyses will be described in the SAP for Part B. Subgroups will include 
a subgroup of patients with FSHD2. 

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9.2.5. 
Statistical Analysis Methodology 
Details of the statistical analyses, methods, and data conventions will be described in the SAP for 
Part B. 
9.2.5.1. 
General Considerations 
Continuous variables will be summarized using n (number of patients with non-missing data), 
mean, standard deviation, standard error, median, first quartile, third quartile, minimum value, 
and maximum value. Categorical variables will be summarized using frequency counts and 
percentages. Data will be presented in data listings. 
Data will be summarized according to sequence of treatment assignment: 
• Losmapimod 15 mg BID/Losmapimod 15 mg BID: This will include patients who are 
assigned to losmapimod at baseline in Part A and continue to losmapimod 15 mg BID in 
Part B. 
• Placebo BID/Losmapimod 15 mg BID: This will include patients who are assigned to 
placebo at baseline in Part A and switch to losmapimod 15 mg BID in Part B. 
9.2.5.2. 
Safety Analyses 
Safety data will be analyzed using the open-label analysis set and summarized by treatment 
sequence and visit (if applicable) using descriptive statistics.  
Treatment-emergent AEs will be summarized by MedDRA system organ class and preferred 
term as well as by relationship to study drug and by severity; separate summaries will be 
produced for AESIs, SAEs, and discontinuations due to AEs. Laboratory tests, vital signs, 
findings from physical examinations, and ECGs will be summarized for changes over time using 
descriptive statistics. 
9.2.5.3. 
Other Analyses  
All other endpoints (detailed in Section 2) will be summarized using descriptive statistics. Linear 
mixed-effects models may be used to analyze continuous longitudinal data to estimate the slopes 
of trend lines and % changes/year, and to explore the possibility that earlier treatment with 
losmapimod is better than delayed treatment and that the placebo group’s progression slows after 
treatment with losmapimod. 
Further details of these endpoints and analyses are presented in Section 2.2 and the SAP for Part 
B. 
Descriptive statistics will be provided for demographics, baseline characteristics, and medical 
history. 
Medical history will be coded using MedDRA and summarized by treatment sequence. 
9.2.6. 
Handing of Missing Data 
Missing values for individual data points will remain as missing, unless otherwise specified. 

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9.3. 
INTERIM ANALYSES 
No formal interim analyses are planned for Part A aside from those safety analyses required to 
support the IDMC (as described in Section 9.1.6.10). 
Once all subjects have completed Part A, primary statistical analyses of Part A data as specified 
in Section 9.1 will be performed. 
The Investigator, study staff, patients, and monitor will remain blinded to patient-level treatment 
assignment until study closure. The Sponsor and/or its designee will remain blinded to the 
treatment until after all patients have completed Part A of the study and the database has been 
locked for statistical analyses of Part A data, after which time they will be unblinded. 
For Part B, the Sponsor may perform periodic safety, PRO reviews, and interim analysis at any 
time to facilitate Sponsor decision-making and communications with health authorities and other 
stakeholders as needed. These reviews and analyses will be performed such that the ongoing 
study integrity is maintained. 
Patients who continue to Part B will remain blinded to their Part A treatment assignment through 
completion of Part B. 

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10. 
DATA QUALITY ASSURANCE 
This study will be conducted according to the ICH E6(R2) risk and quality processes described 
in the applicable procedural documents. The quality management approach to be implemented in 
this study will be documented and will comply with the current ICH guidance on quality and risk 
management. The Sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
10.1. 
DATA MANAGEMENT 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the patients treated as part of the research under this 
protocol. The Investigator agrees to maintain accurate eCRFs and source documentation as part 
of the case histories. These source documents may include laboratory reports, ECG strips, etc. 
Study site personnel will enter patient data into the eCRF program. The analysis data sets will be 
a combination of these data and data from other sources (eg, laboratory data). 
Clinical data management will be performed in accordance with applicable Sponsor or 
designee’s standards and data cleaning procedures to ensure the integrity of the data, eg, 
removing errors and inconsistencies in the data. AE terms will be coded using MedDRA, an 
internal validated medical dictionary, and concomitant medications will be coded using the 
World Health Organization Drug Dictionary. 
All personal data collected related to patients, Investigators, or any person involved in the study, 
which may be included in the Sponsor’s databases, shall be treated in accordance with local data 
protection law.  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
After final database lock, each study site will receive a CD-ROM or other acceptable transfer 
method containing all of their site specific eCRF data as entered into the eCRF program for the 
study, including full discrepancy and audit history. Additionally, a CD-ROM copy or other 
acceptable storage of all of the study site’s data from the study will be created and sent to the 
Sponsor for storage. The Contract Research Organization will maintain a duplicate CD-ROM 
copy or other acceptable storage for their records. In all cases, patient initials will not be 
collected or transmitted to the Sponsor. 

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11. 
ETHICS 
11.1. 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW 
BOARD 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB/IEC 
before participation of human patients in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study patients, and any other 
written information regarding this study to be provided to the patient or the patient’s legal 
guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the 
IRB/IEC compliance with ICH E6(R2): Good Clinical Practice (GCP) will be maintained by the 
site and will be available for review by the Sponsor or its designee. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must identify 
the IRB/IEC name and address, the clinical protocol by title or protocol number or both, and the 
date on which approval or a favorable opinion was granted. 
The Investigator is responsible for providing written summaries of the progress and status of the 
study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC. The Investigator 
must promptly supply the Sponsor or its designee, the IRB/IEC, and, where applicable, the 
institution, with written reports on any changes significantly affecting the conduct of the study or 
increasing the risk to patients. 
11.2. 
ETHICAL CONDUCT OF THE STUDY 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, ICH GCP, the protocol, and all applicable regulations. 
11.3. 
PATIENT INFORMATION AND CONSENT 
A written informed consent approved by the Sponsor and by the IEC/IRB in compliance with 
applicable regulatory authority regulations shall be obtained from each patient before entering 
the study (for both Part A and Part B) or performing any unusual or nonroutine procedure that 
involves risk to the patient. An informed consent template may be provided by the Sponsor to 
investigative sites. If any institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the Sponsor or its designee or 
both before IRB/IEC submission. Once reviewed, the consent will be submitted by the 
Investigator to his or her IRB/IEC for review and approval before the start of the study. If the 
ICF is revised during the course of the study, all active participating patients must sign the 
revised form. 
Before recruitment and enrollment, each prospective patient or his or her legal guardian will be 
given a full explanation of the study and be allowed to read the approved ICF. Once the 
Investigator is assured that the patient/legal guardian understands the implications of 

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participating in the study, the patient/legal guardian will be asked to give consent to participate in 
the study by signing the ICF. 
The Investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient or legal guardian. 

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12. 
INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the Investigator in the conduct of the 
study but may be patient to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB/IEC 
but will not result in protocol amendments. 
12.1. 
CONFIDENTIALITY 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality. All records will be kept in a secure storage 
area with limited access. Clinical information will not be released without the written permission 
of the patient (or the patient’s legal guardian), except as necessary for monitoring and auditing 
by the Sponsor, its designee, applicable regulatory authorities, or the IRB/IEC. 
To ensure privacy, directly identifying information of study patients will not be attached to 
records or samples released to the Sponsor and its service providers for research purposes. 
The Investigator and all employees and coworkers involved with this study may not disclose or 
use for any purpose other than performance of the study any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study. Prior written 
agreement from the Sponsor or its designee must be obtained for the disclosure of any said 
confidential information to other parties. Additional confidentiality requirements and obligations 
will be set forth in the clinical trial agreement to be entered into by the Sponsor, the PI, and the 
institution.  
12.2. 
FINANCIAL DISCLOSURE AND OBLIGATIONS 
Investigators are required to provide financial disclosure information to allow the Sponsor to 
submit the complete and accurate certification or disclosure statements required by applicable 
regulatory authorities. In addition, the Investigator must provide to the Sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the Sponsor nor designee is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence 
of specific arrangements, neither the Sponsor nor designee is financially responsible for further 
treatment of the patient’s disease. 
12.3. 
INVESTIGATOR DOCUMENTATION 
Prior to beginning the study, the Investigator will be asked to comply with ICH E6(R2) 8.2 and, 
for US sites, Title 21 of the Code of Federal Regulations by providing the following essential 
documents, including but not limited to: 
• IRB/IEC approval. 

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• Original Investigator-signed investigator agreement page of the protocol. 
• For US sites, Form FDA 1572, fully executed, and all updates on a new fully executed 
Form FDA 1572. 
• For non-US sites, the Investigator’s current curriculum vitae and/or other documentation 
evidencing qualifications, and any other documents that the IRB/IEC may request. For US 
sites, a curriculum vitae for the Investigator and each subinvestigator listed on Form 
FDA 1572. 
• Financial disclosure information to allow the Sponsor to submit complete and accurate 
certification or disclosure statements required by applicable regulatory authorities. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update 
this information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study. 
• IRB/IEC-approved informed consent, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be provided to 
the patient or legal guardian. 
• Laboratory certifications and normal ranges for any local laboratories used by the site. 
12.4. 
STUDY CONDUCT 
The Investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2). The Investigator will conduct all aspects of this study in accordance with all national, 
state, and local laws or regulations. Study information from this protocol will be posted on 
publicly available clinical trial registers before enrollment of patients begins. 
12.5. 
ADHERENCE TO PROTOCOL 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) and all applicable guidelines and regulations. 
12.6. 
ADVERSE EVENTS AND STUDY REPORT REQUIREMENTS 
By participating in this study, the Investigator agrees to submit reports of SAEs to the Sponsor 
according to the timeline and method outlined in the protocol. The Contract Research 
Organization or site (per local country regulations) will submit annual reports to the study site 
IRB/IEC as appropriate. 
12.7. 
INVESTIGATOR’S FINAL REPORT 
Upon completion of the study, the Investigator, where applicable, should inform the institution; 
the Investigator/institution should provide the IRB/IEC with a summary of the study’s outcome 
and the Sponsor and regulatory authority(ies) with any reports required. 

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12.8. 
RECORDS RETENTION 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/institution as to 
when these documents no longer need to be retained. No records may be transferred to another 
location or party without written notification to the Sponsor. 
12.9. 
PUBLICATIONS  
After completion of the study, the data may be considered for reporting at a scientific meeting or 
for publication in a scientific journal. In these cases, the Sponsor will be responsible for these 
activities and will work with the Investigators to determine how the manuscript is written and 
edited, the number and order of authors, the publication to which it will be submitted, and other 
related issues. The Sponsor has final approval authority over all such issues. 
Data are the property of the Sponsor and cannot be published without prior authorization from 
the Sponsor, but data and publication thereof will not be unduly withheld. Further terms 
concerning publication will be set forth in the clinical trial agreement entered into by the 
Sponsor, the PI, any vendors, and the institution. 

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13. 
STUDY MANAGEMENT 
The administrative structure will include a Safety Review Committee (SRC). 
13.1. 
MONITORING 
13.1.1. 
Sponsor Safety Review  
All safety data will be evaluated on an ongoing basis in accordance with the applicable Sponsor 
and/or designee SOPs. During the conduct of the clinical trial, cumulative safety data will be 
collected and reviewed monthly or on an ad-hoc basis as needed.  
13.1.2. 
Monitoring of the Study 
The Clinical Monitor, as a representative of the Sponsor, has the obligation to follow the study 
closely. In doing so, the monitor will visit the Investigator and study site at periodic intervals, in 
addition to maintaining necessary telephone and letter contact. The monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and personnel. 
All aspects of the study will be carefully monitored, by the Sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
13.1.3. 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all study records. In the 
event of an audit, the Investigator agrees to allow the Sponsor, representatives of the Sponsor, or 
a regulatory agency (eg, FDA or other regulatory agency) access to all study records. 
The Investigator should promptly notify the Sponsor and designee of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor. 
13.2. 
MANAGEMENT OF PROTOCOL AMENDMENTS AND DEVIATIONS 
13.2.1. 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the patient, must be reviewed and approved by the Sponsor or its designee. 
Amendments to the protocol must be submitted in writing to the Investigator’s IRB/IEC for 
approval before patients can be enrolled into an amended protocol. 

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13.2.2. 
Protocol Deviations 
The Investigator or designee must document and explain in the patient’s source documentation 
any deviation from the approved protocol. The Investigator may implement a deviation from or a 
change of the protocol to eliminate an immediate hazard to study patients without prior IRB/IEC 
approval. As soon as possible after such an occurrence, the implemented deviation or change, the 
reasons for it, and any proposed protocol amendments should be submitted to the IRB/IEC for 
review and approval, to the Sponsor for agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the IRB/IEC and agreed to by the Investigator. A 
significant deviation occurs when there is nonadherence to the protocol by the patient or 
Investigator that affects important efficacy and safety assessments (as applicable), the safety or 
mental integrity of a patient, or the scientific value of the trial/project. Significant deviations can 
include nonadherence to inclusion or exclusion criteria or nonadherence to FDA regulations or 
ICH GCP guidelines and may lead to the patient being withdrawn from the study (Section 4.2). 
A list of major protocol deviations will be compiled prior to the start of the study. 
Protocol deviations will be documented by the Clinical Monitor throughout the course of 
monitoring visits. Principal Investigators will be notified in writing by the monitor of deviations. 
The IRB/IEC should be notified of all protocol deviations in a timely manner. 
13.3. 
STUDY TERMINATION 
Although Fulcrum Therapeutics has every intention of completing the study, Fulcrum reserves 
the right to discontinue the study at any time for clinical or administrative reasons. Should 
termination of the study be required, the Sponsor will promptly inform the Investigator and the 
IRB/IEC and provide them with a detailed written explanation. Fulcrum and the Investigator will 
assure that adequate consideration is given to the protection of the patients’ interests. The 
Sponsor has no plans to provide study drug to patients after study closure or termination. The 
obligations to provide study results for patients and reports to IRB/IEC shall continue as required 
by applicable laws and regulations. 
At any time, the Sponsor, the Investigators, or the IRBs/IECs may terminate this study for 
reasonable cause. Conditions that may lead to reasonable cause and warrant termination include, 
but are not limited to the following: 
• Patient or Investigator noncompliance 
• Unsatisfactory patient enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study patients 
• Decision to modify drug development plan 
• Decision by the regulatory authority 

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Written notification that includes the reason for the clinical study termination is required. 
The end of the study is defined as the date on which the last patient completes the last visit 
(includes the safety follow-up visit).  
13.4. 
FINAL REPORT 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that the 
clinical study report is prepared and provided to the regulatory agency(ies) as required by the 
applicable regulatory requirement(s). The Sponsor will also ensure that the clinical study reports 
in marketing applications meet the standards of the ICH harmonised tripartite guideline E3: 
Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the clinical study reports. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results. 
Upon completion of the clinical study reports, the Sponsor will provide the Investigator with the 
full summary of the study results. The Investigator is encouraged to share the summary results 
with the study patients, as appropriate. The study results will be posted on publicly available 
clinical trial registers. 
Irrespective of the outcome of the clinical trial, the Sponsor shall submit a summary of the 
results of the clinical trial to the EU database within 1 year from the end of the trial in all 
Member States concerned.

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14. 
REFERENCES 
Aisen, A. M., and T. L. Chenevert. 1989. 'MR spectroscopy: clinical perspective', Radiology, 
173: 593-9. 
Arjomand, Jamshid, Lisa Bain, June Kinoshita, and Mark Stone. 2020. "Facioscapulohumeral 
Muscular Dystrophy (FSHD) Voice of the Patient Report." In.: FSHD Society. 
Barbour, A. M., M. Magee, B. Shaddinger, N. Arya, L. Tombs, W. Tao, B. R. Patel, M. J. 
Fossler, and R. Glaser. 2015. 'Utility of concentration-effect modeling and simulation in a 
thorough QT study of losmapimod', J Clin Pharmacol, 55: 661-70. 
Barbour, A. M., L. Sarov-Blat, G. Cai, M. J. Fossler, D. L. Sprecher, J. Graggaber, A. T. 
McGeoch, J. Maison, and J. Cheriyan. 2013. 'Safety, tolerability, pharmacokinetics and 
pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy 
volunteers', Br J Clin Pharmacol, 76: 99-106. 
Bosnakovski, D., S. H. Choi, J. M. Strasser, E. A. Toso, M. A. Walters, and M. Kyba. 2014. 
'High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity', 
Skelet Muscle, 4: 4. 
Cella, D., J. S. Lai, C. J. Nowinski, D. Victorson, A. Peterman, D. Miller, F. Bethoux, A. 
Heinemann, S. Rubin, J. E. Cavazos, A. T. Reder, R. Sufit, T. Simuni, G. L. Holmes, A. 
Siderowf, V. Wojna, R. Bode, N. McKinney, T. Podrabsky, K. Wortman, S. Choi, R. 
Gershon, N. Rothrock, and C. Moy. 2012. 'Neuro-QOL: brief measures of health-related 
quality of life for clinical research in neurology', Neurology, 78: 1860-7. 
Chan, V., M. Hatch, G. Kurillo, D. Cadavid, and J. J. Han. 2020. "Abstract: Development of an 
optimized timed up and go (oTUG) for measurement of changes in mobility impairment 
in facioscapulohumeral muscular dystrophy (FSHD) clinical trials." In Annual Meeting of 
the American Academy of Neurology. Toronto, Canada [online]. 
Chen, Tai-Heng, Yan-Zhang Wu, and Yung-Hao Tseng. 2020. 'Early-Onset Infantile 
Facioscapulohumeral Muscular Dystrophy: A Timely Review', International Journal of 
Molecular Sciences, 21: 7783. 
Cheriyan, J., A. J. Webb, L. Sarov-Blat, M. Elkhawad, S. M. Wallace, K. M. Mäki-Petäjä, D. J. 
Collier, J. Morgan, Z. Fang, R. N. Willette, J. J. Lepore, J. R. Cockcroft, D. L. Sprecher, 
and I. B. Wilkinson. 2011. 'Inhibition of p38 mitogen-activated protein kinase improves 
nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia', 
Circulation, 123: 515-23. 
Dahlqvist, J. R., P. Widholm, O. D. Leinhard, and J. Vissing. 2020. 'MRI in neuromuscular 
diseases: An emerging diagnostic tool and biomarker for prognosis and efficacy', Ann 
Neurol, 88: 669-81. 
Deenen, J. C., H. Arnts, S. M. van der Maarel, G. W. Padberg, J. J. Verschuuren, E. Bakker, S. S. 
Weinreich, A. L. Verbeek, and B. G. van Engelen. 2014. 'Population-based incidence and 
prevalence of facioscapulohumeral dystrophy', Neurology, 83: 1056-9. 
Gautschi, O. P., N. R. Smoll, M. V. Corniola, H. Joswig, I. Chau, G. Hildebrandt, K. Schaller, 
and M. N. Stienen. 2016. 'Validity and Reliability of a Measurement of Objective 
Functional Impairment in Lumbar Degenerative Disc Disease: The Timed Up and Go 
(TUG) Test', Neurosurgery, 79: 270-8. 
Goselink, Rianne J.M., Karlien Mul, Caroline R. van Kernebeek, Richard J.L.F. Lemmers, 
Silvère M. van der Maarel, Tim H.A. Schreuder, Corrie E. Erasmus, George W. Padberg, 
Jeffrey M. Statland, Nicol C. Voermans, and Baziel G.M. van Engelen. 2019. 'Early onset 

Protocol 1821-FSH-301, Version 5.1 
Fulcrum Therapeutics, Inc. 
Losmapimod 
Confidential 
Page 87 of 98 
as a marker for disease severity in facioscapulohumeral muscular dystrophy', Neurology, 
92: e378-e85. 
Han, J. J., E. De Bie, A. Nicorici, R. T. Abresch, R. Bajcsy, and G. Kurillo. 2015. 'Reachable 
workspace reflects dynamometer-measured upper extremity strength in 
facioscapulohumeral muscular dystrophy', Muscle Nerve, 52: 948-55. 
Hatch, M. N., K. Kim, G. Kurillo, A. Nicorici, C. M. McDonald, and J. J. Han. 2019. 
'Longitudinal study of upper extremity reachable workspace in fascioscapulohumeral 
muscular dystrophy', Neuromuscul Disord, 29: 503-13. 
Hatch, Maya N. , Vicky  Chan, Alina R.  Nicorici, Gregorij  Kurillo, Tony  Nguyen, Diego  
Cadavid, and Jay J. Han. 2019. "Abstract S10.3 Development of an optimized Timed-Up-
and-Go Test for the FSHD population." In 26th Annual FSHD International Research 
Congress, edited by FSH Society Facioscapulohumeral Muscular Dystrophy. Marseille, 
France. 
Hatch, Maya N., Vicky   Chan, Diego  Cadavid, and Jay J. Han. 2020. "Abstract: Initial Analysis 
of Responsiveness of an FSHD Optimized Timed Up and Go (oTUG) Across the 
Disability Spectrum in FSHD." In Annual Meeting of the American Academy of 
Neurology. Toronto, Canada [online]. 
Hatcher, Robert A. 2007. Contraceptive technology (Ardent Media: New York, N.Y). 
Homma, S., M. L. Beermann, F. M. Boyce, and J. B. Miller. 2015. 'Expression of FSHD-related 
DUX4-FL alters proteostasis and induces TDP-43 aggregation', Ann Clin Transl Neurol, 
2: 151-66. 
Jagannathan, S., S. C. Shadle, R. Resnick, L. Snider, R. N. Tawil, S. M. van der Maarel, R. K. 
Bradley, and S. J. Tapscott. 2016. 'Model systems of DUX4 expression recapitulate the 
transcriptional profile of FSHD cells', Hum Mol Genet, 25: 4419-31. 
Janssen, B., N. Voet, A. Geurts, B. van Engelen, and A. Heerschap. 2016. 'Quantitative MRI 
reveals decelerated fatty infiltration in muscles of active FSHD patients', Neurology, 86: 
1700-7. 
Khiem, D., J. G. Cyster, J. J. Schwarz, and B. L. Black. 2008. 'A p38 MAPK-MEF2C pathway 
regulates B-cell proliferation', Proc Natl Acad Sci U S A, 105: 17067-72. 
Kools, J., N. Voermans, K. Mul, L. Ronco, J. Jiang, J. Shoskes, K. Marshall, D. Cadavid, M. 
Mellion, and B. van Engelen. 2021. "An Open-Label Study of Losmapimod to Evaluate 
the Safety, Tolerability, and Biomarker and Clinical Outcome Assessment Changes in 
Subjects with FSHD1." In World Muscle Society Annual Conference. Virtual. 
Lomas, D. A., D. A. Lipson, B. E. Miller, L. Willits, O. Keene, H. Barnacle, N. C. Barnes, R. 
Tal-Singer, and Investigators Losmapimod Study. 2012. 'An oral inhibitor of p38 MAP 
kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease', 
J Clin Pharmacol, 52: 416-24. 
Mellion, M. L., L. Ronco, C. L. Berends, L. Pagan, S. Brooks, M. J. van Esdonk, E. M. J. van 
Brummelen, A. Odueyungbo, L. A. Thompson, M. Hage, U. A. Badrising, S. Raines, W. 
G. Tracewell, B. van Engelen, D. Cadavid, and G. J. Groeneveld. 2021. 'Phase 1 clinical 
trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, 
pharmacokinetics, and target engagement', Br J Clin Pharmacol, 87: 4658-69. 
Moris, G., L. Wood, R. FernaNdez-Torron, J. A. Gonzalez Coraspe, C. Turner, D. Hilton-Jones, 
F. Norwood, T. Willis, M. Parton, M. Rogers, S. Hammans, M. Roberts, E. Househam, 
M. Williams, H. Lochmuller, and T. Evangelista. 2018. 'Chronic pain has a strong impact 
on quality of life in facioscapulohumeral muscular dystrophy', Muscle Nerve, 57: 380-87. 

Protocol 1821-FSH-301, Version 5.1 
Fulcrum Therapeutics, Inc. 
Losmapimod 
Confidential 
Page 88 of 98 
Oliva, J., S. Galasinski, A. Richey, A. E. Campbell, M. J. Meyers, N. Modi, J. W. Zhong, R. 
Tawil, S. J. Tapscott, and F. M. Sverdrup. 2019. 'Clinically advanced p38 inhibitors 
suppress DUX4 expression in cellular and animal models of facioscapulohumeral 
muscular dystrophy', J Pharmacol Exp Ther, 370: 219-30. 
Padua, L., I. Aprile, R. Frusciante, E. Iannaccone, M. Rossi, R. Renna, S. Messina, G. Frasca, 
and E. Ricci. 2009. 'Quality of life and pain in patients with facioscapulohumeral 
muscular dystrophy', Muscle Nerve, 40: 200-5. 
Pascoe, S., M. Costa, J. Marks-Konczalik, E. McKie, S. Yang, and P. S. Scherbovsky. 2017. 
'Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical 
benefits in COPD', Respir Med, 130: 20-26. 
Preston, M. K., R. Tawil, and L. H. Wang. 2020. 'Facioscapulohumeral Muscular Dystrophy.' in 
M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. W. Gripp, G. 
M. Mirzaa and A. Amemiya (eds.), GeneReviews(®) (University of Washington, Seattle 
(Original work published 1993) 
Copyright © 1993-2022, University of Washington, Seattle. GeneReviews is a registered 
trademark of the University of Washington, Seattle. All rights reserved.: Seattle (WA)). 
Ricci, E., G. Galluzzi, G. Deidda, S. Cacurri, L. Colantoni, B. Merico, N. Piazzo, S. Servidei, E. 
Vigneti, V. Pasceri, G. Silvestri, M. Mirabella, F. Mangiola, P. Tonali, and L. Felicetti. 
1999. 'Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy 
and correlation between the number of KpnI repeats at the 4q35 locus and clinical 
phenotype', Ann Neurol, 45: 751-57. 
Rojas, L. A., E. Valentine, A. Accorsi, J. Maglio, N. Shen, A. Robertson, S. Kazmirski, P. Rahl, 
R. Tawil, D. Cadavid, L. A. Thompson, L. Ronco, A. N. Chang, A. M. Cacace, and O. 
Wallace. 2020. 'p38alpha Regulates Expression of DUX4 in a Model of 
Facioscapulohumeral Muscular Dystrophy', J Pharmacol Exp Ther, 374: 489-98. 
Rubin, Donald B. 1976. 'Inference and missing data', Biometrika, 63: 581-92. 
Statland, J. M., K. J. Odrzywolski, B. Shah, D. Henderson, A. F. Fricke, S. M. van der Maarel, S. 
J. Tapscott, and R. Tawil. 2015. 'Immunohistochemical Characterization of 
Facioscapulohumeral Muscular Dystrophy Muscle Biopsies', J Neuromuscul Dis, 2: 291-
99. 
Statland, J. M., B. Shah, D. Henderson, S. Van Der Maarel, S. J. Tapscott, and R. Tawil. 2015. 
'Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies', Muscle 
Nerve, 52: 521-6. 
Statland, J. M., and R. Tawil. 2014. 'Risk of functional impairment in Facioscapulohumeral 
muscular dystrophy', Muscle Nerve, 49: 520-7. 
Stübgen, J. P., and A. Stipp. 2010. 'Facioscapulohumeral muscular dystrophy: a prospective 
study of weakness and functional impairment', J Neurol, 257: 1457-64. 
Tawil, R., J. T. Kissel, C. Heatwole, S. Pandya, G. Gronseth, and M. Benatar. 2015. 'Evidence-
based guideline summary: Evaluation, diagnosis, and management of 
facioscapulohumeral muscular dystrophy: Report of the Guideline Development, 
Dissemination, and Implementation Subcommittee of the American Academy of 
Neurology and the Practice Issues Review Panel of the American Association of 
Neuromuscular & Electrodiagnostic Medicine', Neurology, 85: 357-64. 
Tawil, R., K. Wagner, J. Statland, L. Wang, A. Genge, Sacconi S., H. Lochmülller, D.R. Leiva, 
J. Diaz-Manera, J. Alonso-Perez, N. Muelas, J.J. Vilchez, A. Pestronik, S. Gibson, N. 
Goyal, J. Hamel, L. Hayward, N. Johnson, S. LoRusso, M. Freimer, P. Shieh, S. 

Protocol 1821-FSH-301, Version 5.1 
Fulcrum Therapeutics, Inc. 
Losmapimod 
Confidential 
Page 89 of 98 
Subramony, D. G. Leung, B. van Engelen, J. Kools, O. Dahlqvist, P. Widholm, J. Jiang, 
A. Odueyungbo, W. Tracewell, A. Rahilly, L. A. Rojas, A. Accorsi, S. Mennen, L. 
Ronco, D. Cadavid, C. Moxham, C. Morabito, R. Gould, and M. Mellion. 2021. "Whole 
Body MRI Quantitative Muscle Analysis to Evaluate Efficacy of Losmapimod in a Phase 
2 Placebo-Controlled Study in Subjects withFSHD (ReDUX4): ReDUX4 
(NCT04003974)." In World Muscle Society Annual Conference. Virtual. 
Wang, L. H., S. D. Friedman, D. Shaw, L. Snider, C. J. Wong, C. B. Budech, S. L. Poliachik, N. 
E. Gove, L. M. Lewis, A. E. Campbell, R. J. F.L Lemmers, S. M. Maarel, S. J. Tapscott, 
and R. N. Tawil. 2019. 'MRI-informed muscle biopsies correlate MRI with pathology and 
DUX4 target gene expression in FSHD', Hum Mol Genet, 28: 476-86. 
Watz, H., H. Barnacle, B. F. Hartley, and R. Chan. 2014. 'Efficacy and safety of the p38 MAPK 
inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a 
randomised, double-blind, placebo-controlled trial', Lancet Respir Med, 2: 63-72. 
West, J., T. Romu, S. Thorell, H. Lindblom, E. Berin, A. S. Holm, L. L. Åstrand, A. Karlsson, 
M. Borga, M. Hammar, and O. D. Leinhard. 2018. 'Precision of MRI-based body 
composition measurements of postmenopausal women', PLoS One, 13: e0192495. 
Williamson, A., and B. Hoggart. 2005. 'Pain: a review of three commonly used pain rating 
scales', J Clin Nurs, 14: 798-804. 
Wong, Chao-Jen, Leo H Wang, Seth D Friedman, Dennis Shaw, Amy E Campbell, Chris B 
Budech, Leann M Lewis, Richard J F L Lemmers, Jeffrey M Statland, Silvère M van der 
Maarel, Rabi N Tawil, and Stephen J Tapscott. 2020. 'Longitudinal measures of RNA 
expression and disease activity in FSHD muscle biopsies', Human Molecular Genetics, 
29: 1030-43. 
Yao, Z., L. Snider, J. Balog, R. J. Lemmers, S. M. Van Der Maarel, R. Tawil, and S. J. Tapscott. 
2014. 'DUX4-induced gene expression is the major molecular signature in FSHD skeletal 
muscle', Hum Mol Genet, 23: 5342-52. 
Yonezawa, A., and K. Inui. 2011. 'Importance of the multidrug and toxin extrusion 
MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and 
pharmacogenomics', Br J Pharmacol, 164: 1817-25. 
 

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APPENDIX 1. SCHEDULES OF ASSESSMENTS 
Table 7: 
Part A: Placebo-Controlled Treatment Period Schedule of Assessments 
Event/Assessment 
Screening 
Baseline 
 
Week 4 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
ET Visita 
Safety F/U 
 after 
last dose of 
study drugb 
Safety F/U 
Phone Screen 
 after 
last dose of 
study drugb 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
- 
Variablec 
Variablec 
Study Day 
 
1 
28 
84 
168 
252 
336 
- 
343 
373 
Visit Window (days)d 
N/A 
±7 
±7 
±7 
±7 
±7 
±7 
 
±3 
±5 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ICF 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Weighte 
X 
X 
 
 
X 
 
X 
X 
X 
 
Heighte and BMI 
X 
 
 
 
 
 
 
 
 
 
Genetic confirmation of 
FSHDf 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screenh 
X 
 
 
 
 
 
 
 
 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Standard 12-lead ECGj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examinationk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum FSHl 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
 

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Event/Assessment 
Screening 
Baseline 
 
Week 4 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
ET Visita 
Safety F/U 
 after 
last dose of 
study drugb 
Safety F/U 
Phone Screen 
 after 
last dose of 
study drugb 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
- 
Variablec 
Variablec 
Study Day 
 
1 
28 
84 
168 
252 
336 
- 
343 
373 
Visit Window (days)d 
N/A 
±7 
±7 
±7 
±7 
±7 
±7 
 
±3 
±5 
Urine pregnancy testn 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistryo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology (HBsAg, HCV, 
and HIV 1/HIV 2)p 
X 
 
 
 
 
 
 
 
 
 
PKq 
 
 
X 
 
 
 
X 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RWS 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
 
Hand-Held 
Dynamometry 
 
X 
X 
X 
X 
X 
X 
Xr 
 
 
Neuro-QoL UE Function 
X 
X 
X 
X 
X 
X 
X 
Xr 
 
 
MSK MRI 
X 
 
 
 
X 
 
X 
Xr 
 
 
PGIC 
 
 
X 
X 
X 
X 
X 
Xr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug dispensation 
 
X 
X 
X 
X 
X 
 
 
 
 

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Event/Assessment 
Screening 
Baseline 
 
Week 4 
Week 
12 
Week 
24 
Week 
36 
Week 
48 
ET Visita 
Safety F/U 
 after 
last dose of 
study drugb 
Safety F/U 
Phone Screen 
 after 
last dose of 
study drugb 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
- 
Variablec 
Variablec 
Study Day 
 
1 
28 
84 
168 
252 
336 
- 
343 
373 
Visit Window (days)d 
N/A 
±7 
±7 
±7 
±7 
±7 
±7 
 
±3 
±5 
Study drug count 
 
 
X 
X 
X 
X 
X 
X 
 
 
Qualitative exit interview 
 
 
 
 
 
 
X 
 
 
 
Medications review 
Continuous from signing ICF through 
 safety follow-up visit 
Concomitant treatments 
and procedures 
Adverse events 
Abbreviations: BMI = body mass index; ECG =  electrocardiogram; 
 ET = early termination; FSH = follicle stimulating hormone; 
FSHD = facioscapulohumeral muscular dystrophy; F/U = follow-up; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; ICF = informed consent form; MRI = magnetic resonance imaging; MSK = musculoskeletal; Neuro-QoL = Quality of Life in 
Neurological Disorders; 
; PGIC = Patient Global Impression of Change; 
; 
PK = pharmacokinetics; PRO = patient-reported outcome; RWS = reachable workspace; UE = upper extremity.  
a If a patient prematurely discontinues study treatment, they will be encouraged to remain in the study and continue with all other aspects of the study. If a 
patient decides to prematurely discontinue study treatment and not continue with all other aspects of the study, they will be considered to have withdrawn 
from the study. If a patient withdraws from the study, they will be asked to complete an ET visit as soon as possible after the decision to terminate study 
participation and to complete the safety follow-up visit 
 days and a safety phone screen 
days after their last dose of study drug. If the ET visit will 
be scheduled more than 
 after the last dose of study drug, the safety follow-up and ET visits may be combined, with no duplication of assessments 
required. 
b The 
and 
 safety follow-up visits will be required for all patients who discontinue study treatment early or do not to rollover into Part B. The 
 safety follow-up visit may be performed as a phone screen, unless ongoing clinical laboratory findings or AEs require additional follow-up. 
c  Patients who do not rollover into Part B only. 
d  Scheduled visits may be split over 2 days, if required, and must be completed within the protocol-defined visit windows. Unscheduled visits may be performed 
if clinically indicated. 
e Weight and height will be measured with shoes off and preferably with the same balance at each visit.  
f Genetic confirmation must be obtained before the patient is randomized. Genetic confirmation can come from previous testing, if verified with appropriate 
documentation from an accredited laboratory. If genetic testing is necessary, the 
 screening window and activities will not start until the results are 
obtained and verified by the Principal Investigator. 
g  Patients must have a Ricci score of 2 to 4 to be eligible. The score will be assigned according to the worst clinical assessment on physical examination. 
Patients who are wheelchair-dependent or dependent on walker or wheelchair for activities are not permitted to enroll in the study. 

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h Urine drug screen is for drugs of abuse including cocaine, amphetamines, opiates (morphine), benzodiazepines, and cannabinoids. 
i Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the patient has been seated or recumbent for at least 5 minutes 
and before any 12-lead ECG assessment or blood sampling is performed.  
j Twelve-lead ECGs will be performed after patients have been recumbent for at least 5 minutes, after the measurement of vital signs, and before any 
procedures that may affect heart rate (eg, blood sampling). 
k Physical examination at the screening visit and safety follow-up includes an evaluation of body systems, including but not limited to the following: skin; head, 
eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological system; and musculoskeletal 
system.  
l Serum follicle-stimulating hormone testing is required for suspected postmenopausal female patients only. 
m Serum pregnancy tests will be performed for all female patients of child-bearing potential at the screening visit. 
n Urine pregnancy tests will be performed for all female patients of child-bearing potential before randomization and before dispensation of study drug at all 
other visits. If pregnancy is found, patients must be terminated from the study effective immediately. Home pregnancy tests will be performed for all female 
subjects of child-bearing potential if required per local regulations.  
o For the screening visit, patients will be required to fast for at least 4 hours prior to laboratory blood samples being taken. 
p  Subjects with a known history of hepatitis infection must be tested to confirm active infection. All subjects will be tested for hepatitis B surface antigen and, if 
positive, will not be allowed to enroll in the study. All subjects will be tested for hepatitis C antibody and, if positive, should be tested for viral RNA. If the 
viral RNA test is negative indicating inactive/resolved hepatitis C infection, then the subject can enroll in the study as long as their liver panel is within range 
of the inclusion and exclusion criteria (Section 4.1). If the viral RNA test is positive, indicating active viral hepatitis C, the subject will not be allowed to 
enroll in the study. For Italy only: Tuberculosis will also be tested at Screening (Appendix 2).  
q Patients will be required to take their study drug dose in-clinic and blood collection for PK will occur immediately predose and 4 hours (±30 minutes) after 
administration of the study dose.  
r If the ET visit occurs ≥12 weeks after the last visit, noted assessments should be performed. If the ET visit occurs ≥24 weeks after the last visit, MRI should be 
performed. 
 
 

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Table 8: 
Part B: Open-Label Extension Schedule of Assessments  
Event/Assessment 
Year 1  
Year 2 
Safety F/U 
 after last 
dose 
Safety F/U Phone 
Screen 
 after last 
dose of study drugb 
Baselinea 
Week 48 
Week 
 
Weeks 
 
  
Week 
 
Weeks 
 
Weeks 
  
Visit number c 
1 
2 
3, 4, 5 
6 
7+ 
8+ 
Variable 
Variable 
Visit window (days) 
+7 
+7 
±14 
±14 
±14 
±14 
±3 
±5 
Clinic visit 
X 
 
X 
X 
 
X 
X 
 
Phone call 
 
X 
 
 
X 
 
 
X 
ICF 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
Weightd 
X 
 
X 
X 
 
X 
X 
 
Heightd and BMI 
X 
 
 
 
 
 
 
 
Vital signse 
X 
 
X 
X 
 
X 
X 
 
Standard 12-lead ECGf 
X 
 
 
X 
 
Xg 
X 
 
Physical examinationh 
X 
 
X 
X 
 
X 
X 
 
Urinalysis 
X 
 
X 
X 
 
X 
X 
 
Urine pregnancy testi 
X 
 
X 
X 
 
X 
X 
 
Hematology 
X 
 
X 
X 
 
X 
X 
 
Serum chemistryj 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
X 
 
X 
X 
 
X 
 
 

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Event/Assessment 
Year 1  
Year 2 
Safety F/U 
 after last 
dose 
Safety F/U Phone 
Screen 
 after last 
dose of study drugb 
Baselinea 
Week 48 
Week 
 
Weeks 
 
  
Week 
 
Weeks 
 
Weeks 
  
Visit number c 
1 
2 
3, 4, 5 
6 
7+ 
8+ 
Variable 
Variable 
Visit window (days) 
+7 
+7 
±14 
±14 
±14 
±14 
±3 
±5 
Clinic visit 
X 
 
X 
X 
 
X 
X 
 
Phone call 
 
X 
 
 
X 
 
 
X 
dispensation 
Study drug count 
 
 
X 
X 
 
X 
 
 
Concomitant meds & 
procedures 
Continuous from signing ICF through 
 safety follow-up visit 
Adverse events 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; 
; FSHD = facioscapulohumeral muscular dystrophy; 
F/U = follow-up; ICF = informed consent form; PRO = patient-reported outcome; RWS = reachable workspace. 
a In most cases, the baseline visit of Part B will occur on the same day as Week 48 visit of Part A, and patients should complete all Part A Week 48 assessments 
before signing the informed consent for Part B. Informed consent for Part B will be signed before any Part B specific assessments are performed. In the event 
that a patient has their baseline visit of Part B after the Part A Week 48 visit (but within the 
 window), they will NOT have to repeat any Part B 
assessments that were specified to be performed at the Week 48 visit of Part A.  
b  The 
 safety follow-up will be required for all patients who discontinue study treatment early. This assessment may be performed as a phone call, unless 
ongoing clinical laboratory findings or adverse events require additional follow-up. 
c  Unscheduled visits may be performed if clinically indicated. 
d Weight and height will be measured with shoes off and preferably with the same balance at each visit.  
e Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the patient has been seated or recumbent for at least 5 minutes 
and before any 12-lead ECG assessment or blood sampling is performed.  
f Twelve-lead ECGs will be performed after patients have been recumbent for at least 5 minutes, after the measurement of vital signs, and before any 
procedures that may affect heart rate (eg, blood sampling). 
g Twelve-lead ECGs will be performed annually after 
 (ie, only at 
)  
h   Physical examinations include an evaluation of body systems, including but not limited to the following: skin; head, eyes, ears, nose, and throat; respiratory 
system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological system; and musculoskeletal system. 
i Urine pregnancy tests will be performed for all female patients of childbearing potential before dispensation of study drug at all other visits. If pregnancy is 
found, patients must be terminated from the study effective immediately. Home pregnancy tests will be performed for all female subjects of child-bearing 
potential if required per local regulations.  
j For baseline visit, patients will be required to fast for at least 4 hours prior to laboratory blood samples being taken. 

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APPENDIX 2. COUNTRY/REGION-SPECIFIC DIFFERENCES 
 
The full history of this protocol is detailed below, including all past and current global and 
country-specific amendments:  
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 17 February 2022 
Original version 
Version 2.0, 03 March 2022 
Global Amendment 1 
Version 2.1, 27 July 2022 
UK-specific amendment 
Version 2.2, 21 September 2022 
Germany-specific amendment 
Version 2.3, 11 October 2022 
Germany-specific amendment 
Version 3.0, 08 August 2022 
Global Amendment 2 
Version 3.1, 12 October 2022 
UK-specific amendment 
Version 3.2, 17 November 2022 
Germany-specific amendment  
Version 3.3, 22 November 2022 
Italy-specific amendment 
Version 4.0, 01 March 2023 
Global Amendment 3 
Version 4.1, 22 March 2023 
UK-specific amendment  
Version 4.2, 22 March 2023 
Italy-specific amendment 
Version 5.1, 21 December 2023 
Global Amendment 4 (current version) 
 
 
Italy-specific differences:  
Change and Rationale 
Affected Sections  
Added exclusion of vaccination with a live attenuated vaccine within 6 
weeks prior to randomization until the safety follow-up visit 
Section 4.1.1.2 
Added tuberculosis to the serology testing at screening 
Section 6.1.5, Table 7 
 
 
 
 
 

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APPENDIX 3. DRUGS POTENTIALLY AFFECTING MUSCLE 
FUNCTION 
Potential list of drugs or supplements that may affect muscle function includes, but is not limited 
to, the following: 
1. Statins 
2. Steroids 
3. Testosterone or other growth hormone agonists 
4. Beta-agonists 
5. Creatine 
6. Colchicine 
7. Benzylpenicillin 
 
For patients who are on drug(s) or supplements that may affect muscle function, patients must be 
on a stable dose of that drug(s) or supplement for at least 3 months prior to the first dose of study 
drug and remain on that stable dose for the duration of the study. Changes to the dose or 
treatment discontinuation during the study can only be done for strict medical reasons by the 
treating physician with clear documentation and notification to the Sponsor. 
Treatment with a statin can be initiated during the study if it is medically required. In this case, 
preference should be given to hydrophilic statins (e.g., pravastatin, rosuvastatin, fluvastatin) over 
lipophilic statins (e.g., simvastatin, atorvastatin, lovastatin.) Particular attention should be paid to 
creatine phosphokinase (already part of the laboratory safety monitoring) in patients who start 
treatment with a statin during the study. 
 
 

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APPENDIX 4. LIST OF OAT1/OAT3 SUBSTRATES WITH A NARROW 
THERAPEUTIC INDEX  
Potential lists of drugs that are substrates of OAT1/OAT3 and have a narrow therapeutic index 
(NTI) are included below. 
  
OAT1/OAT3 Substrates with NTI 
valproic acid 
clofarabine 
methotrexate 
mercaptopurine 
baricitinib 
pemetrexed 
Source: https://go.drugbank.com/categories/DBCAT003983