A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) With Open-Label Extension (OLE)
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy (FSHD)
Sponsor: Fulcrum Therapeutics

Fulcrum Therapeutics 
Losmapimod 
Protocol FIS-002-2019, Version 5.0 
16 August 2022 
Page 1 
CLINICAL STUDY PROTOCOL 
IND: 138739 
EUDRACT: 2019-001181-15 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, 
Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating 
Subjects with Facioscapulohumeral Muscular Dystrophy (FSHD) with Open-
Label Extension (OLE) 
PROTOCOL FIS-002-2019 
Sponsor: 
Fulcrum Therapeutics  
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Sponsor Contact: 
, PharmD 
Senior Clinical Scientist 
Fulcrum Therapeutics  
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Telephone: 
Medical Monitor: 
 MD 
Version of Protocol: 
Date of Protocol: 
Version 5.0  
17 August 2022 
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 
expressed, 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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Losmapimod 
Protocol FIS-002-2019, Version 5.0 
16 August 2022 
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SUMMARY OF CHANGES TO THE PROTOCOL 
Protocol History 
Version and Date of Protocol 
Comments 
Version 1.0, 27 March 2019 
Original version 
Version 2.0, 30 July 2019 
• 
Clarified benefit/risk ratio. 
• 
Clarified exclusion criterion #18. 
• 
Clarified unblinding procedure in the 
event of an emergency. 
• 
Added instructions for missed doses and 
study drug compliance details. 
• 
Added adverse events of special interest 
and stopping criteria for abnormal liver 
tests. 
• 
Updated the process for calculating the 
number of D4Z4 repeats. 
• 
Updated language for the analysis of the 
primary endpoint and secondary endpoints 
to match the statistical analysis plan. 
• 
Clarified collection time points in the 
schedule of events. 
• 
Updated language referencing regulatory 
authorities. 
• 
Clarified that the sponsor has no plans to 
provide study drug to subjects after study 
closure or termination. 
Version 3.0, 27 November 2019 
• 
Added an open-label extension (OLE) to 
the protocol. Added language to 
differentiate the placebo-controlled 
treatment period part of the study versus 
the OLE part of the study. Clarified that 
baseline is prior to the first dose in the 
placebo-controlled treatment period.  

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Protocol FIS-002-2019, Version 5.0 
16 August 2022 
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• 
Change from baseline in lean muscle 
tissue volume and fat fraction in 
facioscapulohumeral muscular dystrophy 
1 (FSHD1) subjects, as measured by 
musculoskeletal (MSK) magnetic 
resonance imaging (MRI), changed from 
exploratory objective/endpoint to a 
secondary objective/endpoint and revised 
to include muscle fat infiltration (MFI). 
• 
Increased the number of randomized 
subjects from approximately 66 to 
approximately 76. 
• 
Clarified that for scheduled study visits 
that are split over 2 days, the visits may 
not be more than 5 business days apart. 
• 
Clarified that subjects can travel for MRI 
or muscle biopsy if needed, but the use of 
a study-approved MRI scanner should be 
consistent during the trial. 
• 
Clarified in inclusion criterion #3 that 
“appropriate documentation” is 
documentation from an accredited 
laboratory. 
• 
Clarified in inclusion criterion #4 that a 
RICCI score between 2 and 4 does not 
include subjects that use wheelchairs or 
walkers for any reason. 
• 
Clarified in exclusion criterion #12 that 
that subjects should not be vaccinated with 
a live attenuated vaccine throughout the 
study. 
• 
Added clarifications on the identity of 
investigational product, study drug 
packaging, study drug accountability, and 
compliance. 
• 
Clarified pregnancy reporting. 

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Protocol FIS-002-2019, Version 5.0 
16 August 2022 
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• 
Removed collection of blood sample for 
coagulation at the early termination visit 
and 7-day safety follow up visit. 
• 
Clarified that a full physical examination 
will be performed at the screening visit 
and the 7-day safety follow up visit and a 
symptom directed physical examination 
will be performed at all other visits. 
• 
Added additional details for the safety and 
tolerability endpoint. Revised the 
secondary and exploratory endpoints to 
include specific time points. 
• 
Clarified that functional workspace is a 
part of the reachable workspace (RWS) 
assessment. 
Version 4.0, 10 April 2020 (COVID-19 Pandemic 
Emergency Amendment) 
• 
This amendment includes permanent 
changes to the ReDUX4 protocol. 
• 
Refer to the ReDUX4 Emergency 
Guidance document implemented 31 
March 2020 for details related to 
temporary procedures enacted during the 
COVID-19 pandemic. 
• 
Extended randomized placebo-controlled 
portion of the study from 24 to 48 weeks 
due to the COVID-19 pandemic and 
disruptions to the protocol-defined clinical 
trial conduct. 
• 
Noted that enrollment has been completed. 
• 
All Week 24 efficacy assessments moved 
to Week 48. 
• 
Muscle biopsies will be performed at 
Week 16 or at Week 36 for those subjects. 
• 
unable to have the biopsy at Week 16 due 
to the COVID-19 pandemic. 
• 
Removed the one-time biopsy from the 
open-label extension (OLE) portion of the 
study. 
• 
Added an interim analysis to be performed 
after a minimum of 22 paired muscle 
biopsies have been collected. 
• 
Removed OLE secondary endpoints 
evaluating long-term efficacy in subjects 
originally randomized to losmapimod and 
in subjects originally randomized to 
placebo during the placebo-controlled 
treatment period, to evaluate the efficacy 
of losmapimod in inhibiting or reducing 
expression of DUX4, the root cause of 
FSHD, as measured by a subset of DUX4-

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Protocol FIS-002-2019, Version 5.0 
16 August 2022 
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regulated gene transcripts in skeletal 
muscle biopsies. 
• 
Elevated placebo-controlled treatment 
period secondary objective and endpoint 
for evaluation of safety and tolerability of 
losmapimod in FSHD1 subjects. 
• 
Removed measurement of the metabolite, 
GSK198602. 
Version 5.0, 16 August 2022  
• 
Removed study assessments for extension: 
MSK MRI, exploratory biomarkers, RWS, 
Timed Up and Go (TUG), dynamometry, 
Motor Function Measure (MFM), FSHD 
Health Index (FSHD-HI), and Patients’ 
Global Impression of Change (PGIC). 
• 
Removed language specifying that the 15-
mg dose of study drug is administered as 
two 7.5-mg tablets. 
• 
Extended study duration for extension. 
• 
Changed name of metabolite from 
GSK198602 to FTX-5508. 
 

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Losmapimod 
Protocol FIS-002-2019, Version 5.0 
16 August 2022 
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DECLARATION OF INVESTIGATOR 
I have read and understood all sections of the protocol entitled “A Phase 2, Randomized, 
Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of 
Losmapimod in Treating Subjects with Facioscapulohumeral Muscular Dystrophy (FSHD) with 
Open-Label Extension (OLE)” and the accompanying 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 5.0, dated 16 August 2022, 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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Losmapimod 
Protocol FIS-002-2019, Version 5.0 
16 August 2022 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
PROTOCOL APPROVAL – SPONSOR SIGNATORY ................................................................7 
PROTOCOL APPROVAL – PRINCIPAL INVESTIGATOR .......................................................8 
DECLARATION OF INVESTIGATOR .........................................................................................9 
PROTOCOL SYNOPSIS...............................................................................................................16 
LIST OF ABBREVIATIONS ........................................................................................................22 
1 
INTRODUCTION ......................................................................................................25 
1.1 
BACKGROUND ........................................................................................................25 
1.2 
NONCLINICAL INFORMATION ............................................................................26 
1.3 
CLINICAL PHARMACOLOGY ...............................................................................27 
1.4 
CLINICAL SAFETY ..................................................................................................28 
1.5 
BENEFIT/RISK ASSESSMENT ...............................................................................29 
Hepatotoxicity ................................................................................................................................29 
Renal Function ...............................................................................................................................30 
Embryo-Fetal Malformations .........................................................................................................30 
Drug-Drug Interactions ..................................................................................................................30 
Infection/Immunity ........................................................................................................................30 
2 
STUDY OBJECTIVES ...............................................................................................32 
2.1 
PLACEBO-CONTROLLED TREATMENT PERIOD ..............................................32 
2.1.1 
PRIMARY OBJECTIVE ............................................................................................32 
2.1.2 
SECONDARY OBJECTIVES ....................................................................................32 
2.1.3 
EXPLORATORY OBJECTIVES ...............................................................................32 
2.2 
OPEN-LABEL EXTENSION ....................................................................................33 
2.2.1 
PRIMARY OBJECTIVE ............................................................................................33 
2.2.2 
SECONDARY OBJECTIVE ......................................................................................33 
3 
INVESTIGATIONAL PLAN .....................................................................................34 
3.1 
STUDY DESIGN ........................................................................................................34 
3.1.1 
PLACEBO-CONTROLLED TREATMENT PERIOD ..............................................34 
3.1.2 
OPEN-LABEL EXTENSION ....................................................................................36 

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3.2 
RATIONALE OF STUDY DESIGN ..........................................................................37 
3.2.1 
RATIONALE OF DOSE SELECTION .....................................................................37 
3.2.2 
RATIONALE OF STUDY DESIGN ..........................................................................38 
4 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ...................................41 
4.1 
SELECTION OF STUDY POPULATION ................................................................41 
4.1.1 
INCLUSION CRITERIA ............................................................................................41 
4.1.2 
EXCLUSION CRITERIA...........................................................................................42 
4.2 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR THE 
STUDY .......................................................................................................................44 
4.1.3 
REASONS FOR WITHDRAWAL/DISCONTINUATION .......................................44 
4.1.4 
HANDLING OF WITHDRAWALS ..........................................................................44 
4.1.5 
REPLACEMENTS .....................................................................................................45 
5 
STUDY TREATMENTS ............................................................................................46 
5.1 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ..................46 
5.2 
TREATMENTS ADMINISTERED .............................................................................46 
5.3 
IDENTITY OF INVESTIGATIONAL PRODUCT ...................................................46 
5.4 
MANAGEMENT OF CLINICAL SUPPLIES ...........................................................47 
5.4.1 
STUDY DRUG PACKAGING AND STORAGE .....................................................47 
5.4.2 
STUDY DRUG ACCOUNTABILITY .......................................................................47 
5.4.3 
MEDICATION ERRORS AND OVERDOSE ...........................................................48 
5.5 
LIFESTYLE RESTRICTIONS...................................................................................48 
5.5.1 
CONTRACEPTION REQUIREMENTS ...................................................................48 
5.6 
BLINDING .................................................................................................................49 
5.7 
TREATMENT COMPLIANCE .................................................................................50 
5.8 
PRIOR AND CONCOMITANT THERAPY .............................................................50 
6 
STUDY ASSESSMENTS AND PROCEDURES ......................................................51 
6.1 
EFFICACY ASSESSMENTS ....................................................................................51 
6.1.1 
SKELETAL MUSCLE NEEDLE BIOPSY ...............................................................51 
6.1.2 
SKELETAL MUSCLE MAGNETIC RESONANCE IMAGING .............................52 
6.2 
SAFETY AND TOLERABILITY ASSESSMENTS .................................................52 
6.2.1 
ADVERSE EVENTS ..................................................................................................52 

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6.2.1.1 
DEFINITIONS OF ADVERSE EVENTS ..................................................................52 
6.2.1.2 
SERIOUS ADVERSE EVENTS ................................................................................52 
6.2.1.3 
ADVERSE EVENTS OF SPECIAL INTEREST .......................................................53 
Liver Tests and Stopping Criteria ..................................................................................................53 
6.2.1.4 
ELICITING AND DOCUMENTING ADVERSE EVENTS .....................................53 
6.2.1.5 
REPORTING ADVERSE EVENTS ..........................................................................54 
6.2.1.6 
REPORTING SERIOUS ADVERSE EVENTS .........................................................54 
6.2.1.7 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS ......................55 
6.2.1.8 
ASSESSMENT OF SEVERITY .................................................................................55 
6.2.1.9 
ASSESSMENT OF CAUSALITY .............................................................................55 
6.2.1.10 
FOLLOW-UP OF SUBJECTS REPORTING ADVERSE EVENTS ........................56 
6.2.2 
LABORATORY ANALYSES ...................................................................................56 
6.2.3 
MEDICAL HISTORY ................................................................................................57 
6.2.4 
VITAL SIGNS ............................................................................................................58 
6.2.5 
PHYSICAL EXAMINATIONS .................................................................................58 
6.2.6 
TWELVE-LEAD ELECTROCARDIOGRAMS ........................................................58 
6.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS .............58 
6.3.1 
PHARMACOKINETIC ASSESSMENTS .................................................................58 
6.3.2 
PHARMACODYNAMIC ASSESSMENTS ..............................................................59 
6.4 
OTHER ASSESSMENTS...........................................................................................59 
6.4.1 
REACHABLE WORK SPACE ..................................................................................59 
6.4.2 
TIMED UP AND GO .................................................................................................60 
6.4.3 
DYNAMOMETRY .....................................................................................................60 
6.4.4 
MOTOR FUNCTION MEASURE DOMAIN 1 ........................................................61 
6.4.5 
FSHD HEALTH INDEX ............................................................................................61 
6.4.6 
PATIENTS’ GLOBAL IMPRESSION OF CHANGE ...............................................61 
6.4.7 
GENETIC CONFIRMATION OF FSHD1.................................................................61 
6.5 
SAFETY REVIEW COMMITTEE ............................................................................62 

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6.6 
PREGNANCY ............................................................................................................63 
6.7 
SAMPLE COLLECTIONS ........................................................................................63 
7 
STATISTICAL AND ANALYTICAL PLAN ...........................................................64 
7.1 
PLACEBO-CONTROLLED TREATMENT PERIOD ..............................................64 
7.1.1 
PRIMARY ENDPOINT .............................................................................................64 
7.1.2 
SECONDARY ENDPOINTS .....................................................................................64 
7.1.3 
EXPLORATORY ENDPOINTS ................................................................................64 
7.2 
OPEN-LABEL EXTENSION ....................................................................................65 
7.2.1 
PRIMARY ENDPOINT .............................................................................................65 
7.2.2 
SECONDARY ENDPOINTS .....................................................................................65 
7.3 
SAMPLE SIZE CALCULATIONS ............................................................................65 
7.4 
ANALYSIS SETS ......................................................................................................65 
7.5 
DESCRIPTION OF SUBGROUPS TO BE ANALYZED .........................................66 
7.6 
STATISTICAL ANALYSIS METHODOLOGY ......................................................66 
7.6.1 
HYPOTHESIS TESTING ON KEY STUDY ENDPOINTS .....................................66 
7.6.2 
ANALYSIS OF PRIMARY ENDPOINTS ................................................................67 
7.6.3 
ANALYSIS OF SECONDARY ENDPOINTS ..........................................................67 
7.6.4 
ANALYSES OF EXPLORATORY ENDPOINTS ....................................................67 
7.6.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ....................68 
7.6.6 
SAFETY ANALYSES ................................................................................................68 
7.6.7 
OTHER ANALYSES .................................................................................................68 
7.6.8 
INTERIM ANALYSES ..............................................................................................69 
8 
DATA QUALITY ASSURANCE ..............................................................................71 
8.1 
DATA MANAGEMENT ............................................................................................71 
9 
ETHICS .......................................................................................................................72 
9.1 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD 
 ........................................................................................................................................
 72 
9.2 
ETHICAL CONDUCT OF THE STUDY ..................................................................72 
9.3 
SUBJECT INFORMATION AND CONSENT ..........................................................72 
10 
INVESTIGATOR’S OBLIGATIONS ........................................................................74 

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10.1 
CONFIDENTIALITY .................................................................................................74 
10.2 
FINANCIAL DISCLOSURE AND OBLIGATIONS ................................................74 
10.3 
INVESTIGATOR DOCUMENTATION ...................................................................74 
10.4 
STUDY CONDUCT ...................................................................................................75 
10.5 
ADHERENCE TO PROTOCOL ................................................................................75 
10.6 
ADVERSE EVENTS AND STUDY REPORT REQUIREMENTS ..........................75 
10.7 
INVESTIGATOR’S FINAL REPORT .......................................................................75 
10.8 
RECORDS RETENTION ...........................................................................................75 
10.9 
PUBLICATIONS ........................................................................................................76 
11 
STUDY MANAGEMENT .........................................................................................77 
11.1 
MONITORING ...........................................................................................................77 
11.1.1 
SAFETY REVIEW COMMITTEE ............................................................................77 
11.1.2 
MONITORING OF THE STUDY ..............................................................................77 
11.1.3 
INSPECTION OF RECORDS ....................................................................................77 
11.2 
MANAGEMENT OF PROTOCOL AMENDMENTS AND DEVIATIONS ...........77 
11.2.1 
MODIFICATION OF THE PROTOCOL ..................................................................77 
11.2.2 
PROTOCOL DEVIATIONS ......................................................................................78 
11.3 
STUDY TERMINATION...........................................................................................78 
11.4 
FINAL REPORT ........................................................................................................79 
12 
REFERENCE LIST ....................................................................................................80 
13 
APPENDICES ............................................................................................................83 
13.1 
APPENDIX: SCHEDULES OF EVENTS .................................................................83 
13.2 
APPENDIX: DRUGS POTENTIALLY AFFECTING MUSCLE FUNCTION .......91 
 

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LIST OF TABLES 
Table 1: ..... Alpha At Interim Analysis and Final Analysis for Different Sample Sizes At 
Interim Analysis (O’Brien-Fleming Method) .............................................................69 
Table 2: ..... Schedule of Events: Placebo-Controlled Treatment Period .......................................84 
Table 3: ..... Schedule of Events: Open-Label Extension (Visits Will Occur Quarterly 
Until 90 Days After Commercial Drug Availability Post Regulatory  
Approval or Study is Discontinued) ...........................................................................89 
 
LIST OF FIGURES 
Figure 1: .... Schematic of Study Design for the Placebo-Controlled Treatment Period ................36 
 
 
 

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PROTOCOL SYNOPSIS 
Protocol Number: 
FIS-002-2019 
Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, 
Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating 
Subjects with Facioscapulohumeral Muscular Dystrophy (FSHD) with 
Open-Label Extension (OLE) 
Sponsor: 
Fulcrum Therapeutics  
26 Landsdowne Street 
Cambridge, MA 02139 USA 
Study Phase: 
2 
Study Sites: 
Up to 25 sites 
Indication: 
FSHD 
Rationale: 
Treatment of FSHD with losmapimod is predicted to reduce double 
homeobox 4 (DUX4) in affected skeletal muscle. It is anticipated that the 
proposed human dose of losmapimod for FSHD at 15 mg orally (PO) twice 
daily (BID) will provide drug concentrations in skeletal muscles sufficient to 
significantly inhibit p38α/β, resulting in the reduction of aberrant expression 
of DUX4. 
This study will be conducted in 2 parts: a randomized, double-blind placebo-
controlled treatment period for 48 weeks, followed by an open-label 
treatment period with losmapimod. The placebo-controlled treatment period 
will evaluate the efficacy and safety of losmapimod in treating subjects with 
FSHD1 over 48 weeks. The open-label extension (OLE) will evaluate the 
safety and tolerability of long-term dosing with losmapimod in treating 
subjects with FSHD1. 
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit 
had the option to roll over into the OLE. Subjects that have already rolled 
over to the OLE prior to the COVID-19 pandemic will remain on open-label 
treatment. Their next clinic visit will follow the assessments for the Week 36 
and Week 48 visit in the placebo-controlled portion of the study in the 
COVID-19 Pandemic Emergency protocol version 4.0. These subjects will 
not undergo the Week 36 biopsy. Subjects who did not roll over prior to the 
COVID-19 pandemic will roll over into the OLE at the Week 48 visit as 
described in the COVID-19 Pandemic Emergency protocol version 4.0. 

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Study Population: 
Males and females between 18 and 65 years of age, inclusive, who have a 
confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size 
of the D4Z4 array on chromosome 4; a clinical severity score of 2 to 4 
(RICCI score; range 0-5), inclusive, at screening; and an MRI-eligible 
muscle for biopsy, as determined by a central reader. Enrollment has 
completed for this study. A total of 80 subjects have been enrolled. 
Study Design: 
This study will be conducted in 2 parts: a randomized, double-blind placebo-
controlled treatment period for 48 weeks, followed by an open-label 
treatment period with losmapimod. The placebo-controlled treatment period 
will evaluate the efficacy and safety of losmapimod in treating subjects with 
FSHD1 over 48 weeks. The OLE will evaluate the safety and tolerability of 
long-term dosing with losmapimod in treating subjects with FSHD1. 
During the placebo-controlled treatment period, a total of approximately 76 
subjects with FSHD1 will be randomized 1:1 to receive 15 mg PO of 
losmapimod (n=38) or placebo (n=38) tablets BID for 48 weeks. Blood 
samples for pharmacokinetic (losmapimod concentrations) endpoints will be 
collected at Day 1, Week 4, Week 16, and Week 36 at the following time 
points: immediately predose and 4 hours (±30 minutes) after administration 
of the study dose. Pharmacokinetic samples will also be taken, when 
feasible, after dosing during the Week 12, Week 24, and Week 48 visits, 
preferably ≥1 hour after dosing. Blood samples for target engagement will be 
collected at Day 1 and Week 16 or Week 36, at the following time points: 
immediately predose and 4 hours (±30 minutes) after administration of the 
study dose. Serum and plasma samples taken at baseline (Day 1; predose) 
and at Weeks 4, 12, 16, 24, 36, and 48 (predose or postdose) will be used to 
aid in the discovery of potential biomarkers of FSHD disease activity and 
treatment effects. 
Musculoskeletal MRIs will be performed at screening, Week 12, and Week 
48. Muscle biopsies will be taken at Day 1 and Week 16 or Week 36 if the 
muscle biopsy could not be performed at Week 16 due to the COVID-19 
pandemic. In skeletal muscle, change from baseline in aberrant DUX4 
activity, losmapimod concentrations, and target engagement will be 
evaluated at Day 1 and Week 16 or Week 36. A portion of the muscle 
biopsies may be used to aid in the discovery of potential biomarkers of 
FSHD disease activity and treatment effects. 
Once subjects reach Week 48, they will have the option to roll over into the 
OLE, with all subjects receiving 15 mg PO of losmapimod tablets BID. 
Subjects who wish to roll over into the OLE must complete all procedures 
from the Week 48 end of placebo-controlled treatment period/start of OLE 
visit. Prior to the COVID-19 pandemic, subjects who reached the Week 24 
visit had the option to roll over into the OLE. Subjects that have already 
rolled over to the OLE prior to the COVID-19 pandemic will remain on 
open-label treatment. Their next clinic visits will follow the assessments for 
the Week 36 and Week 48 visit in the placebo-controlled portion of the study 
in the COVID-19 Pandemic Emergency protocol version 4.0. These subjects 
will not undergo the Week 36 biopsy. Subjects who did not roll over prior to 
the COVID-19 pandemic will roll over into the OLE at the Week 48 visit as 
described in the COVID-19 Pandemic Emergency protocol version 4.0. 

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During the OLE, subjects will attend clinic visits approximately every 12 
weeks until 90 days after commercial drug is available post regulatory 
approval or until the study is discontinued by the sponsor.  
Blood samples for pharmacokinetics (losmapimod concentration) will be 
collected after dosing at the Week 144 clinic visit, preferably ≥1 hour after 
dosing.  
Safety and tolerability will be evaluated throughout the study based on the 
assessment of adverse events (AEs), AEs of special interest (AESIs), serious 
adverse events (SAEs), laboratory tests, electrocardiograms (ECGs), vital 
signs, and physical examinations. 
Estimated Study 
Duration: 
Subjects will complete a 4-week screening period followed by a 48-week 
placebo-controlled treatment period. Subjects who rolled over to the OLE 
portion of the study prior to the COVID-19 pandemic (under protocol 
version 3.0) will remain on open-label treatment. These subjects completed a 
4-week screening period followed by a 24-week placebo-controlled 
treatment period. At their next clinic visits, these subjects will follow the 
assessments for the Week 36 visit followed by the Week 48 visit in the 
placebo-controlled portion of the study under the COVID-19 Pandemic 
Emergency protocol version 4.0. During the OLE, subjects will attend clinic 
visits approximately every 12 weeks until 90 days after commercial drug is 
available post regulatory approval or until the study is discontinued by the 
sponsor. All subjects will complete a safety follow-up visit 7 (±3) days after 
their last dose of study drug. 
Efficacy Assessments: 
• 
Change from baseline in DUX4 activity in affected skeletal muscle, 
as measured by quantitative reverse transcription polymerase chain 
reaction in a panel of DUX4-regulated gene transcripts 
• 
Change from baseline in MFF, LMV, and MFI, as measured by MSK 
MRI 
Pharmacokinetic and 
Pharmacodynamic 
Assessments: 
• 
Plasma concentrations of losmapimod 
• 
Concentrations of losmapimod in skeletal muscle biopsy at steady 
state 
• 
Target engagement parameters in blood and skeletal muscle 
biopsy 
Safety Assessments: 
Adverse events, AESIs, SAEs, laboratory tests, ECGs, vital signs, and 
physical examinations 

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Other Assessments: 
• 
Change from baseline in COAs 
− 
RWS with and without weights 
− 
Classic and FSHD TUG 
− 
Muscle strength by hand-held quantitative dynamometry 
− 
MFM Domain 1 
− 
FSHD-HI 
− PGIC 
• 
Change from baseline in inflammatory, immune, apoptotic, and other 
muscle disease transcripts in muscle biopsy and circulating proteins 
in plasma and serum 
Study Drug, Dosage, 
and Route of 
Administration: 
Placebo-Controlled Treatment Period: 
Losmapimod tablets 15 mg PO BID or matching placebo tablets PO BID for 
48 weeks (or 24 weeks if rolled over to the OLE under protocol version 3.0, 
prior to the COVID-19 pandemic). 
Open-Label Extension: 
Losmapimod tablets 15 mg PO BID until 90 days after commercial drug is 
available post regulatory approval or until the study is discontinued by the 
sponsor. 
Study drug should be administered with food. 
Sample Size: 
Assuming an effect size of 0.70, a sample size of 68 subjects (34 subjects per 
group) will be needed to provide 80% power with a 2-sided test at a 0.05 
significance level to detect a difference between losmapimod and placebo in 
change from baseline in DUX4 activity in affected skeletal muscle after 16 
or 36 weeks (depending upon when the muscle biopsy was performed) 
during the placebo-controlled treatment period. 
Assuming that approximately 10% of subjects will be non-evaluable, 
approximately 76 subjects will be randomly assigned at a 1:1 ratio to 
losmapimod and placebo (38 subjects per group). 
Statistical Methods: 
Continuous variables will be summarized using the mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be 
summarized using frequency counts and percentages. All statistical tests will 
be 2-sided and performed using a 0.05 significance level.  
The primary endpoint for the placebo-controlled treatment period will be 
evaluated using an analysis of covariance (ANCOVA) model to analyze the 
change from baseline in DUX4 activity in affected skeletal muscle after 16 
weeks or 36 weeks of treatment, with repeat number category and treatment 
group as fixed effects and baseline DUX4 activity in affected skeletal muscle 
as a covariate. Least-square (LS) mean, standard error, and 95% confidence 
interval (CI) of the LS mean will be provided for each treatment group. The 
difference in LS means between treatment groups and 95% CI of the 
difference will also be calculated. The final p-value will be compared against 
the significance level of approximately 0.05. All available data will be used. 

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The full analysis set will be used for the primary analysis in the placebo-
controlled treatment period. 
Secondary endpoints will be summarized using descriptive statistics. 
Continuous endpoints with multiple post-baseline assessments will be 
analyzed using mixed-effect model for repeated measures methods including 
repeat number category, treatment group, visit, and treatment-by-visit 
interaction as fixed effects and baseline value as a covariate; continuous 
endpoints with a single post-baseline assessment will be analyzed using 
ANCOVA methods, with repeat number category and treatment group as 
fixed effects and baseline value as a covariate. 
Secondary endpoints in the OLE will be summarized according to the 
treatment assigned at randomization. For all subjects, changes in 
measurements will be calculated relative to measurements obtained at 
baseline (ie, prior to first dose in the placebo-controlled treatment period). 
Hypothesis testing on key study endpoints will be conducted using the FAS. 
A sequential testing procedure will be used to control for Type I Error to test 
the following key study endpoints: DUX4 change from baseline at Week 16 
or Week 36; LMV change from baseline at Week 48, and FSHD TUG 
change from baseline at Week 48. 
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. Safety data in the OLE will be 
analyzed using the open-label analysis set. Treatment-emergent AEs will be 
summarized by Medical Dictionary for Regulatory Activities 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. 
Interim Analysis 
One interim analysis (IA) will be performed after a minimum of 22 paired 
muscle biopsies have been collected. A group sequential method (O’Brien 
Fleming Spending Function) will be used to ensure an overall significance 
level of 0.05 (double- sided) due to multiple looks at the DUX4 primary 
endpoint. 
Version and Date of 
Protocol: 
Version 5.0, 16 August 2022 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
3D 
3-dimensional 
β-hCG 
β-human chorionic gonadotropin 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
AUC 
area under the plasma concentration-time curve 
AUC0-inf 
area under the plasma concentration-time curve extrapolated to infinity 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
COA 
clinical outcome assessment 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
DILI 
drug-induced liver injury 
DUX4 
double homeobox 4 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ET 
early termination 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
FSHD 
facioscapulohumeral muscular dystrophy 
FSHD1 
facioscapulohumeral muscular dystrophy type 1 
FSHD2 
facioscapulohumeral muscular dystrophy type 2 
FSHD-HI 
Facioscapulohumeral Muscular Dystrophy Health Index 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 

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Abbreviation 
Definition 
HSP27 
heat shock protein 27 
IB 
investigator's brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
LMV 
lean muscle volume 
LS 
least-square 
MAPK 
mitogen-activated protein kinase 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFF 
muscle fat fraction 
MFI 
muscle fat infiltration 
MFM 
Motor Function Measure 
MMRM 
mixed-effect model for repeated measures 
MRI 
magnetic resonance imaging 
MSK 
musculoskeletal 
OAT 
organic anion transporter 
OATP 
organic anion transporting polypeptides 
OCT 
organic cation transporter 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
PGIC 
Patients’ Global Impression of Change 
pHSP27 
phosphorylated heat shock protein 27 
PK 
pharmacokinetic(s) 
PO 
orally 
PPS 
per-protocol set 
QRT-PCR 
quantitative reverse transcription polymerase chain reaction 
QTcF 
QT interval corrected for heart rate by Fridericia’s formula 
RWS 
Reachable Workspace 
SAE 
serious adverse event 
SAP 
statistical analysis plan 

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Abbreviation 
Definition 
SRC 
safety review committee 
STIR 
short tau inversion recovery 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
TUG 
Timed Up and Go 
ULN 
upper limit of normal 

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1. 
INTRODUCTION 
1.1. 
BACKGROUND 
Facioscapulohumeral muscular dystrophy (FSHD) is a rare disabling disease with an estimated 
worldwide population prevalence of between 1:15,000 and 1:20,000 (Statland and Tawil, 2014), 
or approximately 16,000 to 21,000 affected individuals in the United States. A higher prevalence 
rate of 12/100,000 was reported in a population-based study in the Netherlands (Deenen et al, 
2014). About two-thirds of cases are familial-inherited in an autosomal dominant fashion, and 
one-third are sporadic. FSHD is characterized by descending progressive skeletal muscle 
weakness affecting the face, shoulders, arms, and trunk, followed by weakness of the distal lower 
extremities and pelvic girdle. Symptoms typically first appear later in the second decade of life 
but can begin at any age (Tawil et al, 2015). Most cases present with shoulder girdle weakness, 
which is eventually found in nearly all patients (Padberg, 1982). Muscle biopsies show 
myopathic or dystrophic changes, including variability in fiber size, rounded fibers, central 
nuclei, necrotic or regenerating fibers, increased connective tissue, and fatty deposition. Up to 
one-third of muscle biopsies show a lymphocyte-predominant perivascular inflammatory 
infiltrate (Statland et al, 2015b). Muscle strength, as measured by quantitative muscle testing, 
decreases at an average rate of 1% to 4% per year (Statland and Tawil, 2014). The most frequent 
newly developed functional motor limitations include difficulty getting up from lying down in 
bed and difficulty using arms for activities of daily living (Statland and Tawil, 2014). The 6-year 
risk of wheelchair use is 24% (Statland et al, 2015a). All quality of life domains on the 36-Item 
Short Form Health Survey are significantly impaired, and over half of patients with FSHD report 
at least mild to moderate pain (Morís et al, 2018; Padua et al, 2009). Asymmetry of muscle 
involvement is common. Cardiac muscle is spared, and respiratory muscles are involved in a 
minority of patients. 
FSHD is caused by aberrant overexpression of the double homeobox 4 (DUX4) gene, a 
homeobox transcription factor. DUX4 is located within D4Z4 macrosatellite repeats on 
chromosome 4q35 and is not normally expressed in adult skeletal muscle when the number of 
repeats is >10. Approximately 95% of patients with FSHD have type 1 (FSHD1), in which the 
D4Z4 repeat array is contracted to 1 to 10 units on one allele (Lemmers et al, 2010; Statland and 
Tawil, 2014). FSHD patients carrying a smaller number of repeats (1 to 3 units) are, on average, 
more severely affected (Tawil et al, 1996). Loss of these repetitive elements (referred to as 
contraction) leads to de-repression of the D4Z4 locus and expression of DUX4 (de Greef et al, 
2008; Statland and Tawil, 2014). Stable inherited transmission of the repeat is reported within 
affected families and kindreds, with the most comprehensive analysis conducted on a larger Utah 
kindred in which the repeat size is the same in multiple, distantly related branches (Flanigan et 
al, 2001; Lemmers et al, 2004). Patients with FSHD type 2 (FSHD2) have a pathological 
mutation in a key regulatory protein encoded by the structural maintenance of chromosomes 
flexible hinge domain 1 (SMCHD1) gene, resulting in reduced methylation of the D4Z4 repeat 
array and aberrant DUX4 expression (Lemmers et al, 2012). DUX4 pathological activation in 
skeletal muscle as a result of the D4Z4 repeat contraction (in FSHD1) or SMCHD1 mutations (in 
FSHD2) leads to a large, well-characterized transcriptional deregulation cascade (Bosnakovski et 

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al, 2014; Homma et al, 2015; Jagannathan et al, 2016; Shadle et al, 2017; Yao et al, 2014). 
DUX4 transcriptional deregulation results in the activation of innumerable pathological cell 
processes, including inflammatory and immune signaling, oxidative stress, and programmed cell 
death. The end result of aberrant DUX4 activity is myofiber death with the replacement of 
skeletal muscle by fat, resulting in a clinical manifestation of progressive loss of strength and 
accumulation of physical disability. 
Compounds that reduce DUX4 and its DUX4-regulated transcripts should provide a robust 
disease-modifying therapeutic approach for the treatment of FSHD at its root cause. 
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). Very few compounds are 
currently in clinical development for FSHD, and 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. 
Fulcrum is developing losmapimod, a selective p38α and β kinase small molecule inhibitor that 
specifically reduces DUX4 in FSHD myotubes, for treatment of FSHD. Extensive exposure and 
safety data from previous clinical studies with losmapimod provide robust evidence supporting 
its safety and tolerability, including during chronic dosing, and provide a rationale for the dosing 
regimen selected. This study will evaluate the efficacy and safety of losmapimod in treating 
subjects with FSHD1. 
1.2. 
NONCLINICAL INFORMATION 
In vitro studies, including absorption, distribution, metabolism, and excretion assessments, 
specifically indicate that losmapimod is a highly selective p38α/β mitogen-activated protein 
kinase (MAPK) inhibitor with a limited risk of significant interaction with 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 apoptosis 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. The PK/PD analysis additionally indicated that significant p38α/β MAPK pathway 

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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). Losmapimod displayed reasonable oral 
bioavailability (>30%) in mouse, rat, and cynomolgus monkey and low clearance (<30% hepatic 
blood flow) in every species tested except dog; these results were supported by in vitro 
microsomal stability experiments. The half-life following oral administration ranged from 1 to 
3.2 hours, depending on the route, dose, and preclinical species. 
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; Ino 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 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 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 also no concerns in carcinogenicity 
studies. 
1.3. 
CLINICAL PHARMACOLOGY 
Elimination of losmapimod is almost exclusively by metabolism, with only 2% of the 
administered dose recovered as unchanged drug in urine and feces. The principal route of 
metabolism is via hydrolysis of the cyclopropylamide group to form a pharmacologically 
inactive metabolite, FTX-5508. 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 absolute oral bioavailability of the tablet formulation is 
62%. 
Following a single intravenous dose of losmapimod, the steady-state volume of distribution 
indicated extensive tissue distribution. After single-dose oral administration of 1 to 60 mg 
losmapimod, the maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve extrapolated to infinity (AUC0-inf) of losmapimod increased in an 
approximately dose-proportional manner for doses up to 20 mg but increased less than 
proportionally from 20 mg to 60 mg, likely due to saturation of absorption. The terminal half-life 
was approximately 10 hours for losmapimod and approximately 12 hours for FTX-5508. After 
single-dose oral administration of losmapimod, exposure (AUC) was approximately 2-fold 
higher for FTX-5508 than it was for its parent losmapimod. The time to maximum plasma 
concentration (Tmax) of losmapimod was reached approximately 1 to 4 hours after dose 
administration, while the Tmax of FTX-5508 was approximately 3 to 4 hours after dose 
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Steady-state plasma concentrations of losmapimod were achieved 2 to 3 days after the initiation 
of repeat dosing. Slight accumulation (up to approximately 30%, on average) for AUC and Cmax 
after once or BID dosing was observed. Consistent with single-dose administration, exposure 
(AUC) was approximately 2-fold higher for the metabolite FTX-5508 than it was for its parent 
losmapimod. Sex, body weight, and age factors did not result in the need for dose adjustments 
(Yang et al, 2013). The PK in healthy Japanese subjects are generally similar to those observed 
in previous studies in healthy non-Japanese subjects with regard to various PK characteristics 
such as exposure, dose proportionality, and half-life for both losmapimod and the metabolite 
FTX-5508 (Ino et al, 2015). 
A high-fat meal with a dose of 15 mg losmapimod increased the AUC (by approximately 10%) 
and Cmax (by approximately 40%) of losmapimod compared to the values observed in the fasted 
state. Tmax was delayed, on average, by 1 hour when losmapimod was administered with a high-
fat meal. The increase in the exposure measures, ie, AUC and Cmax, and the delay in Tmax 
following a high-fat meal compared to the fasted state are not considered clinically significant. 
1.4. 
CLINICAL SAFETY 
Losmapimod, which is currently in Phase 2 clinical studies for the treatment of FSHD, is a potent 
p38α/β inhibitor that has been administered to more than 3,600 subjects in GSK and Fulcrum 
clinical studies, including in a Phase 3 study. 
The original developer of losmapimod (GSK) performed extensive testing across at least 10 
indications but never in FSHD or other muscle disorders in the clinic. Although development 
was discontinued due to lack of efficacy in previously tested indications, losmapimod 
demonstrated a favorable PK, PD, safety, and tolerability profile in more than 3,500 subjects in 
over 20 studies. Subject data are available from 9 GSK-sponsored completed studies in healthy 
subjects (4 single dose studies, 3 repeat dose studies and single and repeat dose studies), 1 single 
dose study in a patient population (rheumatoid arthritis), and 11 completed repeat dose studies in 
patient populations (including cardiovascular disease, chronic obstructive pulmonary disease 
[COPD], renal disease, rheumatoid arthritis, major depressive disorder, and neuropathic pain). 
From the 9 completed Phase 1 clinical trials in healthy subjects, losmapimod was well tolerated 
at single doses up to 60 mg and repeat doses up to 10 mg BID for 2 weeks followed by 20 mg 
daily for 2 weeks. There were no deaths or non-fatal serious adverse events (SAEs) reported 
during any of these studies. In the 11 completed repeat dose studies in patients, adverse events 
(AEs) during treatment were typically reported by a similar proportion of patients on 
losmapimod and placebo (61% [815/1327] and 55% [406/735], respectively). Losmapimod did 
not consistently result in more AEs leading to permanent discontinuation of study drug or 
withdrawal from study than placebo. 
A thorough QT study (PM1116628) was conducted with losmapimod at 7.5 mg BID or 20 mg 
daily or with placebo administered for 5 days. At the 20 mg dose of losmapimod, the upper 
bound of the 90% confidence interval (CI) of the ΔΔQT interval corrected for heart rate by 
Fridericia’s formula (QTcF) (change from baseline in QTcF compared to that for placebo) 

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exceeded the 10 msec threshold at the 24-hour postdose time point. For the 7.5 mg BID 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. Although the upper bound of the 90% CI exceeded the 10 msec regulatory 
threshold of concern in the primary PD analysis, GSK stated that there was no clinically relevant 
effect on the QT interval, 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, supported the lack of a QT effect. PK/PD modeling using the 
raw QTcF and plasma concentration data showed that at plasma losmapimod concentrations 4 
times the exposure at the therapeutic dose (7.5 mg BID), ie, at exposures approximately 2-fold 
higher than 15 mg BID, the predicted upper bound of the 90% CI of QTcF did not exceed 10 
msec and the predicted median QTcF was less than 5 msec. Further details are presented in 
the investigator’s brochure (IB). 
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. 
Further details regarding the nonclinical and clinical data are presented in the IB. 
1.5. 
BENEFIT/RISK ASSESSMENT 
Losmapimod has been widely tested in various subject populations across at least 10 adult 
indications, including coronary artery disease, rheumatoid arthritis, and COPD. The majority of 
these studies lasted 24 weeks, with dosing in one study of up to 52 weeks. The safety data from 
these studies demonstrate satisfactory safety and tolerability; the severe and/or serious events 
that have been reported were generally specific to the population under study. Thus, COPD and 
respiratory events occurred in the studies evaluating subjects with COPD. Similarly, serious 
cardiac events were observed in those studies that evaluated subjects with coronary artery 
disease. As these events were generally indication specific, the risk of their occurrence in the 
FSHD population is considered minimal. 
Hepatotoxicity 
In clinical trials to date, elevations in transaminases have occurred in few subjects among over 
3,500 exposures of losmapimod. These have generally been mild, asymptomatic, and reversible, 
and the majority were confounded by other medications or clinical conditions. In 11 integrated 
repeat-dose studies in various patient populations, the frequency of liver events was 0.9% in the 
losmapimod group (further details are presented in the IB). Preclinical data demonstrate 
reversible increases in rat liver weight with no clinical chemistry or microscopic correlate. 
However, hepatotoxicity has been observed after repeat dose administration of some p38 MAPK 
inhibitors. The mechanism of hepatoxicity for those compounds has not been elucidated and thus 
applicability to losmapimod is unknown. Exclusion criteria (Section 4.1.2), data collection, and 
study drug stopping criteria (Section 6.2.1.3) relating to liver tests are well defined. 

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Renal Function 
In clinical studies with losmapimod, a small asymptomatic increase in serum creatinine of 1% to 
7% was noted; this increase appeared to attenuate with continued therapy as well as with 
discontinuation and may be related to inhibition of renal transporters (further details are 
presented in Section 5.3.2.6.2 of the IB). Individuals with severe renal impairment are excluded 
from the study (Section 4.1.2). Renal function (Section 6.2.2) and AEs (Section 6.2.1) will be 
monitored during the trial. 
Embryo-Fetal Malformations 
Embryo-fetal malformations in rats and rabbits have been observed with losmapimod. Study 
drug will not be administered to women of childbearing potential unless they are employing 
adequate contraceptive measures (Section 5.5.1). Pregnancy testing is required before 
randomization and before dispensation of study drug at all other visits, as specified in the 
schedule of events (Table 2  and Table 3 ). Study drug will be discontinued if a female 
participant becomes pregnant during the treatment period. Unexpected pregnancies will be 
reported with instructions for appropriate follow-up (Section 6.6). 
Drug-Drug Interactions 
Losmapimod is considered unlikely to have a clinically relevant drug-drug interaction with 
substrates or inhibitors of cytochrome P450, P-gp, human organic anion transporting 
polypeptides (OATP) 1B1 and OATP1B3, human organic anion transporter (OAT) 1, or human 
renal organic cation transporter (OCT) 2. Losmapimod inhibits multidrug and toxin extrusion 
(MATE) 1 and MATE2-K renal transporters in vitro with a low risk of clinically relevant 
interaction. Both losmapimod and its major metabolite, FTX-5508, are in vitro inhibitors of 
human breast cancer resistance protein (BCRP), and FTX-5508 is a relatively potent in vitro 
inhibitor of OAT3 (further details are presented in the IB). If possible, avoid co-administration of 
study drug with MATE 1, BCRP, or OAT3 substrates with a narrow therapeutic index. Careful 
monitoring for adverse effects of these agents is advised if, in the opinion of the investigator, co-
administration is warranted (Section 6.2.1). The inhibition of MATE2-K is not considered a 
clinical drug-drug interaction risk when comparing potency of in vitro transporter inhibition to 
projected losmapimod Cmax values at the 15 mg BID dose. 
Infection/Immunity 
Based on its pharmacology, losmapimod has a modest but broad inhibitory influence on various 
inflammatory cytokines. Thus, losmapimod may theoretically have an impact on immunity, and 
be associated with an increased risk of infection. Incidence of infections to date has been similar 
in losmapimod versus placebo in controlled studies (further details are presented in the IB). 
Information for all infections identified as SAEs will be collected (Section 6.2.1.2). Subjects who 
have received attenuated live vaccines within 6 weeks prior to randomization will be excluded 
(Section 4.1.2). 

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Given the lack of approved therapy for FSHD and the progressive debilitating nature of the 
disease, in conjunction with the well characterized current safety profile of losmapimod, the 
potential benefit of therapy with losmapimod outweighs the potential risks of drug 
administration. 

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2. 
STUDY OBJECTIVES 
2.1. 
PLACEBO-CONTROLLED TREATMENT PERIOD 
2.1.1. 
Primary Objective 
The primary objective of the placebo-controlled treatment period is to evaluate the efficacy of 
losmapimod in inhibiting or reducing expression of DUX4, the root cause of FSHD, as measured 
by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies from FSHD1 
subjects. 
2.1.2. 
Secondary Objectives 
The secondary objectives of the placebo-controlled treatment period are as follows: 
• To evaluate the safety and tolerability of losmapimod in FSHD1 subjects 
• To evaluate the change from baseline in muscle fat fraction (MFF), lean muscle volume 
(LMV), and muscle fat infiltration (MFI) in FSHD1 subjects, as measured by 
musculoskeletal (MSK) magnetic resonance imaging (MRI) 
• To evaluate the plasma concentrations of losmapimod in FSHD1 subjects 
• To evaluate the levels of losmapimod in skeletal muscle in FSHD1 subjects 
• To evaluate losmapimod target engagement in blood and in skeletal muscle in FSHD1 
subjects 
2.1.3. 
Exploratory Objectives 
The exploratory objectives of the placebo-controlled treatment period are as follows: 
• To evaluate the change from baseline in the following clinical outcome assessments 
(COAs): 
− Reachable Workspace (RWS) with and without weights 
− Classic and FSHD Timed Up and Go (TUG) 
− Muscle strength by hand-held quantitative dynamometry  
− Motor Function Measure (MFM) Domain 1 
− FSHD Health Index (FSHD-HI) 
− Patients’ Global Impression of Change (PGIC) 
• To evaluate the change from baseline in inflammatory, immune, apoptotic, and other 
muscle disease transcripts in muscle biopsy and circulating proteins in plasma and serum 

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2.2. 
OPEN-LABEL EXTENSION 
2.2.1. 
Primary Objective 
The primary objective of the open-label extension (OLE) is to evaluate the safety and tolerability 
of long-term dosing of losmapimod in FSHD1 subjects. 
2.2.2. 
Secondary Objective 
The secondary objective of the OLE is to evaluate the plasma concentrations of losmapimod in 
FSHD1 subjects. 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
STUDY DESIGN 
This study will be conducted in 2 parts: a randomized, double blind placebo-controlled treatment 
period for 48 weeks, followed by an open-label treatment period with losmapimod. The placebo-
controlled treatment period will evaluate the efficacy and safety of losmapimod in treating 
subjects with FSHD1 over 48 weeks. The OLE will evaluate the safety and tolerability of long-
term dosing with losmapimod in treating subjects with FSHD1. 
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to roll 
over into the OLE. Subjects that have already rolled over to the OLE prior to the COVID-19 
pandemic will remain on open-label treatment. Their next clinic visits will follow the 
assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the study in 
the COVID-19 Pandemic Emergency protocol version 4.0. These subjects will not undergo the 
Week 36 biopsy. Subjects who did not roll over prior to the COVID-19 pandemic will roll over 
into the OLE at the Week 48 visit as described in the COVID-19 Pandemic Emergency protocol 
version 4.0. 
3.1.1. 
Placebo-Controlled Treatment Period 
During the placebo-controlled treatment period, a total of approximately 76 subjects with 
FSHD1 will be randomized 1:1 to receive 15 mg PO of losmapimod (n=38) or placebo (n=38) 
tablets BID for 48 weeks. 
At the time of this protocol amendment (10 April 2020), enrollment was completed. A total of 80 
subjects have been enrolled. Twelve subjects had rolled over to the OLE portion of the study at 
Week 24, prior to the COVID-19 pandemic (under protocol version 3.0). At their next clinic 
visits, these 12 subjects will follow the assessments for the Week 36 visit followed by the Week 
48 visit in the placebo-controlled portion of the study under the COVID-19 Pandemic 
Emergency protocol version 4.0. These subjects will continue to receive open-label losmapimod 
during this time. 
Subjects will participate in the placebo-controlled treatment period for approximately 53 weeks, 
including the following: 
• a 4-week screening period: Day -28 until Day -1 before the first study drug 
administration 
• a 48-week placebo-controlled treatment period 
• for subjects who choose not to roll over into the OLE, a safety follow-up visit 7 days (±3 
days) after the last dose of study drug (OLE visits and procedures are described in  
Section 3.1.2) 
The 12 subjects who rolled over to the OLE portion of the study at Week 24, prior to the 
COVID-19 pandemic (under protocol version 3.0), participated in the placebo-controlled portion 
of the study for approximately 29 weeks including the following: 

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• a 4-week screening period: Day -28 until Day -1 before the first study drug 
administration 
• a 24-week placebo-controlled treatment period 
• for subjects who chose not to roll over into the OLE, a safety follow-up visit 7 days (±3 
days) after the last dose of study drug (OLE visits and procedures are described in 
Section 3.1.2) 
During the placebo-controlled treatment period, subjects will be asked to attend the study clinic 
at each scheduled visit (Table 2 ). Study drug (losmapimod or placebo) will be administered BID 
and should be taken with food. 
Blood samples for PK (losmapimod concentrations) endpoints will be collected at Day 1, Week 
4, Week 16, and Week 36 at the following time points: immediately predose and hours (±30 
minutes) after administration of the study dose. Pharmacokinetic samples will also be taken, 
when feasible, after dosing during the Week 12, Week 24, and Week 48 visits, preferably ≥1 
hour after dosing. Blood samples for target engagement will be collected at Day 1, and Week 16 
or Week 36, at the following time points: immediately predose and hours (±30 minutes) after 
administration of the study dose. Serum and plasma samples taken at baseline (Day 1; predose) 
and at Weeks 4, 12, 16, 24, 36, and 48 (predose or postdose) will be used to aid in the discovery 
of potential biomarkers of FSHD disease activity and treatment effects. 
Musculoskeletal MRIs will be performed at screening, Week 12, and Week 48. Muscle biopsies 
will be taken at Day 1 and Week 16 or Week 36 if the muscle biopsy could not be performed at 
Week 16 due to the COVID-19 pandemic. In skeletal muscle, change from baseline in aberrant 
DUX4 activity, losmapimod concentrations, and target engagement will be evaluated at Day 1 
and Week 16 or Week 36. A portion of the muscle biopsies may be used to aid in the discovery 
of potential biomarkers of FSHD disease activity and treatment effects. 
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 2. Scheduled visits may be split over 2 days if required, with a maximum of business days 
in between visits. Unscheduled visits may be performed if clinically indicated. Subjects can 
travel for MRI or muscle biopsy if needed, but the use of a study- approved MRI scanner should 
be consistent during the trial. 
A schematic of the study design is presented in Figure 1. 
 

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Figure 1: 
Schematic of Study Design for the Placebo-Controlled Treatment Period 
 
Abbreviations: BID, twice daily; MRI, magnetic resonance imaging; OLE, open-label extension. 
3.1.2. 
Open-Label Extension 
Once subjects reach Week 48, they will have the option to roll over into the OLE, with all 
subjects receiving 15 mg PO losmapimod tablets BID. Subjects who wish to roll over into the 
OLE must complete all procedures from the Week 48 end of placebo-controlled treatment 
period/start of OLE visit (Table 2). 
Subjects will remain in the OLE until 90 days after commercial drug is available post regulatory 
approval or until the study is discontinued by the sponsor. All subjects who complete or 
discontinue from treatment will complete a safety follow-up visit 7 days (±3 days) after the last 
dose of study drug. 
During the OLE, subjects will attend clinic visits approximately every 12 weeks (Table 3). Study 
drug (open-label losmapimod) will be administered BID and should be taken with food. 
Blood samples for PK (losmapimod concentration) will be collected after dosing at the Week 
144 clinic visit, preferably ≥1 hour after dosing.  
Safety and tolerability will be evaluated based on the assessment of AEs, AESIs, SAEs, 
laboratory tests, ECGs, vital signs, and physical examinations. 
The full schedule of assessments for the OLE is provided in Table 3. Scheduled visits may be 
split over 2 days if required, with a maximum of 5 business days in between visits. 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 
The placebo-controlled treatment period was designed to evaluate the efficacy of losmapimod for 
treatment of FSHD at its root cause and the safety of losmapimod over placebo in subjects with 
FSHD1 over 48 weeks. The OLE was designed to evaluate the safety, tolerability, and efficacy 
of long-term dosing of losmapimod in subjects with FSHD1. Losmapimod is being developed for 
the treatment of FSHD based on its robust nonclinical efficacy in inhibiting DUX4 expression 
and DUX4-regulated downstream gene transcripts and reducing apoptosis across multiple FSHD 
cell lines at achievable clinical exposures with minimal impact on myotube differentiation. 
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 BID would provide drug concentrations in 
skeletal muscles sufficient to significantly inhibit p38α/β and reduce aberrant expression of 
DUX4. The planned dose to be tested is 15 mg BID. Prior results indicate the excellent safety 
and tolerability of losmapimod for chronic administration in the clinic and include the 
convenience of oral administration. 
Heat shock protein 27 (HSP27) is a phosphorylated substrate of p38α/β 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 phosphorylated HSP27 (pHSP27). Pharmacokinetic/PD modeling 
indicates that the 15 mg PO BID dose should result in 40% to 70% pHSP27 reduction (Barbour 
et al, 2013; Cheriyan et al, 2011, and summarized in the IB). Losmapimod PK in humans has 
been well characterized, including at the exposure levels expected for the planned dose of 15 mg 
BID in the proposed studies. Pharmacokinetic/PD modeling has demonstrated that the inhibition 
of pHSP27 is directly related to the plasma concentration of losmapimod and that as the 
losmapimod concentration changes with time, the resulting change in pHSP27 occurs almost 
instantaneously (Barbour et al, 2013). Preclinical data show that this change in pHSP27 
correlates with a significant reduction in DUX4 levels and transcriptional activity. 
Preclinical in vivo PK/PD studies in non-fasted mice and rats demonstrated that the dose levels 
of losmapimod that achieved clinically relevant plasma exposures also produced significant 
skeletal muscle exposure and p38α/β MAPK pathway inhibition (further details provided in the 
IB). The muscle exposures achieved in rodents that are equivalent to the human 15 mg BID 
exposures in blood are predicted to result in robust target engagement and a >50% reduction in 
DUX4-dependent targets in FSHD subjects’ skeletal muscle based on the in vitro efficacy data in 
FSHD myotubes. 
Although dosing with 7.5 mg losmapimod BID results in target engagement, it may not be 
robust, especially at the minimum plasma concentration (Cmin). In COPD subjects dosed for 12 
weeks, the target engagement inhibition in predose samples was 21%, while the postdose target 
engagement inhibition was 39% to 44% (GSK study MKI102428). The trough losmapimod 
plasma concentrations maintained in that study were generally <20 ng/mL. Importantly, that 
study did not show any loss of target engagement over 12 weeks of dosing. 

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Pharmacokinetic/PD analyses of rodent (Studies FULTX-00002, FULTX-00004, FULTX-00005, 
and FULTX-00006) and human (Barbour et al, 2013) data performed by Fulcrum indicated that 
robust target engagement in muscle should be achieved when plasma losmapimod concentrations 
are >30 ng/mL; therefore, significant p38α/β MAPK inhibition would be expected in skeletal 
muscle with the 15 mg PO BID clinical dose. Although increasing concentrations resulted in 
increases in target engagement in vitro (Study FULTX-00008), there is no evidence that 
increasing the dose above 15 mg PO BID will result in significantly greater target engagement. 
Therefore, clinical dosing beyond 15 mg BID with the current formulation is not warranted 
(further details are provided in the IB). 
Food was found to increase the oral absorption of losmapimod for tablet formulations of the 
drug. An analysis of AUC0-inf and Cmax showed statistically higher systemic exposure in the fed 
state than in the fasted state. Administration of losmapimod in this study should be performed 
under fed conditions to reduce the potential for PK variability. 
Fulcrum anticipates that a 15 mg BID dosing regimen, as proposed under fed conditions for the 
planned phase 2 studies in FSHD, will result in mean steady-state Cmin and Cmax values of 
approximately 30 ng/mL and 75 ng/mL, respectively; the corresponding values for a 7.5 mg PO 
BID dosing regimen are 16 ng/mL and 38 ng/mL, respectively. Thus, the 15 mg BID regimen is 
expected to maintain steady-state losmapimod plasma concentrations above the optimal level of 
30 ng/mL needed for robust target engagement, while the 7.5 mg PO BID dose would fall below 
that at predose levels. Importantly, at the proposed dose level of 15 mg PO BID, exposures in 
FSHD subjects are not expected to exceed those previously demonstrated to be safe in humans in 
multiple previous studies by GSK in healthy volunteers and various patient populations (Barbour 
et al, 2013; Cheriyan et al, 2011; Pascoe et al, 2017; Watz et al, 2014). 
In Study 1821-CLP-101, similar relative bioavailability (AUC) was demonstrated between one 
15-mg losmapimod tablet versus two 7.5-mg losmapimod tablets. Peak exposure (Cmax) of 
losmapimod was reduced by 20% with one 15-mg tablet, although this did not have an impact on 
target engagement, which was consistent with prior Fulcrum studies.  
3.2.2. 
Rationale of Study Design 
The placebo-controlled treatment period is a randomized design that includes an active treatment 
group and a placebo group (Section 3.1). The inclusion of a placebo group is necessary because 
there is no available standard of care. 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 participants to study treatment. The OLE will evaluate 
the safety, tolerability, and efficacy of long-term dosing of losmapimod in subjects with FSHD1. 
Efficacy of the reduction in the expression of DUX4-regulated gene transcripts endpoints will be 
assessed with skeletal muscle needle biopsies from lower extremity muscles that meet the criteria 
for biopsy, are safely accessible, and that have been identified as sites of active disease by MRI. 
Physicians experienced in skeletal muscle needle biopsy will perform the procedure. In general, 
these muscle needle biopsies take a short time and are well tolerated, including when done 

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repeatedly. In one large series, no complications were reported in 400 consecutive skeletal 
muscle needle biopsies. Superficial infection or hematomas are rare (<1%; Edwards et al, 1983). 
Misregulated expression of DUX4 and its downstream transcripts is toxic to muscle and leads to 
muscle atrophy and death and replacement by fat (Bosnakovski et al, 2014; Vanderplanck et al, 
2011; Jones and Jones, 2018). The correlation between MRI characteristics, muscle pathology, 
and expression of DUX4-regulated transcripts was established and showed that the presence of 
an elevated MRI short tau inversion recovery (STIR) signal has substantial predictive value in 
identifying muscles with active disease and DUX4 target gene expression (Wang et al, 2019). 
DUX4 protein and mRNA are present at very low levels in FSHD skeletal muscle (Geng et al, 
2012; Jones et al, 2012). In contrast, DUX4-regulated transcripts are abundant and stably 
expressed. They represent the relevant functional readout of DUX4 protein levels and activity. 
These transcripts are readily measured in skeletal muscle biopsies (Geng et al, 2012; Tasca et al, 
2012; Yao et al, 2014; Jagannathan et al, 2016; Whiddon et al, 2017; Chen et al, 2016; Wang et 
al, 2019). As DUX4-regulated transcripts in skeletal muscle are uniquely and inextricably tied to 
the expression and function of DUX4, a subset of transcripts will be measured in skeletal muscle 
biopsies by quantitative reverse transcription polymerase chain reaction (QRT-PCR) as the 
primary efficacy endpoint to assess treatment effects on aberrant DUX4 activity. 
Standardized MRI protocols for imaging of muscle health and disease in neuromuscular 
disorders, including the measurement of skeletal muscle tissue replacement by fat using the 
Dixon technique (Dixon 1984), have been recommended as a result of 2 consortia organized by 
the TREAT-NMD network (Hollingsworth et al, 2012). The MRI technique to be used in this 
protocol is a standardized, objective, quantitative technique with automatic skeletal muscle 
segmentation for the 3-dimensional (3D) muscle volumes and fat fraction analyses via robust 
algorithms using Dixon imaging to measure the extent of skeletal muscle tissue replacement by 
fat in FSHD patients. Reliable and feasible whole-body MRI acquisition protocols and analysis 
algorithms are readily available for multicenter clinical studies focused on abdominal and liver 
fat. 
It is anticipated that changes in MRI and clinical assessments will take longer to detect than 
changes in DUX4 expression on skeletal muscle biopsy. Evaluation of changes in MRI and 
clinical assessments throughout the study will inform whether treatment with losmapimod could 
slow disease progression by protecting and/or restoring skeletal muscle function. 
Under FIS-002-2019 protocol version 3.0, the randomized, double-blinded, placebo-controlled 
portion of the study was scheduled to end at Week 24 with all primary endpoint visits completed 
by week 16. The COVID-19 pandemic has had a significant impact on the conduct of this 
clinical trial leading to many missing Week 16 and Week 24 visits and preventing the rolling 
over to the long-term OLE part of the study. Research site closures and individual study subjects 
have already missed visits and Fulcrum anticipates that many others will be missed unless rapid 
corrective actions are implemented. In addition, the necessary pandemic restrictions limit the 
assessment of long-term safety in the FSHD1 population in the clinic, as well as collection of 
critically important efficacy data on Week 24 on clinical outcome assessments and MRIs. 

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Further, the investigational drug delivery that currently takes place during the clinic visits is also 
now compromised, resulting in the potential for treatment gaps unless home delivery is rapidly 
enabled.   
Protocol version 4.0 (COVID-19 Pandemic Emergency Amendment), which follows the 
implementation of the ReDUX4 Emergency Guidance Document (31 March 2020), will ensure 
an adequate assessment of long-term safety of losmapimod compared to placebo, allows subjects 
to continue on the study with minimal treatment disruption, while preserving the opportunity to 
participate in an OLE. The amendment additionally enables assessment of the efficacy of 
losmapimod to treat the underlying cause of FSHD by extending the randomized, double-
blinded, placebo-controlled portion of the study from 24 to 48 weeks when sites impacted by 
COVID-19 will likely be up and running again. Collection of critical data impacted by COVID-
19 has been included in additional visits, including muscle biopsy (primary endpoint) and target 
engagement at Week 36 for subjects who missed the Week 16 visit, and clinical outcome 
assessments and MRIs at Week 48 for subjects who missed the Week 24 visit. The increase in 
the duration of the randomized, double-blinded, placebo- controlled portion of the study poses no 
additional risk to subjects and maintains the ability to safely obtain muscle biopsies in the clinic 
while monitoring safety parameters at home. It also allows for rolling over to the long-term OLE 
at the Week 48 visit for those who could not do it at Week 24. The amendment continues to 
provide subjects with the potential for benefit and the relation of the anticipated benefit to the 
risk is at least as favorable as that provided by alternatives as there are no approved treatments 
that can slow, stop, or reverse the effects of FHSD. Additionally, the planned interim analysis 
will provide an early assessment of the potential treatment effect of losmapimod to treat the 
underlying cause of FSHD providing timely data to inform future development.  
 

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4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
SELECTION OF STUDY POPULATION 
During the placebo-controlled treatment period, approximately 76 subjects with FSHD1 will be 
randomized at up to 25 sites. Eligibility will be reviewed and documented by an appropriately 
qualified member of the investigator’s team before subjects are enrolled. Subjects will be 
assigned to study treatment only if they meet all of the inclusion criteria and none of the 
exclusion criteria. (Note: Enrollment has completed for this study. A total of 80 subjects have 
been enrolled.) 
Deviations from the inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
4.1.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be enrolled in this study: 
1. Capable of understanding the written informed consent, and providing signed, dated, and 
witnessed written informed consent. 
2. Male or female subjects between the ages of 18 and 65 years, inclusive. 
3. Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the 
D4Z4 array on chromosome 4. 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). Genetic confirmation must be obtained before the subject is randomized and 
before the baseline muscle biopsy is performed; genetic confirmation can come from 
previous testing if verified with appropriate documentation from an accredited laboratory. 
Due to stable transmission of repeat sizes within families, subjects with a clinical 
diagnosis of FSHD who have a first-degree relative with a genetically confirmed 
diagnosis of FSHD1 may be entered into the study for screening assessments, including 
MRI. During screening, a confirmatory genetic diagnosis is conducted. If genetic testing 
during screening is necessary, the 4-week screening window will not start until the results 
are obtained and verified by the principal investigator. 
4. Clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive, at screening. 
Subjects who use a wheelchair or walker for any activity are not permitted to enroll in the 
study. 
5. Has an MRI-eligible muscle for biopsy, as determined by a central reader. 
6. Willing and able to comply with scheduled visits, treatment plan, study restrictions, 
laboratory tests, contraceptive guidelines, and other study procedures. 
7. Willing to practice an approved method of birth control: 
− A female subject is eligible to participate if she is of non-child-bearing potential, 
defined as premenopausal females with permanent sterilization (includes 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female 

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subject of any age); or postmenopausal, defined as 12 months of spontaneous 
amenorrhea; or, if of child-bearing potential, if she is using a highly effective 
method for avoidance of pregnancy (defined in Section 5.5.1) and will continue to 
use these methods for the duration of the study and until 90 days after the last 
dose of study drug. The decision to include or exclude women of child-bearing 
potential may be made at the discretion of the investigator and in accordance with 
local practice in relation to adequate contraception. 
− Male subjects must agree to use one of the contraception methods listed in 
Section 5.5.1. This criterion must be followed for the duration of the study and 
until 90 days after the last dose of study drug. 
4.1.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Has a 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 subject. This may include, but is not limited to, a history 
of relevant drug or food allergies; history of cardiovascular or central nervous system 
disease; neuromuscular diseases except FSHD (eg, myopathy, neuropathy, 
neuromuscular junction disorders); or 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 subjects who are on drug(s) or supplements that may affect muscle function, as 
determined by the treating physician, or that are included in the list of drugs presented in 
Appendix 13.2: subjects 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 randomization. Subjects 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. Once the 
febrile illness is fully resolved, the subject’s baseline visit can be scheduled. The duration 
of the screening visit in such cases can be extended for up to 35 days. 
5. Known active tuberculosis, active opportunistic, or life-threatening infections. 
6. Acute or chronic history of liver disease or known to have current alanine 
aminotransferase ≥2 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN, or 
known history of hepatitis B or C. 
7. Known severe renal impairment (defined as a glomerular filtration rate of <30 
mL/min/1.73m2). 
8. Positive screen for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV) 
antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2. 

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9. Standard 12-lead ECG demonstrating QTcF >450 msec for male subjects or QTcF >470 
msec for female subjects 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 subject’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 subject’s participation in the study. 
11. Blood donation (of approximately 1 pint [500 mL] or more) or any significant loss of 
blood within 90 days before the first dose of study drug, as determined by the 
investigator. 
12. Vaccination with a live attenuated vaccine within 6 weeks of randomization and 
throughout the study. 
13. Use of any anticoagulants for at least 1 month and anti-platelet agents for at least 1 week 
before the baseline biopsy, as they increase the risk of hematomas following skeletal 
muscle biopsy. 
14. Male subjects with a female partner who is planning to become pregnant during the study 
or within 90 days after the last dose of study drug. 
15. Positive pregnancy test or is known to be pregnant or lactating. All female subjects of 
child-bearing potential must have a negative serum β-human chorionic gonadotropin (β-
hCG) pregnancy test at screening and a negative urine pregnancy test prior to 
randomization. 
16. Alcohol, analgesic/opioid, and/or illicit drug abuse, as defined by the American 
Psychiatric Association 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. 
17. Any current mental condition (psychiatric disorder, senility, or dementia) that, in the 
opinion of the investigator, may affect study compliance or prevent understanding of the 
aims, investigational procedures, or possible consequences of the study. 
18. 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 prospective study 
with an investigational product, whether it concerns an experimental drug or a medical 
device. Note: concurrent participation in natural history studies (non-drug, non-device 
studies) may be acceptable if confirmed in writing by the sponsor. 
19. Anticipated inability to comply with any study procedures, including participation in 
study visits according to the visit schedule. 
20. Abnormal laboratory results indicative of any significant medical disease that, in the 
opinion of the investigator, would preclude the subject’s participation in the study. 
21. Subject, or close relative of the subject, 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. 
22. Contraindication to needle biopsy. 

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23. Contraindication to MRI as per clinic standard practice. 
4.2. 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR THE 
STUDY 
The duration of the placebo-controlled treatment period is defined for each subject as the time 
between the date the written informed consent was signed through 1) the completion of the Week 
48 visit if the subject is rolling over into the OLE or 2) the completion of the safety follow-up 
visit after the end of treatment if the subject is not rolling over into the OLE. The duration of the 
OLE is defined for each subject as the time after completion of the Week 48 visit through 
completion of the safety follow‑up visit after the end of treatment or discontinuation of the study. 
4.2.1. 
Reasons for Withdrawal/Discontinuation 
Subjects 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 
subjects in the study, including if a subject decides to prematurely discontinue study treatment. 
The reasons for subjects not completing the study will be recorded. A subject may be withdrawn 
from the study for any of the following reasons: 
1. The subject does not meet the protocol inclusion or exclusion criteria. 
2. The subject is noncompliant with the protocol. 
3. The subject has a serious or intolerable AE(s) that, in the investigator’s opinion, requires 
withdrawal from the study. 
4. The subject has laboratory safety results that reveal clinically significant hematological or 
biochemical changes from the baseline values. 
5. The subject has symptoms or an intercurrent illness not consistent with the protocol 
requirements or that justify withdrawal. 
6. The subject is lost to follow-up. 
7. Other reasons (eg, pregnancy, development of contraindications of use of study drug). 
8. The subject withdraws consent, or the investigator or sponsor decides to discontinue the 
subject’s participation in the study. 
The investigator will also withdraw a subject if Fulcrum Therapeutics terminates the study. Upon 
occurrence of a serious or intolerable AE, the investigator will confer with the sponsor. If a 
subject is discontinued because of an AE, the event must continue to be followed to satisfactory 
resolution as described in Section 6.2.1.10. Any subject may withdraw his or her consent at any 
time. 
4.2.2. 
Handling of Withdrawals 
Subjects are free to withdraw from the study or study treatment at any time upon request. Subject 
participation in the study may be stopped at any time at the discretion of the investigator or at the 
request of the sponsor. 

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Subjects who discontinue study treatment or active participation in the study will no longer 
receive study drug. When a subject 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 subject prematurely discontinues study treatment, they will be encouraged to remain in the 
study and continue with all other aspects of the study.  
If a subject 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 subject 
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 7 (±3) 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. 
Subjects 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 subjects being lost to follow-up, at least 3 
documented attempts to contact the subject must be made. 
It is vital to obtain follow-up data on any subject withdrawn because of an AE or SAE. In every 
case, efforts must be made to undertake protocol-specified, safety, follow-up procedures. 
4.2.3. 
Replacements 
Subjects who withdraw or discontinue will not be replaced. 

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5. 
STUDY TREATMENTS 
5.1. 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
During the placebo-controlled treatment period, subjects 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). 
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 SAS software Version 9.3 or later (SAS Institute, Cary, NC) for 
IRT, which will link sequential subject randomization numbers to treatment codes. The 
randomization will use an appropriate block size, which will not be revealed. 
Subjects can be randomized only once. 
During the OLE, all subjects will receive open-label losmapimod. 
5.2. 
TREATMENTS ADMINISTERED 
Study drug tablets in the placebo-controlled treatment period (losmapimod or placebo) and the 
OLE (losmapimod) will be dispensed to subjects at the visits detailed in Table 2 and Table 3, 
respectively. Subjects may be provided additional study drug via a courier service, as applicable. 
During the placebo-controlled treatment period, subjects will receive 15 mg losmapimod BID or 
placebo BID. In the OLE, subjects will receive 15 mg losmapimod BID.  
For subjects who rolled over to the OLE under protocol version 3.0, prior to the COVID-19 
pandemic, during the 24-week placebo-controlled treatment period these subjects received 15 mg 
losmapimod BID or placebo BID. These subjects will continue on open-label treatment with 15 
mg losmapimod BID. At their next clinic visits, these specific subjects will follow the 
assessments for the Week 36 visit followed by the Week 48 visit in the placebo-controlled 
portion of the study under the COVID-19 Pandemic Emergency protocol version 4.0. 
Study drug (losmapimod or placebo) should be taken with food. 
If a subject misses a dose and it is more than 6 hours until the next planned dose, the subject 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 subject will be instructed to skip the missed dose and then 
resume study drug dosing as normal. 
5.3. 
IDENTITY OF INVESTIGATIONAL PRODUCT 
Losmapimod tablets for oral administration are available as white, round, biconvex, plain, film-
coated tablets containing losmapimod as the micronized freebase. Losmapimod tablets also 
contain the inactive excipients microcrystalline cellulose, lactose monohydrate, sodium starch 
glycolate, magnesium stearate, and povidone K29/32, and the Opadry White OY-S-28876 film 
coat contains hypromellulose, titanium dioxide (E171), and polyethylene glycol. 

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Placebo tablets are identical in appearance to losmapimod and are manufactured using 
commonly used and recognized tablet excipients that are also employed in the active tablets. 
The sponsor will ensure that the study site is provided with adequate supplies of blinded 
losmapimod and placebo (placebo-controlled treatment period) or open-label losmapimod (OLE) 
and that no expired tablets will be dispensed to study subjects. 
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. 
During the placebo-controlled treatment period, each dispensation will contain a blinded dosage 
for 1 subject with a sufficient quantity to cover until the next scheduled visit plus additional 
tablets to cover the visit window. If needed, subjects may be provided additional study drug via a 
courier service, as applicable. Study drug will be packaged and labelled in accordance with 
regulatory requirements and in a manner to retain the study blind. 
During the OLE, subjects will be supplied with a sufficient quantity of losmapimod to last until 
the next scheduled visit plus additional tablets to cover the visit window or will be provided 
additional study drug via a courier, as applicable. Open-label losmapimod will be packaged and 
labelled in accordance with regulatory requirements. 
Further details of study drug packaging, labeling, and distribution of the study medication will be 
provided in the study reference manual. 
Study drug must be stored in a secure area (eg, a locked cabinet), protected from moisture, and 
kept at a controlled room temperature not to exceed 30°C. 
5.4.2. 
Study Drug Accountability 
During the study, each subject 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, 
subjects may be provided additional study drug via a courier service, as applicable. At the next 
scheduled clinic visit, subjects must return their bottles 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 subject in the study. Reasons for departure from the expected 
dispensing regimen must also be recorded. At the completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all study drug will be reconciled and retained or 
destroyed according to applicable regulations. 

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5.4.3. 
Medication Errors and Overdose 
No specific antidote for losmapimod is known. In case of overdose or medication errors, subjects 
should be observed and be provided with a supportive standard of care. 
5.5. 
LIFESTYLE RESTRICTIONS 
Any nutrients known to modulate cytochrome P450 enzyme activity (eg, grapefruit- or Seville 
orange-containing products or quinine containing drinks [tonic water or bitter lemon]) should be 
avoided 3 days before the first dose of study drug until after the last dose of study drug. 
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. This is especially important on the day of the muscle biopsies and the days before it. 
For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory 
blood samples being taken. For some study visits, if possible, subjects will be asked to take the 
morning medication in the clinic to enable blood sampling before and at specific times after 
taking the study drug. 
5.5.1. 
Contraception Requirements 
Subjects of child-bearing potential must be willing to practice an approved method of birth 
control for the duration of the study and until 90 days after the last dose of study drug. 
A female subject is eligible to participate if she is of non-child-bearing potential, defined as 
premenopausal females with permanent sterilization (includes hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy in a female subject of any age); or postmenopausal, 
defined as 12 months of spontaneous amenorrhea; or, if of child-bearing potential, if she is using 
a highly effective method for avoidance of pregnancy and will continue to use these methods for 
the duration of the study and until 90 days after the last dose of study drug. 
Male subjects must agree to use one of the contraception methods listed below for the duration of 
the study and until 90 days after the last dose of study drug. 
The following is the all-inclusive list of the highly effective methods for avoiding pregnancy in 
females of child-bearing potential (ie, the methods 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 et al, 2007): 
• Complete abstinence from penile-vaginal intercourse when this is the preferred and usual 
lifestyle 
• Oral contraceptive, either combined or progestogen alone 
• Injectable progestogen 
• Implants of etonogestrel or levonorgestrel 
• Estrogenic vaginal ring  

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• Percutaneous contraceptive patches 
• Intrauterine device or intrauterine system 
• Tubal sterilization 
• Essure micro-insert system (provided confirmation of success 3 months after procedure) 
• Male partner sterilization (vasectomy with documentation of azoospermia) prior to the 
female subject’s entry into the study, and this male is the sole partner for that subject. The 
information on the male sterility can come from the site personnel’s review of the 
subject’s medical records; medical examination of the subject, and/or semen analysis; or 
interview with the subject on his medical history. Sterilized males (vasectomy with 
documentation of azoospermia) must use condoms until 90 days after last dose of study 
drug. 
• Male condom combined with a female diaphragm, either with or without a vaginal 
spermicidal (foam, gel, film, cream, or suppository). Nonoxynol-9 is the critical 
component in most spermicides. 
5.6. 
BLINDING 
The placebo-controlled treatment period will be performed in a double-blind fashion. The 
investigator, study staff, subjects, and monitor will remain blinded to subject-level treatment 
assignment until study closure. The sponsor and/or its designee will remain blinded to the 
subject-level treatment assignment until after all subjects have completed the Week 48 visit (or 
have discontinued) and the database from the placebo-controlled treatment period has been 
locked for statistical analyses, after which time they will be unblinded. For the interim analysis 
(IA), DUX4 and demographics data will be presented to the Sponsor as group-level summaries, 
along with associated p-values. 
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 subject’s treatment assignment will not be broken until the end of the study unless medical 
treatment of the subject depends on knowing the study treatment the subject received. In the 
event that the blind needs to be broken because of a medical emergency, the investigator may 
unblind an individual subject’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 subject. 
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. 
During the OLE, no blinding will be performed (subjects will receive open-label losmapimod); 
however, the investigator, study staff, subjects, and monitor will remain blinded to the original 
subject-level treatment assignment from the placebo-controlled treatment period for the duration 

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of the study. The sponsor and/or its designee will be unblinded after all subjects have completed 
the Week 48 visit (or have discontinued) and the database from the placebo-controlled treatment 
period has been locked for statistical analyses. 
5.7. 
TREATMENT COMPLIANCE 
Subject compliance will be monitored by tablet counts in the clinic. In addition, subject diaries 
may only be used for a portion of the placebo-controlled portion of the trial 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 subjects 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 visit (either at the end of the placebo-controlled treatment period or at the end of the 
OLE, as applicable) will be recorded in the subject’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 subject’s eCRF. 
Any concomitant medication deemed necessary for the welfare of the subject 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 prohibited in this study: 
• Vaccination with a live attenuated vaccine from 6 weeks prior to randomization until the 
safety follow-up visit (either at the end of the placebo-controlled treatment period or at 
the end of the OLE, as applicable) 
• Use of any anticoagulants for at least 1 month and anti-platelet agents for at least 1 week 
before each biopsy because these treatments increase the risk of hematomas following 
skeletal muscle needle biopsy 
Subjects who are on drug(s) or supplements that may affect muscle function, as determined by 
the treating physician, or that are included in the list of drugs presented in (Appendix 13.2) 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. 

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6. 
STUDY ASSESSMENTS AND PROCEDURES 
Before performing any study procedures, all potential subjects will sign an informed consent 
form (ICF). Subjects will have the opportunity to have any questions answered before signing 
the ICF. The investigator must address all questions raised by the subject. The investigator or 
designee will also sign the ICF. 
Study visits and the timing of assessments for the placebo-controlled treatment period or the 
OLE are detailed in the schedule of events (Table 2 and Table 3, respectively). 
Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to roll 
over into the OLE. Subjects that have already rolled over to the OLE prior to the COVID-19 
pandemic will remain on open-label treatment. Their next clinic visits will follow the 
assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the study in 
the COVID-19 Pandemic Emergency protocol version 4.0. These subjects will not undergo the 
Week 36 biopsy. Subjects who did not roll over prior to the COVID-19 pandemic will roll over 
into the OLE at the Week 48 visit as described in the COVID-19 Pandemic Emergency protocol 
version 4.0. 
6.1. 
 EFFICACY ASSESSMENTS 
6.1.1. 
Skeletal Muscle Needle Biopsy 
The choice of the muscle(s) to be biopsied in this study will be determined by the investigator, 
informed by skeletal muscle MRI during screening. The bilateral vastus lateralis, vastus 
medialis, lateral gastrocnemius, medial gastrocnemius, and tibialis anterior will be evaluated for 
eligibility by MRI using a central reader. Only those muscles that are STIR positive with the 
predetermined range of MFF will be eligible for biopsy. This information will be communicated 
to the sites that will select the muscle or muscles for biopsy. Sites will select the best muscle(s) 
that meet the MRI criteria based on their own experience with muscle needle biopsy. The Week 
16 or Week 36 muscle needle biopsies (for those subjects unable to have the Week 16 muscle 
biopsy due to the COVID-19 pandemic), will be performed in the same approximate muscle 
region as the pretreatment (Day 1) muscle biopsy. 
The muscle tissue collected at each biopsy will be analyzed for DUX4 activity using a molecular 
panel of DUX4-regulated gene transcripts and for drug concentration and target engagement by 
central laboratories. The tissue will be used to measure other gene transcripts and may be used to 
measure proteins related to the pathology of FSHD as part of exploratory biomarker endpoints. 
The specific details of the biopsy procedures, materials to be provided, materials to be resourced 
locally, personnel qualification, and methods for tissue collection, processing, and analysis will 
be specified in the study reference manual. 

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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 2. Subjects will be screened for any contraindications to MRI as per clinic standard 
practice. 
Details will be described in the study MRI manual. The study MRI manual will also describe, in 
detail, all of the steps involved in the acquisition, transmission, quality evaluation, and analysis 
of MRI images between the study site and the central reader. 
6.2. 
SAFETY AND TOLERABILITY ASSESSMENTS 
6.2.1. 
Adverse Events 
6.2.1.1. 
Definitions of Adverse Events 
The investigator is responsible for reporting all treatment-emergent AEs (TEAEs) that are 
observed or reported during the study, regardless of their relationship to study drug or their 
clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study, 
regardless of its causal relationship to study drug. Subjects will be instructed to contact the 
investigator at any time after randomization if any symptoms develop. 
A TEAE is defined as any event that was not present before exposure to study drug or any event 
that was already present but worsens in either intensity or frequency after exposure to study drug.  
6.2.1.2. 
Serious Adverse Events 
An SAE is defined as any event that 
• results in death 
• is immediately life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/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 
may jeopardize the subject 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. 

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6.2.1.3. 
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 can be appropriate. 
Adverse events of special interest for this study include liver tests that meet the criteria for 
potential drug-induced liver injury (DILI), in accordance with the US Food and Drug 
Administration (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 alanine transaminase or aspartate transaminase 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 subjects 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-up the event until resolution. These steps include, but are not limited 
to: 
• Making every reasonable attempt to have the subject return to the clinic within 24 hours 
for repeat liver 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 subject is 
asymptomatic 
• Obtaining viral hepatitis serology 
• Considering liver imaging and/or hepatology consultation 
6.2.1.4. 
Eliciting and Documenting Adverse Events 
Adverse events and SAEs will be assessed from the time the subject signs the ICF through the 
safety follow-up visit (either at the end of the placebo-controlled treatment period or at the end of 
the OLE, as applicable). Any SAE that occurs after these time periods and that is believed to be 
related to study drug should be reported by the investigator (as described in Section 6.2.1.6). 
At every study visit, subjects 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). 

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In addition to subject 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 subject safety will be documented on the AE page in the 
eCRF. 
6.2.1.5. 
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 
• 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 investigator’s assessment) must also be reported. All AEs must 
continue to be followed to satisfactory resolution as described in Section 6.2.1.10. The Medical 
Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the subject 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. 
Please refer to the ReDUX4 Emergency Guidance Document (31 March 2020) for reporting of 
AEs related to the COVID-19 pandemic. 
Reporting for AESIs is described in Section 6.2.1.3.  
6.2.1.6. 
Reporting Serious Adverse Events 
The investigator must report any AE that meets the SAE criteria (Section 6.2.1.2) to 
 
immediately (ie, within 24 hours after the site personnel first learn about the event) via electronic 
data capture (EDC). In the event that EDC entry is not possible (eg, system failure or access 
problems), the study site staff should complete the paper SAE report form and fax the form to 
 Pharmacovigilance within 24 hours of awareness or call the 
 safety hotline to report. 
The study site staff should update the EDC system as soon as it is available. 
 

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A full description of every SAE will need to be provided to 
 Pharmacovigilance. The 
following contact information should be used if reporting SAEs via fax or phone: 
Pharmacovigilance 
US: 
Rest of world: 
6.2.1.7. 
Suspected Unexpected Serious Adverse Reactions 
The sponsor will promptly evaluate all suspected unexpected serious adverse reactions 
(SUSARs) against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, Institutional Review Boards (IRBs)/Independent 
Ethics Committees (IECs), and applicable regulatory authorities based on applicable legislation. 
To determine reporting requirements for single AE cases, the sponsor will assess the 
expectedness of these events using the IB. 
The sponsor will compare the severity of each SUSAR and the cumulative event frequency 
reported for the study with the severity and frequency reported in the IB. 
Reporting requirements will also be based on the investigator’s assessment of causality and 
seriousness, with allowance for upgrading by the sponsor as needed.   
6.2.1.8. 
Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the subject’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. 
6.2.1.9. 
Assessment of Causality 
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. 

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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 subject’s clinical condition, intercurrent illness, or concomitant drugs 
administered to the subject, 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. 
Probable: This relationship suggests that a reasonable temporal sequence of the event with 
drug administration exists and, 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. 
6.2.1.10. 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. 
6.2.2. 
Laboratory Analyses 
Samples for serum chemistry, hematology, coagulation, and urinalysis will be collected at the 
time points specified in Table 2 and Table 3. Processing, storage, and shipping procedures for all 
clinical laboratory samples are provided in a laboratory manual. Sample collection details are 
presented in Section 6.7. 
For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory 
blood samples being taken. 

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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 in the placebo-controlled treatment period) 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 subject’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.  
Blood and other biological samples will be collected for the following clinical laboratory tests: 
Serum chemistry 
Glucose, sodium, potassium, calcium, inorganic phosphate, total protein, 
albumin, blood urea nitrogen, creatinine, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-
glutamyltransferase, creatine phosphokinase 
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 
Coagulation 
International normalized ratio, prothrombin time, partial thromboplastin time 
Urinalysis 
Leucocytes, 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 β-hCG (all female subjects of child-bearing potential), serum 
follicle-stimulating hormone (suspected postmenopausal female subjects 
only [defined in Section 5.5.1]), urine pregnancy test 
Serology testing 
HbsAg, HCV antibody, HIV-1/HIV-2 antibodies 
Urine drug screen 
Cocaine, amphetamines, opiates (morphine), benzodiazepines, and 
cannabinoids 
6.2.3. 
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 or at a subject’s next scheduled study visit, 
if not previously recorded. 

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6.2.4. 
Vital Signs 
Vital sign (pulse rate, respiration rate, blood pressure, and temperature) assessments will be 
performed at the time points specified in Table 2 and Table 3. Assessments will be taken after 
the subject has been seated or recumbent for at least 5 minutes and before any 12-lead ECG 
assessment or blood sampling is performed. 
6.2.5. 
Physical Examinations 
Physical examinations will be performed at the time points specified in Table 2 and Table 3. 
Physical examinations at the screening visit and the safety follow-up visit 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 MSK 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 2 and Table 3. 
Height (cm) will be recorded and body mass index (BMI) calculated at screening and once 
yearly during the OLE: 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. 
6.2.6. 
Twelve-Lead Electrocardiograms 
Twelve-lead ECGs will be performed at the time points specified in Table 2 and Table 3. The 
primary ECG tracings will be locally read by the investigator. Any ECGs found to have 
abnormalities will be referred for a second opinion by a central reader. 
Twelve-lead ECGs will be performed after subjects 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 subject’s eligibility for the study. 
Any clinically significant changes from baseline should be reported as AEs or SAEs, if 
applicable. 
6.3. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
6.3.1. 
Pharmacokinetic Assessments 
During the placebo-controlled treatment period, blood samples will be collected to measure the 
plasma concentrations of losmapimod at Day 1 (baseline), Week 4, Week 16, and Week 36 at the 

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following time points: immediately predose and 4 hours (±30 minutes) after administration of the 
study dose. Blood samples will also be taken, when feasible, after dosing during the Week 12, 
Week 24, and Week 48 visits, preferably ≥1 hour after dosing (Table 2). During the OLE, blood 
samples will be collected to measure the plasma concentration of losmapimod after dosing at the 
Week 144 visit, preferably ≥1 hour after dosing (Table 3). 
For each plasma PK sample, approximately 3 mL of blood will be collected via an intravenous 
catheter placed in an antecubital vein in the arm into a 3 mL, lavender-capped vacutainer tube 
containing K2-EDTA. The indwelling catheter will be kept patent by saline flush after each 
blood sampling. The exact actual clock time of withdrawal of the blood sample will be recorded. 
 
Skeletal muscle biopsies will be taken at Day 1 (baseline; predose) and at Week 16 or Week 36 
to assess the losmapimod concentrations in muscle during the placebo-controlled treatment 
period (Table 2). Skeletal muscle biopsy procedures are described in Section 6.1.1. 
Further detailed handling, processing, storage, and shipping procedures for plasma and skeletal 
muscle biopsy PK samples are described in laboratory manuals. 
6.3.2. 
Pharmacodynamic Assessments 
During the placebo-controlled treatment period, samples for assessing the target engagement 
estimates of losmapimod in peripheral blood will be collected at Day 1 (baseline) and Week 16 
or Week 36 if it was not possible to collect the sample due to the COVID-19 pandemic, at the 
following time points: immediately predose and 4 hours (±30 minutes) after taking the study 
dose (Table 2). 
For drug target engagement measurements in skeletal muscle tissue during the placebo-
controlled treatment period, each biopsy will be analyzed for pHSP27/total HSP27. Target 
engagement estimates of losmapimod in skeletal muscle biopsy will be taken at Day 1 (baseline; 
predose) and at Week 16 or Week 36 (Table 2). Skeletal muscle biopsy procedures are described 
in Section 6.1.1. Target engagement in muscle will be compared to target engagement in blood 
collected on the same day. 
Further detailed handling, processing, storage, and shipping procedures for target engagement 
samples are described in a laboratory manual. 
6.4. 
OTHER ASSESSMENTS 
6.4.1. 
Reachable Workspace 
The RWS Microsoft Kinect-based movement sensor system will be used at the visits noted in 
Table 2 to determine the subjects’ 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 upper extremity 
function, including shoulder and proximal arm. Previous and ongoing evaluation of the hardware 

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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). 
During the evaluation, subjects 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 TV monitor. The evaluation will be performed with and 
without weights and on both the right and left 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 side’s RWS 
envelope will be divided into 4 quadrants, with the shoulder joint serving as the origin. The 
absolute total RWS surface envelope area (m2) as well as areas for each of the quadrants will be 
calculated. Scaling of the data by each person’s arm length will allow normalization for 
comparison between subjects (Han et al, 2015). RWS includes the functional workspace, where 
patients are instructed to touch certain parts of their body and are rated on their ability to 
complete this task. 
Instructions for equipment assembly, setup, testing, and site certification; a manual of operation; 
and a quick reference guide will be described in a 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. 
6.4.2. 
Timed Up and Go 
The classic and FSHD TUG test will be performed at the visits noted in Table 2. 
The TUG test is a simple test that is used to assess a person’s mobility and requires both static 
and dynamic balance. It measures the time that a person takes to rise from a chair, walk 3 meters, 
turn around, walk back to the chair, and sit down. The optimized TUG test is the classic TUG but 
adds the component of getting up from a laying position on a bed-like table in the clinic at the 
start of the test and laying back down on his or her back at the end of the test. The test will be 
done twice per visit. 
A manual of operation, traditional TUG source documents, and FSHD TUG source document  
will be described in a TUG manual. A central reader will be responsible for training, quality 
control, data analysis, and standardization of the TUG and FSHD TUG across all sites in the 
study.  
6.4.3. 
Dynamometry 
Dynamometry will be performed at the visits noted in Table 2. 
Quantitative isometric dynamometry (hand-held dynamometer) will be used to assess the skeletal 
muscle strength of study subjects in both the upper and lower limbs bilaterally. Shoulders, 
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applicable visit. 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. 
6.4.4. 
Motor Function Measure Domain 1 
The MFM scale Domain 1 assessment will be performed at the visits noted in Table 2.  
The MFM scale assesses the severity of the motor deficit as determined by an experienced 
physical therapist (Bérard et al, 2005). The score is reproducible, the coefficients of the interrater 
reliability are good or excellent. Domain 1 of the MFM provides a clinician’s assessment of 
functional impairment for standing and transfers. 
Instructions for performing the MFM scale Domain 1 assessment will be provided in a study 
reference manual. 
6.4.5. 
FSHD Health Index 
The FSHD-HI will be performed at the visits noted in Table 2. 
The FSHD-HI is an FSHD-specific patient-reported measure of disease burden on activities of 
daily living, quality of life, and symptom prevalence and severity. It consists of a questionnaire 
with 116 items developed from qualitative interviews of patients followed by a national cross-
sectional validation study. The measure consists of 14 subscales that measure a patient’s 
perception of their ambulation and mobility, hand function, shoulder and arm function, 
emotional health, back/chest/abdomen strength, fatigue, pain, eating function, ability to do 
activities, communication ability, satisfaction in social situations, performance in social 
situations, body image and cognition. Scoring is performed centrally by the developer. 
6.4.6. 
Patients’ Global Impression of Change 
The PGIC will be performed at the visits noted in Table 2 to obtain the subjects’ rating of overall 
improvement. 
6.4.7. 
Genetic Confirmation of FSHD1 
Genetic testing for FSHD1 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, 
2015). For this study, only subjects 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. Subjects with 10 repeats 

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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. 
Genetic confirmation must be obtained before the subject is randomized and before the baseline 
muscle biopsy is performed. Genetic confirmation can come from previous testing, if verified 
with appropriate documentation from an accredited laboratory. If genetic testing is necessary, the 
4-week screening window and activities will not start until the results are obtained and verified 
by the principal investigator. 
Due to the stable transmission of repeat sizes within families, subjects with a clinical diagnosis 
of FSHD who have a first-degree relative with a genetically confirmed diagnosis of FSHD1 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 4-week screening window will not start until the results are obtained and verified 
by the principal investigator. 
Further detailed handling, processing, storage, and shipping procedures for genetic testing 
samples are described in a laboratory manual.  
6.5. 
SAFETY REVIEW COMMITTEE 
As detailed in Section 11.1.1, a safety review committee (SRC) will review safety data from the 
study. 

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6.6. 
PREGNANCY 
Pregnancy is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication. Any pregnancy that occurs 
during study participation must be reported as an SAE. Study staff should complete the paper 
Pregnancy Initial Report Form and fax the form to 
 Pharmacovigilance within 24 hours of 
awareness or call the 
 safety hotline to report. To ensure subject safety, irrespective of the 
treatment received by the subject, any pregnancy occurring during study drug administration or 
until follow-up must be reported within 24 hours of the investigator’s knowledge of the event to 
the sponsor. 
If a woman becomes pregnant while on study drug, the study drug must be discontinued 
immediately. The investigator must counsel the subject and discuss the potential risks to the 
pregnancy and the possible effects on the embryo or fetus. The pregnancy must be followed up 
to determine the outcome (including spontaneous miscarriage, elective termination, normal birth, 
or congenital abnormality) and status of mother and child, even if the subject was discontinued 
from the study. Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE. Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy that is brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly related to 
the study drug must be promptly reported to 
 and Fulcrum Therapeutics. 
6.7. 
SAMPLE COLLECTIONS 
Processing, storage, and shipping procedures for all clinical laboratory, PK, and target 
engagement samples are provided in a laboratory manual.  

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7. 
STATISTICAL AND ANALYTICAL PLAN 
Details regarding the statistical methods and definitions will be provided in statistical analysis 
plan(s) (SAP[s]). Separate SAPs will be prepared for each treatment period of the study. The 
SAP for the placebo-controlled treatment period will be finalized prior to database lock/freeze 
for the IA. 
Any deviations from the SAP(s) are to be justified in the clinical study reports. Statistical 
analyses will be performed using Version 9.3 or higher of SAS (SAS Institute, Cary, NC). 
Analyses will be generated separately for the placebo-controlled treatment period and the OLE. 
7.1. 
PLACEBO-CONTROLLED TREATMENT PERIOD 
7.1.1. 
Primary Endpoint 
The primary endpoint of the placebo-controlled treatment period is the change from baseline in 
DUX4 activity in affected skeletal muscle at Week 16 or Week 36, as measured by QRT-PCR in 
a panel of DUX4-regulated gene transcripts. 
7.1.2. 
Secondary Endpoints 
The secondary endpoints of the placebo-controlled treatment period are as follows: 
• Safety and tolerability of losmapimod as defined by the following: 
− Type, frequency, severity, seriousness, and relationship of AEs to losmapimod 
− Incidence of AESIs 
− Number of subjects who prematurely discontinue study drug due to an AE 
− Frequency of clinically significant changes in laboratory test, ECG, vital sign, and 
physical examination results 
• Change from baseline in MFF, LMV, and MFI at Week 12, Week 24 (if applicable) and 
Week 48  
• Plasma concentrations of losmapimod at Week 4, Week 12, Week 16, Week 24, Week 
36, and Week 48 
• Concentrations of losmapimod in skeletal muscle biopsy at steady state at Week 16 or 
Week 36 
• Target engagement parameters in blood, and skeletal muscle biopsy at Week 16 or Week 
36 
7.1.3. 
Exploratory Endpoints 
The exploratory endpoints of the placebo-controlled treatment period are as follows: 
• Change from baseline in COAs, including 
− RWS with and without weights at Week 4, Week 12, Week 24, and Week 36 

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− Classic and FSHD TUG at Week 4, Week 12, Week 24, and Week 36 
− Muscle strength by hand-held quantitative dynamometry at Week 4, 
− Week 12, Week 24, Week 36, and Week 48 
− MFM Domain 1 at Week 12, Week 24, Week 36, and Week 48 
− FSHD-HI at Week 4, Week 12, Week 24, Week 36, and Week 48 
− PGIC at Week 4, Week 12, Week 16, Week 24, Week 36, and Week 48 
• Change from baseline in inflammatory, immune, apoptotic, and other muscle disease 
transcripts may be conducted in muscle biopsy at Week 16 or Week 36 and in circulating 
proteins in plasma and serum at Week 4, Week 12, Week 16, Week 24, Week 36, and 
Week 48. 
7.2. 
OPEN-LABEL EXTENSION 
7.2.1. 
Primary Endpoint 
The primary endpoint of the OLE is the safety and tolerability of long-term treatment of 
losmapimod based on AEs, clinical laboratory tests, ECGs, vital signs, and physical examination. 
7.2.2. 
Secondary Endpoint 
The secondary endpoint of the OLE is the plasma concentrations of losmapimod after long-term 
dosing (at every-12-week time points). 
7.3. 
SAMPLE SIZE CALCULATIONS 
Assuming an effect size of 0.70, a sample size of 68 subjects (34 subjects per group) will be 
needed to provide 80% power with a 2-sided test at a 0.05 significance level to detect a 
difference between losmapimod and placebo in change from baseline in DUX4 activity in 
affected skeletal muscle after 16 or 36 weeks (depending upon when the muscle biopsy was 
performed) during the placebo-controlled treatment period. Assuming that approximately 10% of 
subjects will be non-evaluable, approximately 76 subjects will be randomly assigned at a 1:1 
ratio to losmapimod and placebo (38 subjects per group). 
7.4. 
ANALYSIS SETS 
The following analysis sets will be used in the statistical analyses. 
Full analysis set (FAS): The FAS will consist of all subjects who are randomly assigned to 
receive double-blind study drug in the placebo-controlled treatment period. All analyses using 
the FAS will group subjects according to randomized treatment. The FAS is the main analysis 
population for key study endpoints (Section 7.6.1). For the secondary and exploratory endpoints, 
subjects who already transitioned into the OLE portion under protocol version 3.0 will be 
analyzed as randomized, in this analysis population. 

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Per-protocol set (PPS): The PPS will consist of all FAS subjects who fulfill all 
inclusion/exclusion criteria and do not have any significant protocol deviations. All analyses 
using the PPS will group subjects according to randomized treatment. PPS analyses will be 
conducted for key study endpoints (Section 7.6.1) to assess robustness of key study inferences. 
Safety analysis set: The safety analysis set will consist of all subjects who receive any study 
drug. All analyses using the safety analysis set will group subjects according to treatment 
actually received. 
Pharmacokinetic analysis set: The PK analysis set will consist of all subjects who receive at least 
1 dose of losmapimod and have evaluable PK data for losmapimod. 
Pharmacodynamic analysis set: The PD analysis set will consist of all subjects who receive at 
least 1 dose of losmapimod and have evaluable PD data for losmapimod. 
Open-label losmapimod (Pre-COVID-19) analysis set: This analysis set will consist of subjects 
who were already transitioned into open-label losmapimod under version 3.0 of the protocol. 
This analysis set will be used for sensitivity analysis, to assess secondary/exploratory endpoints 
in this subset of subjects.  
Open-label analysis set: The open-label analysis set will consist of all subjects who complete 24 
weeks of treatment in the placebo-controlled treatment period and receive at least 1 dose of 
open-label losmapimod in the OLE. Safety and efficacy analyses in the OLE will be based on 
this analysis set. 
7.5. 
DESCRIPTION OF SUBGROUPS TO BE ANALYZED 
Any planned subgroup analyses will be described in the SAP(s). 
7.6. 
STATISTICAL ANALYSIS METHODOLOGY 
Continuous variables will be summarized using the mean, standard deviation, median, minimum, 
and maximum. Categorical variables will be summarized using frequency counts and 
percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions are described in the SAP(s). All 
statistical tests will be 2-sided and performed using a 0.05 significance level. 
Details of multiplicity adjustment, if any, will be fully described in the SAP(s). 
7.6.1. 
Hypothesis Testing on Key Study Endpoints 
Hypothesis testing on key study endpoints will be conducted using the FAS. 
A sequential testing procedure will be used to control for Type I Error to test the following key 
study endpoints: 
• DUX4 change from baseline (Week 16 or Week 36) 
• LMV change from baseline (Week 48) 

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• FSHD TUG (Week 48) 
The testing hierarchy will be provided in the SAP. Each endpoint will be tested at approximately 
5% alpha in a hierarchical manner, using the final test-alpha obtained from O’Brien-Fleming 
Spending Function (Section 7.6.8).  
7.6.2. 
Analysis of Primary Endpoints 
The primary endpoint of the placebo-controlled treatment period is the change from baseline in 
DUX4 activity in affected skeletal muscle at Week 16 or Week 36, as measured by QRT-PCR in 
a panel of DUX4-regulated gene transcripts. An analysis of covariance (ANCOVA) model will 
be used to analyze the change from baseline in DUX4 activity in affected skeletal muscle, with 
repeat number category and treatment group as fixed effects and baseline DUX4 activity in 
affected skeletal muscle as a covariate. Least-square (LS) mean, standard error, and 95% CI of 
the LS mean 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 final p-value will 
be compared against the significance level of approximately 0.05 (Section 7.6.8). All available 
data will be used. Details will be provided in the SAP(s). 
The FAS will be used for the primary analysis for the placebo-controlled treatment period.  
The analysis for the primary endpoint for the OLE is described in Section 7.6.6. 
7.6.3. 
Analysis of Secondary Endpoints 
Secondary endpoints (detailed in Section 7.1.2 and Section 7.2.2) will be summarized using 
descriptive statistics. 
Continuous endpoints with multiple post-baseline assessments will be analyzed using mixed-
effect model for repeated measures (MMRM) methods including repeat number category, 
treatment group, visit, and treatment-by-visit interaction as fixed effects and baseline value as a 
covariate. Continuous endpoints with a single post-baseline assessment will be analyzed using 
ANCOVA methods, with repeat number category and treatment group as fixed effects and 
baseline value as a covariate. Secondary endpoints in the OLE will be summarized according to 
the treatment assigned at randomization. For all subjects, changes in measurements will be 
calculated relative to measurements obtained at baseline (ie, prior to first dose in the placebo-
controlled treatment period). 
Further details of these endpoints are presented in Section 7.6.5, Section 7.6.6, and the SAP(s).  
7.6.4. 
Analyses of Exploratory Endpoints 
Exploratory endpoints (detailed in Section 7.1.3) will be summarized using descriptive statistics. 
Confidence intervals will be included as appropriate. When appropriate, continuous exploratory 
endpoints will also be analyzed using ANCOVA or MMRM methods similar to those used for 
the primary and secondary endpoints. Any treatment group comparisons will be in the nature of 
hypothesis generation, and any statistical inference will not have any confirmatory value. 

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Exploratory endpoints in the OLE will be summarized according to the treatment assigned at 
randomization. 
7.6.5. 
Pharmacokinetic and Pharmacodynamic Analyses 
Plasma PK concentrations at each time point for losmapimod will be presented in listings and 
summarized in tables. Losmapimod concentrations in skeletal muscle biopsy at each time point 
will also 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 and the individual and mean concentrations in 
skeletal muscle biopsies will be presented by collection time in figures on linear scales. 
The target engagement estimates of losmapimod in peripheral blood and skeletal muscle biopsies 
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. Within-group LS means, the associated standard errors and 2-sided 
95% CIs, treatment differences in LS means and the associated 2-sided 95% CIs, and 2-sided p-
values will be derived from the ANCOVA model and presented in the tables. 
Population PK and PK/PD 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.  
7.6.6. 
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. 
Safety data in the OLE will be analyzed using the open-label analysis set. 
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. 
7.6.7. 
Other Analyses 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group and overall for the placebo-controlled treatment period and by treatment 
assigned at randomization and entry point in the OLE. 
Efficacy data will be summarized at each scheduled visit in the OLE, and subjects will be 
grouped according to initial treatment assigned at randomization and entry point of OLE. 

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Descriptive statistics will include the number of non-missing observations, mean, standard 
deviation, median, minimum, and maximum for quantitative data. For qualitative data, frequency 
counts and percentage will be determined. A full description of demographic variables will be 
included in the SAP(s). 
Individual subject demographics and baseline information will be provided in data listings. 
Medical history will be coded using MedDRA at the time of each database lock and will be 
summarized using the number of observations and percentages of subjects reporting each 
category and listed for each subject. 
A list of protocol deviations (major or minor) will be finalized prior to each database lock. 
7.6.8. 
Interim Analyses 
One IA will be performed when a minimum of 22 paired muscle biopsies are completed. A 
group sequential method (O’Brien-Fleming Spending Function) will be used to ensure an overall 
significance level of 0.05 (double-sided) due to multiple looks at the DUX4 primary endpoint, if 
the IA is deemed necessary by the Sponsor. 
• With a sample size of approximately 22 subjects at IA, the test alpha at IA is 
approximately 0.001, and the final test alpha is 0.05. If the p-value from the test is 
<0.001, then the study may be stopped for efficacy, or continue as planned as decided by 
the Sponsor. Cumulative exit probability under the alternative hypothesis is 
approximately 2.3% and approximately 82.3% at the IA and final analysis, respectively 
(SAS Version 9.4; nQuery 8 – Power and Sample Size for Group Sequential Trials, 
Version 8.5.1.0). 
• With a sample size of 32 subjects at IA, the test alpha at IA is approximately 0.004, and 
the final test alpha is 0.048. If the p-value from the test is <0.004, then the trial may be 
stopped for efficacy, or continue as planned as decided by Sponsor. Cumulative exit 
probability under the alternative hypothesis is approximately 13.9% and approximately 
82.2% at the IA and final analysis, respectively (SAS Version 9.4; nQuery 8 – Power and 
Sample Size for Group Sequential Trials, Version 8.5.1.0). 
The alphas at the time of the IA for sample sizes ranging from 22 to 32 are provided in Table 1. 
Table 1: 
Alpha At Interim Analysis and Final Analysis for Different Sample Sizes At 
Interim Analysis (O’Brien-Fleming Method) 
Interim Analysis Sample Size 
Alpha at Interim Analysis 
Alpha at Final 
22 
0.000567 
0.049755 
23 
0.000736 
0.049685 
24 
0.000951 
0.049596 
25 
0.001203 
0.049493 
26 
0.001474 
0.049384 
27 
0.001803 
0.049253 

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Interim Analysis Sample Size 
Alpha at Interim Analysis 
Alpha at Final 
28 
0.002173 
0.049107 
29 
0.002556 
0.048959 
30 
0.003005 
0.048787 
31 
0.003496 
0.048602 
32 
0.004027 
0.048405 

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8. 
DATA QUALITY ASSURANCE 
This study will be conducted according to the International Council for Harmonisation (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. 
8.1. 
DATA MANAGEMENT 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects 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 subject data into Medidata RAVE® (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 
 standards and 
data cleaning procedures to ensure the integrity of the data, eg, removing errors and 
inconsistencies in the data. Adverse event terms will be coded using MedDRA, an internal 
validated medical dictionary, and concomitant medications will be coded using the World Health 
Organization Drug Dictionary. 
After final database lock, each study site will receive a CD-ROM containing all of their site 
specific eCRF data as entered into the Medidata RAVE system for the study, including full 
discrepancy and audit history. Additionally, a CD-ROM copy of all of the study site’s data from 
the study will be created and sent to the sponsor for storage. 
 will maintain a duplicate CD-
ROM copy for their records. In all cases, subject initials will not be collected or transmitted to 
the sponsor. 

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9. 
ETHICS 
9.1. 
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 subjects in research studies. Before study onset, the protocol, 
informed consent, advertisements to be used for the recruitment of study subjects, and any other 
written information regarding this study to be provided to the subject or the subject’s legal 
guardian must be approved by the IRB/IEC. Documentation of all IRB/IEC approvals and of the 
IRB/IEC compliance with ICH harmonised tripartite guideline 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 subjects. 
9.2. 
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. 
9.3. 
SUBJECT 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 subject before entering 
the study or performing any unusual or nonroutine procedure that involves risk to the subject. 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 subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject 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 subject/legal guardian understands the implications of 
participating in the study, the subject/legal guardian will be asked to give consent to participate 
in the study by signing the ICF. 

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The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the subject or legal guardian.  

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10. 
INVESTIGATOR’S OBLIGATIONS 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject 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. 
10.1. 
CONFIDENTIALITY 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject 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 subject (or the subject’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 subjects 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 principal 
investigator, and the institution. 
10.2. 
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 
 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 
 is financially responsible for further 
treatment of the subject’s disease. 
10.3. 
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 
• Original investigator-signed investigator agreement page of the protocol 

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• 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 subject or legal guardian, and 
• Laboratory certifications and normal ranges for any local laboratories used by the site. 
10.4. 
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 subjects begins.  
10.5. 
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. 
10.6. 
ADVERSE EVENTS AND STUDY REPORT REQUIREMENTS 
By participating in this study, the investigator agrees to submit reports of SAEs to the sponsor 
and/or IRB/IEC according to the timeline and method outlined in the protocol. In addition, the 
investigator agrees to submit annual reports to the study site IRB/IEC as appropriate. 
10.7. 
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. 
10.8. 
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 

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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. 
10.9. 
PUBLICATIONS 
After completion of the study, the data will be submitted for reporting at a scientific meeting and 
for publication in a peer-reviewed 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 principal investigator, any vendors, and the institution.  

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11. 
STUDY MANAGEMENT 
The administrative structure will include an SRC. 
11.1. 
MONITORING 
11.1.1. 
Safety Review Committee 
An SRC will be formed to review safety data for all subjects at regular intervals throughout the 
study. 
The SRC charter will describe the processes for unblinding subject- or study-level data if the 
SRC requests unblinding. Details on the composition of the SRC and the schedule of SRC 
meetings and data reviews will be presented in the SRC charter. 
11.1.2. 
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. 
11.1.3. 
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 
 of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the sponsor. 
11.2. 
MANAGEMENT OF PROTOCOL AMENDMENTS AND DEVIATIONS 
11.2.1. 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the subject, 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 subjects can be enrolled into an amended protocol. 

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11.2.2. 
Protocol Deviations 
The investigator or designee must document and explain in the subject’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 subjects 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 subject or 
investigator that results in a significant, additional risk to the subject. Significant deviations can 
include nonadherence to inclusion or exclusion criteria or nonadherence to FDA regulations or 
ICH GCP guidelines and will lead to the subject 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.  
11.3. 
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 subjects’ interests. The 
sponsor has no plans to provide study drug to subjects after study closure or termination. The 
obligations to provide study results for subjects 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: 
• Subject or investigator noncompliance 
• Unsatisfactory subject enrollment 
• Lack of adherence to protocol procedures 
• Lack of evaluable and/or complete data 
• Potentially unacceptable risk to study subjects 
• 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 subject completes the last visit 
(includes the safety follow-up visit). 
11.4. 
FINAL REPORT 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are 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 subjects, as appropriate. The study results will be posted on publicly available 
clinical trial registers.  
 

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12. 
REFERENCE LIST 
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pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy 
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Barbour AM, Magee M, Shaddinger B, et al. Utility of concentration-effect modeling and 
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Bérard C, Payan C, Hodgkinson I, et al. A motor function measure scale for neuromuscular 
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Bosnakovski D, Choi SH, Strasser JM, et al. High-throughput screening identifies inhibitors of 
DUX4-induced myoblast toxicity. Skelet Muscle. 2014;4:4. 
Chen JC, King OD, Zhang Y, et al. Morpholino-mediated knockdown of DUX4 toward 
facioscapulohumeral muscular dystrophy therapeutics. Mol Ther. 2016;24(8):1405-11. 
Cheriyan J, Webb AJ, Sarov-Blat L, et al. Inhibition of p38 mitogen-activated protein kinase 
improves nitric oxide-mediated vasodilatation and reduces inflammation in 
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de Greef JC, Lemmers RJ, van Engelen BG, et al. Common epigenetic changes of D4Z4 in 
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Deenen JC, Arnts H, van der Maarel SM, et al. Population-based incidence and prevalence of 
facioscapulohumeral dystrophy. Neurology. 2014;83(12):1056-9. 
Dixon WT. Simple proton spectroscopic imaging. Radiology. 1984;153(1):189-94. 
Edwards RH, Round JM, Jones DA. Occasional Survey. Needle biopsy of skeletal muscle: a 
review of 10 years experience. Muscle Nerve. 1983;6(9):676-83.  
Flanigan KM, Coffeen CM, Sexton L, et al. Genetic characterization of a large, historically 
significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord. 2001;11(6-
7):525-9. 
Geng LN, Yao Z, Snider L, et al. DUX4 activates germline genes, retroelements, and immune 
mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012;22(1):38-51. 
Han JJ, Kurillo G, Abresch RT, et al. Reachable workspace in facioscapulohumeral muscular 
dystrophy (FSHD) by Kinect. Muscle Nerve. 2015;51(2):168-75. 
Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology. New York: Ardent Media; 
2007. 
Hollingsworth KG, de Sousa PL, Straub V, et al. Towards harmonization of protocols for MRI 
outcome measures in skeletal muscle studies: Consensus recommendations from two TREAT-

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NMD NMR workshops, 2 May 2010, Stockholm, Sweden, 1–2 October 2009, Paris, France. 
Neuromuscul Disord. 2012;22 (Suppl 2):S54-67. 
Homma S, Beermann ML, Boyce FM, et al. Expression of FSHD-related DUX4-FL alters 
proteostasis and induces TDP-43 aggregation. Ann Clin Transl Neurol. 2015;2(2):151-66. 
Ino H, Takahashi N, Terao T, et al. Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of losmapimod in healthy Japanese volunteers. Clin Pharmacol Drug Dev. 
2015;4(4):262-9. 
Jagannathan S, Shadle SC, Resnick R, et al. Model systems of DUX4 expression recapitulate the 
transcriptional profile of FSHD cells. Hum Mol Genet. 2016;25(20):4419-31. 
Janssen B, Voet N, Geurts A, et al. Quantitative MRI reveals decelerated fatty infiltration in 
muscles of active FSHD patients. Neurology. 2016;86(18):1700-7. 
Jones TI, Chen JC, Rahimov F, et al. Facioscapulohumeral muscular dystrophy family studies of 
DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. 
Hum Mol Genet. 2012;21(20):4419-30. 
Jones T and Jones PL. A cre-inducible DUX4 transgenic mouse model for investigating 
facioscapulohumeral muscular dystrophy. PLOS One. 2018;13(2):e0192657.  
Lemmers RJ, Wohlgemuth M, Frants RR, et al. Contractions of D4Z4 on 4qB subtelomeres do 
not cause facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2004;75(6):1124-30. 
Lemmers RJ, van der Vliet PJ, Klooster R, et al. A unifying genetic model for 
facioscapulohumeral muscular dystrophy. Science. 2010;329(5999):1650-3. 
Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an 
FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat 
Genet. 2012;44(12):1370-4. 
Lomas DA, Lipson DA, Miller BE et al. An oral inhibitor of p38 MAP kinase reduces plasma 
fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol. 
2012;52(3):416-24. 
Morís G, Wood L, Fernández-Torrón R, et al. Chronic pain has a strong impact on quality of life 
in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2018;57(3):380-7. 
Padberg GW. Facioscapulohumeral disease. Leiden, the Netherlands: Faculty of Medicine, 
Leiden University Medical Center, Leiden University; 1982. 
Padua L, Aprile I, Frusciante R, et al. Quality of life and pain in patients with 
facioscapulohumeral muscular dystrophy. Muscle Nerve. 2009;40(2):200-5. 
Pascoe S, Costa M, Marks-Konczalik J, et al. Biological effects of p38 MAPK inhibitor 
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Ricci E, Galluzzi G, Deidda G, et al. 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. 1999;45(6):751-57. 
Shadle SC, Zhong JW, Campbell AE, et al. DUX4-induced dsRNA and MYC mRNA 
stabilization activate apoptotic pathways in human cell models of facioscapulohumeral 
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Statland JM and Tawil R. Risk of functional impairment in facioscapulohumeral muscular 
dystrophy. Muscle Nerve. 2014;49(4):520-7.  
Statland JM, Shah B, Henderson D, et al. Muscle pathology grade for facioscapulohumeral 
muscular dystrophy biopsies. Muscle Nerve. 2015;52(4):521-6. 
Statland JM, Odrzywolski KJ, Shah B, et al. Immunohistochemical characterization of 
facioscapulohumeral muscular dystrophy muscle biopsies. J Neuromuscul Dis. 2015; 2(3):291-9. 
Tasca G, Pescatori M, Monforte M, et al. Different molecular signatures in magnetic resonance 
imaging-staged facioscapulohumeral muscular dystrophy muscles. PLoS One. 2012;7(6):e38779. 
Tawil R, Forrester J, Griggs RC, et al. Evidence for anticipation and association of deletion size 
with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. 
1996;39(6):744-8. 
Tawil R, Kissel JT, Heatwole C, et al. 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. 2015;85(4):357-64. 
Vanderplanck C, Ansseau E, Charron S, et al. The FSHD atrophic myotube phenotype is caused 
by DUX4 expression. PLOS One. 2011;6(10):e26820. 
Wang LH, Friedman SD, Shaw D, et al. MRI-informed muscle biopsies correlate MRI with 
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blind, placebo-controlled trial. Lancet Respir Med. 2014;2(1):63-72. 
Whiddon JL, Langford AT, Wong CJ, et al. Conservation and innovation in the DUX4-family 
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13. 
APPENDICES 
13.1. 
APPENDIX: SCHEDULES OF EVENTS 

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Table 2: 
Schedule of Events: Placebo-Controlled Treatment Period 
Procedure 
Screening Baseline Week 4 Week 12 Week 16 Week 24 Week 36 
Week 48 End of 
Placebo- 
Controlled 
Treatment Period/Start 
of OLEa 
ET 
Visitb 
Safety Follow-Up 7 
Days After the Last 
Dose of Study 
Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Visit Window (days)d 
–28 to –1 
Day 1 
5 
5 
5 
5 
±14aa 
±5 
 
3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Confirm eligibility via 
inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Height and BMIe 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xf 
 
 
 
 
 
 
 
 
FSHD-specific historyg 
X 
 
 
 
 
 
 
 
 
 
Serology (HBsAg, HCV, 
HIV1/HIV2) 
X 
 
 
 
 
 
 
 
 
 
Urine drug screenh 
X 
 
 
 
 
 
 
 
 
 
Genetic confirmation of FSHD1i 
X 
 
 
 
 
 
 
 
 
 
Serum β-hCGk 
X 
 
 
 
 
 
 
 
 
 
Serum follicle-stimulating hormonel 
X 
 
 
 
 
 
 
 
 
 
Urine pregnancy testm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weighte 
X 
X 
 
 
 
 
 
X 
X 
X 
Vital signsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationo 
X 
 
 
 
 
 
 
 
 
X 

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Procedure 
Screening Baseline Week 4 Week 12 Week 16 Week 24 Week 36 
Week 48 End of 
Placebo- 
Controlled 
Treatment Period/Start 
of OLEa 
ET 
Visitb 
Safety Follow-Up 7 
Days After the Last 
Dose of Study 
Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Visit Window (days)d 
–28 to –1 
Day 1 
5 
5 
5 
5 
±14aa 
±5 
 
3 
Standard 12-lead ECGp 
X 
X 
X 
 
 
 
 
X 
X 
X 
Serum chemistry 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
Xq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for coagulationbb 
Xq 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
X 
X 
MSK MRIr 
X 
 
 
X 
 
 
 
X 
Xs 
 
Muscle needle biopsyt 
 
X 
 
 
X 
 
Xt 
 
 
 
PK samplingu 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Target engagement samplingv 
 
X 
 
 
X 
 
X 
 
 
 
RWS 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
TUG (classic and FSHD) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Manual dynamometry 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
MFM Domain 1 
 
X 
 
X 
 
X 
X 
X 
X 
 
FSHD-HI questionnaire 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
PGIC questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensationx 
 
X 
X 
X 
X 
Xy 
X 
X 
 
 
Study drug count 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Procedure 
Screening Baseline Week 4 Week 12 Week 16 Week 24 Week 36 
Week 48 End of 
Placebo- 
Controlled 
Treatment Period/Start 
of OLEa 
ET 
Visitb 
Safety Follow-Up 7 
Days After the Last 
Dose of Study 
Drugc 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
- 
8 
Visit Window (days)d 
–28 to –1 
Day 1 
5 
5 
5 
5 
±14aa 
±5 
 
3 
Concomitant medicationsz 
Continuous from signing the ICF through the safety follow-up visit 
Concomitant treatments and 
procedures 
Continuous from signing the ICF through the safety follow-up visit 
Adverse event monitoring 
Continuous from signing the ICF through the safety follow-up visit 
Abbreviations: β-hCG, beta human chorionic gonadotropin; BMI, body mass index; ECG, electrocardiogram; ET, early termination; FSHD, 
facioscapulohumeral muscular dystrophy; FSHD-HI, Facioscapulohumeral Muscular Dystrophy Health Index; HBsAg, hepatitis B surface antigen; HCV, 
hepatitis C virus; HIV, human immunodeficiency virus; ICF, informed consent form; MFM, Motor Function Measure; MRI, magnetic resonance imaging; 
MSK, musculoskeletal; OLE, open-label extension; PGIC, Patients’ Global Impression of Change; PK, pharmacokinetic(s); RWS, Reachable Workspace; 
STIR, short tau inversion recovery; TUG, Timed Up and Go. 
Note: Some procedures may not have been performed due to the COVID-19 pandemic. Please refer to the ReDUX4 Emergency Guidance document. 
a Prior to the COVID-19 pandemic, subjects who reached the Week 24 visit had the option to roll over into the OLE. For subjects who had already rolled over, 
their next clinic visits will follow the assessments for the Week 36 and Week 48 visit in the placebo-controlled portion of the study in the COVID-19 
Pandemic Emergency protocol version 4.0; however, these specific subjects will not undergo the Week 36 biopsy. Those subjects who rolled over before the 
COVID-19 pandemic protocol version 4.0 was implemented will remain on open-label treatment. Subjects who did not roll over prior to the COVID-19 
pandemic will roll over when they reach Week 48. Subjects who roll over into the OLE should not complete the ET visit or safety follow-up visit from the 
placebo-controlled treatment period. 
b If a subject prematurely discontinues study treatment during the placebo-controlled treatment period, they will be encouraged to remain in the study and 
continue with all other aspects of the study. If a subject decides to prematurely discontinue study treatment during the placebo-controlled treatment period and 
not continue with all other aspects of the study, they will be considered to have withdrawn from the study. If a subject withdraws from the study during the 
placebo-controlled treatment period, 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 7 (±3) 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. 
c The safety follow-up visit 7 (±3) days after the last dose of study drug should only be completed by subjects who are not rolling over into the OLE.  
d Scheduled visits may be split over 2 days if required, with a maximum of 5 business days in between visits. Unscheduled visits may be performed if clinically 
indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-approved MRI scanner should be consistent during the trial. 
e Weight and height will be measured with shoes off and preferably with the same balance at each visit. Body mass index will be calculated at Screening. 
f Medical history will be reviewed at baseline to ensure no changes have occurred since the screening visit. 
g FSHD-specific history will be recorded at screening or at a subject’s next scheduled study visit, if not previously recorded. 

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h Urine drug screen for drugs of abuse including cocaine, amphetamines, opiates (morphine), benzodiazepines, and cannabinoids. 
i Genetic confirmation must be obtained before the subject is randomized and before the baseline muscle biopsy is performed; genetic confirmation can come 
from previous testing if verified with appropriate documentation from an accredited laboratory. Due to the stable transmission of repeat sizes within families, 
subjects with a clinical diagnosis of FSHD who have a first-degree relative with a genetically confirmed diagnosis of FSHD1 may be entered into the study 
for screening assessments, including MRI. During screening, a confirmatory genetic diagnosis will be conducted. If genetic testing is necessary, the 4-week 
screening window and activities will not start until the results are obtained and verified by the principal investigator. 
k Serum pregnancy tests will be performed at screening for all female subjects of child-bearing potential. 
l Serum follicle-stimulating hormone testing is required for suspected postmenopausal female subjects only. 
m Urine pregnancy tests will be performed for all female subjects of child-bearing potential before randomization at all other visits. If pregnancy is found, 
subjects must be terminated from the study effective immediately. 
n Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has been seated or recumbent for at least 5 minutes 
and before any 12-lead ECG assessment or blood sampling is performed. 
o Physical examination at the screening visit and the safety follow-up visit 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 MSK 
system. Symptom-directed physical examinations can occur at any time during the study if triggered by adverse events or if deemed necessary by the 
investigator. 
p Twelve-lead ECGs will be performed after subjects have been recumbent for at least 5 minutes. Twelve-lead ECGs will be performed after the measurement 
of vital signs and before any procedures that may affect heart rate (eg, blood sampling). 
q For the screening visit, subjects will be required to fast for at least 4 hours prior to laboratory blood samples being taken. 
r Subjects will be screened for any contraindications to MRI as per clinic standard practice. 
s The MRI at the ET visit will not be repeated if an MRI was completed during the previous 8 weeks. 
t The choice of the muscle(s) to be biopsied in this study will be determined by the investigator, informed by skeletal muscle MRI during screening. The 
bilateral vastus lateralis, vastus medialis, lateral gastrocnemius, medial gastrocnemius, and tibialis anterior will be evaluated for eligibility by MRI using a 
central reader. Only those muscles that are STIR positive with the predetermined range of muscle fat fraction will be eligible for biopsy. The 12 patients who 
rolled over at Week 24 will not undergo the Week 36 muscle biopsy. 
u Blood samples for PK will be collected at Day 1 (baseline), Week 4, Week 16, and Week 36 at the following time points: immediately predose and 4 hours 
(±30 minutes) after administration of the study dose. Blood samples will also be taken, when feasible, after dosing during the Week 12, Week 24, and Week 
48 visits, preferably ≥1 hour after dosing. 
v Blood samples for target engagement will be collected on Day 1 (baseline), and Week 16 or Week 36, at the following time points: immediately predose and 4 
hours (±30 minutes) after administration of the study dose. 
x The appropriate amount of study drug supply (losmapimod or placebo) will be given to the subject at each applicable visit to allow for dosing until their next 
scheduled study visit plus additional tablets to cover the visit window. Study drug (losmapimod or placebo) will be administered as 2 tablets taken twice daily 
and should be taken with food. Subject diaries may only be used for a portion of the placebo-controlled portion of the trial to record the date and time of each 
dose taken. This information may also be used to calculate compliance. Subjects will record the date and time of each dose of study drug taken (losmapimod 
or placebo) in the subject diary. Subjects may be provided additional study drug via courier service, as applicable. 

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y Subjects who are rolling over into the OLE will be dispensed open-label losmapimod at the time of the rollover visit. Subjects may be provided open-label 
losmapimod via courier or shipping service, as applicable. 
z All medications taken within 28 days before screening through the safety follow-up visit will be recorded. 
aa  Large window given to accommodate the COVID-19 pandemic. 
bb It is optional to perform coagulation studies prior to muscle biopsies. Refer to your institutional guidelines. 
 
 

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Table 3: 
Schedule of Events: Open-Label Extension (Visits Will Occur Quarterly Until 90 Days After Commercial Drug 
Availability Post Regulatory Approval or Study is Discontinued) 
Procedure 
Week 60 
Week 108 
Week 156 
Week 204 etc. 
Week 72 
Week 120 
Week 168 
Week 216 etc. 
Week 84 
Week 132 
Week 180 etc. 
Week 96 
Week 144 
Week 192 etc. 
ET 
Visita 
Safety Follow-Up 7 
Days After the Last 
Dose of Study Drug 
Visit Window (days)b 
7 
7 
7 
7 
 
3 
Weight, height, and BMIc 
 
X 
 
 
 
 
Urine pregnancy teste 
X 
X 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
X 
X 
Physical examinationg 
 
 
 
 
 
X 
Standard 12-lead ECGh 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
PK samplingi 
 
 
 
X 
X 
 
Clinic visit 
X 
X 
X 
X 
X 
X 
Study drug dispensationj 
X 
X 
X 
X 
 
 
Study drug count 
X 
X 
X 
X 
X 
 
Concomitant medicationsk 
Continuous from signing the ICF through the safety follow-up visit 
Concomitant treatments and procedures 
Continuous from signing the ICF through the safety follow-up visit 
Adverse event monitoring 
Continuous from signing the ICF through the safety follow-up visit 
Abbreviations: BMI, body mass index; ECG, electrocardiogram; ET, early termination; ICF, informed consent form; MRI, magnetic resonance imaging; MSK, 
musculoskeletal; OLE, open-label extension; PK, pharmacokinetic(s). 
a If a subject prematurely discontinues study treatment during the OLE, they will be encouraged to remain in the study and continue with all other aspects of the 
study. If a subject decides to prematurely discontinue study treatment during the OLE and not continue with all other aspects of the study, they will be 
considered to have withdrawn from the study. If a subject withdraws from the study during the OLE, they will be asked to complete the ET visit as soon as 

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possible after the decision to terminate study participation and to complete the safety follow-up visit 7 (±3) 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. 
b Scheduled visits may be split over 2 days if required, with a maximum of 5 business days in between visits. Unscheduled visits may be performed if clinically 
indicated. Subjects can travel for MRI or muscle biopsy if needed, but the use of a study-approved MRI scanner should be consistent during the trial. 
c Weight and height will be measured and BMI will be calculated once a year (ie, Week 72, Week 120, Week 168, Week 216, etc.). Weight and height will be 
measured with shoes off and preferably with the same balance. 
 
e Urine pregnancy tests will be performed for all female subjects of child-bearing potential before dispensation of study drug. If pregnancy is found, subjects 
must be terminated from the study effective immediately. 
f Vital signs (pulse rate, respiration rate, blood pressure, and temperature) will be collected after the subject has been seated or recumbent for at least 5 minutes 
and before any 12-lead ECG assessment or blood sampling is performed. 
g Physical examination at the safety follow-up visit 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 MSK system. Symptom-directed 
physical examinations can occur at any time during the study if triggered by adverse events or if deemed necessary by the investigator. 
h Twelve-lead ECGs will be performed after subjects have been recumbent for at least 5 minutes. Twelve-lead ECGs will be performed after the measurement 
of vital signs and before any procedures that may affect heart rate (eg, blood sampling). 
i Blood samples for PK will be collected after dosing at the Week 144 clinic visit only, preferably ≥1 hour after dosing. 
j The appropriate amount of study drug supply (losmapimod) will be given to the subject at each applicable visit to allow for dosing until their next scheduled 
study visit plus additional tablets to cover the visit window or additional study drug will be provided to the subject via a courier, as applicable. Study drug 
(losmapimod) will be taken twice daily and should be taken with food. 
k All medications taken within 28 days before screening through the safety follow-up visit will be recorded. 
 

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13.2. 
APPENDIX: DRUGS POTENTIALLY AFFECTING MUSCLE FUNCTION 
List of drug(s) or supplements that potentially 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