Efficacy and Safety of Losmapimod in Treating Participants With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH)

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

This is a study to evaluate the safety and efficacy of losmapimod in treating participants with Facioscapulohumeral Muscular Dystrophy (FSHD). Participants diagnosed with Facioscapulohumeral muscular dystrophy type 1 (FSHD1) or Facioscapulohumeral muscular dystrophy type 2 (FSHD2) will participate in Part A (Placebo-controlled treatment period) and will be randomized in a 1:1 ratio to receive losmapimod 15 milligrams (mg) or placebo orally twice daily (BID). Upon completion of Part A, participants will have the option to rollover into Part B (open-label extension) to evaluate the long-term safety, tolerability, and efficacy of losmapimod and will receive losmapimod 15 mg orally BID.

Study Overview

• Status: Terminated
• Conditions: Facioscapulohumeral Muscular Dystrophy (FSHD)
• Intervention / Treatment: Drug: Losmapimod; Drug: Placebo oral tablet

Detailed Description

Patients diagnosed with FSHD 1 and FSHD 2 will participate in this study for approximately 53 weeks. This will include a 4-week screening period, a 48-week, placebo-controlled treatment period and a 7-day safety follow-up period. Patients will be randomized to receive 15 mg of losmapimod or placebo twice daily by mouth for 48 weeks.

• Study Type: Interventional
• Enrollment (Actual): 260
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital Research Institute
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute and Hospital
• Denmark
  • Aarhus, Denmark, 8200
    • Aarhus Universitetshospital
  • Copenhagen, Denmark, 2100
    • Rigshospitalet
• France
  • Paris, France, 75013
    • Institute de Myologie, Groupe Hospitalier Pitié-Salpêtrière
  • PACA
    • Nice, PACA, France, 06001
      • Nice University Hospital - CHU Nice
• Germany
  • Bonn, Germany, 53127
    • University Hospital Bonn
  • München, Germany, 80336
    • LMU Klinikum Ludwig-Maximilians-Universität München
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Italy
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Lombardy
    • Milan, Lombardy, Italy, 20162
      • Fondazione Serena Onlus- Centro Clinico NEMO
• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 9101
      • Radboudumc
  • Southern Holland
    • Leiden, Southern Holland, Netherlands, 2333 ZA
      • Leiden University Medical Centre
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
  • Guipuzkoa
    • San Sebastián, Guipuzkoa, Spain, 20014
      • Hospital Universitario Donostia
• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • University College of London Hospitals
  • Newcastle upon Tyne, United Kingdom, NE1 3BZ
    • Newcastle Upon Tyne NHS Foundation Trust
• United States
  • California
    • Irvine, California, United States, 92868
      • University of California Irvine
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles (UCLA)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Participants must be between 18 and 65 years of age, inclusive.
• Genetically confirmed diagnosis of FSHD 1 or FSHD 2.
• Clinical severity score of 2 to 4 (Ricci Score; Range 0-5), at screening. Participants who are wheelchair-dependent or dependent on walker or wheelchair for activities are not permitted to enroll in the study.
• Screening total RSA (Q1-Q4) without weight in the dominant UE assessed by RWS ≥ 0.2 and ≤ 0.7.
• No contraindications to MRI.

Key Exclusion Criteria:

• 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.
• Participants who are on drug(s) or supplements that may affect muscle function, as determined by the Investigator: participants 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.
• Known active opportunistic or life-threatening infections including Human Immunodeficiency virus (HIV) and hepatitis B or C.
• Known active or inactive tuberculosis infection.
• Acute or chronic history of liver disease.
• Known severe renal impairment.
• History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or evidence of abnormal ECGs.
• Use of another investigational product within 30 days or 5 half-lives (whichever is longer) or currently participating in a study of an investigational device.
• Current or anticipated participation in a natural history study. Previous participation is allowed but participants cannot continue after enrollment in Study 1821-FSH-301.
• Known hypersensitivity to losmapimod or any of its excipients.
• Previous participation in a Fulcrum-sponsored FSHD losmapimod study (FIS-001-2019 or FIS-002-2019).

Note that all other inclusion and exclusion criteria are listed in the protocol and only key are presented.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Placebo-controlled treatment period: Losmapimod; Participants will be randomized to receive losmapimod.	Drug: Losmapimod; Losmapimod 15 mg will be administered BID by mouth along with food.
Placebo Comparator: Part A: Placebo-controlled treatment period: Placebo; Participants will be randomized to receive placebo	Drug: Placebo oral tablet; Placebo will be administered BID by mouth along with food.
Experimental: Part B: Open-label extension; Participants will receive losmapimod, upon completion of all assessments for Part A.	Drug: Losmapimod; Losmapimod 15 mg will be administered BID by mouth along with food.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Change From Baseline in Total Relative Surface Area (RSA) Quadrants 1 to 5 (Q1-Q5) With 500 Grams (g) Wrist Weight Averaged Over Both Arms as Assessed by Reachable Workspace (RWS) at Week 48	Participants are instructed to complete a simple set of standardized movements of each arm centered around the shoulder joint. These arm movements are captured and quantitated with the use of a video camera. The RWS is a clinical outcome measure that measures the relative surface area that a participant may reach with an outstretched arm. Responses are rated on a scale of 0 (no reachable workspace) to 1.25 (maximal reachable workspace). Higher scores indicate better outcomes. Baseline is the last non-missing evaluation prior to first dose of study drug. Change from Baseline was calculated as the post-treatment value minus the value at Baseline.	Baseline (Day 1) and at Week 48
Part B: Number of Participants Reporting Serious Treatment Emergent Adverse Events (Serious TEAEs) and Non-serious TEAEs > 5%	Treatment-emergent adverse event is an AE that begins on or after the first dose of study drug and on or before the stop of study drug + 35 days or begins before the first dose of study drug and worsens on or after the first dose of study drug and on or before the stop of study drug + 35 days. A SAE is defined as an AE that results in any of the following outcomes: death; life-threatening adverse event; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; congenital anomaly/birth defect.	Week 48 to Week 127
Part B: Number of Participants With Clinically Significant Changes in Chemistry Parameters	Blood samples were collected for the analysis of chemistry parameters: Glucose, sodium, potassium, calcium, inorganic phosphate, total protein, albumin, blood urea nitrogen, creatinine, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase and creatine phosphokinase.	Week 48 to Week 127
Part B: Number of Participants With Clinically Significant Changes in Hematology Parameters	Blood samples were collected for the analysis of hematology parameters: 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	Week 48 to Week 127
Part B: Number of Participants With Clinically Significant Changes in Urinalysis	Urine samples were collected for the analysis of urinalysis parameters: Leucocytes, blood, nitrite, protein, urobilinogen, bilirubin, potential of Hydrogen (pH), specific gravity, ketones, glucose.	Week 48 to Week 127
Part B: Number of Participants With Clinically Significant Changes in Vital Parameters	Vital parameters including pulse rate, respiration rate, blood pressure, and temperature were measured in seated or recumbent for at least 5 minutes. Data for number of participants with abnormal clinically significant changes for vital signs have been presented.	Week 48 to Week 127
Part B: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters	Twelve-lead ECGs were performed after participants has been recumbent for at least 5 minutes.	Week 48 to Week 127
Part B: Number of Participants With Clinically Significant Changes in Physical Examinations	Physical examinations included an evaluation of body systems, including but not limited to the following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological system; and musculoskeletal system.	Week 48 to Week 127

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Change From Baseline in Quality of Life in Neurologic Disorders Upper Extremity (Neuro-QoL UE) Scale at Week 48	The Neuro-QoL Upper Extremity (UE) scale is a patient-reported outcome measure designed to assess upper limb function in individuals with neurologic conditions. It evaluates a participant's self-reported difficulty in performing activities for daily living (ADLs) involving digital, manual, and reach-related function and self-care. Responses are divided into 5 ordinal levels (1 = unable to do, 2 = with much difficulty, 3 = with some difficulty, 4 = with a little difficulty, 5 = without any difficulty). Lower scores indicate worse symptoms. Change from Baseline was calculated as the post-treatment value minus the value at Baseline.	Baseline (Day 1) and at Week 48
Part A: Number of Participants With Response to Patient's Global Impression of Change (PGIC) at Week 48	The Patient Global Impression of Change (PGIC) is a standard participant-report outcome that measures the participant's self-reported change in health status compared to the start of the study. The PGIC uses a single question and 7-point patient self-reporting scale of overall improvement during treatment ranging from 1 (very much improved) to 7 (very much worse). Higher scores indicate worse symptoms.	At Week 48
Part A: Change From Baseline in Whole Body (WB) Longitudinal Composite Muscle Fat Infiltration (MFI) of B Muscles at Week 48	The whole-body longitudinal composite muscle fat infiltration (MFI) of predefined B muscles is measured by musculoskeletal (MSK) magnetic resonance imaging (MRI). MFI quantifies the extent of fat replacement in muscle tissue, which is a key marker of disease progression in facioscapulohumeral muscular dystrophy (FSHD). The B muscles are a prespecified subset of muscles that are most relevant to FSHD progression. A decrease or smaller increase in MFI indicates slower disease progression or a potential treatment benefit. Change from Baseline was calculated as the post-treatment value minus the value at Baseline.	Baseline (Day 1) and at Week 48
Part A: Relative Change From Baseline in Average Shoulder Abductor Strength by Hand-held Quantitative Dynamometry at Week 48	Average shoulder abductor strength was assessed using hand-held dynamometry (HHD). Bilateral strength measurements were acquired from both upper limbs, with the average calculated for each participant. The relative change from baseline was expressed as a percentage. This evaluated the effect of losmapimod, relative to placebo, on muscle strength in individuals diagnosed with facioscapulohumeral muscular dystrophy (FSHD). Standardized procedures and equipment were employed across all study sites for strength testing, and trained personnel conducted all measurements to ensure consistency. Baseline is the last non-missing evaluation prior to first dose of study drug. Relative change from Baseline = 100 x (Post-baseline value - Baseline value) / (Baseline value).	Baseline (Day 1) and at Week 48
Part A: Number of Participants Serious TEAEs and TEAEs	Treatment-emergent adverse event is an AE that begins on or after the first dose of study drug and on or before the stop of study drug + 35 days or begins before the first dose of study drug and worsens on or after the first dose of study drug and on or before the stop of study drug + 35 days. A SAE is defined as an AE that results in any of the following outcomes: death; life-threatening adverse event; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; congenital anomaly/birth defect.	Up to Week 48
Part A: Number of Participants With Clinically Significant Changes in Clinical Chemistry Parameters	Blood samples were collected for the analysis of clinical chemistry parameters including Glucose, sodium, potassium, calcium, inorganic phosphate, total protein, albumin, blood urea nitrogen, creatinine, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase and creatine phosphokinase	Up to Week 48
Part A: Number of Participants With Clinically Significant Changes in Hematology Parameters	Blood samples were collected for the analysis of hematology parameters: 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	Up to Week 48
Part A: Number of Participants With Clinically Significant Changes in Urinalysis	Urine samples were collected for the analysis of urinalysis parameters: Leucocytes, blood, nitrite, protein, urobilinogen, bilirubin, potential of Hydrogen (pH), specific gravity, ketones, glucose.	Up to Week 48
Part A: Number of Participants With Clinically Significant Changes in Vital Parameters	Vital parameters including pulse rate, respiration rate, blood pressure, and temperature were measured in seated or recumbent for at least 5 minutes. Data for number of participants with abnormal clinically significant changes for vital signs have been presented.	Up to Week 48
Part A: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG) Parameters	Twelve-lead ECGs was performed after participants has been recumbent for at least 5 minutes.	Up to Week 48
Part A: Number of Participants With Clinically Significant Changes in Physical Examinations	Physical examinations included an evaluation of body systems, including but not limited to the following: skin; head, eyes, ears, nose, and throat; respiratory system; cardiovascular system; abdomen (liver, spleen); lymph nodes; neurological system; and musculoskeletal system.	Up to Week 48

Collaborators and Investigators

• Sponsor: Fulcrum Therapeutics
• Investigators: Study Director: Marie-Helene Jouvin, MD, Fulcrum Therapeutics

Publications and helpful links

General Publications

• Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013 Jul;76(1):99-106. doi: 10.1111/bcp.12063.
• Han JJ, Kurillo G, Abresch RT, de Bie E, Nicorici A, Bajcsy R. Reachable workspace in facioscapulohumeral muscular dystrophy (FSHD) by Kinect. Muscle Nerve. 2015 Feb;51(2):168-75. doi: 10.1002/mus.24287. Epub 2014 Nov 19.
• Mellion ML, Ronco L, Berends CL, Pagan L, Brooks S, van Esdonk MJ, van Brummelen EMJ, Odueyungbo A, Thompson LA, Hage M, Badrising UA, Raines S, Tracewell WG, van Engelen B, Cadavid D, Groeneveld GJ. Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement. Br J Clin Pharmacol. 2021 Dec;87(12):4658-4669. doi: 10.1111/bcp.14884. Epub 2021 May 14.

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2022
• Primary Completion (Actual): November 19, 2024
• Study Completion (Actual): November 19, 2024

Study Registration Dates

• First Submitted: May 4, 2022
• First Submitted That Met QC Criteria: May 25, 2022
• First Posted (Actual): May 31, 2022

Study Record Updates

• Last Update Posted (Estimated): November 7, 2025
• Last Update Submitted That Met QC Criteria: October 24, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Musculoskeletal Diseases; Neuromuscular Diseases; Muscular Dystrophy; Facioscapulohumeral Muscular Disorders; REACH; Facioscapulohumeral muscular dystrophy (FSHD); Facioscapulohumeral muscular dystrophy type 1 (FSHD 1); Facioscapulohumeral muscular dystrophy type 2 (FSHD 2)
• Additional Relevant MeSH Terms: Nervous System Diseases; Muscular Diseases; Genetic Diseases, Inborn; Muscular Disorders, Atrophic; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Muscular Dystrophies; Musculoskeletal Diseases; Muscular Dystrophy, Facioscapulohumeral; Neuromuscular Diseases; 6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide
• Other Study ID Numbers: 1821-FSH-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Upon publication of a manuscript describing the clinical trial data, Fulcrum will provide access to all collected, individual, de-identified participant data and related study documents (e.g., Study Protocol, Statistical Analysis Plan [SAP]) through a third party. Access will be granted upon request from qualified researchers and will be subject to specific criteria and conditions.

Further details, including the IPD sharing URL, will be provided in an update to this posting.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No