Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) (FSHD)

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)

This is a study to evaluate the safety and efficacy of Losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks.

Study Overview

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

Detailed Description

This study is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study designed to evaluate the efficacy and safety of losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks. Patients 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 must have a confirmed diagnosis of FSHD1 and genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy. Patients will be randomized to receive 15 mg of losmapimod or placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks. All patients will be asked to attend the study clinic for each scheduled visit.

The primary endpoint of the study is to evaluate the efficacy of losmapimod in inhibiting or reducing expression of DUX4, as measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies of FSHD patients. Secondary endpoints include evaluation of the safety and tolerability of losmapimod, the plasma concentrations of losmapimod, levels of losmapimod in skeletal muscle and losmapimod target engagement in blood and skeletal muscle in FSHD patients.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Research Institute
  • Quebec
    • Montréal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute and Hospital
• France
  • Nice, France, 06001
    • CHU de NICE- CHU pasteur2
• Spain
  • Barcelona, Spain, 08041
    • Hospital de la Sta Creu i St Pau
  • Valencia, Spain, 46026
    • Hospital UiP La Fe
• United States
  • California
    • Irvine, California, United States, 92868
      • University of California Irvine
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles (UCLA)
  • 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
  • Missouri
    • Saint 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, 43221
      • Ohio State University
  • 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 Washinton Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• The patient must have consented to participate and must have provided signed, dated and witnessed IRB-approved informed consent form that conforms to federal and institutional guidelines.
• Male or female subjects
• Patients must be between 18 and 65 years of age, inclusive
• Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4. Genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy.
• Clinical severity score of 2 to 4 (RICCI Score; Range 0-5), inclusive at screening
• Must have a MRI-eligible muscle for biopsy
• Must be willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines and other study procedures.
• Will practice an approved method of birth control

Exclusion Criteria:

• 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.
• 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 the protocol, 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.
• 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.
• Known severe renal impairment (defined as a glomerular filtration rate of <30 mL/min/1.73m2).
• Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2.
• 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.
• Use of another investigational product within 30 days or 5 half-lives (whichever is longer), or according to local regulations, or currently participating in a study with an investigational product. Note: concurrent participation in other non-drug studies may be acceptable if confirmed in writing by the sponsor.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; FSHD1 patients with genetic confirmation will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks.	Drug: Losmapimod; This study includes a 48 week treatment period. Patients will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The study drug should be taken with food and the date and time of each dose taken recorded in the subject diary.
Placebo Comparator: Placebo; FSHD1 patients with genetic confirmation will receive a Placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks.	Drug: Placebo oral tablet; This study includes a 48 week treatment period. Patients will receive Placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The placebo tablets are identical to the Losmapimod tablets. Placebo should be taken with food and the date and time of each dose taken recorded in the subject diary.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DUX4 activity	Change from baseline in DUX4 activity will be measured by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4-regulated gene transcripts.	Week 16 or Week 36 if the biopsy could not be obtained at Week 16 due to COVID-19

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-Emergent Adverse Events	To evaluate the safety and tolerability of Losmapimod, the incidence of treatment-emergent adverse events will be assessed by clinically significant laboratory test results, ECGs, and vital signs.	Date of enrollment and Weeks 4, 12, 16, 24, 36, 48 and 7 days after the last dose of study drug
Muscle Fat Fraction	The change from baseline in muscle fat fraction (MFF) will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).	Week 12, Week 24 if applicable and Week 48
Lean Muscle Volume	The change from baseline in skeletal lean muscle lean volume will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).	Week 12, Week 24 if applicable and Week 48
Muscle Fat Infiltration	The change from baseline in skeletal muscle tissue replacement by fat will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).	Week 12, Week 24 if applicable and Week 48
Plasma Concentrations of Losmapimod	Blood samples will be collected to measure the plasma concentration of losmapimod at specified timepoints.	Weeks 4, 12, 16, 24, 36 and 48
Concentration of Losmapimod in Skeletal Muscle	Muscle biopsies will be collected at two specified timepoints to measure the concentration of losmapimod in skeletal muscle.	Week 16 or Week 36 if the biopsy could not be obtained at Week 16 due to COVID-19
Target Engagement	Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in peripheral whole blood and muscle.	Week 16 or Week 36

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reachable Work Space (RWS)	Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator with and without weights.	Weeks 4, 12, 24 and 36
Timed Up and Go (TUG).	Subjects are timed as they start from a seated or laying position, rise to a standing position, walk a total of 6 meters and then return to either a seated or laying position.	Weeks 4, 12, 24 and 36
Muscle Strength	Muscle strength will be assessed by Hand-Held Quantitative Dynamometry.	Weeks 4, 12, 24, 36 and 48
Motor Function Measure (MFM) Domain 1.	The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.	Weeks 12, 24, 36 and 48
FSHD Health Index (FSHD-HI).	The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.	Weeks 4, 12, 24, 36 and 48
Patients' Global Impression of Change (PGIC).	The PGIC is a single question that assesses on a scale of 1-7 if there has been an improvement, decline or no change in clinical status.	Weeks 4, 12, 16, 24, 36 and 48
Muscle Disease Transcripts	To evaluate the change from baseline in inflammatory, immune, apoptotic, and muscle disease transcripts in muscle biopsies by quantitative PCR analysis.	Week 16 or Week 36
Circulating Proteins	To evaluate the change from baseline in circulating proteins in plasma and serum by ELISA analysis.	Weeks 4, 12, 16, 24, 36 and 48

Collaborators and Investigators

• Sponsor: Fulcrum Therapeutics
• Investigators: Study Director: Michelle Mellion, 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.
• Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24.
• de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL, Frants RR, Tawil R, van der Maarel SM. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat. 2009 Oct;30(10):1449-59. doi: 10.1002/humu.21091.
• 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.
• Jagannathan S, Shadle SC, Resnick R, Snider L, Tawil RN, van der Maarel SM, Bradley RK, Tapscott SJ. Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells. Hum Mol Genet. 2016 Oct 15;25(20):4419-4431. doi: 10.1093/hmg/ddw271.
• Statland JM, Tawil R. Risk of functional impairment in Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2014 Apr;49(4):520-7. doi: 10.1002/mus.23949. Epub 2014 Feb 10.
• Wang LH, Friedman SD, Shaw D, Snider L, Wong CJ, Budech CB, Poliachik SL, Gove NE, Lewis LM, Campbell AE, Lemmers RJFL, Maarel SM, Tapscott SJ, Tawil RN. MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD. Hum Mol Genet. 2019 Feb 1;28(3):476-486. doi: 10.1093/hmg/ddy364.
• Jagannathan S, de Greef JC, Hayward LJ, Yokomori K, Gabellini D, Mul K, Sacconi S, Arjomand J, Kinoshita J, Harper SQ. Meeting report: the 2021 FSHD International Research Congress. Skelet Muscle. 2022 Jan 17;12(1):1. doi: 10.1186/s13395-022-00287-8. Review.

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2019
• Primary Completion (Actual): January 28, 2021
• Study Completion (Actual): January 28, 2021

Study Registration Dates

• First Submitted: June 25, 2019
• First Submitted That Met QC Criteria: June 28, 2019
• First Posted (Actual): July 1, 2019

Study Record Updates

• Last Update Posted (Actual): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 8, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Musculoskeletal Diseases; Neuromuscular Diseases; FSHD, FSHD1; Muscular Dystrophy; Muscular Dystrophies; Facioscapulohumeral Muscular Disorders
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophy, Facioscapulohumeral
• Other Study ID Numbers: FIS-002-2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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