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

NCT04003974 | Completed Phase 2 Results FDA Drug

• 1 other identifier: FIS-002-2019
• Study Type: interventional
• Target: 80
• Locations: 4 countries
• Sites: 17

Brief Summary

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

Conditions

Facioscapulohumeral Muscular Dystrophy (FSHD)

Keywords

FSHD, FSHD1; Muscular Dystrophies; Muscular Dystrophy; Facioscapulohumeral Muscular Disorders; Musculoskeletal Diseases; Neuromuscular Diseases

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Double Homeobox 4 (DUX4) Activity in Affected Skeletal Muscle

  Skeletal muscle biopsies were collected at Baseline and post-Baseline. DUX4 activity in skeletal muscle biopsies was assessed by measuring expression levels of a panel of 6 genes known to be regulated by DUX4. Expression levels of genes were measured using a validated quantitative RT-PCR assay and expressed as Ct (PCR cycles). Raw Ct for each of the 6 genes was normalized to the specified reference genes to generate a normalized Ct. The DUX4 activity is the average of the normalized Cts of each of the identified 6 genes, where the Ct for each of the 6 genes is first normalized to reference genes before the average is generated. Change in Baseline is calculated as \[average delta Ct across the 6 genes post-baseline\] minus \[average delta Ct across the 6 genes at baseline\].

  Baseline and Week 16 to Week 36

Secondary Outcomes (11)

• Number of Participants With Type of Adverse Events (AEs) to Losmapimod

  Up to Week 48

• Number of Participants With Severity of AEs to Losmapimod

  Up to Week 48

• Number of Participants With Relationship of AEs to Losmapimod

  Up to Week 48

• Number of Participants With Adverse Events of Special Interest (AESIs)

  Up to Week 48

• Number of Participants Who Prematurely Discontinued Study Drug Due to a Treatment Emergent Adverse Event (TEAE)

  Up to Week 48

Other Outcomes (7)

• Change From Baseline in Reachable Work Space (RWS) Dominant and Non-dominant Total Relative Surface Area (RSA) With Weight Quintant (Q)1 to Q5

  Baseline and Week 4, Week 12, Week 24, Week 36 and Week 48

• Change From Baseline in Classic Timed Up and Go (TUG) Average Completion Time

  Baseline and at Week 4, Week 12, Week 24, Week 36 and Week 48

• Change From Baseline in Facioscapulohumeral Muscular Dystrophy (FSDH) TUG Average Completion Time

  Baseline and at Week 4, Week 12, Week 24, Week 36 and Week 48

Study Arms (2)

Treatment

EXPERIMENTAL

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 oral tablet

Placebo

PLACEBO COMPARATOR

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

Interventions

Losmapimod oral tablet DRUG

Losmapimod will be administered with food when possible.

Treatment

Placebo oral tablet DRUG

Placebo will be administered with food when possible

Also known as: Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fulcrum Therapeutics: lead

Study Sites (17)

University of California Irvine

Irvine, California, 92868, United States

Location

University of California Los Angeles (UCLA)

Los Angeles, California, 90095, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Kennedy Krieger Institute

Baltimore, Maryland, 21205, United States

Location

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, 01655, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Ohio State University

Columbus, Ohio, 43221, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

University of Washinton Medical Center

Seattle, Washington, 98195, United States

Location

Ottawa Hospital Research Institute

Ottawa, Ontario, K1Y 4E9, Canada

Location

Montreal Neurological Institute and Hospital

Montreal, Quebec, H3A 2B4, Canada

Location

CHU de NICE- CHU pasteur2

Nice, 06001, France

Location

Hospital de la Sta Creu i St Pau

Barcelona, 08041, Spain

Location

Hospital UiP La Fe

Valencia, 46026, Spain

Location

Related Publications (9)

• 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.

  PMID: 23215699 BACKGROUND

• 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.

  PMID: 21262998 BACKGROUND

• 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.

  PMID: 19728363 BACKGROUND

• 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.

  PMID: 24828906 BACKGROUND

• 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.

  PMID: 28171552 BACKGROUND

• 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.

  PMID: 23873337 BACKGROUND

• 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.

  PMID: 30312408 BACKGROUND

• Tawil R, Wagner KR, Hamel JI, Leung DG, Statland JM, Wang LH, Genge A, Sacconi S, Lochmuller H, Reyes-Leiva D, Diaz-Manera J, Alonso-Perez J, Muelas N, Vilchez JJ, Pestronk A, Gibson S, Goyal NA, Hayward LJ, Johnson N, LoRusso S, Freimer M, Shieh PB, Subramony SH, van Engelen B, Kools J, Leinhard OD, Widholm P, Morabito C, Moxham CM, Cadavid D, Mellion ML, Odueyungbo A, Tracewell WG, Accorsi A, Ronco L, Gould RJ, Shoskes J, Rojas LA, Jiang JG. Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2024 May;23(5):477-486. doi: 10.1016/S1474-4422(24)00073-5.

  PMID: 38631764 DERIVED

• 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.

  PMID: 35039091 DERIVED

MeSH Terms

Conditions

Muscular Dystrophy, Facioscapulohumeral; Muscular Dystrophies; Musculoskeletal Diseases; Neuromuscular Diseases

Interventions

6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide

Condition Hierarchy (Ancestors)

Muscular Disorders, Atrophic; Muscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Call Center
• Organization: Fulcrum Therapeutics

clinicaltrials@fulcrumtx.com

617-651-8853

Study Officials

• Michelle Mellion, MD

  Fulcrum Therapeutics

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This study will be performed in a double-blind fashion. The investigator, study staff, subjects, sponsor and monitor will remain blinded to the treatment until study closure.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This study is a randomized, double-blind, placebo-controlled, 48-week parallel-group study.

Study Record Dates

• First Submitted: June 25, 2019
• First Posted: July 1, 2019
• Study Start: August 9, 2019
• Primary Completion: January 28, 2021
• Study Completion: January 28, 2021
• Last Updated: July 10, 2024
• Results First Posted: July 10, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1); ES (2); US (12); CA (2)