Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) With Open-Label Extension (OLE)

• ClinicalTrials.gov Identifier: NCT04264442
• Recruitment Status: Enrolling by invitation
• First Posted: February 11, 2020
• Last Update Posted: June 22, 2020
• Sponsor: Fulcrum Therapeutics
• Information provided by (Responsible Party): Fulcrum Therapeutics

Study Description

Brief Summary:

This study is an open-label extension to evaluate the safety and tolerability of long-term dosing of Losmapimod in patients with FSHD1 who participated in the ReDux4 study.

Condition or disease	Intervention/treatment	Phase
Facioscapulohumeral Muscular Dystrophy (FSHD)	Drug: Losmapimod	Phase 2

Detailed Description:

This study is an open-label extension study to evaluate the safety and tolerability of long-term dosing of Losmapimod in patients with FSHD1 who participated in the ReDux4 study.

This study is a multi-center clinical trial. It will be conducted in North America, Canada and Europe. Only patients who participated and competed all study procedures in the ReDUX4 Study treatment period will be eligible to participate in this open label extension study.

Patients who complete the randomized, placebo-controlled portion of the study will have the option to roll over into the open-label extension study.

Patients will receive 15 mg of losmapimod by mouth twice daily for a total of 30 mg by mouth daily. All patients will attend clinic visits approximately every 12 weeks and 7 days after the last dose of study drug for safety follow-up assessment.

Participation in this open-label extension study will continue until losmapimod becomes commercially available, the patient withdraws from the study, or the Sponsor decides to close the study.

The primary endpoint of the study is to evaluate the safety and tolerability of long-term dosing of losmapimod in patients with FSHD.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 76 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: This study is part two of NCT04003974 which was a randomized, double-blind placebo-controlled treatment period for 48 weeks. This study is an open-label extension with losmapimod in patients with FSHD1.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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)
• Actual Study Start Date: February 13, 2020
• Estimated Primary Completion Date: February 2024
• Estimated Study Completion Date: February 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Losmapimod; FSHD1 patients with genetic confirmation will receive Losmapimod 15 mg by mouth twice daily for a total of 30 mg daily until study drug approval or until the study is discontinued by the Sponsor.	Drug: Losmapimod; Patients will receive Losmapimod 15 mg by mouth twice daily for a total of 30 mg daily. The study drug should be taken with food and the date and time of each dose taken should be recorded in the subject diary.

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability of Losmapimod [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]

   Safety and tolerability of losmapimod will be evaluated by the following:

   a. Type, frequency, severity and relationship of adverse events (AEs) to losmapimod

Secondary Outcome Measures :

1. Lean Muscle Volume [ Time Frame: Every 24 Weeks from the date of enrollment through study completion, up to 60 months ]
   Change from baseline in lean muscle volume (LMV) after long term dosing will be measured by whole body magnetic resonance imaging (MRI).
2. Muscle Fat Fraction [ Time Frame: Every 24 Weeks from the date of enrollment through study completion, up to 60 months ]
   Change from baseline in muscle fat fraction (MMF) after long term dosing will be measured by whole body magnetic resonance imaging (MRI).
3. Muscle Fat Infiltration [ Time Frame: Every 24 Weeks from the date of enrollment through study completion, up to 60 months ]
   Change from baseline in muscle fat infiltration (MFI) after long term dosing will be measured by whole body magnetic resonance imaging (MRI).
4. Plasma Concentrations of Losmapimod After Long Term Dosing of Losmapimod [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Blood samples will be collected to measure the plasma concentration of losmapimod after long-term dosing.

Other Outcome Measures:

1. Reachable Work Space (RWS) - Clinical Outcome Assessment [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Changes from baseline in the Reachable Work Space clinical outcome assessment performed with and without weights will be evaluated after long-term dosing of losmapimod.
2. Timed Up and Go (TUG) - Clinical Outcome Assessment [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Changes from baseline in the Classic and FSHD TUG clinical outcome assessment will be evaluated after long-term dosing of losmapimod.
3. Muscle Strength - Clinical Outcome Assessment [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Changes from baseline in muscle strength assessed by Hand-Held Quantitative Dynamometry will be evaluated after long-term dosing of losmapimod.
4. Motor Function Measure (MFM) Domain 1 - Clinical Outcome Assessment [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Changes from baseline in the MFM domain 1 will be evaluated after long-term dosing of losmapimod.
5. FSHD Health Index (FSHD-HI) - Clinical Outcome Assessment [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Changes from baseline in the FSHD-HI will be evaluated after long-term dosing of losmapimod.
6. Patients' Global Impression of Change (PGIC) - Clinical Outcome Assessment [ Time Frame: Every 12 Weeks from the date of enrollment through study completion, up to 60 months ]
   Changes from baseline in the PGIC will be evaluated after long-term dosing of losmapimod.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• The patient must have consented to participate and must have provided signed, dated and witnessed an 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 will 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.

Contacts and Locations

Locations

United States, California

University of California Irvine

Irvine, California, United States, 92868

University of California Los Angeles (UCLA)

Los Angeles, California, United States, 90095

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Maryland

Kennedy Krieger Institute

Baltimore, Maryland, United States, 21205

United States, Massachusetts

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States, 01655

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43221

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

University of Washinton Medical Center

Seattle, Washington, United States, 98195

Canada, Ontario

Ottawa Hospital Research Institute

Ottawa, Ontario, Canada, K1Y 4E9

Canada, Quebec

Montreal Neurological Institute and Hospital

Montréal, Quebec, Canada, H3A 2B4

France

CHU de NICE- CHU pasteur2

Nice, France, 06001

Spain

Hospital de la Sta Creu i St Pau

Barcelona, Spain, 08041

Hospital UiP La Fe

Valencia, Spain, 46026

Sponsors and Collaborators

Fulcrum Therapeutics

Investigators

• Study Director: Michelle Mellion, MD; Fulcrum Therapeutics

More Information

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, Mäki-Petäjä 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.

• Responsible Party: Fulcrum Therapeutics
• ClinicalTrials.gov Identifier: NCT04264442
• Other Study ID Numbers: FIS-002-2019 OLE
• First Posted: February 11, 2020
• Last Update Posted: June 22, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Fulcrum Therapeutics:

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

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Facioscapulohumeral; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn