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

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

Detailed Description
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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.

Official Title
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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)

Conditions
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Facioscapulohumeral Muscular Dystrophy (FSHD)

Intervention / Treatment
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* Drug: Losmapimod
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a randomized, double-blind, placebo-controlled, 48-week parallel-group study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>* Other names: Placebo;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuromuscular Diseases, FSHD, FSHD1, Muscular Dystrophies, Muscular Dystrophy, Facioscapulohumeral Muscular Disorders, Musculoskeletal Diseases