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

Fulcrum Therapeutics80 enrolled

Overview

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

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. This study was conducted during the Coronavirus Disease-2019 (COVID-19) Pandemic. The pandemic restrictions limited some assessments in the FSHD1 population in the clinic, including collection of some data for Week 24.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Facioscapulohumeral Muscular Dystrophy (FSHD)

Interventions

Losmapimod oral tabletDRUG

Losmapimod will be administered with food when possible.

Placebo oral tabletDRUG

Placebo will be administered with food when possible

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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 * 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.

Locations (17)

University of California Irvine

Irvine, California, United States

University of California Los Angeles (UCLA)

Los Angeles, California, United States

Outcomes

Primary Outcomes

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 \[average delta Ct across the 6 genes at baseline\].

Time frame: Baseline and Week 16 to Week 36

Secondary Outcomes

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

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A Serious adverse event (SAE) is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. A treatment emergent adverse events (TEAE) is defined as any event that was not present before exposure to study drug or any event that was already present but worsens in either intensity or frequency after exposure to study drug. Number of participants with type of AEs to losmapimod has been presented which included: TEAEs and SAEs.

Time frame: Up to Week 48

Number of Participants With Severity of AEs to Losmapimod

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with severity grading of AEs to losmapimod has been presented: Mild (An event that is usually transient in nature and generally does not interfere with normal activities), Moderate (An AE that is sufficiently discomforting to interfere with normal activities) and Severe (An AE that is incapacitating and prevents normal activities). The higher the grade, the more severe the symptoms.

Data from ClinicalTrials.gov

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University of Florida

Gainesville, Florida, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Kennedy Krieger Institute

Baltimore, Maryland, United States

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Rochester Medical Center

Rochester, New York, United States

Ohio State University

Columbus, Ohio, United States

University of Utah

Salt Lake City, Utah, United States

...and 7 more locations

Time frame: Up to Week 48

Number of Participants With Relationship of AEs to Losmapimod

An AE is any untoward medical occurrence in a clinical study participant,temporally associated with use of a study intervention, whether or not considered related to study intervention. An SAE is any untoward medical occurrence that, at any dose results in death,is life-threatening,requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment. Number of participants with relationship of AEs to losmapimod has been presented:Unlikely related(most likely produced by other factors and temporal relationship of AE to drug makes a causal relationship unlikely),not related (no association between drug and AE), possibly related (treatment with drug caused/contributed to AE),probably related (reasonable temporal sequence of event with drug exists) and definitely related (definite causal relationship exists between drug and AE)

Time frame: Up to Week 48

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

An AESI (serious or non-serious) is one of scientific and medical concern for which ongoing monitoring and rapid communication by the investigator to the sponsor can be appropriate. Adverse events of special interest for this study included liver tests that met the criteria for potential drug-induced liver injury (DILI), in accordance with the Unites States (US) Food and Drug Administration (FDA) Guidance for Industry-Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Number of participants with AESIs has been presented.

Time frame: Up to Week 48

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

TEAE was an AE that began on or after the first dose of study drug and before the stop of study drug + 7 days or begins before the first dose of study drug and worsened in severity on or after the first dose of study drug and before the stop of study drug + 7 days. An AE with completely missing onset and end dates were considered as treatment-emergent AE. Number of participants who prematurely discontinued study drug due to a TEAE has been presented.

Time frame: Up to Week 48

Change From Baseline in Muscle Fat Fraction (MFF) at Week 12, Week 24 and Week 48

Measurement of the extent of skeletal muscle tissue replacement by fat in FSHD participants were done through automatic skeletal muscle segmentation for the 3D muscle volumes and fat fraction analysis via robust algorithms using Dixon imaging. Composite variables, incorporating pre-selected muscles, were derived for longitudinal analysis of MFF. Baseline was defined as the last non-missing evaluation on or before the day of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline and at Week 12, Week 24 and Week 48

Change From Baseline in Lean Muscle Volume (LMV) at Week 12, Week 24 and Week 48

Measurement of the extent of skeletal muscle tissue replacement by fat in FSHD participants were done through automatic skeletal muscle segmentation for the 3D muscle volumes and fat fraction analysis via robust algorithms using Dixon imaging. Composite variables, incorporating pre-selected muscles, were derived for longitudinal analysis of LMV. Baseline was defined as the last non-missing evaluation on or before the day of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline and at Week 12, Week 24 and Week 48

Change From Baseline in Muscle Fat Infiltration (MFI) at Week 12, Week 24 and Week 48

Measurement of the extent of skeletal muscle tissue replacement by fat in FSHD participants were done through automatic skeletal muscle segmentation for the 3D muscle volumes and fat fraction analysis via robust algorithms using Dixon imaging. Composite variables, incorporating pre-selected muscles, were derived for longitudinal analysis of MFI. Baseline was defined as the last non-missing evaluation on or before the day of first dose of study drug. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.

Time frame: Baseline and at Week 12, Week 24 and Week 48

Plasma Concentration After Administration of Losmapimod

Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of losmapimod.

Time frame: Pre dose, 4 hours post dose, Week 4 pre dose, Week 4: 4 hours post dose, Week 12, Week 16 pre dose, Week 16: 4 hours post dose, Week 24, Week 36 pre dose, Week 36: 4 hours post dose, Week 48

Concentration of Losmapimod in Skeletal Muscle Biopsy

Skeletal muscle biopsy samples were collected at indicated time points for the assessment of concentration of losmapimod.

Time frame: Baseline, Week 16 and Week 36

Percent Change From Baseline in Phosphorylated Heat Shock Protein 27 (pHSP27)/Total Heat Shock Protein 27 (tHSP27)

Blood samples were collected for Pharmacodynamic (PD) analysis of pHSP27/tHSP27. Baseline was defined as the last non-missing evaluation on or before the day of first dose of study drug. Percent change from Baseline was defined as value of post Baseline minus Baseline value divided by Baseline value and multiplied by 100.

Time frame: Baseline and at Day 1: 4 hours post dose, Week 16: pre dose, Week 16: 4 hours post dose, Week 36 pre dose, Week 36: 4 hours post dose