Losmapimod is a potential treatment being developed by Fulcrum Therapeutics for the treatment of facioscapulohumeral muscular dystrophy (FSHD) patients with a confirmed genetic diagnosis.

How losmapimod works?

FSHD is characterized by progressive muscle weakness and wastage in the face, shoulders, and upper arms. Mutations in a specific region toward the end of chromosome 4, called the D4Z4 region, are known to contribute to a form of FSHD called FSHD1. These mutations lead to hypomethylation of a gene in the D4Z4 region called DUX4, the production of which is thought to adversely influence the activity of other genes in muscle cells, resulting in FSHD symptoms.

Mitogen-activated protein kinases (MAPKs) are proteins that are activated as a cellular response to external stress and have been shown to regulate the activity of the DUX4 gene. By inhibiting the activity of MAPKs using small molecules such as MAPK inhibitors, the overactive DUX4 gene can be controlled.

Losmapimod is a selective MAPK inhibitor that has been shown to reduce DUX4 gene activity in FSHD patient-derived myotubes (fused muscle cells). Losmapimod does not affect the differentiation of myotubes or alter the production of other proteins in muscle cells. It only inhibits the DUX4 gene and downstream pathways in a concentration-dependent manner in both FSHD1 and FSHD2.

Losmapimod in clinical trials

Fulcrum announced the results of a Phase 1 clinical trial in October, 2019. The study evaluated the safety and tolerability, as well as the pharmacokinetics (how the drug moves through the body), of losmapimod in healthy individuals and participants with FSHD. Ten healthy participants were randomized between placebo and treatment groups in the first cohort of the study. The second cohort consisted of 15 FSHD patients randomized between placebo, 7.5 mg or 15 mg oral doses, given twice daily. No serious adverse events were found in either cohort of patients and the patients receiving the 15 mg dose achieved the desired concentration of drug inside the muscles.

A 24-week randomized Phase 2b clinical trial (NCT04003974) called ReDUX4 is recruiting patients with a confirmed genetic diagnosis of FSHD1 in the United States, Canada, France, Germany, and Spain. The study will evaluate the safety and efficacy of a daily dose of 30 mg of losmapimod in about 66 participants over a total period of 29 weeks.

The primary endpoint of this study is evaluation of the efficacy of losmapimod in inhibiting the activity of the DUX4 gene in skeletal muscles of FSHD patients. Secondary endpoints include the safety and tolerability of losmapimod and its levels in the blood and skeletal muscle. The ability of the treatment to interact with its target (target engagement) will also be evaluated. The study is expected to be completed in August 2020.

A Phase 2 open-label study (NCT04004000) is evaluating the safety, efficacy, and biomarker changes after treatment with 30 mg of losmapimod over a period of 52 weeks. The total duration of this trial spans nearly 68 weeks and is estimated to recruit 16 patients in the Netherlands with a confirmed genetic diagnosis of FSHD1. The study is expected to be completed by January 2021.

The primary endpoint of the study is to evaluate the safety and tolerability of long-term losmapimod treatment in FSHD1 patients with the secondary endpoints being target engagement of losmapimod in blood and skeletal muscles along with the pharmacokinetics (movement in the body) of repeated doses of treatment.

 

Last updated: Nov. 15, 2019

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