Losmapimod is a potential treatment being developed by Fulcrum Therapeutics for people with facioscapulohumeral muscular dystrophy (FSHD).

The investigative oral therapy is now in clinical testing in patients.

How does losmapimod work?

FSHD is characterized by progressive weakness and wasting of muscles 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.

Mutations in the DUX4 gene account for more than 90% of all FSHD cases. They cause excessive gene expression or activity, which leads to muscle degeneration and fat infiltration.

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 seen in early studies 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 is thought to inhibit the DUX4 gene and downstream pathways in a concentration-dependent manner in both FSHD1 and FSHD2.

Losmapimod in clinical trials

A Phase 1 clinical trial assessed the safety and tolerability, as well as the pharmacokinetics (how the drug moves into, through and out of the body) of losmapimod in healthy volunteers and FSHD patients.

In a first study group, 10 healthy people were randomized to placebo or the treatment. A second group consisted of 15 FSHD patients, randomly assigned to either losmapimod (as 7.5 mg or 15 mg tablets) or to a placebo given twice daily for 14 days, while a third patient group was given losmapimod at 15 mg twice daily.

Results showed no serious adverse events, and safety and pharmacology findings were similar in healthy volunteers and people with FSHD. Patients receiving the 15 mg dose were found to reach a higher drug concentration in muscles, and this twice daily dose was selected for further study.

A Phase 2b clinical trial (NCT04003974), called ReDUX4, opened in August 2019 in 80 adults with a confirmed genetic diagnosis of FSHD1 at sites in the United States, Canada, France, and Spain. Enrolled patients were randomized to losmapimod (two 7.5 mg tablets taken twice a day, for a 30 mg total daily dose) or to a placebo for 48 weeks. It concluded in January 2021.

ReDUX4 study results showed it did not meet its primary goal — a statistically significant reduction in the activity of the DUX4 gene in affected skeletal muscles of patients given losmapimod at week 16, or at week 36 due to restrictions caused by the COVID-19 pandemic. This “experimental biomarker endpoint” was hampered by several technical and biological variables, the company reported, and the needle biopsy used for measurements “was not sufficiently robust to detect treatment-related changes over time.”

Clinical gains, however, were seen in secondary trial goals, and losmapimod was reported to show downstream benefits of DUX4 reduction. Specifically, patients treated with losmapimod showed lesser disease progression with significantly less fat infiltration in intermediate muscles than those on placebo. (Fat infiltration into muscle correlates with disease severity in FSHD.) Treated patients also showed improvements in muscle fat fraction and lean muscle mass, but these results were not statistically significant.

Patients seemed to find the therapy was helpful, with four times more people self-reporting a significant improvement — using the Patient Global Impression of Change — following 48 weeks of treatment than did those on placebo. Losmapimod was seen to be generally safe and well-tolerated, with mostly mild or moderate adverse events reported in 29 (72.5%) of treated patients and 23 (57.5%) of those on a placebo.

A majority of patients who finished the ReDUX4 study (76 or 99%) also elected to either continue or start treatment with losmapimod in a five-year, open-label extension trial (NCT04264442). All will given treatment as 15 mg tablets twice daily, and losmapimod’s safety and tolerability, as well as fat infiltration and additional functional measures, will be assessed. Data is expected to be collected for this long-term extension study in February 2024, and the trial to end one year later.

A Phase 2 open-label study (NCT04004000) is also evaluating the safety, efficacy, and biomarker changes with about one year of daily losmapimod (30 mg total) in 14 patients enrolled at a single site in the Netherlands. Adverse events at week 56 is a main trial goal, as is treatment effectiveness as seen through changes in select skeletal muscles, measures of which will continue for about four years (week 204).


Last updated: June 29, 2021


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