Losmapimod for facioscapulohumeral muscular dystrophy

Last updated June 28, 2024, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD

What is losmapimod for facioscapulohumeral muscular dystrophy?

Losmapimod is an experimental oral therapy intended to slow or prevent muscle damage in people with facioscapulohumeral muscular dystrophy (FSHD).

Initially developed by GlaxoSmithKline, the medication was acquired in 2019 by Fulcrum Therapeutics, which is developing it for FSHD in the U.S. Under a 2024 agreement with Fulcrum, Sanofi has secured rights to commercialize losmapimod for FSHD outside the U.S.

As a potential FSHD treatment, losmapimod has been granted fast track and orphan drug designations in the U.S., which are designed to incentivize and speed the development of potentially important new therapies for rare and serious diseases.

Therapy snapshot

How does losmapimod work?

FSHD is caused by mutations that result in the abnormal activation of the DUX4 gene and in the excessive production of the DUX4 protein in skeletal muscle cells. This causes the activation of several other genes that is toxic to cells, resulting in muscle weakness that mainly affects the face, shoulders, and upper arms.

FSHD is divided into two types, depending on the mechanisms that cause the higher than normal production of DUX4. In type 1 (FSHD1), which accounts for the vast majority of cases, patients have an abnormal shortening of the D4Z4 region in chromosome 4.

The D4Z4 region normally is made of 11 to 100 or more repeated segments of DNA. While each segment contains a copy of the DUX4 gene, these genes are normally highly silenced. But people with FSHD1 have only one to 10 repeats in their D4Z4 region, which causes the genes to become more active.

In type 2 (FSHD2), the D4Z4 region is activated through other mechanisms. Most commonly, it results from mutations in a gene called SMCHD1, which is important for silencing genes in the D4Z4 region.

Losmapimod is a small molecule that’s been found to block the activity of certain enzymes that help to regulate the DUX4 gene. Specifically, the therapy blocks an enzyme called p38 mitogen-activated protein kinase (p38 MAPK). By blocking the alpha and beta versions of this enzyme, losmapimod has been shown to reduce DUX4 activity and lessen the production of toxic DUX4 protein.

How will losmapimod be administered in FSHD?

Losmapimod is available as a tablet that must be taken orally with food. In Phase 2 and Phase 3 clinical trials, it is being tested at a dose of 30 mg, taken as two 7.5 mg tablets twice daily (for a total of four tablets a day).

This might be the selected dose and dose regimen should the therapy ultimately be approved by regulatory authorities.

Losmapimod in clinical trials

Losmapimod has been studied in FSHD patients in Phase 1 and in Phase 2 clinical trials. An open-label extension of the Phase 2b ReDUX4 trial is ongoing, as is a Phase 3 study whose findings may support an application to obtain regulatory approval.

Phase 1 trial

A Phase 1 clinical trial assessed the safety, tolerability, and pharmacokinetics (how the drug moves into, through, and out of the body) of losmapimod in healthy volunteers and FSHD1 patients.

In the first part, 10 healthy adults were randomized to a single oral dose of losmapimod — at a dose of 7.5 or 15 mg — or to a placebo, both taken with food. Then, 15 FSHD1 patients were treated with losmapimod at 7.5 mg or 15 mg, or given a matching placebo, 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 pharmacology findings were similar in healthy adults and those with FSHD1. 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.

Phase 2b ReDUX4 study

A Phase 2b clinical trial called ReDUX4 (NCT04003974) enrolled 80 adults with a confirmed genetic diagnosis of FSHD1 at sites in the United States, Canada, France, and Spain. Participants were randomized to losmapimod (15 mg twice a day with food) or to a placebo for 48 weeks, or nearly one year. The study concluded in early 2021.

The trial’s main goal was to test whether losmapimod could reduce activity of the DUX4 gene relative to a placebo. Results showed the trial failed to meet this goal: There was substantial variation in DUX4 gene activity among participants, and average activity for patients on losmapimod did not significantly differ from those given the placebo.

Despite missing its main goal, ReDUX4 showed some promising results. Particularly, MRI data indicated that patients given losmapimod had less fat infiltration into their muscles, which suggests less muscle degeneration. In FSHD, degenerating muscle is replaced by fat tissue, so fat infiltration is considered a marker of disease progression.

Losmapimod also led to improvements relative to the placebo in reachable workspace, a measure of upper arm function that essentially assesses how much of an area a person can reach with their arms.

After the ReDUX4 trial ended, 76 of its 80 participants chose to enter an open-label extension study (NCT04264442), where all participants are being treated with losmapimod and monitored for as long as five years.

Data at nearly two years of treatment showed reachable workspace tended to be stable or to slightly improve over time for patients who started on losmapimod in the parent trial. For those initially on a placebo, reachable workspace tended to worsen during the randomized trial, but stabilized or improved slightly once they started losmapimod treatment in the extension study.

Phase 2 biomarker study

A separate Phase 2 biomarker study (NCT04004000) is tracking outcomes for 14 adults with FSHD1 treated twice daily with 15 mg losmapimod (30 mg daily) at a single site in the Netherlands. Treatment is given for 60 weeks (a little over one year), after which patients may continue receiving long-term losmapimod in an open-label extension study.

The study’s main goal is to evaluate the therapy’s safety profile after about a year. It also is assessing a range of biomarker measurements after one year and functional outcomes after about four years.

Phase 3 REACH trial

Fulcrum now is running a Phase 3 clinical trial dubbed REACH (NCT05397470) to further assess the efficacy and safety of losmapimod in FSHD. The trial has enrolled 260 adults with FSHD1 or FSHD2 at sites across the U.S., Canada, and Europe.

REACH participants have been randomly assigned to take losmapimod (15 mg twice daily with food) or a placebo for 48 weeks, after which they are given the option of entering the trial’s open-label extension, where all will be on long-term losmapimod treatment.

The study’s main goals are to test if losmapimod can outperform a placebo in upper arm function, as measured by reachable workspace after 48 weeks. Other secondary measures will include safety, as well as changes in muscle fat infiltration, muscle strength, and in patient-reported outcomes.

Top-line REACH results are expected in late 2024. If results are positive, they are likely to support regulatory applications seeking the approval of losmapimod for FSHD.

Common side effects of losmapimod

In early clinical trials, losmapimod was found to be generally safe and well tolerated, with no serious side effects related to treatment reported in people with FSHD. The most common side effects potentially related to the treatment included:

• headache
• dizziness
• sleepiness
• gastrointestinal issues such as indigestion
• rash
• high blood levels of alanine aminotransferase, a marker of liver damage.

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