Enrollment complete in Phase 3 trial of losmapimod for FSHD

Study is evaluating efficacy, safety of drug versus a placebo in 260 patients

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by Andrea Lobo |

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Fulcrum Therapeutics has completed patient enrollment for its Phase 3 clinical trial evaluating losmapimod as a potential treatment for people with Facioscapulohumeral muscular dystrophy (FSHD).

The study, dubbed REACH (NCT05397470), is evaluating the efficacy and safety of losmapimod against a placebo in FSHD adult patients across 33 sites in the U.S., Canada, and Europe.

“We are very pleased to have enrolled 260 patients in REACH, our global Phase 3 pivotal clinical trial for patients with FSHD,” Alex C. Sapir, president and CEO of Fulcrum, said in a company press release. “The rapid pace of enrollment is a testament to the high unmet need for a treatment option with potential to slow progression of this rare disease, for which there are currently no approved treatments.”

The company expects to report top-line data from the trial late next year, bringing them “one step closer to potentially delivering the first [approved] therapy for FSHD” in the U.S., Sapir said.

FSHD causes muscle weakness and wasting that gets progressively worse over time, and that characteristically affects the muscles of the face, shoulders, and upper arms. The disease is mainly caused by mutations in the DUX4 gene that make it overly active, leading to muscle degeneration and fat infiltration.

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Losmapimod selectively blocks p38 alpha, p38 beta

Originally developed by GSK and later acquired by Fulcrum, losmapimod is an orally available small molecule that selectively blocks p38 alpha and p38 beta, two enzymes that help regulate DUX4 gene’s activity.

By suppressing these enzymes, the therapy is expected to reduce the excessive activation of DUX4 and prevent further muscle damage.

Losmapimod was granted fast-track and orphan drug designations in the U.S. for the treatment of FSHD. These are meant to expedite the therapy’s development and regulatory review.

In the previous Phase 2 ReDUX4 trial (NCT04003974), which enrolled 80 adults with FSHD, one year of losmapimod treatment (15 mg given twice a day) was shown to slow disease progression and improve function relative to a placebo.

Particularly, losmapimod-treated patients performed significantly better in the reachable workspace (RWS) measure and showed significantly less muscle fat infiltration than those given a placebo. RWS is a measure assessing arm and hand range of motion, which correlates with a person’s ability to perform everyday activities independently.

While the therapy also was shown to be generally safe and well tolerated, the study failed to reach its main goal of showing that losmapimod could reduce DUX4 gene activity in muscle cells.

Most patients completing the trial entered an open-label extension study (NCT04264442), in which all are receiving the experimental therapy for up to five years to assess losmapimod’s long-term outcomes.

Interim, one-year data showed that patients taking losmapimod during both ReDUX4 and the extension study experienced minimal changes in average RWS scores on the dominant arm and 5% score improvements in the nondominant arm.

For those given a placebo in ReDUX4, average RWS scores for both arms worsened gradually over that year, but stabilized or improved slightly once they switched to losmapimod in the extension study.

The Phase 3 REACH study is meant to confirm the therapy’s benefits in a larger number of patients.

In its first part, adults with a genetically confirmed diagnosis of FSHD types 1 or 2 were  randomly assigned to receive two oral tablets of either losmapimod (total dose, 15 mg) or a placebo, twice a day for 48 weeks.

The main goal is to determine changes in RWS. Secondary goals include: changes in quality of life related to arm and hand function in daily activities; Patient Global Impression of Change,  a measure of a patient’s belief about a treatment’s efficacy; and muscle fat infiltration, as well as safety measures.

After completing the one-year treatment period, participants will have the choice to move to the trial’s second part, in which all will take losmapimod for nearly three years.

Losmapimod also has been evaluated in more than 3,600 participants in clinical trials for several other indications, without reports of treatment-related safety issues, according to Fulcrum.