Losmapimod improved, stabilized FSHD upper limb function: Study

Yearlong study didn't establish if DUX4-driven gene activity was reduced

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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One year of losmapimod taken twice a day improved or stabilized upper limb function and muscle strength in adults with facioscapulohumeral muscular dystrophy (FSHD), according to an open-label pilot study.

Blood and muscle tests also showed the therapy candidate successfully engaged with its intended target and had a favorable safety and tolerability profile.

Details of the small study, “An open-label pilot study of losmapimod to evaluate the safety, tolerability, and changes in biomarker and clinical outcome assessments in participants with facioscapulohumeral muscular dystrophy type 1,” were published in the Journal of the Neurological Sciences.

FSHD1 is a form of muscular dystrophy marked by progressive muscle weakness that mainly affects the face, shoulders, and upper arms. It’s caused by mutations in the DUX4 gene and results in the excessive production of the DUX4 protein. Too much DUX4 activates several other genes that are toxic to skeletal muscle cells.

Developed by Fulcrum Therapeutics, losmapimod is a small molecule that blocks the activity of certain enzymes that help regulate the DUX4 gene, thereby reducing toxic DUX4 production and preventing muscle damage.

A previous Phase 2 clinical trial called ReDUX4 (NCT04003974) tested the therapy in 80 adults with FSHD1, given twice daily for a year. Losmapimod slowed disease progression and improved arm and hand function relative to a placebo. The study failed to reach its primary goal of reducing DUX4 gene activity in muscle cells despite these promising findings, however.

Most ReDUX4 participants entered an ongoing open-label extension study (NCT04264442) where they all received losmapimod. Patients who’d been taking losmapimod since the start of the ReDUX4 study generally maintained upper limb function, interim data after two years of treatment showed. Those who switched from the placebo to losmapimod saw stabilization or slight improvement in their upper limb function.

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This separate study, which was sponsored by Fulcrum, was an open-label Phase 2 biomarker study (NCT04004000) that tracked 14 adults with FSHD1, ages 23-58, who were treated with losmapimod at a single site in the Netherlands for a year. Outcomes included safety, tolerability, biomarker levels, and exploratory efficacy. Afterward, the participants may continue to receive long-term losmapimod in an open-label extension study.

To determine if losmapimod blocked the activity of DUX4-regulating enzymes, the researchers measured levels of phosphorylated heat shock protein 27 (pHSP27) against total HSP27 in blood and muscle. In FSHD1, too much DUX4 increases pHSP27 levels relative to total HSP27.

In the blood, the ratio of pHSP27 to total HSP27 decreased by about 40% to 50% on weeks 4 and 44 from the study’s start, or its baseline, “indicating target engagement,” said the researchers. In muscles, the ratio of pHSP27 to total HSP27 decreased by 10.8% from baseline to week four. DUX4-driven gene activity was highly variable among the evaluable muscle biopsies samples, with no meaningful mean changes from baseline in DUX4 activity.

In exploratory efficacy outcomes, a year of losmapimod improved reachable workspace with or without a 500-gram weight, an assessment of upper arm function that assesses how much of an area a person can reach with their arms. As measured by a handheld dynamometer, losmapimod stabilized or improved muscle strength from baseline in most muscles evaluated.

Ten of 12 participants (83%) reported stability or improvement in the Patient Global Impression of Change, a measure of patients’ views of treatment. The other two participants said their status was slightly worse.

Regarding safety, the most common treatment-emergent adverse event (TEAEs) was a mild increase in liver enzymes, a sign of liver injury, which was transient and resolved with continued dosing. Other side effects included dry skin, eczema, COVID-19, and an increase in white blood cells. Most TEAEs were mild to moderate in severity and most resolved. No TEAEs led to discontinuing losmapimod and no deaths were reported.

“Losmapimod is a twice-daily oral therapy that showed a tolerable safety profile after 52 weeks of treatment in participants with FSHD,” the researchers said. “Although reduction in DUX4-driven gene expression could not be established, clinical outcome assessments showed stability or improvement after 52 weeks of treatment with losmapimod.”

Fulcrum is conducting the Phase 3 REACH trial (NCT05397470) to further evaluate losmapimod’s efficacy and safety in FSHD. The trial has completed enrollment at 260 adults with FSHD1 or FSHD2 at sites across the U.S., Canada, and Europe. Top-line results are expected later this year.