Losmapimod Fails at FSHD Trial’s Primary Goal, But Shows Potential

Oral losmapimod, an investigational treatment for people with facioscapulohumeral muscular dystrophy (FSHD), showed clinically relevant benefits over a placebo on multiple measures of disease progression and patient-reported outcomes after almost a year, according to data from the ReDUX4 Phase 2b clinical trial.

But the therapy failed to reach trial’s primary goal: changes in the activity of the DUX4 gene in affected skeletal muscle.  According to Fulcrum Therapeutics, losmapimod’s developer, this “experimental biomarker endpoint” was hampered by several technical and biological challenges.

Fulcrum plans to meet with U.S. Food and Drug Administration regulators later this year to discuss steps necessary for losmapimod to be considered for approval, it said a press release.

“We are thrilled with the data reported from ReDUX4,” said Bryan Stuart, Fulcrum’s president and CEO. “These structural, functional, and patient-reported results … are unprecedented in FSHD. In particular, we are pleased by the fact that we observed these results within a 48-week time period.”

Trial data were recently presented at the 2021 FSHD International Research Congress in the study, “ReDUX4, a Phase 2b Clinical Trial with Losmapimod in Facioscapulohumeral Muscular Dystrophy (FSHD).”

Mutations in the DUX4 gene, accounting for more than 90% of FSHD cases, cause excessive gene expression or activity, which leads to muscle degeneration and fat infiltration. This initially affects the movement of the face and eventually the arms, legs, and trunk.

Losmapimod is an oral medicine that blocks the activity of the proteins p38 alpha and p38 beta, aiming to reduce the disease-causing activity of DUX4.

The ReDUX4 trial (NCT04003974) investigated the safety and efficacy of losmapimod against a placebo in 80 adults with FSHD. Losmapimod, given twice daily at 15 mg, was randomly assigned to 40 patients, and a placebo tablet to the remaining 40. The mean age of all participants was 45.7 years.

The trial’s primary goal was a change from pre-treatment (baseline) in DUX4-driven gene activity in affected muscles via biopsies assessed at week 16 or 36. While losmapimod lowered gene activity in preclinical models, it did not differentiate DUX4 activity in biopsy data.

Results showed a 1,000-fold variation in DUX4 expression among biopsy samples, few DUX4-positive nuclei in skeletal muscle (attached to bone) fibers, and an imprecise needle biopsy procedure at multiple trial sites, according to the company.

“Sampling a dynamic, scarce signal in a heterogenous cell population with needle biopsy was not sufficiently robust to detect treatment-related changes over time,” the company reported in its study.

“Our broader molecular insights confirm the variability in DUX4 expression in skeletal muscle and can play an important role in guiding future research,” Stuart said.

Although the trial did not meet this primary goal, losmapimod showed downstream benefits of DUX4 reduction. As fat infiltration into muscle correlates with disease severity in FSHD, trial participants were assessed with whole-body MRI scans to measure disease progression by fat replacement of skeletal muscle.

Patients treated with losmapimod showed decreased progression with significantly less fat infiltration than those on placebo in intermediate muscles, which were most likely to change in FSHD. Muscle fat fraction and lean muscle mass were also improved, but the results were not statistically significant. Normal appearing muscles were preserved in the losmapimod group versus placebo.

Reachable Workspace (RWS) was an assessment of upper extremity range of motion and function, which correlates with the ability of patients to perform daily activities independently.

Losmapimod-treated patients showed a slower rate of decline and improved accessible surface area in RWS measures, including improvements of up to 1.5% from baseline in accessible surface area with a 500 gram weight (over 1 lb) on their wrist relative to placebo patients. Those in the placebo group showed less access to total surface area (2 to 4% less) with and without weights after 48 weeks.

The Patient Global Impression of Change assessment is a self-reported measure of how a patient feels and functions. Four times more patients reported feeling significantly better following losmapimod treatment than those on placebo after 48 weeks. Notably, fewer losmapimod-treated patients compared with placebo reported a worsening, and none reported being “much worse” — as did more than 13% of placebo recipients.

“People living with FSHD experience a progressive loss of function,” said Fran Sverdrup, PhD, a FSHD parent and disease researcher at Saint Louis University. “The ReDUX4 trial with losmapimod is the first trial to demonstrate a positive benefit in several measures of FSHD, including slower disease progression and patient-reported improvement over time. I am excited about today’s findings and hopeful for the many patients who suffer from this devastating disease.”

Further assessments, including a dynamometer test measuring muscle strength, showed the placebo group lost about 15% of shoulder and ankle strength after 48 weeks, two muscle groups particularly affected in FSHD. In contrast, the losmapimod group showed a trend toward slower progression and meaningful improvements in strength (12 to 27%) in the shoulder and ankles. Consistently, the Timed Up and Go (TUG) test, which measures the time to stand up, walk three meters (about 10 feet), and back, was faster in the treatment group compared to placebo.

Two newly designed scales, FSHD TUG and FSHD Health Index, did not demonstrate changes from baseline in either group, suggesting these tests did not detect progression over the 48 weeks. A motor function assessment also showed no changes.

Losmapimod was seen to be generally safe and well-tolerated, with adverse events reported in 29 (72.5%) of those on the treatment and 23 (57.5%) of placebo participants. Most were rated as mild or moderate, and deemed unlikely or not related to losmapimod. No adverse events led to treatment discontinuation or study withdrawal. Three serious adverse events were deemed unrelated to study treatment.

Most trial patients — 76 or 99% of those who completed ReDUX4 — elected to continue or start treatment in an open-label extension study (NCT04264442), which will assess the five-year safety and tolerability of losmapimod (twice daily 15 mg tablets) as well as fat infiltration and additional functional measures.

“These results provide strong support that treatment with losmapimod has a meaningful clinical benefit in relevant measures of FSHD disease progression, despite the challenges of measuring DUX4,” said Rabi Tawil, MD, a ReDUX4 principal investigator at the University of Rochester Medical Center. “I am enthusiastic about the potential for losmapimod to offer meaningful improvements in preserving muscle function and patient quality of life.”

Added Stuart: “I would like to thank the patients, caregivers, and clinicians who participated in ReDUX4 for their important contributions and dedication.”