Losmapimod fails to significantly improve FSHD outcomes: Study
Fulcrum Therapeutics will discontinue its development, focus on other programs
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Losmapimod, an investigational medication from Fulcrum Therapeutics, failed to significantly outperform a placebo at improving upper limb function and other clinical measures in people with facioscapulohumeral muscular dystrophy (FSHD), according to top-line data from the REACH Phase 3 trial.
Participants given losmapimod did see improvements over 48 weeks, but the placebo group didn’t show a functional status decline as seen in previous trials, meaning the difference between the groups didn’t reach statistical significance. As the findings failed to repeat the clinically relevant improvements in the Phase 2 ReDUX4 (NCT04003974) trial, the company plans to stop developing losmapimod and focus on other clinical programs.
“We are deeply disappointed that the REACH trial did not replicate the clinical results observed in the Phase 2 ReDUX4 trial,” Alex C. Sapir, president and CEO of Fulcrum, said in a company press release. “In light of these results, we plan to suspend the losmapimod program in FSHD. We would like to thank the FSHD patients who participated in losmapimod clinical trials, their families, the investigators, the FSHD Society, and the broader FSHD community for their unwavering support for this program.”
FSHD is a form of muscular dystrophy caused by mutations in the DUX4 gene, which is normally active only in early development and is then “turned off” in most cell types. As a result of mutations, the gene becomes abnormally active and DUX4 protein is produced in cells where it wouldn’t normally be found. When the protein accumulates to toxic levels in muscle cells, it causes fat infiltration and muscle weakness that mainly affect the face, shoulders, and upper arms, the hallmark symptoms of FSHD.
The disease is divided into two types, FSHD type 1 (FSHD1) and type 2 (FSHD2) depending on the mechanisms that cause the abnormal production of DUX4. There are no approved medications to treat any FSHD type.
REACH study fails to show significant gains
Losmapimod is a small molecule that blocks the activity of certain enzymes that help regulate DUX4, thereby reducing toxic DUX4 production and preventing muscle damage.
In the ReDUX4 trial, which tested a year of twice-daily losmapimod in 80 adults with FSHD1, the treatment failed to meet the main goal of reducing DUX4 gene activity. It did result in slower disease progression, as measured by the amount of fat infiltration into muscles, and in gains in reachable workspace, a measure of upper arm function that assesses the area a person can reach.
The benefits continued to be observed at two years among patients who joined an open-label extension study (NCT04264442), where all received losmapimod for as long as five years.
The REACH trial (NCT05397470) was designed to confirm losmapimod’s benefits in a larger population. It enrolled 260 adults with FSHD1 or FSHD2 across the U.S., Canada, and Europe, and its participants were randomly assigned to losmapimod (15 mg twice daily) or a placebo for 48 weeks, after which all could enter the open-label extension phase and receive losmapimod several more years.
The main goal was to assess improvements in reachable workspace, which was measured by changes in the relative surface area (RSA). Data showed RSA improved by 0.013 points in losmapimod-treated patients and by 0.010 points in the placebo group, failing to meet that goal.
No significant differences were observed in other secondary measures, including muscle fat infiltration, shoulder abductor strength, or patient-reported outcomes. In most measures, gains were seen in both groups, but tended to be slightly better with losmapimod.
“In contrast to what was seen in the ReDUX4 study as well as what has been reported in other FSHD studies, the patients receiving placebo in REACH did not show a decline in functional status … over the 48 weeks of the study,” Pat Horn, MD, Fulcrum’s chief medical officer, said.
Losmapimod’s safety profile was consistent with past studies, with no treatment-related serious adverse events. The company plans to present full data from the trial at an upcoming meeting.
“As the largest interventional study ever completed in FSHD, we intend to share the full trial results with patients, study investigators, and the broader FSHD community to ensure others developing treatments for FSHD can benefit from these data,” Horn said.
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