Lessons from final losmapimod trial data help inform future studies
Findings from Phase 2 trial offer insights into best outcome measures
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Findings from a Phase 2 trial testing losmapimod in adults with facioscapulohumeral muscular dystrophy (FSHD) have offered new insights into the best outcome measures for future clinical trials, according to final published data from the clinical study, which wrapped up in 2021.
The Fulcrum Therapeutics treatment, as previously reported, did not significantly reduce signs of DUX4 activity — the underlying driver of muscle weakness in the disease — but showed other signs of clinically meaningful benefit in the Phase 2 ReDUX4 trial (NCT04003974).
According to the researchers, the final data also showcase other lessons learned.
“ReDUX4 has increased understanding of the usefulness of biomarkers and identified relevant clinical outcome assessments that were sensitive to treatment for facioscapulohumeral muscular dystrophy,” the researchers wrote.
The study, sponsored by Fulcrum and titled “Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial,” was published in The Lancet Neurology.
“The publication of these results, which informed the design and choice of efficacy endpoints in our Phase 3 clinical trial, also provide important validation for the therapeutic potential of losmapimod,” Patrick Horn, MD, PhD, Fulcrum’s chief medical officer, said in a company press release.
Losmapimod now being tested in Phase 3 clinical trial
In a commentary accompanying the publication, Nicol Voermans, MD, PhD, of Radboud University Medical Center, in the Netherlands, and John Vissing, MD, of the University of Copenhagen, in Denmark — both investigators in Fulcrum trials in FSHD — noted that earlier studies did not address the genetic causes of the disease or how that affects the testing of potential treatments.
“[This] trial has provided important lessons for upcoming trials,” the duo wrote.
Particularly, the data “challenged the use of changes in DUX4 expression as an endpoint,” the scientists wrote, noting that MRI measures looking at fat infiltration in selected muscle groups and other functional assessments — where benefits were seen in the Phase 2 study — might instead be better indicators of therapeutic effect.
Indeed, DUX4 activity won’t be one of the outcome measures in the now fully enrolled and ongoing Phase 3 REACH trial (NCT05397470), which is designed to confirm losmapimod’s safety and effectiveness in adults with FSHD types 1 and 2. The trial instead favors indicators of functional gains as its primary efficacy goal.
[This] trial has provided important lessons for upcoming trials.
FSHD is a form of muscular dystrophy in which progressively advancing muscle weakness and wasting lead to worsening disability and a loss of daily independence.
The condition is caused by the overactivity of DUX4, a protein involved in activating other genes. While the gene encoding DUX4 is normally suppressed after early development, FSHD-causing mutations allow it to remain active. Thus, DUX4 and the genes it influences become too active, which is toxic to muscles.
No disease-modifying therapies — treatments targeting a disease’s underlying cause — have been approved to date for the rare progressive disease.
Losmapimod targets DUX4 activity underlying muscle weakness in FSHD
Losmapimod is an oral small molecule that selectively blocks two enzymes, p38 alpha and p38 beta, that are involved in regulating DUX4. Essentially, it aims to lower DUX4’s activation and prevent subsequent muscle damage.
ReDUX4 enrolled 80 adults, ages 18-65, with FSHD type 1 who were randomly assigned to receive oral losmapimod (15 mg) or a placebo twice daily for about a year.
Its main goal was to indirectly look at DUX4’s activity in muscle tissue by measuring the composite activity of genes it activates. As previously reported, neither losmapimod nor the placebo was associated with any notable changes in DUX4 activity during the trial, contrasting with earlier preclinical data.
Likewise, there were no observed changes in prespecified patient subgroups, divided based on DUX4-driven gene activity before treatment.
The researchers emphasized that there was high variability in DUX4-associated gene activity at both the start and end of the trial. Fulcrum has previously indicated that this could have precluded the ability to see a meaningful treatment effect.
Losmapimod was, however, associated with smaller increases in fat infiltration into certain muscles relative to the placebo, as assessed by MRI scans, which was a secondary trial goal.
Relative to placebo-treated patients, those given losmapimod showed improvements in shoulder function, as assessed by the reachable workspace (RWS) test. RWS measures arm and hand range of motion and is believed to reflect a person’s ability to perform daily activities independently.
In patient-reported outcome measures, more patients on the investigational therapy (20%) indicated that they experienced significant improvements as compared with those on the placebo (5%). In addition, fewer individuals on the therapy versus the placebo reported experiencing disease worsening (23% vs. 30%).
The therapy was generally well tolerated, with most adverse events being mild or moderate in severity. No serious adverse events were deemed related to treatment.
“For the first time, an interventional drug has been associated with potential improvements in structural, functional, and participant-reported disease modification outcomes in [FSHD],” the researchers wrote.
Despite these promising signals, the researchers emphasized that the findings “need to be interpreted with caution,” given the fact that the trial was not formally designed to look at efficacy in secondary and exploratory outcomes.
Extension study still tracking patients treated in ReDUX4 trial
As the REACH trial seeks to confirm these findings, most ReDUX4 participants have meanwhile entered into an ongoing open-label extension study (NCT04264442) in which all are receiving daily losmapimod for as long as five years. The findings of that study will offer additional data about the therapy candidate’s long-term benefits.
Interim data reported last year showed that upper limb function was generally preserved among patients who had been taking losmapimod since the beginning of ReDUX4, and stabilized or slightly improved among patients who switched over from the placebo.
“Looking ahead, we remain on track to report topline data for REACH in the fourth quarter of 2024, which will bring us one step closer to addressing the high unmet needs of the FSHD patient community,” Horn said.
Earlier this month, Fulcrum announced that it has granted Sanofi exclusive rights to market losmapimod outside the U.S., according to a separate press release.
“This deal aligns with our core strategy, allowing Fulcrum to remain focused on preparations for commercialization of losmapimod in the U.S., while leveraging Sanofi’s exceptional global commercial capabilities and established infrastructure in key markets around the world,” said Alex C. Sapir, Fulcrum’s president and CEO.
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