COURAGE-ALS trial stopping after reldesemtiv fails to show benefits

Analysis at 24 weeks finds no substantive gains in treated ALS patients

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Cytokinetics announced that it is stopping COURAGE-ALS, a Phase 3 trial investigating oral reldesemtiv in treating people with amyotrophic lateral sclerosis (ALS), due to a lack of efficacy compared with a placebo.

In a review of unblinded interim trial findings at a second planned data monitoring committee meeting, reldesemtiv showed no evidence of being able to slow disease progression, as assessed with the ALS Functional Rating Scale-Revised (ALSFRS-R). As such, it failed to meet the study’s main goal. Other key measures of efficacy also were not met.

Following the analysis, committee members said that COURAGE-ALS met the criteria for futility, meaning the likelihood of reldesemtiv achieving trial goals was poor, and they recommended it stop.

“We are extremely disappointed with this outcome and would like to thank the people with ALS, caregivers, investigators and clinical trial staff for their participation in COURAGE-ALS,” Robert Blum, Cytokinetics’ CEO and president, said in a company press release.

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Reldesemtiv was intended to slow the progressive muscle weakness of ALS

“Cytokinetics has been committed to the ALS community for more than a decade and recognizes the urgency to bring new potential medicines to the forefront for this grievous disease,” Blum said.

Reldesemtiv is designed to activate troponin, a protein in fast-twitch muscle fibers required for brief and high-intensity physical activity requiring strength, such as sprinting.

Troponin activation is thought to increase the ability of muscles to respond to weak nerve signals, potentially slowing the progressive muscle weakness that marks ALS and other neuromuscular diseases.

COURAGE-ALS (NCT04944784) planned to evaluate reldesemtiv in up to 555 adults with ALS. Eligible participants were those whose symptoms began within the last two years and showed moderate-to-fast disease progression.

Eligibility was chosen based on data from the Phase 2 FORTITUDE-ALS trial (NCT03160898). Despite not reaching its overall efficacy goal, trial results showed a potential for benefit in patients with shorter disease duration and moderate-to-fast progression.

People enrolled in COURAGE-ALS were randomly assigned to either twice-daily oral reldesemtiv or a matched placebo for 24 weeks (about six months). After that, all were to receive the therapy for another 24 weeks.

The trial’s main goal was to determine if reldesemtiv could slow disability progression as assessed by ALSFRS-R scores after the first 24-week period. Secondary measures included changes in lung function, muscle strength, and quality of life, as well as a combined measure of changes in functional status, time to respiratory problems, and death.

After completing 48 weeks in COURAGE-ALS, patients were being invited to join COURAGE OLE (NCT05442775), an open-label extension study where all would continue with reldesemtiv twice daily for another 48 weeks (about one year). About 400 people were expected to enroll.

A first interim analysis of COURAGE-ALS took place about 12 weeks after at least one-third of its intended number of patients were either on treatment or a placebo. The data monitoring committee then recommended the trial continue as planned.

The second interim analysis was conducted at 24 weeks, with about 460 patients enrolled and randomized, and more than 200 having reached the 24-week assessment point. The goal was to assess for futility and provide guidance for a potential increase in target enrollment.

Interim trial data met the criteria for futility due to a lack of changes in ALSFRS-R or key secondary outcomes after 24 weeks of treatment compared with a placebo, the committee decided.

Cytokinetics then announced that it is stopping the trial before its planned conclusion, and all patients in COURAGE-ALS and its open-label extension will discontinue treatment with reldesemtiv.

Investigators involved in the COURAGE-ALS study, as well as regulatory agencies, will be notified of the futility finding, the company added. Trial data is currently being analyzed, and details will be presented at an upcoming meeting.

“In the coming months, we will assess next steps relating to our neuromuscular development programs,” Blum said.