Reldesemtiv (formerly known as CK-2127107) reduces lung function decline and overall disease progression, without significant adverse events, in people with amyotrophic lateral sclerosis (ALS), a Phase 2 trial shows.
The study, however, did not meet its primary endpoint.
The new findings from the randomized, double-blind, placebo-controlled, Phase 2 FORTITUDE-ALS trial (NCT03160898) were presented by Jeremy Shefner, MD, PhD, the trial’s lead investigator, at the 2019 American Academy of Neurology (AAN) Annual Meeting, running through May 10 in Philadelphia.
Reldesemtiv is an investigational, next-generation fast skeletal muscle troponin activator (FSTA) developed by Cytokinetics in collaboration with Astellas. It was designed to ease muscle contraction with minimal nerve stimulation to slow the decline of muscle function associated with ALS.
The FORTITUDE-ALS trial assessed the effects of reldesemtiv on respiratory function and other muscle function parameters in people with ALS. A total 458 patients, recruited from centers across the U.S., Canada, Europe, and Australia, were randomly assigned to receive either reldesemtiv (at a dose of 150, 300 or 450 mg) or a placebo, orally, twice a day, for 12 weeks.
The primary goal was to assess the change, from the trial’s start, in the percent predicted slow vital capacity (SVC), a standard measure of respiratory function, after 12 weeks of treatment.
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Researchers also evaluated changes from baseline in the ALS Functional Rating Scale Revised (ALSFRS-R), muscle strength, hand grip, plasma concentrations of reldesemtiv, and treatment-emergent adverse events (TEAEs) at Week 12.
All doses of reldesemtiv showed small improvements in the percent predicted SVC compared with placebo after 12 weeks of treatment. However, the results failed to reach statistical significance. Analyses of ALSFRS-R and overall muscle strength led to similar findings.
Although dose-response analyses in primary and secondary endpoints failed to reach statistical significance, the researchers said the study still showed “clinically meaningful” results.
In a post-hoc analysis in which data from all dosed patients was pooled together, patients treated with reldesemtiv showed a 27% reduction in the decline of SVC and a 25% reduction in the decline of ALSFRS-R compared with those treated with placebo.
Remarkably, these differences were still present at follow-up, four weeks after patients received the last dose of reldesemtiv, the researchers said.
“Results from FORTITUDE-ALS are among the most impressive we have seen in a Phase 2 clinical trial in ALS,” Shefner, the lead investigator, said in a press release.
“Especially noteworthy are the consistency and durability of effects observed across treatment arms on clinically meaningful endpoints,” said Shefner, also professor and chair of neurology at the Barrow Neurological Institute in Arizona, and professor and executive chair of neurology at the University of Arizona, Phoenix.
The incidence of treatment discontinuations, adverse events, and serious adverse events were identical in patients treated with reldesemtiv and in those treated with a placebo. The most common adverse events reported were fatigue, nausea and headache.
“While FORTITUDE-ALS did not meet the primary endpoint, we are encouraged by the results of the trial as they further validate the potential of skeletal muscle activation in treating patients battling ALS,” said Fady I. Malik, MD, PhD, executive vice president of research and development at Cytokinetics. “This Phase 2 trial of reldesemtiv demonstrated consistency of effect for doses, endpoints and timepoints and we believe the results support progression of reldesemtiv in further clinical trials toward potential registration.”