Analyses Support Design of COURAGE-ALS Trial of Reldesemtiv
Cytokinetic presents data at the Virtual 33rd International Symposium on ALS/MND
The COURAGE-ALS Phase 3 clinical trial, testing Cytokinetic’s experimental therapy reldesemtiv in people with amyotrophic lateral sclerosis (ALS), is expected to enroll patients who are most likely to benefit from the potential treatment.
That’s according to a new analysis of data from an earlier Phase 2 study of reldesemtiv called FORTITUDE-ALS. Cytokinetic presented the analysis at the Virtual 33rd International Symposium on ALS/MND.
“We look forward to continuing the conduct of COURAGE-ALS and completing patient enrollment in the first half of 2023,” Fady Malik, MD, PhD, executive vice president of research and development at Cytokinetics, said in a press release.
Reldesemtiv is an orally available small molecule designed to increase a muscle’s ability to respond to weak nerve signals. It works by activating the troponin protein in fast-twitch skeletal muscle fibers, which mediate quick, powerful movements like sprinting and blinking the eyes.
The FORTITUDE-ALS trial (NCT03160898) enrolled more than 450 people with ALS, who were assigned randomly to take either reldesemtiv or a placebo for 12 weeks. The study’s main goal was to assess the impact of treatment on lung function and a key secondary goal was to determine changes in disease progression, as measured with the ALS Functional Rating Scale Revised (ALSFRS-R).
Although some promising trends were seen in these measures, they did not reach statistical significance, meaning the study failed to meet its efficacy goals.
In post hoc analyses — studies designed and carried out after the trial was already completed and data were unblinded — researchers divided the participants in this Phase 2 trial into three groups based on the rate of ALSFRS-R progression: fast, intermediate, and slow. These analyses indicated that patients with fast or intermediate progression experienced the most benefit from reldesemtiv treatment.
Notably, almost all patients in these two groups had been experiencing symptoms for a total of 24 months or less, and all had a starting ALSFRS-R score of 44 or less. These are referred to as the 24/44 criteria.
In the new analysis, researchers looked at predicted survival outcomes in FORTITUDE-ALS using the ENCALS survival model, a statistical model that predicts ALS survival based on factors including age at onset, lung function, diagnostic delay, genetic data, and total ALSFRS-R decline. Based on their ENCALS score, participants were divided into five groups based on predicted survival: very short, short, intermediate, long, and very long.
Results showed that participants who met the 24/44 criteria were more likely to have predicted survival that was very short, short, or intermediate. Conversely, patients not meeting these criteria were more likely to have long or very long predicted survival.
Understanding disease progression
“This analysis from FORTITUDE-ALS helps to build our understanding of disease progression in ALS, which is complex and heterogenous, and is an important element in the conduct of clinical research and the design of our clinical trials,” Malik said.
Cytokinetics is now running a Phase 3 trial called COURAGE-ALS (NCT04944784) that aims to test reldesemtiv against placebo in 555 ALS patients. The trial is recruiting participants at more than 80 locations in North America, Europe, and Australia.
Notably, one of the enrollment requirements for the study is that participants meet the 24/44 criteria. As such, the new analysis from FORTIDUE-ALS “suggests the inclusion criteria we selected for the ongoing Phase 3 trial, COURAGE-ALS, may have the intended outcome of enrolling patients most likely to benefit from the investigational therapy,” Malik said.
“Given the urgent need to deliver new therapies for people with ALS, it’s essential that clinical trials are designed with rigor to enhance the sensitivity of detecting a potential treatment effect,” Malik added.
Cytokinetic recently announced the completion of the first planned interim analysis from COURAGE-ALS. This analysis by an independent monitoring committee assessed “futility” — checking the data collected so far to ensure there’s still a reasonable chance the trial will hit its main goal of slowing decline on ALSFRS-R. The committee recommended the trial continue as planned.
A second interim analysis, which also will check for futility and will assess whether the number of participants in the trial should be adjusted, is planned.
After completing COURAGE, participants will be able to enter its open-label extension study called COURAGE OLE (NCT05442775), wherein all will be given the experimental therapy for one year. A compassionate use program then will allow these patients to continue treatment ahead of reldesemtiv’s regulatory approval.