Background
Cytokinetics is a company that was founded in 1997 to develop treatments targeting impairments in muscle function.
Cytokinetics has recently tested reldesemtiv after previously working on their initial ALS drug tirasemtiv. Tirasemtiv showed promising results in a Phase 2 clinical trial (BENEFIT-ALS) in 2014, and was followed by a phase 3 clinical trial (VITALITY-ALS) that failed to show any significant positive effects on the disease. One of the key problems with tirasemtiv was tolerability. Despite targeting muscle, it also entered the brain and caused nausea, dizziness and other symptoms that were considered safe, but not particularly tolerable, as it caused participants to drop out of trials, thereby reducing the statistical power needed to determine any benefit.
Prior to the completion of the phase 3 trial, Cytokinetics also conducted a phase 2 trial of reldesemtiv, which had all the muscle benefits of tirasemtiv, but without the ability to cross the blood-brain barrier into the central nervous system and cause the unwanted side effects of dizziness and nausea. This was a large phase 2 clinical trial (over 400 participants) that had vastly improved tolerance but did not meet it’s goals of showing statistically significant slowing of breathing capacity, disease progression rate or muscle strength. However, as the dosing was only for 12 weeks and the trends were in the direction of a positive result, the interpretation was not necessarily that of a failed trial, but rather one that would need further testing to determine if reldesemtiv has value for treating ALS.
Cytokinetics commenced a phase 3 clinical trial in 2021, called Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation of ALS (COURAGE-ALS), with a goal of enrolling 555 participants at sites across multiple countries. The trial included two planned unblinded interim analyses conducted by the Data Monitoring Committee. The first interim analysis assessed for futility, 12 weeks after approximately one-third or more of the planned sample size were randomized. The second interim analysis assessed for futility with the option for a fixed increase in total enrollment, if it had been deemed necessary, to augment the statistical power of the trial.
At the first interim analysis in October 2022, the DMC reviewed unblinded data from COURAGE-ALS and recommended that conduct of the clinical trial of reldesemtiv continue. However, following the 2nd interim review in March 2023, the DMC reviewed further accumulated unblinded data from COURAGE-ALS and recommended the discontinuation of the clinical trial due to futility. This was due to it finding no evidence of effect in patients treated with reldesemtiv relative to placebo on the primary endpoint of change from baseline to 24 weeks in ALSFRS-R or in key secondary endpoints. In addition, Cytokinetics plans to discontinue treatment with reldesemtiv in all patients including those in the open-label extension study, COURAGE-ALS OLE.
Although a negative outcome, Cytokinetics should be commended for their strong study design incorporating these interim reviews which curtailed the unnecessary burden for participants in continuing on an ineffective treatment or placebo.
We sincerely thank Cytokinetics for their commitment to trying to bring new treatments to the MND/ALS community. During their involvement in developing new MND/ALS treatments Cytokinetics have been a fantastic supporter of the community.
Recommendation
The failure of the COURAGE-ALS trial has demonstrated that reldesemtiv will not be an effective therapy for MND/ALS.
International Alliance of ALS/MND Associations
April 2023
The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.