Phase III Failure Leaves Cytokinetics with One Last Late-Stage Hopeful

Pictured: FDA Headquarters/Courtesy of Getty Images

Cytokinetics is discontinuing the Phase III COURAGE-ALS trial in amyotrophic lateral sclerosis (ALS) after its candidate, reldesemtiv, failed a planned interim analysis, the company announced Friday.

This decision comes after a Data Monitoring Committee reviewed unblinded data from COURAGE-ALS and found that reldesemtiv could not significantly improve disease severity, as measured by the ALSFRS-R scale, compared with placebo. COURAGE-ALS met the criteria for futility, and the committee recommended its termination.

Cytokinetics will also stop all reldesemtiv dosing in the open-label extension phase of COURAGE-ALS.

The Data Monitoring Committee also found no benefit associated with reldesemtiv in key secondary endpoints.

At the time of the scheduled interim analysis of about 460 COURAGE-ALS participants, more than 200 had reached the 24-week follow-up point. The interim analysis was meant to assess futility or provide for a potential increase in enrollment to boost the study’s statistical power.

Reldesemtiv is a small molecule candidate that slows the rate at which calcium is released from the regulatory troponin complex in fast skeletal muscle fibers. In turn, this mechanism of action allows reldesemtiv to sensitize sarcomeres to calcium and improve muscle contractility.

Down to the Last Candidate

Previously, the candidate failed its Phase II FORTITUDE-ALS study in May 2019 after it showed no significant effect on slow vital capacity after 12 weeks of treatment.

Despite these results, Cytokinetics drew out some positive signals of efficacy from a post hoc analysis of the data. After consulting with the FDA, the company decided to push through with a Phase III study of reldesemtiv, Robert Blum, president and CEO, Cytokinetics, told BioSpace in an email.

Friday’s Phase III data is only the latest setback for Cytokinetics.

In March, the FDA rejected the New Drug Application for omecamtiv mecarbil, the company’s candidate for heart failure, citing the lack of evidence to establish its clinical benefit. In its Complete Response Letter, the regulator noted the need for another trial to confirm that omecamtiv mecarbil’s benefits outweigh its risks.

The FDA’s rejection comes after a December 2022 meeting of the Cardiovascular and Renal Drugs Advisory Committee, where the panel voted 8-3 against the heart failure hopeful.

Cytokinetics is now down to its last late-stage candidate, aficamten, a small molecule myosin inhibitor being studied for hypertrophic cardiomyopathy (HCM). Aficamten works by disrupting the action of myosin, thereby preventing the heart muscle thickening and hypercontractility associated with HCM.

This mechanism of action will be tested in the Phase III SEQUOIA-HCM study, which kicked off in February 2022 and was undergoing site activation in November 2022. Results from this study are expected in the fourth quarter of 2023, and the company and the company expect to bat for approval by the first half of 2024, Blum said.

Cytokinetics is also looking to begin two more Phase III trials for aficamten this year, Blum said.

The candidate cleared Phase II and showed it could significantly cut the average resting left ventricular outflow tract pressure gradient in the REDWOOD-HCM study. The FDA gave aficamten its Breakthrough Therapy designation in December 2021.