FDA Provides Feedback for Reldesemtiv Clinical Trial End Points in SMA

Fady I. Malik, MD, PhD

The FDA has informed Cytokinetics that the use of the 6-minute walk test (6MWT) will be acceptable as a primary efficacy end point for a potential registration program of reldesemtiv, its fast skeletal muscle troponin activator (FSTA) being tested in patients with spinal muscular atrophy (SMA) with maintained ambulatory function.¹

The agency additionally recommended the addition of a global function scale as a secondary efficacy end point, such as the Hammersmith Functional Motor Scale-Expanded (HFMSE), to the program. Cytokinetics is currently in the process of discussing the next steps for the ongoing development of the treatment with its collaborator, Astellas.

Recently, phase 2 results of a clinical trial of reldesemtiv (also known as CK-2127107) in 70 patients with SMA showed a significant exposure-response relationship in 6-minute walk distance (6MWD) changes from baseline. This measurement was “a sub-maximal exercise test of aerobic capacity and endurance,” according to Cytokinetics. Additionally, there were significant increases in maximal expiratory pressure (MEP), though no differences between the treatment and placebo were seen in other assessments, including the HFMSE.

Thus far, there have been 5 phase 1 clinical trials of the treatment in healthy volunteers, which explored its safety, tolerability, bioavailability, pharmacokinetics, and pharmacodynamics. According to the company, another phase 1 study is planned for the FSTA treatment in healthy volunteers, with the intention of exploring if the higher doses evaluated in the phase 2 trial result in higher plasma concentrations. Cytokinetics expects this trial to begin in the first quarter of 2019.

Astellas conducted a phase 1b clinical trial to assess the effect of reldesemtiv on skeletal muscle fatigue in approximately 60 patients between 70 and 89 years of age with have limited mobility.² In October 2018, Astellas announced along with Cytokinetics that the Independent Data Monitoring Committee determined that the pre-defined criteria for lack of efficacy of reldesemtiv had been met, and enrollment was halted after the interim analysis.

Additionally, patient enrollment for the FORTITUDE-ALS trial (NCT03160898), a phase 2 assessment of the therapy’s effect on respiratory function and skeletal muscle function in amyotrophic lateral sclerosis (ALS), has been completed. That trial will feature 445 patients randomized to either placebo or 1 of 3 doses (300 mg, 600 mg, or 900 mg) of reldesemtiv for 12 weeks, with the change from baseline in the percent predicted slow vital capacity (SVC) as the primary outcome measure. That trial is expected to be completed in March.

Fady I. Malik, MD, PhD, Cytokinetics’ executive vice president of Research & Development said in July 2017, at the time FORTITUDE-ALS was announced, that undertaking the trial “reflects our increased commitment to explore the potential of our muscle-biology directed investigational therapies for the potential treatment of people with ALS.”³

“Under our collaboration with Astellas, we look forward to now exploring the potential of this next-generation FSTA in a fourth patient population in which it may alter the decline of muscle function and performance,” Malik added. This clinical trial offers an opportunity to assess exploratory measures of patient function that may also prove informative in further quantifying ALS disease progression.”

As well, reldesemtiv was the subject of a phase 2 trial in approximately 40 patients with chronic obstructive pulmonary disease (COPD). That trial assessed its effect compared to placebo on exercise tolerance, defined as the change from baseline in Constant Work Rate endurance time over a 2-week period. In October 2018, Cytokinetics and Astellas announced that the trial did not meet the primary end point, nor did it demonstrate a statistically significant treatment difference in any of secondary outcome measures. The adverse events between groups receiving reldesemtiv and placebo were similar.

REFERENCES

1. Cytokinetics Announces Receipt of FDA Feedback Regarding Reldesemtiv in Patients With SMA [press release]. South San Francisco, CA: Cytokinetics Inc; Published January 22, 2019. globenewswire.com/news-release/2019/01/22/1703290/0/en/Cytokinetics-Announces-Receipt-of-FDA-Feedback-Regarding-Reldesemtiv-in-Patients-With-SMA.html. Accessed January 22, 2019.

2. Reldesemtiv. Cytokinetics website. cytokinetics.com/reldesemtiv. Accessed January 22, 2019.

3. Cytokinetics Announces Start of FORTITUDE-ALS, a Phase 2 Clinical Trial of CK-2127107 in Patients with Amyotrophic Lateral Sclerosis [press release]. South San Francisco, CA: Cytokinetics Inc; Published July 27, 2017. ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-start-fortitude-als-phase-2-clinical. Accessed January 22, 2019.