SOUTH SAN FRANCISCO, Calif., and TOKYO, Oct. 5, 2018 – Cytokinetics, Incorporated (Nasdaq: CYTK, “Cytokinetics”) and Astellas Pharma Inc. (TSE: 4503, “Astellas”) today provided an update for their collaborative skeletal muscle program, including clinical trial updates for reldesemtiv in neuromuscular and non-neuromuscular conditions. In addition to reldesemtiv, the companies are advancing another fast skeletal muscle troponin activator (FSTA) into Investigational New Drug (IND)-enabling studies and continuing their joint research program through 2019. Cytokinetics has been developing reldesemtiv as a potential treatment for people with Spinal Muscular Atrophy (SMA), Amyotrophic Lateral Sclerosis (ALS), and other debilitating neuromuscular diseases and conditions associated with skeletal muscle weakness and/or fatigue. In parallel, Astellas has been conducting non-neuromuscular clinical trials with reldesemtiv to investigate a potential path forward for a next generation FSTA in patients with Chronic Obstructive Pulmonary Disease (COPD) and Frailty. Cytokinetics and Astellas are also conducting joint research to discover and advance additional small molecule activators of skeletal muscle, which may be developed as drug candidates for a broad array of diseases associated with skeletal muscle weakness and fatigue.
Spinal Muscular Atrophy (SMA)
- In June, Cytokinetics announced data from a Phase 2 double-blind, randomized, placebo-controlled clinical study in patients with SMA which was designed to determine potential pharmacodynamic effects of a suspension formulation of reldesemtiv following 8 weeks of oral dosing in each of two cohorts of 36 patients with Type II, Type III, or Type IV disease. Secondary objectives were to evaluate the safety, tolerability and pharmacokinetics of reldesemtiv. The study showed statistically significant concentration-dependent increases in changes from baseline in Six Minute Walk Distance (6MWD), a sub-maximal exercise test of aerobic capacity and endurance. The study also showed statistically significant increases for Maximal Expiratory Pressure (MEP), a measure of strength of respiratory muscles. Other assessments, including the Hammersmith Functional Motor Score - Extended, (a functional motor scale that was assessed in the development program that led to the FDA approval of the first therapy for patients with SMA), Revised Upper Limb Module, Timed Up-and-Go, Forced Vital Capacity, and the SMA Health Index (SMA-HI), a patient reported outcome measure (PROM) developed to comply with FDA standards for PROMs, did not demonstrate differences between reldesemtiv versus placebo. Adverse events were similar between groups receiving reldesemtiv and placebo.
- Additional results presented at the 2018 Muscle Study Group Scientific Meeting in Oxford, U.K., showed sustained increases in 6MWD and MEP four weeks after discontinuation of study drug (i.e., Follow-up). The mean increase versus placebo in the change from baseline in 6MWD on 450 mg twice daily was 24.89 m after 8 weeks of treatment (p = 0.0584) and 30.81 m at Follow-up (p = 0.0381). Similarly, the mean increase versus placebo in the change from baseline in MEP on 450 mg twice daily was 13.15 cm H2O after 8 weeks of treatment (p = 0.0298) and 9.47 cm H2O at Follow-up (p = 0.1344).
- A post-hoc analysis also showed that changes from baseline in the 6MWD at 450 mg twice daily were significantly correlated with changes from baseline on certain domains of the SMA-HI intended to reflect improved endurance, especially Fatigue (correlation coefficient [r] = -0.90, p = 0.01) and Activity Participation (r = -0.82, p = 0.05). Of note, decreases in SMA-HI scores reflect reduced disease burden as measured by that PROM; therefore, the negative correlation coefficients indicate that as 6MWD increases, disease burden assessed by that domain of the SMA-HI is reduced.
- Cytokinetics recently convened an expert advisor meeting to discuss the Phase 2 clinical study of reldesemtiv in patients with SMA and received encouraging and constructive feedback as well as recommendations to inform potential next steps.
- Cytokinetics will be seeking a Type C regulatory interaction with the FDA this year regarding the acceptability of 6MWD as an endpoint for a potential registration program for reldesemtiv in patients with SMA.
Amyotrophic Lateral Sclerosis (ALS)
- Cytokinetics is conducting FORTITUDE-ALS (Functional Outcomes in a Randomized Trial of Investigational Treatment with CK-2127107 to Understand Decline in Endpoints – in ALS) which is expected to enroll 445 patients with ALS and is designed to assess the change from baseline on reldesemtiv versus placebo in the percent predicted slow vital capacity (SVC) and other measures of skeletal muscle function after 12 weeks of treatment. Secondary endpoints include the slope of the change from baseline in the mega-score of muscle strength measured by hand held dynamometry (HHD) and handgrip dynamometry; change from baseline in the ALS Functional Rating Scale – Revised (ALSFRS-R); incidence and severity of treatment-emergent adverse events; and plasma concentrations of reldesemtiv at sampled time points in the trial.
- This trial has now enrolled more than 350 patients with ALS and enrollment is expected to be completed in Q4 2018 with results from the clinical trial expected in the first half of 2019.
Chronic Obstructive Pulmonary Disease (COPD)
- Astellas recently completed a Phase 2 clinical trial designed to assess the potential effect of reldesemtiv compared to placebo on exercise tolerance, assessed as change from baseline in Constant Work Rate (CWR) endurance time over two weeks, in approximately 40 patients with COPD. Additionally, the trial assessed other cardiopulmonary and neuromuscular effects and resting spirometry. In addition, the safety, tolerability and pharmacokinetics of reldesemtiv were assessed.
- This trial of reldesemtiv did not meet the primary endpoint and did not demonstrate a statistically significant treatment difference in any of the secondary endpoints. Adverse events were similar between groups receiving reldesemtiv and placebo.
- Astellas has been conducting a Phase 1b clinical trial designed to assess the effect of reldesemtiv versus placebo on skeletal muscle fatigue in approximately 60 subjects who are 70 to 89 years of age and who have limited mobility. Endpoints measured include the change from baseline versus 14 days of treatment in sum of peak torque during isokinetic knee extensions. Additionally, the trial is designed to assess the effects of reldesemtiv on physical performance as well as the safety, tolerability and pharmacokinetics of reldesemtiv.
- An interim analysis of this study was recently conducted, and the Independent Data Monitoring Committee determined that the pre-defined criteria for lack of efficacy of reldesemtiv had been met; Astellas has notified investigators to halt further enrollment in the trial.
Other Research & Development
As recently announced, Cytokinetics and Astellas are advancing a next-generation FSTA into IND-enabling studies, which triggers a $2 million milestone payment from Astellas to Cytokinetics. This potential drug candidate was designed to have different physicochemical properties than reldesemtiv and may be developed for the treatment of diseases and conditions associated with non-neuromuscular etiology and pathogenesis. The companies are also continuing their joint research program with Astellas providing sponsorship of Cytokinetics’ activities through 2019.