A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis

Abstract

Our objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo-controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirasemtiv, escalating to a maximum tolerated dose up to 250 mg b.i.d. The primary endpoint was the change from baseline in ALSFRS-R; secondary endpoints included SVC, maximum voluntary ventilation, sniff nasal inspiratory pressure, isometric muscle strength, and sub-maximum handgrip fatigue. Of 711 patients enrolled, 596 were randomized and received at least one dose of double-blind treatment. The primary endpoint showed no treatment effect (tirasemtiv: −2.98 ± 0.28, placebo: −2.40 ± 0.25, p = 0.114); however, SVC and muscle strength declined significantly more slowly on tirasemtiv (95% CI p = 0.0006, p = 0.0158, respectively). Dropouts and serious adverse events occurred more frequently in the tirasemtiv group. In conclusion, this was a negative study with respect to the primary endpoint; however, the effects on SVC and muscle strength suggest a potentially important effect of tirasemtiv warranting further evaluation over a longer period in ALS.

Key words:

• Clinical trial
• tirasemtiv
• troponin activator
• amyotrophic lateral sclerosis

Acknowledgments

We thank Xavier A. Figueroa, (Sciencia Incognita Consulting LLC), Julia R. Gage (Gage Medical Writing, LLC) for assistance with editing the manuscript.

Declaration of interest

J. M. Shefner reports personal fees and grants from Cytokinetics, Inc. during the conduct of the study; personal fees from Biogen-Idec, ISIS Pharmaceuticals, grants from GlaxoSmithKline, grants from NIH, ALS Association, grants from Muscular Dystrophy Association, and grants from ALS Therapy Alliance outside the submitted work.

Messrs. Wolff, Meng, Bian, Lee, Barragan, and Andrews are employees of Cytokinetics, Inc.