Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis

Abstract

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

Key words::

• Amyotrophic lateral sclerosis
• clinical trials
• muscle
• riluzole
• pharmacokinetics

Acknowledgements

The authors wish to thank ACI for copyediting assistance. This study was sponsored by Cytokinetics, Inc. South San Francisco, CA.

Declaration of interest: Jeremy Shefner serves as a consultant for Cytokinetics, Glaxo-SmithKline, Trophos and Biogenidec; he receives or has received research support from Teva Pharmaceuticals, Neurostem, Isis Pharmaceuticals, Cytokinetics, Glaxo SmithKline, Biogen-Idec, Knopp Pharmaceuticals, Sanofi-Aventis, NIH and the ALS Association. He is the neuromuscular section editor for UpToDate, and receives royalties for his services.

Merit E. Cudkowicz has served as a consultant to Cytokinetics and to Trophos; she has received research support from Biogen-Idec, Cytokinetics, Trophos, INDS and the ALS Association. Nicholas Maragakis has been a scientific advisor to Q Therapeutics (2009–2011), serves as a consultant to Johnson & Johnson, Inc. and has received research support from NINDS, the US Department of Defense, and Cytokinetics, Inc. He receives royalties from UpToDate-AmyotrophicLateralSclerosis.

Jesse Cedarbaum, Jacqueline Lee, Drew Jones, Michael Chen, John Mao, Fady Malik, and Andrew Wolf are employees of Cytokinetics, Inc. Khalil Saikali, Alan Russell and Richard Hansen at the time of the conduct of this study were employees of Cytokinetics, Inc.

NEALS/Cytokinetics Study Team Coinvestigators: Nazem Atassi, Massachusetts General Hospital; Richard Bedlack, Duke University; Kevin Boylan, Mayo Clinic Florida; Deborah Bradshaw, SUNY Upstate Med University; Kimberly Goslin, Providence ALS Center; Terry Heiman Patterson, Drexel University College of Medicine; Carlayne Jackson, University of Texas Health Science Center; Edward J. Kasarskis, University of Kentucky; Jonathan Katz, California Pacific Medical Center; Todd Levine, Phoenix Neurological Associates; Nicholas J. Maragakis, Johns Hopkins University; Alan Pestronk, Washington University; Zachary Simmons, Penn State University