The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS

Abstract

Tirasemtiv is a fast skeletal muscle activator that increases efficiency of muscle contraction. Both single and repeated dose studies suggested beneficial effects on measures of function, muscle strength and endurance. As the outcomes measured were identical in previous studies and the duration of all studies was 21 days or less, we pooled data from all studies and assessed the relationship between outcomes and plasma tirasemtiv concentration to assess consistency of observations as well as to increase sensitivity. We pooled data for ALSFRS-R, three pulmonary function measures, quantitative muscle strength, and submaximal handgrip endurance. Up to 855 values from 143 patients were plotted against tirasemtiv concentrations. Linear associations between tirasemtiv concentrations and changes from baseline of clinical measures were estimated using a repeated-measures mixed model. Trends toward improvement were noted in all measures except for vital capacity, despite the fact that time was not included as a factor so that any time-related decline acted to reduce the magnitude of any noted trend. In conclusion, tirasemtiv appears to have concentration-dependent beneficial effects on both function and measures of strength and endurance when administered for up to 21 days, even when time is eliminated as a cofactor. These findings further support the development of this agent in ALS.

Key words::

• Clinical trials
• therapy
• muscle activation

Declaration of interest: Jeremy Shefner has received compensation as a consultant for Cytokinetics. L. Meng and A. A. Wolff are employees of Cytokinetics. The authors alone are responsible for the writing of the paper and interpretation of data. The authors gratefully acknowledge the participation of the following clinical study sites, who participated in the studies from which the data in this paper was generated:

Mary Lou Watson, RRT, Deborah Bradshaw, MD, Upstate Medical University, Syracuse, NY; Richard Barohn MD, University of Kansas, Kansas City, KS; Kevin Boylan, MD, Mayo Clinic, Jacksonville, FL; Benjamin Brooks, MD, Carolinas Medical Center, Charlotte, NC; Terry Heiman-Patterson, MD, Drexel University, Philadelphia, PA; Jonathan Katz, MD, California Pacific Medical Center, San Francisco, CA, Nicholas Maragakis, MD, Johns Hopkins University, Baltimore, MD; Hiroshi Mitsumoto, MD, Columbia University, New York, NY; Zachary Simmons, MD, Penn State University, Hershey, PA; Richard Bedlack, MD, Duke University, Durham, NC; James Berry, MD, Nazem Atassi, MD, Massachusetts General Hospital, Boston, MA; Kimberly Goslin, Providence ALS Center, Portland, OR; Carlayne Jackson, University of Texas, San Antonio, TX; John Kissel, MD, Ohio State University, Columbus Ohio: Dale Lange, MD, Hospital for Special Surgery, New York, NY; Jonathan Licht, Coordinated Clinical Research, La Jolla, CA; Tahseen Mozaffar, MD, University of California, Irvine, CA; Kevin Boylan, MD, Mayo Clinic Florida; Edward J. Kasarskis, MD, University of Kentucky; Todd Levine, MD, Phoenix Neurological Associates; Alan Pestronk, MD, Washington University Kara Burroughs, Cytokinetics, Inc; Karen Calloway, Esq, Cytokinetics, Inc; Jesse Cedarbaum, MD, Cytokinetics, Inc; Michael M. Chen, Cytokinetics, Inc; Garrett Collins, Cytokinetics, Inc; Erin Donnelly, Cytokinetics, Inc; Bradley Fugate, Cytokinetics, Inc; Jacqueline Lee, Cytokinetics, Inc; Jean Masonek, Cytokinetics, Inc; Mark O’Neill, Cytokinetics, Inc; Joe Serooge, Cytokinetics, Inc; Jun Zhang, Cytokinetics, Inc.