A Double-Blinded, Randomized, Placebo-Controlled Trial to Evaluate Efficacy, Safety, and Tolerability of Single Doses of Tirasemtiv in Patients with Acetylcholine Receptor-Binding Antibody-Positive Myasthenia Gravis

Donald B. Sanders, Jeffrey Rosenfeld, Mazen M. Dimachkie, Lisa Meng, Fady I. Malik, Jinsy Andrews, Richard Barohn, Andrea Corse, Anahita Deboo, Kevin Felice, Yadollah Harati, Terry Heiman-Patterson, James F. Howard, Carlayne Jackson, Vern Juel, Jonathan Katz, Jacqueline Lee, Janice Massey, April McVey, Tahseen MozaffarMamatha Pasnoor, George Small, Yuen So, Annabel K. Wang, David Weinberg, A. Andrew Wolff

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium and increases muscle force following subtetanic nerve input. In an animal model of myasthenia gravis (MG), single oral doses of tirasemtiv improved muscle force and reduced fatigability. The purpose of this study was to determine the effect of single doses of tirasemtiv on skeletal muscle function and fatigability in patients with generalized MG. Thirty-two patients with acetylcholine receptor-antibody positive MG and muscle weakness received single doses of tirasemtiv (250 mg or 500 mg) or placebo in a double-blind, randomized treatment sequence with each treatment separated by at least 1 week. Outcome measures included the Quantitative MG Score (QMG), MG Composite, Manual Muscle Testing, and forced vital capacity. At 6 h after dosing, tirasemtiv produced dose-related improvements from baseline in the QMG score (slope: –0.49 QMG point per 250 mg; p = 0.02) and in percent predicted forced vital capacity (slope: 2.2 % per 250 mg; p = 0.04). QMG improved >3 points in twice as many patients after 500 mg tirasemtiv than after placebo. Both doses of tirasemtiv were well tolerated; there were no premature terminations or serious adverse events. The results of this study suggest that tirasemtiv may improve muscle function in MG and will be used to support further development of tirasemtiv in neuromuscular diseases.

Original languageEnglish (US)
Pages (from-to)455-460
Number of pages6
JournalNeurotherapeutics
Volume12
Issue number2
DOIs
StatePublished - Apr 1 2015

Keywords

  • CK-2017357
  • Myasthenia gravis
  • fast skeletal troponin activator
  • tirasemtiv

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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