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

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.

Figures

Fig. 1
Fig. 1
Quantitative Myasthenia Gravis (QMG) total scores and patients with change in QMG total score ≥3 points at 6 h after dosing. The (A) least square mean change in QMG total score by treatment and (B) number of patients who achieved a ≥3-point change in QMG total score (indicating clinical improvement) are shown. Error bars represent SE. *p = 0.02 vs placebo; †p = 0.098 vs placebo based on χ2 test

References

    1. Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797–1810. doi: 10.1056/NEJM199406233302507.
    1. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006;116:2843–2854. doi: 10.1172/JCI29894.
    1. Russell AJ, Hartman JJ, Hinken AC, et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med. 2012;18:452–455. doi: 10.1038/nm.2618.
    1. Hansen R, Saikali KG, Chou W, et al. Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. 2014;50:925–931. doi: 10.1002/mus.24239.
    1. Shefner J, Cedarbaum JM, Cudkowicz ME, et al. Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012;13:430–438. doi: 10.3109/17482968.2012.684214.
    1. Bauer TA, Wolff AA, Hirsch AT, et al. Effect of tirasemtiv, a selective activator of the fast skeletal muscle troponin complex, in patients with peripheral artery disease. Vasc Med. 2014;19:297–306. doi: 10.1177/1358863X14534516.
    1. Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998;841:769–772. doi: 10.1111/j.1749-6632.1998.tb11015.x.
    1. Burns TM, Conaway M, Sanders DB, MG Composite and MG-QOL15 Study Group The MG Composite: A valid and reliable outcome measure for myasthenia gravis. Neurology. 2010;74:1434–1440. doi: 10.1212/WNL.0b013e3181dc1b1e.
    1. Sanders DB, Tucker-Lipscomb B, Massey JM. A simple manual muscle test for myasthenia gravis: validation and comparison with the QMG score. Ann N Y Acad Sci. 2003;998:440–444. doi: 10.1196/annals.1254.057.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit