Background:

Tirasemtiv is an activator of the fast skeletal muscle troponin complex. Troponin[1]

Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Tirasemtiv selectively sensitizes fast skeletal muscle troponin to calcium (Ca2+), and slows the rate of Ca2+ release from the regulatory troponin complex of fast skeletal muscle[1].

A single dose of Tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in Tirasemtiv-treated female B6SJL-SOD1G93A mice. At the 25% deficit milestone, vehicle-treated B6SJL-SOD1G93A mice demonstrated forelimb grip strength of 49.6±4.6 g. Tirasemtiv increases grip strength by 38% to 68.6±8.1g (p<0.05, single tailed t-test). Tirasemtiv doses of 2, 2, 2, and 4 mg/kg given at approximately 20 min intervals to achieve a cumulative dose of 10 mg/kg. Regression analysis of the log dose vs. response relationship indicated that Tirasemtiv significantly increased muscle force in WT and mid-stage B6SJL-SOD1G93A mice (WT p<0.0001; mid-stage p=0.0028). At later stages of disease, the mice exhibited a trend for increased muscle function in response to Tirasemtivcompared to baseline (p=0.064)[1].

[1]. Hwee DT, et al. Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. PLoS One. 2014 May 7;9(5):e96921.