Fast Skeletal Muscle Troponin Activator Tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model (P1.081)

Abstract

OBJECTIVE: To evaluate the effects of tirasemtiv on muscle function in a mouse model of ALS. BACKGROUND: Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium and amplifies the response of muscle to neuromuscular input. DESIGN/METHODS: Forelimb grip strength in female B6SJL-SOD1^G93A transgenic mice was monitored weekly starting at 10 weeks of age (baseline). In order to minimize disease variability, mice were each subjected to a battery of functional assessments when their forelimb grip strength declined by 25% from baseline. Mice were then dosed with single oral doses of either vehicle or tirasemtiv (10 mg/kg) and forelimb grip strength, grid hang time, or rotarod performance was evaluated. Respiratory parameters of vehicle and tirasemtiv-treated WT and B6SJL-SOD1^G93A mice were assessed by whole body plethysmography. In a separate cohort of B6SJL-SOD1^G93A mice, isometric extensor digitorum longus muscle force output was assessed at Age=90-100 days and 110-115 days. RESULTS: Following oral tirasemtiv dosing, forelimb grip strength (p<0.05), grid hang time (P<0.01), and rotarod performance (p<0.01) all significantly increased in the B6SJL-SOD1^G93A transgenic mice. Compared to vehicle-treatment, tirasemtiv (10 mg/kg) significantly increased tidal volume in mice breathing room air following a 30 minute hypercapnic challenge (p < 0.001). Furthermore, in 90-100 day B6SJL-SOD1^G93A mice, the specific in situ isometric tension at 30 Hz stimulation increased from 5.81 ± 0.46 N/cm² to 10.8 ± 0.71 N/cm² (p=0.0028), and in 110-115 day mice the specific tension trended toward an increase from 3.34 ± 0.73 N/cm² to 5.05 ± 1.4 N/cm² (p=0.064) with IV tirasemtiv treatment compared to baseline. CONCLUSIONS: Tirasemtiv increased both isometric in situ sub-maximal muscle force and also muscle performance in conscious SOD1^G93A mice. Tirasemtiv also increased respiratory function. These results indicate that tirasemtiv has the potential to improve muscle function and respiration in patients suffering from ALS.

Disclosure: Dr. Malik has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Malik holds stock and/or stock options in Cytokinetics Inc. which sponsored research in which Dr. Malik was involved as an investigator. Dr. Malik has received research support from Cytokinetics Inc. Dr. Hwee has received personal compensation for activities with Cytokinetics, Inc. Dr. Kennedy has received personal compensation for activities with Cytokinetics, Inc. as an employee. Ms. Ryans has received personal compensation for activities with Cytokinetics, Inc. as an employee. Dr. Jasper has received personal compensation for activities with Cytokinetics Inc. Dr. Jasper holds stock and/or stock options in Altos Therapeutics which sponsored research in which Dr. Jasper was involved as an investigator. Dr. Jasper has received research support from Cytokinetics Inc.