The Fast Skeletal Troponin Activator, CK-2017357, Increases Muscle Function and Survival in SOD1 (G93A) Mice; a Model of ALS (P05.169) (2012)

Objective: To examine the effects of CK-2017357 in a mouse model of ALS. Background CK-2017357 is a small molecule activator of fast skeletal troponin that sensitizes the sarcomere to calcium and amplifies the muscle9s response to motor neuron input at sub-tetanic forces. Design/Methods: The potential effects of CK-2017357 were examined on muscle force, respiratory function and survival in SOD1 G93A mutant transgenic mice, a model of amyotrophic lateral sclerosis (ALS) in humans. Results: Extensor digitorum longus (EDL) muscle was stimulated via the peroneal nerve over a range of frequencies (10-200 Hz, 350 ms trains) to establish the force-frequency relationship. EDL tetanic force (26.3 ± 4.4 N/cm 2 ) was reduced by 44% ± 3.9% in 90-100 day-old SOD1 vs. WT and 66% ± 7.7% in 100-110 day-old SOD1 vs. WT, reflecting progressive loss of muscle force with disease progression. Infusion of CK-2017357 resulted in dose-dependent increases (mean ± SEM) in force at 30 Hz compared to baseline in WT (206% ± 29%), 90-100 day-old (200% ± 52%) and 100-110 day-old (153% ± 55%) SOD1 G93A mice. In female SOD1 G93A mice fed chow containing CK-2017357 (400 ppm) beginning at 11 weeks of age, animals survived to a humane endpoint longer compared to control chow-fed mice (p=0.024; hazard ratio=0.66). Body weight was similar in the two groups. There were no differences in respiratory parameters (breathing frequency, tidal volume and ventilation during hypercapnic challenge) in CK-2017357 chow-fed SOD1 G93A mice compared to WT mice. SOD1 G93A mice fed 400 ppm CK-2017357 chow exhibited a significant increase in hindlimb grip strength compared to control chow fed SOD1 G93A mice, while forelimb grip strength was not altered. Conclusions: CK-2017357 increased isometric in situ muscle force and hindlimb grip strength in SOD1 G93A mice and improved survival. These results indicate that CK-2017357 has the potential to improve muscle function in patients suffering from ALS. Supported by: Cytokinetics, Inc. Disclosure: Dr. Malik has received personal compensation for activities with Cytokinetics, Inc. Dr. Malik holds stock and/or stock options in Cytokinetics, Inc. Dr. Malik has received research support from Cytokinetics, Inc. Mr. Russell holds stock and/or stock options in Former Cytokinetics, Inc. which sponsored research in which Mr. Russell was involved as an investigator. Dr. Pannirselvam holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Pannirselvam was involved as an investigator.Dr. Pannirselvam has received research support from Cytokinetics, Inc. Dr. Hinken holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Hinken was involved as an investigator.Dr. Hinken has received research support from Cytokinetics, Inc. Dr. Thomsen holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Thomsen was involved as an investigator. Dr. Thomsen has received research support from Cytokinetics, Inc. Dr. Ardiana holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Ardiana was involved as an investigator. Dr. Ardiana has received research support from Cytokinetics, Inc. as an employee. Dr. Godinez holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Godinez was involved as an investigator. Dr. Jia holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Jia was involved as an investigator. Dr. Saikali holds stock and/or stock options in Cytokinetics, Inc. Dr. Saikali has received research support from Cytokinetics, Inc. Dr. Chen holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Chen was involved as an investigator. Dr. Chen has received research support from Cytokinetics, Inc. Dr. Morgans holds stock and/or stock options in Cytokinetics, Inc. Dr. Morgans has received research support from Cytokinetics, Inc. Dr. Jasper holds stock and/or stock options in Cytokinetics, Inc., which sponsored research in which Dr. Jasper was involved as an investigator.Dr. Jasper has received research support from Cytokinetics, Inc..