CK-107 (Reldesemtiv)

CK-107 (Reldesemtiv)

CK-107 is a troponin complex activator that slows calcium release from fast skeletal muscle troponin.1 This effectively sensitizes the sarcomere to calcium. Consequently, muscles can produce a higher level of force output at submaximal motor nerve stimulation frequencies. Rather than focus on the genetic cause of spinal muscular atrophy (SMA), CK-107 is a “muscle-enhancing” investigational drug intended to improve muscle force. Increased contractility at submaximal stimulation also appears to reduce muscle fatigue ability in rats.1

CK-107 was formerly developed under the name CK-2127107, and future clinical development will be under the name reldesemtiv. Cytokinetics is developing CK-107 in conjunction with Astellas, who holds worldwide licensing for the molecule. The FDA granted reldesemtiv orphan drug status as an investigational treatment for SMA in May 2017. 

CK-107 performed well in preclinical studies in mice with experimental forms of SMA. Treatment with single doses of the molecule increased skeletal muscle force in “intermediate” SMA (2B/2B-NEO SMA mice; SMA Type 2 mouse model) and Hung Li SMA mice (SMA Type 3 mouse model).2 Singles doses of the investigational drug up to doses of 4,000 mg were well tolerated by healthy volunteers in Phase 1 clinical trials.3

Researchers recently completed recruitment for a triple-blind, randomized, placebo-controlled Phase 2 clinical trial studying the effects of CK-107 (NCT02644668). The study enrolled patients 12 years and older with SMA Type 2, 3 and 4. Cohorts were separated into ambulatory and non-ambulatory cohorts and received escalating doses of the drug from 150 mg up to 450 mg twice daily. Change from baseline and slope of change from baseline in various pulmonary function, motor function, and physical performance tests. 

Cytokinetics/Astellas released some results of a clinical trial at the 2018 Annual Cure SMA Conference in Dallas. After eight weeks of treatment with CK-107, trial participants with SMA had dose- and concentration- dependent increases in time to muscle fatigue (6 minute walk test) and measures of respiratory muscle strength (Maximal Expiratory Pressure) compared to baseline and placebo. Conversely, other primary endpoints were not significantly different between active and placebo groups (Hammersmith Functional Motor Score – Extended, Revised Upper Limb Module, Timed Up-and-Go and Forced Vital Capacity).  

Four patients had serious adverse events that caused early withdrawal from the study; however, in all cases the adverse events were deemed to be unrelated to reldesemtiv. The most commonly observed adverse effects were headache, constipation and nausea. The promising safety profile, lack of dose-limiting toxicity, and promising clinical benefit signal has prompted Cytokinetics/Astellas to consider further phase 2 clinical trials at higher doses and treatment durations.

References

1. Hwee DT, Kennedy AR, Hartman JJ, et al. The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure. J Pharmacol Exp Ther. Apr 2015;353(1):159-168.

2. Hwee DT DC, Malik FI, Chin ER. The Fast Skeletal Troponin Activator, CK-2127107, Improves Muscle Function in Mouse Models of Spinal Muscular Atrophy. 2017 MDA Scientific Conference. Arlington, VA, March 2017. https://cytokinetics.com/wp-content/uploads/2015/10/MDA2017_SMA-CK107-Mouse-Model.pdf.

3. Andrews JA, Miller TM, Vijayakumar V, et al. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. May 2018;57(5):729-734.