Preclinical data published on fast skeletal muscle troponin activator

Rat model suggests possible effectiveness in treating heart failure-related exercise intolerance

Jim Cirigliano
SOUTH SAN FRANCISCO, Calif.—Clinical-stage biopharmaceutical company Cytokinetics Inc. announced in February the completion and publication of a preclinical study of its novel fast skeletal muscle troponin activator CK-2127107 being developed for the potential treatment of spinal muscular atrophy. A manuscript describing the study was published in the April 2015 edition of the Journal of Pharmacology and Experimental Therapeutics (and online in advance of that in February).
 
The objective of the study, according to an abstract of the manuscript posted by the American Society for Pharmacology and Experimental Therapeutics, was to investigate the effect of CK-2127107 on skeletal muscle function and exercise performance in rats exhibiting heart failure-mediated skeletal myopathy. Rats underwent a left anterior descending coronary artery ligation, resulting in myocardial infarction and a progressive decline in cardiac function. These rats exhibited significant atrophy of the hindlimb and diaphragm muscles consistent with the development of heart failure. Their performance was compared against sham-operated control rats. Exercise performance was assessed by rotarod running in this model.
 
The rats were given an oral dose of 10 mg/kg of CK-2127107. The results of the study showed that a single dose of the compound increased the running times of the left anterior descending heart failure rats to levels similar to the control rats receiving the same dosage.
 
The authors concluded that CK-2127107 appears to substantially increase exercise performance in this heart failure model in rats, which suggests treating skeletal muscle function with a fast skeletal troponin activator could be a valuable therapeutic approach in exercise intolerance associated with heart failure.
 
“We are pleased to share additional preclinical data on CK-2127107 that highlight the potential application of its mechanism of action in patients with conditions such as heart failure, which can result in exercise intolerance due to skeletal muscle weakness and fatigue,” Dr. Fady I. Malik, Cytokinetics’ senior vice president of research and development, stated in a media release about the publication of the study’s results. “We believe that the results summarized in this peer-reviewed manuscript support the development of CK-2127107 in diseases and conditions characterized by muscle weakness and fatigue.”
 
CK-2127107 (2-aminoalkyl-5-N-heteroarylpyrimidine) is a novel fast skeletal muscle troponin activator that developed from Cytokinetics’ skeletal muscle contractility research program. The compound functions by slowing the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers. This action sensitizes the sarcomere—the bodies’ fundamental unit of skeletal muscle contraction—to calcium, thus leading to an increase in skeletal muscle contractility.
 
Cytokinetics is developing CK-2127107 in collaboration with Tokyo-based global pharmaceutical company Astellas Pharma Inc. Astellas holds an exclusive worldwide license to develop and commercialize CK-2127107, subject to specified development and commercialization participation rights retained by Cytokinetics.
 
CK-2127107 has been the subject of five completed Phase 1 clinical trials that evaluated the compound’s safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics in healthy volunteers. CK-2127107 has demonstrated pharmacological activity that indicates its potential as a driver of new therapeutic options for diseases associated with muscle weakness and fatigue. Under its collaboration with Astellas, Cytokinetics plans to begin a Phase 2 clinical trial of CK-2127107 in patients with spinal muscular atrophy later this year.
 
The compound arose from Cytokinetics’ muscle biology-focused research activities surrounding the cytoskeleton, a complex biological infrastructure that plays a fundamental role within every human cell.
 
Aside from CK-2127107 Cytokinetics’s pipeline includes several other novel small-molecule therapeutics intended to treat diseases and medical conditions by modulating muscle function. Cytokinetics is developing tirasemtiv, a fast skeletal muscle activator, as a potential treatment for amyotrophic lateral sclerosis. The company is also collaborating with Amgen Inc. to develop a cardiac muscle activator called omecamtiv mecarbil for the potential treatment of heart failure.

Jim Cirigliano

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