Putting some muscle behind SMA treatment

Preclinical trial of CK-2127107 shows improved muscle function in mouse models of spinal muscular atrophy

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SOUTH SAN FRANCISCO, Calif.—Targeted toward developing a long-awaited, fast-acting treatment for spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) patients, Cytokinetics Inc.—in collaboration with Tokyo-based Astellas Pharma Inc.—has announced that preclinical data for CK-2127107 (also known as CK-107), led to increased muscle function in mouse models. The study bodes well for a treatment tailored for humans a few years down the road.
The CK-107 data, presented at the MDA Scientific Conference in Arlington, Va., in March, show that this next-generation fast skeletal troponin activator (FSTA) improves muscle function in mouse models of SMA.
A severe neuromuscular disease that occurs in one in every 6,000 to 10,000 live births each year and is one of the most common fatal genetic disorders, SMA manifests in various degrees of severity as progressive muscle weakness resulting in respiratory and mobility impairment.
 “These data support our ongoing Phase 2 clinical trial of CK-107 in adolescent and adult patients with SMA,” says Dr. Fady I. Malik, Cytokinetics’ executive vice president of research and development. “The increased muscle force at submaximal nerve stimulation frequencies in mice inform the potential for CK-107 to increase muscle function in patients living with motor neuron dysfunction.”
Until a few months ago, “there were no therapies available to treat SMA,” Malik tells DDNews. “Spinraza (nusinersan) is the first approved therapy. This is a gene-directed therapy with a different mechanism than CK-107. The two drugs could potentially be complementary.”
Two additional clinical trials of CK-107 are planned to begin in 2017, one in patients with ALS and one in elderly subjects with limited mobility, Malik says.
“We expect both trials to begin later this year, and we expect data from the Phase 2 trial in patients with SMA in the second half of 2017,” he says. “If the upcoming Phase 2 trials are successful, we would discuss the data with regulatory authorities in preparation for a Phase 3 clinical program.”
In neuromuscular diseases such ALS (also known as Lou Gehrig’s disease) and SMA, patients experience progressive, often fatal, muscle weakness, Malik says. CK-107 has the potential to increase muscle force, power and the time to relieve muscle fatigue.
“There hasn’t been a therapy approved for ALS in more than 20 years,” he adds. “This is a huge unmet need.”
The company’s potential therapy for ALS is tirasemtiv—which, like CK-107, is intended to slow the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers—and it is “the first investigational therapy to demonstrate an effect on slowing the decline of respiratory function in patients with ALS (in our Phase 2 trial),” Malik says. “Patients typically die of respiratory failure.”
Tirasemtiv has been granted Orphan Drug Designation and Fast Track status by the U.S. Food and Drug Administration and Orphan Medicinal Product designation by the European Medicines Agency for the potential treatment of ALS.
“We are currently conducting a Phase 3 trial in patients with ALS which is aimed at confirming this finding and extending it to a longer period of time,” he tells DDNews, noting that Phase 2 was three months and Phase 3 is one year.
In addition to the preclinical work with CK-107, Malik says Phase 1 trial work has shed light on the potential for the investigational compound to increase muscle force. Results of three double-blind, randomized, placebo-controlled Phase 1 studies of CK-107 in healthy volunteers were presented in a poster at the 19th International SMA Researcher Meeting during the 2015 Annual SMA Conference.
CK-107 has demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with muscle weakness and fatigue. In nonclinical models of SMA, a skeletal muscle activator has demonstrated increases in submaximal skeletal muscle force in response to neuronal input and delays in the onset and reductions in the degree of muscle fatigue.
CK-107 has now been the subject of five completed Phase 1 clinical trials. In addition to a Phase 2 clinical trial in patients with SMA, Cytokinetics is collaborating with Astellas on the conduct of a Phase 2 clinical trial in patients with chronic obstructive pulmonary disease.
In 2013, Astellas and Cytokinetics formed a partnership focused on the research, development and commercialization of skeletal muscle activators, with the primary objective to advance novel therapies for diseases and medical conditions associated with muscle impairment and weakness. Under the collaboration, Cytokinetics exclusively licensed to Astellas rights to co-develop and potentially co-commercialize CK-107.
In 2014, Astellas and Cytokinetics agreed to expand the collaboration to include certain neuromuscular indications, including SMA, and to advance CK-107 into Phase 2 clinical development, initially in SMA.
The agreement was further amended in 2016 to provide Astellas with exclusive rights to co-develop and commercialize CK-107 and other FSTAs in non-neuromuscular indications (including SMA and ALS) and other novel mechanism skeletal muscle activators in all indications, subject to certain of Cytokinetics’ development and commercialization rights. Cytokinetics may co-promote and conduct certain commercial activities in North America and Europe under agreed scenarios.

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