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Cytokinetics (CYTK) Updates on Tirasemtiv in ALS Patients

December 7, 2012 7:36 AM EST Send to a Friend
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Cytokinetics, Incorporated (Nasdaq: CYTK) announced a platform presentation of pharmacokinetic data and pharmacokinetic/pharmacodynamic analyses from three previously-reported clinical trials of tirasemtiv in patients with amyotrophic lateral sclerosis (ALS) at the 23rd International Symposium on ALS and Motor Neurone Diseases (ALS/MND) in Chicago, IL. Tirasemtiv is the lead drug candidate that has emerged from the company`s skeletal muscle contractility program. Tirasemtiv selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium, which increases skeletal muscle force in response to neuronal input. In preclinical studies, this mechanism has been shown to delay the onset and reduce the degree of muscle fatigue. Tirasemtiv is currently being evaluated in BENEFIT-ALS, an international, double-blind, randomized, placebo-controlled, Phase IIb clinical trial designed to evaluate the safety, tolerability and potential efficacy of this novel drug candidate in patients with ALS.

Platform Presentation at the 23rd International Symposium on ALS/MND

These analyses included data from three completed Phase II clinical trials and were presented in a platform presentation titled, "Pharmacokinetics and Interactive Effects of the Fast Skeletal Muscle Activator CK-2017357 and Riluzole," by Jeffrey M. Shefner, M.D., Ph.D., Professor and Chair, Department of Neurology at the Upstate Medical University, State University of New York, and Lead Investigator of BENEFIT-ALS. In this presentation, the authors concluded that the pharmacokinetic properties of tirasemtiv are predictable with linear kinetics and were not affected by the presence of riluzole. In addition, the authors concluded that riluzole exposure is approximately doubled in the presence of tirasemtiv so that reducing the riluzole dose to 50 mg once daily in the presence of tirasemtiv results in levels that are approximately the same as riluzole 50 mg twice daily in the absence of tirasemtiv.

Across all of these three clinical trials, tirasemtiv appeared to produce positive and concentration dependent positive effects on multiple functional measures, including maximum grip strength in the stronger hand (p=0.093), handgrip fatigability (stronger hand, p=0.078; weaker hand, p=0.039), maximum voluntary ventilation (p=0.022), maximal inspiratory pressure (p=0.0036) and the ALS Functional Rating Scale - Revised (ALSFRS-R) (p=0.089). These analyses, in conjunction with previously reported results showing potential benefit of tirasemtiv in single dose and multiple dose trials of up to three weeks in duration, support the further development of tirasemtiv in ALS.

Development Status of Tirasemtiv

Tirasemtiv (formerly CK-2017357) is currently being evaluated in BENEFIT-ALS, an international, double-blind, randomized, placebo-controlled, Phase IIb clinical trial designed to evaluate the safety, tolerability and potential efficacy of this novel drug candidate in patients with ALS. Tirasemtiv has been granted orphan drug designation and fast track status by the United States Food and Drug Administration and orphan medicinal product designation by the European Medicines Agency for the potential treatment of ALS.

Data from two completed randomized, double-blind, placebo-controlled, multiple-dose, Phase II clinical trials of tirasemtiv in patients with ALS were presented at the April 2012 American Academy of Neurology Annual Meeting. In one of these trials, tirasemtiv appeared to be generally safe and well-tolerated when dosed daily for two weeks at 125 mg, 250 mg, or 375 mg, first in a cohort of patients not receiving riluzole, and then in a cohort of patients receiving riluzole at a reduced dose of 50 mg daily. Adverse events and clinical assessments during treatment with tirasemtiv appeared similar, with or without co-administration of riluzole. While the trial was not designed or powered to evaluate statistically the effects of tirasemtiv on the various outcome measures that were assessed during the study, a combined analysis of patients from two separate cohorts suggested encouraging trends in the ALSFRS-R and in MVV that appeared dose-related and potentially clinically meaningful in magnitude. In the other Phase II clinical trial, a twice-daily dose titration regimen of tirasemtiv also appeared to be generally safe and well-tolerated. The majority of patients in this trial were titrated successfully to a tirasemtiv dose level of 250 mg twice daily. While this trial also was not designed or powered to evaluate statistically the effects of tirasemtiv on the various outcome measures that were assessed during the study, increases were observed in ALSFRS-R that were similar in direction, and in MVV that were similar in direction and magnitude, to those observed in the aforementioned trial. In addition, in December 2010, data from a Phase IIa clinical trial evaluating single doses of tirasemtiv were presented at the 21st International Symposium on ALS and Motor Neurone Diseases. In all three of these Phase II clinical trials, tirasemtiv appeared to be safe and well-tolerated, and demonstrated encouraging trends to improvement in patients` functional abilities, and in measures of respiratory and skeletal muscle strength and endurance.




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