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Cytokinetics Announces Opening of Third Phase II Clinical Trial of CK-2017357 in Patients with ALS


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Cytokinetics, Incorporated has announced that the company has opened enrollment in a third Phase II clinical trial of CK-2017357 in patients with amyotrophic lateral sclerosis (ALS).

CK-2017357 selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium, which increases skeletal muscle force in response to neuronal input and delays the onset and reduces the degree of muscle fatigue.

CK-2017357 is the lead drug candidate that has emerged from the company's skeletal muscle contractility program.

This clinical trial is a double-blind, randomized, placebo-controlled, ascending dose titration study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamic effects of multiple ascending doses of CK-2017357.

An estimated 24 patients with ALS who are also receiving riluzole are planned to be enrolled at eight to ten study centers in the United States. Patients will be randomized to one of two dosing groups and receive twice daily oral ascending doses of CK-2017357 or placebo.

Clinical assessments will take place at pre-determined times during the course of treatment; patients will also participate in follow-up evaluations one week after their final dose.

The primary objective of this clinical trial is to assess the safety and tolerability of this alternative dosing regimen of CK-2017357 in patients with ALS.

The secondary objectives of this clinical trial are to evaluate the ALS Functional Rating Scale-Revised (ALSFRS-R), other measures of pulmonary function, muscle strength and fatigue, relationships between dose, plasma concentrations and functional effects and physician and patient global assessments in these patients while receiving two weeks of treatment with CK-2017357 at the indicated doses or placebo.

Development Status of CK-2017357 in ALS
Cytokinetics is developing CK-2017357, a skeletal muscle activator, as a potential treatment for diseases and conditions associated with aging, muscle wasting or neuromuscular dysfunction.

CK-2017357 is currently the subject of a Phase II clinical trials program and has been granted orphan-drug designation by the U.S. Food and Drug Administration for the potential treatment of ALS, a debilitating disease of neuromuscular impairment.

The company recently concluded enrollment of the first cohort, or Part A, of an ongoing Phase II clinical trial, which was designed to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics of multiple fixed daily doses of CK-2017357 in ALS patients who are not receiving riluzole.

Data from Part A of this trial will be presented November 30-December 2, 2011 at the 22nd International Symposium on ALS/MND in Sydney, Australia. Cytokinetics recently announced the initiation of a second cohort, or Part B, of this ongoing Phase II clinical trial of CK-2017357 in patients with ALS who are receiving riluzole.

CK-2017357 demonstrated potentially clinically relevant pharmacodynamic effects in a completed Phase IIa Evidence of Effect clinical trial in ALS patients. In that trial, the single doses of CK-2017357 evaluated appeared safe and generally well-tolerated.

In addition, both patients and investigators perceived a positive change in the patients' overall status, in a dose-dependent fashion, at 6 hours after dosing with CK-2017357, based on a Global Assessment in which the patient and the investigator each independently assessed patients' status compared to prior to dosing.

Furthermore, there was a clear relationship between improvements in Global Assessments and the CK-2017357 plasma concentration. Also at this 6-hour time point, there was a trend towards decreased muscle fatigability, as evidenced by data from a test of sub-maximal hand-grip endurance.

Data from this clinical trial also demonstrated a statistically significant, dose-related increase in the maximum volume of air patients could inhale and exhale in ten seconds (Maximum Voluntary Ventilation) at both 6 and 24 hours after 500 mg of CK-2017357, as well as small but statistically significant increases in maximum strength of certain muscle groups tested.

Cytokinetics recently met with the U.S. Food and Drug Administration Center for Drug Evaluation and Research's Division of Neurology Products to discuss the progress in the development of CK-2017357 as a potential treatment for patients with ALS and the company's strategy for its further development, including potential registration strategies.

Based on this discussion, Cytokinetics is assessing options that may enable the initiation of a clinical trial of CK-2017357 in ALS patients that could potentially serve as a pivotal trial for global registration purposes.

Background on Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that afflicts 20,000 to 30,000 people in the United States. Approximately 5,600 new cases of ALS are diagnosed each year. The average life expectancy of an ALS patient is approximately three to five years and only 10% of patients survive for more than 10 years.

Death is usually due to respiratory failure because of diminished strength in the skeletal muscles responsible for breathing. Few treatment options exist for these patients, resulting in a high unmet need for new therapeutic options to address the symptoms and modify the disease progression of this grievous illness.

Background on Cytokinetics Skeletal Muscle Contractility Program
CK-2017357, a fast skeletal muscle troponin activator, is the lead drug candidate from the company's skeletal muscle contractility program. CK-2017357 selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium, leading to an increase in skeletal muscle force.

This mechanism of action has demonstrated encouraging pharmacological activity in preclinical models that may relate to the potential treatment of diseases associated with aging, muscle wasting or neuromuscular dysfunction.

Skeletal muscle contractility is driven by the sarcomere, the fundamental unit of skeletal muscle contraction. The sarcomere is a highly ordered cytoskeletal structure composed of skeletal muscle myosin, the cytoskeletal motor that is directly responsible for converting chemical energy into mechanical force, as well as actin, and a set of regulatory proteins, troponins and tropomyosin, which make the actin-myosin interaction dependent on changes in intracellular calcium levels.

Cytokinetics' skeletal muscle contractility program is focused to the discovery and development of small molecule skeletal sarcomere activators and leverages Cytokinetics' expertise developed in its ongoing discovery and development of cardiac sarcomere activators, including the cardiac myosin activator omecamtiv mecarbil, now in clinical development as a potential treatment for heart failure.

Skeletal sarcomere activators have demonstrated pharmacological activity in preclinical models that may lead to new therapeutic options for diseases associated with aging, muscle wasting and neuromuscular dysfunction.

The clinical effects of muscle wasting, fatigue and loss of mobility can range from decreased quality of life to, in some instances, life-threatening complications.

By directly improving skeletal muscle function, a small molecule activator of the skeletal sarcomere may potentially enhance physical performance and quality of life in aging patients.

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