Cytokinetics Announces Opening Of A Phase IIa "Evidence Of Effect" Clinical Trial Of CK-2017357 For Patients With Amyotrophic Lateral Sclerosis

http://www.medicalnewstoday.com/articles/182954.php

Cytokinetics, Incorporated (NASDAQ: CYTK) announced that the company has opened a Phase IIa "Evidence of Effect" (EoE) clinical trial of CK-2017357 for patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. CK-2017357 is a fast skeletal muscle troponin activator and is the lead drug candidate that has emerged from the company's skeletal muscle contractility program. CK-2017357 selectively activates the fast skeletal muscle troponin complex and increases its sensitivity to calcium, resulting in increased skeletal muscle force. In March 2010, CK-2017357 was granted an orphan-drug designation by the United States Food and Drug Administration (FDA) for the potential treatment of ALS.

This Phase IIa EOE clinical trial is a double-blind, randomized, placebo-controlled, three-period crossover, pharmacokinetic and pharmacodynamic study of CK-2017357 in male and female patients with ALS. At least 36 and up to 72 patients may be enrolled in this trial. The primary objective of this trial is to evaluate the pharmacodynamic effects of CK-2017357 on measures of skeletal muscle function or fatigability in patients with ALS. Accordingly, in this hypothesis-generating trial, multiple pharmacodynamic assessments will be made without specifying a single primary pharmacodynamic endpoint. These assessments will include various measures of maximum voluntary muscle strength, development of fatigue at maximum and sub-maximum voluntary muscle contraction, and pulmonary function, measured at baseline, and at 3, 6 and 24 hours post-dosing after each of two single doses of CK-2017357 and placebo. The secondary objectives of this clinical trial are to evaluate the relationship between the plasma concentration of CK-2017357 and its pharmacodynamic effects, to evaluate the safety and tolerability of the two single doses of CK-2017357 administered orally to patients with ALS, and to evaluate the effects of CK-2017357 on patient- and investigator-determined global functional assessments.

"This hypothesis-generating clinical trial is designed to evaluate evidence of pharmacodynamic effects of CK-2017357 associated with potentially increased skeletal muscle performance in patients with ALS. Based on non-clinical and clinical results, we believe that we may demonstrate relevant effects with CK-2017357, even after single dose administration," stated Andrew A. Wolff, MD, FACC, Cytokinetics' Senior Vice President of Clinical Research and Development and Chief Medical Officer. "We believe that results from this trial, as well as those from our other planned Phase IIa 'Evidence of Effect' trial in patients with claudication, have the potential to further inform our understandings of potential therapeutic applications that this novel drug candidate may have in diseases of impaired muscle function."

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.

Development Status of CK-2017357

Cytokinetics recently announced data from two Phase I clinical trials evaluating CK-2017357. The first trial is a two-part, single-dose, Phase I clinical trial of CK-2017357. Part A of this trial is designed to assess the safety, tolerability and pharmacokinetic profile of increasing single doses of this drug candidate in healthy volunteers and to determine its maximum-tolerated dose and associated plasma concentrations. To date, single doses up to 2000 mg have been administered without intolerable adverse events being observed. Part B of this trial was designed to assess the pharmacodynamic effects of CK-2017357 on skeletal muscle function after single oral doses of 250, 500 and 1000 mg, and to assess the relationship of the effects observed to the associated plasma concentrations of CK-2017357, also in healthy volunteers. In Part B, CK-2017357 produced concentration-dependent, statistically significant increases versus placebo in the force developed by the tibialis anterior, the muscle evaluated in Part B of this trial. CK-2017357 was well-tolerated and no serious adverse events were reported.

The second trial was a multiple-dose, Phase I clinical trial of CK-2017357 designed to investigate the safety, tolerability and pharmacokinetic profile of CK-2017357 after multiple oral doses to steady state in healthy male volunteers. The trial evaluated doses that produced plasma concentrations in the range associated with pharmacodynamic activity in Part B of the single-dose Phase I study. At steady state, both the maximum plasma concentration and the area under the CK-2017357 plasma concentration versus time curve from before dosing until 24 hours after dosing were generally dose-proportional. In general, systemic exposure to CK-2017357 in this trial was high and inter-subject variability was low. In addition, these multiple-dose regimens of CK-2017357 were well-tolerated, and no serious adverse events were reported. The company believes that these results, in combination with the single-dose Phase I clinical trial data, support progression into Phase IIa "Evidence of Effect" (EoE) clinical trials in patients with neuromuscular diseases and other conditions that may limit mobility, such as the recently opened Phase IIa EOE clinical trial for patients with ALS and a planned Phase IIa EOE clinical trial for patients with claudication.

CK-2017357 has been granted orphan-drug designation by the United States Food and Drug Administration for the potential treatment of ALS.

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 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. It 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