Cytokinetics Announces Presentation of Data From a Phase IIa Clinical Trial of CK-2017357 in Patients With ALS at the 63rd Annual Meeting of the American Academy of Neurology

Cytokinetics, Incorporated has announced that clinical data from its recently completed Phase IIa "Evidence of Effect" (EoE) clinical trial of CK-2017357 in patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, were presented in the 2011 Clinical Trials Session at the 63rd Annual Meeting of the American Academy of Neurology in Honolulu, Hawaii on Friday, April 15th.

A presentation titled, "A Phase 2A, Double-Blind, Randomized, Placebo-Controlled, Single-Dose, Crossover Study of the Selective Fast Skeletal Muscle Troponin Activator, CK-2017357, in Patients with ALS," was made by Jeremy M. Shefner, MD, PhD, Professor and Chair, Department of Neurology, Upstate Medical University, State University of New York. CK-2017357 is the lead drug candidate from the company's skeletal muscle contractility program.

Data from this trial were initially presented at the 21st International Symposium on ALS and Motor Neurone Diseases in December of last year. Additional results presented at this meeting relate to the effects of CK-2017357 on the strength of selected muscle groups, as well as concentration-response relationships for key outcome measures.

More recent analyses showed that, at 24 hours after each of the 250 and 500 mg doses of CK-2017357, dose-related increases in the change from the Day 1 baseline in percent predicted muscle strength achieved nominal statistical significance for elbow flexion (p = 0.005 and p = 0.0004, respectively), shoulder flexion (p = 0.008 and p = 0.002, respectively) and knee extension (p = 0.003 and p = 0.001, respectively).

In addition, a statistically significant relationship to the CK-2017357 plasma concentration was observed for improvements in both the patients' and investigators' Global Assessments of Change (p = 0.03 and p = 0.01, respectively), and in the Sniff Inspiratory Pressure (p = 0.03).

"I am honored to have the opportunity to present these data to my fellow neurologists at the American Academy of Neurology's 63rd Annual Meeting," said Dr. Shefner. "The additional results presented at this meeting, together with the data presented late last year, suggest that a skeletal muscle activator such as CK-2017357 may offer a novel approach to improving muscle function in patients suffering from amyotrophic lateral sclerosis. All of these results support further study of this class of compounds to evaluate the potential for sustained functional benefit in patients with ALS."

"We are pleased that data from this Phase IIa clinical trial were selected for presentation in the Clinical Trials Session at this prestigious clinical conference," stated Andrew A. Wolff, MD, FACC, Cytokinetics' Senior Vice President of Clinical Research and Development and Chief Medical Officer. "Importantly, this trial has now generated clinically relevant hypotheses that warrant further exploration in larger and longer proof-of-concept clinical trials in patients with ALS."

Phase IIa Clinical Trial Results

In this Phase IIa clinical trial, a single 250 mg dose of CK-2017357, a single 500 mg dose of CK-2017357, and a single matching dose of placebo were each administered once, in a double-blind fashion and in random order, at least 6 days apart to male and female ALS patients. The maximum CK-2017357 plasma concentration generally was achieved between 3 and 6 hours after dosing, which is when most assessments were made; some were also repeated at 24 hours after dosing.

Dr. Shefner reported that both patients and investigators perceived a positive change in the patients' overall status at 6 hours after dosing with CK-2017357, based on a Global Assessment in which the patient and the investigator each independently assessed whether the patient was "better," "same," or "worse" compared to just before dosing on that day. At 6 hours after receiving 500 mg of CK-2017357, 29 of 65 patients assessed themselves as "better," compared to 18 of 63 on placebo (p = 0.04). Similarly, at that time point, the investigators assessed only 8 of 63 patients on placebo as "better," compared with 15 of 62 after 250 mg of CK-2017357 (p = 0.06) and 20 of 65 after 500 mg of CK-2017357 (p = 0.004). Conventional nominal statistical significance for the dose response for these improvements in Global Assessments at 6 hours after dosing was approached for the patients' assessments (p = 0.07) and achieved for the investigators' (p = 0.01).

Furthermore, there was a clear relationship between improvements in Global Assessments and the CK-2017357 plasma concentration. Patients were more than twice as likely to assess themselves as "better" when their plasma concentrations were above 9 mcg/mL than on placebo (odds ratio 2.45; p = 0.01), while the investigators were almost four times more likely to assess their patients as "better" when the patients' plasma concentrations were in that range (odds ratio 3.81; p = 0.0007). In addition, the relationship between the likelihood of a "better" assessment and the CK-2017357 plasma concentration was nominally statistically significant both for the patients' assessments (p = 0.03) and for the investigators' (p = 0.01).

Dr. Shefner proposed that these improvements in the patients' and investigators' Global Assessments may have resulted from a decrease in muscle fatigability of their muscles, as evidenced by data from a test of sub-maximal hand-grip fatigability. For this measurement, each patient was asked to maintain a sub-maximal target force set at 30% of his or her individually measured maximal handgrip force for as long as possible (up to 2 minutes). The times when the patient's hand-grip force fell below 100%, 90%, 80%, 70% and 60% of this target were then recorded. Both hands were studied, and the weaker hands were analyzed separately from the stronger hands.

At 6 hours after dosing, dose-related trends to prolong the times patients could maintain the grip force in the weaker hand above 80%, 70%, and 60% of the target force were apparent. At 6 hours after the 500 mg dose of CK-2017357, these prolongations in the weaker hand approached nominal statistical significance for the times grip force could be maintained above 70% and 60% of the target force (7.8 seconds [p = 0.08] and 7.2 seconds [p = 0.06] versus placebo, respectively). Similarly, the dose response for these prolongations in the patients' ability to maintain sub-maximal grip force in the weaker hand at 6 hours after dosing also approached nominal statistical significance for the times grip force could be maintained above 70% and 60% of the target force (p = 0.08 and p = 0.06, respectively).

In analyses not presented last December, muscle strength improved slightly in some muscle groups, but not others. At 24 hours after each of the 250 and 500 mg doses, dose-related increases in the change from the Day 1 baseline in percent predicted muscle strength achieved nominal statistical significance for elbow flexion (p = 0.005 and p = 0.0004, respectively), shoulder flexion (p = 0.008 and p = 0.002, respectively) and knee extension (p = 0.003 and p = 0.001, respectively).

Data from this clinical trial demonstrated a dose-related trend to increase the maximum volume of air patients could inhale and exhale in one minute (Maximum Voluntary Ventilation) which achieved nominal statistical significance at both 6 and 24 hours after 500 mg of CK-2017357 (3.5 liters [p = 0.05] and 4.2 liters [p = 0.02] versus placebo, respectively). Trends to increase the patients' force of inhalation, a measure of pulmonary function known as the Sniff Inspiratory Pressure, were also observed, and approached nominal statistical significance at 6 hours after the 500 mg dose of CK-2017375 (2.84 cm H2O versus placebo; p = 0.10). In addition, the relationship between increases in Sniff Inspiratory Pressure and increasing CK-2017375 plasma concentrations achieved nominal statistical significance (p = 0.03).

Finally, the investigators also concluded that these single doses of CK-2017357 were safe and generally well-tolerated by the patients in this trial. There were no serious adverse events that were judged to have been related to treatment with the study drug. Most adverse events were classified by the investigators as mild, including dizziness, the most commonly-reported and most clearly dose-related adverse event. All reports of dizziness by patients receiving 250 mg of CK-2017357 were classified as mild, as were 88% of those reported by patients receiving 500 mg of CK-2017357. The other complaints of dizziness by patients receiving 500 mg of CK-2017357 were classified as moderate; none were determined to be severe.