Cytokinetics Clinical Trial

Cytokinetics Reported on “Evidence of Effect” Clinical Trial at ALS Association Hosted ALS/MND International Symposium

Cytokinetics, Inc. announced the successful completion of its Phase IIA “Evidence of Effect” clinical trial of CK-2017357 in patients with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, during an oral presentation included in the Clinical Trials Session at the 21st International ALS/MND Symposium in Orlando, Fla.

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, M.D., Ph.D., Professor and Chair of the Department of Neurology at the Upstate Medical University at the State University of New York.  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 study suggests that CK-2017357 may play a significant role in the treatment of patients with ALS,” stated Dr. Shefner.  “We assessed multiple variables associated with muscle function in these patients.  Based on these encouraging results, I believe that CK-2017357 may offer a new way of thinking about symptom relief and quality of life for these patients.”

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.

The investigators concluded 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.  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 and 20 of 65 after 500 mg. of CK-2017357.  Conventional nominal statistical significance for the apparent dose response for these improvements in global assessments at 6 hours after dosing was approached for the patients’ assessments and achieved for the investigators’.

At 6 hours after dosing, clear, 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 and 7.2 seconds versus placebo, respectively).  Similarly, the apparent 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 versus placebo, respectively.  Moreover, the relationship between prolongations in grip force above 60% of target in the weaker hand and increasing CK-2017375 plasma concentrations achieved nominal statistical significance.

The investigators also proposed that trends toward increases in parameters of pulmonary function may underlie the improvements in the patients’ and investigators’ global assessments.  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 and 4.2 liters, 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).  In addition, the relationship between increases in Sniff Inspiratory Pressure and increasing CK-2017375 plasma concentrations achieved nominal statistical significance.

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.

“We are pleased that this clinical trial has successfully generated results in patients with ALS that are both encouraging and consistent with data generated in our preclinical studies and our Phase I clinical trials with CK-2017357.  Importantly, this clinical trial has now generated clinically relevant hypotheses that warrant further exploration in proof-of-concept clinical trials in patients with ALS,” stated Andrew A. Wolff, MD, FACC, Cytokinetics’ Senior Vice President of Clinical Research and Development and Chief Medical Officer.  “We are now planning to proceed into a multiple-dose clinical trial to understand how longer-term dosing of CK-2017357 may impact the functional status of these patients.”

Although not funding this research, The ALS Association is excited to see such promising data and is pleased that Cytokinetics working closely with the ALS community and will continue to explore the potential of the compound as a treatment for ALS.