Poster Presentation at the American Academy of Neurology 64th Annual Meeting
A poster titled "A Study to Evaluate Safety and Tolerability of CK-2017357 in Patients with Amyotrophic Lateral Sclerosis Using a Twice-Daily, Dose-Titration Regimen" was also presented by Dr. Shefner. The poster summarized data from a Phase II clinical trial evaluating CK-2017357 in patients with ALS (CY 4025). The authors concluded that the twice-daily dose-titration regimen evaluated in the trial was generally safe and well-tolerated, that the majority of patients could be titrated successfully to a CK-2017357 dose level of 250 mg twice daily, and that encouraging trends toward functional improvements were observed on CK-2017357 versus placebo.
Design and Results
This Phase II clinical trial was a randomized, double-blind, placebo-controlled study in which CK-2017357 was administered for 21 days using a twice-daily, dose titration regimen to patients with ALS taking riluzole at the reduced dose of 50 mg per day. Patients were randomized 3:1 to receive twice daily oral doses of CK-2017357 or placebo. After seven days of treatment with CK-2017357 at the starting dose of 125 mg twice daily, the dose was escalated to 125 mg in the morning and 250 mg in the evening, and after seven days at this dose, to 250 mg twice daily for the final seven days of dosing. Patients who did not tolerate a dose escalation returned to the previous tolerated dose level and remained at that dose level to complete the study. Placebo patients underwent a similar dummy dose titration to maintain the blind. The primary objective of CY 4025 was to assess the safety and tolerability of CK-2017357 when administered using this twice-daily dose titration regimen to patients with ALS and to determine if the total daily dose of CK-2017357 could be increased from the 375 mg once daily dose (that had been evaluated in earlier trials of CK-2017357 in patients with ALS) to a target of 250 mg dosed twice daily in patients enrolled in this trial.
Twenty-seven patients were treated in CY 4025. All six patients randomized to placebo completed three weeks of dosing. Of the 21 patients randomized to treatment with CK-2017357, 14 were escalated to the highest dose of 250 mg twice daily and completed three weeks of dosing; two others terminated the study prematurely while receiving 250 mg twice daily due to adverse events that required hospitalization. One of these patients was admitted for ataxia and confusion believed to be related to treatment with CK-2017357; the other was hospitalized for treatment of cellulitis believed to be unrelated to treatment with CK-2017357. Three other patients also withdrew from the study prematurely. One patient was hospitalized for an upper respiratory infection believed to be unrelated to treatment with CK-2017357 after receiving a week of treatment with CK-2017357 125 mg in the morning and 250 mg in the evening. Two patients withdrew from study for non-serious adverse events while receiving 125 mg of CK-2017357 twice daily, one for dysarthria and another for complaints of unsteadiness, decreased appetite, fatigue, dizziness, and nausea. Finally, two patients completed the study after a downward dose titration. As was observed in CY 4024, dizziness was the most frequently reported adverse event in CY 4025. None of the six patients who received placebo in CY 4025 reported dizziness, while 12 of 21 patients experienced dizziness during dose titration with CK-2017357. In 10 of these patients, dizziness was mild; the other two patients experienced moderate dizziness.
CY 4025 was not designed or powered to evaluate statistically the effects of CK-2017357 on the various outcome measures that were assessed during the study; nevertheless, increases in the ALSFRS-R and MVV were observed on CK-2017357 relative to placebo that were similar in direction and magnitude to those observed in CY 4024. For example, on Day 22, within 2 hours after the final dose of double-blind study drug, the mean change from baseline in the ALSFRS-R was -1.9 points in the six patients who had received placebo, while the mean difference from placebo was +0.3 points in the 16 patients who had competed three weeks of dosing with CK-2017357 (14 on 250 mg dosed twice daily, one on 125 mg dosed twice daily, and one on 125 mg dosed once daily. Similarly, the mean change from baseline to Day 22 in the MVV was -0.4 L/min on placebo, while the mean difference from placebo was +3.6 L/min on CK-2017357.
Additional Poster Presentation at the American Academy of Neurology 64th Annual Meeting
Cytokinetics' scientists presented a poster titled "The Fast Skeletal Troponin Activator, CK-2017357, Increases Muscle Function and Survival in SOD1 (G93A) Mice; a Model of ALS". The objective of this preclinical study was to examine the effects of CK-2017357 in SOD1G93A mutant transgenic mice, a model of ALS in humans. The authors concluded that mice treated with CK-2017357 maintained hindlimb grip strength during disease progression and that CK-2017357 increased muscle strength of a nerve-muscle pair in situ. In addition, there appeared to be a delay in the time to a pre-specified humane endpoint in the CK-2017357-treated mice compared to the age-matched control SOD1 mice. Overall, the authors concluded that the current preclinical findings support the hypothesis that CK-2017357 may benefit patients with ALS by increasing force generation in fast skeletal muscle fibers.
