Cytokinetics:PhaseII Trials Of Tirasemtiv In Patients With ALS'Results Published

(RTTNews) - Cytokinetics, Inc. (CYTK) announced the publication of two manuscripts reporting data from two clinical trials of tirasemtiv, a novel mechanism fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis or ALS.

One manuscript reports data from two Phase II clinical trials, designated as CY 4024 and CY 4025. In these trials, tirasemtiv appeared to be well-tolerated by patients with ALS, including when receiving a reduced dose of riluzole. The trials cited in this manuscript evaluated the tolerability of tirasemtiv at doses up to 500 mg daily for up to three weeks. In CY 4024, tirasemtiv was given in single daily doses of 125 mg, 250 mg, or 375 mg versus placebo for two weeks, in one cohort without concomitant riluzole and in a second cohort with riluzole administered at a reduced dose of 50 mg once daily. In CY 4025, the dose of tirasemtiv was titrated over three weeks of administration, beginning with 125 mg twice daily to a target of 250 mg twice daily.

Results showed that tirasemtiv was well-tolerated in these patients, with dizziness the most common adverse event. Co-administration of tirasemtiv with riluzole approximately doubled the plasma concentration of riluzole compared to the administration of riluzole without tirasemtiv. Trends were noted for improvement in the ALS Functional Rating Scale-Revised (ALSFRS-R), Maximum Minute Ventilation, and Sniff Nasal Inspiratory Pressure. The authors concluded that positive trends in multiple exploratory outcome measures support the further study of this drug candidate for the potential treatment of ALS.

In the second manuscript, the authors concluded that tirasemtiv appears to have concentration-dependent effects on both function and measures of strength and endurance when administered for up to 21 days, even when time is eliminated as a cofactor. In addition, they reported that both single and repeated dose studies suggested potentially beneficial effects on measures of function, muscle strength and endurance. Since the outcomes measured were identical in previous Phase II clinical trials of tirasemtiv in patients with ALS and the duration of all the trials was 21 days or less, the authors pooled data from all the trials and assessed the relationship between outcomes and plasma concentrations of tirasemtiv to assess consistency of observations and to increase sensitivity.

The authors pooled data for ALSFRS-R, three pulmonary function measures, quantitative muscle strength, and submaximal handgrip endurance. Up to 855 values from 143 patients were plotted against concentrations of tirasemtiv. Linear associations between concentrations of tirasemtiv and changes from baseline of clinical measures were estimated using a repeated-measures mixed model. Statistically significant relationships between increases in these functional measures and increasing plasma concentration of tirasemtiv were observed for all measures except for vital capacity.

The authors concluded that these findings support the development of this drug candidate for the potential treatment of ALS.

Tirasemtiv (formerly CK-2017357) is currently being evaluated in BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS). BENEFIT-ALS is designed to enroll approximately 680 patients who will first complete one week of treatment with open-label tirasemtiv at 125 mg twice daily.

Following completion of the open-label period, patients will be randomized to receive 12 weeks of double-blind treatment with twice-daily oral ascending doses of tirasemtiv beginning at 125 mg twice daily and increasing weekly up to 250 mg twice daily or a dummy dose titration with placebo.