Cytokinetics said today its lead drug candidate tirasemtiv failed to meet its primary efficacy endpoint in a Phase IIb trial assessing the compound’s effects on people with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). 

The Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS (BENEFIT-ALS) trial showed a mean change from baseline in the revised ALS Functional Rating Scale (ALSFRS-R) on tirasemtiv versus placebo of -2.98 points in the tirasemtiv group, compared with -2.40 points in the placebo group.

Secondary endpoints—which evaluated measures of respiratory performance and other measures of skeletal muscle function and fatigability—produced mixed results, the company added, without elaborating. Cytokinetics plans to present detailed results on Tuesday during the 66th Annual Meeting of the American Academy of Neurology in Philadelphia.

“Once we have fully evaluated the data from BENEFIT-ALS, we expect to determine whether there is a potential development path forward for tirasemtiv for the potential treatment of ALS and what may be the appropriate next steps,” Robert I. Blum, Cytokinetics’ president and CEO, said in a statement. “Patients with ALS desperately need new therapeutic alternatives to slow the course of their disease and loss of function. We stand with the ALS community in our disappointment that BENEFIT-ALS did not achieve its primary efficacy endpoint.”

Tirasemtiv is a skeletal muscle activator designed to work by selectively activating the fast skeletal muscle troponin complex by increasing its sensitivity to calcium. The drug has been granted FDA’s orphan drug designation and fast track status, as well as the European Medicines Agency’s orphan medicinal product designation.

In preclinical studies and earlier clinical trials, tirasemtiv showed increases in skeletal muscle force in response to neuronal input, as well as delays in the onset and reductions in the degree of muscle fatigue.

BENEFIT-ALS enrolled 711 patients in 73 centers in 8 countries in a trial designed to evaluate tirasemtiv’s safety, tolerability and efficacy in ALS patients. Patients began treatment with open-label tirasemtiv at 125 mg twice daily. Patients who tolerated this open-label treatment for one week were randomized to receive 12 weeks of double-blind treatment with twice-daily oral ascending doses of tirasemtiv or placebo, beginning at 125 mg twice daily and increasing weekly up to 250 mg twice daily (or a dummy dose titration with placebo).

Clinical assessments occurred monthly during double-blind treatment. Patients also returned for follow-up evaluations at one and four weeks after their final dose of double-blind study medication, the company said.

It is not known what effect, if any, the trial failure will have on the company’s previously announced plan to release first-quarter results on May 6.

The Phase IIb failure comes about a year after Cytokinetics was forced to delay results of the trial by three months after a dosing error in which 58 patients in the treatment arm were instead given placebo. A data management vendor told the company that a programming error in an electronic data capture system accounted for the error, which prompted the company to increase that trial’s number of patients from 500 to 680.

Tirasemtiv is the second Cytokinetics compound to fail a Phase IIb trial in less than a year. The company partnered with Amgen on omecamtiv mecarbil, but an intravenous formulation of the heart failure drug candidate failed to show significant improvement in dyspnea patients compared to placebo in a 613-patient study, Amgen disclosed in September.

The companies are awaiting results of another Phase II trial assessing an oral form of omecamtiv mecarbil before deciding whether to terminate the program or continue its development into Phase III.

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