Cytokinetics has announced that international phase 3 clinical trial of tirasemtiv in patients with amyotrophic lateral sclerosis (ALS) has did not meet the primary endpoint.

The VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices after Treatment for a Year in ALS) is a phase 3 clinical trial of tirasemtiv in patients with amyotrophic lateral sclerosis (ALS) that did not meet the primary endpoint of change from baseline in slow vital capacity (SVC) which was evaluated at 24 weeks following randomization or any of the secondary endpoints in the trial which were evaluated at 48 weeks. 

No new safety or tolerability findings related to tirasemtiv were identified in VITALITY-ALS.  Serious adverse events were similar between patients who received tirasemtiv or placebo but more patients discontinued double-blind treatment on tirasemtiv than on placebo primarily due to non-serious adverse events related to tolerability.

The decline in SVC from baseline to 24 weeks was smaller in patients who received any dose of tirasemtiv in VITALITY-ALS compared to the decline in patients receiving placebo.  The largest differences from placebo were observed in patients randomized to the mid- and high-dose groups of tirasemtiv who could tolerate and remain on their target dose, although those differences were not statistically significant.

"While we are deeply disappointed by the results of VITALITY-ALS, we remain committed to people with ALS who are fighting this devastating disease and who need new therapies to slow the decline of respiratory function and muscle strength that are key hallmarks of disease progression," said Robert I. Blum, Cytokinetics’ President and CEO.

The results of VITALITY-ALS will be presented on December 8, 2017 at the 27th Annual International ALS/MND Symposium in Boston, MA by Jeremy Shefner, M.D., Ph.D., Lead Investigator of VITALITY-ALS, Professor and Chair of Neurology at Barrow Neurological Institute, and Professor and Executive Chair of Neurology at University of Arizona, Phoenix.

VITALITY-ALS was a multi-national, randomized, double-blind, placebo-controlled trial in patients with possible, probable or definite ALS, diagnosed within 24 months, and with SVC at baseline ≥ 70 percent predicted.

The primary endpoint of the trial assessed change from baseline in SVC, after 24 weeks of double-blind, placebo-controlled treatment.

Secondary endpoints, assessed at 48 weeks, included change from baseline in the score of the three respiratory items of the ALSFRS-R (i.e., the sum of items 10, 11 and 12) at 48 weeks; slope of the mega-score of muscle strength at 48 weeks; time to the first occurrence of a decline from baseline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death through 48 weeks; time to the first occurrence of a decline in SVC to ≤50% predicted or the onset of respiratory insufficiency or death through 48 weeks; change from baseline in the ALSFRS-R total score at 48 weeks; and time to the first use of mechanical ventilatory assistance or death through 48 weeks.

Patients enrolled in VITALITY-ALS received two-weeks of open-label treatment with tirasemtiv administered at 250 mg/day. Patients were then randomized into a double-blind treatment phase to placebo or one of three target tirasemtiv dose levels (250 mg/day, 375 mg/day, 500 mg/day) in a 3:2:2:2 ratio.

After 48 weeks of randomized, double-blind, placebo-controlled treatment, patients who received tirasemtiv during those 48 weeks of double-blind treatment were randomized to continue the dose of tirasemtiv at which they completed the 48 weeks of double-blind treatment or to placebo for a four-week double-blind, tirasemtiv withdrawal phase.  Patients who received placebo during the 48 weeks of double-blind treatment continued to receive placebo during the double-blind, tirasemtiv withdrawal phase.

Following their participation in VITALITY-ALS, patients were eligible to participate in an open-label extension study of tirasemtiv, VIGOR-ALS (Ventilatory Investigations in Global Open-label Research in ALS), designed to assess the long-term safety and tolerability of tirasemtiv in patients with ALS. Currently, over 200 patients are receiving tirasemtiv in VIGOR-ALS. 

Cytokinetics will seek advice from the academic leadership of VITALITY-ALS and its clinical investigators, regulatory authorities and other consultants before making decisions about continuing treatment with tirasemtiv in VIGOR-ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that afflicts approximately 30,000 people in the United States and a comparable number of patients in Europe. Approximately 6,000 new cases of ALS are diagnosed each year in the United States.

 The average life expectancy of an ALS patient is approximately three to five years after diagnosis and only 10 percent of patients survive for more than 10 years. Death is usually due to respiratory failure because of diminished strength in the skeletal muscles responsible for breathing. Few treatment options exist for these patients, resulting in a high unmet need for new therapies to address functional deficits and disease progression.

Tirasemtiv is a fast skeletal muscle troponin activator (FSTA) that selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium and, in preclinical studies and early clinical trials, demonstrated increases in skeletal muscle force in response to neuronal input and delays in the onset and reductions in the degree of muscle fatigue. Tirasemtiv has been studied in clinical trials that have enrolled over 1000 people internationally.

CK-2127107 is a next-generation FSTA arising from Cytokinetics' skeletal muscle contractility program. CK-2127107 was derived from a different chemical structural class and was designed to have certain advantages relative to tirasemtiv. 

CK-2127107 appears to be more potent than tirasemtiv in preclinical models and in humans and appears better tolerated compared to tirasemtiv.  CK-2127107 has demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with muscle weakness and fatigue. CK-2127107 has been the subject of five completed Phase 1 clinical trials in healthy volunteers, which evaluated the safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics of the drug candidate.

CK-2127107 is the subject of an ongoing clinical development program in neuromuscular and non-neuromuscular diseases and conditions associated with muscle dysfunction and weakness, including three Phase 2 trials currently underway in patients with each of SMA, ALS, or COPD, as well as a Phase 1b trial in elderly subjects with limited mobility.