Cytokinetics said today it has halted development of its lead drug tirasemtiv after it failed a Phase III trial in patients with amyotrophic lateral sclerosis (ALS).
Without offering details, Cytokinetics said tirasemtiv missed its primary endpoint in the Phase III VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices after Treatment for a Year in ALS) by failing to show change from baseline in slow vital capacity (SVC) following 24 weeks of double-blind, placebo-controlled treatment.
Cytokinetics added that the decline in SVC from baseline to 24 weeks was smaller in patients who received any dose of tirasemtiv in VITALITY-ALS than the decline seen in patients receiving placebo.
And while the largest differences from placebo were seen in patients randomized to the mid- and high-dose groups of tirasemtiv who could tolerate and remain on their target dose, the company acknowledged that those differences were not statistically significant.
Tirasemtiv also missed the study’s secondary endpoints, which were assessed at 48 weeks after the start of treatment. Those secondary endpoints included:
- Change from baseline in the score of the three respiratory items of the ALS Functional Rating Scale Revised (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;
- Time to the first use of mechanical ventilatory assistance or death through 48 weeks.
“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,” Robert I. Blum, Cytokinetics’ president and CEO, said in a statement.
Investors responded to the failure of tirasemtiv with a stock selloff that saw the price of the company’s shares plummet nearly 37% from yesterday’s close of $11.10, to $7.00 as of 9:28 a.m.
VITALITY-ALS identified no new safety or tolerability findings related to tirasemtiv, while serious adverse events were similar between patients who received the drug and those randomized to placebo. However, more patients discontinued double-blind treatment on tirasemtiv than on placebo, mainly as a result of nonserious adverse events related to tolerability, Cytokinetics said.
In VITALITY-ALS, patients received two-weeks of open-label treatment with tirasemtiv 250 mg/day, 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, patients treated with tirasemtiv were randomized to continue their dose or receive placebo for a four-week double-blind withdrawal phase, while patients originally randomized to placebo continued to receive it.
Following their participation in VITALITY-ALS, patients were eligible to participate in an open-label extension study 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. More than 200 patients have been randomized to tirasemtiv in VIGOR-ALS.
While VITALITY-ALS demonstrated pharmacologic activity for the mechanism of action, Brum said, Cytokinetics believes that tirasemtiv’s limitations could be addressed with its next-generation fast skeletal muscle activator CK-2127107.
“Based on previous Phase I clinical studies, we believe CK-2127107 will be better tolerated and potentially more effective than tirasemtiv in patients with ALS and look forward to Phase II trial results in 2018,” Brum added.
Cytokinetics said results of VITALITY-ALS will be presented on December 8 at the 27th Annual International ALS/MND Symposium in Boston 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.