Robert I. Blum, president and chief executive officer of the San Francisco-based biotech, announced negative results for VITALITY-ALS (NCT02496767) after tirasemtiv, a fast skeletal muscle troponin activator, failed to meet the primary endpoint or any of the secondary endpoints of the Phase 3 clinical trial.
Mainly, tirasemtiv failed to demonstrate greater improvements in slow vital capacity (SVC), a key measure of lung capacity, over a 24-week period compared to placebo. In addition, ALS patients taking the drug did no better than those on placebo when it came to the 48-week secondary endpoints assessing functional ability and muscle strength.
“This is a disappointing day for patients with ALS and their caregivers who are in desperate need of new therapies,” Blum said in a Nov. 21 conference call. “All of us at Cytokinetics have been dedicated so diligently for so many years to find a potential new medicine for patients with ALS. We also recognize this is a disappointing day for shareholders and others who shared our hope for potential positive results.”
Issues included dizziness, light-headedness and nausea, which were also the main side effects seen in the Phase 2 BENEFIT-ALS trial (NCT01709149), the company said. Most tolerability issues were due to off-target effects of the drug on the brain, since tirasemtiv crosses the blood-brain barrier. This physical barrier shields the brain from the overall blood circulation, tightly regulating molecules that can enter the brain from the bloodstream, including drugs.
“Based on previous Phase 1 clinical studies, we believe CK-2127107 will be better tolerated and potentially more effective than tirasemtiv in patients with ALS,” said Blum, who expects to release Phase 2 trial (NCT03160898) results sometime in 2018. CK-2127107, researchers believe, is unable to cross the blood-brain barrier, a marked difference from tirasemtiv.
Three such trials are now underway, in ALS patients and those with spinal muscular atrophy (NCT02644668) and chronic obstructive pulmonary disease (NCT02662582). Cytokinetics is also studying CK-2127107 in a Phase 1b trial of elderly subjects with limited mobility (NCT03065959).
“We believe we did the right thing to test the hypothesis that tirasemtiv may potentially reduce the decline in SVC [slow vital capacity] in patients afflicted with ALS, by seeking to confirm the results of BENEFIT-ALS [the last of four Phase 2 trials of tirasemtiv],” he said. “We designed VITALITY-ALS to ask key scientific and clinical questions.”
VITALITY enrolled 744 ALS patients at 81 investigative centers in 11 countries, said Dr. Fady I. Malik, the company’s executive vice president of research and development.
Patients received 125 mg of tirasemtiv twice a day for two weeks, and were then randomly assigned to one of three tirasemtiv doses — 125 mg, 375 mg or 500 mg — twice a day, or placebo.
“There were no new safety or tolerability findings, and serious adverse events were similar to placebo,” he said. “More patients discontinued double-blind treatments of tirasemtiv than placebo, however. We believe poor tolerability of tirasemtiv may have contributed to these results.”
Cytokinetics will present final results of its study Dec. 8 at the 28th ALS/MND Symposium in Boston.
“Until then, we believe the results are clear, and we’ve concluded that the tolerability profile interferes with our ability to meaningfully demonstrate a therapeutic signal,” Malik said. “The right thing to do now is suspend further development of tirasemtiv.”
Dr. Andrew Wolff, chief medical officer at Cytokinetics, cited “higher than expected dropouts,” as well as “an excess of non-serious adverse effects that contributed to more early terminations.” In all, tirasemtiv had been studied in clinical trials that enrolled more than 1,000 people around the world.
“We conduct trials like this to generate and test scientific and clinical hypotheses, and we know how much patients and their caregivers were hoping for a different outcome. So were we,” Blum said. “These results only reinforce our resolve, however, to keep up the fight alongside you.”
The Washington-based ALS Association said it, too, is saddened by the results of the VITALITY-ALS trial.
“We are grateful that Cytokinetics has already expressed its commitment to finding new therapies for people with ALS and hopeful that its next treatment, which is currently in clinical trials, will be successful,” the nonprofit organization said in a brief statement. “We thank Cytokinetics for its unwavering support of the ALS community.”