Pivotal Phase 3 clinical trial results presented at this year’s 28th International Symposium on ALS/MND reveal that Cytokinetics‘ investigational therapy tirasemtiv failed to provide a positive therapeutic impact on both muscle strength and slow vital capacity (SVC) in ALS patients.
The results, which were presented by Jeremy Shefner, MD, lead investigator of the Phase 3 VITALITY-ALS study (NCT02496767), noted that tolerability issues played a key role in in the study’s failure.
The VITALITY-ALS study sought to build off the company’s previous Phase 2b BENEFIT-ALS trial, which suggested that tirasemtiv had the potential to preserve slow vital capacity and strength over three months in study participants.
Results from BENEFIT-ALS, which included 711 patients from eight countries, revealed that tirasemtiv had potentially clinically meaningful benefits, slowing the rate of decline of slow vital capacity (SVC), a measure of lung function, when compared to patients treated with placebo.
In spite of previous promising findings, the drug failed to meet the primary endpoint of VITALITY-ALS: a positive change from patients’ baseline in SVC, which investigators measured 24 weeks after participants were randomized to receive either the drug at various doses, or placebo. A less than 1 percent change was noted in all three tirasemtiv doses tested versus placebo.
Additionally, the study’s secondary endpoint, which evaluated a change from baseline in the ALS Fuctional Rating Scale (ALSFRS-R), measured at 48 weeks into the study, also failed to show a clinically relevant improvement compared to placebo.
The 54-week trial randomized study participants with ALS into groups who received either one of three daily doses of tirasemtiv (250, 375, or 500 mg) or a placebo. The patients’ daily dose was increased every two weeks to either the target dose level established by the study’s design or to their maximum tolerated dose.
A lack of tolerability to tirasemtiv, however, played a major role in the findings, with a large number of patients leaving the study early due to adverse events caused by the drug. Participants were randomized into the testing groups after two weeks of open-label tirasemtiv (125 mg twice a day) — a week longer than in BENEFIT-ALS.
Previous safety and tolerability profiles for tirasemtiv appeared satisfactory. In a Cytokinetics press release from 2012, similar early dosing levels were well-tolerated over a short period of time.
“Dr. Shefner concluded that CK-2017357 [tirasemtiv] appeared to be safe and well-tolerated dosed daily at 125 mg, 250 mg, and 375 for two weeks,” the press released stated, adding that “encouraging trends were observed in the ALSFRS-R and MVV.”
At the ALS/MND symposium, held Dec. 8-10 in Boston, Shefner acknowledged that “tolerability was a significant issue,” with only 65.8 percent of participants completing 24 weeks of treatment. It appears that the higher 500 mg dose used in VITALITY-ALS, as well as the longer testing durations of 24 and 48 weeks compared to previous studies, revealed the longer-term tolerability issues with the drug.
Interestingly, patients on the lowest dose experienced the highest point of effect from tirasemtiv.
Robert I. Blum, Cytokinetics’ president and CEO, stated in a press release that the company is “profoundly disappointed with these results,” but remains optimistic that insights from both the VITALITY-ALS trial as well as the previous BENEFIT-ALS study suggest that the mechanism of action central to Cytokinetics’ therapeutic technologies is still viable for treating ALS.