Poor Tolerability Leads to Failure of ALS Therapy Candidate Tirasemtiv in Phase 3 Trial

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by Bionews Staff |

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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.

“The  effects of tirasemtiv observed in patients with ALS support the future development of CK-2127107, our next-generation fast skeletal muscle troponin activator which is the subject of FORTITUDE-ALS, our ongoing Phase 2 clinical trial in patients with ALS,” Blum said. “As recently published Phase 1 studies demonstrate, CK-2127107 may be more effective and better tolerated than tirasemtiv.”