On April 25, Cytokinetics announced top-line results of BENEFIT-ALS (Blinded Evaluation of Neuromuscular Effects and Functional Improvement with Tirasemtiv in ALS). In a second press release announced today, they provided greater data suggesting a potential impact on Slow Vital Capacity (SVC), a key measure of respiratory ability, among those in the trial taking tirasemtiv.
According to the 4/25 announcement (
Link), BENEFIT-ALS did not achieve its primary endpoint of efficacy. Efficacy is a measure of the effect that the drug has on slowing or stopping the disease. Efficacy was measured in this study using the ALSFRS-R scale. According to the limited information in the press release, the difference between progression rates of those on tirasemtiv and those taking a placebo in the study did not reach statistical significance, which is typically thought to be p=0.05 or less. In this case, the p value was reported in the top line results including in the press release as 0.11.
Additionally in the 4/25 release, there were mixed results on secondary efficacy analyses of the effect of tirasemtiv on respiratory function and other measures of skeletal muscle function. The original press release did not go into detail on those topics or include more information. However, respiratory function was measured in the trial in a number of ways, including the SNIP test and tests to measure slow vital capacity (SVC).
In the second press release announced today, April 29, 2014 (
Link), Cytokinetics provided a detailed analysis of additional measures, which suggested that the trial may have been the first to show a statistically significant effect on slow vital capacity. The following graph was recreated from that press release and shows various additional measures and the statistical significance of each:
Detailed results were presented during the 66th Annual Meeting of the American Academy of Neurology (AAN) today, April 29th at the Pennsylvania Convention Center in Philadelphia, PA. There also will be a reception for patient advocacy groups on April 30th at AAN. There will be a webinar given by Dr. Jeremy Shefner of SUNY Medicine, principal investigator of the trial, to discuss BENEFIT-ALS results in May. The exact date is unknown at this time.
The Phase IIB clinical trial of tirasemtiv enrolled more than 700 PALS worldwide. More than 400 in the US, 100 in Canada, and dozens in countries like the UK, Spain, France, and the Netherlands. 605 PALS were randomized into the 12-week double blind placebo controlled clinical trial, code named “BENEFIT-ALS.” 116 of these PALS that were in the control group inadvertently received active compound midway through the clinical trial, and as a result, they were eliminated from the analysis of clinical trial results. This error was the result of a trial management issue and Cytokinetics took full responsibility -- recruiting additional PALS to ensure sufficient numbers of participants would be included to fully evaluate the benefits of the drug.
During a presentation given by Dr. Jeremy Shefner at a conference in Milan in 2013, it was reported that the most common side effects of the drug occurred during the first week and was reported as dizziness, fatigue, or nausea. In today’s press release, it was suggested that some of these serious adverse events (SAE) or similar SAE reported may have played a role in the trial missing statistical significance on the primary endpoint.
The first week of the study was open label (all people got active compound) in order to determine the severity of the side effects in each person. Just under 100 PALS were eliminated from the study after the first week as they were not able to tolerate a dose of 250mg. This was done to attempt to reduce dropouts after randomization and to help ensure that the study remained blinded all the way through according to Dr. Shefner. However, the majority of people living with ALS in the clinical trial were able to sustain the maximum dose in the study, which was 500mg per day, according to Dr. Shefner.
Robert I. Blum, Cytokinetics’ President and Chief Executive Officer said, “The results from BENEFIT-ALS are just now becoming available to our team at Cytokinetics and will be shared in more detail with the broader scientific and medical community focused to research in ALS in the next few days. Understanding these results will require significant further review. Once we have fully evaluated the data from BENEFIT-ALS, we expect to determine whether there is a potential development path forward for
tirasemtiv for the potential treatment of ALS and what may be the appropriate next steps.”