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Drug for Spinocerebellar Ataxia Gets a Second Lease on Life

A drug that was initially rejected for its failure to distinguish itself from placebo in a pivotal trial for spinocerebellar ataxia (SCA) is being reconsidered, researchers reported at the virtual 2021 AAN Annual Meeting.

Treatment with troriluzole is being studied after a three-year open-label trial appears to show a stabilization of the degenerative balance disorder, said Melissa Beiner, MD, director of research and development at Biohaven Pharmaceuticals in Madison, CT.

Troriluzole is a glutamate-modulating agent with some pleiotropic effects, such as potential activation of some calcium-activated channels.

“Even though this isn't a really good comparison with a natural history cohort, we were encouraged by the 96-week outcomes because, at the very least, we think we are seeing disease attenuation in this population with troriluzole," said Dr. Beiner in her oral presentation.

There are no US Food and Drug Administration-approved treatments for SCAs, a group of rare neurodegenerative disorders that can present with balance and gait abnormalities, incoordination of limbs, and dysarthria, as well as cognitive dysfunction, dysphagia, and motor pathology, Dr. Beiner said. Most treatments used are palliative, she added.

In the phase 2/3 double-blind, placebo-controlled trial of troriluzole in adult subjects with SCA, the researchers used preclinical data and two early- stage trials from Italy, which suggested that glutamate modulation had a role in SCA. After a screening period, the study had an eight-week randomization phase, followed by a 48-week open-label phase.

“At the end of our randomization phase we did not hit our primary endpoint, which was the change in the Scale for the Assessment and Rating of Ataxia [SARA] score from baseline to the end of the eight weeks," Dr. Beiner said. 

“In hindsight, the study suffered from a very high placebo performance and the eight-week period was not enough to see a difference. Our patients then proceeded into the open-label [phase]. At the end of the open-label [period], we started hearing from our investigators that an overwhelming number of patients felt that they were declining while they were coming off troriluzole," she said. “The patients felt that they had been more stable on the drug and we were getting request after request for patients to remain on it."

The company re-booted the trial. “We looked at our 48-week data in comparison to an unmatched natural history cohort," she said. “We matched patients from our cohort with the genotype, age, sex, severity of disease, and the baseline SARA score with those in the natural history cohort. After one year, the 81 patients in the troriluzole arm had a change in their SARA score of -0.34 points versus an increase in SARA at 48 weeks among the 112 patients in the natural history cohort, which had an increase of about one point. The difference was 1.41 points which was statistically significant (p=0.0007), she said.

“This gave us the information we needed to start another open-label phase for 96 weeks within the same study to look at this drug over a longer period of time," she said.

“When patients were on the drug, their SARA scores improved by about a point and then were stable until they came off the drug, and their scores increased," Dr. Beiner said. “When they were back on the drug their score stabilized again about at a level of 0.5 points above their original baseline. We would have expected patients at two years, without drug, to have declined two to four points. The patients who were off the drug for less than 180 days had about a 0.5 point increase above baseline, but in those who had a gap of more than 180 days their SARA score was about .75 points above baseline."

Based on the results, Dr. Beiner said the company has launched another phase 3 trial, but this time the randomization phase will last 48 weeks, followed by an open-label phase of another 48 weeks. The outcome measure will use a modified SARA score to try to tease out more functional aspects of the disorder.

“Typically, when you have a negative outcome measure, you will believe the medication is not going to be beneficial," said Deborah Hall, MD, PhD, FAAN, professor of neurological sciences at Rush University in Chicago. “But this study's data suggest that either the patients need longer duration of treatment, the drug is slowing progression, or that there is an impact on participant quality of life that needs to be a primary outcome measure."

“We do need another placebo-controlled study with modification of the protocol to account for findings in the first study, and we need to see the troriluzole data published after peer review," she said. “Stabilization may be the more accurate description for what this drug is doing in patients with SCA if the follow-up studies confirm this study's findings."

Albert La Spada, MD, PhD, Distinguished Professor of Neurology, Pathology & Laboratory Medicine, and Biological Chemistry at University of California, Irvine School of Medicine, agreed that although the findings are promising, it would be “premature to draw definitive conclusions from an open-label trial. However, as many SCA patients show disease progression over time, this initial study is encouraging and now requires that a comprehensive placebo-controlled clinical trial be pursued."

Dr. Beiner is an employee of Biohaven. Dr. Hall, who is an associate editor of Neurology Today, disclosed relationships with Biohaven, CHDI

AAN Abstract S3.002: Beiner M, Wirtz V, L'Italien G, et al. Analysis of 96 week, long-term open label extension phase of study BHV4157-201: A phase IIb/III, randomized, double-blind, placebo-controlled trial of the safety and efficacy of troriluzole in adult subjects with spinocerebellar ataxia.