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Biohaven Says Troriluzole Fails to Meet Primary Endpoint in Phase 3 Study in Spinocerebellar Ataxia

May 23, 2022

Biohaven Pharma reported top-line results from a phase 3 clinical trial evaluating the efficacy and safety of its investigational therapy, troriluzole, in patients with spinocerebellar ataxia, which did not reach statistical significance.

Photo: Vlad Coric, CEO of Biohaven

The primary endpoint, change from baseline to Week 48 on the modified functional Scale for the Assessment and Rating of Ataxia (f-SARA), did not reach statistical significance in the overall SCA population as there was less than expected disease progression over the course of the study.

In the overall study population, the troriluzole and placebo groups each had mean baseline scores of 4.9 on the f-SARA and the two groups showed minimal change at the 48-week endpoint with f-SARA scores of 5.1 and 5.2, respectively.

Spinocerebellar ataxia (SCA) is a group of dominantly inherited disorders characterized by progressive ataxia affecting coordination of hands, arms, and legs as well as balance and speech. Patients experience significant morbidity, including progression to a wheelchair, impaired gait leading to falls, inability to communicate due to speech impairment, difficulty swallowing, and premature death. While signs and symptoms can appear anytime from childhood to late adulthood, SCA typically presents in early adulthood and progresses over the years. The range of symptoms and rate of progression of disease depend on the type of SCA, age of onset, and other genetic factors. Currently, there are no FDA-approved treatments and there is no cure for SCA.

Post hoc analysis of efficacy measures by genotype suggests a treatment effect in patients with the SCA Type 3 (SCA3) genotype, which represents the most common form of SCA and accounted for 41 percent of the study population.  In the SCA3 subgroup, troriluzole showed a numerical treatment benefit on the change in f-SARA score from baseline to Week 48 compared to placebo. SCA patients treated with troriluzole showed minimal disease progression over the study period. Further, in patients in the SCA3 subgroup who were able to walk without assistance at baseline, troriluzole demonstrated a greater numerical treatment benefit on the change in f-SARA score from baseline to Week 48 compared to placebo. Notably, the f-SARA is a novel, 16-point scale developed in collaboration with FDA as the primary outcome measure for this trial; the scale was designed to limit subjectivity of the scale and focus on functional aspects of the disease so that significant changes would be considered clinically meaningful.

Across all genotypes, patients who were able to ambulate at baseline showed a reduction in the relative risk of falls in troriluzole-treated patients versus placebo. Patient reported falls, as measured by adverse events reveal an approximately 58 percent reduction of fall risk in the troriluzole group (10 percent versus 23 percent AE incidence of falls in the troriluzole and placebo groups, respectively). Overall, troriluzole demonstrated a favorable safety and tolerability profile, consistent with past clinical trial experience.

“The fact that the overall study population did not show significant disease progression on the f-SARA at 1 year, as would have been anticipated, and failed to meet the study’s primary outcome measure, highlight some of the challenges of studying rare diseases such as SCA,” said Vlad Coric, CEO of Biohaven. “However, the post hoc analyses by SCA genotype suggest early and sustained improvements in the f-SARA over 48 weeks for SCA3 patients treated with troriluzole compared to placebo. The scale improvements were clinically meaningful, consistent with the role that glutamate excitotoxicity is thought to play in the underlying pathogenesis of this disease and was associated with an important risk reduction in falls in the same SCA3 study population, as well as across all SCA genotypes.”

He noted that patients with SCA3 have no approved therapies and suffer severe disease-related morbidities, including being at high risk for falling due to incoordination of gait. Given the debilitating nature of this disease, he said the company would be sharing the SCA3 genotype data with regulators and work with the FDA to address the high unmet need in this patient population.

Troriluzole is a third-generation prodrug and new chemical entity that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. The primary mode of action of troriluzole is reducing synaptic levels of glutamate. Troriluzole increases glutamate uptake from the synapse, by augmenting the expression and function of excitatory amino acid transporters located on glial cells that play a key role in clearing glutamate from the synapse.

Biohaven is also evaluating the efficacy of troriluzole in a number of other diseases associated with excessive glutamate, including obsessive compulsive disorder.

Author: Rare Daily Staff

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