Biohaven SCA Therapy Meets Primary Endpoint in Pivotal Study

Rare Daily Staff

Biohaven a pivotal study of its experimental therapy troriluzole to treat the rare neurodegenerative disorders spinocerebellar ataxia met its primary endpoint and showed statistically significant improvement on nine primary and secondary measures.

Spinocerebellar ataxia (SCA) is a group of dominantly inherited neurodegenerative disorders characterized by progressive loss of voluntary motor control and atrophy of the cerebellum, brainstem and spinal cord. 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 a number of years. Currently, there are no FDA-approved treatments and no cure for SCA.

SCA is a rare, progressively debilitating neurodegenerative disease that affects approximately 15,000 people in the United States and 24,000 in Europe and the United Kingdom. There are no FDA approved treatments for SCA.

Troriluzole is a third-generation novel prodrug 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.

Data across multiple analyses demonstrate a robust and clinically meaningful slowing of disease progression in people with SCA. These treatment benefits translate into a 50 to 70 percent slower rate of decline compared to untreated patients, representing 1.5 to 2.2 years delay in disease progression over the three-year study period.

Troriluzole 200 mg dosed orally, once daily, in patients with SCA met the study’s primary endpoint on the change from baseline in the modified functional Scale for the Assessment and Rating of Ataxia (f-SARA) at three years in all study population genotypes.

The study utilized phase 3 data and an external control of matched, untreated SCA subjects from the U.S. Clinical Research Consortium for the Study of Cerebellar Ataxia (CRC-SCA) in accordance with FDA’s Guidance on Real-World Evidence (RWE) of effectiveness. All endpoints were prespecified, and both the study protocol and statistical analysis plan were submitted to, and reviewed by, FDA prior to topline data analysis.

The new analysis doubled the previously available three-year data with 63 subjects now completing three years of treatment with troriluzole and matched to the external control arm. Propensity Score Matching (PSM) was used to ensure that untreated patients from the CRC-SCA study were rigorously matched to treated patients from Study BHV4157-206 on baseline characteristics.

The primary objective was to examine the treatment effects of troriluzole for up to 3 years, by comparing data on the f-SARA from patients treated with troriluzole in Study BHV4157-206 to untreated patients from the natural history study. Troriluzole-treated patients demonstrated statistically significant and sustained benefits at years 1, 2 and 3 on the f-SARA compared to a rigorously matched natural history control.

Additionally, prespecified analyses in the protocol employed a separate, independent natural history control from the European SCA natural history study (EUROSCA) for global regulatory purposes. The addition of EUROSCA data increased the external control sample size and added to the robustness of the statistically significant treatment differences at years 1, 2, and 3, favoring troriluzole.

Based on the topline data from pivotal study and previous safety and efficacy data from the troriluzole development program in SCA, Biohaven said it plans to submit a New Drug Application to the FDA in fourth quarter of 2024.

Biohaven has previously received both Fast-Track and Orphan Drug designation from the FDA, and Orphan Drug designation from the European Medicines Agency, for troriluzole in SCA. Troriluzole is eligible for FDA priority review. The company said it will be prepared to commercialize SCA in the United States in 2025 if approved under priority review timelines.

“SCA is a debilitating, relentlessly progressive disease that destroys quality of life, leaving patients unable to care for themselves, walk, or speak,” said Susan Perlman, director of Ataxia Clinic and Neurogenetics Clinical Trials at the David Geffen School of Medicine at UCLA. “Troriluzole is the very first treatment to show a delay in disease progression that can give patients additional years of independence, where they can walk without assistance, continue to work, play with their children, and participate in daily activities.”

Photo: Susan Perlman, director of Ataxia Clinic and Neurogenetics Clinical Trials at the David Geffen School of Medicine at UCLA