FDA Accepts NDA Application for Troriluzole as Potential First Treatment for Spinocerebellar Ataxia

Melissa Beiner, MD

According to a new announcement from Biohaven, the FDA has accepted the company’s new drug application (NDA) for its investigational agent troriluzole, a third-generation prodrug that modulates glutamate, for the treatment of patients with spinocerebellar ataxia (SCA). The agency is expected to have a decision sometime in Q3 of this year and if approved, troriluzole would become the first marketed treatment specific to SCA.¹

Troriluzole’s submission comprised data from the pivotal Study BHV4157-206-RWE (NCT06529146) along with confirmatory and supportive data from studies BHV4157-201 and BHV4157-206 (NCT03701399). Study BHV4157-206-RWE, which met its primary end point, comprised of multiple sources of real-world data, including the Clinical Research Conosrtium for the Study of Cerebellar Ataxia cohort (CRC-SCA), the European Integrated Project on Spinocerebellar Ataxias cohort (EUROSCA), and the 3-year open-label extension (OLE) data from troriluzole-treated patients from the previously completed Study BHV4157-206.

In its most notable study, troriluzole achieved its primary end point, with treated patients demonstrating statistically significant improvements in the modified functional Scale for the Assessment and Rating of Ataxia (f-SARA) at 1 and 2 years of treatment. Over the 3-year treatment period, those on 200 mg daily doses of the active agent demonstrated a 50-70% slower rate of decline compared with untreated patients, representing a 1.5-2.2-year delayed in disease progression. In a responder sensitivity analysis, investigators reported an odds ratio of 4.1 (95% CI, 2.1-8.1) for disease progression for untreated external controls vs troriluzole-treated patients when defined by a 2-point or greater worsening on f-SARA after 2 years (P <.0001; pooled analysis).²

"Our NDA filing is the culmination of over 8 years of clinical research and represents an important collaboration across the SCA community,” Melissa Beiner, MD, SCA Clinical Development Lead, Biohaven, said in a statement.¹ “The FDA decision to grant Priority Review demonstrates the extremely high unmet need in this rare neurodegenerative disease. Time is of the essence for patients with SCA, who are suffering relentless and irreversible functional decline including impairments in coordination and balance leading to falls, loss of ambulation, and difficulties with vision, speech and swallowing."

She added, "The robust clinical data presented in the NDA demonstrate sustained and compelling treatment benefit in SCA patients treated with troriluzole, a once-daily, oral pill. We look forward to working closely with the FDA throughout the review process to bring the very first treatment to patients and families suffering from SCA."

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In BHV4157-206, troriluzole-treated patients with a SCA3 genotype demonstrated stable disability vs placebo, with P values of 0.045 on f-SARA after 48 weeks. Patients on the medication also demonstrated a substantial risk reduction in falls, regardless of SCA genotype. Specifically, all SCA types had a cumulative 51% reduction (P = .008) while those with baseline gait 1 or 2 demonstrated a 57.4% reduction (P = .004).

Across the studies, results have shown that untreated patients with SCA have a greater risk of significant disease worsening than those on troriluzole. In BHV4157-206-RWE, the odds of at least a 2-point worsening of f-SARA in untreated patients was 2.4 times higher in external controls (P = .0359), 6.1 times as high in EU external controls (P <.0001), and 4.1 times higher among global external controls (P <.0001) in comparison with troriluzole.³

"The FDA acceptance for review of this NDA represents a critical milestone for SCA patients. Since the discovery of the first gene for SCA in 1993, patients and families affected by SCA have watched generation after generation suffer severe, progressive disability and premature death with no treatment options. The need for an intervention that can slow disease progression and help patients maintain their independence is urgent,” Jeremy Schmahmann, MD, professor of neurology at Harvard Medical School and founding director of the Ataxia Center and the Martha and Robert Fogelman Endowed Chair in Ataxia and Cerebellar Neurology at Massachusetts General Hospital, said in a statement.¹

"The delay in disease decline shown in the real-world evidence study is a watershed in the history of the SCAs.This is what patients have been waiting for. It is what the doctors who have been powerless, have been waiting for. Additionally, the importance of troriluzole's effects on reducing falls in this patient population cannot be overstated. I applaud the FDA for recognizing this urgency by granting a Priority Review and look forward to using troriluzole in the clinic if approved,” he added.

REFERENCES
1. Biohaven Announces FDA Acceptance and Priority Review of Troriluzole New Drug Application for the Treatment of Spinocerebellar Ataxia. News release. Biohaven. February 11, 2025. Accessed February 11, 2025. https://www.prnewswire.com/news-releases/biohaven-announces-fda-acceptance-and-priority-review-of-troriluzole-new-drug-application-for-the-treatment-of-spinocerebellar-ataxia-302373056.html
2. Biohaven achieves positive topline results in pivotal study of troriluzole in spinocerebellar ataxia (SCA). News release. Biohaven. September 23, 2024. Accessed February 11, 2025. https://www.prnewswire.com/news-releases/biohaven-achieves-positive-topline-results-in-pivotal-study-of-troriluzole-in-spinocerebellar-ataxia-sca-302255056.html
3. Biohaven provides overview of clinical progress, regulatory updates, and pipeline developments at R&D day. News release. Biohaven Pharmaceuticals. May 31, 2023. Accessed February 11, 2025. https://www.prnewswire.com/news-releases/biohaven-provides-overview-of-clinical-progress-regulatory-updates-and-pipeline-developments-at-rd-day-301838058.html