FDA Issues Complete Response Letter for Spinocerebellar Ataxia Agent Troriluzole

In recent news, the FDA has issued Biohaven a complete response letter (CRL) for its clinical application regarding troriluzole, an investigational agent for patients with spinocerebellar ataxia (SCA). Troriluzole, a novel, third-generation tripeptide prodrug of riluzole, the FDA-approved drug for ALS, was aiming to become the first approved treatment for SCA, a rare neuromuscular disorder that lacks effective options.¹

According to Biohaven, the reasons behind the CRL were related to issues with the data included in the new drug application (NDA), such as the decision to use real-world data and external controls. Ultimately, the agency felt that this led to potential bias, design flaws, and lack of pre-specification and unmeasured confounding factors. The company is expected to work with the FDA to discuss next steps for the investigational agent in efforts to bring the treatment to the SCA community.

"We are extremely disappointed on behalf of patients by this action from the Office of Neuroscience at FDA," Vlad Coric, MD, chairman and chief executive officer at Biohaven, said in a statement.¹ "Beyond substantial evidence of safety and efficacy, patients with rare diseases also deserve an efficient, fair and flexible regulatory process that aligns with the urgency of their high unmet medical needs. Such an approach has been mandated by Congress to empower the FDA with maximum regulatory flexibility for rare disease."

The submission for troriluzole included data from the pivotal study BHV4157-206-RWE (NCT06529146), supported by findings from Studies BHV4157-201 and BHV4157-206 (NCT03701399). The BHV4157-206-RWE study, which achieved its primary end point, integrated multiple real-world data sources—specifically, the Clinical Research Consortium for the Study of Cerebellar Ataxia (CRC-SCA), the European Integrated Project on Spinocerebellar Ataxias (EUROSCA), and three-year open-label extension (OLE) data from troriluzole-treated participants in the completed BHV4157-206 trial.²

In BHV4157-206-RWE, also known as 206-RWE, the primary end point was change in Scale for the Assessment and Rating of Ataxia (SARA) score at 48 weeks and beyond, compared with natural-history progression. All told, results revealed that treatment with troriluzole was associated with an approximately 50-70% slowing of disease progression when compared with matched real-world controls from CRC-SCA and EUROSCA cohorts. Ultimately, the drug met its primary end point, with no new safety signals observed compared with prior studies.

According to Biohaven, a March 2024 meeting with the FDA established the fact that a large treatment effect would be needed to overcome the biases of an externally controlled trial such as 206-RWE. The company felt as though the totality of the evidence submitted in the application was enough to overcome the limitations of a real-world study, noting that the trial “clearly met criteria of a large and robust treatment effect.”

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In the company’s statement, Coric added, "Real-world evidence is an important research approach to assessing and delivering new therapies for complex rare diseases but, despite FDA policy initiatives supporting such tools, the front-line review divisions are not yet embracing FDA policy for the use of real-world evidence or the application of regulatory flexibility for rare disease."

The NDA for troriluzole was accepted by the FDA in early February; however, the review period was extended by three months as the agency continued evaluating the submission. Biohaven had been expected to participate in an advisory committee meeting for troriluzole, but the FDA canceled the session just weeks before its scheduled date, effectively halting further clinical discussion.¹

"Patients with SCA and clinicians who treat them deserve to be heard on this important NDA filing,” Jeremy Schmahmann, MD, professor of neurology at Harvard Medical School, and director of the Ataxia Unit, said in a statement.¹ "There is too much at stake for patients. The FDA decision not to listen to disease experts and respect the patient perspective before taking action represents a misstep in the due process, and a failure to deploy regulatory flexibility to evaluate benefit:risk of a medication that has proven to be safe and effective for this rare, debilitating neurodegenerative disease that has no current treatment."

In 206-RWE, 200 mg daily doses of troriluzole led to a 1.5-2.2-year delay in disease progression, which was further supported in sensitivity analyses. There, 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). Notably, treatment with troriluzole also led to a risk reduction in falls that was seen across all SCA types (51%; P = .008) and those with ambulatory SCA (57%; P = .004).³

In the BHV4157-206 trial, troriluzole-treated patients with the SCA3 genotype maintained stable disability compared with placebo (f-SARA, P = .045 at 48 weeks) and showed a marked reduction in fall risk across all genotypes—a 51% cumulative decrease overall (P = .008) and 57.4% among those with baseline gait scores of 1–2 (P = .004). Complementary findings from BHV4157-206-RWE further supported these benefits, showing that untreated patients had a significantly higher likelihood of disease progression, with 2.4- to 6.1-fold greater odds of at least a 2-point f-SARA worsening across multiple external control cohorts (P ≤ .0359).⁴

"The leading SCA experts in the United States directly communicated their support of the troriluzole data to the FDA but unfortunately the Office of Neuroscience's inability to collaboratively engage with Biohaven, the patient community and leading experts leave us with concerns about the lack of regulatory flexibility that is being applied for rare, life-threatening conditions," Coric added.

He went on to say, "There are a number of common sense solutions and regulatory tools that the Office of Neuroscience could have applied including a fair hearing of the drug's efficacy and safety risks at an Advisory Committee of experts and patients, post-marketing studies, labelling limitations or an accelerated approval pathway. Patients are waiting and the certainty of disease progression for SCA patients far outweighs any residual uncertainty regarding potential design bias or interpretation of study data, especially when the primary outcome measure was achieved in a study protocol and statistical analysis plan that was reviewed by the FDA prior to data analysis. SCA patients deserved approval of VYGLXIA and certainly a more balanced interpretation of benefit:risks."

REFERENCES
1. FDA Issues Complete Response Letter for Biohaven's VYGLXIA (troriluzole) New Drug Application for Spinocerebellar Ataxia. News release. Biohaven. November 4, 2025. Accessed November 5, 2025. https://www.prnewswire.com/news-releases/fda-issues-complete-response-letter-for-biohavens-vyglxia-troriluzole-new-drug-application-for-spinocerebellar-ataxia-302604884.html
2. 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 November 5, 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
3. Biohaven achieves positive topline results in pivotal study of troriluzole in spinocerebellar ataxia (SCA). News release. Biohaven. September 23, 2024. Accessed November 5, 2025. https://www.prnewswire.com/news-releases/biohaven-achieves-positive-topline-results-in-pivotal-study-of-troriluzole-in-spinocerebellar-ataxia-sca-302255056.html
4. Biohaven provides overview of clinical progress, regulatory updates, and pipeline developments at R&D day. News release. Biohaven Pharmaceuticals. May 31, 2023. Accessed November 5, 2025. https://www.prnewswire.com/news-releases/biohaven-provides-overview-of-clinical-progress-regulatory-updates-and-pipeline-developments-at-rd-day-301838058.html