FDA Rejects Biohaven’s Vyglxia for Spinocerebellar Ataxia Citing External Control Study Concerns

Biohaven Pharmaceuticals received a significant setback when the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) in November 2025, rejecting the New Drug Application (NDA) for Vyglxia (troriluzole) intended to treat spinocerebellar ataxia (SCA), a rare neurodegenerative disorder. Despite data showing a 50-70% slowing of disease progression in treated patients over three years, the FDA cited multiple concerns primarily centered around the company’s reliance on an externally controlled study using real-world evidence (RWE). These issues include potential bias, design flaws, lack of pre-specification, and unmeasured confounding factors inherent in such study designs.

Details of FDA Concerns and Study Design Issues

Vyglxia application was supported by data from a pivotal three-year, real-world evidence (RWE) study involving over 900 SCA patients. The study achieved statistical significance on primary and multiple secondary endpoints, showing a purported 50–70% reduction in disease progression rates compared to external historical controls. However, the FDA expressed skepticism about the robustness of externally controlled study designs. Specific criticisms included:

Potential bias and confounding variables not adequately addressed

Design flaws and lack of pre-specified protocols

Inherent limitations in real-world data and difficulties in isolating true drug effects

Due to these methodological concerns, the agency concluded that Biohaven’s results did not meet the rigorous standard required for a new drug approval in the U.S., despite the company’s assertion that the magnitude of clinical benefit seen should have been sufficient

Biohaven announced plans to request a Type A meeting with the FDA to clarify the evidence required to support a future resubmission. The agency recommended such a meeting to discuss the specific data and trials needed for regulatory approval.

Market and Company Implications

Following the announcement, Biohaven’s shares plunged over 40%, reflecting investor concerns about the setback and the uncertain path forward without additional trial data. The company responded by initiating a major restructuring to reduce its annual research and development expenditures by approximately 60%, prioritizing its other late-stage programs targeting diseases such as IgA nephropathy, Graves’ disease, epilepsy, and obesity-related disorders. Bruce Car, Ph.D., Chief Scientific Officer at Biohaven, commented, “As drug developers, we recognize that setbacks are part of the discovery process. Our diversified pipeline allows us to pivot strategically and redirect efforts toward other late-stage programs with strong commercial potential.

Biohaven’s CEO, Dr. Vlad Coric, expressed extreme disappointment on behalf of patients on this action from the Office of Neuroscience at FDA, emphasizing the urgent unmet need in SCA and advocating for a flexible regulatory approach reflecting the realities of rare disease drug development.

Dr. Jeremy Schmahmann, Professor of Neurology at Harvard Medical School and Founding Director of the Ataxia Unit at Massachusetts General Hospital, expressed strong criticism of the FDA’s decision. He stated, “Patients with SCA and clinicians who treat them deserve to be heard on this important NDA filing. 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.”

Dr. Coric also added the scientific rigor and commitment behind Vyglxia development. He noted, “The development of Vyglxia embodies a strong scientific process and deep commitment that is critical to bringing safe and effective treatments to patients with rare diseases like SCA. Our efforts over eight years included developing the f-SARA scale in collaboration with the FDA and a real-world evidence study in SCA that showed Vyglxia achieved highly consistent, sustained, robust and clinically meaningful treatment effects with a safe, once-daily oral pill that slowed disease progression by 50-70%.”

The FDA’s CRL for Vyglxia highlights ongoing challenges in leveraging real-world evidence and externally controlled study designs for regulatory approval, especially in rare diseases. Biohaven’s willingness to work with the agency and pursue further discussions marks a critical confluence in the drug’s development. The outcome of these interactions and any subsequent studies will determine if Vyglxia can eventually become the first FDA-approved therapy for spinocerebellar ataxia, fulfilling a significant unmet medical need.