FDA Issues Complete Response Letter for Biohaven's VYGLXIA (troriluzole) for Spinocerebellar Ataxia

Key Insights

• The FDA issued a Complete Response Letter rejecting Biohaven's New Drug Application for VYGLXIA (troriluzole) to treat spinocerebellar ataxia, a rare neurodegenerative disorder affecting approximately 15,000 Americans.
• Biohaven's real-world evidence study demonstrated that VYGLXIA slowed disease progression by 50-70% and reduced fall risk in SCA patients, but the FDA's Office of Neuroscience declined to approve the treatment.
• The company will pivot resources to other pipeline programs and implement a 60% reduction in annual direct R&D spending while continuing to seek a path forward for troriluzole approval.

The U.S. Food and Drug Administration has issued a Complete Response Letter (CRL) to Biohaven Ltd. (NYSE: BHVN) rejecting the company's New Drug Application for VYGLXIA (troriluzole) as a treatment for spinocerebellar ataxia (SCA), marking a significant setback for patients with this rare neurodegenerative disorder that currently has no approved therapies.

The rejection comes despite what Biohaven characterizes as substantial evidence of safety and efficacy, including real-world evidence demonstrating that VYGLXIA slowed disease progression by 50-70% in SCA patients. The company's eight-year development program also showed the once-daily oral medication reduced the risk of falls and delayed time to becoming wheelchair bound.

Company Response and Regulatory Concerns

Vlad Coric, M.D., Chairman and Chief Executive Officer of Biohaven, expressed strong disappointment with the FDA's decision, stating: "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."

The company criticized the FDA's Office of Neuroscience for not embracing real-world evidence approaches or applying regulatory flexibility for rare diseases, despite FDA policy initiatives supporting such tools. Coric noted that leading SCA experts in the United States had directly communicated their support of the troriluzole data to the FDA.

Jeremy Schmahmann, M.D., Professor of Neurology at Harvard Medical School and Founding Director of the Ataxia Unit at Massachusetts General Hospital, supported Biohaven's position, calling the FDA's decision "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."

Clinical Evidence and Development History

Biohaven's development program for VYGLXIA spanned eight years and included collaboration with the FDA to develop the f-SARA scale for measuring treatment effects. The company's real-world evidence study showed the drug achieved "highly consistent, sustained, robust and clinically meaningful treatment effects" in SCA patients.

The primary outcome measure was achieved in a study protocol and statistical analysis plan that had been reviewed by the FDA prior to data analysis, according to the company. Biohaven argued that the certainty of disease progression for SCA patients "far outweighs any residual uncertainty regarding potential design bias or interpretation of study data."

Strategic Pivot and Cost Reduction

Following the CRL, Biohaven announced a strategic restructuring that will reduce annual direct R&D spending by approximately 60%, excluding personnel and stock-based compensation. The company will focus resources on three key priority programs over the next year:

1. Clinical-stage extracellular degraders for IgA nephropathy (BHV-1400) and Graves' disease (BHV-1300)
2. Opakalim, a Kv7 ion channel activator, for pivotal trials in adult focal epilepsy and depression
3. Taldefgrobep alfa, a myostatin-activin pathway inhibitor, for spinal muscular atrophy and obesity

Bruce Car Ph.D., Chief Scientific Officer at Biohaven, commented: "As drug developers we expect setbacks and our diversified portfolio affords us the opportunity to pivot to other key programs."

Disease Background and Unmet Need

Spinocerebellar ataxia represents a group of dominantly inherited neurodegenerative disorders characterized by progressive loss of voluntary motor control and atrophy of the cerebellum and brainstem. The condition affects approximately 15,000 people in the United States and 24,000 in Europe and the United Kingdom.

Patients experience significant morbidity, including impaired gait leading to falls, loss of ambulation and progression to wheelchair dependency, inability to communicate due to speech impairment, difficulty swallowing, and premature death. While symptoms can appear from childhood to late adulthood, SCA typically presents in early adulthood and progresses over several years. Currently, there are no FDA-approved treatments and no cure for SCA.

Mechanism of Action

Troriluzole is a third-generation novel prodrug that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. The drug's primary mode of action involves reducing synaptic levels of glutamate by increasing glutamate uptake from the synapse and augmenting the expression and function of excitatory amino acid transporters located on glial cells.

This glutamate modulating activity addresses the widely documented glutamate deregulation that underlies neurodegeneration and Purkinje cell dysfunction in patients with SCA. The mechanism also positions troriluzole for potential development in other diseases associated with excessive glutamate.

Next Steps

Biohaven remains committed to working with the FDA to find a path forward for its NDA for VYGLXIA and plans to meet with the agency to discuss potential next steps. The company suggested several regulatory tools that could have been applied, including an Advisory Committee hearing, post-marketing studies, labeling limitations, or an accelerated approval pathway.