The FDA has rejected Biohaven’s request for approval of a neurological disorder therapy, prompting the biopharma to reprioritize its pipeline in order to shrink its annual R&D spend by 60%.
Biohaven first sought FDA approval for troriluzole in spinocerebellar ataxia on the strength of a phase 3 trial that missed its primary endpoint. The FDA refused to review that submission in 2023, but Biohaven continued to seek a path forward, leading to talks about the potential to use real-world evidence (RWE) to support a resubmission. Biohaven hailed positive three-year RWE findings in September 2024.
After a three-month delay, the FDA has now rejected an approval request based on the RWE. According to Biohaven, the FDA’s complete response letter “cited issues that can be inherent to real-world evidence and external control studies including potential bias, design flaws, lack of pre-specification and unmeasured confounding factors.”
Such issues were on the agenda when Biohaven met with the FDA to discuss the RWE study in 2024. The biopharma said it changed its RWE study protocol in response to the feedback, including by only using the U.S. natural history cohort as an external control for the primary analysis.
Quoting official meeting minutes, Biohaven said the FDA’s view was that “a large and robust treatment effect would be needed to overcome the biases of an externally controlled trial, in order for it to be used as the primary basis for substantial evidence for effectiveness.” Biohaven executives believe their RWE study cleared that bar.
Yet the FDA, which has undergone a change in leadership and direction since the 2024 meeting, ruled that the submission cannot support approval. The agency recommended Biohaven meet with its team to discuss the evidence it wants to see in a future filing for approval. Biohaven is in the process of formally requesting a meeting.
In the wake of the news, Biohaven's stock dropped 44% to $7.76 in premarket trading Wednesday from a Tuesday closing price of $13.95.
While Biohaven said it remains committed to finding a path forward for troriluzole, the FDA rejection has prompted the biopharma to prioritize other late-stage programs that management believes have the most potential for value generation.
Biohaven’s priorities for the next year are the extracellular degraders BHV-1400 in IgA nephropathy and BHV-1300 in Graves’ disease, Kv7 ion channel activator opakalim in adult focal epilepsy and depression and myostatin-activin pathway inhibitor taldefgrobep alfa in obesity and spinal muscular atrophy.
The company may pause or delay other programs to extend its cash runway. Biohaven ended June with $408.2 million. The pipeline prioritization is intended to cut annual direct R&D spending, which excludes personnel costs, by 60%.
The implications of the CRL could extend beyond Biohaven. The Division of Neurology I that handled the troriluzole review at the FDA has a record of regulatory flexibility dating back to its first big decision—the approval of Biogen and Eisai’s Aduhelm—but it was unclear whether that ethos had survived recent changes at the agency. Biohaven CEO Vlad Coric, M.D., shared a potential read-through from the rejection.
“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,” Coric said in a statement.
William Blair analysts described the FDA's decision as “clearly disappointing given troriluzole showed greater than 50% disease slowing over three years compared to natural history and did so without liver toxicity.”
“With the FDA now pushing back on regulatory pathways for both uniQure and Biohaven using comparisons to natural history for potential approval in rare neurological disorders, the question will now be if the FDA is becoming more restrictive despite sponsors aligning on prior feedback,” the analysts added.