Biohaven is on the cusp of a new drug application filing in a rare neurodegenerative disorder that currently has no approved therapies, a surprising development for a molecule with a long list of clinical trial and regulatory setbacks, including the FDA’s refusal to even review the pill more than a year ago.
But Biohaven did not give up on the drug, and apparently, neither did the FDA. The agency is welcoming more real-world data to generate the evidence for its regulatory decisions. Based on a clinical trial design and endpoints that were blessed by the regulator, this approach for the Biohaven drug, troriluzole, led to more data, new analyses, and positive results in the treatment of the neurological disease spinocerebellar ataxia (SCA).
Troriluzole is a prodrug, a compound that converts into an active drug inside the body. According to New Haven, Connecticut-based Biohaven, this once-daily pill treats diseases by reducing synaptic levels of glutamate, a neurotransmitter. While this brain chemical is key to brain function, excess glutamate is associated with a range of neurodegenerative disorders. However, Biohaven’s earlier work with the molecule in both anxiety and Alzheimer’s disease ended up failing in pivotal trials. A Phase 3 test is ongoing testing the molecule in obsessive compulsive disorder.
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SCA is a group of inherited neurodegenerative disorders characterized by progressive loss of voluntary motor control and atrophy of the cerebellum, brainstem and spinal cord. The disease affects mobility, as patients fall frequently and eventually must use a wheelchair. The disease also causes speech impairment, swallowing difficulty, and premature death. SCA, which typically presents in early adulthood, affects an estimated 15,000 patients in the U.S. and 24,000 in Europe and the U.K., according to a Biohaven investor presentation.
In 2022, Biohaven reported preliminary Phase 3 data showing troriluzole failed a Phase 3 study in SCA. Biohaven attributed this result to less-than-expected disease progression in the placebo arm over the course of the study. However, the company noted that a post-hoc analysis found a treatment effect in patients with SCA type 3, the most common of the more than 40 types of SCA.
Last year, Biohaven submitted a new drug application seeking approval in adult SCA3 patients. This application did not even reach the point of an FDA review. The regulator sent Biohaven a refuse-to-file letter, noting that the drug failed to meet the main goal of its pivotal study.
Discussions with the FDA led Biohaven to design a new protocol that used real-world evidence to assess troriluzole’s efficacy. Patients treated with the study drug were compared to two natural history external control groups matched for baseline characteristics, one cohort in the U.S. and the other in Europe. This analysis incorporates new data that were unavailable for the 2023 new drug application. Whereas the initial Phase 3 study spanned 48 weeks, the new real-world evidence study has data spanning three years. The main goal is measuring the change in score, from baseline, according to a scale used to assess SCA severity and progression. These are the results unveiled Monday.
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According to Biohaven, preliminary results show the study achieved the primary endpoint by showing statistically significant and sustained benefit measured at years one, two, and three in all types of SCA compared to the natural history controls. The company added that data across multiple analyses demonstrate a robust and clinically meaningful 50% to 70% slower rate of decline compared to untreated patients. That translates to one-and-a-half to two-year delay in disease progression over the three-year study period. The study drug was safe and well tolerated by study participants.
Based on these positive results, Biohaven executives say they now plan to seek FDA approval of troriluzole as a treatment for all SCA types. The company expects to submit a new drug application in the fourth quarter of this year. Last year, Biohaven submitted a marketing authorization application in Europe for troriluzole in SCA. That application is still under review.
In a note sent to investors, William Blair analysts wrote that they are encouraged by the degree FDA guidance was incorporated into the troriluzole trial design. However, they also expect the regulator will convene an advisory committee meeting to discuss the differences between the failed Phase 3 study and the positive natural history-comparator study. Other potential discussion topics include differences in standard of care for subjects in the natural history studies that were initiated 15 to 20 years ago.
“Overall, we are encouraged by the consistent signals of benefit across measures in the study in a population with extremely limited treatment options in a progressive disease,” the William Blair analysts said.
Marc Goodman of Leerink Partners offered a more cautious take on the results. Though he acknowledged that the real-world evidence trial was based on input from the FDA, the drug carries “significant regulatory risk” in light of its Phase 2/3 and Phase 3 failures. Goodman also noted that the drug had received a refuse-to-file letter based on the subgroup analyses. He also expects an advisory committee meeting to discuss the mixed data package and the real-world evidence clinical trial design.
Image: koto_feja, Getty Images
