Real-world data saves Biohaven drug and paves way for FDA approval in neurological diseases without approved drugs

Biohaven is close to submitting a new drug application for a rare neurodegenerative disease that currently has no approved therapy. This is a surprising development for a molecule that already has a long list of clinical trial and regulatory setbacks, including the FDA's refusal to even review the pill over a year ago.

But Biohaven didn't give up on the drug, and neither did the FDA, apparently. The agency is open to more real-world data to inform its approval decisions. This approach for Biohaven's drug troriluzole, based on an agency-approved clinical trial design and endpoints, resulted in more data, new analyses and positive results in the treatment of the neurological disorder spinocerebellar ataxia (SCA).

Troriluzole is a prodrug, a compound that converts into an active drug in the body. According to New Haven, Connecticut-based Biohaven, this once-daily pill treats disease by lowering synaptic levels of the neurotransmitter glutamate. Although this chemical is vital to brain function, excess glutamate has been linked to a number of neurodegenerative diseases. However, Biohaven's previous work with the molecule in both anxiety and Alzheimer's failed in crucial trials. A Phase 3 trial is currently underway testing the molecule in obsessive-compulsive disorder.

SCA is a group of inherited neurodegenerative diseases characterized by progressive loss of voluntary motor control and atrophy of the cerebellum, brain stem and spinal cord. The disease affects mobility, with patients frequently falling and eventually requiring the use of a wheelchair. The disease also causes speech impairment, difficulty swallowing and premature death. SCA, which typically appears in early adulthood, affects an estimated 15,000 patients in the U.S. and 24,000 in Europe and the U.K., according to an investor presentation from Biohaven.

In 2022, Biohaven reported interim Phase 3 data showing that 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 SCA types.

Last year, Biohaven submitted a New Drug Application for adult SCA3 patients. That application never even made it to FDA review. The regulator sent Biohaven a rejection letter, saying the drug did not meet the primary goal of the registration trial.

Discussions with the FDA led Biohaven to develop a new protocol that assesses the effectiveness of troriluzole using real-world evidence. Patients treated with the study drug were compared to two natural history control groups matched on their baseline characteristics, one cohort in the US and the other in Europe. This analysis includes new data that were not available for the new drug's regulatory filing in 2023. While the initial Phase 3 study lasted 48 weeks, the new real-world evidence study includes three years of data. The main objective is to measure the change in the score from baseline on a scale used to assess the severity and progression of SCA. These are the results presented on Monday.

According to Biohaven, preliminary results show that the study met the primary endpoint by demonstrating a statistically significant and sustained benefit measured at years one, two and three in all types of SCA compared to natural control groups. The company added that data from multiple analyses show a robust and clinically meaningful 50 to 70 percent slower rate of decline compared to untreated patients. This equates to a delay in disease progression of one and a half to two years over the three-year study period. The study drug was safe and well tolerated by study participants.

Based on these positive results, Biohaven now plans to seek FDA approval of troriluzole for the treatment of all types of SCA. The company expects to submit an application for approval of the new drug in the fourth quarter of this year. Last year, Biohaven submitted an application for approval of troriluzole for the treatment of SCA in Europe. This application is currently under review.

In a note to investors, analysts at William Blair wrote that they were encouraged by the level of incorporation of FDA guidelines into the trial design for troriluzole. However, they also expect the regulator to convene an advisory committee meeting to discuss the differences between the failed Phase 3 trial and the positive comparator natural history trial. Other potential topics for discussion include differences in the standard of care for subjects in the natural history trials that began 15 to 20 years ago.

“Overall, we are encouraged by the consistent signals of benefit from all interventions studied in the trial in a population with extremely limited treatment options for a progressive disease,” said analysts at William Blair.

Marc Goodman of Leerink Partners was more cautious about the results. While he acknowledged that the real-world evidence study was based on FDA data, the drug poses “significant regulatory risks” given the failures in Phase 2/3 and Phase 3. Goodman also noted that an application for approval of the drug was rejected based on the subgroup analyses. He also expects an advisory committee meeting to discuss the mixed data package and the design of the real-world evidence clinical trial.

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