FDA Denies Approval of Troriluzole for Spinocerebellar Ataxia

The Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Biohaven regarding the New Drug Application (NDA) for troriluzole for the treatment of adults with spinocerebellar ataxia (SCA). 

Troriluzole is a third generation prodrug of the glutamate modulating agent, riluzole. By increasing glutamate uptake from the synapse, troriluzole is expected to improve the glutamate deregulation commonly seen in neurodegenerative disorders such as SCA. 

The NDA for troriluzole was supported by pivotal data from the BH4157-206-RWE study (ClinicalTrials.gov Identifier: NCT06529146), as well as supportive data from the BHV4157-201 (ClinicalTrials.gov Identifier: NCT02960893) and BHV4157-206 (ClinicalTrials.gov Identifier: NCT03701399) studies. 

Findings from BH4157-206-RWE showed troriluzole statistically significantly improved functional Scale for the Assessment and Rating of Ataxia scores after 3 years, resulting in a 50 to 70% slower rate of decline (representing 1.5-2.2 years delay in disease progression) vs matched untreated patients from natural history controls. 

In the CRL, the Agency cited issues related to the use of real-world evidence and external control studies, including potential bias, design flaws, lack of pre-specification and unmeasured confounding factors, as reasons for rejecting the application. 

According to Biohaven, prior to finalizing the study protocol, the FDA stated 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”. The Company believes that the statistically significant data demonstrated by the real world evidence trial, which includes external controls from the 2 largest natural history studies of SCA in the US and Europe, satisfied these requirements.

In response to the letter, Vlad Coric, MD, Chairman and Chief Executive Officer of Biohaven, said: “We are extremely disappointed on behalf of patients by this action from the Office of Neuroscience at FDA. 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.”

Biohaven is in the process of requesting a formal meeting to resolve this issue given the large number of participants being treated in the expanded access program (ClinicalTrials.gov Identifier: NCT06034886).

This article originally appeared on MPR