Biohaven Therapeutics, Ltd.: troriluzole

We noted that such a study would likely be inadequate to provide substantial evidence of effectiveness, particularly with consideration that Study 206, the randomized, double-blind, placebo-controlled study, failed on all primary and secondary endpoints in the pre-specified analysis population.

, during which we stated that Study 206-RWE was not considered to be an adequate and well-controlled investigation, and therefore, it would not be capable of providing the primary support for demonstration of substantial evidence of effectiveness.

After a comprehensive and detailed review of the submission, we have determined that substantial evidence of effectiveness has not been established for troriluzole for the treatment of spinocerebellar ataxia.

Noncompleters in the troriluzole group had significantly higher baseline disease severity (worse f-SARA scores: 5.4 versus 4.7, p=0.0335).

The Jump-toReference (J2R) analysis, which assumes treatment benefits are lost when subjects discontinue, and was a pre-specified sensitivity analysis, showed the 3-year result became statistically non-significant (p=0.1023 instead of p=0.0301).

When timing was properly aligned in sensitivity analyses, the results failed to achieve nominal statistical significance, (p=0.0997), indicating that the 90-day timing difference in the assessment may not fully explain the entire observed benefit but accounted for a statistically meaningful portion of the effect.

You have stated that the protocol and statistical analysis plan for Study 206-RWE were "prespecified", based on the argument that the analysis included data on 21 subjects whose year 3 data in the open-label extension of Study 206 had not yet been analyzed at the time of the drafting of the protocol and SAP for Study 206RWE.

Study 206-RWE was drafted in 2024, with prior knowledge of the results of the MAIC analyses presented to the Agency in 2023. In addition, the source data used in Study 206-RWE and the prior MAIC analyses largely overlap, and the same outcome measure was evaluated at the same time points.

Products (February 2023), that recommends finalizing study protocols and selecting external control arms before initiating externally controlled trials and greatly affects the strength of evidence from the study because unconscious and conscious biases may be introduced.

The treatment difference of -0.79 observed on the f-SARA at Year 3 (p=0.0301) between the troriluzole-treated group and the CRC-SCA cohort is of uncertain clinical meaningfulness.

Therefore, 206-RWE is unable to serve as an adequate and well-controlled study that can contribute to substantial evidence of effectiveness.

| Methodological issues preclude the ability to use the secondary efficacy analyses of Study 206-RWE and post hoc analyses of Study 206 as confirmatory evidence.

Post hoc SCA genotype 3 subgroup analyses of Study 206: Study 206 failed to achieve statistical significance on its prespecified primary endpoint of the f-SARA at 48 weeks.

Post hoc subgroup analyses in the SCA genotype 3 population were not prespecified.

Fall Risk Analysis of Study 206: Your analysis of fall risk reduction based on adverse event reporting does not support effectiveness.

Inspections identified systematic under-reporting of adverse events and incorrect coding of fall events in the original adverse event dataset.

In order to address these deficiencies, you will need to provide data from an adequate and well-controlled study that demonstrates an effect on a clinically meaningful endpoint in order to establish the effectiveness of troriluzole for the treatment of spinocerebellar ataxia.