Biohaven Submits New Drug Application for Troriluzole as Spinocerebellar Ataxia Type 3 Therapy


In a phase 3 study, a subgroup of patients with spinocerebellar ataxia treated with troriluzole demonstrated a numerical treatment benefit relative to placebo on the primary end point of change in f-SARA scores.

Vlad Coric, chief executive officer and chairman of Biohaven

Vlad Coric

According to a recent announcement, Biohaven Pharmaceuticals submitted a new drug application (NDA) for its investigational agent troriluzole, a third-generation prodrug and new chemical entity that modulates glutamate, for the treatment of spinocerebellar ataxia type 3 (SCA3).1

The NDA was supported by data from the phase 3 Study BHV4157-206 (NCT03701399), with confirmatory evidence from the 3-year, long-term open-label extension (OLE) phase of that study, and an additional study (BHV4157-201) using a matching adjusted indirect comparison analysis. In study BHV4157-206, the agent failed to reach statistical significance on its primary end point; however, there were numerical treatment benefits observed in a subgroup of those with SCA3, the most common form of SCA. In total, SCA3 represented 41% of study participants.

"The NDA we submitted for troriluzole for SCA3 represents approximately seven years of effort by the Biohaven team to bring forward a potentially new treatment for this ultra-rare disease," Vlad Coric, chief executive officer and chairman of Biohaven, said in a statement.1 "Advancing a new investigational drug for a rare disease that has no current therapy is a multi-year process that is the culmination of not only our own internal efforts but also close coordination with patient advocacy groups including the National Ataxia Foundation (NAF), leading academic researchers and regulatory agencies. Rare brain diseases are particularly challenging to research given relatively small populations of patients to run / participate in clinical trials, the need to rely on real-world data and often a lack of standardized ratings scales or biomarkers."

Study BHV4157-206, which featured 213 individuals with SCA, showed Functional Scale for the Assessment and Rating of Ataxia (f-SARA) scores, the primary end point, of 5.1 and 5.2 in the trolizule and placebo groups, respectively, at 48 weeks. Despite only a minimal change in the overall study population, a subgroup of patients with SCA3 showed numerical treatment benefit in the same measure at week 48 compared with placebo (least squares [LS] mean change difference, –0.55; 95% CI, –1.12 to 0.01; nominal P = .053).2

READ MORE: Vatiquinone Shows Additional Benefits on Friedreich Ataxia Disease Progression Despite Failing to Meet Primary End Point

Additional findings showed that for those with SCA3 who were able to walk without assistance at baseline or who had f-SARA Gait Item scores of 1, troriluzole continued to show a greater treatment benefit relative to placebo at the end of the treatment period (LS mean change difference, –0.71; 95% CI, –1.36 to –0.07; nominal =.031). Across all genotypes, treatment with troriluzole resulted in a58% reduction of fall risk as well (10% vs 23% adverse event [AE] incidence; nominal P = .043) among those who were able to ambulate at baseline.

"We could not have advanced the SCA program this far without the leadership from the National Ataxia Foundation that has supported basic science research as well as the development of natural history cohorts in SCA that serve as an external control for longitudinal studies,” Coric added. "The Biohaven clinical trials in SCA were a first of its kind in this area and utilized a newly developed rating scale (the functional SARA or f-SARA) that was developed in close consultation with the FDA using standard regulatory pathways to elucidate this new scale. We look forward to interactions with the US FDA, EMA and other regulatory agencies across the globe as our submissions advance in the review process."1

The full 96-week results of study BHV4157-201 were published in Neurology in 2021, with findings that were consistent with the initial analysis of the 1-year data showing no increase in SARA score in patients on troriluzole. The study was comprised of an 8-week randomization phase, followed by a 48-week OLE, and included those with the following hereditary ataxias: SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA10.

After 96 weeks of OLE treatment with troriluzole, the mean change from baseline in total SARA score was 0.3 (±0.30). Patients who had a gap in troriluzole treatment (3 weeks to 12 months) while awaiting approval of the protocol extension showed a greater than 1 point worsening during the off-treatment period. This worsening increased with longer duration off troriluzole.3

1. Biohaven provides overview of clinical progress, regulatory updates, and pipeline developments at R&D day. News release. Biohaven Pharmaceuticals. May 31, 2023. Accessed June 23, 2023.
2. Biohaven provides update on phase 3 clinical trial evaluating troriluzole for spinocerebellar ataxia (SCA). News release. Biohaven Pharmaceuticals. May 23, 2022. Accessed June 23, 2023.
3. Beiner M, Wirtz V, L’Italien G, Ruggiero L, Berman R, Coric V. Analysis of 96 week, long-term open label extension phase of study BHV 4157-201: a phase 2b/3, randomized, double-blind, placebo-controlled trila of the safety and efficacy of troriluzole in adult subjects with spinocerebellar ataxia. Neurology. 2021;96(15 suppl).
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