Troriluzole Shows Promise in Spinocerebellar Ataxia Type 3 Subgroup Despite Failing to Achieve Primary End Point


Falls, a common occurrence for patients with spinocerebellar ataxia, were significantly reduced following treatment with troriluzole after 48 weeks.

Susan Perlman, MD

Susan Perlman, MD

Newly announced findings from a phase 3 study (NCT03701399) evaluating troriluzole (Biohaven Pharmaceuticals), an investigational therapy to treat spinocerebellar ataxia (SCA), showed that 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 SCA type 3 (SCA3), the most common form of SCA.1

In the overall study population (n = 213), investigators recorded Functional Scale for the Assessment and Rating of Ataxia (f-SARA) scores, the primary end point, of 5.1 and 5.2 in the troriluzole and placebo groups, respectively, a minimal change from baseline scores of 4.9. In the subgroup of patients with SCA3, troriluzole showed a 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).

"The f-SARA scale, with a total of 16 points, was specifically designed to detect significant clinically meaningful change in this patient population. The f-SARA change in the SCA3 troriluzole treated group is compelling,” Susan Perlman, MD, director, Ataxia Clinic and Neurogenetics Clinical Trials, David Geffen School of Medicine, UCLA, said in a statement.1 "Given the excellent safety profile of troriluzole, and the fact that there are no approved treatment options for patients with this devastating neurodegenerative disorder, I am thrilled for my patients that Biohaven is planning to engage with the FDA to potentially move this program forward."

Troriluzole is a third-generation prodrug and new chemical entity that modulates glutamate, the most abundant excitatory neurotransmitter in the body. 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 P =.031).

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Treatment with troriluzole also resulted in a positive impact on patient-reported falls, a common occurrence in this patient population, typically caused by impaired gait. Across all genotypes, there was an approximately 58% reduction of fall risk in the troriluzole group (10% vs 23% adverse event [AE] incidence; nominal P =.043) among those who were able to ambulate at baseline. Notably, the agent showcased a safety profile that was consistent with prior clinical trials.

"The importance of morbidity related to falls in this patient population cannot be overstated. The reduction of falls in the troriluzole group, combined with the progression of f-SARA scores in the untreated SCA3 group compared to SCA3 patients on troriluzole, demonstrates that SCA3 patients are experiencing a clinically meaningful improvement in ataxia symptoms on troriluzole treatment," Jeremy Schmahmann, MD, professor of neurology, Harvard Medical School, and founding director, Ataxia Center, Massachusetts General Hospital, said in a statement.1

With regard to the primary end point, this was not the first time troriluzole came up short in a clinical trial. In 2017, Biohaven announced results from a phase 2/3 study in which the investigational agent once again did not differentiate from placebo on the primary end point of SARA, this time after 8 weeks of treatment. Individuals on troriluzole showed an improvement of –0.81 points (95% CI, –1.4 to 0.2) on the SARA vs –1.05 points (95% CI, –1.6 to –0.4) improvement in placebo (P =.52). Troriluzole also did not differentiate on the key secondary end point of Patient’s Global Impression of Change, with 50.8% of individuals on study drug considered improved vs 59.1% of those on placebo (P =.28).2

In addition to SCA, troriluzole is currently being evaluated in ongoing trials in obsessive compulsive disorder and has completed trials in neurodegenerative disorders such as Alzheimer disease (AD). In January 2021, topline data from the phase 2/3 clinical T2 Protect AD trial (NCT03605667) showed that troriluzole was not found to be statistically different from placebo at 48 weeks on coprimary endpoints, the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 and the Clinical Dementia Rating Scale Sum of Boxes in patients with mild-to-moderate AD. Additionally, the medication did not significantly differ from placebo on the key secondary measure of hippocampal volume assessed by MRI in the overall population.3

1. Biohaven provides update on phase 3 clinical trial evaluating troriluzole for spinocerebellar ataxia (SCA). News release. Biohaven Pharmaceuticals. May 23, 2022. Accessed May 24, 2022.
2. Biohaven reports negative topline data from spinocerebellar ataxia (SCA) phase 2/3 trial. News release. Biohaven Pharmaceuticals. October 2, 2017. Accessed May 24, 2022.
3. Biohaven provides update on phase 2/3 trial and Alzheimer's Disease program. News release. Biohaven Pharmaceuticals. January 18, 2021. Accessed May 24, 2022.
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