Troriluzole Slowed Spinocerebellar Ataxia Progression in Long-Term Clinical Trial
Post hoc analysis of data from a phase 2/3 clinical trial (NCT02960893) of troriluzole (Biohaven; New Haven, CT) for spinocerebellar ataxia (SCA) showed a lack of progression on the Scale for Assessment and Rating of Ataxia (SARA) over a 144-week period that included up to 96 weeks of treatment. After 96 weeks of troriluzole treatment (plus a treatment gap of 3-52 weeks as described below), the mean change on SARA was 0.3±0.30. This contrasts with the typically expected rate of a 1- to 2-point increase per year based on natural history data. Higher scores on SARA reflect worsening ataxia.
Vlad Coric, MD, chief executive officer of Biohaven, commented, “Analysis of our long-term, open-label data from this study provides compelling reason to believe that troriluzole attenuates progression of ataxia symptoms in SCA patients. We are eagerly awaiting topline results from our current phase 3 study of troriluzole in SCA, which will fully test the therapeutic potential of troriluzole in this population over the course of 1 year.”
In this study, an 8-week placebo-controlled double-blind period in which participants received 140 mg/day troriluzole or placebo was followed by 48 weeks of open-label use. No statistically significant improvement was seen during the 8-week double-blind period (the prespecified primary endpoint). Toward the end of the open-label extension, however, patient and provider feedback suggested discontinuing troriluzole resulted in clinical decline, and preliminary analysis showed participants had no progression of ataxia at week 48.
Post hoc analysis compared change in SARA scores for participants in the 48-week open-label extension treated with troriluzole (n=81) with individuals in a natural history cohort (n=112). Individuals in the compared groups were matched by SCA genotype, age, sex, baseline SARA score (≥8 and ≤30), and initial gait item score on SARA ≥2. Those treated with troriluzole had a least squares mean point change of -0.34 (95% CI: -0.94, 0.26) compared with 1.07 (95% CI: 0.56, 1.58; P<.001) in the natural history cohort. These results prompted a second 48-week open-label extension trial.
While waiting for the second open-label trial to start, individuals experienced a treatment gap of 3 to 52 weeks and had more than a 1-point increase on SARA, consistent with consistent with natural history study data. Score increases correlated with the amount of time without troriluzole. During the second open-label period, SARA scores stabilized back to participants' average baseline score at the start of the trial.
Participants in the trial had genetically confirmed SCA (types 1, 2, 3, 6, 7, 8 or 10), SARA scores of 8 to 30 (corresponding to mild-to-moderate disease), and the ability to walk with or without assistive devices. During the second extension, a subset of participants received 280 mg/day troriluzole because of clinical worsening, defined as at least a 2-point decline on SARA from initial baseline in 2 consecutive evaluations 1 month apart and clinician's impression of decline.
A new phase 3 (NCT03701399) placebo-controlled study of troriluzole is fully enrolled with 218 participants randomly assigned to receive 200 mg/day troriluzole or placebo for 48 weeks followed by an open-label period of 48 weeks. In this trial, the dose of troriluzole was increased to 200mg, and a revised SARA scale, the modified functional-SARA (f-SARA) is being used to assess meaningful clinical change. Topline results from this trial are expected in the first quarter of 2022.
Melissa Wolfe Beiner, MD, director of Research and Development and Medical Lead for the ataxia development program at Biohaven, stated, “Biohaven has worked closely with leading experts in the ataxia field to advance this phase 3 trial of troriluzole in this area of high unmet need. We feel confident this study will appropriately test the therapeutic benefit of troriluzole in the treatment of patients with SCA and hope that we will be able to bring forward a new treatment for patients with this disease.”