Biohaven to Submit NDA for Troriluzole for All Spinocerebellar Ataxia Forms Following Positive Phase 3 Data

Susan Perlman, MD

In newly announced data from a pivotal long-term study (NCT06529146), treatment with investigational troriluzole (Biohaven Pharmaceuticals) met its primary end point on change in modified functional Scale for the Assessment and Rating of Ataxia (f-SARA) in patients with spinocerebellar ataxia (SCA). Based on these findings, Biohaven plans to submit a new drug application (NDA) to the FDA for troriluzole as a potential treatment of all SCA genotypes in Q4 later this year.¹

Also known as Study BHV4157-206-RWE, the trial comprises multiple sources of real-world data (RWD), including the Clinical Research Consortium for the Study of Cerebellar Ataxia cohort (CRC-SCA), the European Integrated Project on Spinocerebellar Ataxias cohort (EUROSCA), and the 3-year open-label extension (OLE) data from troriluzole-treated patients from the previously completed Study BHV4157-206 (NCT03701399). The newly announced data doubled the previously available 3-year data with 63 patients with SCA now completing 3 years of treatment with troriluzole and matched to the external control arm.

In the study, which was designed in discussion with the FDA, troriluzole achieved its primary end point, with treated patients demonstrating statistically significant improvements on f-SARA at years 1 and 2 of treatment. Troriluzole, a third-generation prodrug that modulates glutamate, achieved statistically significant superiority on 9 consecutive, prespecified primary and secondary end points.

"SCA is a debilitating, relentlessly progressive disease that destroys quality of life, leaving patients unable to care for themselves, walk, or speak,” Susan Perlman, MD, director of the Ataxia Clinic and Neurogenetics Clinical Trials at the David Geffen School of Medicine, UCLA, said in a statement.¹ "Troriluzole is the very first treatment to show a delay in disease progression that can give patients additional years of independence, where they can walk without assistance, continue to work, play with their children, and participate in daily activities. This is an exciting and hopeful moment for the SCA community."

The primary objective of the study was to test the treatment effects of troriluzole for up to 3 years, by comparing data on the f-SARA from patients treated with troriluzole in the previously completed phase 2 study to untreated patients from the natural history study. All told, over the 3-year period, those on the active agent demonstrated a 50-70% slower rate of decline compared with untreated patients, representing a 1.5-2.2 year delay in disease progression. In a responder sensitivity analysis, investigators reported an odds ratio of 4.1 (95% CI, 2.1-8.1) for disease progression for untreated external controls vs troriluzole-treated patients when defined by a 2-point or greater worsening on f-SARA after 2 years (P <.0001; pooled analysis).

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Results using patients from EUROSCA, in addition to a pooled analysis using both CRC-SCA and EUROSCA patients, as the external controls were also statistically significant and consistent with the primary efficacy analysis at all time points. Across all 3 years of treatment, troriluzole continued to show statistically significant differences, further adding to its treatment profile and robustness of data.

"The stabilization of SCA symptoms as reflected by the topline data at 3 years along with the previously reported reductions in falls show the therapeutic potential of troriluzole. I cannot underscore enough the impact of a potential treatment that can slow SCA disease progression and the effect on patients and caregivers who have helplessly watched generations of family members deteriorate and die from SCA," Jeremy Schmahmann, MD, a professor of neurology at Harvard Medical School and founding director of the Ataxia Center at Massachusetts General Hospital, said in a statement.¹ "These new data provide support for troriluzole as a safe and effective once daily treatment for patients with SCA."

In the original Study BHV4157-206, the troriluzole and placebo groups demonstrated changes of 5.1 and 5.2, respectively, over the 48-week period. Despite only a minimal change in the overall study population (n = 213), a subgroup of patients with SCA type 3 showed numerical treatment benefit in the same measure at week 48 relative to placebo (least square [LS] mean change difference, –0.55; 95% CI, –1.12 to 0.01; P = .53). Based on those data, in June 2023, Biohaven then submitted an NDA for the treatment of SCA type 3.^2,3

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 P =.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.

REFERENCES
1. Biohaven achieves positive topline results in pivotal study of troriluzole in spinocerebellar ataxia (SCA). News release. Biohaven. September 23, 2024. Accessed September 23, 2024. https://www.prnewswire.com/news-releases/biohaven-achieves-positive-topline-results-in-pivotal-study-of-troriluzole-in-spinocerebellar-ataxia-sca-302255056.html
2. Biohaven provides overview of clinical progress, regulatory updates, and pipeline developments at R&D day. News release. Biohaven Pharmaceuticals. May 31, 2023. Accessed September 23, 2024. https://www.prnewswire.com/news-releases/biohaven-provides-overview-of-clinical-progress-regulatory-updates-and-pipeline-developments-at-rd-day-301838058.html
3. Biohaven provides update on phase 3 clinical trial evaluating troriluzole for spinocerebellar ataxia (SCA). News release. Biohaven Pharmaceuticals. May 23, 2022. Accessed September 23, 2024. https://www.prnewswire.com/news-releases/biohaven-provides-update-on-phase-3-clinical-trial-evaluating-troriluzole-for-spinocerebellar-ataxia-sca-301552633.html