Matching-adjusted Indirect Comparison of Troriluzole Versus Untreated Natural History Cohort in Spinocerebellar Ataxia
Melissa Beiner1, Lauren Powell2, Basia Rogula2, Michele Potashman1, Victoria Wirtz1, Jeremy Schmahmann3, Susan Perlman4, Vladimir Coric1, Gilbert L'Italien1
1Biohaven Pharmaceuticals, Inc., 2Broadstreet HEOR, 3Massachusettes General Hospital, 4UCLA School of Medicine
Objective:
To understand the treatment effect of troriluzole over 3 years in patients with spinocerebellar ataxia (SCA) by conducting a matching-adjusted indirect comparison (MAIC) of troriluzole-treated subjects vs subjects in a pooled natural history cohort.
Background:
SCAs are rare inherited neurodegenerative disorders characterized by progressive ataxia affecting limb coordination, balance, and speech. BHV4157-206 (NCT03701399) was a pivotal efficacy trial examining troriluzole vs placebo, consisting of a 48-week double blinded period followed by a 3-year open-label extension.
Design/Methods:
A MAIC was conducted for all SCA genotypes and SCA3 genotype only, to compare ataxia symptoms over 3 years between troriluzole-treated subjects and an untreated natural history cohort. Patient-level natural history data were weighted to match the overall baseline characteristics of troriluzole-treated subjects (modified-functional Scale for the Assessment and Rating of Ataxia [f-SARA], genotype, sex, age, and age of symptom onset). The between-group least squares (LS) mean change from baseline differences on f-SARA were derived, for years 1, 2, and 3.
Results:
A total of 96 troriluzole-treated subjects and 611 untreated natural history subjects informed the all SCA genotype analysis. LS mean change differences in f-SARA for all SCA genotypes were -0.64, -1.16, and -1.34 at years 1, 2, and 3, favoring troriluzole (p=0.0008, <0.0001, and <0.0001 respectively). Thirty-eight troriluzole-treated SCA3 subjects were compared to 205 untreated. LS mean change differences for the SCA3 genotype were -0.75, -1.11, and -1.92, favoring troriluzole (p=0.0181, 0.0009, and <0.0001 respectively). These results indicate greater ataxia-related impairment and clinical decline amongst the natural history cohort compared to troriluzole-treated subjects.
Conclusions:
Compelling and sustained treatment effects were observed out to 3 years when troriluzole-treated subjects were compared to a matched untreated natural history cohort. These results demonstrate that long-term daily dosing of troriluzole attenuates the progression of disease among subjects with SCA3 over 3-years and, to a lesser extent, for all SCA genotypes.