Arbaclofen Extended-Release for Spasticity in Multiple Sclerosis: Responder Analysis of a Phase 3 Randomized, Placebo-Controlled Clinical Study OS440-3004

Background: Arbaclofen is the active R-enantiomer of racemic baclofen. Arbaclofen extended-release (ER) tablets have demonstrated efficacy and safety in two Phase 3 studies in subjects with multiple sclerosis (MS)-related spasticity. Objectives: To provide assessment of arbaclofen ER effect on MS-related spasticity from a Phase 3 placebo-controlled study using a responder-analysis model. Methods: This was an FDA-requested, post-hoc, responder analysis of a double-blind, multi-center study in which adults with MS-related spasticity were randomized to receive twice-daily arbaclofen ER (40 mg/day or 80 mg/day) or placebo for 12 weeks (NCT03290131 [OS440-3004]). The co-primary efficacy endpoints were the Visit 5/Day 84 change from baseline in Total Numeric-Transformed Modified Ashworth Scale–Most-Affected Limb (TNmAS-MAL) and Clinician Global Impression of Change (CGIC) scores. Responders were defined using prespecified degrees of improvement over baseline in TNmAS-MAL scores (10% through 70%). Repeated measures logistic analysis was conducted using Generalized Estimating Equations containing baseline, treatment (arbaclofen ER 40 mg/day, 80 mg/day, and placebo), post-treatment visit (Visit 4/Day 42 [±5 days] and Visit 5/Day 84 [±5 days]), and the treatment-by-visit interaction. Using the intention-to-treat (ITT) dataset, the odds of response were obtained to provide a model-based odds ratio and significance level for arbaclofen ER 40 mg/day and arbaclofen ER 80 mg/day vs placebo under an unstructured covariance assumption. Results: Of the 536 subjects enrolled in the study, 418 were included in the responder analysis of observed data at the end-of-maintenance, ie, Visit 5/Day 84 (arbaclofen ER 40 mg/day = 139, arbaclofen ER 80 mg/day = 115, and placebo = 164). In the ITT population, 38.8% of the arbaclofen ER 40 mg/day group achieved a 30% response vs 26.8% of the placebo group (odds ratio [OR] 1.62; 95% confidence interval [CI] 1.00, 2.61; p=0.0484) and 30.2% vs 18.9% achieved a 40% response (OR 1.75; 95% CI 1.04, 2.96; p=0.0359), respectively. In the arbaclofen 80 mg/day group, 32.2% of subjects vs 18.9% of subjects in the placebo group achieved a 40% response (OR 1.97; 95% CI 1.16, 3.37; p=0.0128) and 27.0% vs 15.2% achieved a 50% response (OR 2.06; 95% CI 1.16, 3.69; p=0.0143), respectively. Data for all response levels will be provided. Conclusions: Subjects with MS-related spasticity were more likely to respond to twice-daily oral arbaclofen ER than placebo.

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