Neurol Clin Pract. 2026 Jun;16(3):e200612. doi: 10.1212/CPJ.0000000000200612. Epub 2026 Apr 6.
ABSTRACT
OBJECTIVES: The aim of this study was to evaluate whether the treatment effects of tolebrutinib on confirmed disability worsening (CDW) diverge from its effects on relapse prevention compared with other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (MS).
METHODS: We extracted published effect estimates for annualized relapse rate (ARR) and CDW confirmed at 24 weeks from all phase 3 trials with teriflunomide as the active comparator: ASCLEPIOS (ofatumumab), OPTIMUM (ponesimod), ULTIMATE (ublituximab), EVOLUTION (evobrutinib), and GEMINI (tolebrutinib). When duplicate trials were available, pooled estimates were derived. Log-transformed estimates were used in a weighted linear regression of CDW vs ARR, with bubble size reflecting statistical precision. Tolebrutinib was excluded from the regression fit but displayed for comparison.
RESULTS: Across 4 DMTs other than tolebrutinib, a strong linear association was observed between treatment effects on ARR and CDW (R2 = 0.997), indicating that disability benefit was generally proportional to relapse reduction. By contrast, tolebrutinib deviated from this relationship, with a hazard ratio for CDW of 0.71 (95% CI 0.53-0.95) despite a relapse rate ratio of 1.03 (95% CI 0.85-1.25).
DISCUSSION: Tolebrutinib was the only therapy to show a benefit on CDW without a measurable effect on relapses, highlighting a dissociation between disability worsening and relapse suppression not observed with other DMTs.
PMID:42114075 | DOI:10.1212/CPJ.0000000000200612
