Signori A, Montobbio N, Bovis F, Ponzano M, Schiavetti I, Krenn A, Sormani MP. Uncoupling Relapse Reduction and Disability Progression: Evidence From Tolebrutinib Studies. Neurol Clin Pract. 2026; 16:e200612.
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) So this says that in most studies that progression is associated with lesional/relapse activity and so the concept of PIRA after drugs like anti-CD20 is all tosh as I have been saying for years because progression is inter related to events associated with diseae activity,, indicating that disability benefit was generally proportional to relapse reduction. This not surprising because the drugs don’t really get into the brain and so again the CNS….Why have the great and the good not got this?….Maybe good that I was put out to grass. 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.
So tolebrutinib should be given to people on something elses that controls relapses. Shame the FDA didn’t buy the Idea but the EMA in Europe did.
Source: multiple-sclerosis-research.org