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Uncoupling Relapse Reduction and Disability Progression: Evidence From Tolebrutinib Studies
Alessio Signori1,2, Noemi Montobbio1, Francesca Bovis1
1Department of Health Sciences, University of Genoa, Italy; and.
Neurology. Clinical Practice
|May 11, 2026
Summary
Tolebrutinib uniquely improved disability in relapsing multiple sclerosis (MS) without reducing relapses, unlike other disease-modifying therapies (DMTs). This dissociation suggests a novel mechanism of action for tolebrutinib in MS management.
Area of Science:
- Neurology
- Immunology
- Pharmacology
Background:
- Relapsing multiple sclerosis (MS) is characterized by relapses and progressive disability.
- Disease-modifying therapies (DMTs) aim to reduce both relapse frequency and disability worsening.
- Understanding the relationship between relapse prevention and disability reduction is crucial for evaluating DMT efficacy.
Purpose of the Study:
- To compare the effects of tolebrutinib on confirmed disability worsening (CDW) versus relapse prevention against other DMTs in relapsing MS.
- To determine if tolebrutinib's treatment effects on CDW diverge from its effects on relapse prevention.
Main Methods:
- A meta-analysis of phase 3 trials comparing DMTs (ofatumumab, ponesimod, ublituximab, evobrutinib, tolebrutinib) against teriflunomide was conducted.
- Effect estimates for annualized relapse rate (ARR) and CDW (at 24 weeks) were extracted and analyzed.
- Weighted linear regression assessed the association between treatment effects on CDW and ARR, with tolebrutinib analyzed separately.
Main Results:
- A strong linear association (R² = 0.997) was found between ARR reduction and CDW improvement for four DMTs, indicating proportional benefits.
- Tolebrutinib demonstrated a significant reduction in CDW (HR 0.71) but showed no significant effect on ARR (RR 1.03).
- This represents a dissociation between disability and relapse outcomes for tolebrutinib compared to other DMTs.
Conclusions:
- Tolebrutinib is the first DMT observed to improve disability without a measurable impact on relapse rates in relapsing MS.
- This dissociation suggests a potential distinct mechanism of action for tolebrutinib in managing MS progression.
- Further research is warranted to elucidate the specific pathways through which tolebrutinib exerts its disability-sparing effects.
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