Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis

N Engl J Med. 2025 May 15;392(19):1893-1904. doi: 10.1056/NEJMoa2415985. Epub 2025 Apr 8.

Abstract

Background: Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton's tyrosine kinase inhibitor that modulates peripheral inflammation and persistent immune activation within the central nervous system, including disease-associated microglia and B cells. More data are needed on its efficacy and safety in treating relapsing multiple sclerosis.

Methods: In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials.

Results: A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P = 0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P = 0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%).

Conclusions: Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.).

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study

MeSH terms

  • Adult
  • Agammaglobulinaemia Tyrosine Kinase* / antagonists & inhibitors
  • Crotonates
  • Disability Evaluation
  • Double-Blind Method
  • Female
  • Hemorrhage / chemically induced
  • Hemorrhage / epidemiology
  • Humans
  • Hydroxybutyrates
  • Male
  • Middle Aged
  • Multiple Sclerosis, Relapsing-Remitting* / diagnosis
  • Multiple Sclerosis, Relapsing-Remitting* / drug therapy
  • Nitriles
  • Recurrence
  • Toluidines
  • Treatment Outcome
  • Tyrosine Kinase Inhibitors* / administration & dosage
  • Tyrosine Kinase Inhibitors* / adverse effects

Substances

  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • teriflunomide
  • Tyrosine Kinase Inhibitors
  • Crotonates
  • Hydroxybutyrates
  • Nitriles
  • Toluidines

Associated data

  • ClinicalTrials.gov/NCT04410978
  • ClinicalTrials.gov/NCT04410991