Tolebrutinib vs Teriflunomide Treatment for Individuals with Relapsing MS
Analysis of results from two clinical trials presented at the American Academy of Neurology (AAN) 2025 Annual Meeting revealed no significant difference in the adjusted annualized relapse rate (ARR) in individuals with relapsing multiple sclerosis (RMS) treated with either tolebrutinib (Sanofi; Bridgewater, NJ) or teriflunomide, or matching placebo. Researchers did find a significant difference in the 6-month confirmed disability worsening (CDW) rate between treatment groups with individuals treated with tolebrutinib experiencing a 29% risk reduction in CDW compared with those in the teriflunomide treatment group (nominal P=.023).
GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) were double-blind randomized phase 3 clinical studies evaluating the efficacy and safety of tolebrutinib compared to teriflunomide in individuals with RMS. Participants were randomized in both studies (1:1) to receive either 60 mg tolebrutinib or 14 mg teriflunomide, or matching placebo daily.
Participants (n=1873) enlisted in these studies were aged 18 to 55 years diagnosed with RMS with Expanded Disability Status Scale (EDSS) scores ≤5.5 who had experienced either ≥1 relapse within the previous year, ≥2 relapses within the previous 2 years, or ≥1 gadolinium-enhancing T1 brain lesion within the previous year.
Although no significant difference was observed in the reported ARR between the two treatment arms in either GEMINI 1 (0.13 for tolebrutinib vs. 0.12 for teriflunomide, P=.67) or GEMINI 2 (0.11 in both arms, P=.98), individuals who were treated with tolebrutinib demonstrated a 29% risk reduction in 6-month confirmed disability worsening (CDW) compared to teriflunomide (nominal P=.023).
Adverse events noted in both trials were equivalent, although rare instances of elevated liver enzymes were noted within 90 days of initiation of tolebrutinib therapy which resolved without long-term effects. The study authors hypothesize that tolebrutinib may impact disability accumulation through mechanisms beyond relapse reduction, potentially by modulating smoldering neuroinflammation.