Tolebrutinib vs Teriflunomide in MS: Safety, Efficacy Results From GEMINI Trials

Compared with teriflunomide, tolebrutinib leads to a reduction in disability accumulation in patients with relapsing multiple sclerosis (RMS), according to study results to be presented at the 2025 American Academy of Neurology (AAN) annual meeting, held from April 5 to 9, 2025, in San Diego, California.

Studies have shown that tolebrutinib has a role in smoldering neuroinflammation, which is believed to be a major driver of disability accumulation.

Researchers compared the safety and efficacy of tolebrutinib vs teriflunomide in RMS, using data from the GEMINI 1 and 2 trials (ClinicalTrials.gov Identifiers: NCT04410978 and NCT04410991, respectively).

Participants in the GEMINI trials were aged between 18 and 55 years; had RMS; Expanded Disability Status Scale (EDSS) score of 5.5 or lesser; and at least 1 relapse within the previous year, at least 2 relapses within the previous 2 years, or at least 1 gadolinium-enhancing T1 brain lesion within the previous year.

All participants were randomly assigned 1:1 to receive 60 mg once-daily tolebrutinib or 14 mg once-daily teriflunomide, or matching placebo for each treatment.

Primary endpoint of the study was annualized relapse rate (ARR) and secondary endpoint was time to 6-month confirmed disability worsening (CDW).

A total of 1873 participants (974 in GEMINI 1 and 899 in GEMINI 2; 67% women; mean age, 36.5 years) were included in the current analysis. Mean time since MS diagnosis was 4.3 years, baseline EDSS score was 2.4, and mean relapses in the previous year was 1.2. Adjusted ARR was 0.13 and 0.12 for tolebrutinib and teriflunomide, respectively, in GEMINI 1 (P =.67) and 0.11 for both in GEMINI 2 (P =.98).

Tolebrutinib vs teriflunomide had a 29% risk reduction in 6-month CDW (nominal P =.023).

While treatment with tolebrutinib and teriflunomide had similar adverse events, high liver enzyme increases were observed with tolebrutinib that occurred within 90 days of start of treatment, with all resolving without sequelae.

Although there were no differences in relapses, tolebrutinib vs teriflunomide led to a reduction in disability accumulation.

“Results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are [2] distinct biological processes,” the researchers concluded.