Tolebrutinib reduces disability accumulation in relapsing MS

Treatment with tolebrutinib results in a clear reduction in disability accumulation in patients with relapsing multiple sclerosis (MS) compared with teriflunomide despite no difference in relapses, according to the findings of the GEMINI 1 and 2 trials presented at AAN 2025.

“Current MS therapies reduce acute focal inflammation but are less effective at slowing disability accumulation,” said lead author Dr Jiwon Oh from St. Michael’s Hospital, University of Toronto in Toronto, Canada.

“Tolebrutinib is a brain-penetrant and bioactive Bruton’s tyrosine kinase (BTK) inhibitor that modulates persistent immune activation within the central nervous system, including disease-associated microglia and B-cells,” she added. [Clin Transl Sci 2024;17:e13693; Drugs R D 2024;24:263-274; Nat Rev Neurol 2023;19:289304]

GEMINI 1 and 2 were phase III, double-blind, event-driven trials that enrolled patients (aged 18–55 years) with relapsing MS, Expanded Disability Status Scale (EDSS) score ≤5.5, and 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.

Individuals with prior diagnosis of primary progressive MS or nonrelapsing secondary progressive MS were excluded from the trial. Subsequently, Oh and her team randomly allocated 1,873 eligible participants (GEMINI 1: n=974; GEMINI 2: n=899) to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo.

The annualized relapse rate (ARR) served as the primary endpoint, while the time to 6-month confirmed disability worsening (CDW) was secondary. Six-month CDW was defined as a sustained increase from baseline in EDSS score ≥1.5 points when baseline score was 0, ≥1.0 point when baseline score was 0.5 to ≤5.5, or ≥0.5 point when baseline score was >5.5.

Of the participants (mean age 36.5 years), 67 percent were female, 64 percent were treatment-naive, and 34 percent had gadolinium-enhancing T1 lesions. The mean time since diagnosis was 4.3 years, and the mean baseline EDSS score was 2.4. In the previous year, the mean number of relapses was 1.2.

“Baseline characteristics were well-balanced across both treatment arms and between trials,” Oh said.

Relapse rate

The adjusted ARRs were 0.13 with tolebrutinib and 0.12 with teriflunomide in GEMINI 1 (p=0.67) and 0.11 in both treatment arms in GEMINI 2 (p=0.98). The pooled ARR was 0.12 for both arms (pooled ARR rate ratio, 1.03, 95 percent confidence interval [CI], 0.84–1.25; p=0.80).

“ARR was low in the teruflunomide arm in both GEMINI 1 and 2, and no difference was observed between tolebrutinib and teruflunomide,” Oh said.

For the secondary endpoint, tolebrutinib showed a 29-percent decrease in the risk of 6-month CDW when compared with teriflunomide (hazard ratio, 0.71, 95 percent CI, 0.53–0.95; nominal p=0.023).

“[T]olebrutinib demonstrated clear separation from teriflunomide in a population with very low relapse activity,” Oh said.

In terms of safety, adverse events were comparable between the two treatment arms, with rare occurrences (5.6 percent) of high liver enzyme increases in the tolebrutinib arm. These events occurred within 90 days of tolebrutinib initiation and resolved without sequelae.

"These results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes,” Oh said.