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Data from the Phase III GEMINI 1 (NCT04410978) and GEMINI 2 trials (NCT04410991) show that compared to Aubagio (teriflunomide), tolebrutinib did not achieve superiority in lowering annualized relapse rates or MRI-detected inflammatory activity in patients with relapsing multiple sclerosis (MS). The authors of the study, published by The New England Journal of Medicine, stated that although preliminary data indicate a potential benefit with tolebrutinib in slowing disability progression, these findings were unable to be confirmed, which highlights the need for additional long-term and comparative studies to clarify the drug’s efficacy and safety.1-3
“Existing disease-modifying therapies have a limited effect on disability, probably because they act predominantly on acute focal inflammatory activity in the periphery, whereas tolebrutinib is thought to modulate immunologic drivers of chronic inflammation behind the blood–brain barrier,” the study authors wrote. “Preclinical data suggest that disease-associated microglia are a potential target of tolebrutinib, and fluid and radiographic biomarker analyses from the tolebrutinib clinical development program may provide further insights into the potential mechanisms by which tolebrutinib affects the biologic features of nonrelapsing disease.”1
Tolebrutinib was designed to target smoldering neuroinflammation, which is among the primary drivers of disability progression in patients with MS. Recently published findings from the Phase III HERCULES trial (NCT04411641) found that tolebrutinib produced a significant delay in disability progression in patients with non-relapsing secondary progressive MS (nrSPMS). The study authors said these results indicate the significant potential of tolebrutinib as a first-in-class, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor for treating nrSPMS.
“Preventing disability accrual and fostering sustained improvement in neurologic functioning remain unmet clinical needs across all stages of multiple sclerosis,” the authors of the current study wrote. “Tolebrutinib is a brain-penetrant and bioactive inhibitor of (BTK), which is implicated in the signaling of myeloid cells, including central nervous system–resident microglia, as well as in B-cell maturation and function, thus participating in both innate and adaptive immunity. Tolebrutinib is being investigated as a treatment for relapse activity and central nervous system–compartmentalized neuroinflammation associated with disability accrual.”1
Trial Design
Both GEMINI 1 and 2 were double-blind, randomized trials comparing the efficacy and safety of tolebrutinib at a dose of 60 mg once daily vs. Aubagio at a dose of 14 mg once daily in patients with relapsing MS. GEMINI 1 enrolled 974 patients and GEMINI 2 enrolled 899 patients, who were randomly assigned in a 1:1 ratio to receive daily tolebrutinib and placebo or daily Aubagio and placebo.
Both trials had a primary endpoint of annualized relapse rate for up to approximately 36 months, which was defined as amount of confirmed adjudicated protocol defined relapses. The trial’s secondary endpoints included time to onset of confirmed disability worsening (CDW) across at least six months and defined as an increase of ≥1.5 points from baseline EDSS score if the score is 0; increase of ≥1.0 point from baseline EDSS score when score is 0.5 to ≤5.5; or increase of ≥0.5 point from baseline EDSS score when baseline score was >5.5. Secondary endpoints also included increase of total number of new and/or enlarging T2 hyperintense lesions detected by MRI from baseline through trial end date, amount of Gd-enhancing T1 hyperintense lesions detected by MRI from baseline through trial end date, and safety and tolerability.
Across a median follow-up of 139 weeks, the annualized relapse rate among patients administered tolebrutinib was 0.13 compared to 0.12 among those administered Aubagio in the GEMINI 1 trial (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P=0.67). Meanwhile, these rates were 0.11 and 0.11, respectively, in the GEMINI 2 trial (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P=0.98).
The pooled percentage of patients experiencing confirmed disability worsening that was sustained for at least six months was 8.3% in the tolebrutinib cohort compared to 11.3% in the Aubagio cohort (hazard ratio, 0.71; 95% CI, 0.53 to 0.95). In terms of safety, reports of adverse events were similar among both cohorts; however, 4.5% of patients administered tolebrutinib experienced minor bleeding compared to 0.3% with Aubagio.
“In the GEMINI 1 and GEMINI 2 trials, treatment with tolebrutinib did not result in a lower annualized relapse rate or less acute inflammatory activity on MRI than treatment with teriflunomide,” the study authors concluded. “Whether the rates of disability worsening with tolebrutinib are significantly better than comparator agents will require further study. Continued follow-up of participants in these trial cohorts is required to characterize fully the long-term efficacy and safety of tolebrutinib.”1
References
1. Oh J., et al. Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med 2025. DOI: 10.1056/NEJMoa2415985.
2. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1) (GEMINI 1). ClinicalTrials.gov. Updated September 19, 2024. Accessed April 22, 2025. https://clinicaltrials.gov/study/NCT04410978
3. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2) (GEMINI 2). ClinicalTrials.gov. Updated September 9, 2024. Accessed April 22, 2025. https://clinicaltrials.gov/study/NCT04410991