Tolebrutinib Versus Teriflunomide in Relapsing Multiple Sclerosis: Efficacy and Safety Results from the Phase 3 GEMINI 1 and 2 Trials
Jiwon Oh1, Douglas L. Arnold2, Bruce A.C. Cree3, Carolina Ionete4, Ho Jin Kim5, Maria Pia Sormani6, Sana Syed7, Yixin Chen7, Christina R. Maxwell7, Patrick Benoit8, Timothy J. Turner7, Erik Wallstroem7, Heinz Wiendl9
1St. Michael’s Hospital, University of Toronto, Toronto, Canada, 2NeuroRx Research, Montréal, Canada, 3UCSF Weill Institute for Neurosciences, University of California San Francisco, Department of Neurology, San Francisco, United States, 4UMass Chan Medical School, Worcester, United States, 5National Cancer Center, Department of Neurology, Goyang, South Korea, 6University of Genoa, Department of Health Sciences, Genoa, Italy, 7Sanofi, Cambridge, United States, 8Sanofi, Chilly-Mazarin, France, 9Department of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany
Objective:
To evaluate the efficacy and safety of tolebrutinib versus teriflunomide in relapsing multiple sclerosis (MS).
Background:
Tolebrutinib is a brain-penetrant and bioactive Bruton’s tyrosine kinase inhibitor that modulates persistent immune activation within the central nervous system, including disease-associated microglia and B cells, potentially affecting smoldering neuroinflammation thought to be a major driver of disability accumulation.
Design/Methods:
GEMINI 1 (NCT04410978) and 2 (NCT04410991) were phase 3, double-blind, event-driven trials. Participants were 18-55 years old 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. Participants were randomized 1:1 to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary endpoint was annualized relapse rate (ARR) and the key secondary endpoint was time to 6-month confirmed disability worsening (CDW).
Results:
The trials enrolled 1873 participants (974/899 in GEMINI 1/2), of which 67% were female, 64% were treatment-naïve, and 34% had gadolinium-enhancing T1 lesions. Mean age was 36.5 years, mean time since diagnosis was 4.3 years, mean baseline EDSS score was 2.4, and mean number of relapses in the previous year was 1.2. Adjusted ARR was 0.13 with tolebrutinib and 0.12 with teriflunomide (P=0.67) in GEMINI 1 and 0.11 in both arms (P=0.98) in GEMINI 2. Tolebrutinib demonstrated a 29% risk reduction in 6-month CDW versus teriflunomide (nominal P=0.023). Adverse events were generally balanced between groups. Rare events of high liver enzyme increases were observed with tolebrutinib and occurred within 90 days of tolebrutinib start, all resolving without sequelae.
Conclusions:
Tolebrutinib showed a clear reduction in disability accumulation versus teriflunomide despite no difference in relapses. Results are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are two distinct biological processes.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.