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N. Engl. J. Med., Apr 08 2025, | https://doi.org/10.1056/NEJMoa2415985
Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis
Jiwon Oh 1, Douglas L Arnold 2,3, Bruce A C Cree 4, Carolina Ionete 5, Ho Jin Kim 6, Maria Pia Sormani 7,8, Sana Syed 9, Yixin Chen 9, Christina R Maxwell 9, Patrick Benoit 10, Timothy J Turner 9, Erik Wallstroem 9, Heinz Wiendl 11,12; Tolebrutinib Phase 3 GEMINI 1 and 2 Trial Group
1St. Michael's Hospital, University of Toronto, Toronto.
2McGill University, Montreal.
3NeuroRx Research, Montreal.
4Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.
5Department of Neurology, UMass Chan Medical School, Worcester, MA.
6Department of Neurology, National Cancer Center, Goyang, South Korea.
7Department of Health Sciences, University of Genoa, Genoa, Italy.
8IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
9Sanofi, Cambridge, MA.
10Sanofi, Chilly-Mazarin, France.
11Department of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany.
12Brain and Mind Center, University of Sydney, Sydney.
Corresponding author : Jiwon Oh
1St. Michael's Hospital, University of Toronto, Toronto.
2McGill University, Montreal.
3NeuroRx Research, Montreal.
4Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.
5Department of Neurology, UMass Chan Medical School, Worcester, MA.
6Department of Neurology, National Cancer Center, Goyang, South Korea.
7Department of Health Sciences, University of Genoa, Genoa, Italy.
8IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
9Sanofi, Cambridge, MA.
10Sanofi, Chilly-Mazarin, France.
11Department of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany.
12Brain and Mind Center, University of Sydney, Sydney.
Corresponding author : Jiwon Oh
Abstract
Background: Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton's tyrosine kinase inhibitor that modulates peripheral inflammation and persistent immune activation within the central nervous system, including disease-associated microglia and B cells. More data are needed on its efficacy and safety in treating relapsing multiple sclerosis.
Methods: In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials.
Results: A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P = 0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P = 0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%).
Conclusions: Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.).
Methods: In two phase 3, double-blind, double-dummy, event-driven trials (GEMINI 1 and GEMINI 2), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive tolebrutinib (60 mg once daily) or teriflunomide (14 mg once daily), each with matching placebo. The primary end point was the annualized relapse rate. The key secondary end point was confirmed worsening of disability that was sustained for at least 6 months, which was assessed in a time-to-event analysis that was pooled across trials.
Results: A total of 974 participants were enrolled in GEMINI 1, and 899 were enrolled in GEMINI 2. The median follow-up was 139 weeks. The annualized relapse rate in the tolebrutinib and teriflunomide groups was 0.13 and 0.12, respectively, in GEMINI 1 (rate ratio, 1.06; 95% confidence interval [CI], 0.81 to 1.39; P = 0.67) and 0.11 and 0.11, respectively, in GEMINI 2 (rate ratio, 1.00; 95% CI, 0.75 to 1.32; P = 0.98). The pooled percentage of participants with confirmed disability worsening sustained for at least 6 months was 8.3% with tolebrutinib and 11.3% with teriflunomide (hazard ratio, 0.71; 95% CI, 0.53 to 0.95; no formal hypothesis testing was conducted owing to the prespecified hierarchical testing plan, and the width of the confidence interval is not adjusted for multiple testing). The percentage of participants who had adverse events was similar in the two treatment groups, although the percentage with minor bleeding was higher in the tolebrutinib group than in the teriflunomide group (petechiae occurred in 4.5% vs. 0.3%, and heavy menses in 2.6% vs. 1.0%).
Conclusions: Tolebrutinib was not superior to teriflunomide in decreasing annualized relapse rates among participants with relapsing multiple sclerosis. (Funded by Sanofi; GEMINI 1 and GEMINI 2 ClinicalTrials.gov numbers, NCT04410978 and NCT04410991, respectively.).
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-05-09)
- 국내+국외 연구진
- 의약학 > 신경의학
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