GEMINI 2
What it found
The main measure did not show a significant benefit.
| Measure | Estimate | 95% CI | p |
|---|---|---|---|
| Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses | Relative risk 0.996 | 0.754–1.315 | 0.9758 |
Statistical analysis as posted on ClinicalTrials.gov.
What was tested
Treatment tested
- Tolebrutinib
Tyrosine-protein kinase BTK inhibitor
Compared with
- Teriflunomide
Dihydroorotate dehydrogenase inhibitor
Placebo or sham
- Placebo to match Tolebrutinib
- Placebo to match Teriflunomide
Results by group
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses
Baseline (Day 1) to approximately 48 months
| Group | Value | Interval | Number analysed |
|---|---|---|---|
| Teriflunomide 14 mg | 0.109 relapses per participant year | 0.088–0.134 | 452 |
| Tolebrutinib 60 mg | 0.108 relapses per participant year | 0.089–0.131 | 447 |
Teriflunomide 14 mg
Tolebrutinib 60 mg
p = 0.9758; Relative risk 0.996 (95% CI 0.754–1.315)
Values as posted on ClinicalTrials.gov. Outcomes measured differently across trials are not directly comparable.
Safety
| Group | Participants at risk | Serious adverse events | Deaths |
|---|---|---|---|
| Teriflunomide 14 mg | 451 | 37 (8.2%) | 2 |
| Tolebrutinib 60 mg | 447 | 49 (11.0%) | 1 |
As posted on ClinicalTrials.gov. Serious adverse events include any serious health event during the trial, whether or not the treatment caused it.
What it measured
Main measures
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses
Baseline (Day 1) to approximately 48 months
RelapsesAnnualized Adjudicated Relapse Rate : Number of confirmed protocol defined relapses ; Annualized Adjudicated Relapse Rate : Number of confirmed protocol defined adjudicated relapses
Relapses
Other measures (13)
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
Baseline (Day 1) to approximately 48 months
Disability progressionBladder, bowel and sexual functionTime to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
Baseline (Day 1) to approximately 48 months
Disability progressionBladder, bowel and sexual functionMean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year
Baseline (Day 1) to approximately 48 months
MRI lesionsMean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan
Baseline (Day 1) to approximately 48 months
MRI lesionsChange From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS
Baseline (Day 1) to EOS (up to approximately 48 months)
Thinking and memoryChange From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS
Baseline (Day 1) to EOS (up to approximately 48 months)
Thinking and memoryTime to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale
Baseline (Day 1) to approximately 48 months
Disability progressionBladder, bowel and sexual functionPercent Change in Brain Volume Loss at EOS Compared to Month 6
Month 6 to EOS (up to approximately 48 months)
MRI lesionsBrain volume lossChange From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS
Baseline (Day 1) to EOS (up to approximately 48 months)
Thinking and memoryBladder, bowel and sexual functionPainQuality of life (reported by participants)Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Adverse Events of Special Interest (AESIs)
From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months
Safety
Who could take part
Relapsing MS · 18 to 55
Inclusion criteria : * The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent * The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria * The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first Screening Visit * The participant must have at least 1 of the following prior to screening: * ≥1 documented relapse within the previous year OR * ≥2 documented relapses within the previous 2 years, OR * ≥1 documented Gd enhancing lesion on an MRI scan within the previous year * Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies * Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure: * Refrain from donating sperm Plus either: * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR * Must agree to use contraception/barrier as detailed below * Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant - A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply: * Is not a WOCBP OR * Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of \<1% per year), preferably with low user dependency during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last dose of SAR442168, if the case was unblinded) and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during the study and for the same period of time. * A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24hours before the first dose of study intervention. * If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. * The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. * The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant's legally authorized representative Exclusion criteria: * The participant has been diagnosed with primary progressive multiplesclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiplesclerosis (SPMS) * The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, hepatitis B or C, any persistent chronic or active recurring infection * Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening. * The participant has conditions or situations that would adversely affect participation in this study, including but not limited to: * A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist * Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator * A requirement for concomitant treatment that could bias the primary evaluation * The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study * At screening, the participant is positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or is positive for hepatitis C antibody * The participant has any of the following: * A bleeding disorder or known platelet dysfunction at any time prior to the screening visit * A platelet count \<150 000/μL at the screening visit * The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit * The presence of psychiatric disturbance or substance abuse * Prior/concomitant therapy * The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes * The participant is receiving anticoagulant/antiplatelet therapies * The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial
As registered. Criteria can change, so ask the trial team or your neurologist.
About this trial
In the sponsor's words
Primary Objective: To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS Secondary Objective: To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life To evaluate the safety and tolerability of daily SAR442168 To evaluate pharmacodynamics (PD) of SAR442168
Papers
Results
First-in-Human Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of BIIB091, an Oral BTK Inhibitor, in Healthy Adult Participants.Drug Des Devel Ther · 2026
Results
Tolebrutinib versus Teriflunomide in Relapsing Multiple Sclerosis.N Engl J Med · 2025
Results
Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.Lancet Neurol · 2021
Results
Maxwell CR, Turner TJ, Wallstroem E, Patel S, Pappas SC, Lewis JH, Andrade RJ, Syed S. Tolebrutinib liver safety: A detailed overview. Mult Scler Relat Disord. 2026 Jul 23;113:107404. doi: 10.1016/j.msard.2026.107404. Online ahead of print.
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History
Started
Jun 2020
Main results due
Jul 2024
Finished
Jul 2024
Results posted
Jun 2025
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