NCT04410991: GEMINI 2

Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2)

Completed Phase 3 Results posted Last updated 2 July 2025

What this trial tests

Phase 3 trial testing Tolebrutinib in Relapsing Multiple Sclerosis in 899 participants. Completed in 16 July 2024.

Timeline

11 June 2020

Primary endpoint
16 July 2024

16 July 2024

Quick facts

Lead sponsor	Sanofi
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	899
Start date	11 June 2020
Primary completion	16 July 2024
Estimated completion	16 July 2024
Sites	186 locations across South Korea, Croatia, Netherlands, Russia, Belgium, Czechia, Portugal, United States

Drugs / interventions tested

• Tolebrutinib — full drug profile →
• Teriflunomide HMR1726 — full drug profile →
• Placebo to match Tolebrutinib — full drug profile →
• Placebo to match Teriflunomide — full drug profile →

Conditions studied

• Relapsing Multiple Sclerosis — all drugs for Relapsing Multiple Sclerosis →

Sponsor

Sanofi — full company profile →

Who can join

Adults 18 to 55, any sex, with Relapsing Multiple Sclerosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses Primary · Baseline (Day 1) to approximately 48 months

Multiple sclerosis (MS) relapse was defined as a monophasic, acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature, and preceded by \>=30 days of clinical stability.

Group	Value	95% CI
Teriflunomide 14 mg	0.109	0.088 – 0.134
Tolebrutinib 60 mg	0.108	0.089 – 0.131

Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale Secondary · Baseline (Day 1) to approximately 48 months

The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 6-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5,

Group	Value	95% CI
Teriflunomide 14 mg	12.14	1.4 – 38.9
Tolebrutinib 60 mg	15.12	2.0 – 37.1

Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale Secondary · Baseline (Day 1) to approximately 48 months

The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 3-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5,

Group	Value	95% CI
Teriflunomide 14 mg	12.11	1.4 – 39.1
Tolebrutinib 60 mg	12.11	2.0 – 42.1

Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year Secondary · Baseline (Day 1) to approximately 48 months

Magnetic resonance imaging (MRI) of the brain was performed to identify number of new and/or enlarging T2-hyperintense lesions defined as the sum of the individual number of new and/or enlarging T2 lesions starting from baseline up to and including the EOS visit.

Group	Value	95% CI
Teriflunomide 14 mg	4.369	3.587 – 5.322
Tolebrutinib 60 mg	5.092	4.340 – 5.975

Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan Secondary · Baseline (Day 1) to approximately 48 months

MRI of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions defined as the sum of the individual number of new Gd- enhancing T1-hyperintense lesions starting from baseline up to and including the EOS visit.

Group	Value	95% CI
Teriflunomide 14 mg	0.217	0.169 – 0.280
Tolebrutinib 60 mg	0.460	0.365 – 0.581

Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS Secondary · Baseline (Day 1) to EOS (up to approximately 48 months)

The SDMT was used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involved a simple substitution task using a reference key. The number of correct substitutions and number of items completed within a 90 second interval (maximum 110 seconds) were recorded. A decrease of 4 points from baseline on the SDMT was considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicating a better outcome. Baseline was defined as the last available value prior to the first dose of study intervention

Group	Value	95% CI
Teriflunomide 14 mg	0.428	± 0.0373
Tolebrutinib 60 mg	0.374	± 0.0370

Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS Secondary · Baseline (Day 1) to EOS (up to approximately 48 months)

The CVLT-II was a verbal learning and memory test consisting of recall and recognition of a list of 16 words. For each assessment, 5 trials were completed. Total Correct Recall Trials 1-5 was scaled to a normalized T-score metric, which had a mean of 50 and standard deviation of 10, the maximum possible score was 80 and a minimum was 0. Higher values indicated improved cognitive function. Baseline was defined as the last available value prior to the first dose of study intervention.

Group	Value	95% CI
Teriflunomide 14 mg	16.431	± 0.6825
Tolebrutinib 60 mg	15.819	± 0.6740

Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale Secondary · Baseline (Day 1) to approximately 48 months

The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. CDI was defined as a decrease of \>=1 point from baseline in the EDSS score lasting at least 6 months.

Group	Value	95% CI
Teriflunomide 14 mg	12.05	2.8 – 30.6
Tolebrutinib 60 mg	9.04	2.6 – 33.5

Percent Change in Brain Volume Loss at EOS Compared to Month 6 Secondary · Month 6 to EOS (up to approximately 48 months)

MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss.

Group	Value	95% CI
Teriflunomide 14 mg	-0.740	± 0.0394
Tolebrutinib 60 mg	-0.696	± 0.0387

Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS Secondary · Baseline (Day 1) to EOS (up to approximately 48 months)

MSQoL-54 was standardized instrument comprising generic and MS-specific items. This 54-item instrument generated 12 subscales and 2 single-item measures (satisfaction with sexual function \[1 item\]; change in health \[1 item\]). 12 subscales were: a: physical health (10 items), b: health perceptions (5 items), c: energy (5 items), d: role limit physical (4 items), e: sexual function (4 items), f: pain (3 items), g: social function (3 items), h: health distress (4 items), i: overall quality of life (2 items), j: emotional well-being (5 items), k: role limitations emotional (3 items) and l: cog

Physical health composite score

Group	Value	95% CI
Teriflunomide 14 mg	-1.040	± 0.7404
Tolebrutinib 60 mg	-1.199	± 0.7304

Mental health composite score

Group	Value	95% CI
Teriflunomide 14 mg	-1.657	± 0.8709
Tolebrutinib 60 mg	-1.390	± 0.8581

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) Secondary · 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

An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the S

TEAEs

Group	Value	95% CI
Teriflunomide 14 mg	387
Tolebrutinib 60 mg	385

TESAEs

Group	Value	95% CI
Teriflunomide 14 mg	37
Tolebrutinib 60 mg	49

TEAEs leading to permanent study intervention discontinuation

Group	Value	95% CI
Teriflunomide 14 mg	17
Tolebrutinib 60 mg	19

TEAESIs

Group	Value	95% CI
Teriflunomide 14 mg	40
Tolebrutinib 60 mg	46

Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS Secondary · Baseline (Day 1) to EOS (up to approximately 48 months)

Blood samples were collected at specified timepoints to assess change from baseline in NfL and Chi3L1. Baseline was defined as the last available value prior to the first dose of study intervention.

NfL

Group	Value	95% CI
Teriflunomide 14 mg	-0.900	-4.390 – 0.770
Tolebrutinib 60 mg	-0.150	-3.560 – 2.750

Chi3L1

Group	Value	95% CI
Teriflunomide 14 mg	-281.100	-6148.400 – 5647.000
Tolebrutinib 60 mg	1462.500	-4578.600 – 7002.700

Adverse events — posted to ClinicalTrials.gov

Time frame: 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. Deaths were collected from baseline (Day 1) up to end of follow-up, approximately 48 months.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Teriflunomide 14 mg

Serious: 37/451 (8%)

Deaths: 2/452

Tolebrutinib 60 mg

Serious: 49/447 (11%)

Deaths: 1/447

Serious adverse events (79 terms)

Reaction	System	Teriflunomide 14 mg	Tolebrutinib 60 mg
Suicide Attempt	Psychiatric disorders	—	—
Appendicitis	Infections and infestations	—	—
Gastroenteritis	Infections and infestations	—	—
Covid-19	Infections and infestations	—	—
Covid-19 Pneumonia	Infections and infestations	—	—
Escherichia Pyelonephritis	Infections and infestations	—	—
Breast Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Uterine Leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Relapsing-Remitting Multiple Sclerosis	Nervous system disorders	—	—
Acute Sinusitis	Infections and infestations	—	—
Bone Abscess	Infections and infestations	—	—
Bronchitis	Infections and infestations	—	—
Dengue Fever	Infections and infestations	—	—
Diverticulitis	Infections and infestations	—	—
Gastroenteritis Norovirus	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Pneumonia Aspiration	Infections and infestations	—	—
Tonsillitis	Infections and infestations	—	—
Urinary Tract Infection	Infections and infestations	—	—
Urinary Tract Infection Bacterial	Infections and infestations	—	—
Intraductal Proliferative Breast Lesion	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Invasive Ductal Breast Carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Oligodendroglioma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Prostate Cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Squamous Cell Carcinoma Of Skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—

Other adverse events (17 terms — click to expand)

Reaction	System	Teriflunomide 14 mg	Tolebrutinib 60 mg
Covid-19	Infections and infestations	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Headache	Nervous system disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Upper Respiratory Tract Infection	Infections and infestations	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Hypertension	Vascular disorders	—	—
Urinary Tract Infection	Infections and infestations	—	—
Fatigue	General disorders	—	—
Anxiety	Psychiatric disorders	—	—
Influenza	Infections and infestations	—	—
Back Pain	Musculoskeletal and connective tissue disorders	—	—
Paraesthesia	Nervous system disorders	—	—
Viral Upper Respiratory Tract Infection	Infections and infestations	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Alanine Aminotransferase Increased	Investigations	—	—

Most-reported serious reactions: Suicide Attempt, Appendicitis, Gastroenteritis, Covid-19, Covid-19 Pneumonia, Escherichia Pyelonephritis, Breast Cancer, Uterine Leiomyoma.

Data from ClinicalTrials.gov NCT04410991 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. B cell depletion therapies in autoimmune disease: advances and mechanistic insights.
   Lee DSW, Rojas OL, Gommerman JL. · · 2021 · cited 496× · PMID 33324003 · DOI 10.1038/s41573-020-00092-2
2. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.
   Reich DS, Arnold DL, Vermersch P, Bar-Or A, et al · · 2021 · cited 144× · PMID 34418400 · DOI 10.1016/s1474-4422(21)00237-4
3. Bruton tyrosine kinase inhibitors for multiple sclerosis.
   Krämer J, Bar-Or A, Turner TJ, Wiendl H. · · 2023 · cited 119× · PMID 37055617 · DOI 10.1038/s41582-023-00800-7
4. Targeted Immunotherapy for Autoimmune Disease.
   Jung SM, Kim WU. · · 2022 · cited 113× · PMID 35291650 · DOI 10.4110/in.2022.22.e9
5. Updates and advances in multiple sclerosis neurotherapeutics.
   Amin M, Hersh CM. · · 2023 · cited 89× · PMID 36314777 · DOI 10.2217/nmt-2021-0058
6. BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies.
   Alu A, Lei H, Han X, Wei Y, et al · · 2022 · cited 88× · PMID 36183125 · DOI 10.1186/s13045-022-01353-w
7. Therapeutic Advances in Multiple Sclerosis.
   Yang JH, Rempe T, Whitmire N, Dunn-Pirio A, et al · · 2022 · cited 75× · PMID 35720070 · DOI 10.3389/fneur.2022.824926
8. Targeting Bruton's Tyrosine Kinase in Inflammatory and Autoimmune Pathologies.
   Neys SFH, Hendriks RW, Corneth OBJ. · · 2021 · cited 53× · PMID 34150760 · DOI 10.3389/fcell.2021.668131