Tolebrutinib for Multiple Sclerosis

Recruiting at 491 trial locations

Overseen By Trial Transparency email recommended (Toll free for US & Canada)

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sanofi

Must not be taking: CYP3A inducers, CYP2C8 inhibitors

Disqualifiers: Infections, Alcohol abuse, Liver disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 years

2500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and tolerability of tolebrutinib for individuals with various forms of multiple sclerosis (MS), a condition where the immune system attacks the protective covering of nerves. It continues for those who participated in earlier study phases and involves taking tolebrutinib, a new potential drug, or another medication, teriflunomide. Individuals diagnosed with relapsing MS, primary progressive MS, or non-relapsing secondary progressive MS who participated in prior studies may be suitable candidates. The trial aims to ensure the long-term safety of the treatments for those experiencing ongoing MS symptoms. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to the potential availability of a new MS treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but it does mention that you cannot take certain drugs that affect liver enzymes. It's best to discuss your current medications with the study team to see if they are allowed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tolebrutinib has generally been well-tolerated in earlier studies. In a study involving people with multiple sclerosis, most participants did not experience serious side effects. However, some common issues included headaches and colds. Long-term safety information for tolebrutinib in multiple sclerosis is not yet available, as research is ongoing.

Prospective trial participants should understand that while early results are promising, the complete safety profile is still under investigation. Participants are encouraged to ask questions and discuss any concerns with the research team. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for multiple sclerosis?

Researchers are excited about Tolebrutinib for multiple sclerosis (MS) because it offers a novel approach by targeting Bruton's tyrosine kinase (BTK), a key enzyme involved in the immune response. Unlike traditional MS treatments such as interferons or glatiramer acetate, Tolebrutinib may reduce inflammation by inhibiting BTK, potentially offering better management of disease activity. This new mechanism of action could lead to improved outcomes for patients by slowing disease progression and reducing relapses, making it a promising option in the fight against MS.

What evidence suggests that this trial's treatments could be effective for multiple sclerosis?

Research has shown that tolebrutinib, which participants in this trial may receive, may help treat multiple sclerosis (MS). One study found that tolebrutinib slowed the worsening of disability in people with secondary progressive MS. MRI scans revealed that it helped reduce inflammation in the brain. Although some safety concerns, such as MS relapses, were noted, the treatment was generally considered safe. Overall, these findings suggest that tolebrutinib could help manage symptoms in people with MS. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with Relapsing Multiple Sclerosis (RMS), Primary Progressive MS (PPMS), or Non-Relapsing Secondary Progressive MS (NRSPMS) who were part of earlier Phase 2b or Phase 3 tolebrutinib studies. It's not open to new patients; only those who completed previous trials on the medication, including during emergencies.

Inclusion Criteria

Participants with RMS, PPMS, or NRSPMS who completed the Phase 2b LTS (LTS16004) or 1 of the 4 Phase 3 pivotal tolebrutinib trials (EFC16033, EFC16034, EFC16645, EFC16035) on IMP

Participants who temporarily discontinued IMP due to a national emergency and completed the trial visits

Exclusion Criteria

I have a significant health condition affecting my whole body.

Current alcohol intake exceeding specified limits

Active alcohol use disorder or a history of alcohol or drug abuse within 1 year prior to the opt-in visit

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive open-label tolebrutinib or continue their parent study treatment for approximately 3 years

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants continue to receive open-label tolebrutinib to assess long-term safety and tolerability

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Tolebrutinib

Trial Overview

The study is testing the long-term safety and tolerability of a drug called Tolebrutinib in people with different types of Multiple Sclerosis. Participants from prior related studies continue treatment to see how they do over time. Some may receive Teriflunomide or a placebo as comparisons.

How Is the Trial Designed?

Group I: Tolebrutinib Experimental Treatment 2 Interventions

* Participants will receive OL tolebrunitib 60 mg once daily. * RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment as per their randomization from the parent study.

Group II: Teriflunomide Active Control 2 Interventions

* participants will receive teriflunomide 14 mg daily * RMS participants who are not eligible for OL tolebrutinib per Health Authority and/or ethics committee decisions on the study conduct (ie, partial hold on initiation of tolebrutinib) will continue their parent study treatment assignment (either tolebrutinib or teriflunomide) as per their randomization from the parent study. If unblinded to teriflunomide parent study treatment assignment, these RMS participants will continue teriflunomide in the LTS17043 study.

Who Is Running the Clinical Trial?

Sanofi

Lead Sponsor

Trials

2,246

Recruited

4,085,000+

Paul Hudson

Sanofi

Chief Executive Officer since 2019

Degree in Economics from Manchester Metropolitan University

Christopher Corsico

Sanofi

Chief Medical Officer

MD from Cornell University, MPH in Chronic Disease Epidemiology from Yale University

Published Research Related to This Trial

In a 16-week study involving 130 participants with relapsing multiple sclerosis, tolebrutinib demonstrated a dose-dependent reduction in new active brain lesions, with the highest efficacy observed at the 60 mg dose.

Tolebrutinib was well tolerated, with only one serious adverse event reported and no treatment-related deaths, suggesting it is a safe option for reducing inflammation in multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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., et al.[2023]

Tolebrutinib, a BTK inhibitor, was found to be well-tolerated in a first-in-human study involving multiple dose levels, with all treatment-related side effects being mild, indicating a favorable safety profile.

The drug effectively crosses the blood-brain barrier and shows significant BTK occupancy in both peripheral and central nervous system cells, suggesting its potential for targeting inflammation in various conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168). Owens, TD., Smith, PF., Redfern, A., et al.[2022]

Tolebrutinib, a drug targeting Bruton's tyrosine kinase, is rapidly absorbed and extensively metabolized in the body, with 78% of the administered dose eliminated through feces.

One of its metabolites, M2, retains significant inhibitory activity against Bruton's tyrosine kinase, similar to the parent drug, suggesting that both tolebrutinib and M2 contribute to its therapeutic effects in treating inflammation related to multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity. Nicolas, O., Moliner, P., Soubayrol, P., et al.[2023]

Acalabrutinib and zanubrutinib, second-generation BTK inhibitors, show significantly lower rates of adverse events such as atrial fibrillation, bleeding, diarrhea, hypertension, and infections compared to ibrutinib, based on an analysis of 1386 patients from three major clinical trials.

The favorable safety profile of acalabrutinib and zanubrutinib supports their use as preferred treatment options for patients with relapsed/refractory B-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined analysis of the impact of second-generation BTK inhibitors on patient outcomes. Redd, RA., Ford, J., Lei, M., et al.[2023]

Bruton's tyrosine kinase (BTK) is significantly upregulated in active and chronic active multiple sclerosis (MS) lesions, particularly in microglia and macrophages, suggesting that BTK inhibitors could effectively target these cells to modulate inflammation and tissue damage.

The study found that BTK expression increases during the progression of MS lesions, indicating that BTK inhibitors may help limit microglia activation and potentially reduce damage in chronic active lesions, making them a promising therapeutic option for MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of Bruton´s tyrosine kinase in different type of brain lesions of multiple sclerosis patients and during experimental demyelination. Elkjaer, ML., Waede, MR., Kingo, C., et al.[2023]

Remibrutinib, a selective BTK inhibitor, effectively reduced neurological symptoms in mouse models of multiple sclerosis (MS) by inhibiting B cell-driven pathology and showing strong BTK occupancy in immune organs and the brain.

The drug demonstrated a dual mechanism of action: it inhibited pathogenic B cell activity without depleting B cells or broadly inhibiting T cells, while also exerting direct anti-inflammatory effects on microglia, suggesting it could be a promising new treatment for MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. Nuesslein-Hildesheim, B., Ferrero, E., Schmid, C., et al.[2023]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03996291

NCT03996291 | Long Term Safety and Efficacy Study of ...

Long Term Safety and Efficacy Study of Tolebrutinib (SAR442168) in Participants With Relapsing Multiple Sclerosis · Study Overview · Contacts and ...

2.

icer.org

icer.org/wp-content/uploads/2025/07/ICER_MS_Final-Report_For-Publication_071525.pdf

Tolebrutinib for Secondary Progressive Multiple Sclerosis

The trial met the primary endpoint of confirmed disability progression sustained for ≥6 months, with fewer participants in the tolebrutinib ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8434816/

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK ...

One serious (and severe) AE was reported, an MS relapse, in the tolebrutinib 60-mg arm. No other serious or severe AEs occurred over the study ...

4.

sanofi.com

sanofi.com/en/media-room/press-releases/2025/2025-09-22-05-00-00-3153624

Press Release: Update on the US regulatory review of ...

The safety and efficacy of tolebrutinib have not been established by the FDA, and it remains under review by regulatory authorities worldwide, ...

5.

neurology.org

neurology.org/doi/10.1212/WN9.0000000000000028

Tolebrutinib Phase 2b Long-Term Extension Study

The Phase 2b trial established that tolebrutinib improved MRI measures of acute inflammation and supported the use of a daily 60-mg dose for ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8841436/

Phase 1 clinical trial evaluating safety, exposure and ...

Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168). Timothy D Owens ...

7.

icer.org

icer.org/wp-content/uploads/2025/05/ICER_SPMS_Evidence-Report_For-Publication_052925.pdf

Tolebrutinib for Secondary Progressive Multiple Sclerosis

Furthermore, we do not have long-term safety data on tolebrutinib in MS, so as with any drug with a new mechanism of action, additional ...

8.

sciencedirect.com

sciencedirect.com/science/article/pii/S3050623925000574

Safety and efficacy of Bruton's tyrosine kinase inhibitors in ...

Safety and efficacy of evobrutinib and tolebrutinib in relapsing multiple sclerosis: a meta-analysis of recent randomized control trials.