Tolebrutinib for Multiple Sclerosis

Recruiting at 330 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

Trial Summary

What is the purpose of this trial?

This is a Phase 3 extension, global, multicenter study to assess the long-term safety and tolerability of tolebrutinib in adult participants (aged ≥18 years) with RMS, PPMS, or NRSPMS who were previously enrolled in the Phase 2b LTS (LTS16004) or 1 of the 4 Phase 3 tolebrutinib pivotal trials (GEMINI 1 \[EFC16033\], GEMINI 2 \[EFC16034\], HERCULES \[EFC16645\], or PERSEUS \[EFC16035\]). SUBSTUDY: ToleDYNAMIC substudy

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 Tolebrutinib safe for humans?

Tolebrutinib has been tested in humans and was generally well-tolerated, with any side effects being mild. It was studied in a trial where different doses were given, and it showed a good safety profile. ^{1 2 3 4 5}

What makes the drug tolebrutinib unique for treating multiple sclerosis?

Tolebrutinib is unique because it is an oral drug that can cross the blood-brain barrier to inhibit Bruton's tyrosine kinase (BTK), which plays a role in inflammation in the brain. This makes it different from other treatments as it targets both B cells and microglia, potentially reducing inflammation in the central nervous system. ^{1 2 3 4 6}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168). [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity. [2023]

3. Switzerland 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. [2023]

4. England 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Combined analysis of the impact of second-generation BTK inhibitors on patient outcomes. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis. [2023]