Tolebrutinib for Multiple Sclerosis

Overseen By Daniel S Reich, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Must be taking: Anti-CD20 therapy

Must not be taking: Corticosteroids, Dimethyl fumarate

Disqualifiers: Pregnancy, HIV-positive, Hepatitis, others

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

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

Compensation: Varies

Number of Visits: 16

Duration: 48-96 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a new drug, tolebrutinib, can reduce inflammation in brain lesions caused by multiple sclerosis (MS), an issue current MS medications do not address. Participants will either take tolebrutinib or continue their existing anti-CD20 therapy to determine which better calms inflammation. This study may suit adults with MS who have been on anti-CD20 therapy for at least six months. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important MS research.

Will I have to stop taking my current medications?

If you are in the tolebrutinib group, you will need to stop your anti-CD20 therapy. If you are in the control group, you will continue your anti-CD20 therapy. Some other medications have specific 'washout' periods (time without taking certain medications) before you can join the study.

Is there any evidence suggesting that tolebrutinib is likely to be safe for humans?

Research has shown that tolebrutinib is generally well-tolerated. In earlier studies, participants who took single doses up to 120 mg and daily doses of 90 mg for 10 days did not experience major problems. Evidence indicates that the drug effectively targets BTK (Bruton's tyrosine kinase) in the body, which is a positive sign for its effectiveness.

However, one study reported a serious issue: a participant taking the 60 mg dose experienced a relapse of multiple sclerosis (MS). No other serious or severe problems were noted. It is important to understand that while tolebrutinib appears promising, there is no long-term safety data for MS yet, which means there could be unknown risks with long-term use.

Overall, the drug shows potential, but like any new treatment, it is important to consider both the benefits and risks. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for multiple sclerosis, which often include medications like interferons or monoclonal antibodies, Tolebrutinib acts on a new target in the body's immune system. It works by inhibiting Bruton's tyrosine kinase (BTK), a protein that plays a key role in the immune response and inflammation. By targeting BTK, Tolebrutinib could potentially reduce the harmful immune activity that contributes to multiple sclerosis symptoms. Researchers are excited about Tolebrutinib because this novel approach might offer improved efficacy and safety compared to existing therapies.

What evidence suggests that tolebrutinib might be an effective treatment for multiple sclerosis?

Research shows that tolebrutinib may help treat multiple sclerosis (MS). Studies have found that tolebrutinib can lower brain inflammation in people with MS by targeting a protein called BTK, crucial for immune cell function. Participants who took tolebrutinib developed fewer new active brain lesions. In this trial, participants will receive different dosages of tolebrutinib, with some receiving up to 120 mg daily. Tolebrutinib was well-tolerated at these doses, suggesting it could effectively manage MS symptoms related to inflammation. ^{1 2 3 5 6}

Who Is on the Research Team?

Daniel S Reich, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Are You a Good Fit for This Trial?

Adults over 18 with Multiple Sclerosis (MS) who have been on anti-CD20 therapy for at least 6 months are eligible. They must have a specific type of MS lesion visible on an MRI, be vaccinated against COVID-19, and agree to not receive any other MS treatments during the trial. Women must use effective contraception, and men should ensure they do not father children or donate sperm during and after the study.

Inclusion Criteria

Able to provide informed consent

I am willing and able to follow all study requirements.

I have been diagnosed with multiple sclerosis and my MRI scans show no new lesions in the last 6 months.

Exclusion Criteria

I am not taking strong drugs that affect liver enzymes CYP3A or CYP2C8.

Has a history or presence of significant other concomitant illness that, according to the PI or MAI's judgment, would adversely affect participation in this study

Unwilling to allow coded samples to be processed offsite

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive tolebrutinib 60 mg daily for 48 weeks, with some escalating to 120 mg daily for 96 weeks

48-96 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 weeks

5 visits (in-person)

Optional Long-term Extension

Participants may continue treatment until tolebrutinib is marketed or commercial development is halted

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Tolebrutinib

Trial Overview The trial is testing Tolebrutinib pills in two doses (60mg and 120mg) taken daily to see if it can reduce inflammation in chronic brain lesions caused by MS. Participants will either take Tolebrutinib or continue their current anti-CD20 therapy for at least 96 weeks while undergoing regular MRIs, neurological exams, blood tests, heart activity measurements, and possibly spinal taps.

How Is the Trial Designed?

Group I: tolebrutinib (initial cohort) Experimental Treatment 1 Intervention

Tolebrutinib 60 mg daily

Group II: Tolebrutinib (cohort B) Experimental Treatment 1 Intervention

Tolebrutinib 120 mg daily

Group III: Tolebrutinib (Cohort A) Experimental Treatment 2 Interventions

Tolebrutinib 60 mg/day for 48 weeks, Tolebrutinib 120 mg/day for 96 weeks

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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 We reviewed the clinical effectiveness of tolebrutinib for the treatment of non-relapsing SPMS compared to best supportive care, defined as ...

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

Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK ... The aim of this study was to determine the dose-response relationship between tolebrutinib and the reduction in new active brain lesions in ...

4. 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 ...

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

Phase 1 clinical trial evaluating safety, exposure and ... Tolebrutinib was well‐tolerated in single doses up to 120 mg and 90 mg with 10 days q.d. dosing. High levels of systemic BTK occupancy were ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03996291?intr=SAR442168&aggFilters=studyType:int&viewType=Table&rank=2

Long Term Safety and Efficacy Study of Tolebrutinib ... Primary Objective: To determine the long-term safety and tolerability of SAR442168 in RMS participants. Secondary Objective: To evaluate efficacy of ...