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

12 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Some multiple sclerosis (MS) lesions stay inflamed for very long periods of time. This type of inflammation is not affected by any MS medications. These lesions can lead to slow worsening of MS symptoms. Researchers want to see if a new drug can help. Objective: To see if tolebrutinib can help clear inflammation in MS brain lesions. Eligibility: Adults ages 18 and older with MS who are on an anti-CD20 therapy. Design: Participants will be screened under protocol #89-N-0045. Participants will have a medical history. They will have physical and neurological exams. They will have blood and urine tests. The progression of their MS will be assessed. Participants will have MRIs of the brain. The MRI scanner is shaped like a cylinder. It uses a magnetic field and radio waves to take pictures of the body. During the MRIs, participants will lie on a table that slides in and out of the scanner. Soft padding or a coil will be placed around their head. Participants may have electrocardiograms to measure the heart s electrical activity. Participants may have lumbar punctures ( spinal taps ). A small needle will be inserted into the spinal canal in the lower back. Fluid will be collected. Some participants will take tolebrutinib pills by mouth once a day for at least 96 weeks. They will stop their anti-CD20 therapy. They will have at least 10 study visits. Some participants will not take tolebrutinib. They will stay on their anti-CD20 therapy. They will have 5 study visits. Participation will last at least 96 weeks.

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 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 participants took different doses, and it showed a good safety profile. ^{1 2 3 4 5}

How is 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, an enzyme involved in inflammation in the brain, which is a key factor in multiple sclerosis. This makes it different from other treatments that may not target this specific enzyme or penetrate the central nervous system as effectively. ^{1 2 3 4 6}

Research Team

Daniel S Reich, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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]

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 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]

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. 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]

3. 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]

4. 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]

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]