Multiple Sclerosis Society of Canada

Tolebrutinib

Overview:

  • Also known as: SAR442168
  • Pharmaceutical Company: Sanofi-Genzyme
  • Route and Dose of Administration: Oral (once daily)
  • Type: Immunomodulator
  • Emerging Treatment for: Relapsing Multiple Sclerosis (RMS); Non-relapsing Secondary Progressive Multiple Sclerosis (SPMS); Primary Progressive Multiple Sclerosis (PPMS)
  • Status: In Phase III clinical trial

How it works

Tolebrutinib selectively inhibits the protein, Bruton’s tyrosine kinase or BTK, in order to reduce the activation of B cells that contribute to brain and spinal cord inflammation in MS. Tolebrutinib has also been proposed to prevent the activity of specific immune cells in the brain called microglia, which have been linked to MS progression.

Research and Results

Relapsing MS Trials
Phase II Trial

A phase II, double-blind, placebo-controlled clinical trial recruited 130 people with relapsing MS to determine the dose-response relationship for tolebrutinib in reducing the number of new active (T1) brain lesions. Participants received placebo for four weeks and one of four doses of tolebrutinib (5, 15, 30, or 60 mg) for 12 weeks. The study results showed that compared to placebo, treatment with the highest dose of tolebrutinib resulted in 85% reduction in new active gadolinium-enhancing T1 lesions. The most common side effects of tolebrutinib treatment were headaches, chest infections and the common cold.

Phase III Trial: GEMINI 1 and GEMINI 2

GEMINI 1 and 2 are phase III, randomized, double-blind, multi-center clinical trials testing the efficacy and safety of tolebrutinib compared with Aubagio (teriflunomide). Both trials are recruiting 900 adults that will be randomly assigned to receive either oral tolebrutinib or oral Aubagio once daily for up to three years. The primary outcome measures will evaluate changes in annualized relapse rates between the two treatment groups. The trials will also assess the efficacy of tolebrutinib compared to Aubagio on disability progression, MRI lesions, cognitive performance, and quality of life.

Participant recruitment for the GEMINI trials is ongoing. The anticipated completion date for both trials is August 2023.

Progressive MS Trials
Phase II Trial

A phase II, double-blind, placebo-controlled clinical trial recruited 130 people with relapsing MS to determine the dose-response relationship for tolebrutinib in reducing the number of new active (T1) brain lesions. Participants received placebo for four weeks and one of four doses of tolebrutinib (5, 15, 30, or 60 mg) for 12 weeks. The study results showed that compared to placebo, treatment with the highest dose of tolebrutinib resulted in 85% reduction in new active gadolinium-enhancing T1 lesions. The most common side effects of tolebrutinib treatment were headaches, chest infections and the common cold.

Phase III Trial: HERCULES
HERCULES is a phase III, randomized, double-blind, multi-center clinical trial testing the efficacy of tolebrutinib in non-relapsing SPMS. The trial is recruiting 1290 adults that will be randomly assigned to receive either oral tolebrutinib or placebo once daily over a period of two to four years. The primary outcome measures will evaluate the efficacy of tolebrutinib in delaying disability progression in people with non-relapsing SPMS. The trial will also assess the efficacy of tolebrutinib compared to placebo on MRI lesions, cognitive performance and quality of life. 

Participant recruitment for the HERCULES trial is ongoing. The anticipated study completion date is August 2024.

Phase III Trial: PERSEUS
PERSEUS is a phase III, randomized, double-blind, multi-center clinical trial testing the efficacy of tolebrutinib in PPMS. The trial is recruiting 990 adults that will be randomly assigned to receive either oral tolebrutinib or placebo once daily over a period of two to four years. The primary outcome measures will evaluate the efficacy of tolebrutinib in delaying disability progression in people with PPMS. The trial will also assess the efficacy of tolebrutinib compared to placebo on MRI lesions, cognitive performance, physical function and quality of life.

Participant recruitment for the PERSEUS trial is ongoing. The anticipated study completion date is August 2024.

References:

Sanofi. Sanofi brain penetrant BTK inhibitor significantly reduced disease activity in Phase 2 trial in relapsing multiple sclerosis. 2020; retrieved from Sanofi Press Release.

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