Introduction
B lymphocytes and myeloids are the major contributors of inflammation in multiple sclerosis. Tolebrutinib, an oral, CNS-penetrant, is an irreversible inhibitor of Bruton’s tyrosine kinase which is an enzyme expressed on B lymphocytes, myeloid cells and microglia. It reduces acute inflammation, with a potential to modulate the immune response within the CNS.
Study Design
A 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial.
Objective
To evaluate the dose-response relationship between tolebrutinib in patients with relapsing multiple sclerosis. The reduction in new active brain MRI lesions with the treatment was also assessed.
Patients
130 patients (aged 18-55 years) diagnosed with relapsing multiple sclerosis were enrolled in the study after satisfying following criteria:
- Confirmed presence of either relapsing-remitting or relapsing secondary progressive multiple sclerosis
One or more of the following:
- at least one relapse within the previous year
- at least two relapses within the previous 2 years; or
- at least one active gadolinium-enhancing brain lesion in the 6 months before screening.
Patients with a diagnosis of primary progressive multiple sclerosis or of secondary progressive multiple sclerosis without relapse were excluded from the study.
Randomization
Patients underwent two-step randomisation process in to two cohorts:
Cohort 1: Tolebrutinib for 12 weeks followed by placebo for 4 weeks
- Tolebrutinib 5 mg qd
- Tolebrutinib 15 mg qd
- Tolebrutinib 30 mg qd
- Tolebrutinib 60 mg qd
Cohort 2: Placebo for 4 weeks followed by tolebrutinib for 12 weeks
- Tolebrutinib 5 mg qd
- Tolebrutinib 15 mg qd
- Tolebrutinib 30 mg qd
- Tolebrutinib 60 mg qd
Assessment Parameters
- MRI scans at baseline and every 4 weeks over 16 weeks
- Safety analysis
Primary efficacy endpoint:
- Number of new gadolinium-enhancing lesions after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done during placebo run-in periods, respectively.
Results
- 129 patients completed the treatment regimen while only 126 were included in the primary analysis.
- A dose-dependent reduction in the number of new gadolinium-enhancing lesions was found at 12th week of treatment with the best efficacy observed with 60 mg dose.
- One serious adverse event was reported in the 60 mg group with multiple sclerosis relapse.
- The common adverse event during tolebrutinib treatment was headache.
- No discontinuations due to adverse events occurred.
- No treatment-related deaths occurred.
Conclusion
A dose-dependent reduction in new gadolinium-enhancing lesions was observed with tolebrutinib with a good tolerability profile.