• Burton’s tyrosine kinases are nonreceptor kinases expressed in most hematopoietic cells (excluding T cells and plasma cells) that link extracellular cytokines/factors signals with immune cell activation. In the context of MS, BTK signaling is important in B lymphocytes, myeloid cells including peripheral myeloid cells and macrophages, and CNS-resident microglia. (here)
• The existing MS disease modifying treatments (DMTs) are effective in reducing relapsing rates with annualized release rates if 0.10, in other words, if 10 people are treated with DMTs over a year, only 1 is expected to experience relapse. These DMTs such as ocrelizumab (Ocrevus) affect peripheral adaptive immunity only (peripheral B cells) and do not halt or reverse disability progression. One reason is that they do not target CNS-resident immune cells.
• Chronic CNS neuroinflammation is thought to contribute to MRI lesions accumulation and disability progression. Currently no approved DMT target CNS immune compartment.
• BTK inhibitors are CNS-penetrant and, thus, are expected to target both peripheral adaptive immunity as well as CNS-resident immune cells (here).
• Tolebrutinib binds irreversibly to BTK inhibitor that is given orally. The CNS-penetrant property of tolebrutinib was confirmed in a phase 1 trial in healthy people given a single dose of 120 mg tolebrutinib that achieved therapeutically relevant concentrations in the CSF.
• This was a phase 2b, randomized, double-blind, placebo-controlled, crossover, dose-finding to establish safe and efficacious dose of tolebrutinib in people with relapsing MS (pwRMS).

• The study enrolled 130 pwRMS (aged 18-55 years; EDSS, less than 5.5 at screening) at 40 sites across 10 countries in Europe and the United States. The study included 128 people with relapsing-remitting MS and 2 with secondary progressive MS with relapses.
• The study participants were randomized 1:1 to 2 cohorts. Within each cohort, participants were randomized 1:1:1:1 to tolebrutinib 5 mg, 15 mg, 30 mg, or 60 mg daily oral dose groups.
• In cohort 1 (tolebrutinib-to-placebo), all participants first received tolebrutinib at dose according to the group assignment for 12 weeks followed by all participants crossover to 4 weeks of placebo; in cohort 2 (placebo-to-tolebrutinib), all participants first received 4 weeks of placebo following by 12 weeks of tolebrutinib.

-- This unique crossover study design allowed all participants to receive active treatment for 12 weeks, thus, allowing reduction of risk to the patients.
-- The data from the 4-week placebo period from cohort 2 was used as control data in this study. The 4-week placebo run-out period in cohort 1 was used to maintain blind and this data was only used for safety evaluation.

• The entry criteria required diagnosis of relapsing-remitting MS or secondary progressive MS with relapses; documentation of at least 1 replace in prior 1 year, at least 2 relapses in past 2 years or at least 1 active Gd-enhancing brain lesion in past 6 months prior to screening.
• The length of the trial was 16 weeks. MRI scans were performed every 4 weeks until the end of study at week 16.
• The primary objective was to determine the dose-response relationship between tolebrutinib and new active brain lesions detected using MRI. The primary efficacy endpoint was the number of new Gd-enhancing lesions detected on the scan performed after 12 weeks of tolebrutinib treatment (at week 12 for Cohort 1 and week 16 for Cohort 2), relative to the scan 4 weeks prior.
• Secondary endpoints were the number of new or enlarging T2 lesions detected on the same scan observed after 12 weeks of treatment, the total number of Gd-enhancing lesions after 12 weeks of tolebrutinib treatment (ie, all Gd-enhancing lesions on the scan at the end of 12 weeks of treatment), as well as adverse events (AEs), serious AEs, and AEs of special interest.

• Baseline characteristics were similar across all groups with mean age of 36 to 39 years; ~66 to 70% female; median time from onset of MS symptoms of ~7.5 years; and mean EDSS score of ~2.5.
• Median exposure to study drug was ~80 days across four tolebrutinib dose group and 28 days for placebo group. The duration of exposure to active study drug was 12 weeks.
• Primary endpoint: using an exponential model, a dose-response relationship was observed between tolebrutinib and new Gd-enhancing lesions (p=0.03). The 60-mg dose showed maximal effect with 85% reduction (95% CI, 28–97%) in new Gd-enhancing lesions versus placebo after 12 weeks of treatment.
• The mean ± SD number of lesions was 0·13 ± 0·43 for tolebrutinib 60 mg versus 1·03 ± 2·50 for placebo.

• Secondary endpoints: dose-response relationship for the number of new or enlarging T2 lesions was established (p <0.0001). A maximal effect was again observed with the 60-mg dose, with an 89% (95% CI, 68–96%) versus placebo.
• Safety: Headache was the most common nonserious adverse event.

• The primary objective of the trial was met and the null hypothesis of a flat dose-response curve was rejected.
• The 60 mg dose was most efficacious in reducing acute inflammation in brain (new Gd-enhancing lesions). Reduction in new Gd-enhancing and/or enlarging T2 lesions is established in literature to correlate with reduction in relapse rates; this provides rationale to further study tolebrutinib in larger MS trials.
• Currently following tolebrutinib MS trials are ongoing: long-term safety study NCT03996291) and phase 3 studies including in relapsing MS (NCT04410978 and NCT04410991), PPMS (NCT04458051), and nonrelapsing SPMS (NCT04411641).