Treatment with tolebrutinib for 12 weeks led to a dose-dependent reduction in new gadolinium-enhancing lesions and new or enlarging T2 lesions in patients with relapsing multiple sclerosis (MS), according study findings published in the Lancet Neurology.

Disease-modifying treatments (DMTs) for MS primarily affect lymphocytes with a limited impact on microglia. Tolebrutinib, which is not approved by the US Food and Drug Administration (FDA), is an oral, central nervous system (CNS)-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase that is considered a crucial signaling element in B lymphocytes and myeloid cells, according to the researchers. The objective of the current study was to assess the dose-dependent relationship between tolebrutinib and the reduction in new, active brain lesions in patients with relapsing MS.

The 16-week, phase 2b, randomized, double-blind, placebo-controlled trial was conducted at 40 centers in Europe and North America in which participants received tolebrutinib. Eligible participants were aged 18 to 55 years with a diagnosis of relapsing MS (either relapsing-remitting or relapsing secondary progressive MS).


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The patients were grouped into 1 of 2 cohorts and then randomly assigned (1:1:1:1) to 1 of 4 tolebrutinib dose groups (5 mg, 15 mg, 30 mg, or 60 mg). Cohort 1 began a 12-week tolebrutinib regimen and crossed over to placebo for the remaining 4 weeks. Cohort 2 patients started with 4 weeks of placebo treatment as a run-in and then crossed over to 12 weeks of tolebrutinib.

The number of new gadolinium-enhancing lesions detected after 12 weeks of tolebrutinib treatment (at week 12 for cohort 1 and week 16 for cohort 2), relative to the previous scan 4 weeks earlier, was the primary efficacy endpoint.

Patients (n=130) who received tolebrutinib had a mean (Standard Deviation [SD]) age of 37 (10) years, and those who received placebo (n=66) had a mean age of 36 (10). Both groups had 70% female and 92% White participants.

From May 14, 2019, to January 2, 2020, 64 participants were assigned to cohort 1 and 66 to cohort 2. They were then assigned to 1 of the dose groups (33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg); 129 (99%) participants completed the treatment.

The study authors found a dose-dependent decrease in the number of new gadolinium-enhancing lesions at treatment week 12. The maximum effect occurred in patients who received the 60-mg dose of tolebrutinib and corresponded with an adjusted relative reduction in new lesions of 85% (95% Confidence Interval [CI], 28 to 97) compared with placebo. The mean number of lesions that occurred was 0.13 (SD 0.43) for tolebrutinib 60 mg and 1.03 (2.50) for placebo. A total of 28 (90%) of 31 participants who received tolebrutinib 60 mg had no new gadolinium-enhancing lesions after 12 weeks, compared with 44 (75%) of 59 participants in the cohort 2 placebo period at week 4.

Participants also had a dose-response relationship regarding the number of new or enlarging T2 lesions (P <.0001).

A total of 70 patients had an adverse event, and the rates were similar for all tolebrutinib groups. Headache was the most common nonserious adverse event during tolebrutinib treatment, occurring in 1 patient in the 5-mg group, 3 patients in the 15-mg group, 1 patient in the 30-mg group, and 4 patients in the 60-mg group.

Study limitations include the relatively small sample size for each dosing group and the 12-week treatment period.

“Effective treatment for acute inflammation, combined with the potential to directly modulate the immune response within the CNS—known to be a key driver of clinical progression in multiple sclerosis—provides scientific rationale to pursue phase 3 clinical trials in patients with both relapsing and progressive forms of multiple sclerosis,” the researchers concluded.

Disclosure: This research was funded by Sanofi. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Reich DS, Arnold DL, Vermersch P, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. Published online September 1, 2021. doi: 10.1016/S1474-4422(21)00237-4