Affiliation:
1. Department of Neurology, Medical University of Vienna, Vienna, Austria
2. Department of Neurology, Landesklinikum Mistelbach-Gänserndorf, Mistelbach, Austria
Abstract
:
Significant progress has been made to understand the immunopathogenesis of multiple sclerosis (MS)
over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated
the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage
are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved
in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to
attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact
compartmentalized inflammation and neurodegeneration within the central nervous system by targeting
brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an
impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated
the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib,
a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting
MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing
lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase
2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are
eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and
trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmacology
Cited by
16 articles.
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