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Review Article

Bruton's Tyrosine Kinase Inhibition in the Treatment of Preclinical Models and Multiple Sclerosis

Author(s): Anja Steinmaurer, Isabella Wimmer, Thomas Berger, Paulus S Rommer and Johann Sellner*

Volume 28, Issue 6, 2022

Published on: 01 July, 2021

Page: [437 - 444] Pages: 8

DOI: 10.2174/1381612827666210701152934

Price: $65

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.

Keywords: Multiple sclerosis, immunopathogenesis, B cell, Bruton's tyrosine kinase, disease-modifying therapy, immunomodulation, demyelination.

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