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

Abstract

: Significant progress has been made in understanding 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.

Bruton tyrosine kinase inhibitors for multiple sclerosis

“…Although the severe adverse effects of BTK inhibitors seen in patients with haematological malignancies have not yet been reported in individuals with MS, the small sample sizes and short observation periods of the available trials do not enable a comprehensive evaluation of these aspects. The safety profiles of BTK inhibitors might also vary between MS and other diseases targeted with these agents owing to the presence of differing comorbidities and pathophysiological processes 198 . Several clinical trials are underway that are expected to provide more robust data on the long-term efficacy and safety of BTK inhibitors in patients with MS. We anticipate that differences in their pharmacological properties (such as pharmacodynamics, selectivity and CNS penetration) could lead to differences in their efficacy and safety profiles in phase III trials as well as in clinical practice 66,184 .…”

Therapeutic targeting of gut‐originating regulatory B cells in neuroinflammatory diseases

“…Currently, novel B cell‐targeting drugs are being investigated. One promising approach is the therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme directly involved in the activation and functioning of B cells and myeloid cells [167]. Brain‐penetrant BTK inhibitors are suggested to target (preferentially differentiated) B cells as well as microglia by inhibiting BCR‐mediated signaling of B cells and Fc receptor‐mediated activation of myeloid cells [168].…”

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

“…Preclinical studies in animal models of MS indicate that BTKis influence meningeal inflammation and cortical demyelination [ 120 , 121 ]. Hence, several irreversible (evobrutinib, tolebrutininb, and orelabrutinib) and reversible BTKis (fenebrutinib and BIIB091) might be effective in the treatment of patients with MS [ 122 ].…”