A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis

Abstract

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

Keywords: BTK inhibitors; disease-modifying therapies; long-term administration; multiple sclerosis; safety; selectivity.

Figure 1.

Simplified mechanisms of MS pathogenesis relevant to BTK inhibition. Proposed, simplified, MS-relevant BTK molecular mechanism of action following inhibition. In myeloid cells, BTK is activated through Fcγ receptor signalling and then signals through Plc-γ2 to activate the NFĸβ and NFAT pathway, leading to transcriptional activation. In B-cells, BTK is activated through B-cell receptor signalling; BTK inhibition may increase pro-inflammatory cytokine production. BTK is expressed in myeloid cells, with important roles in their function,^, including brain-specific microglia, and peripheral macrophages. In MS pathogenesis, B-cells can undergo antigen-triggered activation, a BTK-mediated pathway, to release pro-inflammatory cytokines including IFNƴ and TNFα. Release of pro-inflammatory cytokines can lead to the differentiation of pro-inflammatory CD4+ T-cells, implicated in demyelination. Pro-inflammatory cytokine release from B-cells also leads to macrophage polarization, promoting transformation to the pro-inflammatory M1 phenotype. These have been implicated in myelin phagocytosis, resulting in foam cells, which have been found in active neuronal lesions in MS.^, BTK is also expressed in the microglia, CNS-specific macrophages, leading to microglial activation. Activated microglia are also implicated in demyelination and are abundant in active neuronal MS lesions.^, Inhibition of BTK may have potential in the mediation of these mechanisms, thus it is of interest for novel MS therapeutics. BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; CNS, central nervous system; IFNƴ, interferon gamma; MS, multiple sclerosis; NFAT, nuclear factor of activated T cells; NFκβ, nuclear factor kappa-light-chain-enhancer of activated B cells; TNFα, tumour necrosis factor alpha.