Investigations of remibrutinib in models pertinent to multiple sclerosis

Inhibitors of Bruton tyrosine kinase (BTK) are actively being pursued as potential disease-modifying therapies for multiple sclerosis (MS), as attested by several completed or ongoing Phase 3 clinical trials. Yet, key aspects of BTK inhibitors biology remain unclear. Here, we assessed the effects of remibrutinib, a BTK inhibitor in Phase 3 MS trials, in preclinical models of MS. Remibrutinib was evaluated in the myelin oligodendrocyte glycoprotein (MOG)35-55 model of experimental autoimmune encephalomyelitis (EAE) and in the lysolecithin model of demyelination. In culture, we assessed its ability to reduce tumor necrosis factor-α (TNF-α) elicited by immune complex-activation of primary human and mouse microglia, mouse macrophages, and human inducible pluripotent stem cell (iPS)-derived microglia. We also examined the impact of remibrutinib on T-bet⁺ memory B cells, increasingly implicated in neuroinflammation. Remibrutinib attenuated clinical disability of MOG-induced EAE, accompanied by decreased lesional burden in the spinal cord. In lysolecithin-induced demyelination, remibrutinib did not affect oligodendrogenesis in young mice with robust repair capacity, or in middle-aged mice where remyelination is deficient. Across microglia and macrophage cultures of human or murine origin, remibrutinib effectively reduced immune complex-induced TNF-α. Multiplex cytokine analyses showed that this reduction coincided with increased interleukin-10, suggesting a shift toward a more regulatory functional state. In T-bet⁺ memory B cells, remibrutinib decreased production of pro-inflammatory cytokines in culture and reduced expression of markers associated with T-bet⁺ memory B cells in mice. While Phase 3 clinical trial results in MS are awaited, the drug favorably affects inflammatory outcomes in MS models.