Tolebrutinib. Bruton tyrosine kinase (BTK) inhibitor Treatment of multiple sclerosis

Despite the demonstrated efficacy of B cell-depleting treatments in patients with multiple sclerosis (MS), concern has emerged regarding long-term safety and tolerability of such therapies, in terms of increased risk of immune functioning impairment. Hence, the need for safer and more sustainable treatments has fostered the search of different approaches for B-cell targeting, the most promising of which being the inhibition of Bruton tyrosine kinase (BTK). BTK is a crucial enzyme for the signaling pathways that regulate B-cell and myeloid cell (including microglia) activation, proliferation and homeostasis. Several studies have shown that BTK inhibitors (BTKi) are effective treatments in vitro and in animal models of MS. Tolebrutinib, a small, orally available, irreversible BTKi, is a promising molecule as it exerts its function both in the periphery and the central nervous system, thus having the potential to address new pathogenetic targets such as chronic active lesions. A phase I study on healthy volunteers has shown good tolerability of the treatment and only mild adverse events. These data have been confirmed by a phase II trial on relapsing MS patients, which also showed a dose dependent reduction in new gadolinium-enhancing lesions at MRI scans. Confirmatory larger phase III trials are ongoing.