Remibrutinib, a covalent BTK inhibitor with best-in-class selectivity: discovery and clinical results

Bruton’s Tyrosine Kinase (BTK), a cytoplasmic tyrosine kinase, is selectively expressed in a subset of immune cells, including macrophages, mast cells, and B cells. BTK is a key regulator of B cell antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. It is likely that a BTK inhibitor will have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. First generation BTK inhibitors have been approved for the treatment of B-cell malignancies, but their use is associated with adverse events due to inhibition of off-target kinases. The presentation will cover the design, characterization, and medicinal chemistry optimization of a series of highly selective covalent BTK inhibitors stabilizing an inactive confirmation of BTK. The efforts resulted in the identification of remibrutinib (LOU064) as a highly potent inhibitor with a best-in-class selectivity profile. Remibrutinib showed high potency and was well tolerated in Ph1 and Ph2 clinical trials and is currently in Ph3 clinical studies for chronic spontaneous urticaria and multiple sclerosis. We will report the preclinical profile as well as clinical data of remibrutinib.