Efficacy in collagen induced arthritis models with a selective, reversible covalent Bruton’s tyrosine kinase inhibitor PRN473 is driven by durable target occupancy rather than extended plasma exposure (THER5P.904)

Bruton’s Tyrosine Kinase (BTK) is an essential signaling element downstream of the B-cell receptor (BCR). Inhibition of BTK activity in B cells produces phenotypic changes consistent with blockade of the BCR, including inhibition of cell proliferation, differentiation, maturation, and survival. A selective BTK inhibitor has the potential to treat diseases involving inflammation and autoimmunity. Using Principia Biopharma’s proprietary Tailored Covalency™ technology, we discovered PRN473, a reversible covalent BTK inhibitor that selectively binds BTK with a slow off-rate as assessed in biochemical and cell based assays. A slow off-rate molecule with rapid systemic clearance may lead to a long duration of action and high efficacy, while reducing the potential for off target toxicities. The duration of binding of PRN473 was measured in vivo, with prolonged BTK occupancy confirmed after drug was cleared from plasma. In mouse and rat collagen-induced arthritis (CIA) models, PRN473 when dosed therapeutically demonstrated dose-dependent inhibition, reversal of arthritis, with almost complete abrogation of clinical scores and preservation of joint integrity and histology. BTK occupancy in splenocytes was found to be a robust measure of BTK inhibition and correlated with efficacy in the CIA models. These data in combination with GLP toxicology studies, where no organ specific toxicities were observed, validate using a reversible covalent BTK inhibitor to treat autoimmune diseases.