Bruton’s tyrosine kinase (BTK) plays a critical role in B cell differentiation, activation and maturation and also regulates the activation of other hematopoietic cells, such as basophils, mast cells, macrophages, and neutrophils. Inhibitors of BTK are therefore expected to find broad utility in the treatment of a variety of autoimmune and inflammatory disorders. Principia is actively pursuing the development of covalent reversible inhibitors, taking advantage of the durable inhibition driven by covalent interactions with non-catalytic cysteines, while mitigating risks associated with irreversible binding of off-target nucleophiles. This presentation will describe the SAR, PKPD, and preclinical <i>in vivo</i> data leading to the selection and development of BTK inhibitor PRN1008. Principia is currently evaluating PRN1008 in a Ph II clinical trial for treatment of the rare chronic blistering skin disease, Pemphigus Vulgaris. Initial results from Ph 1 and ongoing clinical trials will be shared.

Discovery of PRN1008: A reversible covalent BTK inhibitor for treatment of autoimmune diseases

255th National Meeting (2018)

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