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Preclinical Mechanism of Action of PRN1008, a Reversible Covalent Bruton’s Tyrosine Kinase Inhibitor in Clinical Development for Pemphigus

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49th Annual ESDR Meeting

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Abstract

BTK is expressed in B cells, innate immune cells such as macrophages, neutrophils and mast cells, but not T cells or plasma cells. BTK is an essential signaling element downstream of the B-cell receptor and Fc-receptors and is a promising therapeutic target for autoimmunity. Unlike currently marketed BTKi, PRN1008 is a reversible covalent inhibitor designed and optimized to preferentially bind BTK versus other kinases sharing a homologous cysteine. This tailored covalent bond enables durable target occupancy with lower systemic exposures thereby reducing the potential for off-target toxicities. PRN1008 has shown rapid and durable anti-inflammatory effects in multiple animal models, via inhibition of B cell activation and blockade of antibody mediated innate immune cell activation via Fc receptor signaling blockade. In skin, PRN1008 significantly improved immune complex mediated inflammation and injury in an IgG antibody (FcgammaR) driven acute arthus model in rats. PRN1008 inhibited mast cell activation in a passive cutaneous anaphylaxis mouse model, supporting a key role for BTK in IgE antibody (FcepsilonR) mediated immune responses. In addition to neutralizing pathogenic antibody signaling, B cell studies demonstrated that BTK inhibition also blocked antibody production. In autoantibody-driven naturally occurring canine pemphigus foliaceus, PRN1008 safely and rapidly controlled disease without corticosteroids. Overall, PRN1008 demonstrates three simultaneous MOA benefits that, combined, allow for a fast-acting and sustained response: rapid anti-inflammatory effects, neutralization of pathogenic autoantibody signaling, and blockade of pathogenic autoantibody production. PRN1008 has the potential to treat B cell and autoantibody driven autoimmune disorders and is under investigation clinically.

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© Copyright 2019 Morressier GmbH.
All rights reserved.