BTK is present in the signaling pathways of most types of white blood cells except for T cells and plasma cells. PRN1008 is designed to form a reversible covalent bond to selectively target BTK, inhibition of this enzyme results in the immediate blockade and downregulation of several cellular activities that drive autoimmunity and inflammation. Inhibition of BTK results in rapid anti-inflammatory effects and neutralization of pathogenic autoantibodies and blocks the production of new autoantibodies without depleting B cells. Preclinically, PRN1008 has shown rapid and durable anti-inflammatory effects in various preclinical animal models, via inhibition of B cell activation and antibody (IgG, IgE) mediated activation of various innate immune cells via Fc receptor signaling blockade. PRN1008 has completed comprehensive GLP toxicology evaluations (chronic studies in rats and dogs, genotoxicity assessments, embryo and fetal development in rats and rabbits) that enabled chronic dosing in humans.
PRN1008 demonstrated dose-dependent inhibition of clinical scores and joint pathology in a rat model of collagen induced arthritis, with reversal of disease achieved at trough BTK occupancy levels >70%. The therapeutic effects of PRN1008 in autoantibody-driven diseases was obtained by studying daily therapy in newly diagnosed, naturally occurring canine pemphigus foliaceus disease. PRN1008 safely and rapidly controlled disease without the need for corticosteroid treatment and confirmed the desired therapeutic BTK occupancy target level. PRN1008’s reversible covalency and ability to achieve high levels of target BTK occupancy may provide a unique opportunity to address B cell driven autoimmune disorders.