569 Rilzabrutinib (PRN1008) shows BTK-mediated mechanisms of action supporting clinical development for immune-mediated diseases

Bruton tyrosine kinase (BTK) is a critical immune signaling enzyme expressed in B and innate immune cells and is an essential element downstream of BCR and FcR signaling. Rilzabrutinib (PRN1008) is an oral, reversible, covalent BTK inhibitor that drives durable BTK occupancy with low off-target effects shown by other BTK inhibitors. Preclinical PRN1008 activity was evaluated in biochemical studies and in vivo models of inflammation and canine pemphigus. PRN1008 showed kinase selectivity for BTK with an enzyme inhibition IC50 of 1.3 nM; functional BTK target occupancy of 91% (±2%) was achieved in PBMCs at 4 h. In a skin IgG antibody (FcγR)-mediated acute Arthus reaction rat model, PRN1008 10, 20, and 40 mg/kg led to significant, dose-dependent improvements in immune complex-mediated inflammation and injury (P<0.01 all doses vs vehicle). In a passive cutaneous anaphylaxis mouse model that utilizes mechanisms similar to human allergic disease, PRN1008 20 and 40 mg/kg significantly inhibited IgE antibody (FcεR)-mediated immune responses (P<0.01 both doses vs vehicle). In naturally occurring canine pemphigus foliaceus, an autoantibody-mediated autoimmune disease that dogs and human share, 4 dogs treated with PRN1008 showed a rapid clinical improvement. All animals achieved complete or substantial disease control measurable by improved canine PDAI scores and without requiring corticosteroid use. Anti-inflammatory effects in dogs were visible within 2 wk and tolerability was excellent. BTK target occupancy in PBMCs from dogs was >70% within 4 h of PRN1008 treatment. Overall, PRN1008 preclinical results show simultaneous mechanisms of rapid and sustained anti-inflammatory effects by blocking inflammatory immune cells, eliminating autoantibody destructive signaling, and preventing new autoantibody production. These results provide a strong biologic basis for rilzabrutinib (PRN1008) in B cell- and autoantibody-driven autoimmune disorders, supporting ongoing clinical studies of pemphigus (phase 3) and immune thrombocytopenia (phase 2).