1109 First-in-class oral peptide systemically targeting the IL-23 pathway

Human genetic associations and transformational efficacy of antibody therapeutics have defined the interleukin (IL)-23 pathway as a pathogenic driver in psoriasis, psoriatic arthritis, inflammatory bowel disease. There are currently no orally delivered selectively targeting this pathway. JNJ-2113 is macrocyclic peptide that binds to IL-23 receptor with high affinity (KD 2 pM), demonstrated potent, selective concentration-dependent inhibition signaling human T cells (IC50 4.7 IL-23-induced cytokine production NK 18.4 pM). Upon oral dosing rat TNBS-induced colitis model, was observed doses low 0.3 mg/kg/day. Although peptides typically bioavailability, exquisite potency indicated potential for systemic activity beyond gastrointestinal tract. This possibility investigated models. Oral rats resulted exposure-dependent ex vivo IL-23-stimulated IL-17A whole blood. Pharmacodynamic (PD) also an skin inflammation model. Orally dosed inhibited thickening, IL-17A, -17F -22 gene induction skin, 20 mg/kg/day giving equivalent anti-IL-23 antibody. IFNγ vitro blood from healthy donors psoriasis patients. Importantly, volunteers stimulated treatment provided preclinical models successfully translated PD volunteers, indicating first-in-class therapy IL-23-mediated diseases.