JNJ-77242113, a Highly Potent, Selective Peptide Targeting the IL-23 Receptor, Provides Robust IL-23 Pathway Inhibition Upon Oral Dosing in Rats and Humans

The interleukin (IL)-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. Currently, no oral therapeutics selectively target this pathway. JNJ-77242113 is a peptide targeting the IL-23 receptor with high affinity (KD: 7.1 pM). In human cells, JNJ-77242113 potently and selectively inhibited proximal IL-23 signaling (IC50: 5.6 pM) without impacting IL-12 signaling. JNJ-77242113 inhibited IL-23-induced interferon (IFN)gamma production in NK cells, and in blood from healthy donors and psoriasis patients (IC50: 18.4, 11 and 9 pM, respectively). In a rat trinitrobenzene sulfonic acid-induced colitis model, oral JNJ-77242113 attenuated disease parameters at doses >= 0.3 mg/kg/day. Pharmacologic activity beyond the gastrointestinal tract was also demonstrated. In blood from rats receiving oral JNJ-77242113, dose-dependent inhibition of ex vivo IL-23-stimulated IL-17A production was observed. In an IL-23-induced rat skin inflammation model, JNJ-77242113 inhibited IL-23-induced skin thickening and IL-17A, -17F and -22 gene induction. Oral dosing of JNJ-77242113 in healthy human volunteers inhibited ex vivo IL-23-stimulated IFN gamma production in whole blood. Thus, JNJ-77242113 provided selective, systemic IL-23 pathway inhibition in preclinical models which translated to pharmacodynamic activity in healthy human volunteers, supporting the potential for JNJ-77242113 as a selective oral therapy for IL-23-driven immune-mediated diseases.