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