Characterization of a First-in-Class Oral Therapy Selectively Targeting the IL-23 Pathway

Introduction: The IL-23 pathway is a pathogenic driver in psoriasis, psoriatic arthritis, and inflammatory bowel disease. While IL-23 antibody therapies are available, there are currently no orally delivered therapies selectively targeting this pathway. JNJ-77242113 (JNJ-2113) is an oral peptide antagonist that binds to the IL-23 receptor with high affinity, and potently and selectively inhibits IL-23 proximal signaling and downstream cytokine production in human blood cells.*To support potential development in IL-23 mediated diseases, we studied the effect of orally dosed JNJ-2113 in a rat TNBS-induced colitis model, and pharmacodynamic (PD) activity in blood from JNJ-2113 dosed rats and healthy human volunteers. Methods: To evaluate systemic PD activity in rats, blood was collected after dosing with JNJ-2113, followed by ex vivo IL-23-stimulation and measurement of IL-17A production. JNJ-2113 was dosed orally in a rat model of TNBS-induced colitis. Body weight was measured daily throughout the study, after which assessments of colonic inflammation were performed. Single and multiple ascending doses of JNJ-2113 were orally administered to healthy volunteers (HV) (NCT04621630). Plasma concentrations were measured at time points on days 1 and 10, and in parallel ex vivo IL-23-induced IFNγ production was used to measure systemic JNJ-2113 PD activity in blood. Results: After oral dosing of JNJ-2113 in rats, dose-dependent inhibition of ex vivo IL-23-stimulated IL-17A production in blood was observed. In rat TNBS-induced colitis, oral dosing of JNJ-2113 significantly attenuated weight loss and colon inflammation (Figure 1, A and B respectively) at doses as low as 0.1 mg/kg/day. In HV, single and multiple oral doses of JNJ-2113 were well tolerated with no safety signal of concern. Oral dosing of JNJ-2113 resulted in increasing exposures across the dose range and inhibition of ex vivo IL-23 stimulated IFN γ production in whole blood. Thus, JNJ-2113 demonstrated robust systemic PD activity and IL-23 pathway engagement in humans. Conclusion: These data support the potential for JNJ-2113 as a first-in-class oral therapy targeting IL-23-mediated diseases. Of note, clinical activity of JNJ-2113 has recently been demonstrated in a Phase 2 study in moderate-to-severe plaque psoriasis patients (NCT05223868) where JNJ-2113 met its primary efficacy endpoint 2. 1 Fourie et al. JID 143(5) S190, May 2023 2 https://feeds.issuerdirect.com/news-release.html?newsid=6598557738756234Figure 1.: Rat TNBS-induced Colitis Model Results: A) body weight changes; B) colon edema and shortening; ns=not significant, **p <0.01, ****p <0.0001.