医学
离体
药理学
加药
溃疡性结肠炎
口服
体内
药代动力学
炎症
细胞因子
药效学
银屑病
炎症性肠病
内科学
免疫学
疾病
生物技术
生物
作者
Anne M. Fourie,Xiaoli Cheng,Leon Chang,Carrie Greving,Aaron Patrick,Beverly Knight,David Polidori,Raymond J. Patch,Ashok Bhandari,David Liu,Keith Huie,Shu Li,Michael Rodriguez,Arun K. Kannan,Jonathan P. Sherlock,Nishit B. Modi
标识
DOI:10.14309/01.ajg.0000953752.29003.56
摘要
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.
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