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

Abstract

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 (K_D: 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)γ 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 IFNγ 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.

Figure 1

Chemical structure of JNJ-77242113 (S^3,1,S^3,6-cyclo[N-acetyl-3-sulfanyl-L-valyl-L-asparaginyl-L-threonyl-7-methyl-L-tryptophyl-N⁶-acetyl-L-lysyl-3-sulfanyl-L-valyl-O-(2-aminoethyl)-L-tyrosyl-3-(naphthalen-2-yl)-L-alanyl-4-aminooxan-4-carbonyl-L-α-glutamyl-L-asparaginyl-3-(pyridin-3-yl)-L-alanyl-N²-methylglycinamide]).

Figure 2

JNJ-77242113 inhibited IL-23 receptor–mediated proximal signaling and downstream cytokine production in immune cells. IL-23–induced pSTAT3 (A) and (B) IL-12–induced pSTAT4 in human PBMCs. Concentration-dependent inhibition of IFNγ production in whole blood from (C) a healthy donor and (D) a donor with psoriasis. Panels (A) and (B) show data from one donor that is representative of 3 and 2 experiments, respectively. Panels (C) and (D) show data from one donor that is representative of data from 15 and 4 donors, respectively (see Table 1 for data summary). Each point represents the mean of duplicate values (A,B) or triplicate values (C,D); error bars denote SD. An arbitrary concentration value on the log(x) axis was used to plot mean values for the unstimulated or IL-23/IL-12–stimulated controls. IFN interferon, IL interleukin, MSD Meso Scale Discovery, PBMC peripheral blood mononuclear cells, pSTAT phosphorylated signal transducer and activator of transcription, SD standard deviation.

Figure 3

Treatment with JNJ-77242113 protected against body weight loss and signs of inflammation in a TNBS-induced colitis rat model. (A) Mean percent change in body weight from baseline over time (error bars represent SEM; **P < 0.001, ****P < 0.0001), (B) colon weight/length ratio at Day 7 (**P < 0.01, ****P < 0.0001). Bars represent medians and error bars denote interquartile ranges. n = 10 per dose group per experiment; data from up to 3 experiments were combined. ns not significant, SEM standard error of the mean, TNBS trinitrobenzene sulfonic acid.

Figure 4

Inhibition of ex vivo IL-23–stimulated IL-17A production in rat whole blood following oral dosing with JNJ-77242113. IL-17A levels produced in whole blood samples (diluted 5 × in media) after addition of 4 ng/mL IL-1β were subtracted from IL-17A levels produced with 20 ng/mL IL-23 and 4 ng/mL IL-1β. Doses below 1 mg/kg (not shown; 0.03, 0.1, and 0.3 mg/kg) showed no significant difference from vehicle control. Bars represent medians and error bars denote interquartile ranges. Data from 5 experiments were combined. Plasma samples from each animal were analyzed using an LC–MS/MS method and dilution adjusted to report concentrations of JNJ-77242113 in the assay. IL interleukin, LC–MS/MS liquid chromatography tandem mass spectrophotometry, ns not significant, PO orally. *P < 0.05, ****P < 0.0001.

Figure 5

In a rat skin inflammation model, oral JNJ-77242113 showed systemic pharmacodynamic activity. Inhibition of IL-23 stimulated (A) IL-17A, (B) IL-17F, and (C) IL-22 expression in rat skin. (D) Change in ear thickness (Day 4–Day 0) was ameliorated by oral pretreatment with JNJ-77242113. Boxes show medians and interquartile ranges and error bars denote minima and maxima. n = 10 per dose group or n = 5 for vehicle groups per experiment; data from up to 3 experiments were combined. BID twice daily, IL interleukin, ns not significant, PO orally. *P < 0.05, ***P < 0.001, ****P < 0.0001.

Figure 6

Pharmacokinetics and pharmacodynamics of orally administered JNJ-77242113 in a first-in-human study of healthy participants. (A) Mean plasma concentrations of JNJ-77242113 in healthy participants from Part 2 (Day 1 in multiple ascending dose cohorts). Error bars denote standard deviation. (B) Mean concentrations of IL-23–induced IFNγ in whole blood from participants after they had received a single oral dose of JNJ-77242113. Error bars denote standard error of the mean. IFN interferon, IL interleukin.