SUMMARY

• Icotrokinra (JNJ-77242113) is the first targeted oral peptide that selectively binds the interleukin (IL)-23 receptor (IL-23R) and inhibits IL-23 pathway signaling.¹ 
  • Despite being a peptide, icotrokinra displayed high affinity, potency, and selectivity in in vitro, in vivo, and ex vivo studies.
  • Icotrokinra achieves high concentrations in gut tissue, demonstrated by its pharmacologic activity in colon tissue (rat colitis model and human colon explants), and sufficient systemic exposure, demonstrated by measurable plasma concentrations, dose-proportional pharmacokinetics, and pharmacodynamic effects in both blood and peripheral tissues after oral dosing.
• Icotrokinra binds IL-23R with single-digit picomolar affinity (dissociation constant [K_D]: 7.1 picomolar [pM]), blocking IL-23-driven signal transducer and activator of transcription (STAT)3 activation and cytokine production in a concentration-dependent manner (half-maximal inhibitory concentration [IC₅₀]: 5.6 pM) without affecting IL-12 signaling in human cells, and thereby minimizing off-target effects. It also suppresses IL-23-induced interferon gamma (IFN-γ) production in human natural killer (NK) cells, in whole blood from healthy donors, and in whole blood from patients with psoriasis (PsO; IC₅₀: 18.4, 11, and 9 pM, respectively).¹ 
• Icotrokinra demonstrated potent IL-23 pathway inhibition by reducing colon inflammation in a rat trinitrobenzenesulfonic acid (TNBS)-induced colitis model and suppressing IL-17A, IL-17F, and IL-22 in a rat IL-23-induced skin inflammation model in vivo, while ex vivo studies showed dose-dependent inhibition of IL-23–induced IL-17A in rat whole blood and significant suppression of IL-23–induced IL-22 in human colon tissue after oral dosing.¹

BACKGROUND

• Icotrokinra is a chemically synthesized macrocyclic peptide designed to antagonize the IL-23R. It is the first oral IL-23 pathway modulator, in contrast to injectable monoclonal antibodies.¹
• IL-23 is a pro-inflammatory cytokine composed of the p19 and p40 subunits. IL-23R also has two subunits: IL-23R (binds to p19) and IL-12R beta 1 (IL-12Rβ1; binds to both IL-23 or IL-12 through a shared p40 subunit).¹
• Binding of IL-23 to its receptor activates janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) enzymes, leading to subsequent phosphorylation of STAT proteins, which then drives expression of cytokines such as IL-17A, IL-17F, IL-22, and IFN-γ. Of note, the biological effects of IL-23 activity are believed to be mediated primarily through STAT3. This IL-23 signaling plays a pathogenic role in certain immune-mediated inflammatory diseases including PsO, psoriatic arthritis, and inflammatory bowel disease (IBD).¹
• Genetic evidence (eg, IL-23R R381Q loss-of-function mutation being protective in PsO and IBD) and clinically validated IL-23-targeted biologics underscore the IL-23 pathway as a therapeutic target.¹
• Icotrokinra selectively binds the IL-23R and blocks IL-23 pathway signaling. See Figure: Icotrokinra Blocks IL-23 from Binding to its Receptor.² 

MECHANISM OF ACTION

Molecular Properties

• Icotrokinra is a macrocyclic peptide with a complex structure and a molecular weight of approximately 1898.19 g/mol.¹

Binding Affinity and Specificity of Icotrokinra to IL-23R

• Icotrokinra binds the extracellular domain of human IL-23R, specifically the p19 binding subunit, with high affinity (K_D≈7.1 pM at 37 °C, measured by surface plasmon resonance). It shows similar affinity for rat IL-23R (K_D≈17.5 pM), supporting cross-species pharmacology (see Table: Icotrokinra Binding Affinity to IL-23R).¹

• Icotrokinra functions as a receptor antagonist, binding to IL-23R and blocking IL-23 from engaging the receptor, thereby inhibiting the downstream JAK-STAT signaling cascade.¹
• In human peripheral blood mononuclear cells, icotrokinra shows no measurable impact on IL-12 signaling, even at high concentrations.¹

IL-23 Signaling Inhibition in Immune Cells

• In human peripheral blood mononuclear cells (PBMCs), icotrokinra potently inhibited the proximal signaling events triggered by IL-23. IL-23 normally induces STAT3 phosphorylation in T and NK cells. Icotrokinra reduced phosphorylation of STAT3 in a concentration-dependent manner (IC₅₀≈5.6 pM). In contrast, IL-12-induced STAT4 phosphorylation remained unaffected, indicating selectivity of icotrokinra for the IL-23R.¹
  • This selectivity differentiates icotrokinra from IL-12/23 p40 antibodies (which block both IL-23 and IL-12) and from downstream kinase inhibitors.
• Experiments in human diffuse large B-cell lymphoma (DB) cells at varying IL-23 concentrations showed that icotrokinra acts as a simple competitive antagonist of the IL-23R, meaning it competes with IL-23 for the same binding site, preventing receptor activation.¹

Downstream Cytokine Production (IFN-γ) in NK Cells and Whole Blood

• In human NK cell assays, icotrokinra blocked IL-23-driven IFN-γ production in the presence of IL-2 and IL-8 (IC₅₀≈18.4 pM), confirming potent functional blockade of IL-23 signaling.¹
• In healthy donor (n=15) whole blood assays, which reflect a complex immune environment, icotrokinra suppressed IL-23-induced IFN-γ in a dose-dependent manner, with a median IC₅₀ of ~11 pM. A similar inhibitory potency was observed in blood from donors with PsO (n=4), with a median IC₅₀ of ~9 pM, indicating that IL-23-induced IFN-γ production is also drug-sensitive in disease.¹
• A broad panel screen of potential secondary pharmacodynamic targets (44 receptors, enzymes, ion channels, and transporters) showed <50% activation or inhibition for all targets with 10 µM of icotrokinra, indicating high selectivity for IL-23R. Icotrokinra did not significantly affect other pathways, even at concentrations 1000-fold above those measured in humans dosed with 1000 mg of icotrokinra.¹

Pharmacologic/Pharmacodynamic Evidence of IL-23R Antagonism (In Vivo and Ex Vivo)

• In a rat TNBSinduced colitis model, icotrokinra significantly attenuated disease severity. Rats treated with oral doses of ≥0.3 to 10 mg/kg/day experienced less TNBS-induced weight loss at day 7 compared to the TNBS plus vehicle group (P<0.001).¹
• Similarly, TNBS-exposed rats that received icotrokinra at oral doses of ≥0.1 to 10 mg/kg/day had reduced colon weight/length ratios (P<0.01), compared to the TNBS plus vehicle group.¹ See Figure: Icotrokinra Attenuates Weight Loss and Colon Inflammation in the Rat TNBS-induced Colitis Model.

• In a rat IL-23-induced skin inflammation model, icotrokinra dose-dependently suppressed IL-17A, IL-17F, and IL-22 expression and prevented IL-23-induced ear thickening. At doses ≥10 mg/kg twice daily, its effect on gene expression matched or superseded that of an anti-IL-23 antibody, showing systemic reach beyond the gut.¹ See Figure: Icotrokinra Inhibits IL-23 Induced Rat Skin Inflammation Comparable to Anti IL-23 Antibody.

• In a pharmacodynamic study, rats were given various doses of oral icotrokinra before drawn blood was stimulated ex vivo with IL-23 and IL-1β. Results revealed dose-dependent IL-17A suppression, linking plasma exposure to functional IL-23 pathway inhibition.¹ See Figure: Ex vivo IL-23-Stimulated IL-17A Inhibition in Rat Whole Blood.

• In a phase 1 study, healthy volunteers received single or multiple oral doses of icotrokinra. Blood samples collected after dosing were stimulated ex vivo with IL-23, IL-2, and IL-18 to measure IFN-γ production. Results demonstrated dose-dependent inhibition, confirming target engagement¹:
  • After 10mg icotrokinra (single dose), a partial reduction in IL-23-induced IFN-γ was observed compared with placebo (PBO).
  • After 1000mg icotrokinra (single dose), IL-23-stimulated IFN-γ production was completely suppressed for 24 hours post-dose.

IL-23-Induced IL-22 Suppression in Colon Tissue (Explants)

• Human colon explants exposed to icotrokinra or JNJ-2100 (a tool molecule with similar affinity and potency) exhibited dose-dependent suppression of IL-23-induced IL-22 expression, achieving >90% inhibition at the highest doses.⁴ 
• In a phase 1 study, colon biopsies from healthy volunteers dosed with icotrokinra demonstrated significant reductions in IL-23-induced IL-22 vs PBO (P<0.05), with mean inhibition of ~65% in sigmoid colon biopsies and ~66% in rectum biopsies.⁴ 

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 24 December 2025.