SUMMARY

• Icotrokinra (JNJ-77242113) is a targeted oral peptide that selectively binds to the interleukin (IL)-23 receptor and inhibits IL-23 pathway signaling.¹ 
• A translational pharmacokinetics (PK) study evaluated the absorption, distribution, metabolism, and excretion (ADME) properties of icotrokinra and drug-drug interactions (DDIs) through in vitro and in vivo nonclinical studies. Additionally, phase 1 clinical studies were conducted to characterize the PK profile and safety of icotrokinra in healthy participants.²
  • Icotrokinra demonstrated low in-vitro protein binding, with mean percent bound ranging from 49.7-55.2% in human plasma.³ 
  • Icotrokinra (up to 100 µM) did not show concentration-dependent inhibition of major human cytochrome (CYP) enzymes.²
  • In monkeys, following single oral doses of 2.5 mg/kg, 7.5 mg/kg, or 22.5 mg/kg, plasma concentrations peaked at 1-2 hours post-dose, with mean maximum plasma concentration (C_max) values of 11.0, 27.8, and 84.3 ng/mL, respectively, showing an approximately dose-proportional increase.²
  • Following an oral dose of [¹⁴C]-icotrokinra (300 mg/kg), fecal excretion was the primary route of elimination within 96 hours in both rats (96.8% recovered) and monkeys (67.0% recovered), with most of the dose eliminated in the first 24 hours.²
  • In a relative bioavailability study under fasted conditions, a single oral dose of icotrokinra 200 mg resulted in a median time to maximum plasma concentration (t_max) of 2 hours for both 1×200 mg tablet and 2×100 mg tablet.²
• A population PK and exposure-response (ER) modeling analysis was conducted using integrated data from a phase 1 study (healthy participants) and a phase 2 study (patients with moderate to severe plaque psoriasis [PsO] who received icotrokinra) to characterize the relationship between systemic exposure to icotrokinra and clinical response.⁴ 
  • At week 16, ER analysis predicted that icotrokinra 200 mg once daily (QD) and icotrokinra 100 mg twice daily (BID) would result in similar response rates for Psoriasis Area and Severity Index (PASI) 75, PASI 90, PASI 100, and Investigator’s Global Assessment (IGA) 0/1.
• A serum and tissue biomarker analysis was conducted to evaluate the pharmacodynamic (PD) effects of icotrokinra using data from the ICONIC-LEAD trial through week 24.⁵ 
  • Icotrokinra reduced serum levels of PsO-related biomarkers as early as week 4, with continued reductions observed through week 16.
  • After 24 weeks of icotrokinra treatment, gene expression levels approached those seen in baseline non-lesional skin.

Pre-Clinical and clinical data

Pharmacokinetics/Pharmacodynamics

Knight et al (2025)² evaluated the ADME properties of icotrokinra and DDIs through in vitro and in vivo nonclinical studies. Additionally, phase 1 clinical studies were conducted to characterize the PK profile and safety of icotrokinra in healthy participants.

Methods

Nonclinical in Vitro Studies

• In vitro assays were conducted to evaluate the permeability, plasma protein binding, blood-to-plasma partitioning, metabolic stability, and potential interactions of icotrokinra with drug transporters and CYP P450 metabolic enzymes.²

Nonclinical in Vivo Studies

• Nonclinical in vivo PK studies were conducted in rats and monkeys.²
• Plasma PK profiles were evaluated in:
  • Fasted Sprague Dawley rats (n=3/group) following single dose of [¹⁴C]-icotrokinra (2 mg/kg) intravenous (IV) or oral doses (20 mg/kg, 30 mg/kg, 100 mg/kg, and 300 mg/kg).
  • Fasted cynomolgus monkeys (n=4/group) after single 1 mg/kg IV or oral doses (2.5 mg/kg, 7.5 mg/kg, and 22.5 mg/kg).
• Blood samples were collected for up to 24 hours in both species.
• Tissue distribution was evaluated in cynomolgus monkeys (n=4) following a 1 mg/kg IV dose on two consecutive days.
• Metabolism and excretion were evaluated in:
  • Fasted Sprague Dawley rats following a single oral dose of [¹⁴C]-icotrokinra (300 mg/kg); in fasted rats (n=2); urine, feces, and blood samples were collected through 24 hours for metabolite profiling.
  • Fed Sprague Dawley rats (n=3), urine and feces were collected for 96 hours.
  • Fasted cynomolgus monkeys (n=2) following a single oral dose of [¹⁴C]-icotrokinra (300 mg/kg); blood samples were collected up to 48 hours and urine and feces through 96 hours.

Phase 1 Studies

FIH Study

• A single-center, randomized, double-blind, placebo (PBO)-controlled study was conducted to evaluate the safety, tolerability, PK, and PD of icotrokinra in healthy adults aged 18-65 years with a body mass index (BMI) of 18-32 mg/kg².²
• The study included two parts: single ascending dose (SAD) and multiple ascending dose (MAD), with different participants.

Relative Bioavailability Study

• A single-dose, open-label, randomized crossover study was conducted to compare the phase 3 200 mg and phase 2 100 mg tablet formulations of icotrokinra in healthy adults aged 18-60 years and with a BMI of 18-30 mg/kg².²
• The study included a washout period of ≥7 days between treatment periods.
• The full PK profile was assessed over 48 hours post-dose in each treatment period, with plasma concentrations measured using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.
• Safety was assessed through physical examination, vital signs, electrocardiograms, clinical laboratory tests, adverse events (AEs) and serious adverse events (SAEs).

Results

In Vitro Characterization

Permeability Assessment in Lilly Laboratories Cell-Porcine Kidney (LLC‑PK1) Cell Monolayers

• Across the tested concentration range (1-300 µM), icotrokinra showed low, non-saturable permeability in polarized cell monolayers expressing the gene that encodes for human P-glycoprotein (P-gp). In addition, efflux ratios were <2 in both the absence and presence of the P-gp inhibitor valspodar, indicating that icotrokinra is not a P-gp substrate.² 

Plasma Protein Binding

• Icotrokinra demonstrated low protein binding across species, with mean percent bound ranging from 43.7-56.0% in mouse, rat, and monkey plasma, and 49.7-55.2% in human plasma.³ These findings suggest a low potential for DDIs mediated by plasma protein binding.

Metabolic Stability

• Icotrokinra 50 uM showed in vitro stability in feces, gastrointestinal (GI) mucosa, and hepatocytes in rats, monkeys, and human species, with mean half-life (t_1/2) values exceeding 24 hours for all species in fecal and GI mucosal matrices.^2,3 
• Icotrokinra was found to be stable in simulated gastric fluid (SGF) alone and solutions containing purified GI enzymes, with mean t_1/2 values exceeding 24 hours and percentages of icotrokinra remaining after 24 hours ranging between 84.4-100% across matrices.^2,3 
• Icotrokinra showed low turnover when incubated with hepatocytes, with t_1/2 (>6 hours) and intrinsic clearance (CL_int) <1.8 µL/min/10⁶ cells.^2,3 
  • After 2 hours of hepatocyte incubation, 95.7%, 92.8%, and 96.6% of the drug was found largely unchanged in rat, monkey, and human hepatocytes, respectively, indicating that it is not subject to significant hepatic metabolic clearance.

DDI Studies

• At the highest tested concentrations (24.7 µM for organic anion transporter [OAT]P1B1 and 24.2 µM for OATP1B3), icotrokinra showed 43.9% and 48.0% inhibition of OATP1B1 and OATP1B3 activity, respectively. However, interaction with these transporters is not expected at clinically relevant concentrations (the maximum plasma concentration for a 200 mg dose is about 0.002 uM).^2,3 
• Icotrokinra (up to 100 µM) did not show concentration-dependent inhibition of major human CYP enzymes, with half-maximal inhibitory concentration (IC₅₀) values ≥100 µM across all isoforms, showing low potential for CYP-mediated DDIs. At 100 µM, maximum inhibition was <10% for most isoforms, with only weak inhibition observed for CYP1A2 (19%) and CYP2E1 (30%).² 

Nonclinical In Vivo Studies

PK Profile in Rats and Monkeys

• Icotrokinra showed moderate distribution following a single IV dose (2 mg/kg in rats, 1 mg/kg in monkeys), with steady-state volumes of distribution (V_ss) of 459 mL/kg in rats and 299 mL/kg in monkeys.² 
• In monkeys, following single oral doses of 2.5 mg/kg, 7.5 mg/kg, or 22.5 mg/kg, plasma concentrations peaked at 1-2 hours post-dose, with mean C_max values of 11.0, 27.8, and 84.3 ng/mL, respectively, showing an approximately dose-proportional increase.
• Oral bioavailability of icotrokinra in monkeys was low, with values of 0.27%, 0.25%, and 0.30% at doses of 2.5, 7.5, and 22.5 mg/kg, respectively. However, even at the lowest dose of 2.5 mg/kg, icotrokinra plasma concentrations exceeded its IC₅₀ for IL-23-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in human peripheral blood mononuclear cell (PBMCs).

Tissue Distribution in Monkeys

• In monkeys, icotrokinra 1 mg/kg IV was found to be well distributed to tissues relevant to PsO, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD), including skin, joints, and GI tissues; see Figure: Tissue Distribution of Icotrokinra (1 mL/kg IV) and Risankizumab (2 mL/kg IV) in Monkeys.

Excretion in Rats and Monkeys

• After oral dosing of [¹⁴C]-icotrokinra 300 mg/kg, unchanged drug was predominant in plasma and feces. Within 96 hours, 96.8% and 67% of the total dose was recovered in feces in rats and monkeys, respectively, with most of the drug eliminated in the first 24 hours.²

Phase 1 Studies

Relative Bioavailability Study: Participant Disposition and Demographics

• Of the 24 healthy participants enrolled in the relative bioavailability study, 23 completed the study; one discontinued due to treatment-emergent otitis media.²
• A total of 79.2% participants were males with a median age was 55 years.
• The median weight and BMI were 79.7 kg and 26.0 kg/m², respectively.

Relative Bioavailability Study: PK Profile in Humans

• Following a single oral dose of icotrokinra 200 mg, a t_max of 2 hours was observed for both 1×200 mg (phase 3) or 2×100 mg (phase 2) tablets under fasted conditions. For details, see Table: Summary of Icotrokinra Relative Bioavailability in Phase 1 Healthy Volunteers.²

• The mean t_1/2 ranging from 12.4-13 hours was consistent across formulations.
• Plasma concentrations showed a biphasic decline after reaching C_max with both 1×200 mg (phase 3) or 2×100 mg (phase 2) tablets.
• Point estimates of geometric mean ratios (GMRs) for the 1×200 mg tablet compared with the 2×100 mg tablets showed relative bioavailability of 88.1% for C_max, 94.2% for AUC from time zero to the time of the last measurable concentration (AUC_0-last), and 94.9% for AUC_0-∞.

Metabolic Profiling and Excretion in Humans

• In both the SAD and MAD cohorts, unchanged icotrokinra was the only drug-related material detected in plasma.²
• Urinary excretion of unchanged icotrokinra was negligible (<0.001%), while fecal excretion increased with dose, ranging from 37.2% at 10 mg to 80.7% at 1000 mg.
• No metabolites were detected in plasma or urine.
• Detectable levels of icotrokinra were observed in sigmoid colon and rectal biopsy samples from participants who received 25 mg and 100 mg doses.

Population PK and ER Analyses

Bozenhardt et al (2025)⁴ conducted population PK and ER modeling analyses using data from phase 1 (healthy patients) and phase 2 studies (patients with moderate to severe plaque PsO) to characterize the relationship between systemic exposure to icotrokinra and clinical response.

Study Design/Analyses

• Data was collected from the phase 2b FRONTIER 1 and FRONTIER 2 studies, which informed dose selection for phase 3 trials.⁴
  • Eligible patients (N=255) were randomized in a 1:1:1:1:1:1 ratio to 1 of 6 treatment arms as seen in Figure: FRONTIER 1 and FRONTIER 2 Study Design.

• Population PK analyses were conducted using integrated data from phase 1 (healthy patients) and phase 2 studies (FRONTIER 1 and FRONTIER 2).⁴
  • PK data were described using a one-compartment model with first-order absorption and linear elimination. The relationship between clinical response and population PK-predicted average concentration (C_avg) was modeled using ordinal logistic regression.
• The ER analyses dataset included individual PK exposure metrics and PASI/IGA data from 231 patients, including those who received PBO.
  • Since the PBO group was not maintained after week 16, PBO response rates at week 16 were extrapolated to weeks 24 and 52.
  • Observed and model-predicted, PBO-corrected response rates were plotted against C_avg at steady-state concentration (C_avg,ss).

Results

• Overall exposures between icotrokinra 200 mg QD and 100 mg BID were reported to be similar at steady-state.
• At week 16, ER analysis predicted that icotrokinra 200 mg QD and icotrokinra 100 mg BID would achieve similar response rates for PASI 75, PASI 90, PASI 100 and IGA 0/1.
• Model-predicted PBO-corrected PASI and IGA maximal response rates were expected to be maintained or increased from week 16 to week 24 and week 52.

Serum/Tissue Biomarker Analysis

Angsana et al (2025)⁵ conducted a serum and tissue biomarker analysis to evaluate the PD effects of icotrokinra using data from the ICONIC-LEAD trial through week 24.

Study Design/Methods

• ICONIC-LEAD is an ongoing, phase 3, multicenter, randomized, double-blind, placebo (PBO)-controlled study (NCT06095115) evaluating the efficacy and safety of icotrokinra 200 mg by mouth (PO) daily in patients ≥12 years of age with moderate to severe plaque PsO.⁶

Systemic PD

• Serum samples were analyzed at weeks 0, 4, and 16 from a sub-cohort of 166 patients for IL-22 and 167 patients for IL-17A, IL-17F, IL-19, and beta-defensin-2 (BD-2).
• Serum samples of 30 healthy participants were included as control.

Tissue PD

• Using ribonucleic acid (RNA) sequencing, skin biopsy samples were used for transcriptomic analysis.
• Skin biopsies were analyzed from 46-65 consenting participants in an optional sub-study at week 0 for lesional and non-lesional samples and at week 24 for lesional samples (8 weeks post-PBO crossover).

Results

Systemic PD

• Patients receiving icotrokinra had reduced serum levels of PsO-related biomarkers as early as week 4, with reductions observed through week 16, see Figure: Serum Levels of PsO-related Biomarkers through Week 16.

Tissue PD

• In a paired sample analysis, 1020 genes were significantly upregulated and 917 were downregulated in lesional versus non-lesional skin samples at baseline.
• As early as 8 weeks after crossover from PBO to icotrokinra, downregulation of PsO-related genes was observed (IL-17A, IL-17F, IL-19, IL-22, IL-23A, defensin beta 4A [DEFB4A]).
• At week 24, gene expression levels approached those seen in baseline non-lesional skin.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 December 2025.