SUMMARY

• Guselkumab is a human monoclonal immunoglobulin G1λ (IgG1λ) antibody that selectively binds to interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.¹
• The mean half-life (T_1/2) of guselkumab was approximately 17 days in patients with ulcerative colitis (UC) or Crohn’s disease (CD).¹
• Simulated pharmacokinetic (PK) profiles for guselkumab in UC and CD demonstrated that steady-state serum guselkumab concentrations were reached by week 24, regardless of intravenous (IV) or subcutaneous (SC) induction.^2,3

Company core data sheet

PD Properties

Mechanism of Action

Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the

IL-23 protein with high specificity and affinity through the antigen binding site. IL-23, a regulatory cytokine, affects the differentiation, expansion, and survival of T-cell subsets (eg, T helper 17 [Th17] cells, T cytotoxic 17 [Tc17] cells) and innate immune cell subsets, which produce effector cytokines such as IL-17A, IL-17F, and IL-22, which drive inflammatory disease. In humans, selective blockade of IL-23 was shown to normalize production of these cytokines.¹

In patients with UC and CD, IL-23 levels are elevated in the colon tissue. In in vitro models, guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with the cell surface IL-23 receptor, disrupting IL-23-mediated signaling, activation, and cytokine cascades. Guselkumab exerts clinical effects in plaque psoriasis (PsO), psoriatic arthritis, UC, and CD through blockade of the IL-23 cytokine pathway.¹

PD Effects

In patients with UC and CD, guselkumab reduced inflammatory markers, including C-reactive protein (CRP) and fecal calprotectin (FCP), through induction week 12, which were sustained through 1 year of maintenance treatment. Serum protein levels of IL-17A, IL-22, and interferon gamma (IFNγ) were reduced as early as week 4 and continued to decrease through induction week 12. Guselkumab also reduced colon mucosal biopsy RNA levels of IL-17A, IL-22, and IFNγ at week 12.¹

PK Properties

Absorption

The PK of TREMFYA were similar in subjects with UC and CD. Following the recommended IV induction dose regimen of TREMFYA 200 mg at weeks 0, 4, and 8, the mean guselkumab peak serum concentration (C_max) at week 8 was 68.3 mcg/mL in patients with UC and 70.5 mcg/mL in patients with CD.¹

Following the recommended SC induction dose regimen of TREMFYA 400 mg at weeks 0, 4, and 8, the mean guselkumab C_max was estimated to be 28.8 mcg/mL in patients with UC and 27.7 mcg/mL in patients with CD. The total systemic exposure area under the concentration-time curve (AUC) after the recommended induction dose regimens was similar following SC and IV induction in CD and UC.¹

In patients with UC, following SC maintenance dosing of TREMFYA 100 mg every 8 weeks (q8w) or TREMFYA 200 mg q4w, the mean steady-state guselkumab trough serum concentration (C_trough) was approximately 1.4 mcg/mL and 10.7 mcg/mL, respectively.¹

In patients with CD, following SC maintenance dosing of TREMFYA 100 mg q8w or 200 mg q4w, the mean steady-state guselkumab C_trough was approximately 1.2 mcg/mL and 10.1 mcg/mL, respectively.¹

The absolute bioavailability of guselkumab following a single 100 mg SC injection was estimated to be 49% in healthy subjects.¹

Distribution

The mean volume of distribution during the terminal phase (Vz) following a single IV administration in healthy subjects ranged from approximately 7 to 10 L (98-123 mL/kg) across studies.¹

Metabolism

The exact metabolic pathway of guselkumab has not been characterized. As a human IgG mAb, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways, in the same manner as endogenous IgG.¹

Elimination

The mean systemic clearance (CL) following a single IV administration in healthy subjects ranged from 0.288 to 0.479 L/day (3.6-6.0 mL/day/kg) across studies.¹

The mean T_1/2 of guselkumab was approximately 17 days in healthy subjects, approximately 17 days in patients with UC and CD.¹

Dose Linearity

Serum guselkumab concentrations were approximately dose proportional following IV administration in patients with UC or CD.¹

Population PK Analysis

In a population PK analysis, in patients with UC, the apparent CL and apparent volume of distribution at steady state were 0.53 L/day and 10.1 L, respectively, with a T_1/2 of approximately 17 days. In patients with CD, the apparent CL and apparent volume of distribution at steady state were 0.568 L/day and 11.4 L, respectively, with a T_1/2 of approximately 17 days.¹

The effects of baseline demographics (weight, age, sex, and race), immunogenicity, baseline disease characteristics, comorbidities (past and current history of diabetes, hypertension, and hyperlipidemia), past use of therapeutic biologics, past use of methotrexate or cyclosporine, concomitant medications (nonsteroidal anti-inflammatory drugs, corticosteroids, and conventional synthetic disease-modifying antirheumatic drugs such as methotrexate, azathioprine, 6-mercaptopurine), use of alcohol, or current smoking status on guselkumab PK were evaluated. Only the effects of body weight on CL and volume of distribution (CL/F and V/F) were found to be significant, with a trend toward higher CL/F in heavier subjects. However, a subsequent E-R modeling analysis suggested that no dose adjustment is warranted for body weight.¹

Cytochrome P450 Substrates

An in vitro study using human hepatocytes showed that IL-23 did not alter the expression or activity of multiple cytochrome P450 (CYP450) enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).¹

The effects of guselkumab on the PK of representative probe substrates of CYP isozymes (midazolam [CYP3A4], warfarin [CYP2C9], omeprazole [CYP2C19], dextromethorphan [CYP2D6], and caffeine [CYP1A2]) were evaluated in patients with moderate to severe plaque PsO. Results indicate that changes in C_max and AUC_inf (area under the serum [or other biological fluids] concentration-time curve from time 0 to infinity with extrapolation of the terminal phase) of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine after a single dose of guselkumab were not clinically relevant.¹

There is no need for dose adjustment when coadministering guselkumab and CYP450 substrates.¹

CLINICAL DATA

Population PK Model

Population PK analyses were conducted to evaluate PK parameters of guselkumab in patients with moderately to severely active CD or UC using integrated data from the following programs/studies.^2,3

• CD: A phase 2 dose-ranging study (GALAXI 1) and 3 phase 3 studies (GALAXI 2, GALAXI 3, and GRAVITI)²
• UC: A phase 2b/3 clinical program (QUASAR) and a phase 3 study (ASTRO)³

Crohn’s Disease: Comparison of Predicted Serum Guselkumab Exposure Between IV and SC Induction Dose Regimens

The TREMFYA 400 mg SC q4w induction dose regimen in GRAVITI resulted in higher trough serum concentrations at week 12 (C_{trough,week12}), lower C_max values, similar average concentrations from week 0 to week 12 (C_ave,week0-12) and similar AUC values from week 0 to week 12 (AUC_week0-12) when compared with the corresponding exposure metrics of the 200 mg IV q4w induction regimen evaluated in the GALAXI studies.² See Table: Simulated Exposure Metrics at Week 12 After IV or SC Induction Regimens.

Simulated Guselkumab Concentration-Time Profiles through Week 48 Following SC and IV Induction Regimens

PK model-based simulations showed that steady-state concentrations for the 200 mg SC q4w or 100 mg SC q8w maintenance dose were reached by 24 weeks regardless of induction route (IV or SC).² See Figures: Simulated Guselkumab PK Profiles Comparing 200 mg IV q4w x3 and 400 mg SC q4w x3 in the Induction Period Followed by 200 mg SC q4w Maintenance Therapy and Simulated Guselkumab PK Profiles Comparing 200 mg IV q4w x3 and 400 mg SC q4w x3 in the Induction Period Followed by 100 mg SC q8w Maintenance Therapy.

Ulcerative Colitis: Comparison of Predicted Serum Guselkumab Exposure Between IV and SC Induction Regimens

The TREMFYA 400 mg SC q4w induction dose regimen in ASTRO resulted in higher trough serum concentrations at week 12 (C_{trough,week12}), lower C_max values at week 8, similar average concentrations from week 0 to week 12 (C_ave,week0-12), and similar AUC values from week 0 to week 12 (AUC_week0-12) compared with those for IV induction. These are consistent with model predictions.³ For details, See Table: Comparison of Model-Predicted Guselkumab PK Exposures Following IV and SC Induction Dose Regimens.

Simulated Guselkumab Concentration-Time Profiles through Week 56 Following SC and IV Induction Regimens

Steady-state serum concentration of TREMFYA was achieved by week 24 regardless of IV or SC induction. Population PK model-based simulations demonstrated that serum guselkumab concentrations were comparable by week 24 after the same maintenance dose regimen, regardless of induction route (IV or SC).³ See Figures: Simulated Guselkumab PK Profiles Comparing 200 mg IV q4w x3 and 400 mg SC q4w x3 in the Induction period followed by 200 mg SC q4w Maintenance Therapy and Simulated Guselkumab PK Profiles Comparing 200 mg IV q4w x3 and 400 mg SC q4w x3 in the Induction period followed by 100 mg SC q8w Maintenance Therapy.

PD Analysis from GALAXI and GRAVITI Studies

Richards et al (2025)⁴ conducted an analysis comparing pharmacodynamic (PD) and mechanistic responses of TREMFYA SC vs TREMFYA IV induction using data from the GALAXI and GRAVITI studies.

Study Design/Methods

• Using a 92-analyte inflammatory protein panel, serum proteins were analyzed at weeks 0 and 12 in patients randomized to receive TREMFYA 400 mg SC q4w or placebo (PBO) in the GRAVITI trial (n=290) and in a subset of patients randomized to TREMFYA 200 mg IV q4w or PBO in the GALAXI trial (n=292).
• In the GRAVITI trial, transcriptional profiling from each of the 5 anatomic segments was performed at weeks 0 and 12 in 277 patients using RNA sequencing.
• Segmental molecular inflammation was assessed using a tissue inflammation score (biopsy-based molecular inflammation score [bMIS]), which correlates with segmental histology scores (ie, Global Histologic Disease Activity Score), endoscopic scores, and subscores defined by Simple Endoscopic Score for Crohn’s Disease (SES-CD).
• Treatment effect was analyzed using molecularly inflamed samples (bMIS >0) from segments with SES-CD >0 at baseline, and transcriptional gene modules were assessed for differential expression.

Results

• Serum protein changes at week 12 with TREMFYA 400 mg SC q4w induction were highly correlated with those seen with TREMFYA 200 mg IV q4w induction (R=0.96; P<0.05). Similar reductions were observed in IFNγ, IL-17A, CRP, and FCP (P<0.05).
• In tissue, segmental molecular inflammation assessed by bMIS correlated with segmental histological and endoscopic subscores.
• At week 12, TREMFYA SC induction reduced key cellular and inflammatory transcriptional modules across all anatomic segments, including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology.
• Reduction in molecular inflammation across the 5 anatomic segments corresponded to segmental endoscopic improvement observed in isolated ileal, ileocolonic, and colonic patient subgroups.
• For anti-inflammatory effects of TREMFYA IV and SC induction at week 12, see Figure: TREMFYA IV and SC Induction Show Similar Anti-inflammatory Effects in Serum at Week 12.

Molecular Effects of TREMFYA

Sohn et al (2025)⁵ conducted an analysis to compare tissue molecular effects of TREMFYA SC vs TREMFYA IV induction using data from the GALAXI and GRAVITI studies.

Study Design/Methods

• Serum IL-22 levels were measured at weeks 0 and 12 using a high-sensitivity assay, and changes in protein abundance were evaluated for the following groups: GRAVITI (TREMFYA 400 mg SC q4w induction [n=202] vs PBO [n=86]); GALAXI (TREMFYA 200 mg IV q4w induction [n=50] vs PBO [n=50] and independent healthy control sera [n=30]).
• Transcriptional profiling of ileum and rectum segments was performed at weeks 0 and 12 using bulk RNA sequencing in GRAVITI patients (n=277) randomized to TREMFYA SC or PBO and in a subset of GALAXI patients (n=259) randomized to TREMFYA IV or PBO.
• Gene coexpression modules were analyzed for differential expression in bulk RNA sequencing datasets from ileum and rectum segments, including patients stratified by prior inadequate response or intolerance to biologics.
• Tissue treatment effects were assessed in inflamed samples (defined as those with bMIS >0) from segments with SES-CD >0 at baseline.

Results

• At week 12, TREMFYA SC and IV induction resulted in similar reductions in serum IL-22 (SC, -0.93 logFC; IV, -1.10 logFC; P<0.05), consistent with previously reported decreases in IFNγ, IL-17A, CRP, and FCP (P<0.05).
• Changes in tissue gene modules observed with TREMFYA SC 400 mg q4w induction at week 12 were significantly correlated with those observed with TREMFYA IV 200 mg q4w (R=0.97 in ileum; R=0.93 in rectum; P<0.05).
• Similar PD and molecular treatment effects were observed in patients stratified by prior biologic exposure.
• In both ileum and rectum, TREMFYA SC and IV induction reduced key inflammatory transcriptional modules, including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology (false discovery rate <0.05) at week 12.
• Similar reductions in tissue gene expression of IL-22, IL-17A, and IFNγ were observed, with levels approaching those of noninflammatory bowel disease controls at week 12.

Comparison of Population PK Parameters Between Patients with CD and UC

• There was no appreciable difference in structural PK parameters between participants with CD and those with UC. In addition, the T_1/2 of guselkumab was similar (16.8 and 16.5 days for CD and UC, respectively).⁶ See Table: Comparison of Parameter Estimates from the Final Population PK Model - CD or UC.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 24 February 2026.