Targeting IL-23p19 in Inflammatory Bowel Disease: The Road Ahead

Abstract

Selective interleukin-23p19 (IL-23p19) inhibition represents a major advance in the management of inflammatory bowel disease (IBD). Risankizumab, mirikizumab, and guselkumab – three monoclonal antibodies targeting the p19 subunit of IL-23 – have each completed Phase 3 clinical development programs in both Crohn’s disease (CD) and ulcerative colitis (UC), demonstrating consistent efficacy across a broad spectrum of disease severity. Unlike ustekinumab, which blocks the shared p40 subunit of IL-12 and IL-23, selective p19 inhibition preserves IL-12-mediated host defense while more precisely targeting the IL-23/Th17 axis implicated in chronic intestinal inflammation. In phase 3 trials, all three agents significantly outperformed placebo for co-primary endpoints combining clinical remission and endoscopic response or remission, with benefits sustained across both induction and maintenance phases. Head-to-head data from the SEQUENCE trial demonstrate superiority of risankizumab over ustekinumab for endoscopic remission in CD, a finding corroborated by active comparator arms in GALAXI-2/3. Network meta-analyses consistently rank IL-23p19 inhibitors among the most effective therapies for moderate-to-severe CD. Real-world data, predominantly available for risankizumab in CD and mirikizumab in UC, confirm meaningful clinical and endoscopic responses in refractory populations, including patients with prior ustekinumab exposure. Safety profiles are favorable across indications, with no class-specific signals for serious infection, malignancy, or cardiovascular events. Approved indications for psoriasis and psoriatic arthritis (risankizumab and guselkumab) and pediatric psoriasis (guselkumab) offer additional therapeutic value for IBD patients with extraintestinal manifestations. Key evidence gaps persist, including the absence of head-to-head data in UC, limited long-term outcomes beyond 52 weeks, and the lack of validated predictive biomarkers for patient stratification. This narrative review synthesizes the biological rationale, clinical trial evidence, real-world data, and safety profiles, focusing on clinical positioning of IL-23p19 inhibitors in IBD in the context of precision medicine.

Introduction

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), represents a heterogeneous group of chronic immune-mediated disorders characterized by relapsing-remitting intestinal inflammation.¹ The therapeutic landscape of IBD has been transformed over the past decade, yet a substantial proportion of patients with moderate-to-severe CD or UC still fail to achieve or sustain remission: this residual burden of refractory disease underscores the continued need for mechanistically distinct, effective, and safe therapeutic strategies.²

The interleukin-23 (IL-23) pathway has emerged as one of the most compelling targets in IBD pathogenesis. Genetic, experimental, and translational evidence converges to identify IL-23 – a heterodimer composed of p19 and p40 subunits produced by activated myeloid cells in the inflamed intestinal mucosa – as a central orchestrator of chronic mucosal inflammation.³ Critically, IL-23 rather than IL-12 (which shares the p40 subunit but carries a distinct p35 chain) appears to be the dominant pathogenic cytokine in experimental models of colitis: this distinction provided the biological rationale to move beyond dual IL-12/IL-23 blockade with ustekinumab and develop agents that selectively inhibit the p19 subunit,^4–6 preserving IL-12-dependent antimicrobial immunity while more precisely targeting the pathogenic IL-23/Th17 axis.

Mechanistically, IL-23 drives the expansion and maintenance of Th17 cells and other innate lymphoid populations that sustain chronic mucosal inflammation, contributing to persistent epithelial and immune activation.⁷ These mechanisms are discussed in detail in the dedicated section on IL-23 biology below and provide a conceptual bridge between the unmet clinical need and the rationale for selective IL-23p19 inhibition.

Beyond the IL-23/Th17 axis, several emerging therapeutic targets are attracting interest in IBD, including reactive oxygen species (ROS) and cell-free DNA (cfDNA), both of which may contribute to the perpetuation of mucosal inflammation. Preclinical approaches targeting ROS or cfDNA, including nanomaterial-based and cfDNA- scavenging strategies, have shown preliminary therapeutic potential.^8,9 However, among immunological pathways supported by genetic, translational, and clinical validation, IL-23 remains the most robustly defined therapeutic target.

Three selective IL-23p19 inhibitors – risankizumab, mirikizumab, and guselkumab – have now completed phase 3 clinical programs in both CD and UC, establishing the class as a significant addition to the IBD armamentarium. Head-to-head evidence supports the superiority of selected IL-23p19 inhibitors over ustekinumab for specific outcomes in CD, while network meta-analyses support the high comparative efficacy of IL-23p19 inhibitors across both CD and UC, and real-world cohorts are beginning to characterize outcomes in the complex, multi-refractory populations seen in clinical practice.

However, whether the available evidence supports a class-wide therapeutic effect or clinically meaningful differences between individual IL-23p19 inhibitors remains incompletely defined, particularly given differences in trial populations, endpoint definitions, and treatment strategies.

This narrative review provides a comprehensive synthesis of clinical evidence supporting selective IL-23p19 inhibition in IBD. We examine the biological rationale for p19-specific blockade, evaluate phase 3 efficacy data and emerging real-world evidence for each agent in CD and UC, and critically assess safety profiles and coverage of extraintestinal manifestations. We then address the practical questions most relevant to clinicians: clinical positioning within contemporary treatment algorithms, optimal sequencing strategies, and integration with treat-to-target principles.

Methods

This narrative review synthesizes published evidence on selective IL-23p19 inhibitors (risankizumab, mirikizumab, guselkumab) in inflammatory bowel disease. We conducted literature searches in PubMed/MEDLINE and Embase, from January 2005 through March 2026, combining terms for the three agents (“risankizumab” OR “mirikizumab” OR “guselkumab” OR “IL-23p19 inhibitor”) with disease terms (“inflammatory bowel disease” OR “Crohn’s disease” OR “ulcerative colitis” OR their abbreviations). We included randomized controlled trials evaluating these agents in adults or adolescents with moderate-to-severe CD or UC, real-world observational studies reporting effectiveness or safety in routine practice, and network meta-analyses comparing IL-23p19 inhibitors to other biologics or small molecules. Preclinical studies, case reports, editorials, and studies not reporting IBD-specific outcomes were excluded. Relevant studies were identified, reviewed, and narratively synthesized by two authors (EB and GP), with input from all co-authors. Findings are presented in dedicated sections on efficacy, safety, real-world evidence, comparative research, and clinical positioning. This review was conducted using a structured literature search strategy consistent with PRISMA 2020 reporting principles, although it was not conducted as a systematic review or meta-analysis.

Role of Il-23 in Intestinal Inflammation

IL-23 is a heterodimeric cytokine composed of two subunits, p19 and p40, and is primarily produced by activated dendritic cells and macrophages in response to microbial stimuli in the intestinal environment.¹ Under physiological conditions, IL-23 contributes to the regulation of mucosal immunity by coordinating innate and adaptive immune responses and maintaining intestinal homeostasis.¹⁰ During inflammatory or infectious conditions, including inflammatory bowel disease (IBD), IL-23 is markedly upregulated in the intestinal mucosa, highlighting its important role in intestinal inflammation.¹⁰ Importantly, IL-23 shares the p40 subunit with IL-12, which is composed of p35 and p40: earlier therapeutic strategies – most notably, ustekinumab – targeted the shared p40 subunit, thereby inhibiting both IL-12 and IL-23 simultaneously. However, IL-12 and IL-23 have distinct biological roles: IL-12 primarily drives Th1 differentiation and IFN-γ production, whereas IL-23 sustains Th17 responses and chronic mucosal inflammation. Selective p19 blockade therefore inhibits IL-23 while preserving IL-12 signaling, which is important for host defense against intracellular pathogens – a key rationale for the development of p19-specific agents.⁴

The biological effects of IL-23 are mediated through its receptor complex, composed of IL-23R and IL-12Rβ1 subunits, which is expressed on multiple immune cell populations including T helper 17 (Th17) cells,¹¹ innate lymphoid cells type 3 (ILC3s), and certain subsets of γδ T cells. Upon IL-23 binding, receptor-mediated signaling through the JAK-STAT pathway promotes the expansion, survival, and effector function of these cell populations. For instance, naïve CD4⁺ T cells upregulate IL-23 receptor expression in the presence of cytokines such as IL-6 and transforming growth factor (TGF)-β, promoting their differentiation into Th17 cells.¹² More broadly, IL23 signaling amplifies Th17 responses, promoting the production of pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22, which contribute to the recruitment of immune cells and amplification of the inflammatory response in the intestinal tissue.

Genetic studies have provided strong evidence linking the IL-23 signaling pathway to the pathogenesis of IBD. Genome-wide association studies have identified several susceptibility loci associated with this pathway, including polymorphisms in the IL23R gene (which encodes one subunit of the IL-23 receptor).¹ One well-characterized variant (Arg381Gln) has been shown to confer significant protection against CD, whereas other single nucleotide polymorphisms increase the risk of developing CD and UC.¹ Additional genes involved in IL-23 signaling, such as IL12B, JAK2, and STAT3, have also been associated with increased susceptibility to IBD.⁶ These findings emphasize the critical role of IL-23 signaling in maintaining immune balance within the intestinal mucosa.

Experimental models have directly demonstrated the pathogenic role of IL-23. In a T cell transfer model of colitis, adoptive transfer of naïve T cells lacking Il23r induces minimal intestinal inflammation in immunodeficient mice, highlighting the importance of IL-23 signaling in T cell-mediated colitis. Furthermore, Il10-deficient mice lacking the IL-23p19 subunit are protected from colitis, whereas Il12p35 knockouts — which retain intact IL-23 signaling — still develop intestinal inflammation, directly demonstrating that IL-23, rather than IL-12, is the dominant pathogenic cytokine in this model.⁵

Human data corroborate these findings. Elevated IL-23p19 mRNA and IL-23 and IL-17 protein levels have been consistently observed in intestinal tissue from IBD patients.¹⁰ Immunohistochemical studies have localized IL-23 production to lamina propria myeloid cells, particularly in areas of active ulceration and transmural inflammation in CD,^6,13 and IL-23R-expressing cells, including Th17 cells and ILC3s, are correspondingly enriched in the inflamed mucosa.¹⁴

Collectively, these observations establish IL-23 as a central and tractable therapeutic target in IBD and provide the mechanistic foundation for selective p19 inhibition.

Efficacy in Randomized Controlled Trials

The design, study population, and primary endpoints of the registration trials for each agent are described below; efficacy results for primary and key secondary endpoints are summarized in Table 1 and Table 2.

Table 1.

Efficacy Outcomes – Crohn’s Disease Trials

Trial	Drug (dose) vs Comparator (Randomization)	Population included	Primary Endpoint	Relevant Secondary Endpoint(s)
ADVANCE	RZB 600 mg or 1200 mg IV at weeks 0-4-8 vs placebo (randomization 2:2:1)	931 patients (16–80 y) with moderate-to-severely active CD (CDAI 220–450 with SF ≥ 4 and/or AP ≥ 2 + SES-CD ≥ 6 OR ≥ 4 in isolated ileal disease)	Co-primary endpoints: Clinical remission (CDAI < 150 OR SF ≤ 2.8 and AP ≤ 1): 45% (RZB 600 mg) and 42% (RZB 1200 mg) vs 25% (placebo), p<0.0001 PRO-remission: 43% (RZB 600 mg) and 41% (RZB 1200 mg) vs 19% (placebo), p<0.0001 + Endoscopic response (decrease in SES-CD > 50% OR reduction ≥ 2 points for isolated ileal disease and a baseline SES-CD of 4) at week 12: 40% (RZB 600 mg) and 32% (RZB 1200 mg) vs 12% (placebo) p<0.0001	Endoscopic remission (SES-CD ≤ 4 and reduction ≥ 2 points with no subscore > 1 in any individual variable) at week 12: 24% (RZB 600 mg) and 24% (RZB 1200 mg) vs 9% (placebo), p<0.0001
MOTIVATE	RZB 600 mg or 1200 mg IV at weeks 0-4-8 vs placebo (randomization 1:1:1)	618 patients (16–80 y) with moderate-to-severely active CD (CDAI 220–450 with SF ≥ 4 and/or AP ≥ 2 + SES-CD ≥ 6 OR ≥ 4 in isolated ileal disease)	Co-primary endpoints: Clinical remission (CDAI <150 OR SF ≤2.8 and AP ≤1): 42% (RZB 600 mg) and 40% (RZB 1200 mg) vs 20% (placebo), p ≤ 0.0001 PRO-remission: 35% (RZB 600 mg) and 40% (RZB 1200 mg) vs 19% (placebo), p ≤ 0.0001 + Endoscopic response (decrease in SES-CD >50% OR reduction ≥2-points for isolated ileal disease and baseline SES-CD 4) at week 12: 29% (RZB 600 mg) and 34% (RZB 1200 mg) vs 11% (placebo), p ≤ 0.0001	Endoscopic remission (SES-CD ≤ 4 and reduction ≥ 2 points with no subscore > 1 in any individual variable) at week 12: 15% (RZB 600 mg) and 17% (RZB 1200 mg) vs 5% (placebo), p < 0.0001
FORTIFY	RZB 180 mg SC or 360 mg SC every 8 weeks vs withdrawal (SC placebo) (randomization 1:1:1)	542 patients with clinical response to IV induction (ADVANCE/MOTIVATE)	Co-primary endpoints: Clinical remission (CDAI <150 OR SF ≤2.8 and AP ≤1): 55% (RZB 180 mg) and 52% (RZB 360 mg) vs 41% (placebo), p < 0.05 PRO-remission: 52% (RZB 360 mg) vs 40% placebo (p < 0.05); 180 mg: 46%, not significant (p = 0.124) + Endoscopic response (decrease in SES-CD >50% OR reduction ≥2-points for isolated ileal disease and baseline SES-CD 4) at week 52: 47% (RZB 180 mg) and 47% (RZB 360 mg) vs 22% (placebo), p < 0.0001	Ulcer free endoscopy at week 52 (SES-CD ulcerated surface subscore of 0 in participants with SES-CD ulcerated surface subscore ≥1 at baseline): 24% (RZB 180mg) and 31% (RZB 360mg) vs 10% (placebo), p<0.0001 Endoscopic remission at week 52 (SES-CD ≤ 4 and reduction ≥ 2 points with no subscore > 1 in any individual variable): 30% (RZB 180mg) and 39% (RZB 360mg) vs 13% (placebo), p<0.0001
VIVID-1	MIR 900 mg IV at weeks 0-4-8 → 300 mg SC every 4 weeks vs placebo (randomization 6:3:2)	1150 patients (16–80y) with moderate-to-severely active CD (SF ≥4 and/or AP ≥2 + SES-CD ≥7 OR ≥4 in isolated ileal disease)	Co-primary composite endpoints: PRO clinical response at week 12 + endoscopic response at week 52 (decrease in SES-CD ≥50%): 38.0% (MIR) vs 9.0% (placebo), p<0.0001 PRO clinical response at week 12 + CDAI clinical remission at week 52 (CDAI <150): 45.4% (MIR) vs 19.6% (placebo), p<0.0001	Clinical response by PRO at week 12 (≥30% improvement in SF or AP without worsening) and corticosteroid-free clinical remission by CDAI at week 52 (CDAI <150 with no systemic corticosteroids from W40–52): 43.7% (MIR) vs 18.6% (placebo)
GALAXI-2	GSK 200 mg IV at weeks 0-4-8 → 200 mg SC every 4 weeks or GSK 200 mg IV at weeks 0-4-8 → 100 mg SC every 8 weeks vs UST vs placebo (randomization 2:2:2:1)	508 patients (≥18 y) with moderate to severely CD (CDAI 220–450; SF >3 and/or AP >1; SES-CD ≥6 or ≥4 in isolated ileal disease; ulceration required)	Co-primary composite endpoints: Clinical response at week 12 (≥100-point decrease in CDAI or CDAI <150) + Clinical remission at week 48 (CDAI <150): 55% (GSK 200 mg) and 49% (GSK 100 mg) vs 12% (placebo), p<0.0001 Clinical response at week 12 (≥100-point decrease in CDAI or CDAI <150) + Endoscopic response at week 48 (decrease in SES-CD ≥50% or SES-CD ≤2): 38% (GSK 200mg) and 39% (GSK 100mg) vs 5% (placebo), p<0.0001	Clinical remission at Week 12 (CDAI <150): 47% (GSK combined) vs 22% (placebo) p<0.0001 Fatigue response at week 12 (≥7-point improvement in PROMIS–Fatigue SF-7a): 45% (GSK combined) vs 29% (placebo), p 0.0064
GALAXI-3	GSK 200 mg IV at weeks 0-4-8 → 200 mg SC every 4 weeks or GSK 200 mg IV at weeks 0-4-8 → 100 mg SC every 8 vs UST vs placebo (randomization 2:2:2:1)	513 patients (≥18 y) with moderate–severe CD (CDAI 220–450; SF >3 and/or AP >1; SES-CD ≥6 or ≥4 in isolated ileal disease; ulceration required)	Co-primary composite endpoints: Clinical response at week 12 (≥100-point decrease in CDAI or CDAI <150) + Clinical remission at week 48 (CDAI <150): 48% (GSK 200mg) and 47% (GSK 100 mg) vs 13% (placebo); p < 0.0001 Clinical response at week 12 (≥100-point decrease in CDAI or CDAI <150) + Endoscopic response at week 48 (decrease in SES-CD ≥50% or SES-CD ≤2): 36% (GSK 200 mg) and 34% (GSK 100 mg) vs 6% (placebo), p < 0.0001	Clinical remission at Week 12 (CDAI <150): 47% (GSK combined) vs 14% (placebo), p<0.0001 Fatigue response (≥7-point improvement in PROMIS–Fatigue SF-7a): 43% (GSK combined) vs 18% (placebo), p <0.0001 Clinical response at week 12 + corticosteroid free remission at 48 week: GSK > placebo Clinical response at week 12+ endoscopic remission: GSK > placebo
GRAVITI	GSK 400 mg SC at weeks 0-4-8 → 100 mg SC every 8 weeks or 200 mg SC every 4 weeks vs placebo (randomization 1:1:1)	347 patients (≥18 y) with moderate–severe CD (CDAI 220–450; SF ≥ 4 or AP ≥2) + SES-CD ≥6 or ≥4 in isolated ileal disease; ulceration required)	Clinical remission at week 12 (CDAI <150): 56.1% (GSK 400mg) vs 21.4% (placebo) + Endoscopic response at week 12 (decrease in SES-CD ≥50%): 41.3%(GSK 400mg) vs 21.4% (placebo)	Clinical remission at week 48 (CDAI <150): 60.0% (GSK 100 mg) and 66.1% (GSK 200 mg) vs 17.1% (placebo), p<0.001 Endoscopic response at week 48 (decrease in SES-CD ≥50%): 44.3% (GSK 100 mg) and 51.3% (GSK 200 mg) vs 6.8% (placebo), p < 0.001

Abbreviations: RZB, risankizumab; MIR, mirikizumab; GSK, guselkumab; UST= ustekinumab; IV, intravenous; SC, subcutaneous; CDAI, Crohn’s Disease Activity Index; PRO, patient-reported outcomes; AP, abdominal pain; SF, stool frequency.

Table 2.

Efficacy Outcomes – Ulcerative Colitis Trials

Trial	Drug (dose) vs comparator (Randomization)	Population included	Primary Endpoint	Relevant Secondary Endpoint(s)
INSPIRE	RZB 1200 mg IV at weeks 0-4-8 vs placebo (randomization 2:1)	975 adults (18–80 y) with moderate-to-severely active UC (adapted Mayo 5–9; endoscopic subscore 2–3 confirmed centrally)	Clinical remission at week 12 (SF ≤1, no worsening, RBS = 0, endoscopic subscore ≤1 without friability): 20.3% (RZB 1200 mg) vs 6.2% (placebo), p < 0.001	Endoscopic remission (subscore 0) at week 12: 10.8% (RZB 1200 mg) vs 1.5% (placebo) Absence of bowel urgency at week 12: 24.2% (RZB 1200 mg) vs 10.5% (placebo)
COMMAND	RZB 180 mg SC or 360 mg SC every 8 weeks vs placebo (randomization 1:1:1)	548 responders to IV risankizumab induction	Clinical remission at week 52 (SF ≤1, no worsening, RBS = 0, endoscopic subscore ≤1 without friability): 40.2% (RZB 180 mg) and 37.6% (RZB 360 mg) vs 25.1% (placebo) p < 0.001 and p = 0.002	Histological, endoscopic, and mucosal remission (endoscopic subscore of 0 and Geboes score <2.0) at week 52: 8.0% (RZB) vs 0.6% (placebo)
LUCENT 1	MIR 300 mg IV at weeks 0-4-8 vs placebo (randomization 3:1)	1281 adults (18–80 y) with moderate-to-severely active UC (modified Mayo 4–9; endoscopic subscore 2–3)	Clinical remission at week 12 (SF 0–1, ≥1-point decrease if baseline 1, RBS = 0, endoscopic subscore 0–1, no friability): 24.2% (MIR 300mg) vs 13.3% (placebo), p < 0.001	Endoscopic remission (0–1, no friability) at week 12: 36.0% (MIR 300mg) vs 21.0% (placebo), p < 0.001
LUCENT 2	MIR 200 mg SC every 4 weeks vs withdrawal (placebo) (randomization 2:1)	544 responders to IV MIR induction	Clinical remission at Week 40 (SF 0–1, ≥1-point decrease if baseline 1; RBS = 0; endoscopic subscore 0–1 without friability): 49.9% (MIR 200mg) vs 25.1% (placebo)	Endoscopic remission at Week 40 (Endoscopic subscore 0–1 without friability): 45% (MIR 200mg) vs 23% (placebo), p < 0.001 Histologic–endoscopic mucosal remission (HEMR) at Week 40 (Endoscopic remission + Geboes 0 in grades 2b–5): 40% (MIR 200mg) vs 20% (placebo), p < 0.001 Urgency improvement at Week 40 (Any reduction in Urgency NRS): 70% (MIR 200mg) vs 45% (placebo), p < 0.001
QUASAR	GSK 200mg at weeks 0-4-8 vs placebo (randomization 3:2) GSK 200mg every 4 weeks or 100mg every 8 weeks or placebo (randomization 1:1:1)	701 adults (≥18y) with moderate-to- severely active UC, mMayo 5–9 568 adults responders to GSK	Clinical remission at Week 12 (SF 0–1, not increased from baseline; RBS = 0; endoscopic subscore 0–1 without friability): 23% (GSK 200 mg) vs 8% (placebo), p < 0.0001 Clinical remission at Week 44 (SFS 0–1, not increased from baseline, RBS = 0, MES 0–1 no friability): 50% (GSK 200 mg) and 45% (GSK 100 mg) vs 19% (placebo), p < 0.0001	Endoscopic remission at Week 12 (MES 0): 15% (GSK 200 mg) vs 5% (placebo), p < 0.0001 Fatigue response at week 12 (≥7-point improvement PROMIS-Fatigue SF-7a): 40% (GSK 200 mg) vs 20% (placebo), p < 0.0001 Endoscopic remission at week 44 (MES 0): 34% (GSK 200 mg), 31% (GSK 100 mg) vs 17% (placebo), p < 0.0001 Histo-endoscopic mucosal improvement (HEMI) at week 44 (MES 0–1, no friability + histological improvement Geboes ≤3.1): 48% (GSK 200 mg) and 44% (GSK 100 mg) vs 27% (placebo), p < 0.0001
ASTRO	GSK 400 mg SC at weeks 0-4-8 → 100 mg SC every 8 weeks or GSK 200 mg every 4 weeks vs placebo SC (rescue W16: GSK 400 mg at weeks 16–20-24 → 100 mg every 8 weeks)	418 adults (≥18y) with moderate-to-severely active UC, mMayo 5–9, MES ≥2, RBS ≥1	Clinical remission at week 12 (SFS 0–1 not increased from baseline; RBS 0; MES 0–1 no friability): 28% (GSK 400mg) vs 6% (placebo), p < 0.0001	Endoscopic improvement at week 12 (MES 0–1 with no friability): 45% (GSK 400mg) vs 18% (placebo), p < 0.0001 Endoscopic improvement at week 24 (MES 0–1 with no friability): 54% (GSK 400/100 mg) and 57% (400/200 mg) vs 23% placebo, p < 0.0001

Abbreviations: RZB, risankizumab; MIR, mirikizumab; GSK, guselkumab; IV, intravenous; SC, subcutaneous; RBS= rectal bleeding score; AP, abdominal pain; SF, stool frequency; MES, Mayo endoscopic subscore; HEMI, histo-endoscopic mucosal improvement; HEMR, histologic-endoscopic mucosal remission; NRS, numeric rating scale; PROMIS, Patient-Reported Outcomes Measurement Information System.

Risankizumab in Crohn’s Disease

ADVANCE and MOTIVATE were two phase 3, randomized, double-blind, placebo-controlled induction trials evaluating risankizumab in adults with moderately to severely active CD.¹⁵ ADVANCE enrolled both biologic-naïve and biologic-experienced (58%) patients, including those with prior failure to ustekinumab, while MOTIVATE was restricted to patients with documented failure to at least one biologic (53% with history of multiple failures); of note, approximately 22% of ADVANCE and 19% of MOTIVATE patients had prior exposure to ustekinumab. Both trials showed consistent efficacy of risankizumab across clinically relevant treatment-experience subgroups, with benefits observed across both clinical and endoscopic outcomes. Risankizumab met both co-primary endpoints at week 12, with comparable efficacy across the two induction regimens and consistent responses in biologic-naïve and biologic-experienced populations. These findings support risankizumab as an effective induction option across a broad spectrum of disease severity and prior treatment exposure, including biologic-refractory CD.

FORTIFY was a phase 3, multicentre, randomized, double-blind, placebo-controlled maintenance withdrawal study enrolling patients who achieved clinical response to risankizumab induction in ADVANCE or MOTIVATE.¹⁶ Responders were randomized to maintenance risankizumab or withdrawal to placebo. Both risankizumab doses were significantly superior to placebo withdrawal for the co-primary endpoints of clinical remission and endoscopic response at week 52, with consistent improvements across endoscopic and biomarker outcomes. The two active doses showed comparable efficacy without a statistically significant difference between them. As a withdrawal design, placebo remission rates were higher than expected, reflecting a carry-over effect from prior induction: patients re-randomized to placebo had already responded to active treatment and retained partial benefit for several weeks. This design feature inflates placebo response and narrows the absolute treatment–placebo delta, particularly for clinical endpoints, while endoscopic outcomes showed wider and more interpretable separation. Notably, the risankizumab clinical program was unique in its inclusion of patients as young as 16 years, providing valuable efficacy data for the adolescent population with moderate-to-severe CD.

Mirikizumab in Crohn’s Disease

VIVID-1 was a global phase 3, randomized, double-blind, double-dummy, placebo-controlled and active-controlled treat-through study in patients with moderately-to-severely active CD.¹⁷ Patients were randomized to mirikizumab, ustekinumab, or placebo; placebo non-responders at week 12 were switched to blinded mirikizumab. The study population included both biologic-naïve and biologic-experienced patients, with approximately half having prior biologic failure. Mirikizumab met both co-primary composite endpoints versus placebo, linking PRO clinical response at week 12 to either CDAI clinical remission or endoscopic response at week 52. Continued treatment was associated with increasing response rates through week 52 across treat-through analyses, suggesting that some patients without an early response may still benefit from continued therapy beyond the 12-week induction period. A secondary composite endpoint incorporating corticosteroid-free clinical remission at week 52 was also achieved.

Although mirikizumab met both co-primary composite endpoints versus placebo, it did not demonstrate superiority over ustekinumab for endoscopic response at week 52. This finding differs from what has been observed with other IL-23p19 inhibitors in separate head-to-head studies, although direct comparisons across trials are limited by differences in study design and patient populations. Several methodological and population-related aspects of VIVID-1 should therefore be considered when interpreting this finding. VIVID-1 employed a treat-through design, with patients remaining on their assigned treatment during the maintenance period. In addition, the study included patients with previous inadequate response, loss of response, or intolerance to biological or conventional therapies, whereas SEQUENCE specifically enrolled patients with prior anti-TNF failure. These differences in patient characteristics, prior treatment exposure, endpoint definitions, and treatment design may have contributed to the different magnitude of treatment effects observed across trials.

Importantly, the absence of superiority for endoscopic response over ustekinumab in VIVID-1 should not be interpreted as evidence of inferior efficacy of mirikizumab, as mirikizumab met the predefined non-inferiority criterion for clinical remission. Whether the differing results across head-to-head trials reflect clinically meaningful differences within the IL-23p19 class or differences in study populations and methodology remains uncertain. Further direct comparative studies will be needed to clarify potential intra-class differences. A more detailed comparison across IL-23p19 programs is provided in the dedicated comparative section of this review.

Guselkumab in Crohn’s Disease

GALAXI-2 and GALAXI-3 were identically designed phase 3, randomized, double-blind, triple-dummy treat-through trials with active and placebo comparators.¹⁸ Participants were randomized to guselkumab, ustekinumab, or placebo, with two guselkumab maintenance regimens evaluated. At week 12, nonresponders to placebo received masked rescue therapy with ustekinumab. The study population included biologic-naïve and biologic-experienced patients, with approximately half having prior inadequate response or intolerance to one or more advanced therapies. The co-primary composite endpoints linked clinical response at week 12 to clinical remission or endoscopic response at week 48. Both trials demonstrated superiority of guselkumab over placebo across the co-primary and key secondary endpoints. Prespecified pooled analyses also showed favorable efficacy of guselkumab compared with ustekinumab across multiple clinical and endoscopic outcomes, including objective endoscopic measures at week 48. These findings support guselkumab as an effective therapeutic option in CD, with consistent efficacy across the two maintenance regimens and across biologic treatment-experience subgroups.

GRAVITI was a phase 3, randomized, double-blind, placebo-controlled treat-through trial evaluating a fully subcutaneous induction and maintenance regimen of guselkumab in adults with moderately to severely active CD.¹⁹ Participants assigned to placebo who met predefined rescue criteria were switched to guselkumab from week 16 onward. The study enrolled a highly treatment-experienced population, with no restriction on the number of prior biologic failures. The co-primary endpoints were clinical remission and endoscopic response at week 12. GRAVITI demonstrated the efficacy of a fully subcutaneous guselkumab regimen, supporting a treatment approach that avoids intravenous induction even in patients with extensive prior treatment exposure.

Two additional trials are ongoing. The FUZION CD trial aims to evaluate guselkumab efficacy in perianal fistulizing disease, with co-primary endpoints of clinical and radiological remission (complete fistula closure confirmed by MRI) at weeks 24 and 48.²⁰ The REASON study evaluates transmural healing at week 48 using magnetic resonance enterography and the Magnetic Resonance Index of Activity (MaRIA) score, reflecting the growing interest in deeper treatment targets beyond mucosal healing in CD.²¹

Risankizumab in Ulcerative Colitis

INSPIRE was a phase 3, randomized, double-blind, placebo-controlled induction trial evaluating risankizumab in adults with moderately to severely active UC.²² The study population included patients who had failed or were intolerant to conventional therapies or at least one advanced therapy; prior exposure to IL-23 or IL-12/23 inhibitors was not permitted. Risankizumab significantly improved clinical remission, clinical response, endoscopic remission, and histologic–endoscopic mucosal improvement compared with placebo, with symptomatic benefits observed early and accompanied by improvements in fatigue and health-related quality of life.

Patients achieving an adequate clinical response during induction were eligible for the phase 3 COMMAND maintenance trial.²² Responders were re-randomized to receive subcutaneous risankizumab or placebo for 52 weeks, with open-label rescue available from week 16 in patients who lost adequate clinical response. Risankizumab met the primary endpoint of clinical remission at week 52 and key secondary endpoints. As with FORTIFY in CD, the withdrawal design of COMMAND resulted in inflated placebo remission rates reflecting residual carry-over from induction, which should be considered when interpreting the absolute treatment–placebo differences.

Mirikizumab in Ulcerative Colitis

Mirikizumab was evaluated in the LUCENT-1 induction and LUCENT-2 maintenance trials.²³ LUCENT-1 was a phase 3, randomized, double-blind, placebo-controlled trial in adults with moderately to severely active UC. The study population included patients with inadequate response or intolerance to conventional therapies, biologic agents, or JAK inhibitors, with exclusion of those previously exposed to anti-IL-12/23 or anti-IL-23 antibodies or who had failed three or more biologic therapies. The primary endpoint was clinical remission at week 12. Patients without a clinical response at week 12 were eligible for an extended induction phase of up to three additional intravenous doses; among initial non-responders, 53.7% achieved clinical response by week 24. Mirikizumab was superior to placebo for the primary endpoint and for secondary endpoints including clinical response and endoscopic remission.

LUCENT-2 was the corresponding maintenance trial, in which clinical responders from induction were re-randomized to subcutaneous mirikizumab or placebo for 40 weeks. Mirikizumab showed consistently higher efficacy than placebo across all assessed domains at week 40, including clinical remission, endoscopic remission, and histologic-endoscopic mucosal remission. A distinctive feature of the LUCENT program was the pre-specified assessment of bowel urgency using the Urgency Numeric Rating Scale as a key secondary endpoint: mirikizumab led to a significant reduction in urgency as early as the induction phase, a benefit sustained throughout maintenance.

Guselkumab in Ulcerative Colitis

QUASAR was a phase 3 randomized, double-blind, placebo-controlled clinical program that included a phase 2b dose-ranging study followed by a pivotal induction and maintenance trial evaluating guselkumab in adults with moderately to severely active UC;²⁴ approximately half of enrolled participants had prior exposure to one or more biologics or JAK inhibitors. During induction, guselkumab demonstrated superiority over placebo for clinical remission at week 12, with consistent benefits across key secondary endpoints including endoscopic improvement and histologic-endoscopic mucosal improvement. Clinical responders entered the maintenance phase, in which guselkumab continued to demonstrate efficacy across clinical, endoscopic, histologic, and corticosteroid-free outcomes at week 44. Patients without clinical response at week 12 could receive extended induction with subcutaneous guselkumab, highlighting the potential for continued benefit beyond the initial induction period.

The ASTRO phase 3 trial evaluated a fully subcutaneous induction and maintenance regimen of guselkumab in adults with moderately to severely active UC.²⁵ The study population was notably refractory, with a high proportion of patients having severe endoscopic disease at baseline and prior failure to advanced therapies. Guselkumab met the co-primary endpoints of clinical remission and endoscopic response at week 12, and all multiplicity-controlled secondary endpoints were also achieved. A prespecified comparative analysis evaluated the efficacy of subcutaneous induction relative to the intravenous regimen used in QUASAR, supporting the use of fully subcutaneous induction as an alternative to intravenous induction and providing greater flexibility in route of administration.

Real World Evidence

Crohn’s Disease

Real-world studies have confirmed the effectiveness and safety of risankizumab in patients with refractory CD. In a large multicenter retrospective cohort of 520 patients, including 54.8% previously exposed to ustekinumab and 45% with ≥3 prior biologic failures, 76.5% achieved a clinical response at week 12 and 60.8% attained steroid-free clinical remission (defined as Harvey–Bradshaw Index [HBI] <5 in the absence of systemic corticosteroids or budesonide).²⁶ By week 52, steroid-free clinical remission was maintained in 65.6%, while 37.5% achieved endoscopic remission (SES-CD ≤2 or Rutgeerts i0–i1), 24.6% achieved radiologic remission (BWT ≤4 mm without increased enhancement/hyperemia and no complications on cross-sectional imaging), and 9.8% showed transmural healing (BWT ≤3 mm with the same ancillary requirements). Early clinical outcomes and endoscopic remission rates were higher in ustekinumab-naïve patients, although one-year effectiveness was comparable regardless of the number of prior biologic failures.

In a second multicenter, retrospective cohort of 309 patients, most of whom (85.8%) previously exposed to advanced therapies and 54.7% to ustekinumab, week-12 clinical remission (HBI of ≤4 or remission based on physician global assessment in those without HBI or with ileostomy) was observed in 49.7% overall, with 57.1% in ustekinumab-naïve versus 44.2% in ustekinumab-exposed patients (p=ns). Among those with active baseline endoscopy, 52.4% achieved endoscopic remission (simplified endoscopic mucosal assessment [SEMA]-CD ≤1) at six months, and cumulative 12-month clinical and endoscopic remission rates were 65.0% and 49.5%, respectively, with superior outcomes in ustekinumab-naïve patients (endoscopic remission 68.1% vs 33.9%, p<0.001).²⁷ The observation that differences in endoscopic scores, but not in clinical indices, reached statistical significance may reflect the inherent subjectivity of symptom-based measures and the potential overlap with functional gastrointestinal symptoms in this patient population.

A further multicenter retrospective study including 174 highly refractory patients (all treated with ≥3 prior biologics with 62% having prior intestinal resection) assessed long-term outcomes over a median follow-up of 13.7 months.²⁸ At week 26 and 52, respectively, 47% and 46% achieved steroid-free clinical remission (HBI <5 and absence of steroid at the time of evaluation). Treatment persistence remained high, with 94%, 89%, and 79% of patients continuing therapy at weeks 12, 26, and 52, respectively. Discontinuations occurred in 26% of patients (primarily due to loss of response or primary failure), hospitalizations affected 21%, and 12.6% required intestinal resection.

Finally, a multicenter retrospective cohort study from Asia of 49 patients with moderate-to-severe CD (CDAI 220–450) treated with risankizumab demonstrated rapid clinical improvements, with clinical response (decrease in baseline CDAI ≥ 100 points) rates of 53.1%, 75.5%, and 91.8% at weeks 4, 8, and 12, and clinical remission (CDAI < 150 or HBI < 5), reaching 42.9% by week 12.²⁹ Transmural healing, defined as bowel wall thickness <3 mm on intestinal ultrasound or absence of transmural inflammation on magnetic resonance enterography or computed tomography enterography, was noted in 16.3% of patients. Notably, efficacy was consistent regardless of prior ustekinumab exposure or biologic-naïve status.

Collectively, these real-world observations – obtained across heterogeneous populations, definitions, and follow-up durations – support risankizumab as an effective option in refractory CD, with sustained clinical and endoscopic benefits over one year. Real-world data on mirikizumab and guselkumab in CD are currently lacking.

Ulcerative Colitis

Real-world evidence for mirikizumab in UC is accumulating, though most available studies are limited by small sample sizes, short follow-up, and retrospective designs. In the earliest report, a prospective observational study from a large tertiary center in the United States evaluating mirikizumab in 20 patients with active UC reported rapid clinical improvements. Clinical remission (Simple Clinical Colitis Activity Index (SCCAI) score <3), increased from 30% at baseline to 83% at week 12, while corticosteroid-free remission, defined as remission without systemic corticosteroids, reached 78%.³⁰ Median symptom scores decreased significantly from 3.5 to 0.5 (p < 0.001), driven primarily by improvements in general well-being and urgency.

In a two-center international retrospective cohort including 74 adults receiving mirikizumab, mostly previously treated with biologics or small molecules (93%), clinical response (reduction in SCCAI of ≥3 points), clinical remission (SCCAI≤2), and corticosteroid-free remission at week 12 were 70.3%, 17.6%, and 16%, respectively.³¹ Week-12 outcomes were comparable between patients with and without prior exposure to anti-TNF agents, ustekinumab, vedolizumab, or JAK inhibitors. Therapy discontinuation due to lack of efficacy or adverse events was low (8.1%).

A further multicenter retrospective study of 52 patients treated with mirikizumab demonstrated significant reductions in partial Mayo scores, as well as improvements in inflammatory biomarkers, including CRP and leucine-rich α2-glycoprotein (LRG).³² Rates of clinical remission, CRP remission, and LRG remission at week 12 were 44.2%, 67.3%, and 27.3%, respectively.

The largest available dataset comes from the Italian prospective multicenter MIRACLE-UC study promoted by IG-IBD, which included 407 adults with active UC treated with mirikizumab in routine clinical practice (reported as a congress abstract). Clinical response (defined as a ≥2-point reduction in the partial Mayo score with improvement in rectal bleeding) was achieved in 55.6% of patients at 3 months and 69.4% at 6 months, while clinical remission (partial Mayo ≤2, no subscore >1, and absence of rectal bleeding) increased from 41.2% to 55.5%. Steroid-free clinical response and remission followed a similar pattern, reaching 63.9% and 53.1% at 6 months. Endoscopic improvement (MES ≤1) and endoscopic remission (MES = 0) were achieved in 49.3% and 42.1% of patients at 6 months, respectively. Biomarkers improved markedly, and treatment discontinuation remained low (4.9%).³³

Overall, these real-world observations indicate that mirikizumab is effective in short-term induction therapy for moderate-to-severe UC, including in heavily treatment-experienced patients, with an encouraging endoscopic and biomarker signal at 6 months. Data on risankizumab and guselkumab in UC are currently lacking.

Comparative Efficacy

An important question has emerged as to whether selective inhibition of IL-23p19 confers improved efficacy compared with ustekinumab, which targets both IL-12 and IL-23 via the shared p40 subunit. The phase 3b, open-label SEQUENCE trial,³⁴ enrolling patients with moderate-to-severe CD previously exposed to TNF antagonists, demonstrated that risankizumab was noninferior to ustekinumab for clinical remission at week 24 (58.6% vs 39.5%) – adjusted difference of 18.4 percentage points (95% CI 6.6–30.3), meeting the prespecified non-inferiority margin (−10 percentage points). Risankizumab was also superior for endoscopic remission at week 48 (31.8% vs 16.2%; p<0.001). Beyond the primary endpoints, risankizumab demonstrated consistently greater efficacy than ustekinumab across several key secondary outcomes at week 48: clinical remission (52.0% vs 30.6%; P <0.001), endoscopic response (61.6% vs 39.5%; P <0.001), mucosal healing (40.4% vs 12.6%; P <0.001), and deep remission (25.1% vs 10.2%; P <0.001). Improvements in patient-reported outcomes were similarly greater, including daily stool frequency and abdominal pain scores. Notably, risankizumab was associated with a lower exposure-adjusted incidence of both CD–related and all-cause hospitalizations by week 48, suggesting a meaningful reduction in overall healthcare burden. While the open-label design represents a limitation, the use of blinded central readers for endoscopic assessment, together with consistent improvements in objective biomarkers and hospitalization rates, supports the clinical advantage of selective p19 inhibition in anti-TNF-experienced patients.

Additional insights come from the GALAXI and VIVID programs, which, although primarily designed as placebo-controlled pivotal trials for guselkumab and mirikizumab registration, included ustekinumab as an active comparator across both biologic-naïve and biologic-experienced patients – broadening the comparative evidence base beyond the exclusively anti-TNF-experienced population enrolled in SEQUENCE. In VIVID-1, mirikizumab demonstrated non-inferiority to ustekinumab for CDAI clinical remission at week 52, meeting the pre-specified 10% non-inferiority margin (54.1% vs 48.4%); however, it did not achieve superiority for endoscopic response at week 52, with numerically similar rates between the two agents (48.4% vs 46.3%, p=0.51). Across GALAXI-2 and GALAXI-3, both guselkumab maintenance regimens were statistically superior to ustekinumab on all endpoints at week 48: combined clinical remission and endoscopic response was achieved in 47% (200 mg q4w) and 42% (100 mg q8w) versus 34% with ustekinumab (both p ≤ 0.05), and endoscopic remission in 37% and 33% versus 25%, respectively.

Real-world data provide preliminary comparative insights consistent with findings from RCTs. A retrospective study from Japan compared 111 patients treated with ustekinumab and 29 with risankizumab – noting that the small risankizumab cohort limits interpretation – assessing clinical remission (HBI ≤4) at weeks 8 and 28.³⁵ Risankizumab demonstrated higher remission rates than ustekinumab at week 8 (82.8% vs 62.2%, p = 0.0465) and week 28 (79.3% vs 56.8%, p = 0.0321). Among patients with clinically active disease and prior anti-TNF exposure, the differences were more pronounced at week 8 (55.6% vs 18.4%, p = 0.0352) and week 28 (66.7% vs 18.4%, p = 0.0083).

Comparative data with molecules other than ustekinumab are limited. One real-world study, including adults with clinically active UC, compared the effectiveness and safety of upadacitinib and Risankizumab.³⁶ In this retrospective cohort of 161 patients (100 treated with upadacitinib and 61 with risankizumab) followed for up to 52 weeks, baseline characteristics were largely comparable, although the upadacitinib group showed more severe baseline disease and more frequent prior exposure to anti-TNF agents. Upadacitinib was associated with significantly higher odds of steroid-free clinical remission at both 12 and 26 weeks compared with risankizumab, a finding confirmed in sensitivity analyses adjusting for baseline SCCAI and fecal calprotectin. In contrast, endoscopic response, endoscopic remission, and treatment persistence were similar between groups, possibly reflecting incomplete endoscopic follow-up or the more rapid symptomatic response typically observed with JAK inhibitors, which may precede mucosal healing.

NMAs provide an important complement to the head-to-head evidence by enabling indirect comparisons across a broader range of agents and patient populations. A systematic review and meta-analysis by Dziegielewski et al³⁷ reported that selective IL-23p19 inhibitors are likely more effective than ustekinumab in achieving both clinical and endoscopic remission in CD, particularly in patients with prior exposure to anti-TNF agents. Similarly, Al Hayek et al,³⁸ found that all three IL-23p19 inhibitors ranked consistently above ustekinumab for endoscopic outcomes during both induction and maintenance, with guselkumab emerging as the top-ranked agent for clinical remission and mirikizumab for endoscopic remission. Two main hypotheses can be proposed: first, selective p19 blockade provides more targeted suppression of the IL-23 pathway compared with ustekinumab, which also inhibits IL-12 via p40; second, the inflammatory profile of CD may evolve over time, with early disease driven predominantly by IL-12–mediated pathways and chronic disease increasingly dependent on IL-23. This shift may be further amplified in patients previously treated with anti-TNF therapies, as biopsy studies suggest upregulation of the IL-23 receptor in this population. Another NMA,³⁹ focusing exclusively on IL-23 inhibitors, reached complementary conclusions with some nuance: guselkumab showed the most rapid clinical improvement, risankizumab provided the most balanced profile with strong endoscopic efficacy and favorable safety, and mirikizumab had the lowest incidence of serious adverse events – a finding that may partly reflect differences in trial populations rather than true pharmacological distinctions.

Broader NMAs comparing IL-23p19 inhibitors with the full spectrum of advanced therapies for CD further support their positioning. In the comprehensive NMA by Shehab et al,⁴⁰ IL-23p19 inhibitors ranked among the most effective agents for inducing clinical and endoscopic remission, with guselkumab and risankizumab consistently performing at the top across multiple outcomes. Finally, an NMA by Disher et al showed that guselkumab ranked highly across clinical and endoscopic outcomes at the end of the maintenance phase, with significant efficacy advantages over several advanced therapies depending on the specific endpoint, including infliximab and upadacitinib for clinical outcomes and ustekinumab, adalimumab, and upadacitinib for endoscopic response.⁴¹ Collectively, these analyses position IL-23p19 inhibitors among the most effective therapeutic options for moderate-to-severe CD, with advantages over IL-12/23p40 blockade and competitive performance relative to other biologic and small-molecule therapies.

In UC, comparative evidence from a 2025 NMA suggests meaningful intra-class differences among IL-23p19 inhibitors, with risankizumab demonstrating the highest induction efficacy for both clinical remission and endoscopic improvement versus placebo, while guselkumab achieved the highest maintenance efficacy, including superiority over risankizumab for endoscopic improvement during maintenance.⁴² In a broader NMA of all licensed advanced therapies as maintenance treatment in UC, which stratified results according to trial design, guselkumab 200 mg every 4 weeks ranked second overall for clinical remission in re-randomised studies, after upadacitinib, and was significantly superior to both risankizumab doses and ustekinumab on direct and indirect comparison; mirikizumab ranked second among advanced therapy-exposed patients, also demonstrating superiority over risankizumab in this subgroup.⁴³

Safety

Across the clinical development programs for CD and UC, the overall safety profile of IL-23p19 inhibitors was consistent across indications.^{15–19,22–25} The most common adverse events included headache, nasopharyngitis, upper respiratory tract infections, anemia, and COVID-19. No evidence of differential toxicity was observed across the dose regimens evaluated within each program. Serious infections occurred infrequently, with rates in active treatment arms generally similar to or lower than those in placebo groups – a pattern partly attributable to higher rates of disease-related complications, including bowel infections and abscesses, in placebo non-responders. Opportunistic infections (including mild herpes zoster, candidiasis, and isolated cases of CMV colitis) were rare, typically mild to moderate, and resolved without sequelae. Hepatic laboratory abnormalities were uncommon and transient; one case meeting Hy’s Law criteria was reported in the mirikizumab program, though no confirmed drug-induced liver injury was identified for any of the three agents. Hypersensitivity and injection-site reactions were generally mild and rarely led to discontinuation. Immunogenicity remained low across all agents, with anti-drug antibodies showing no meaningful impact on efficacy or safety.

Long-term extension data in IBD, together with extensive experience from psoriasis and psoriatic arthritis programs, confirm the stability of the safety profile over time, with no emerging safety signals beyond those identified in the pivotal trials.^44–50 Real-world evidence from multicenter cohorts in both CD and UC similarly supports the favorable safety profile, reporting low discontinuation rates due to adverse events and no unexpected toxicities.^26–33

Malignancies were rare across trials, long-term extension studies, and real-world datasets, occurring at rates consistent with background risk in IBD populations and without a pattern suggestive of causal association with IL-23 inhibition. Reported cases included non-melanoma skin cancer and isolated instances of colon adenocarcinoma, breast cancer, or lung cancer, without a clear causal association with IL-23 inhibition. Large psoriasis datasets for guselkumab and risankizumab similarly show no increased overall cancer risk compared with general or disease-matched populations, reinforcing the absence of a malignancy signal for the class.^51,52 Major adverse cardiovascular events (MACE) were uncommon across all IBD trials and did not differ from placebo. Long-term data from dermatologic indications similarly show no increased incidence of MACE with IL-23p19 inhibitors. Cardiovascular events reported in IBD programs occurred in patients with pre-existing risk factors, and no causal relationship with treatment has been established.⁵³

Pregnancy data for IL-23p19 inhibitors remain limited but increasingly reassuring: across prospective cohorts in IBD and large real-world datasets,^54–56 maternal exposure to risankizumab has not been associated with increased rates of adverse obstetric or neonatal outcomes, with studies reporting no preterm births, very low frequencies of miscarriage or hypertensive disorders, and no signal of congenital anomalies beyond background rates, though the small size of individual cohorts warrants cautious interpretation. Similarly, global safety database analyses of guselkumab show pregnancy outcomes comparable to those expected in the general population.⁵⁶ As IgG1 monoclonal antibodies, placental transfer increases in late gestation, but available follow-up of exposed infants shows no developmental concerns. Overall, current evidence supports individualized continuation of IL-23p19 inhibitors during pregnancy when needed for disease control, in line with a benefit-risk assessment conducted in shared decision-making with the patient.

Efficacy on Extra-Intestinal Manifestations

Given the central role of the IL-23/Th17 axis in the pathogenesis of plaque psoriasis and psoriatic arthritis, selective IL-23p19 inhibitors have received regulatory approval for these conditions independently of their IBD indications. Risankizumab and guselkumab are both approved for moderate-to-severe plaque psoriasis and psoriatic arthritis in adults; guselkumab additionally holds approval for pediatric plaque psoriasis in patients aged ≥6 years. Mirikizumab, by contrast, does not currently have approvals in either dermatological or rheumatological indications.

In psoriatic arthritis, the pivotal evidence comes from the DISCOVER program for guselkumab and the KEEPsAKE program for risankizumab. In DISCOVER-1 and DISCOVER-2, guselkumab achieved American College of Rheumatology 20% improvement (ACR20) responses of 52–64% versus 22–33% with placebo at week 24 across biologic-naïve and anti-TNF-experienced populations, with consistent improvements in enthesitis, dactylitis, physical function, and skin involvement. DISCOVER-2, conducted exclusively in biologic-naïve patients, also demonstrated inhibition of radiographic progression.^44,45 In KEEPSAKE-1 and KEEPSAKE-2, which enrolled patients with inadequate responses to conventional synthetic DMARDs with or without prior biologic exposure, risankizumab achieved ACR20 responses of 51–57% versus 27–34% with placebo at week 24, sustained through week 100, with meaningful improvements in enthesitis, dactylitis, and skin psoriasis. Both agents demonstrated favorable and stable safety profiles across these programs.^57,58

In plaque psoriasis, efficacy was established in the VOYAGE trials for guselkumab and the UltIMMa trials for risankizumab. Guselkumab achieved rapid and profound skin clearance, with PASI90 responses – defined as ≥90% improvement in the Psoriasis Area and Severity Index – of 73.3% in VOYAGE-1 and 70.0% in VOYAGE-2 versus 2.9% and 2.4% with placebo (P <0.001), with demonstrated superiority over adalimumab across all key skin endpoints.^48,49 Risankizumab achieved PASI90 responses of 75.3% in UltIMMa-1 and 74.8% in UltIMMa-2 versus 4.9% and 2.0% with placebo, and 42.0% and 47.5% with ustekinumab (P <0.0001 for all comparisons), supporting the superiority of selective p19 inhibition over dual IL-12/23 blockade for skin clearance in psoriasis.⁵⁰

One important limitation applies to axial spondyloarthritis: IL-23p19 inhibitors are not approved for this indication, and randomized trial evidence has been largely negative or inconclusive. This distinguishes them from anti-TNF agents and JAK inhibitors, which remain the preferred options for IBD patients with predominant axial involvement. Preliminary evidence suggests guselkumab may confer some benefit in psoriatic arthritis patients with concomitant axial features, but this does not extend to established ankylosing spondylitis or non-radiographic axial spondyloarthritis, and should not be interpreted as an approved indication.

Finally, it is worth noting that none of the IBD phase 3 trials have systematically evaluated extraintestinal manifestation outcomes as pre-specified endpoints, leaving the magnitude and durability of benefit for IBD-associated extra-intestinal manifestations largely inferred from dermatological and rheumatological programs rather than directly measured in the target population.

Discussion

The evidence reviewed here supports a coherent and clinically actionable picture of selective IL-23p19 inhibition in IBD, while also revealing important gaps that will shape the research agenda for the coming years (Figure 1).

Figure 1.

Selective IL-23p19 inhibition in inflammatory bowel disease: current evidence, clinical positioning, and future perspectives. The figure summarizes key evidence regarding efficacy across treatment-experienced populations, comparative efficacy versus ustekinumab in Crohn’s disease, flexibility of subcutaneous administration, relevance for extraintestinal manifestations, integration into treat-to-target strategies, and future perspectives for personalized medicine.

Abbreviations: CD, Crohn’s disease; UC, ulcerative colitis; EIMs, extraintestinal manifestations; RZB, risankizumab; GSK, guselkumab; MIR, mirikizumab; UST, ustekinumab; IV, intravenous; SC, subcutaneous; JAK, Janus kinase; TNF, tumor necrosis factor.

Efficacy Across Naïve and Experienced Populations with a Favorable Safety Profile

All three IL-23p19 inhibitors have demonstrated efficacy in patients with prior exposure to advanced therapies. Response rates are consistently numerically higher in biologic-naïve individuals, as expected from the cumulative impact of prior treatment failures on immune responsiveness, but clinically meaningful effects are preserved across exposure categories. These agents therefore represent appropriate therapeutic options throughout the disease course, from earlier lines of therapy to highly refractory settings. In patients with prior ustekinumab exposure, real-world data indicate attenuated but still clinically meaningful response rates, with endoscopic remission of approximately 34% in ustekinumab-exposed versus 68% in ustekinumab-naïve patients at 6 months.²⁷

Several evidence gaps remain. Data on sequencing after JAK inhibitor failure are limited, as trials that included JAK inhibitor-experienced patients have not yet reported detailed subgroup analyses. In addition, no trials have been specifically designed to evaluate switching strategies – for instance, from ustekinumab to a p19 inhibitor versus to a therapy with a different mechanism of action – nor cycling within the IL-23p19 class.

Head-to-Head Superiority Over Ustekinumab in Crohn’s Disease

The SEQUENCE trial provided definitive head-to-head evidence in IBD, demonstrating that risankizumab is both non-inferior and superior to ustekinumab for clinical remission at week 24, and superior for endoscopic remission at week 48. Complementary data from GALAXI-2/3 – where guselkumab was superior to ustekinumab across all prespecified pooled endoscopic endpoints – reinforce the class-level advantage of p19 selectivity for mucosal outcomes. In VIVID-1, mirikizumab met non-inferiority for clinical remission but did not achieve superiority for endoscopic response, highlighting the need to determine whether differences observed across head-to-head trials reflect clinically meaningful heterogeneity within the class or differences in study design and patient populations.

Clinically, this evidence supports positioning selective IL-23p19 inhibitors ahead of ustekinumab in anti-TNF-experienced CD patients, particularly when endoscopic healing is a primary treatment goal. Mechanistically, the advantage likely reflects more targeted suppression of the IL-23/Th17 axis, which may be especially relevant in chronic refractory disease characterized by upregulated IL-23 receptor expression in the inflamed mucosa.

The critical remaining gap is the absence of head-to-head data in UC: INSPIRE, LUCENT, and QUASAR did not have an active comparator and real-world data are lacking, leaving the comparative positioning of IL-23p19 inhibitors versus ustekinumab in UC entirely based on indirect evidence.

Subcutaneous Formulations Enable Flexible, Patient-Centered Administration

The GRAVITI and ASTRO trials established that guselkumab is effective when administered through a fully subcutaneous induction and maintenance regimen, with efficacy comparable to intravenous induction strategies in GALAXI and QUASAR. Risankizumab and mirikizumab programs have employed intravenous induction followed by subcutaneous maintenance – a design that requires multiple outpatient visits. The availability of a fully subcutaneous alternative expands treatment flexibility for patients who prefer to avoid infusions due to logistical constraints, poor venous access, or personal preference, without apparent compromise in efficacy.

Key evidence gaps include the absence of direct randomized comparisons between IV and SC induction; current equivalence data rely on cross-trial comparisons with methodological limitations. Additionally, patient-centered outcomes such as adherence, satisfaction, and long-term treatment persistence according to route of administration remain insufficiently characterized in real-world setting.

Differential Coverage of Extraintestinal Manifestations (EIMs)

Risankizumab and guselkumab are approved for moderate-to-severe plaque psoriasis and psoriatic arthritis, with guselkumab also approved for pediatric psoriasis (≥6 years), whereas mirikizumab does not currently hold approvals in these indications. In IBD patients with concomitant psoriasis or psoriatic arthritis – estimated to affect 10–20% of the IBD population — risankizumab or guselkumab enable dual-indication treatment with a single agent, potentially improving adherence and reducing polypharmacy.⁵³ For patients with axial spondyloarthritis, however, IL-23p19 inhibitors are not approved, and anti-TNF agents and JAK inhibitors remain the preferred options. Importantly, IBD phase 3 trials have not systematically evaluated EIM outcomes as prespecified endpoints, so the magnitude of benefit for IBD-associated manifestations is inferred from dermatological and rheumatological programs rather than directly established.

Integration into Treat-to-Target Algorithms: Positioning for Deep Remission

Phase 3 programs for all three IL-23p19 inhibitors incorporated endoscopic endpoints as either co-primary or key secondary outcomes, with endoscopic remission rates at one year ranging from 34–58% depending on the agent, trial population, and endpoint definition used. Emerging data from GRAVITI and real-world studies further suggest the potential to achieve transmural healing as assessed by MRI and deep remission, defined as the combination of clinical remission, endoscopic healing, and biomarker normalization.

These findings support the integration of IL-23p19 inhibitors into contemporary treat-to-target strategies, which increasingly emphasize objective measures of mucosal healing rather than symptom control alone. Furthermore, histologic endpoints have been reported in UC trials, and the REASON trial is currently investigating the efficacy of guselkumab on transmural healing in CD. In patients who fail to achieve endoscopic remission, switching to a p19 inhibitor represents a rational escalation strategy. Several questions remain unresolved, including the optimal strategy to achieve such outcomes – for instance, the role of therapy optimization or reinduction in partial responders – the optimal timing of endoscopic and imaging reassessment, and the prospective validation that these intermediate targets, within a treat-to-target strategy, translate into meaningful long-term outcomes such as surgery-free survival and prevention of disease progression.

Personalization and Precision Medicine

The identification of predictive biomarkers for response to IL-23p19 inhibition remains among the most important unmet needs in the field. Baseline inflammatory markers such as CRP and fecal calprotectin correlate with endoscopic activity but have limited predictive value for treatment response to specific agents. Genetic variants and mucosal immune signatures including Th17-related gene expression profiles represent biologically plausible candidates for patient stratification, but have not been prospectively validated in the context of p19 inhibitor therapy. This gap is particularly relevant when choosing between IL-23p19 inhibitors and agents with distinct mechanisms of action: if mucosal IL-23 expression or IL-23R upregulation could identify patients most likely to benefit from p19 blockade, treatment selection could move from empirical to evidence-based. Similarly, within the IL-23p19 class, pharmacokinetic differences – including guselkumab additional binding to CD64 on inflammatory monocytes, which may enrich drug concentration at the site of inflammation – could possibly translate into differential tissue penetration and efficacy in specific disease phenotypes, but this hypothesis requires prospective testing.⁵⁹ Integration of genomic, transcriptomic, and proteomic data from ongoing trial biobanks holds genuine promise for advancing precision medicine in IBD, though the path from association to validated clinical tool has proven long and difficult in this field.

Conclusion

Selective IL-23p19 inhibition has fundamentally expanded the therapeutic landscape of IBD. Risankizumab, mirikizumab, and guselkumab have each demonstrated efficacy across a broad spectrum of patients with moderate-to-severe CD and UC, encompassing both naïve individuals and those with multiple prior treatment failures, including anti-TNF–experienced and ustekinumab-exposed populations. Their safety profiles are consistent and favorable, with no class-specific signals of concern identified across pivotal programs, long-term extension studies, and growing real-world datasets. The accumulating evidence, especially in CD, supports consideration of selected IL-23p19 inhibitors ahead of ustekinumab in the treatment algorithm. The availability of subcutaneous induction regimens (guselkumab) and adolescent-inclusive programs (risankizumab) further broadens their clinical applicability. At the same time, important evidence gaps remain. No head-to-head data exist in UC, long-term outcomes beyond 52 weeks are limited, and predictive biomarkers capable of guiding individualized treatment selection have yet to be validated. The cost-effectiveness of these agents relative to other advanced therapies – particularly in the context of emerging ustekinumab biosimilars and anti-TNF biosimilar use – requires dedicated health economic analyses accounting for both direct and indirect costs, including hospitalization, surgery, and productivity losses. Ongoing and future trials addressing fistulizing disease, transmural healing, intra-class cycling strategies, and pediatric-specific populations will be critical to fully define the role of selective IL-23p19 inhibition in IBD. In the meantime, the available evidence positions this class as among the most effective and best-tolerated options currently available for moderate-to-severe IBD, with a scientific rationale that continues to strengthen as real-world experience accumulates.

Funding Statement

The authors declare that no funding was received for this study.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

E.B.,G.P., A.D.B., R.G., L.L., and G.M.: Conceptualization, writing – original draft, writing – review & editing. C.B. and A.A.: Conceptualization, writing – review & editing, supervision. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Giuseppe Privitera received speaker and/or consultancy fees from Abbvie, Johnson and Johnson, and Pfizer. Arianna Dal Buono has received speaker’s fees from MSD, Eli-Lilly, Janssen, AbbVie, Galapagos, Celltrion and Pfizer; and consulting fees from Ferring. Roberto Gabbiadini has received speaker’s fees from Pfizer, AbbVie, Janssen, MSD, Eli-Lilly, Ferring,Celltrion and Takeda; and consulting fees from Pfizer, AbbVie, Janssen, Takeda and Alfasigma. Cristina Bezzio received lecture fees and served as a consultant for Takeda, MSD, Ferring, Abbvie, Galapagos and Janssen. Alessandro Armuzzi has received consulting and/or advisory board fees from AbbVie, Abivax, Alfa Sigma, Astra Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Enthera, Ferring, Galapagos, Gilead, Giuliani, Janssen, Lionhealth, MSD, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Sanofi, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceuticals, Tillots Pharma; lecture and/or speaker bureau fees from AbbVie, AG Pharma, Alfa Sigma, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Novartis, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda, Teva Pharmaceuticals; and research grants from MSD, Pfizer, Takeda and Biogen. The remaining authors declare no competing interests.