Interleukin-23 Inhibitors in Inflammatory Bowel Disease

Abstract

Selective inhibition of interleukin-23 (IL-23) has emerged as a highly effective therapeutic strategy in inflammatory bowel disease, targeting a central pathway of chronic intestinal inflammation while preserving host defense mechanisms. Across phase II and phase III randomized controlled trials, risankizumab, mirikizumab, and guselkumab consistently demonstrated robust efficacy in both ulcerative colitis and Crohn’s disease, achieving clinical remission rates approaching 40–50% in ulcerative colitis and exceeding 50% in Crohn’s disease during maintenance, with parallel improvements in endoscopic and histological outcomes. Notably, mirikizumab and guselkumab showed particularly high rates of endoscopic and histological remission in ulcerative colitis, whereas guselkumab achieved some of the highest induction remission rates in Crohn’s disease. These benefits were durable over time, with long-term extension studies confirming sustained remission beyond two years in a substantial proportion of patients. Across trials, IL-23 inhibitors displayed a favorable safety profile, with low rates of serious adverse events, infections, and major cardiovascular events, supporting their use in long-term disease management. Real-world evidence further reinforces these findings, demonstrating consistent effectiveness in heavily pretreated and complex patient populations, including those with prior biologic failure, comorbidities, or difficult-to-treat disease phenotypes. In particular, risankizumab has shown strong performance in multi-refractory Crohn’s disease cohorts, while emerging data for mirikizumab confirm its effectiveness in real-life ulcerative colitis settings. Beyond clinical outcomes, differences in molecular structure, pharmacokinetics, and Fc-mediated interactions may contribute to subtle distinctions among agents, potentially influencing therapeutic positioning. Ongoing development of oral compounds and combination strategies targeting complementary inflammatory pathways is expected to further expand the role of IL-23 inhibition. Overall, interleukin-23 inhibitors represent a cornerstone of modern inflammatory bowel disease therapy, combining high efficacy, durable responses, and an excellent safety profile, with growing evidence supporting their use across a broad spectrum of patients.

Key Points

Medicines that block interleukin-23 are effective treatments for both Crohn’s disease and ulcerative colitis.

Studies from clinical trials and real-world practice show that these therapies work well and are generally safe, even in patients who have not responded to other advanced medications.

Interleukin-23 inhibitors could also offer a reliable therapeutic tool in special populations, including elderly and pediatric patients as well as in patients with pouchitis.

Introduction

Inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing–remitting inflammatory conditions of the gastrointestinal tract characterized by a complex interplay among genetic predisposition, environmental factors, the gut microbiota, and dysregulated immune responses. Over the past two decades, biologic therapies have profoundly changed the natural history of IBD, improving clinical outcomes and reducing surgery and hospitalization rates. However, primary non-response and secondary loss of response to existing biologics, including anti-tumor necrosis factor (anti-TNFα) agents, vedolizumab, and ustekinumab, remain significant unmet needs [1, 2].

Among cytokine networks implicated in IBD pathogenesis, the interleukin (IL)-23/Th17 axis has emerged as a key driver of chronic intestinal inflammation. IL-23, a heterodimer composed of a unique p19 subunit and a p40 subunit shared with IL-12, promotes differentiation, survival, and expansion of pathogenic Th17 cells, leading to production of proinflammatory cytokines such as IL-17, IL-22, and TNFα. The success of ustekinumab, an antibody targeting the shared p40 subunit, validated IL-23 as a therapeutic target. However, preclinical and translational studies have shown that selective inhibition of the p19 subunit may provide more specific and durable suppression of pathogenic inflammation while preserving IL-12–mediated host defense mechanisms [3]. The development of monoclonal antibodies selectively targeting the IL-23p19 subunit, namely risankizumab, guselkumab, and mirikizumab, represents the most recent evolution in biologic therapy for IBD. These agents have shown remarkable efficacy in pivotal phase III trials and real-world cohorts, leading to regulatory approvals across both primary indications. All three medications have been approved for both UC and CD. The availability of multiple IL-23p19 inhibitors provides clinicians with several effective and safe options to individualize treatment strategies across different disease phenotypes and clinical settings [4, 5]. The rapid expansion of IL-23 inhibitors in inflammatory bowel disease has generated a complex body of evidence spanning distinct molecular mechanisms, randomized controlled trials (RCTs), and emerging real-world data. At the same time, additional agents targeting the IL-23 pathway are progressing through clinical development, further increasing therapeutic complexity. This review aims to synthesize these data to support informed clinical positioning and future treatment strategies for IL-23 inhibition in inflammatory bowel disease.

Molecular Aspects of IL-23 Inhibition

IL-23 is a heterodimeric cytokine composed of a unique p19 subunit and a p40 subunit shared with IL-12. It binds to a heterodimeric receptor complex formed by IL-23R and IL-12Rβ1, which is predominantly expressed on activated Th17 cells, innate lymphoid cells, and macrophages. Activation of this receptor triggers the JAK2–TYK2–STAT3/STAT4 signaling cascade, leading to the transcription of proinflammatory mediators such as IL-17A, IL-17F, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF), and TNFα, which collectively sustain chronic intestinal inflammation [3, 6]. IL-12 and IL-23 share structural components but have divergent immunologic roles: IL-12 promotes Th1 differentiation and interferon-γ production, which are crucial for host defense, whereas IL-23 supports the persistence of pathogenic Th17 responses associated with mucosal inflammation and tissue damage. This biological distinction provided the rationale for the development of selective IL-23 blockade, aimed at suppressing pathogenic inflammation without compromising antimicrobial immunity [6–8].

Failure of anti-TNFα in IBD reflects a shift in the dominant inflammatory axis from TNFα-driven to IL-23/Th17-driven pathways. Evidence from translational and clinical studies demonstrates that IL-23 production by dendritic cells and inflammatory macrophages is upregulated in chronically inflamed mucosa during TNFα blockade, sustaining pathogenic Th17 cells, innate lymphoid cell type 3, and IL-23–responsive myeloid populations that maintain IL-17A, IL-22, and GM-CSF production despite adequate TNFα suppression [9]. Biopsy studies in patients with secondary loss of response to anti-TNFα show enrichment of IL-23/Th17 signatures and IL-23R–expressing lymphocytes compared with anti-TNF–naïve tissue, supporting a cytokine shift during treatment. Clinically, p19-selective inhibitors (guselkumab, risankizumab, mirikizumab) achieve robust remission and endoscopic response in CD and UC cohorts heavily pre-treated with anti-TNFα, indicating that residual inflammation is effectively IL-23-driven and therapeutically targetable [10]. These data support a model in which IL-23 acts as an adaptive escape pathway under TNFα pressure, providing a mechanistic rationale for sequencing IL-23 inhibitors after anti-TNFα failure in IBD [9, 11–13].

Ustekinumab, the first approved IL-12/23 inhibitor targeting the shared p40 subunit, demonstrated efficacy in both CD and UC, thereby validating this cytokine family as a therapeutic target. However, p19-selective inhibitors bind specifically to the IL-23p19 subunit, thereby inhibiting IL-23 signaling while preserving IL-12–dependent pathways [4].

Although all three agents share the same molecular target, they differ in epitope binding, molecular structure, and pharmacokinetic characteristics. Risankizumab is a humanized IgG1 monoclonal antibody that binds to an epitope on p19, preventing IL-23 from engaging its receptor; it is available in both intravenous and subcutaneous formulations, with a long terminal half-life (≈28 days) [14]. Recent data on patients with psoriasis treated with risankizumab showed that it induces IL10⁺ M2-macrophage polarization, thereby reducing pro-inflammatory cytokine production [15].

Guselkumab is a fully human IgG1λ antibody that binds a distinct, non-overlapping epitope on p19, with a similar pharmacokinetic profile but dual induction options (IV or SC). Of note, this molecule is characterized by a native Fc domain that binds CD64 (FcγRI), expressed on the surface of IL-23-producing myeloid cells [16]. An in-vitro study on THP-1 cells demonstrated higher potency of guselkumab than risankizumab in inhibiting IL-23 production, with Fc-binding-dependent effects. The binding to FcγRI, moreover, does not increase IL-23 production, but instead promotes internalization into endolysosomal compartments [17]. Mirikizumab is a humanized IgG4 monoclonal antibody targeting a unique p19 conformational epitope; its IgG4 backbone confers reduced effector function and minimal Fc-mediated cytotoxicity. IgG4 antibodies have reduced capacity to activate the classical complement pathway compared with IgG1 antibodies, due to structural differences in the Fc region [18]. In particular, this occurs because they have a poor ability to bind C1q and form the hexameric structures required for efficient classical complement pathway activation [19, 20].

However, these molecular design differences seem to affect pharmacokinetics minimally: guselkumab and risankizumab showed longer terminal half-lives (approximately 14–19 days and 22–28 days, respectively). In comparison, mirikizumab showed a reduced half-life (about 9.5 days).

Figure 1 shows differences in molecular structure, pharmacodynamics, and pharmacokinetics among IL-23 inhibitors.

Fig. 1.

Structural, pharmacokinetic, and mechanistic differences among selective interleukin-23 p19 inhibitors used in inflammatory bowel disease. Key molecular and pharmacologic features of IL-23 inhibitors. The upper panels illustrate differences in antibody structure, including immunoglobulin subclass and Fc domain characteristics. The central panels summarize routes of administration and dosing strategies, including intravenous induction followed by subcutaneous maintenance, and differences in maintenance dosing intervals. The lower panels report approximate terminal half-life ranges and potential additional mechanisms of action beyond interleukin-23 neutralization. CD64 Fc gamma receptor I, Fc fragment crystallizable, IgG immunoglobulin G, IL-23 interleukin-23, IV intravenous, SC subcutaneous

By selectively inhibiting IL-23 signaling, these agents attenuate Th17-driven inflammation, reduce IL-17 and IL-22 secretion, and promote mucosal healing and restoration of the epithelial barrier. Their selective mechanism is believed to underpin the favorable safety profile observed across large RCTs, with low rates of serious infections, malignancies, and cardiovascular events compared with those of broader cytokine inhibitors [4].

Data from Randomized Controlled Trials (RCTs)

Efficacy in Ulcerative Colitis (UC)

Across phase II and III RCTs, all three IL-23p19 inhibitors demonstrated significant induction and maintenance efficacy in UC, with consistent effects on clinical, endoscopic, and histologic outcomes. Efficacy data for IL-23 inhibitors in UC are summarized in Table 1. Safety is discussed in Sect. 3.3.

Table 1.

Efficacy data from phase III randomized controlled trials in ulcerative colitis

Drug	Program	Phase (weeks of follow up)	Dosing	Clinical remission (%)	Steroid-free remission (%)	Endoscopic remission (%)	Histological remission (%)
Risankizumab	INSPIRE substudy 2 [21]	Induction (12)	1200 mg at weeks 0, 4, 8	20.3**		10.6**	6.3**
Risankizumab	COMMAND substudy 1 [21]	Maintenance (52)	180 mg e4w	40.2**	39.6*	23.2*	12.9
			360 mg e4w	37.6**	37.1*	24.3*	15.6
Mirikizumab	LUCENT-1 [22]	Induction (12)	300 mg at weeks 0, 4, 8	24.2**		36.3**	27.1**
Mirikizumab	LUCENT-2 [22]	Maintenance (52)	200 mg e4w	49.9**	44.9**	58.6**	43.3**
Guselkumab	QUASAR induction [24]	Induction (12)	200 mg at weeks 0, 4, 8	23.0**		15.0**	40.0**
Guselkumab	QUASAR maintenance [24]	Maintenance (44)	100 mg e8w	45.0**	45**	35**	59**
			200 mg e4w	50.0**	49**	34**	61**
Guselkumab	ASTRO [26, 27]	Induction (12)	400 mg SC at weeks 0, 4, 8	28**		17**	44**
		Maintenance (24)	100 mg e8w	35**	35**	21**
			200 mg e4w	36**	35**	26**

All induction regimens were administered intravenously unless otherwise specified; maintenance regimens were administered subcutaneously

e4w every 4 weeks, e8w every 8 weeks, SC subcutaneous; * p < 0.05; ** p < 0.001

Regarding UC, risankizumab showed marked induction efficacy in INSPIRE substudy 2, with clinical remission at week 12 achieved in 20.3% of patients, along with significant improvements in endoscopic remission (10.6%) and histologic remission (6.3%) [21]. These early effects were sustained and amplified during the COMMAND maintenance study, in which clinical remission rates at week 52 increased to 40.2% and 37.6% for the evaluated regimens (180 mg every 4 weeks [e4w] and 360 mg e4w, respectively), accompanied by steroid-free remission rates of approximately 37–40% and endoscopic remission rates exceeding 23% [21]. Collectively, these findings indicate both durable symptom control and objective mucosal healing under risankizumab therapy.

Mirikizumab demonstrated robust efficacy across the LUCENT program. During induction in LUCENT-1, clinical remission at week 12 was achieved in 24.2% of treated patients, with notably high rates of endoscopic remission (36.3%) and histological remission (27.1%), suggesting early and substantial impact on mucosal inflammation [22]. Results for 52 weeks of maintenance from LUCENT-2 further reinforced these benefits, with nearly half of patients achieving clinical remission (49.9%) and steroid-free remission (44.9%), combined with high endoscopic remission rates (58.6%) and histologic remission of 43.3% [22]. Guselkumab efficacy was demonstrated in the phase III QUASAR program and additional induction studies. In the QUASAR induction trial, clinical remission at week 12 reached 23.0%, with significant endoscopic remission (15.0%) and a striking histologic remission rate of 40.0% [24]. Maintenance therapy at week 44 yielded higher remission rates, with clinical remission approaching 45–50%, steroid-free remission near 45–49%, and endoscopic remission around 34–35%. Histologic remission rates were particularly notable, reaching 59–61%, underscoring potent effects on microscopic inflammation [24]. These rates were also demonstrated in the ASTRO study, where guselkumab was administered subcutaneously (400 mg e4w) for the first three doses; at week 12, the clinical remission rate was 28% in guselkumab-treated patients, with an increase to 35–36% at 24 weeks [26]. Endoscopic remission was obtained in 17% of patients at 12 weeks (with 44% also achieving histological remission) and 21–26% at 24 weeks. Steroid-free clinical remission was achieved in 35% of patients at week 24 [26].

As a general consideration for UC, all agents demonstrated statistically significant efficacy across induction and maintenance phases, with convergence of clinical and objective endpoints. Mirikizumab and guselkumab appeared to achieve exceptionally high rates of endoscopic and histologic remission during maintenance and long-term follow-up, while risankizumab showed consistent steroid-sparing effects following induction.

Efficacy in CD

In CD, anti-IL-23 therapies also demonstrated strong induction and maintenance efficacy, though absolute remission rates and patterns differed slightly from UC. Efficacy data for IL-23 inhibitors in CD are summarized in Table 2. Safety is discussed in Sect. 3.3.

Table 2.

Efficacy data from phase III randomized controlled trials in Crohn’s disease

Drug	Program	Phase (weeks of follow up)	Dosing	Clinical remission (%)	Steroid-free remission (%)	Endoscopic remission (%)
Risankizumab	ADVANCE [28]	Induction (12)	600 mg at weeks 0, 4, 8	45**		24**
			1200 mg at weeks 0, 4, 8	42**		24**
Risankizumab	MOTIVATE [28]	Induction (12)	600 mg at weeks 0, 4, 8	45**		19**
			1200 mg at weeks 0, 4, 8	42**		20**
Risankizumab	FORTIFY [29]	Maintenance (52)	180 mg e4w	55*		30**
			360 mg e4w	52*		39**
Mirikizumab	VIVID-1 [30]	Induction (12)	900 mg at weeks 0, 4, 8	37.7*		10.9*
Mirikizumab		Maintenance (52)	300 mg e4w	54.1**	43.7**	28.5**
Guselkumab	GRAVITI [31]	Induction (12)	400 mg SC at weeks 0, 4, 8	56.1**
Guselkumab		Maintenance (48)	100 mg e8w	60.0**	58.3	30.4*
			200 mg e4w	66.1**	65.2	38.3*
Guselkumab	GALAXI-2 and GALAXI-3 [32]	Induction (12)	200 mg at weeks 0, 4, 8	47.1**
Guselkumab		Maintenance (48)	100 mg e8w	48.3	46–47*	33.2**
Guselkumab		Maintenance (48)	200 mg e4w	50.3	45–51*	37.2**

All induction regimens were administered intravenously unless otherwise specified. Maintenance regimens were administered subcutaneously

e4w every 4 weeks, e8w every 8 weeks, SAE serious adverse events, SC subcutaneous; * p < 0.05; ** p < 0.001

Risankizumab exhibited consistent induction efficacy in both the ADVANCE and MOTIVATE trials, with week 12 clinical remission rates ranging from 42% to 45% [28]. Endoscopic remission during induction was approximately 19–24% across the two studies, confirming objective disease modification [28]. Maintenance results from the FORTIFY trial indicated durable benefit, with clinical remission rates of 52% to 55% and endoscopic remission rates ranging from 30% to 39%, reflecting ongoing mucosal improvement during long-term therapy [29].

Mirikizumab showed moderate induction efficacy in the VIVID-1 trial, with clinical remission at 12 weeks achieved in 37.7% of patients, whereas initial endoscopic remission rates were more modest at 10.9% [30]. However, maintenance outcomes (assessed at week 52) demonstrated significant gains with prolonged treatment: clinical remission increased to 54.1%, steroid-free remission was observed in 43.7% (p < 0.001), and endoscopic remission reached 28.5%, indicating that sustained therapy was associated with progressive mucosal healing [30].

Guselkumab achieved some of the highest reported induction remission rates in CD. In the GRAVITI induction trial, clinical remission at week 12 was achieved in 56.1% of patients [31]. Maintenance therapy further improved outcomes, with remission rates rising to 60.0–66.1% and steroid-free remission exceeding 58–65%. Endoscopic remission during maintenance ranged from 30.4% to 38.3% [31]. Similar patterns emerged in the GALAXI program. Induction in GALAXI-2 and GALAXI-3 yielded clinical remission near 47% at 12 weeks [32]. During maintenance, clinical remission remained at 48–50%, steroid-free remission at 45–51%, and endoscopic remission at 33–37%, demonstrating sustained clinical benefit accompanied by objective mucosal improvement [32].

Across CD trials, all three anti-IL-23 agents produced statistically significant improvements in clinical remission at induction, with increasing steroid-free and endoscopic remission during maintenance phases. Guselkumab consistently achieved the highest induction remission rates, while risankizumab showed dependable mucosal healing and durable effects. Mirikizumab data suggested a more gradual accrual of benefit, with notable enhancement of endoscopic outcomes during maintenance.

Safety Data from RCTs

Across phase II and III randomized trials, anti-IL-23 agents demonstrated a favorable and consistent safety profile in both UC and CD. Safety data are summarized in Table 3. The most reported adverse events were nasopharyngitis, upper respiratory tract infections, headache, and injection-site reactions, which were generally mild to moderate and comparable to placebo rates. Serious adverse events and treatment discontinuations were infrequent, and no clear dose-related safety signals emerged. Rates of serious infections remained low, with no meaningful increase in opportunistic infections or tuberculosis reactivation observed across programs. Importantly, no new safety concerns were identified during long-term extension studies, supporting the durability of the safety profile with sustained exposure [33].

Table 3.

Summary of common and serious adverse events during maintenance therapy with interleukin-23 inhibitors in phase III randomized controlled trials

Drug	Study	Serious AEs
Risankizumab	FORTIFY CD [29]	- Common AE 2–12% (CD worsening, nasopharyngitis, arthralgia, headache, nausea, abdominal pain, diarrhea, anemia, hepatic events) - Serious infections 4% - Opportunistic infections 1%, zoster 1% - MACE 1% - Cancer 1% - Hepatic events 4%
Risankizumab	COMMAND UC [21]	- Common AE 0.5–13% (COVID-19, anemia, arthralgia, headache, nasopharyngitis, UC worsening) - Serious infections 1% - Opportunistic infections 0.5% + zoster 1% + tuberculosis 0% - MACE 0% - Cancer 1% - Hepatic events 6.7%
Guselkumab	GALAXI CD [32]	- Common AE 4–18% (CD worsening, COVID-19, upper respiratory tract infection, abdominal pain, pyrexia, arthralgia, headache, nasopharyngitis, anemia) - Opportunistic infections 1% + tuberculosis 1% - Cancer 1% - MACE 1%
Guselkumab	GRAVITI CD [31]	- Common AE 8–14% (COVID-19, abdominal pain, upper respiratory tract infections) - Opportunistic infections 0.4% + tuberculosis 0% - Cancer 0.4% - MACE 0%
Guselkumab	QUASAR UC [24]	- Common AE 2–13% (UC, anemia, COVID-19, headache, arthralgia, upper respiratory tract infection) - Serious infections 1% - Opportunistic infections 0% - MACE 1% - Cancer 1%
Mirikizumab	VIVID CD [30]	- Common AE 5–16% (COVID-19, anemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis) - Serious infection 2.2% - Opportunistic infections 1.1% - Cerebrovascular accidents 0.5% - MACE 0% - Cancer 0.3%
Mirikizumab	LUCENT UC [22]	- Common AE 2–7% (nasopharyngitis, arthralgia, UC worsening, injection-site pain, headache, rash, pyrexia, anemia) - Serious infection 0.8% - Opportunistic infections 1.3% (including zoster and tuberculosis) - Cancer 0.3% - Cerebrovascular accidents 0%

Serious adverse events were defined according to the International Council for Harmonisation (ICH) Good Clinical Practice guidelines

AE adverse events, CD Crohn’s disease, MACE major adverse cardiovascular events, UC ulcerative colitis

Long-Term Extensions from RCTs

Table 4 summarizes the main effectiveness data from open-label extensions. The first data from a long-term extension study was presented in LUCENT-3, where the durability of response in UC was confirmed [23]. Among patients treated with mirikizumab, over 80% of patients were in clinical remission by week 104, with consistent maintenance of steroid-free status (68.5% for responders at week 52 and 82.5% for remitters at week 52) and endoscopic healing (~70%). This data shows sustained disease control over extended follow-up. Severe adverse events were reported in only 15 patients (5.2%), mainly related to SARS-CoV-2 infections or UC worsening. Major adverse cardiovascular events (MACE) were observed in 0.7% of patients, suggesting the treatment's safety [23].

Table 4.

Effectiveness data from long-term extension programs

Drug	Program	Phase (weeks of follow up)	Dose	Clinical remission (%)	Steroid-free remission (%)	Endoscopic remission (%)	Histological remission (%)
Guselkumab (UC)	QUASAR LTE [25]	Maintenance (92)	100 mg e8w	71	71	42
			200 mg e4w	75	75	44
Guselkumab (UC)	QUASAR LTE [35]	Maintenance (140)	100 mg e8w	80.1		55.9
			200 mg e4w	81.5		51.2
Mirikizumab (UC)	LUCENT-3 [23]	Long-term extension (104)	200 mg e4w	84.2	82.5	69.5	69.5
Mirikizumab (CD)	VIVID-2 [34]	Long-term extension (104)	300 mg e4w	80.9	79.1	41.7

All maintenance regimens were administered subcutaneously

CD Crohn’s disease, e4w every 4 weeks, e8w every 8 weeks, UC ulcerative colitis

Long-term follow-up for CD patients treated with mirikizumab has been shown in the VIVID-2 study [34]. While 80.9% of patients achieved clinical remission (and 79.1% achieved steroid-free remission), only 41.7% of observed patients achieved endoscopic remission at 104 weeks. Notably, significant differences were observed between endoscopic responders and non-responders at week 52. The first group, who continued the maintenance dosing, maintained endoscopic remission in 78.6% of cases. The non-responder group, which received an additional three doses, had only 16.0% of patients achieve endoscopic remission. With regards to safety, 3.7% of patients experienced severe adverse events, with only three patients (0.6%) experiencing MACE [34].

Preliminary long-term data confirm the efficacy and safety of guselkumab in UC. Results from the QUASAR long-term extension at 92 weeks further supported durability, with sustained clinical and endoscopic remission rates (71–75%) and persistent histologic remission (approximately 42–44%) [25]. The most recent data from 140 weeks of follow-up shows 80.1% and 81.5% clinical remission rates, from those who received 100 mg e8w and 200 mg e4w, respectively. Endoscopic remission was achieved by 55.9% and 51.2%, respectively [35].

Real-World Evidence and Special Populations

Real-world evidence (RWE) complements RCTs by describing how therapies perform in routine clinical practice, where comorbidities, prior drug exposure, adherence, and access to care influence treatment decisions. Unlike RCTs—designed to maximize internal validity through strict inclusion criteria—RWE reflects the heterogeneity of IBD seen in everyday clinical practice. For anti-IL23, the use of such medications in individuals with multiple comorbidities, older age, pregnancy, prior biologic failure, associated immunosuppression, active extra-intestinal manifestations, or more complex disease phenotypes can be assessed [36]. The evidence included in this review reflects the literature available up to March 2026.

Although guselkumab has been widely demonstrated to be effective and safe in other diseases (e.g., psoriasis) [37], as of 2025, real-world evidence for guselkumab in IBD remains preliminary and limited. Available data are primarily derived from early observational cohorts and conference abstracts, often with small sample sizes and short follow-up, and therefore should be interpreted with caution [38]. These initial reports mainly include highly selected, refractory patients and provide only early signals of effectiveness and tolerability. Patients receiving the drug for indications other than IBD are also included [39].

Regarding mirikizumab, RWE can help define the drug's positioning in the biologic sequencing. Currently, the majority of RWE focuses on the induction period, with mainly short follow-up periods available, thereby confirming rates of clinical response and remission, as well as biochemical response [40]. In a tertiary center population including patients with previous failure to multiple drugs, previous exposure to anti-TNFα had a positive effect on biochemical remission, whilst previous exposure to Janus kinase (JAK) inhibitors hurt clinical remission [41]. Conversely, in a short-term evaluation, Levartovsky and colleagues found no differences in week12 clinical response and clinical remission rates between naïve patients and those exposed to anti-TNFα, ustekinumab, vedolizumab, or JAK inhibitors [42]. Patients with a history of difficult-to-treat disease were also present in a US cohort of 20 individuals; 83% of them achieved clinical remission at the end of the induction period. Interestingly, three patients in this cohort received mirikizumab in combination therapy with upadacitinib, without experiencing side effects [43]. RWE also confirms the good safety profile observed in RCTs. The most common side effects are injection-site pain, fatigue, and mild infectious episodes. An episode of streptococcal pharyngitis during the induction period was reported [40, 43].

Risankizumab demonstrates robust real-world efficacy in heavily pretreated IBD populations. In a Belgian multicenter cohort of 69 multirefractory CD patients (85.5% exposed to ≥4 advanced therapies), 61.8% achieved steroid-free clinical response and 27.3% achieved steroid-free clinical remission by week 52, with surgery-free survival of 75.2% [44]. A prospective Middle Eastern cohort of 60 CD patients reported clinical remission rates of 72.9% and biochemical remission of 70.8% at maintenance (10–14 months), with advanced therapy-naïve patients showing significantly higher biochemical remission (88.9% vs 60%; p = 0.047). Critically, prior ustekinumab exposure independently predicted lower remission rates and a higher need for dose intensification, suggesting potential cross-resistance within the IL-23 pathway; however, dose escalation from every 8 weeks to every 4 weeks restored clinical response in 62.5% of secondary non-responders [45]. An extensive French nationwide real-world study confirmed that approximately 50% of luminal CD patients with multiple prior drug failures, including ustekinumab, achieved steroid-free clinical remission at week 52 [46]. Overall, these studies show that risankizumab works effectively even in patients with a previous failure of ustekinumab. However, such effectiveness could not be immediate. In fact, in an Asian cohort of CD patients treated with risankizumab, clinical remission at week 12 was consistent regardless of prior ustekinumab exposure or biologic-naïve status [47]. Finally, the largest RWE on risankizumab in CD is the Italian RESOLVE study, enrolling 520 patients. In this cohort, week 52 steroid-free clinical remission was achieved in 65% of cases, whilst endoscopic remission was achieved in 37% of patients. Also in this study, the endpoints were better for ustekinumab-naïve patients compared with those exposed to ustekinumab; however, no differences were detected among patients with two or three previous biologic failures [48].

Evidence supporting the efficacy of IL-23 inhibitors in pouchitis is minimal. Patients with pouchitis are usually excluded from RCTs, and RWE is restricted to small case series and single prospective cohort data [49]. Risankizumab represents the most extensively studied agent in this setting, with a prospective multicenter case series of 10 patients with CD of the pouch showing inconsistent responses; some patients demonstrated endoscopic improvement regarding inflammation with minimal clinical symptom improvement, while those with fibrostenotic disease, fistulae, or concurrent structural complications showed poor clinical responses despite therapeutic levels, suggesting that medical therapy alone may be insufficient for patients with transmural or stricturing phenotypes [50]. More encouraging is a larger, prospective, multicenter observational study from the PROP-RD registry examining 26 patients with CD of the pouch treated with risankizumab, in which clinical remission was achieved in 50% at 12 weeks and notably in 69.2% at 24 weeks, with combined steroid- and antibiotic-free remission in 30.8% at 12 weeks. Among 16 patients previously exposed to ustekinumab, risankizumab achieved clinical remission in 43.8% of patients, without a significant difference compared with ustekinumab-naïve patients, indicating that prior IL-23/12 inhibition does not preclude subsequent IL-23p19-selective benefit. Notably, in this cohort, fistula healing and stricture resolution occurred in 83.3% and 66.7% of patients, respectively, at 24 weeks, a remarkable finding suggesting that risankizumab may address structural complications beyond simple mucosal inflammation [51]. By contrast, mirikizumab and guselkumab lack any published RWE or case series data in pouchitis or CD of the pouch.

With regards to pregnancy, the safety profile in pregnancy remains reassuring but under-documented for p19-selective agents. In psoriasis trials, guselkumab pregnancy data encompassed seven full-term births with no anomalies and zero premature births. At the same time, tildrakizumab (a related IL-23 inhibitor) documented 14 pregnancies with spontaneous abortion rates (14%) comparable to the general population (12–15%) [52]. Similarly, large pharmacovigilance databases do not highlight fetal and neonatal adverse drug events for women receiving these medications during pregnancy [53]. In IBD, a case report of successful mirikizumab use in a pregnant woman with acute severe ulcerative colitis is available [54].

Real-world data on IL-23p19 inhibitors in complex IBD patients—encompassing elderly individuals, those with significant comorbidities, and immunocompromised populations—must yet be derived from RWE of anti-IL23 in other pathologies. Anti-IL23 emerges as a potential tool in patients with IBD with several forms of fragility. In a cohort of 93 patients aged >65 years with psoriasis, guselkumab and risankizumab demonstrated sustained efficacy and persistence, with no serious adverse events and no drug discontinuations due to adverse events [55]. For immunocompromised and infection-prone patients, IL-23p19 selective inhibitors offer substantial advantages over conventional anti-TNFα therapy. Propensity-matched real-world analyses demonstrate that risankizumab and guselkumab are associated with significantly lower infection risk compared with TNFα inhibitors, including reduced incidence of otitis media, herpes zoster, and severe opportunistic infections [56]. Clinical experience with anti-IL-23 agents in HIV-positive patients with associated inflammatory conditions indicates efficacy and safety when viral suppression and CD4 counts remain adequate on antiretroviral therapy, and these agents demonstrate favorable safety profiles in patients with chronic hepatitis C or a history of tuberculosis exposure compared with anti-TNFα alternatives [57]. Serious adverse event surveillance across the maintenance and induction phases reveals that mirikizumab consistently demonstrates the lowest incidence of serious adverse events among IL-23p19 inhibitors, with safety advantages for infections and malignancy in older populations [58].

Similarly to older patients, evidence on the use of anti-IL-23 in pediatric patients is being accumulated. Pediatric patients are usually excluded from registrative RCTs. In a recent phase II clinical trial, mirikizumab was administered to pediatric participants (aged 2 to <18 years) with UC refractory to corticosteroids, immunomodulators, or first-line biological therapy. According to Pediatric Ulcerative Colitis Activity Index (PUCAI) score, 10 out of 26 patients were in clinical remission after 12 weeks of therapy and 13 were in clinical remission at week 52. With regards to safety, three (12%) participants experienced serious adverse events (non-infective appendicitis, worsening of UC, and pseudarthrosis). The most common adverse events were COVID-19, injection-site pain, headache, pyrexia and viral upper respiratory tract infection [59]. Mirikizumab was also tested in a 28-patient pediatric population enrolled by Jimbo and colleagues; prolonged clinical remission was observed in 96% (27/28), with a mean time to achieve this endpoint of 10 weeks. No adverse events were observed within the first year of therapy [60]. Beyond sparse case series reporting efficacy and safety in children [61], risankizumab pediatric development encompasses two dedicated phase II trials: ClinicalTrials.gov identifier NCT05995353 in CD and the MIGHTY trial (NCT07071519) in pediatric UC. Pharmacokinetic targets and efficacy endpoints remain consistent with adult trials, utilizing Pediatric Crohn's Disease Activity Index and modified Mayo scores, respectively.

Looking Forward: What’s in the Pipeline?

IL-23 Inhibitors Under Development

Since the inhibition of IL23 has proven to be an effective mechanism of action in the treatment of chronic intestinal inflammation, new research efforts are being focused on this cytokine, and new drugs are in the development pipeline [62]. Table 5 summarizes the IL-23 inhibitors in the pipeline.

Table 5.

Emerging therapies targeting the interleukin-23 pathway currently under clinical development for ulcerative colitis

Drug name	Target	NCT number/RCT trial name	Phase	Estimated time of study completion
Icotrokinra (JNJ-2113)	IL-23 receptor	Anthem-UC	IIb	Completed
		NCT07196748	III	2032
SOR102	IL-23 and TNFα (oral)	NCT06080048	I	Completed
PF-07261271 (now RO7837195)	IL-23 and TL1A	NCT05536440	I	Completed
		NCT06979336	IIb	2028
Picankibart (IBI-112)	IL-23	NCT04511624	I	Completed
		NCT05377580	IIb	Completed
SPY003	IL-23 (extended half-life)	NCT07012395	II	2028

IL interleukin, NCT number ClinicalTrials.gov identifier, RCT randomized controlled trial, TNFα tumor necrosis factor alpha

The administration of oral drugs targeting IL-23 also represent a frontier. Icotrokinra (JNJ-2113) represents a first-in-class targeted oral peptide that selectively blocks the IL-23 receptor rather than targeting the IL-23 ligand itself [63]. Phase IIb ANTHEM-UC trial results demonstrated that all three tested doses (100, 200, and 400 mg once daily, oral) achieved the primary endpoint of clinical response at week 12, with the highest dose achieving 36.5% endoscopic improvement and 30.2% clinical remission. The formulation was well tolerated with safety profiles comparable to placebo [64]. A phase III investigation is now ongoing, enrolling adults and adolescents with both CD (NCT07196722) and UC (NCT07196748). Even more interestingly, SOR102 is an orally administered bispecific antibody that targets both TNFα and IL-23 [65]. In a phase I trial, the drug was administered to 48 subjects including healthy individuals and UC patients. The drug showed a favorable safety profile, with mild diarrhea and dysmenorrhea being the main side effects. Two of the seven patients with UC experienced a disease worsening. Another bi-specific agent is PF-07261271 (now RO7837195), an antibody targeting both the p40 subunit of IL-12/23 and TNF-like cytokine 1A (TL1A). Preliminary results have shown a good safety profile in healthy volunteers [66] and the drug is now undergoing a phase II clinical trial in UC patients (NCT06979336).

Picankibart (IBI-112) is a subcutaneously administered recombinant monoclonal antibody targeting the IL-23p19 subunit that demonstrates p19-selective inhibition without cross-reactivity with IL-12 [67]. In a phase IIb RCT in moderately to severely active UC performed in China, preliminary data show that picankibart achieved superior clinical remission and clinical response rates at week 12 compared with placebo. The safety profile was favorable and consistent with the IL-23p19 inhibitor class [68].

SPY003 is a novel extended half-life IL-23p19 monoclonal antibody demonstrating equivalent potency to risankizumab while offering dramatically prolonged serum half-life of approximately 85 days, potentially enabling quarterly or semi-annual maintenance dosing compared with current every 4–8-week schedules. This agent is concurrently being investigated for UC in combination with an anti-TL1A drug (SPY002), and with an anti-integrin drug (SPY001).

IL-23 Inhibitors in Combination Therapy

In consideration of the favorable safety profile of IL-23 inhibitors, current research is also investigating the possible role of these agents in combination with other known or experimental biologic agents [62].

The phase II TARGET CD trial (NCT06548542) evaluates dual and triple therapeutic combinations targeting complementary inflammatory pathways in approximately 500 CD patients across several sites worldwide. The trial randomizes participants to risankizumab monotherapy (1200 mg IV induction followed by subcutaneous maintenance), risankizumab plus lutikizumab (a dual IL-1α/1β antagonist), risankizumab plus ABBV-382 (an integrin inhibitor), or single-agent comparators, with 12-week induction and maintenance periods followed by optional long-term extension. This combination approach is mechanistically driven; risankizumab targets IL-23-driven Th17 pathways, lutikizumab addresses IL-1–mediated innate inflammation and neutrophil recruitment, and ABBV-382 blocks lymphocyte trafficking and extravasation. Lutikizumab alone previously demonstrated insufficient efficacy as UC monotherapy (NCT03768219), supporting exploration of combination strategies [69]. While formal efficacy or safety results from TARGET CD remain unpublished, the trial design reflects an emerging paradigm of achieving higher remission rates by simultaneously addressing multiple pathogenic axes rather than sequential single-pathway targeting [70].

Parallel phase II DUET trials (NCT05242471 in CD, NCT05242484 in UC) are being conducted, investigating guselkumab plus golimumab combination versus monotherapies in IBD patients.

In the UC phase II VEGA trial (NCT03662542), the combination therapy with guselkumab and golimumab was more effective for UC than therapy with either drug alone. Of the 214 patients enrolled, clinical response at week 12 was achieved in 83% of patients receiving combination therapy, in 75% of patients receiving guselkumab alone and in 61% of patients receiving golimumab alone. Safety profiles were comparable across arms, especially in terms of infection rates. Molecular analysis revealed guselkumab drove tissue healing while golimumab dampened innate myeloid inflammation, demonstrating complementary mechanisms [71, 72].

These trials establish proof-of-concept that dual IL-23/TNFα blockade yields superior induction efficacy compared with monotherapy, supporting combination approaches in difficult-to-treat populations [73]. The administration of IL-23 inhibitors in combination with other advanced therapies has also been tested in RCTs of investigational agents, as mentioned above for SPY003 (NCT07012395).

Discussion

The advent of selective IL-23p19 blockade represents one of the most significant therapeutic advances in inflammatory bowel disease since the introduction of anti-TNFα therapy. Risankizumab, guselkumab, and mirikizumab have each demonstrated robust efficacy, durable remission, and favorable safety in both RCTs and real-world settings, confirming the pivotal role of the IL-23/Th17 axis in the pathogenesis of IBD. From a mechanistic standpoint, selective inhibition of IL-23 offers a more refined approach than p40 blockade or broad immunosuppression. By preserving IL-12-mediated pathways essential for host defense, IL-23p19 inhibitors achieve high efficacy while maintaining an exceptional safety margin. This targeted mechanism explains their low rates of infection, malignancy, and vascular events compared with other advanced therapies, including JAK inhibitors. Clinically, IL-23p19 inhibitors now occupy an increasingly central role in the biologic treatment algorithm for moderate-to-severe IBD. For CD, risankizumab currently holds the most mature evidence base, supported by long-term extension and extensive real-world data. Guselkumab, with its dual IV and SC induction flexibility, provides an attractive alternative. Mirikizumab, initially approved for UC, shows similar efficacy and may become an option for CD pending broader regulatory alignment. In UC, all three agents deliver comparable induction and maintenance efficacy, exceeding that observed with ustekinumab. Mirikizumab was the first IL-23p19 inhibitor approved, paving the way for risankizumab and guselkumab [74]. While direct head-to-head trials are lacking, available meta-analyses consistently suggest similar rates of clinical and endoscopic remission across the class. The highest amount of data has been collected for UC, with a 2024 meta-analysis by Ananthakrishnan and colleagues suggesting a slight advantage of risankizumab over guselkumab and mirikizumab with regards to induction of clinical remission and independently from previous biologic exposure [75]. The optimal sequencing of biologic and small-molecule therapies remains an open question. Emerging RWE suggests that IL-23p19 inhibitors perform well both as first-line biologics and after failure of anti-TNFα, vedolizumab, or ustekinumab, with strong outcomes following ustekinumab exposure. Based on these data, the positioning and efficacy of these drugs in clinical practice is being gradually defined by guidelines. Whilst European Crohn’s and Colitis Organization guidelines (dating back to 2022) do not contemplate these drugs yet [76], American Gastroenterological Association [77] and British Society of Gastroenterology [78] guidelines (updated respectively in 2024 and 2025) advise IL-23 inhibitors both for bio-naïve and bio-experienced patients; moreover, both these guidelines prefer risankizumab and guselkumab over mirikizumab (especially for UC), although this preference is expressed in consideration of the amount and certainty of evidence collected so far more than the magnitude of efficacy.

The favorable safety profile and ease of use of this class of medications also make them an appealing option for pediatric as well as elderly or comorbid patients, for whom JAK inhibitors or corticosteroids may be contraindicated. Biomarker-guided therapy may further refine the positioning of IL-23 inhibitors. Elevated baseline IL-23 gene expression, mucosal Th17 signatures, or serum IL-22 levels have been proposed as predictors of response, although prospective validation is ongoing. Current research has the potential to provide new scenarios in the anti-IL-23 landscape, including oral IL-23 blockers and proposing such drugs in combination with other biologic agents. Finally, durability of remission and prevention of disease progression are becoming key therapeutic goals. Long-term extension data up to 3 years show sustained efficacy of IL-23p19 inhibitors with minimal attenuation over time. RWE continues to expand, confirming consistent outcomes across practice settings and patient subgroups. Overall, IL-23p19 inhibition has transitioned from an experimental approach to a core therapeutic strategy in IBD. Ongoing studies will clarify optimal sequencing, combination potential, and biomarker-driven selection, ultimately paving the way for a precision medicine approach that matches mechanism with patient phenotype [79].

Conclusions

Selective inhibition of IL-23 has emerged as a major therapeutic advance in the management of inflammatory bowel disease. Clinical trials and real-world studies consistently demonstrate that these agents are effective and safe in inducing and maintaining remission. Differences in molecular structure and pharmacologic characteristics may contribute to subtle biological and clinical distinctions among available therapies. At the same time, ongoing research is focusing on new molecules, alternative delivery strategies, and combination approaches. Over the next years, IL-23 inhibition is likely to play a central role in the treatment of IBD.

Funding

Open access funding provided by Università Cattolica del Sacro Cuore within the CRUI-CARE Agreement. No funds received for this article.

Declarations

Competing interests

No conflict of interests to declare from any of the authors.

Author contributions

All authors contributed to the study conception and design. Literature search and manuscript preparation were performed by PP, GC, and SP, and SC, LRL, and FS reviewed the manuscript. AP, AG, and AT supervised the entire work. All authors read and approved the final manuscript and provided their consent for publication.

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