The Evolving Landscape of Advanced Therapies in Inflammatory Bowel Disease: Current Evidence and Emerging Targets

Abstract

Background: Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic conditions that affect the gastrointestinal tract. Since the initial approval of infliximab (IFX), a monoclonal antibody targeting TNF-α, numerous novel therapeutic targets have been identified, and many new therapies have been approved for the treatment of IBD. Methods: We conducted a narrative review of the literature using major biomedical databases, including EMBASE, Scopus, PubMed, CENTRAL, and ClinicalTrials.gov (last search date: 10 December 2025). Results: This review summarizes the current evidence on therapies approved for IBD (both CD and UC) and provides an overview of investigational agents currently being evaluated in ongoing phase II and III clinical trials. Conclusions: Moderate optimism arises from the expanding array of therapeutic targets under investigation and from emerging treatment strategies. However, only through a deeper understanding of the pathophysiological mechanisms underlying IBD will substantial improvements in treatment outcomes be achieved for conditions that continue to impose a significant burden on patients’ quality of life.

1. Introduction

The history of advanced therapies in inflammatory bowel disease (IBD) dates back to the first small case series published in 1995, which reported the efficacy of infliximab (IFX) in patients with Crohn’s disease (CD) [1]. This case series reported that a single infusion of IFX produced remarkable clinical improvement in 8 of 10 consecutive patients with steroid-refractory CD. This landmark discovery initiated a paradigm shift in disease management, transitioning from non-specific immunosuppression to mechanism-based treatment strategies.

Since then, a plethora of novel biologic and advanced therapies has emerged, each offering incremental benefits. However, none of these treatments has achieved fully satisfactory results, either in clinical trials or in real-world practice.

In the following years, several therapies targeting distinct immune pathways—such as anti-integrins and anti-interleukins—expanded the therapeutic landscape. More recently, the introduction of oral small molecules, including Janus kinase inhibitors (JAKi) and sphingosine-1-phosphate (S1P) receptor modulators, has further diversified treatment options.

As oral therapies with favorable safety profiles, JAKi and S1P receptor modulators represent a promising addition to the therapeutic landscape of IBD.

Collectively, these advances have redefined therapeutic goals, emphasizing early intervention, mucosal healing, and long-term disease modification.

In this article, we provide a comprehensive review of advanced therapies currently approved for inflammatory bowel disease, as well as an overview of investigational agents in ongoing phase II and III clinical trials (Figure 1 and Figure 2). We conducted a narrative review of the literature using major biomedical databases, including EMBASE, Scopus, PubMed, CENTRAL, and ClinicalTrials.gov (last search date: 10 December 2025).

2. Anti-TNF-α

2.1. Infliximab

IFX is a chimeric monoclonal antibody targeting tumor necrosis factor-α (TNF-α) and was the first biologic approved for CD, with subsequent approval for UC. Following the initial 1995 case series, subsequent pivotal randomized controlled trials confirmed these findings, establishing anti-TNF therapy as the first targeted biologic approach for IBD.

2.1.1. Crohn’s Disease

The Phase III ACCENT I trial demonstrated that IFX is effective in maintaining clinical remission in patients with moderate-to-severe Crohn’s disease. Patients who achieved an initial response to a single infusion were randomized to receive either placebo (group I), IFX 5 mg/kg at weeks 2 and 6 followed by dosing every 8 weeks (group II), or IFX 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg every 8 weeks (group III) [2]. Moreover, the Phase III ACCENT II trial showed that IFX provides effective maintenance therapy for patients with fistulizing Crohn’s disease who achieved an initial response to induction therapy [3].

Crohn’s Disease: Real-World Evidence

Given its earlier approval and longer clinical use, IFX is supported by a more extensive and mature evidence base than newer advanced therapies.

One of the longest real-world observational studies available (a 13-year follow-up study) compared IFX therapy with non-biologic treatments in patients with Crohn’s disease. The analysis demonstrated that serious adverse events and serious infections (2.15 per 100 patient-years), particularly among patients older than 52 years, occurred more frequently in the infliximab-treated cohort. Non-serious cerebrovascular accidents (13 events, 0.06 per 100 patient-years vs. 5 events, 0.03 per 100 patient-years) and pulmonary embolisms (11 events, 0.05 per 100 patient-years vs. 4 events, 0.03 per 100 patient-years) were also reported at higher rates in the IFX group. In contrast, mortality (0.57 vs. 0.67 per 100 patient-years) and malignancy incidence (0.69 vs. 0.71 per 100 patient-years) were comparable between the two treatment groups [4].

A separate long-term, real-world study with a median follow-up of 60 months evaluated the efficacy and safety of IFX in patients with Crohn’s disease [5]. Among patients treated with IFX, clinical remission was maintained in 72.5%, while mucosal healing and steroid-free remission were achieved in 63.9%.

Another important indication for IFX is the prevention of postoperative recurrence (POR) in patients with CD who are at high risk of relapse following ileocolic resection, as highlighted in the ECCO Guidelines on Therapeutics in Crohn’s Disease: Surgical Treatment [6]. The PREVENT trial evaluated the efficacy of IFX in preventing POR of CD in 297 patients. Treatment with IFX (5 mg/kg) significantly reduced the rate of endoscopic recurrence at week 76 compared with placebo (30.6% vs. 60.0%; absolute risk reduction, 29.4%; p < 0.001), although no significant reduction in clinical recurrence was observed [7]. A network meta-analysis of randomized controlled trials comparing seven treatment strategies ranked anti-TNF monotherapy as the most effective approach for preventing postoperative recurrence, with relative risks of 0.01 for endoscopic recurrence and 0.04 for clinical recurrence [8].

2.1.2. Ulcerative Colitis

Concerning UC, the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2) demonstrated that IFX was effective for the induction and maintenance of clinical remission in adults with moderate-to-severe active UC. Patients received infusions of IFX at doses of 5 mg/kg or 10 mg/kg at weeks 0, 2, and 6 for the induction and then every 8 weeks for maintenance through week 46 (ACT 1) or week 22 (ACT 2). In the ACT 1 (54 weeks) and ACT 2 (30 weeks) trials, infliximab-treated patients were significantly more likely than those receiving placebo to achieve clinical response, remission, and mucosal healing at weeks 8 and 30, and at week 54 in ACT 1 [9]. Clinical response (≥3-point and ≥30% reduction in Mayo score with improvement in rectal bleeding), remission (Mayo ≤ 2, with no subscore >1), and mucosal healing (endoscopic subscore 0–1) all occurred at higher rates with IFX. Clinical improvement was evident by week 2, and sustained response and remission were more frequent with IFX throughout follow-up. Adverse event rates were comparable across treatment groups [9] (Table 1 and Table 2).

Ulcerative Colitis: Real-World Evidence

A long-term, real-world study with a median follow-up of 60 months evaluated the efficacy of IFX and adalimumab (ADA) in UC. Regarding IFX, 65.8% of patients maintained clinical remission, while 77.0% achieved mucosal healing [5]. A multicenter, observational, real-world cohort study conducted by Z. Huang et al. [10] compared the clinical and endoscopic effectiveness of IFX and vedolizumab (VDZ) in patients with UC who were biologic-naïve. The study showed no differences in efficacy between IFX and VDZ at week 14 with respect to steroid-free remission, clinical response, clinical remission, and mucosal healing, although VDZ appeared to be superior at week 52. No notable differences in safety outcomes were observed between the groups.

2.2. Adalimumab

Adalimumab (ADA), a fully human anti-TNF-α monoclonal antibody, was the second biologic approved for both CD and UC. It was designed to minimize immunogenicity and has proven effective for the induction and maintenance of remission in major clinical trials.

2.2.1. Crohn’s Disease

The CLASSIC I trial evaluated ADA for induction therapy in anti-TNF-naïve patients with moderate-to-severe Crohn’s disease, demonstrating a dose–response relationship, with 36% achieving remission at week 4 using the highest regimen (160 mg/80 mg) versus 12% with placebo [11]. In CLASSIC II, responders maintained remission in 79–83% of cases with ADA administered every other week or weekly through week 56, compared with 44% on placebo [12]. Of the 204 patients who entered the open-label arm, 93 (46%) were in clinical remission at week 56.

The GAIN study in IFX-failure or -intolerant patients showed superior remission (21% vs. 7%) and response rates (52% vs. 34%) with ADA versus placebo [13]. In the CHARM trial, remission at week 26 was achieved in 47% of patients receiving ADA versus 17% of those receiving placebo and was maintained through week 56 [14]. The ADHERE extension confirmed long-term benefit, with 30% of early responders in remission at 4 years, sustained corticosteroid-free remission in 16%, and fistula healing in 24% of cases [15].

Crohn’s Disease: Real-World Evidence

The PYRAMID registry is a large, real-world observational study that followed over 2000 adult patients with moderate-to-severe CD. After one year of ADA treatment, 68% achieved remission, and 75% maintained stable remission after six years. The study also showed consistent improvements in disease activity, quality of life, and work productivity. ADA was well tolerated, with 11% of patients experiencing serious infections, but no new safety signals were identified [16]. A Dutch study of 438 patients with Crohn’s disease treated with ADA also showed high induction response rates (92.5% in the first 3 months) and sustained clinical benefit: 83% remained on treatment after one year and 74% after two years. About one-third of patients achieved steroid-free remission. Factors like intestinal strictures or longer disease duration were associated with poorer responses [17]. A Japanese study involving 389 patients found clinical remission rates of 73.9% at week 4 with ADA, sustained above 70% over three years. Serious adverse events occurred in 11%, with a low rate of serious infections and no cases of tuberculosis or hepatitis B reactivation [18]. Finally, a long-term Italian study of 181 patients with IBD also demonstrated the effectiveness and long-term benefits of ADA in real-world settings for Crohn’s disease [19].

Regarding POR, the effectiveness of ADA was evaluated in the POCER trial, which demonstrated significantly lower rates of postsurgical endoscopic recurrence in patients treated with ADA compared with thiopurines (21% vs. 45%) [20]. Similarly, Savarino et al. reported a marked advantage for ADA, with recurrence rates of 6.3% compared with 64.7% for azathioprine and 83.3% for mesalamine [21]. In contrast, the randomized APPRECIA trial, which compared ADA with azathioprine in a risk-unselected population and combined both treatments with metronidazole, found no statistically significant difference in endoscopic recurrence at 1 year (29.7% vs. 33.3%). However, ADA demonstrated a significantly better safety profile, with fewer discontinuations due to adverse events compared with azathioprine (4.4% vs. 23.1%) [22].

Large real-world data from the Spanish ENEIDA registry, which included patients frequently exposed to previous biologic therapies (82%), suggest comparable effectiveness between ADA and IFX in clinical practice. At 18 months, endoscopic recurrence rates were 30% with ADA and 40% with IFX, with no statistically significant difference [23].

2.2.2. Ulcerative Colitis

In UC, ADA efficacy was established in ULTRA 1 and 2. ULTRA 1 (focused on induction and included 390 biologic-naïve patients) showed higher week-8 remission rates with ADA (18.5% vs. 9.2%, p = 0.031) [24], whereas ULTRA 2 confirmed both induction and maintenance benefits (week-52 remission 17.3% vs. 8.5%, p = 0.004), particularly in biologic-naïve patients [25].

Ulcerative Colitis: Real-World Evidence

A large post-marketing study in Japan involving over 1500 patients with UC assessed the long-term effectiveness and safety of ADA over 52 weeks. Clinical remission improved significantly, from 49.7% at week 4 to 74.4% at week 52, while steroid-free remission reached 50% by the end of the study. Mucosal healing was observed in more than 60% of patients at both 24 and 52 weeks [26].

A retrospective study conducted in Italy involving 381 patients with UC treated with ADA across 19 hospitals, with a 12-month follow-up, showed that, by week 8, 46% of patients had achieved a clinical response, and over 35% had achieved clinical remission. After 1 year, 33% remained in remission, and 45% continued ADA therapy. However, about 11% required a colectomy, indicating that some patients did not respond adequately [27].

The UC an ADA study in Canada was a 52-week prospective study that included 100 patients across 23 centers. The results showed that 65% of patients with UC treated with ADA achieved a clinical response, and nearly 48% achieved remission. The study also highlighted significant improvements in quality of life, work performance, and reduced fatigue, with no new safety concerns [28].

2.3. Golimumab

Golimumab (GOL) is a fully human monoclonal antibody targeting TNF-α, developed as a subcutaneous anti-TNF therapy. It is approved for the treatment of moderate-to-severe UC in patients who have had an inadequate response to conventional therapies.

2.3.1. Ulcerative Colitis

PURSUIT-SC (induction study) was a randomized, placebo-controlled trial that demonstrated that subcutaneous GOL (200 mg at week 0 and 100 mg at week 2) induced a clinical response in 51% of patients compared to 30% with placebo (p < 0.001), clinical remission in 17.8% vs. 6.4% (p < 0.001), and endoscopic improvement in 42% vs. 29% (p = 0.001) [29].

The PURSUIT-M trial was a phase III, multicenter, randomized, placebo-controlled study that assessed the efficacy and safety of GOL as maintenance therapy for moderate-to-severe ulcerative colitis. The results showed that GOL 100 mg every 4 weeks was significantly more effective than placebo in maintaining clinical remission through week 54. Steroid-free remission was also higher with GOL (23.2%) compared to placebo (12.2%), and endoscopic healing occurred in 42.4% of golimumab-treated patients, compared to 26.6% in the placebo group. GOL was well tolerated in terms of safety [30].

Ulcerative Colitis: Real-World Evidence

A retrospective study in Italy evaluated real-world use of GOL in 178 patients with ulcerative colitis over 33 months. About one-third achieved clinical remission, with a similar number showing symptom improvement. Only 13% reached steroid-free remission, and mucosal healing was observed in about one-third of patients. Despite initial positive results, long-term response rates declined, with few patients maintaining clinical remission at 42 months [31].

A real-world study on GOL in ulcerative colitis by Bressle et al. showed that about 40% of patients achieved a clinical response, and around 30% reached clinical remission regardless of prior anti-TNF exposure. Treatment persistence at one year was approximately 50%, indicating sustained effectiveness and good tolerability in a diverse patient population [32].

Similar findings were reported in another study that demonstrated the effectiveness of GOL in patients with ulcerative colitis over 12 months. Approximately 35% of patients achieved clinical remission by week 14, with steroid-free remission around 25%. Endoscopic healing was observed in 28% of patients. After one year, around 45% of patients continued GOL therapy, demonstrating its sustained benefit and tolerability in routine clinical use [33].

3. Anti-Integrin

3.1. Vedolizumab

Vedolizumab (VDZ) is a gut-selective, humanized monoclonal antibody that targets the α4β7 integrin, blocking its interaction with mucosal addressing cell adhesion molecule-1 (MAdCAM-1) and thereby inhibiting lymphocyte trafficking to the gastrointestinal tract. This mechanism confers localized immunosuppression with minimal systemic effects. VDZ is approved for the treatment of moderate-to-severe ulcerative colitis and Crohn’s disease [34].

Its safety profile is favorable, with low rates of systemic or opportunistic infections and no clear signal for malignancy or progressive multifocal leukoencephalopathy [35].

3.1.1. Crohn’s Disease

Phase III trials have demonstrated the efficacy and safety of intravenous and subcutaneous VDZ in both CD and UC. In CD, GEMINI II showed modest induction remission with VDZ-IV at week 6 (14.5% vs. 6.8% with placebo) but significantly higher maintenance remission at week 52 (39% vs. 21.6%, p = 0.004), while GEMINI III demonstrated delayed efficacy in anti-TNF-experienced patients (week 10 remission 26.6% vs. 12.1%, p = 0.001) [36,37]. VISIBLE 2 confirmed that VDZ-SC (108 mg every 2 weeks) maintained remission at week 52 in IV responders (48% vs. 34.3% with placebo), with consistent safety [38].

Crohn’s Disease: Real-World Evidence

The Victory Consortium, a large U.S.-based observational cohort, demonstrated favorable clinical remission and mucosal healing rates, particularly among anti-TNF-naïve patients [39]. In the VDZ-IBD study, VDZ achieved lower induction remission rates than anti-TNF agents but demonstrated superior long-term remission and treatment persistence over two years [40].

The large, prospective EVOLVE study, which included over 1000 biologic-naïve patients with UC or CD, further confirmed the effectiveness of VDZ. By 24 months, clinical outcomes were comparable to those observed with anti-TNF-α therapy, but the incidence of serious adverse events and infections was significantly lower in the VDZ group [41].

Long-term extension data from the GEMINI LTS program confirmed durable remission and a consistent safety profile with prolonged VDZ use in CD [35]. More recently, a real-world study demonstrated the feasibility of switching from intravenous to subcutaneous VDZ maintenance therapy in patients who achieved a response with IV induction, showing high treatment persistence and good safety outcomes [42].

Another relevant setting for VDZ use is the prevention of POR following bowel resection in CD. Real-world evidence from a small case series demonstrated the effectiveness of VDZ in maintaining remission among six postoperative patients with CD [43]. These findings were recently corroborated by a randomized controlled trial published in 2025 [44]. Among the 84 patients included, severe endoscopic recurrence occurred in 23.3% (10/43) of those treated with VDZ compared with 62.2% (23/37) of those receiving placebo (difference −38.9% [95% CI −56.0 to −17.3]; p = 0.0004), supporting VDZ as an effective strategy for POR prevention in CD.

3.1.2. Ulcerative Colitis

In UC, GEMINI 1 showed that VDZ-IV induced higher clinical response and remission rates than placebo (47% vs. 26% for induction; 41.8–44.8% vs. 15.9% for maintenance), and VISIBLE 1 confirmed that VDZ-SC maintained remission at week 52 (46.2% vs. 14.3% with placebo), with safety consistent with IV administration [45,46].

Ulcerative Colitis: Real-World Evidence

Several real-world studies have confirmed the effectiveness and safety of VDZ in UC. A systematic review of nine observational cohorts (n = 571) reported clinical response and remission rates of 43% and 32% at week 6, 51% and 30% at weeks 14–22, and 48% and 39% at week 52 [47]. In a UK–Australia cohort (n = 303), the clinical response rate at 3 months was 79%, with remission rates of 56%, 62%, and 60% at 3, 6, and 12 months; outcomes were significantly better in anti-TNF-naïve patients [48]. A Swedish nationwide study reported week-52 remission, response, and steroid-free remission rates of 59%, 64%, and 54%, respectively [49].

In biologic-naïve patients, VDZ induced a clinical response in 68% and steroid-free remission in 47% by week 14, with remission maintained in 60–61% at week 52 [50]. Long-term follow-up from the Dutch ICC registry (n = 119) showed corticosteroid-free remission in 27% at week 52 and 28% at week 104, with 59% maintaining remission between years 1 and 2 [51]. Additional multicenter cohorts confirmed high real-world effectiveness and safety in routine clinical practice [52,53]. Recent Italian data further support these findings: at 6 months, 62.9% achieved clinical remission, with mucosal healing and steroid discontinuation occurring more frequently in UC; safety remained favorable [54]. Long-term pooled data from GEMINI LTS (n = 2243; median follow-up, 42.4 months) confirmed a sustained safety profile, with low rates of serious infections, malignancies, and infusion reactions [55]. Finally, a recent Italian multicenter study demonstrated the feasibility and safety of subcutaneous VDZ in clinical practice, supporting its use as an effective maintenance option [56].

4. Anti-Interleukin

4.1. Ustekinumab

Ustekinumab (UST) is a fully human monoclonal antibody targeting the p40 subunit shared by interleukin-12 and interleukin-23, key cytokines in the Th1 and Th17 inflammatory pathways. It is approved for the treatment of moderate-to-severe Crohn’s disease and ulcerative colitis in adults who have had an inadequate response to or intolerance of conventional or biologic therapy. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to TNF antagonists or who had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy had failed or who had experienced unacceptable side effects. Approval was based on the pivotal UNITI and UNIFI trials, which demonstrated superior induction and maintenance of clinical remission versus placebo, with a favorable safety profile [57,58].

4.1.1. Crohn’s Disease

The UNITI-1 and UNITI-2 induction trials, followed by IM-UNITI maintenance, demonstrated the superior efficacy of intravenous UST (130 mg or ~6 mg/kg) over placebo in moderate-to-severe Crohn’s disease. Response rates at week 6 were significantly higher with UST (UNITI-1: 34.3% and 33.7% vs. 21.5%; UNITI-2: 51.7% and 55.5% vs. 28.7%; p ≤ 0.003 for all comparisons). During maintenance, remission at week 44 was achieved in 53.1% and 48.8% of patients receiving UST every 8 or 12 weeks, respectively, versus 35.9% with placebo (p = 0.005 and p = 0.04). Adverse event rates were comparable across groups [58].

Crohn’s Disease: Real-World Evidence

Italian and other national real-world cohorts have confirmed the effectiveness of UST in Crohn’s disease. In one study, clinical remission was achieved in 75% and mucosal healing in 53.2% at week 12, particularly when UST was used as second-line therapy [59]. A recent retrospective analysis confirmed long-term effectiveness, with clinical remission achieved in 80% over 12 months and a median follow-up of 24 months [60]. A prospective cohort study reported that over half of patients remained on UST at week 104, with one-third achieving corticosteroid-free remission [61]. A nationwide study with 104 weeks of follow-up confirmed sustained clinical effectiveness and improved quality of life [62].

4.1.2. Ulcerative Colitis

The UNIFI trial demonstrated that intravenous induction followed by subcutaneous UST maintenance (90 mg every 8 or 12 weeks) was significantly more effective than placebo in inducing and maintaining remission in moderate-to-severe ulcerative colitis. Clinical remission was achieved in 15% vs. 5% at week 8 and maintained in 38% and 44% at week 44 [57].

Ulcerative Colitis: Real-World Evidence

Multiple real-world studies have confirmed the effectiveness of UST in ulcerative colitis. In a U.S. cohort, clinical remission was achieved in 43% at 3 months and 45% at 12 months [63], whereas a Spanish study reported remission rates of 59%, 57%, and 69% at weeks 8, 24, and 52, respectively [64]. In a propensity –score-matched cohort of 476 patients (UST = 147, anti-TNF = 168, VDZ = 161), 12-month treatment persistence favored UST (93.9%) over VDZ (87.0%) and anti-TNF (75.0%; p < 0.001), although clinical remission rates at month 12 were not significantly different (UST 26.9%, anti-TNF 34.7%, VDZ 40.9%; p = 0.063) [63].

4.2. Risankizumab

Risankizumab (RISA) is a humanized IgG1 monoclonal antibody that selectively targets the p19 subunit of interleukin-23 (IL-23), thereby inhibiting IL-23 receptor signaling and subsequent activation of the Th17 pathway, with downstream suppression of pro-inflammatory cytokine production [65]. IL-23 is a central driver of chronic intestinal inflammation in UC and CD, making it an attractive therapeutic target. RISA has been approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of CD, UC, plaque psoriasis, and psoriatic arthritis.

4.2.1. Crohn’s Disease

The ADVANCE and MOTIVATE trials assessed RISA induction therapy (600 mg and 1200 mg IV) in adults with moderate-to-severe CD. In ADVANCE, clinical remission at week 12 was achieved in 45% (600 mg) and 42% (1200 mg) vs. 25% with placebo; corresponding endoscopic response rates were 40% and 32% vs. 12%, respectively. In MOTIVATE, remission rates were 42% and 40% vs. 20%, and endoscopic response rates were 29% and 34% vs. 11% [66].

In the Phase III FORTIFY maintenance trial (substudy 1), patients were re-randomized in a 1:1:1 ratio to subcutaneous RISA 180 mg, 360 mg, or withdrawal to placebo every 8 weeks. Among the 542 randomized patients, RISA 360 mg achieved significantly higher rates of clinical remission compared with placebo. CDAI remission occurred in 52% of patients receiving 360 mg versus 41% with placebo, and stool frequency/abdominal pain remission occurred in 52% versus 40%, respectively [67].

Crohn’s Disease: Real-World Evidence

The GETAID retrospective cohort (174 patients, all refractory, with ≥3 prior biologics) reported steroid-free clinical remission at week 26 in 47% and at week 52 in 46%; overall clinical remission rates were 52% at week 26 and 48% at week 52 [68]. Additionally, a multicenter real-world study including 309 patients (85.8% were advanced therapy-exposed, and 54.7% had prior UST exposure) reported effective 12-week clinical remission and 6-month endoscopic remission in both advanced therapy-exposed and naïve populations, including those with prior exposure to UST [69].

4.2.2. Ulcerative Colitis

In UC, RISA has been evaluated in two phase III RCTs (an induction trial and a maintenance trial). Among the 975 patients analyzed in the induction trial, the clinical remission rates at week 12 were 20.3% for 1200 mg of RISA and 6.2% for placebo. Among the 548 patients analyzed in the maintenance trial, the clinical remission rates at week 52 were 40.2% for 180 mg of RISA, 37.6% for 360 mg of RISA, and 25.1% for placebo [70].

Real-world and head-to-head data for RISA in UC remain unavailable given its recent approval and pending post-marketing cohort studies.

4.3. Mirikizumab

Mirikizumab (MIRI), a humanized IgG4 monoclonal antibody that selectively binds the p19 subunit of IL-23MIRI, was the first anti-IL-23p19 agent to receive regulatory approval for UC in the United States (October 2023) and was subsequently approved for CD in January 2025 [71].

4.3.1. Crohn’s Disease

In CD, the Phase III VIVID-1 trial compared MIRI with a placebo and included UST as an active comparator. Both co-primary composite endpoints (week-12 patient-reported clinical response plus week-52 endoscopic response, and week-12 clinical response plus week-52 CDAI remission) were met: the endoscopic response composite endpoint was reached in 220 (38%) of 579 patients receiving MIRI versus 18 (9%) of 199 receiving placebo (99.5% CI 20.6–36.8; p < 0·0001); the CDAI clinical remission composite endpoint was reached in 263 (45.4%) of 579 patients receiving MIRI versus 39 (19.6%) of 199 patients receiving placebo (99.5% CI 15.9–35.6; p < 0.0001) [72]. Although UST was included, the trial was not powered for formal superiority testing between active arms.

As MIRI has only recently been approved for the treatment of CD, no real-world data have yet been published.

4.3.2. Ulcerative Colitis

In UC, efficacy was established in the Phase III LUCENT program. In LUCENT-1, patients with moderate-to-severe disease receiving intravenous MIRI achieved significantly higher rates of clinical remission at week 12 compared with placebo (24.2% vs. 13.3%, p < 0.001), along with higher rates of endoscopic remission (36.3% vs. 21.1%), bowel urgency improvement, and improved patient-reported outcomes [71]. Responders in LUCENT-2 maintained clinical remission at week 40 in 49.9% versus 25.1% with placebo; corticosteroid-free clinical remission and histologic-endoscopic remission rates were also superior in the active arm (44.9% vs. 21.8% and 43.3% vs. 21.9%, respectively). Opportunistic infections (including herpes zoster) and malignancies were infrequent [71].

Long-term extension data from LUCENT-3 confirmed durability, with more than half of initial responders maintaining remission through 2 years, most of whom were steroid-free (52.7%) and with an endoscopic response (65.3%). Notably, 47.7% of responders at week 52 showed histological-endoscopic mucosal remission at week 104, suggesting strong long-term efficacy, including deep remission [73].

Ulcerative Colitis: Real-World Evidence

Emerging real-world cohorts report similar short-term effectiveness without unexpected safety issues [74]. In a Japanese retrospective cohort of 52 patients, the partial Mayo score decreased significantly from baseline to week 12 (median 5 [3–6] to 2 [0–3], p < 0.001). At week 12, clinical and CRP remission rates were 44.2% and 67.3%, respectively. No adverse events leading to permanent discontinuation of MIRI or death were reported [75].

4.4. Guselkumab

Guselkumab (GUSE) is a fully human IgG1λ monoclonal antibody that targets IL-23 p19, preventing receptor engagement, and binds to CD64 on myeloid cells, potentially reducing the production of IL-23. Initially approved for plaque psoriasis and psoriatic arthritis, it has an established long-term safety record in immune-mediated diseases [76,77,78].

4.4.1. Crohn’s Disease

In CD, GUSE demonstrated efficacy in the Phase II GALAXI-1 trial, showing significant clinical and endoscopic improvements at week 12 after intravenous induction [79]. The Phase III GALAXI-2 and GALAXI-3 trials, which included UST as an active comparator, met all co-primary endpoints—(1) clinical response at week 12 and clinical remission at week 48, and (2) clinical response at week 12 and endoscopic response at week 48—and reported the superiority of both GUSE 100 mg SC and 200 mg SC over UST in several secondary outcomes, including endoscopic response (48% and 53% vs. 37%), endoscopic remission (33% and 37% vs. 25%), and deep remission (30% and 34% vs. 22%) at week 48 [80]. These results supported FDA approval for CD in March 2025. Moreover, in the GRAVITI study, GUSE proved effective for the treatment of CD, including with a fully subcutaneous induction and maintenance regimen [81].

4.4.2. Ulcerative Colitis

In September 2024, the FDA approved GUSE for UC based on the Phase III QUASAR program [82]. During intravenous induction, week-12 clinical remission was achieved in 23% of guselkumab-treated patients versus 8% with placebo (p < 0.001). In the maintenance phase, week 44 clinical remission was maintained in 50% of patients receiving GUSE 200 mg subcutaneously every 4 weeks and 45% of those receiving GUSE 100 mg subcutaneously every 8 weeks, versus 19% with placebo; endoscopic and histologic outcomes were similarly superior [82]. Adverse event rates were comparable between groups, with no new safety signals. Long-term extension data through 92 weeks, recently presented at Digestive Disease Week, confirmed sustained benefit [83].

5. Janus Kinase Inhibitors

5.1. Tofacitinib

Tofacitinib (TOFA) is the first oral small-molecule, non-selective inhibitor of Janus kinases (JAK1 and JAK2) that modulates multiple cytokine signaling pathways involved in inflammation. It is approved for the treatment of moderate-to-severe UC.

5.1.1. Ulcerative Colitis

The Phase III OCTAVE program demonstrated that TOFA is more effective than placebo for both induction and maintenance therapy in patients with moderate-to-severe UC. In the OCTAVE Induction 1 trial, clinical remission was achieved in 18.5% of patients treated with TOFA compared to 8.2% in the placebo group (p = 0.007). Similar results were observed in OCTAVE Induction 2, with remission rates of 16.6% vs. 3.6%, respectively (p < 0.001). These findings were further supported by the OCTAVE Sustain trial: at 52 weeks, clinical remission was maintained in 34.3% of patients receiving TOFA 5 mg twice daily and in 40.6% of those receiving 10 mg, compared to 11.1% in the placebo group (p < 0.001). In terms of safety, overall infection rates, including herpes zoster, were higher in the TOFA groups than in the placebo group. In OCTAVE Sustain, infections occurred in 35.9% of patients in the 5 mg group, 39.8% in the 10 mg group, and 24.2% in the placebo group. Nevertheless, the majority of infections were mild or moderate in severity [84]. TOFA was also associated with increased lipid levels and creatine kinase compared to placebo; however, no cases of myopathy or rhabdomyolysis were reported. Finally, five patients receiving TOFA experienced cardiovascular events, whereas no such events were reported in the placebo group [84].

Ulcerative Colitis: Real-World Evidence

In real-world studies, short-term clinical remission with TOFA was achieved in 39% of patients (range, 31–44%) at week 8 and 43% (range, 37–49%) at weeks 12–16 [85]. Seven studies with ≥1-year follow-up reported mean remission rates of 35–53% [86,87,88,89,90,91,92]. Corticosteroid-free remission was achieved in 24–46.5% at week 8, 44–50% at weeks 12–16, and 31–50% at one year [85,88,90].

Endoscopic remission data were limited but ranged from 23–54% at week 8, 9–64% at weeks 12–16, and 31–50% after 48–52 weeks [86,90,93].

Adverse events were mostly mild (nasopharyngitis, non-serious infections, dyslipidemia). The incidence of serious events ranged from 5.9 to 11.8 per 100 patient-years, and herpes zoster occurred in <10% [85,88,93]. Discontinuation rates varied between 12 and 56% [85]. Malignancy incidence was low (0.47–0.8/100 patient-years), with two non-melanoma skin cancers [94].

Despite safety concerns commonly associated with JAKi, no major adverse cardiovascular events were reported. Thromboembolic complications were rare: one case of deep vein thrombosis (DVT) was observed in an Asian cohort, four cases of DVT or pulmonary embolism occurred in a Canadian study by Chaparro et al., and two additional cases of DVT were reported in a U.S. cohort. Notably, most affected patients had identifiable risk factors [92,95].

5.2. Filgotinib

Filgotinib (FIL) is an oral, selective Janus kinase 1 (JAK1) inhibitor that modulates the JAK–STAT signaling pathway, thereby reducing cytokine-driven inflammation implicated in ulcerative colitis pathogenesis [96]. By preferentially targeting JAK1 over JAK2 or JAK3, FIL is designed to achieve anti-inflammatory efficacy while potentially minimizing hematopoietic and immunological adverse effects associated with broader JAK inhibition [97].

5.2.1. Ulcerative Colitis

The Phase IIb/III SELECTION trial evaluated FIL for the induction and maintenance of remission in moderate-to-severe UC [96]. Two 10-week induction cohorts (biologic-naïve, n = 659; biologic-experienced, n = 689) were followed by a 58-week maintenance phase (n = 664). At week 10, FIL 200 mg achieved higher clinical remission rates than placebo in both biologic-naïve (26.1% vs. 15.3%; p = 0.0157) and biologic-experienced patients (11.5% vs. 4.2%; p = 0.0103). The 100 mg dose was not superior to placebo. Among biologic-naïve patients, FIL 200 mg also improved endoscopic (12.2% vs. 3.6%; p = 0.0047) and histologic remission rates (35.1% vs. 16.1%; p < 0.0001).

At week 58 in the maintenance phase, clinical remission rates were 37.2% with FIL 200 mg vs. 11.2% with placebo (p < 0.0001) and 23.8% with FIL 100 mg vs. 13.5% with placebo (p = 0.042). Endoscopic remission (15.6% vs. 6.1%) and corticosteroid-free remission ≥6 months (27.2% vs. 6.4%) were also higher with FIL 200 mg.

Serious adverse events (SAEs) were comparable across groups during both phases (≈4–5%), with no treatment-related deaths or thromboembolic events.

In the long-term extension safety, over >4 years (n = 873), exposure-adjusted incidence rates per 100 patient-years were low: serious infections (2.5), herpes zoster (1.5), malignancies (0.5), non-melanoma skin cancer (0.6), MACE (0.2), and VTE (≈ 0.0) [97].

Ulcerative Colitis: Real-World Evidence

Real-world evidence on FIL in UC is limited and heterogeneous. A Japanese retrospective cohort (n = 238; 54% biologic/JAK-exposed) reported steroid-free clinical remission in 36.5% of patients; herpes zoster occurred in 1.3%, and no thrombosis or deaths were observed [98]. A smaller cohort (n = 91) reported clinical remission rates of 71.9% at 12 weeks and 76.4% at 24 weeks [99]. Endoscopic remission at 24 weeks was observed in 47% of 25 patients treated with FIL 200 mg [100].

Comparative data show that upadacitinib (UPA) was superior to FIL at week 8 for clinical response (71.4% vs. 55.1%) and remission (65.7% vs. 46.9%) (RR for remission, 1.54; 95% CI, 1.16–2.05; RR for response, 1.40; 95% CI, 1.09–1.80), although differences were attenuated and nonsignificant in biologic-naïve patients [101]. In a three-arm real-world comparison (TOFA, FIL, UPA), week-8 steroid-free remission rates were 44.4%, 41.4%, and 55.3%, respectively, with no overall difference after propensity adjustment; however, among anti-TNF-exposed patients, UPA was significantly superior (aORs, 5.57–9.00) [102].

5.3. Upadacitinib

UPA is an oral, second-generation JAK inhibitor with preferential selectivity for JAK1. It has been approved for treating CD, UC, and other immune-mediated inflammatory diseases, including psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and atopic dermatitis.

5.3.1. Crohn’s Disease

The U-EXCEL and U-EXCEED 12-week induction trials and the 52-week U-ENDURE maintenance trial evaluated optimized UPA regimens in moderate-to-severe CD across 277 sites in 43 countries [103,104]. Induction with UPA 45 mg produced significantly higher clinical remission rates (U-EXCEL, 49.5% vs. 29.1%; U-EXCEED, 38.9% vs. 21.1%) and endoscopic response rates (U-EXCEL, 45.5% vs. 13.1%; U-EXCEED, 34.6% vs. 3.5%) versus placebo (p < 0.001). At week 52 in U-ENDURE, remission rates were 37.3% (15 mg) and 47.6% (30 mg) versus 15.1% with placebo; endoscopic response rates also favored active treatment (p < 0.001) [103,104]. Overall, AE rates were similar across arms; common AEs included acne, nasopharyngitis, headache, anemia, and creatine kinase elevations, with herpes zoster and hepatic disorders more frequent at higher doses. Serious infections were uncommon. The ongoing 240-week LTE showed sustained clinical and endoscopic benefits through two years, with a consistent safety profile.

A post hoc analysis in patients with baseline perianal fistulae found greater drainage resolution with 45 mg at induction (44.7% vs. 5.6%; p = 0.003). During maintenance, higher closure and drainage resolution rates were observed with UPA 15 mg and 30 mg vs. placebo, although statistical significance was not always reached [105].

Crohn’s Disease: Real-World Evidence

Given the efficacy of UPA in pivotal trials, several real-world studies have evaluated its performance in routine practice. In a U.S. multicenter retrospective cohort (n = 334), induction with UPA 45 mg achieved clinical remission in 52.1% at week 12 and 55.9% at 6 months, with endoscopic remission in 42.7%. Remission rates were highest in treatment-naïve patients (12 weeks, 58.6%; 6 months, 97.7%). AEs occurred in 13.5%, mainly acne (3.3%), herpes zoster (2.4%), and VTE (0.6%) [106]. In the GETAID cohort (n = 223, all bio-exposed), week-12 clinical, biomarker, and endoscopic/radiologic remission rates were 56%, 52%, and 47%, respectively; AEs occurred in 26% (17 serious, including one EBV-related lymphoproliferative disorder) [107]. Another multicenter study (n = 246; 115 CD, 131 UC) reported, in CD, clinical remission in 76.2% at week 12, corticosteroid-free remission in 76.9% at week 24 and 66.7% at week 52, and endoscopic remission in 50.0% and 54.5%, respectively; stricturing or penetrating phenotypes predicted a lower response (p = 0.04) [108].

A large international analysis (n = 2183) found acne in 12.5% of JAKi-treated patients with IBD, most frequently with UPA (15.9%) versus TOFA (4.3%) or FIL (1.9%). Acne was generally mild to moderate, dose-dependent, and associated with a prior history of acne (OR 4.88); 18% required JAKi dose reduction or discontinuation [109].

5.3.2. Ulcerative Colitis

UPA was evaluated in the Phase III U-ACHIEVE and U-ACCOMPLISH programs, comprising two 8-week induction studies (UC1 and UC2) and a 52-week maintenance trial (U-ACHIEVE UC3). In the induction trials, patients with moderate-to-severe ulcerative colitis received UPA 45 mg once daily or placebo. Clinical remission rates were significantly higher with UPA (26.1% vs. 4.8% in UC1; 33.5% vs. 4.1% in UC2; both p < 0.001), with an early response observed as soon as week 2 (60% vs. 27% in UC1; 63% vs. 26% in UC2; p < 0.0001) [110,111]. In the maintenance trial, responders to induction were re-randomized to UPA 15 mg, 30 mg, or placebo once daily. Clinical remission was maintained in 42% (15 mg) and 52% (30 mg) versus 12% with placebo (p < 0.001). Efficacy was consistent across prior biologic exposure: remission occurred in 43.9% and 54% of biologic-naïve patients and in 40.5% and 49.1% of biologic-experienced patients (vs 17.6% and 7.5% with placebo; all p < 0.001).

Adverse event rates were comparable among treatment groups. No venous thromboembolic events (VTEs) occurred during UC induction; in rheumatology trials, six VTEs were reported over 461 patient-years versus one over 366 placebo patient-years.

In the long-term extension of the Phase III U-ACHIEVE maintenance study (n = 369), clinical remission was sustained through week 96 with UPA 15 mg and 30 mg in 76% and 74% of patients, respectively. Among those in remission at study entry, ≥78% maintained remission. Endoscopic remission was observed in ~46–49% at week 48 and ~45–47% at week 96, persisting in ~65–76% of initial responders. In the safety cohort (n = 467; 1028 patient-years), overall adverse event rates were comparable between doses (~233–238 events per 100 patient-years), with serious adverse events at ~12 events per 100 patient-years. The most common events were hepatic disorders, lymphopenia, creatine kinase elevation, infections, neutropenia, and herpes zoster [112].

Ulcerative Colitis: Real-World Evidence

Real-world data are essential to confirm clinical trial outcomes; however, current evidence on JAK inhibitors in UC remains limited and based on small cohorts. In a multicenter retrospective study including 236 patients with IBD (80 UC), Wu et al. reported week-8 steroid-free remission in 64.0%, clinical remission in 57.6%, and a clinical response in 81.8% of patients with UC; endoscopic and histologic remission were achieved in 35.8% and 29.2%, respectively [113]. Another multicenter study (n = 246; 131 UC, 115 CD; median follow-up, 7.5 months) found corticosteroid-free clinical remission at week 24 in 80.6% (UC) and 76.9% (CD), with endoscopic remission rates of 36.1% and 50.0%, respectively. At week 52, remission persisted in 86.2% (UC) and 66.7% (CD). UPA remained effective in UC despite prior TOFA failure, although patients with stricturing or penetrating CD responded less frequently (p = 0.04). Hyperlipidemia (9.7–9.8%) was the most frequent adverse event [108]. In the Spanish UREAL study (n = 100; 68 CD, 32 UC), remission rates were 59%, 64%, and 42% at weeks 8, 12, and 52, respectively; discontinuation was more frequent in CD and in patients < 40 years. Among patients with UC previously treated with TOFA, remission rates were 78% (week 12) and 50% (week 52) [114].

Current evidence on UPA in acute severe ulcerative colitis (ASUC) remains limited, and its use is off-label. A multicenter retrospective study including 111 hospitalized patients treated with TOFA (n = 60) or UPA (n = 51) reported a JAK inhibitor-induced response in 77% and maintenance of response in 23% at a median follow-up of 31 weeks. Early response (days 3–7) was higher with UPA (84% vs. 54%; p = 0.02), whereas remission and colectomy-free survival at days 98 and 182 were similar between agents. Adverse events and treatment failure rates were comparable, highlighting the need for larger prospective trials to validate these findings [115].

Regarding safety, in FIL vs. UPA comparisons, overall AEs were more frequent with UPA (45.7% vs. 24.5%; p = 0.0049), whereas no significant differences emerged in serious AEs in the short term [101]. In the three-arm comparison (TOFA vs. FIL vs. UPA), overall AE rates at 8 weeks were 16% for TOFA, 14% for FIL, and 36% for UPA, with treatment discontinuation due to AEs in 5%, 5%, and 11%, respectively [102]. UPA was associated with a higher incidence of acne and a lower risk of treatment discontinuation compared with FIL and TFB, whereas no oncologic or thrombotic signals emerged [116]. Overall AEs were more frequent with TOFA (53.8% vs. 33.3%), with an estimated incidence of herpes zoster of 3.1 per 100 patient-years for TOFA, along with higher rates of upper respiratory infections and anemia, but no deaths [117].

6. Sphingosine-1-Phosphate Receptor Modulators

6.1. Ozanimod

Ozanimod (OZA) is a selective, once-daily oral sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of UC. It exerts its therapeutic effects by reducing lymphocyte egress from lymphoid tissues, thereby limiting intestinal inflammation. Clinical studies have demonstrated its efficacy in inducing and maintaining clinical remission in patients with moderate-to-severe UC. Its oral administration and targeted mechanism of action offer an effective alternative to traditional systemic therapies.

6.1.1. Ulcerative Colitis

OZA is a selective S1P receptor modulator. It was investigated in UC at a dose of 1 mg once daily by the True North Study Group in a phase III, multicenter, randomized, double-blind, placebo-controlled study. This trial included a 10-week induction period (645 patients in cohort 1 were randomized to receive OZA (429) or placebo (216); 367 patients in cohort 2 received open-label OZA). At week 10, patients (457) with a clinical response to OZA (233 in cohort 1 and 224 in cohort 2) were randomized to receive OZA (230) or placebo (227) for the 52-week maintenance period. OZA showed efficacy during both the induction and maintenance periods. The most frequent AEs were infections (although the percentage of serious infections was very low) and reductions in absolute lymphocyte count [118].

Ulcerative Colitis: Real-World Evidence

The effectiveness of OZA was confirmed in a real-world prospective study including 45 patients with ulcerative colitis, of whom 76% were biologic-experienced. At the end of the study period, 25% of patients achieved clinical remission. Among the 12 patients (39%) who experienced a >75% reduction in absolute lymphocyte count, numerically higher induction clinical response and remission rates were observed compared with those without such a reduction (80% vs. 54%, p = 0.4; and 75% vs. 53%, p = 0.4, respectively). Finally, only one patient required treatment discontinuation due to a treatment-related adverse event [119].

6.2. Etrasimod

Etrasimod (ETM) is a selective, once-daily S1P receptor modulator developed for the treatment of UC. By reducing lymphocyte trafficking to the intestinal mucosa, it modulates immune-mediated inflammation.

6.2.1. Ulcerative Colitis

ETM safety and efficacy were demonstrated in the ELEVATE UC 12 and ELEVATE UC 52 trials, two independent, randomized, multicenter, double-blind, placebo-controlled studies. These trials enrolled adults with moderately to severely active UC who had an inadequate response to, loss of response to, or intolerance of at least one prior UC therapy. Participants were randomized in a 2:1 ratio to receive once-daily oral ETM 2 mg or placebo.

ELEVATE UC 12 evaluated induction therapy over 12 weeks in 354 patients (238 ETM, 116 placebo). ELEVATE UC 52 included 433 patients (289 ETM, 144 placebo) and assessed a 12-week induction period followed by a 40-week maintenance phase using a treat-through design. ELEVATE UC 12 demonstrated the efficacy of ETM in inducing clinical remission at the end of the 12-week induction period. Furthermore, at week 52, 88 of 274 patients (32%) treated with ETM achieved clinical remission compared with 9 of 135 patients (7%) receiving placebo (p < 0.0001).

Regarding safety, the incidence of serious adverse events was low and comparable between the ETM and placebo groups in both trials (7% vs. 6% in ELEVATE UC 52, and 3% vs. 2% in ELEVATE UC 12) [120].

As ETM has only recently been approved for the treatment of UC, no real-world data have yet been published.

Table 1. Efficacy and safety outcomes from randomized placebo-controlled clinical trials of approved advanced therapies for Crohn’s disease.

Drug	Trial Publication	Trial Name	Randomization Type	Outcome
				Steroid-Free Clinical Remission (Week)		Clinical Remission (Week)		Endoscopic Remission (Week)		Severe Adverse Events
				Intervention	Placebo	Intervention	Placebo	Intervention	Placebo	Intervention	Placebo
Infliximab	May 2002	ACCENT-1 [2]	Treat-through	n.a.	n.a.	39% (5 mg) 45% (10 mg) (30)	21%	n.a.	n.a.	8% 6%	7%
Adalimumab	February 2007	CLASSIC-1 [11]	Induction biologic-naïve	n.a.	n.a.	36% (6)	12% (6)	n.a.	n.a.	1%	5%
	September 2007	CLASSIC-2 [12]	Re-randomized maintenance 56 weeks	88%	57%	79%	44%	n.a.	n.a.	2%	1%
Vedolizumab	August 2013	GEMINI-2 [36]	Induction biologic-naïve	n.a.	n.a.	14.5% (6)	6.8% (6)	n.a.	n.a.	n.a.	n.a.
		GEMINI-2 [37]	Re-randomized maintenance 52 weeks	31.7% q8w 28.8% qw4	15.9%	39% q8w 36.4% q4w	21.6%	n.a.	n.a.	24.4%	15.3%
Ustekinumab	November 2016	UNITI-2 [58]	Induction biologic-naïve	n.a.	n.a.	55.5 (6)	28.7%(6)	n.a.	n.a.	2.9%	5.8%
		IM-UNITI [58]	Re-randomized maintenance 44 weeks	46.9 q8w 42.6 q12w	29.8	53.1% q8w 48% q12w	35.9	n.a.	n.a.	9.9% 12.1%	15%
Risankizumab	May 2022	ADVANCE [66]	Induction biologic/conventional-experienced 12 weeks	n.a.	n.a.	600 mg: 45% 1200 mg: 42%	25%	600 mg: 24% 1200 mg: 24%	9%	600 mg: 6% 1200 mg: 5%	10%
		MOTIVATE [66]	Induction biologic-experienced 12 weeks	n.a.	n.a.	600 mg: 42% 1200 mg: 40%	20% (12)	600 mg: 19% 1200 mg: 20%	4%	600 mg: 3% 1200 mg: 6%	12%
	May 2022	FORTIFY [67]	Re-randomized maintenance 52 weeks	n.a.	n.a.	180 mg:62% 360 mg: 59%	49%	180 mg: 47% 360 mg: 55%	21%	180 mg: 7% 360 mg: 12%	13%
Mirikizumab	January 2025	VIVID-1 [72]	Treat-through 52 weeks	43.7%	18.6%	37.7% (12) 54.1%	25.1% (12) 19.6%	10.9% (12) 15.9% (composite)	4% (12) 2% (composite)	9.2%	15.2%
Guselkumab	March 2025	GALAXI-2 [80]	Treat-through 48 weeks	100 mg: 47% 200 mg: 51%	9%	47% (12)	22% (12)	100 mg: 27% 200 mg: 33% (48)	3%	200 mg: 7% 100 mg: 11%	15%
		GALAXI-3 [80]	Treat-through 48 weeks	100 mg: 46% 200 mg: 45%	13%	47% (12)	15% (12)	100 mg: 24% 200 mg: 23%	6%
Upadacitinib	May 2023	U-EXCEL [103]	Induction 12 weeks	45 mg: 42.9%	15.7%	45 mg: 49.5	29.1%	45 mg: 28.9%	7.4%	45 mg: 8.9%	8.5%
		U-EXCEED [103]		45 mg: 34.3%	11.7%	45 mg: 38.9	21.1%	45 mg: 19.1%	2.3%	45 mg:11.7%	8.6%
		U-ENDURE [104]	Re-randomized maintenance 52 weeks	15 mg: 36.7% 30 mg: 46.4%	14.5%	15 mg: 37.3% 30 mg: 47.6%	15.1%	15 mg: 19.1% 30 mg: 28.6%	5.5%	15 mg: 25% 30 mg: 18.6%	35.5%

n.a: not available.

Table 1. Efficacy and safety outcomes from randomized placebo-controlled clinical trials of approved advanced therapies for Crohn’s disease.

Drug	Trial Publication	Trial Name	Randomization Type	Outcome
				Steroid-Free Clinical Remission (Week)		Clinical Remission (Week)		Endoscopic Remission (Week)		Severe Adverse Events
				Intervention	Placebo	Intervention	Placebo	Intervention	Placebo	Intervention	Placebo
Infliximab	May 2002	ACCENT-1 [2]	Treat-through	n.a.	n.a.	39% (5 mg) 45% (10 mg) (30)	21%	n.a.	n.a.	8% 6%	7%
Adalimumab	February 2007	CLASSIC-1 [11]	Induction biologic-naïve	n.a.	n.a.	36% (6)	12% (6)	n.a.	n.a.	1%	5%
	September 2007	CLASSIC-2 [12]	Re-randomized maintenance 56 weeks	88%	57%	79%	44%	n.a.	n.a.	2%	1%
Vedolizumab	August 2013	GEMINI-2 [36]	Induction biologic-naïve	n.a.	n.a.	14.5% (6)	6.8% (6)	n.a.	n.a.	n.a.	n.a.
		GEMINI-2 [37]	Re-randomized maintenance 52 weeks	31.7% q8w 28.8% qw4	15.9%	39% q8w 36.4% q4w	21.6%	n.a.	n.a.	24.4%	15.3%
Ustekinumab	November 2016	UNITI-2 [58]	Induction biologic-naïve	n.a.	n.a.	55.5 (6)	28.7%(6)	n.a.	n.a.	2.9%	5.8%
		IM-UNITI [58]	Re-randomized maintenance 44 weeks	46.9 q8w 42.6 q12w	29.8	53.1% q8w 48% q12w	35.9	n.a.	n.a.	9.9% 12.1%	15%
Risankizumab	May 2022	ADVANCE [66]	Induction biologic/conventional-experienced 12 weeks	n.a.	n.a.	600 mg: 45% 1200 mg: 42%	25%	600 mg: 24% 1200 mg: 24%	9%	600 mg: 6% 1200 mg: 5%	10%
		MOTIVATE [66]	Induction biologic-experienced 12 weeks	n.a.	n.a.	600 mg: 42% 1200 mg: 40%	20% (12)	600 mg: 19% 1200 mg: 20%	4%	600 mg: 3% 1200 mg: 6%	12%
	May 2022	FORTIFY [67]	Re-randomized maintenance 52 weeks	n.a.	n.a.	180 mg:62% 360 mg: 59%	49%	180 mg: 47% 360 mg: 55%	21%	180 mg: 7% 360 mg: 12%	13%
Mirikizumab	January 2025	VIVID-1 [72]	Treat-through 52 weeks	43.7%	18.6%	37.7% (12) 54.1%	25.1% (12) 19.6%	10.9% (12) 15.9% (composite)	4% (12) 2% (composite)	9.2%	15.2%
Guselkumab	March 2025	GALAXI-2 [80]	Treat-through 48 weeks	100 mg: 47% 200 mg: 51%	9%	47% (12)	22% (12)	100 mg: 27% 200 mg: 33% (48)	3%	200 mg: 7% 100 mg: 11%	15%
		GALAXI-3 [80]	Treat-through 48 weeks	100 mg: 46% 200 mg: 45%	13%	47% (12)	15% (12)	100 mg: 24% 200 mg: 23%	6%
Upadacitinib	May 2023	U-EXCEL [103]	Induction 12 weeks	45 mg: 42.9%	15.7%	45 mg: 49.5	29.1%	45 mg: 28.9%	7.4%	45 mg: 8.9%	8.5%
		U-EXCEED [103]		45 mg: 34.3%	11.7%	45 mg: 38.9	21.1%	45 mg: 19.1%	2.3%	45 mg:11.7%	8.6%
		U-ENDURE [104]	Re-randomized maintenance 52 weeks	15 mg: 36.7% 30 mg: 46.4%	14.5%	15 mg: 37.3% 30 mg: 47.6%	15.1%	15 mg: 19.1% 30 mg: 28.6%	5.5%	15 mg: 25% 30 mg: 18.6%	35.5%

n.a: not available.

Table 2. Efficacy and safety outcomes from randomized, placebo-controlled clinical trials of approved advanced therapies for ulcerative colitis.

Drug	Trial Publication	Trial Name	Randomization Type	Outcome
				Steroid-Free Clinical Remission (Week)		Clinical Remission (Week)		Endoscopic Remission (Week)		Severe Adverse Events
				Intervention	Placebo	Intervention	Placebo	Intervention	Placebo	Intervention	Placebo
Infliximab	December 2005	ACT 1 [9]	Induction 8 weeks	n.a	n.a	38.8% (5 mg) 32.0% (10 mg)	14.9%	62.0% (5 mg) 59.0% (10 mg)	30.9%	n.a	n.a
			Treat-through 54 weeks	n.a	n.a	34.7% (5 mg) 34.4%(10 mg)	16.5%	45.5% (5 mg) 46.7%(10 mg)	18.2%	21.5% (5 mg) 23.8%(10 mg)	25.6%
Adalimumab	February 2012	ULTRA-1 [24]	Induction 8 weeks	n.a	n.a	18,5% (160/80 mg) 10% (80/40 mg) (8)	9.2% (8)	n.a	n.a	7,6%	4%
		ULTRA-2 [25]	Treat-through 52 weeks	13.6%	6.2%	17.3% (54)	8.5% (54)	25% (54)	15.4% (54)	4%	5%
Golimumab	January 2014	PURSUIT SC [29]	Induction 6 weeks	n.a	n.a	17.9%	6.4%	45.1%	28.7%	6.1%	3%
		PURSUIT-M [30]	Re-randomized maintenance 52 weeks	23.2%	12.2%	49.7%	31.2%	42.4%	26.6%	14.3%	7.7%
Vedolizumab	August 2013	GEMINI-1 [45]	Induction 6 weeks	n.a	n.a	16.9%	5.4%	40.9%	24.8%	n.a	n.a
			Re-randomized maintenance 52 weeks	31.4% q8w 45.2% q4w	13.9%	41.8% q8w 44.8% q4w	15.9%	51.6% q8w 56% q4w	19.8%	12.4%	13.5%
Ustekinumab	September 2019	UNIFI [57]	Induction 8 weeks		n.a	15.6% (130 mg) 15.5%(~6 mg/kg) 15%	5.3%	20.3%/130 mg) 18.4%(~6 mg/kg	8.9%	n.a	n.a
			Re-randomized maintenance 44 weeks	37.8% q12w 42% q8w	23.4%	38.4% q12w 43.8%q8w	24.0%	n.a	n.a	12% q12w 11% q8w	22%
Risankizumab	July 2024	INSPIRE [70]	Induction	n.a	n.a	20.3% (12)	6.2%(12)	10.6% (12)	3.4%	2.5%	10.2%
		COMMAND [70]	Re-randomized maintenance 52 weeks	39.6% (180 mg) 37.1% (360 mg)	25.1%	40.2% (180 mg) 37.6% (360 mg)	25.1%	23.2% (180 mg) 24.3% (360 mg)	14.8%	1.6% 3.1%	5.1%
Mirikizumab	October 2023	LUCENT-1 [71]	Induction 12 weeks		n.a	24.2%	13.2%	36.3%	21.1%	2.1%	2.2%
	October 2023	LUCENT-2 [71]	Re-randomized 40 weeks	44.9%	21.8%	63.6%	36.9%	58.6%	29.1%	3.3%	5.2%
Guselkumab	September 2024	QUASAR [82]	Induction 12 weeks	n.a	n.a	23%	8%	15%	5%	2%	7%
			Re-randomized maintenance 52 weeks	45% 100 mg 49% 200 mg	18%	61% 100 mg 72% 200 mg	34%	35% 100 mg 34% 200 mg	15%	3% 100 mg 6% 200 mg	1%
Tofacitinib	May 2017	OCTAVE induction 1 and 2 [84]	Induction 8 weeks	n.a	n.a	18.5%	8.2%	31.3%	15.6%	3.4%	4.1%
			Induction 8 weeks	n.a	n.a	16.6%	3.6%	28.4%	11.6%	4.2%	8%
		OCTAVE sustain [84]	Re-randomized maintenance 52 weeks	n.a	n.a	5 mg: 34.3% 10 mg: 40.6%	11.1%	5 mg: 37.4% 10 mg: 45.7%	13.1%	5 mg: 5.1% 10 mg: 5.6%	6.6%
Filgotinib	June 2021	SELECTION Bio-naïve [97]	Induction 10 weeks	n.a	n.a	100 mg: 19.1% 200 mg: 26.1%	15.3%	100 mg: 5.8% 200 mg: 12.2%	3.6%	100 mg: 5% 200 mg: 4%	4.7%
		SELECTION Bio-experienced [97]	Induction 10 weeks	n.a	n.a	100 mg: 9.5% 200 mg: 11.5%	4.2%	100 mg: 2.1% 200 mg: 3.4%	2.1%
		SELECTION maintenance [97]	Re-randomized maintenance 58 weeks	100 mg: 13.6% 200 mg: 27.2%	5.4% 6.4%	100 mg: 23.8% 200 mg: 37.2%	13.5% 11.2%	100 mg: 13.4% 200 mg: 15.6%	7.9% 6.1%	100 mg: 4.5% 200 mg: 4.5%	7.7% 0%
Upadacitinib	June 2022	U-ACHIEVE Induction [110]	Induction 8 weeks	n.a	n.a	26%	5%	14%	1%	6%	3%
		U-ACCOMPLISH Induction [111]	Induction 8 weeks	n.a	n.a	33%	4%	18%	2%	5%	3%
		U-ACHIEVE maintenance [110]	Re-randomized maintenance 52 weeks	15 mg: 57% 30 mg: 68%	22%	15 mg: 42% 30 mg: 52%	12%	15 mg: 24% 30 mg: 26%	6%	15 mg: 7% 30 mg: 6%	13%
Ozanimod	October 2021	TRUE NORTH [118]	Induction 10 weeks	n.a	n.a	18.4%	6%	27.3%	11.6%	4%(chort1) 6.3%(chort2)	3.2%(chort1)
			Re-randomized maintenance 52 weeks	31.7%	16.7%	37%	18.5%	45.7%	26.4%	5.2%	7.9%
Etrasimod	March 2023	ELEVATE UC [120]	Induction 12 weeks	n.a	n.a	25% (12)	15%(12)	33 (12)	19 (12)	3%	2%
		ELEVATE UC [120]	Treat-through 52 weeks	33%	7%	27% (12) 32% (52)	7%(12) 7%(52)	37%(12) 39%(52)	17%(12) 13%(52)	7%	6%

n.a: not available.

Table 2. Efficacy and safety outcomes from randomized, placebo-controlled clinical trials of approved advanced therapies for ulcerative colitis.

Drug	Trial Publication	Trial Name	Randomization Type	Outcome
				Steroid-Free Clinical Remission (Week)		Clinical Remission (Week)		Endoscopic Remission (Week)		Severe Adverse Events
				Intervention	Placebo	Intervention	Placebo	Intervention	Placebo	Intervention	Placebo
Infliximab	December 2005	ACT 1 [9]	Induction 8 weeks	n.a	n.a	38.8% (5 mg) 32.0% (10 mg)	14.9%	62.0% (5 mg) 59.0% (10 mg)	30.9%	n.a	n.a
			Treat-through 54 weeks	n.a	n.a	34.7% (5 mg) 34.4%(10 mg)	16.5%	45.5% (5 mg) 46.7%(10 mg)	18.2%	21.5% (5 mg) 23.8%(10 mg)	25.6%
Adalimumab	February 2012	ULTRA-1 [24]	Induction 8 weeks	n.a	n.a	18,5% (160/80 mg) 10% (80/40 mg) (8)	9.2% (8)	n.a	n.a	7,6%	4%
		ULTRA-2 [25]	Treat-through 52 weeks	13.6%	6.2%	17.3% (54)	8.5% (54)	25% (54)	15.4% (54)	4%	5%
Golimumab	January 2014	PURSUIT SC [29]	Induction 6 weeks	n.a	n.a	17.9%	6.4%	45.1%	28.7%	6.1%	3%
		PURSUIT-M [30]	Re-randomized maintenance 52 weeks	23.2%	12.2%	49.7%	31.2%	42.4%	26.6%	14.3%	7.7%
Vedolizumab	August 2013	GEMINI-1 [45]	Induction 6 weeks	n.a	n.a	16.9%	5.4%	40.9%	24.8%	n.a	n.a
			Re-randomized maintenance 52 weeks	31.4% q8w 45.2% q4w	13.9%	41.8% q8w 44.8% q4w	15.9%	51.6% q8w 56% q4w	19.8%	12.4%	13.5%
Ustekinumab	September 2019	UNIFI [57]	Induction 8 weeks		n.a	15.6% (130 mg) 15.5%(~6 mg/kg) 15%	5.3%	20.3%/130 mg) 18.4%(~6 mg/kg	8.9%	n.a	n.a
			Re-randomized maintenance 44 weeks	37.8% q12w 42% q8w	23.4%	38.4% q12w 43.8%q8w	24.0%	n.a	n.a	12% q12w 11% q8w	22%
Risankizumab	July 2024	INSPIRE [70]	Induction	n.a	n.a	20.3% (12)	6.2%(12)	10.6% (12)	3.4%	2.5%	10.2%
		COMMAND [70]	Re-randomized maintenance 52 weeks	39.6% (180 mg) 37.1% (360 mg)	25.1%	40.2% (180 mg) 37.6% (360 mg)	25.1%	23.2% (180 mg) 24.3% (360 mg)	14.8%	1.6% 3.1%	5.1%
Mirikizumab	October 2023	LUCENT-1 [71]	Induction 12 weeks		n.a	24.2%	13.2%	36.3%	21.1%	2.1%	2.2%
	October 2023	LUCENT-2 [71]	Re-randomized 40 weeks	44.9%	21.8%	63.6%	36.9%	58.6%	29.1%	3.3%	5.2%
Guselkumab	September 2024	QUASAR [82]	Induction 12 weeks	n.a	n.a	23%	8%	15%	5%	2%	7%
			Re-randomized maintenance 52 weeks	45% 100 mg 49% 200 mg	18%	61% 100 mg 72% 200 mg	34%	35% 100 mg 34% 200 mg	15%	3% 100 mg 6% 200 mg	1%
Tofacitinib	May 2017	OCTAVE induction 1 and 2 [84]	Induction 8 weeks	n.a	n.a	18.5%	8.2%	31.3%	15.6%	3.4%	4.1%
			Induction 8 weeks	n.a	n.a	16.6%	3.6%	28.4%	11.6%	4.2%	8%
		OCTAVE sustain [84]	Re-randomized maintenance 52 weeks	n.a	n.a	5 mg: 34.3% 10 mg: 40.6%	11.1%	5 mg: 37.4% 10 mg: 45.7%	13.1%	5 mg: 5.1% 10 mg: 5.6%	6.6%
Filgotinib	June 2021	SELECTION Bio-naïve [97]	Induction 10 weeks	n.a	n.a	100 mg: 19.1% 200 mg: 26.1%	15.3%	100 mg: 5.8% 200 mg: 12.2%	3.6%	100 mg: 5% 200 mg: 4%	4.7%
		SELECTION Bio-experienced [97]	Induction 10 weeks	n.a	n.a	100 mg: 9.5% 200 mg: 11.5%	4.2%	100 mg: 2.1% 200 mg: 3.4%	2.1%
		SELECTION maintenance [97]	Re-randomized maintenance 58 weeks	100 mg: 13.6% 200 mg: 27.2%	5.4% 6.4%	100 mg: 23.8% 200 mg: 37.2%	13.5% 11.2%	100 mg: 13.4% 200 mg: 15.6%	7.9% 6.1%	100 mg: 4.5% 200 mg: 4.5%	7.7% 0%
Upadacitinib	June 2022	U-ACHIEVE Induction [110]	Induction 8 weeks	n.a	n.a	26%	5%	14%	1%	6%	3%
		U-ACCOMPLISH Induction [111]	Induction 8 weeks	n.a	n.a	33%	4%	18%	2%	5%	3%
		U-ACHIEVE maintenance [110]	Re-randomized maintenance 52 weeks	15 mg: 57% 30 mg: 68%	22%	15 mg: 42% 30 mg: 52%	12%	15 mg: 24% 30 mg: 26%	6%	15 mg: 7% 30 mg: 6%	13%
Ozanimod	October 2021	TRUE NORTH [118]	Induction 10 weeks	n.a	n.a	18.4%	6%	27.3%	11.6%	4%(chort1) 6.3%(chort2)	3.2%(chort1)
			Re-randomized maintenance 52 weeks	31.7%	16.7%	37%	18.5%	45.7%	26.4%	5.2%	7.9%
Etrasimod	March 2023	ELEVATE UC [120]	Induction 12 weeks	n.a	n.a	25% (12)	15%(12)	33 (12)	19 (12)	3%	2%
		ELEVATE UC [120]	Treat-through 52 weeks	33%	7%	27% (12) 32% (52)	7%(12) 7%(52)	37%(12) 39%(52)	17%(12) 13%(52)	7%	6%

n.a: not available.

7. Head-to-Head Trials

Despite the growing number of therapeutic options for IBD, direct head-to-head comparative trials remain scarce. Most evidence derives from placebo-controlled studies, indirect comparisons, or network meta-analyses, thereby limiting the ability to clearly define the relative efficacy and safety of available treatments. This scarcity complicates clinical decision-making and highlights the need for more robust comparative studies to guide optimal therapy selection. Marked heterogeneity in trial design, study populations, and outcome reporting reduces the predictive value of placebo-controlled trials. Randomized head-to-head trials are therefore essential to optimize therapeutic strategies in IBD [121].

To date, the only head-to-head randomized controlled trial directly comparing VDZ with another biologic agent in UC is the VARSITY trial. This phase IIIb, multicenter, double-blind study randomized 769 patients with moderately to severely active UC to receive either VDZ or ADA over 52 weeks. VDZ demonstrated superior efficacy in achieving clinical remission at week 52 (31.3% vs. 22.5%, p = 0.006) and endoscopic improvement (39.7% vs. 27.7%, p < 0.001) [122].

However, concerns have been raised regarding the generalizability of these findings. As noted by Biemans et al., the inclusion criteria allowed enrollment of patients who had failed prior anti-TNF therapy, despite current guidelines recommending a switch to a different therapeutic class because of the reduced efficacy of a second anti-TNF agent [123,124].

Moreover, dose intensification was not permitted in the study protocol, whereas real-world data indicate that dose escalation occurs more frequently during the first year in patients treated with ADA (55–65%) than in those receiving VDZ (21%) [51,125].

Finally, corticosteroid-free clinical remission was considered a secondary outcome and was achieved more frequently in the ADA group compared with the VDZ group [123].

The SEQUENCE trial compared RISA with UST in patients with CD who had an inadequate response to or unacceptable adverse effects from prior anti-TNF therapy. RISA was noninferior to UST in achieving clinical remission at week 24 (58.6% vs. 39.5%; 95% CI, 6.6–30.3) and was superior in achieving endoscopic remission at week 48 (31.8% vs. 16.2%; 95% CI, 8.4–22.9; p < 0.001). The incidence of adverse events was comparable between the two treatment groups [126].The SEAVUE trial was a landmark study involving about 386 participants that compared ADA and UST in treating moderate-to-severe Crohn’s disease in biologic-naïve patients; after one year, 65% of patients receiving UST and 61% receiving ADA achieved clinical remission. Other outcomes, like steroid-free remission, quality of life, and endoscopic healing, were similar between the two groups. Both medications were well tolerated, with few serious adverse events and no new safety concerns. The trial concluded that ADA and UST are equally effective for biologic-naïve patients [127].

8. Indirect Comparison—Network Meta-Analysis Evidence

8.1. Crohn’s Disease: Indirect Comparison—Network Meta-Analysis Evidence

Although no head-to-head studies have directly compared IFX with other advanced therapies in Crohn’s disease, some indirect analyses have provided information on its efficacy [128]. A network meta-analysis (NMA) by S. Singh et al. evaluated the efficacy of induction and maintenance remission in biologic-naïve and biologic-experienced patients receiving IFX versus other biological treatments (ADA, certolizumab pegol, VDZ, UST, and RISA) [129]. IFX alone or IFX + azathioprine was associated with a greater likelihood of inducing remission than certolizumab pegol, and IFX + azathioprine was associated with a greater likelihood of inducing remission than VDZ. In this analysis, there was moderate confidence in the evidence supporting the efficacy of IFX (alone or in combination), UST, RISA, VDZ, and certolizumab pegol over placebo as maintenance therapies. In contrast, there was very low confidence in the evidence comparing IFX + azathioprine with VDZ or RISA for maintaining remission. Overall, IFX combined with azathioprine (SUCRA 0.87) and ADA (SUCRA 0.78) ranked highest, followed by IFX monotherapy (SUCRA 0.63).

An indirect comparison of IFX and VDZ trials included in the meta-analysis by Peyrin-Biroulet et al. showed that IFX provided superior efficacy during the induction phase (CDAI-70 and CDAI-100 responses, and clinical remission) and comparable efficacy during maintenance in adults with moderate-to-severe Crohn’s disease. Overall safety was similar between treatments, although infection rates were higher among infliximab-treated patients [130].

In a separate meta-analysis, Cholapranee et al. [131] reported comparable remission rates between IFX and ADA. Across two placebo-controlled trials (88 anti-TNF-treated vs. 75 placebo), pooled mucosal healing rates were 28% versus 1%, respectively (OR 19.71; 95% CI, 3.51–110.84).

Finally, a network meta-analysis by Vuyyuru et al. [132] indirectly compared multiple biologics using endoscopic response and remission as primary endpoints. However, data for IFX were limited, as early Crohn’s disease trials did not routinely assess endoscopic outcomes, thereby restricting its inclusion in the analysis.

8.2. Ulcerative Colitis: Indirect Comparison—Network Meta-Analysis Evidence

Recent network meta-analyses have compared the efficacy of biologics in moderate-to-severe UC. Chu et al. [133] found IFX to be most effective for endoscopic improvement (SUCRA 92.6%) and maintenance outcomes, while VDZ ranked highest for inducing clinical remission (94.1%). IFX + azathioprine, IFX monotherapy, and ADA were significantly superior to placebo for mucosal healing. Peyrin-Biroulet et al. [130] reported greater induction efficacy with IFX than VDZ, with similar maintenance efficacy and safety; infection rates were higher with VDZ. Cholapranee et al. [131] confirmed that both anti-TNF and anti-integrin agents were superior to placebo for inducing (45% vs. 30%) and maintaining (33% vs. 18%) mucosal healing. ADA was less effective than IFX or IFX + azathioprine, while VDZ and anti-TNFs showed comparable efficacy. Trigo-Vicente et al. [134] identified IFX as the most effective induction therapy, superior to ADA and GOL for clinical response, remission, and mucosal healing. OZA ranked highest for overall efficacy, while IFX 5 mg/kg had the most favorable infection safety profile.

9. New Targets and Ongoing Trials

Despite the remarkable expansion of the therapeutic armamentarium for IBD, particularly over the past five years, several key unmet needs remain. Unfortunately, of the many molecules under investigation, only a few progress to phase III, and an even smaller subset demonstrates sufficient efficacy in clinical trials to gain approval and become part of the therapeutic armamentarium for IBD. While novel targets continue to emerge, including interleukin-7, currently targeted by agents such as lusvertikimab, future research should prioritize achieving durable deep remission; optimizing and simplifying routes of drug administration; and, critically, developing therapies capable of modifying the natural history of the disease by promoting regression of intestinal fibrosis [135,136]. In this context, although no single agent has yet demonstrated clear superiority in sustaining long-term deep remission, several novel molecules currently under investigation aim to address other clinically relevant unmet needs. For instance, oral peptide therapeutics represent an area of intense investigation across multiple therapeutic fields; however, none is currently approved for the treatment of immune-mediated inflammatory diseases. Icotrokinra demonstrated encouraging results in a recent phase II clinical trial, with high rates of clinical remission observed at a dose of 400 mg after 12 weeks of follow-up [135]

Data on anti-tumor necrosis factor-like ligand (TL1A) therapies in CD remain limited. Duvakitug, for example, has demonstrated reductions in inflammation and fibrosis in preclinical colitis models. Moreover, in a recent phase II clinical trial, duvakitug showed statistically significant and clinically meaningful endoscopic responses compared with placebo, with no emergent safety signals observed [136].

In

Table 3. New targets and ongoing trials in IBD.

Molecules	Year	Mechanism of Action	Trial (Disease)	RCT Number—Phase	Status
IMU-838 (Vidofludimus Calcium)	2017	Dihydroorotate dehydrogenase inhibitor	CALDOSE	NCT03341962	Discontinued (unpublished data)
TD-1473 (Izencitinib)	2018	Pan-JAK inhibitor	DIONE (CD)	NCT03635112	Discontinued
BI-655130 (Spesolimab)	2018	Full humanized antibody vs. IL-36 receptors	(UC)	NCT03482635	Discontinued
UTTR1147A (efmarodocokin alfa)	2018–2022	Recombinant fusion protein vs. IL-22	(CD and UC)	NCT03558152	Discontinued
GS-4875 (Tilpisertib)	2019-	Small-molecule inhibitor TPL2	(UC)	NCT04130919	Discontinued
Hemay007	2019	Small-molecule inhibitor TNF-α	(UC)	NCT03977480	Discontinued
DIMS0150 (Cobitolimod)	2021–2023	Oligonucleotide TLR9 agonist	CONDUCT (UC) COLLECT (UC)	-II NCT04985968—III	Discontinued
CU104	2023	Blockers of endothelial/vascular dysfunction	(UC)	NCT05907330—II	Not yet recruiting
SHP-647 (Ontamalimab)	2017–2024	IgG2 monoclonal antibody vs. MAdCAM-1	TURANDOT (UC) FIGARO (UC) OPERA (CD) CARMEN (CD)	NCT01620255—II NCT03290781—III NCT01298492—II NCT03627091—III	Discontinued
OSE-127 (Lusvertikimab)	2021–2025	Humanized monoclonal antibody vs. IL-7	CoTikiS (UC)	NCT04882007—II	Ongoing
GS-5290 (Tilpisertib Fosmecarbil)	2023	Small-molecule kinase inhibitor	PALEKONA (UC)	NCT06029972—II	Ongoing
MK-724 (Tulisokibart)	2023–2025	Humanized monoclonal antibody vs. TNF-like ligand 1A	ATLAS (UC) ARES (CD)	NCT06052059—III NCT06430801—III NCT06651281—extension	Ongoing
SAR441566 (balinatunfib)	2024	Small-molecule inhibitor TNF-α	SPECIFI-CD SPECIFI-UC SPECIFI-IBD-LTS (CD and UC)	NCT06637631—II NCT06867094 NCT07222189—II	Ongoing
MORF-057	2024	Small-molecule inhibitor α4β7 inhibitor	GARNET (CD) EMERALD-2 (UC)	NCT06226883—II NCT05291689—II	Ongoing
SHR0302 (Ivarmacitinib)	2018–2025	JAK 1 inhibitor	(UC) (UC)	NCT03677648—II NCT05181137—III	Ongoing
E6011 (Quetmolimab)	2019–2025	Humanized antibody vs. CX3CL1 (blocking leukocyte trafficking)	CD	NCT03733314	Under investigation
AJM 300 (Carotegrast Methyl)	2022	Small molecules against α4β1 and α4β7 anti-integrin	UC	NCT03531892—III NCT06897150 -IV	Approved in Japan (Carogra)
SAR441344 (Duvakitug)	2025	Anti-tumor necrosis factor-like ligand	UC CD	NCT07185009—III NCT07184996 NCT07184944—III NCT07184931	Ongoing
JNJ-77242113 (Icotrokinra)	2025	Oral peptide against IL-23R	ICONIC (UC) ICONIC (CD)	NCT07196748-III NCT07196722—II/III	Ongoing
TAK-279 (Zasocitinib)	2025	Allosteric inhibitor of tyrosine kinase 2	CD and UC	NCT06764615—II	Ongoing
SAR442970 (Brivekimig)	2025	Nanobody (VHH) against TNF-α and OX40L	CHROMA (CD) COLOR (UC)	NCT06958536—II NCT06975722—II	Ongoing
D-2570	2025	Small-molecule inhibitor tyrosine kinase 2	UC	NCT07035041	Ongoing

, we provide an overview of phase II and III studies of the most recent molecules currently in development or recently discontinued due to lack of efficacy in IBD.

10. Advanced IBD Therapies: Current Status

Since the first approval of IFX, a monoclonal antibody targeting TNF-α, numerous novel therapeutic targets have been identified, and many new therapies have been approved.

Over the past decade, a reduction in hard outcomes, such as the need for surgery in Crohn’s disease, has been observed [137,138]. However, as noted by several authors, this decline may be attributable not only to therapeutic advances but also to overall improvements in IBD management, including earlier diagnosis and greater patient adherence to structured medical follow-up [139,140].

In fact, a major limitation of RCTs is their relatively short duration of follow-up. Given that inflammatory bowel disease is a lifelong, relapsing condition, follow-up periods of 44–56 weeks capture only a limited phase of the disease trajectory. Consequently, the durability of response and the true long-term effectiveness of advanced therapies remain insufficiently characterized, with observational and population-based studies often reporting heterogeneous and, at times, conflicting findings [137,138,139,140].

When comparing efficacy outcomes from phase III clinical trials, overall response rates appear broadly similar across available agents, with observed differences largely attributable to variations in study design.

This apparent similarity in efficacy is also supported by NMAs. These analyses have often suggested higher effectiveness for newer therapies, particularly those evaluated using novel trial designs such as re-randomization. However, such methodological differences, together with the inherent limitations of NMAs, preclude firm conclusions regarding comparative efficacy.

Taken together, these factors, along with the scarcity of head-to-head clinical trials, substantially limit our ability to distinguish among available treatments and to guide therapeutic decision-making on the basis of efficacy alone, shifting treatment choice toward economic considerations and patient-specific factors such as comorbidities and extraintestinal manifestations of IBD.

Moderate optimism arises from the many novel therapeutic targets under investigation and from emerging treatment strategies, such as dual therapy, which are being proposed with increasing confidence, partly due to the improved safety profiles of newer agents [141,142]; together, these developments offer hope for better management of the burden of IBD in the near future.

11. Conclusions

Only through a deeper understanding of the pathophysiological mechanisms underlying these diseases will it be possible to substantially improve therapeutic outcomes in conditions that continue to impose a considerable burden on patients’ quality of life. Integrating mechanistic insights with translational research and well-designed clinical trials will be essential to guide the development of more targeted, effective, and durable treatment strategies. Ultimately, this approach may enable a shift from symptom control toward true disease modification, thereby aligning therapeutic advances with the long-term needs and expectations of patients with IBD.