IL-23) plays a pivotal role in the development of IBD [67]. As a member of the IL-12 cytokine family, it is essential for the differentiation and maintenance of T-helper 17 (Th17) cells, which produce pro-inflammatory cytokines [68]. This IL-23/Th17 axis is critical to chronic inflammation in IBD [68, 69]. Recognizing the critical role of IL-23 in disease progression, biopharmaceutical agents have been developed that neutralize IL-23 and reduce inflammation more precisely than broad-spectrum immunosuppressants [68].

The first drug of this type, ustekinumab, was originally developed for psoriasis but was approved for CD due to its efficacy. It targets the common subunit p40 of IL-12 and IL-23 and inhibits their activity. Clinical trials have shown that ustekinumab is effective in inducing and maintaining remission in patients with CD, even in patients who have not responded to previous biologics [70].

Targeting specifically the p19 subunit of IL-23 these agents offer a more selective therapeutic approach [71]. Early clinical studies have shown promising results for risankizumab in both UC (Table 4) and CD (Table 5). Subsequent studies have supported the efficacy of risankizumab, suggesting that it could become an important tool in the treatment of IBD [17, 18, 72,73,74,75].

The INSPIRE study, a double-blind, placebo-controlled phase 3 study, evaluated the efficacy and safety of risankizumab in patients with UC who had not responded well to conventional or advanced therapies [76]. Excluding those previously treated with ustekinumab or other IL-23 inhibitors, the study randomized 975 patients 2:1 to receive either placebo or 1200 mg of risankizumab intravenously at weeks 0, 4, 8 and 12. Risankizumab achieved significantly higher clinical remission rate at week 12 compared to placebo (20.3% vs. 6.2%, P < 0.00001). The most common AEs included COVID-19 infections, anemia, and worsening of UC symptoms. Overall, 9.4% of patients receiving risankizumab and 8.0% of patients in the placebo group experienced AEs possibly related to the drug. However, more patients in the placebo group experienced severe AEs (10.2%) than in the risankizumab group (2.5%). No significant cardiovascular events, active tuberculosis or severe hypersensitivity reactions were observed. Only 0.6% of risankizumab patients discontinued treatment due to AEs, compared to 3.7% in the placebo group [76].

Patients who responded to induction therapy were eligible for participation in the COMMAND maintenance study (NCT03398135) [77], while patients who did not respond were eligible for a further 12 weeks of induction therapy.

In the COMMAND study (NCT03398135), the role of risankizumab in the maintenance treatment of moderate to severe UC was further investigated [77]. Patients who responded to induction therapy received 180 mg, 360 mg risankizumab or placebo every 8 weeks for 52 weeks. Patients receiving 180 mg and 360 mg achieved significantly higher clinical remission rates (40.2% and 37.6%, respectively) compared to placebo (25.1%).

The overall rates of AEs and serious infections were similar among treatment groups. Serious events per 100 patient-years (E/100 PY) were lower in the risankizumab arms compared to placebo (risankizumab 180 mg: 5.9; risankizumab 360 mg: 6.3; placebo: 11.4), and serious AEs were also lower in the risankizumab arms (risankizumab 180 mg: 1.6; risankizumab 360 mg: 4.0; placebo: 8.0). No cases of active tuberculosis, anaphylaxis, severe hypersensitivity reactions or serious adverse cardiovascular events were reported in any of the treatment groups [77].

The role of risankizumab in the treatment of CD has been investigated in several studies, [74, 78,79,80,81] (Table 5), most notably in the phase 3 ADVANCE and MOTIVATE studies [80]. These randomized, double-blind, placebo-controlled studies involved adults with moderate to severe CD who had not responded adequately to one or more approved biologics or conventional therapy (ADVANCE) or biologics (MOTIVATE). Participants received either 600 mg or 1200 mg intravenous risankizumab or placebo at weeks 0, 4 and 8. The primary analysis included 850 participants from the ADVANCE study and 569 from the MOTIVATE study.

In the ADVANCE study, the clinical remission rate at week 12 according to CDAI was 45% with 600 mg and 42% with 1200 mg risankizumab, compared to 25% with placebo (p < 0.0001). The endoscopic response rates were also significantly higher in the risankizumab groups. The endoscopic response rate was 40% with risankizumab 600 mg and 32% with risankizumab 1200 mg compared to 12% with placebo (p < 0.0001). In the MOTIVATE study, clinical remission rates of 42% and 40% were also recorded for the respective doses compared to 20% with placebo (p < 0.0001). In addition, the endoscopic response rate was 29% with risankizumab 600 mg and 34% with risankizumab 1200 mg compared to 11% with placebo (p < 0.0001). In terms of safety, the rates of adverse events in the two treatment groups were comparable overall (ADVANCE: 56% in the risankizumab 600 mg group vs. 51% in the risankizumab 1200 mg group vs. 56% in the placebo group, MOTIVATE: 48% vs. 59% and 66%, respectively). In both studies, the most common AEs in the risankizumab groups were headache and nasopharyngitis. Three deaths occurred, during the induction phase, two in the placebo group (ADVANCE) and one in the risankizumab 1200 mg group (MOTIVATE) none of which were associated with the drug [79, 80].

The FORTIFY study, a phase 3 study, investigated the efficacy of risankizumab as maintenance therapy [81]. Participants who had responded to treatment in ADVANCE or MOTIVATE received a subcutaneous dose of 180 mg or 360 mg risankizumab every 8 weeks for 52 weeks. Clinical remission rates, as defined by the CDAI, at week 52 were 52% for the 360 mg dose and 55% for the 180 mg dose, both significantly higher than placebo (p = 0.0054 and p < 0–0001, respectively). Endoscopic response rates were 47% on risankizumab compared to 22% on placebo. In addition, higher rates of clinical CDAI remission and endoscopic response were observed at week 52 with a 180 mg dose of risankizumab compared to placebo (p = 0–0031 and p < 0–0001, respectively). Specifically, CDAI clinical remission was achieved in 55% with risankizumab 180 mg, and endoscopic response in 47%. The incidence of AEs was comparable in all groups (72% for risankizumab 180 vs. 72% for risankizumab 360 mg vs. 73% in the placebo group), with the most frequently reported AE in each treatment group being exacerbation of CD (11% for risankizumab 180 vs. 12% for risankizumab 360 mg vs. 17% in the placebo group), following by arthralgia (8% for risankizumab 180 vs. 9% for risankizumab 360 mg vs. 11% in the placebo group) and headache (5% for risankizumab 180 vs. 6% for risankizumab 360 mg vs. 6% in the placebo group) [81].

Real-world data from Belgium and tertiary reference centers confirmed these results. In particular, in the Belgian multicenter cohort study, 69 patients with CD were examined, most of whom had previously undergone at least four advanced therapies (85.5% with ≥ 4 different advanced therapies and 98.6% with ustekinumab, 14 with a stoma). All participants received three induction infusions of 600 mg risankizumab at weeks 0, 4 and 8, followed by a subcutaneous maintenance dose of 180 or 360 mg every 8 weeks, starting at week 12 [74].

Clinical remission was measured by an average daily stool frequency of ≤ 2.8 and a daily abdominal pain score of ≤ 1. Endoscopic response required a reduction of 50% or more from baseline. At week 24, 18.2% of patients without a stoma achieved steroid-free clinical remission, which increased to 27.3% by week 52. Half of the 32 patients with endoscopic data achieved an endoscopic response within 52 weeks, with similar remission rates in the patients with a stoma (steroid-free clinical remission rates of 14.3%). At a median follow-up of 68.3 weeks, 18.8% of patients discontinued risankizumab and 20.3% underwent bowel resection. The estimated surgery-free survival rate at week 52 was 75.2% and no new safety concerns were identified [74].

Again, 145 patients with CD were examined at a tertiary reference center [75]. The efficacy cohort included 80 patients with active luminal CD characterized by a Harvey-Bradshaw Index (HBI) of 5 or higher, or with active disease confirmed by imaging, ileocolonoscopy, or elevated fecal calprotectin levels. They received intravenous risankizumab (600 mg) at weeks 0, 4 and 8.

Most patients (61%) had undergone bowel resection in the past and only 8% did not respond to advanced therapies. HBI scores declined steadily throughout the induction period, dropping from 6 at baseline to 2 at week 12. Clinical remission rates gradually improved, reaching 70% at week 12. Three patients discontinued treatment before week 12 due to disease worsening. In the efficacy cohort, 36 patients (45%) had never received ustekinumab and 44 (55%) had previous experience with this drug. At week 12, 78% of ustekinumab-naïve patients and 64% of ustekinumab-experienced patients achieved clinical remission (p = 0.222). Steroid-free clinical remission was achieved by 75% of ustekinumab-naïve patients and 52% of ustekinumab-experienced patients (p = 0.041). Overall, 63% of patients achieved a steroid-free clinical remission. In the multivariate analysis, a history of bowel resection and a high baseline HBI reduced the likelihood of achieving steroid-free remission by week 12 (p = 0.005 for both). Safety data from 145 patients showed that 7.5% of patients experienced a disease exacerbation requiring steroid therapy, treatment modification or surgery. One patient discontinued treatment due to hypersensitivity after the first infusion. Other adverse events included fatigue, upper respiratory tract infections, joint pain and worsening of eczema [75].

Another multicenter, real-world study found that induction therapy with risankizumab in highly refractory patients with luminal Crohn's disease (CD) and multiple treatment failure, including ustekinumab, resulted in clinical response in approximately 75% of patients and steroid-free clinical remission in approximately 50% [82]. In addition, the ongoing APRISE study (NCT05841537) is collecting real-world post-marketing data on the efficacy and safety of risankizumab in the treatment of CD (Table 5).

Two randomized, double-blind, placebo-controlled phase 3 trials of mirikizumab were conducted in adults with moderately to severely active ulcerative colitis (NCT03518086 and NCT03524092) [83]. In the induction trial, 1281 patients were randomized in a 3:1 ratio and received either mirikizumab (300 mg) or placebo intravenously every 4 weeks for 12 weeks. In the maintenance trial, 544 patients who had shown a positive response to induction therapy with mirikizumab were randomized in a 2:1 ratio to receive either mirikizumab 200 mg or placebo subcutaneously every 4 weeks for 40 weeks. Patients who did not respond during the induction trial were offered the option to receive mirikizumab as extended induction therapy during the initial 12 weeks of the maintenance trial. In both the induction trial (week 12) and the maintenance trial (week 52), the proportion of patients achieving clinical remission was significantly higher in the mirikizumab group than in the placebo group (24.2% vs. 13.3%, p < 0.001 and 49.9% vs. 25.1%, p < 0.001, respectively). Among the 1217 patients who received mirikizumab during the controlled and uncontrolled phases covering the open-label extension and maintenance phases of both trials, opportunistic infections occurred in 15 patients (including 6 cases of herpes zoster infection) and cancer was diagnosed in 8 patients (including 3 with colorectal cancer). In contrast, among patients receiving placebo in the induction trial, only one had a herpes zoster infection and none were diagnosed with cancer [83].

In addition, there are two ongoing studies evaluating the long-term efficacy and safety of mirikizumab in UC (NCT03519945) with a particular focus on the symptom of bowel urgency (NCT05767021) (Table 6). Preliminary data show that among patients who achieved clinical remission at week 52, the rate of maintenance of clinical remission at week 104 was 65.6%. In patients without prior biologic failure, the rate was 67.3%, while in patients with prior biologic failure, the rate was 61.7%. Among patients who were in clinical remission at week 52, 74% of them maintained symptomatic remission at week 104, and 64.3% were also in corticosteroid-free remission at week 104 [84].

The efficacy and safety of mirikizumab in CD were investigated in a randomized phase 2 study [85]. In this trial, 191 patients were randomized (2:1:1:2) to receive placebo, 200, 600 or 1000 mg mirikizumab, administered intravenously (IV) every 4 weeks. Patients who received mirikizumab and achieved at least a 1-point improvement in Simple Endoscopic Score-CD at week 12 (rerandomized maintenance cohort) were re-randomized to continue their induction IV treatment (combined IV groups [IVC]) or to receive 300 mg of mirikizumab subcutaneously (SC) every 4 weeks. The non-randomized maintenance cohort included endoscopic non-improvers (1000 mg) and placebo patients (placebo/1000 mg) who received 1000 mg mirikizumab IV starting at week 12. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving an endoscopic response (50% reduction in Simple Endoscopic Score-CD from baseline) at week 12. At week 12, the endoscopic response was significantly higher at the predefined two-sided significance level of 0.1 for all mirikizumab groups compared to placebo (200 mg: 25.8%, 8/31, 95% confidence interval CI 10.4–41.2, P = 0.079; 600 mg: 37.5%, 12/32, 95% CI 20.7–54.3, P = 0.003; 1000 mg: 43.8%, 28/64, 95% CI 31.6–55.9, P < 0.001; placebo: 10.9%, 7/64, 95% CI 3.3–18.6). Endoscopic response at week 52 was 58.5% (24/41) and 58.7% (27/46) in the IV-C and SC groups, respectively. The incidence of AEs in the mirikizumab groups during the first 12 weeks was similar to that in the placebo (treatment-related AEs: 70.3% for placebo, 58.1% for mirikizumab 200 mg, 65.6% for mirikizumab 600 mg and 65.6% for mirikizumab 1000 mg). Until week 52, the incidence of treatment-related serious AEs was similar in all groups. The incidence of serious AE and discontinuation due to AE was higher in the non-randomized maintenance group than in the randomized maintenance group (13.6% and 10% vs. 0 and 3.4%; 11.9% and 10% vs. 2.4% and 2.2%, respectively) [85].

The two other studies on the use of mirikizumab in CD are VIVID-1 (NCT03926130) and the ongoing long-term extension VIVID-2 (NCT04232553) (Table 6). Notably, preliminary data show that mirikizumab was non-inferior to ustekinumab in clinical remission as assessed by CDAI (p = 0.113) [86].

These antibodies, which also target the p19 subunit, are currently under investigation. Preliminary data suggest a potential benefit in the treatment of IBD.

The potential role of guselkumab in moderate to severe CD was investigated in GALAXI-1, a double-blind, placebo-controlled phase 2 trial [87]. In this study, patients were randomized 1:1:1:1:1 to receive either intravenous guselkumab at 200 mg, 600 mg or 1200 mg at weeks 0, 4 and 8, intravenous ustekinumab at a dose of approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8, or placebo. The primary endpoint was the change from baseline in the CDAI. Of the 309 patients studied, approximately 50% were refractory to prior biologic therapy. At week 12, a significantly greater reduction from baseline in CDAI was observed in each guselkumab group compared to placebo (least squares means: 200 mg: –160.4, 600 mg: –138.9, and 1200 mg: –144.9 versus placebo: –36.2; all, P < 0.05). Moreover, a significantly greater proportion of patients in each guselkumab group achieved clinical remission compared to placebo (CDAI < 150; 57.4%, 55.6% and 45.9% vs. 16.4%; all, P < 0.05). Rates of safety-related events were generally similar across treatment groups: in the 360 patients analyzed, a comparable proportion of patients experienced one or more AEs in all treatment groups by week 12 (placebo: 60.0%; guselkumab combined: 45.7%; and ustekinumab: 50.7%) [87].

After the efficacy of guselkumab as an induction therapy in moderate to severe CD was demonstrated, the role of guselkumab as a meta-drug therapy was investigated in a randomized, multicenter, double-blind phase 2 trial in adult patients [88]. In this study, 309 patients (112 biologics-naïve; 197 biologics-experienced) were randomly assigned to one of five treatment groups. Treatment regimens consisted of an intravenous induction phase followed by a subcutaneous maintenance phase beginning at week 12 in a treat-through design: from the guselkumab 200 to 100 mg group: 200 mg intravenously at weeks 0, 4 and 8, followed by 100 mg subcutaneously every 8 weeks (61 patients); from the guselkumab 600 to 200 mg group: 600 mg intravenously at weeks 0, 4 and 8, followed by 200 mg subcutaneously every 4 weeks (63 patients); from guselkumab 1200 to 200 mg group: 1200 mg intravenously at weeks 0, 4 and 8, followed by 200 mg subcutaneously every 4 weeks (61 patients); ustekinumab group: approximately 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks (63 patients) and placebo group (61 patients): Placebo induction followed by either placebo maintenance (for those with clinical response according to CDAI at week 12) or crossover to ustekinumab (for those without CDAI clinical response at week 12). At week 48, the number of patients who achieved a clinical CDAI response (CDAI score < 150) was as follows: 39 (64%) in the guselkumab 200 → 100 mg group, 46 (73%) in the guselkumab 600 → 200 mg group, 35 (57%) in the guselkumab 1200 → 200 mg group and 37 (59%) in the ustekinumab group. The corresponding number of patients who achieved an endoscopic response (≥ 50% improvement in SES-CD or SES-CD score ≤ 2) was 27 (44%), 29 (46%), 27 (44%) and 19 (30%), respectively, and endoscopic remission (SES-CD score ≤ 2) was observed in 11 (18%), 11 (17%), 20 (33%) and four (6%) patients, respectively. In the placebo group, 15 patients were in clinical CDAI remission (either clinical CDAI remission or a decrease in CDAI score of ≥ 100 points from baseline) at week 12 and continued placebo treatment; of these, nine (60%) were in clinical remission at week 48. Forty-four patients in the placebo group were not in clinical CDAI remission at week 12 and switched to ustekinumab; of these, 26 (59%) were in clinical remission at week 48. Up to week 48, the frequencies of AEs in the safety population (n = 360) were as follows: 46 of 70 patients (66%) in the placebo group (464.9 events per 100 patient-years of follow-up), 163 of 220 patients (74%) in the three guselkumab groups combined (353.1 per 100 patient-years), and 60 of 71 patients (85%) in the ustekinumab group (350–7 per 100 patient-years). Among patients treated with guselkumab or ustekinumab, the most commonly reported infections through week 48 were nasopharyngitis (25 [11%] of 220 guselkumab recipients, 12 [11%] of 114 ustekinumab recipients) and upper respiratory tract infections (13 [6%] guselkumab recipients, eight [7%] ustekinumab recipients). After week 12, severe infections occurred in one patient who responded to placebo induction and in two patients treated with guselkumab. There were no cases of active tuberculosis, opportunistic infections or deaths [88].

Two other ongoing studies on the use of guselkumab in CD are GRAVITI (NCT05197049) and FUNZION CD (NCT05347095), which focus on fistulating, perianal CD (Table 7).

The efficacy and safety of guselkumab as induction therapy in moderate to severe CU was investigated in QUASAR, a randomized, double-blind phase 2b trial [89]. This study involved 313 patients who had previously been treated with conventional or advanced therapy. Patients were randomly assigned to either placebo or guselkumab at a dose of 200 mg every 4 weeks or guselkumab at a dose of 400 mg every 4 weeks. At week 12 of the induction phase, the percentage of patients exhibiting a clinical response was 27.6% in the placebo group, 61.4% in the lower-dose guselkumab group and 60.7% in the higher-dose guselkumab group (P < 0.001). The safety results were largely consistent with previous studies in approved indications. The incidence of serious AEs was significantly lower at 1% in the guselkumab groups compared to 5.7% in the placebo group. Rare AEs requiring discontinuation of treatment were reported in 0.5% of patients in the guselkumab groups compared to 1.9% in the placebo group. Infection rates were comparable at 10.6% and 11.4%, respectively, with no serious infections occurring in the guselkumab groups compared to 1.9% in the placebo group. It is noteworthy that no deaths were recorded during the entire duration of the study [89].

The role of brazikumab (MEDI2070) in the treatment of moderate to severe CD was investigated in a double-blind, placebo-controlled phase 2a study [90]. In this study, 119 adults who had previously failed treatment with tumor necrosis factor antagonists were randomized to receive either 700 mg brazikumab or placebo intravenously at weeks 0 and 4, followed by subcutaneous doses of 210 mg starting at week 12. At week 8, a clinical response (defined as either a 100-point decrease in CDAI score from baseline or clinical remission with a CDAI < 150) was observed in 49.2% of patients treated with brazikumab compared to 26.7% in the placebo group, an absolute difference of 22.5%. At week 24, a clinical response was observed in 53.8% of patients who continued to receive open-label MEDI2070 and in 57.7% of patients who received placebo and then open-label MEDI2070 during the double-blind phase. Both groups had similar rates of AEs at week 12 (67.8% and 68.3%, respectively), with headache and nasopharyngitis being the most common [90].

Moreover, the safety of brazikumab was also investigated in an open-label phase of this study [91].

Patients who successfully completed the 12-week, received subcutaneous brazikumab every 4 weeks for 100 weeks. Of the 104 patients, 57 (54.8%) completed the entire treatment period, while 47 (45.2%) discontinued treatment, mainly due to lack of response (14.4%) or treatment-emergent AEs (TEAEs) (11.5%). Overall, TEAEs occurred in 44 (84.6%) of patients in the group that switched from placebo to brazikumab (placebo/brazikumab) and 43 (82.7%) in the group that continued with brazikumab (brazikumab/brazikumab), with mild to moderate infections being the most common (40.4% of patients in the placebo/brazikumab group and 50% in the brazikumab/brazikumab group).

No major adverse cardiac events, malignancies or deaths were reported during the study period [91].

The efficacy and safety of brazikumab in CD is also being investigated in the 52-week INTREPID study (NCT03759288) and its open-label extension (NCT03961815), but results are not yet available. (Table 8).

The role of brazikumab in moderate to severe UC was investigated in a 54-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 study (Expedition Lead-in- NCT03616821). In addition, the long-term efficacy and safety of this therapy in moderate to severe UC was analyzed in an open-label extension of the study (NCT04277546) (Table 8). The results of these studies are currently not available.