IL-23

IL-23 is a key mediator of inflammation in IBD via the JAK-STAT pathway. The monoclonal antibodies risankizumab, mirikizumab, and guselkumab were developed to target the p19 subunit of IL-23.¹ Risankizumab was evaluated in patients with moderately to severely active CD in the phase 3 ADVANCE and MOTIVATE induction studies followed by the FORTIFY maintenance study.^2,3

The induction studies demonstrated a superior rate of clinical remission and endoscopic response with 12 weeks of risankizumab vs placebo in previously treated patients. Importantly, the trials showed similar rates of clinical remission and endoscopic response with risankizumab in patients who had failed prior conventional therapy and in patients who had failed prior biologic therapy. In the FORTIFY study, patients with a response from the induction studies were randomized to 52 weeks of therapy with risankizumab or matched placebo. The study showed a clear superiority with risankizumab vs placebo. The endoscopic response rate was 47% with risankizumab— more than double the rate achieved with placebo. Furthermore, risankizumab yielded high rates of clinical remission and deep remission compared with placebo. In a subsequent data analysis, risankizumab elicited a numerically higher rate of clinical remission and endoscopic response among patients who had failed therapy with ustekinumab.⁴

The SEQUENCE study compared risankizumab with ustekinumab in patients with moderately to severely active CD who had failed therapy with at least 1 TNF inhibitor.⁵ A total of 520 patients were evenly randomized into the 2 arms. The first primary endpoint was demonstration of noninferiority of risankizumab vs ustekinumab based on clinical remission at week 24, assessed by the CD activity index (CDAI) score. The second primary endpoint was the superiority of risankizumab vs ustekinumab based on endoscopic remission at week 48. The trial successfully met its first endpoint, showing a CDAI clinical remission rate of 58.6% with risankizumab vs 39.5% with ustekinumab (P<.01) (Figure 3). The trial also met its secondary endpoint by showing a superior endoscopic remission rate with risankizumab vs ustekinumab (31.8% vs 16.2%; P<.0001). Moreover, all secondary endpoints showed that risankizumab was superior to ustekinumab, and publication of these trial results in a peer-reviewed journal is expected. Further, a welcome feature of the IL-23 inhibitors is their record of tolerability. In the SEQUENCE trial, the rate of severe treatment-emergent AEs was 16.0% with risankizumab and 19.2% with ustekinumab, and the rate of serious treatment-emergent AEs was 10.3% vs 17.4%, respectively, with no deaths in either arm.

Figure 3.

Clinical remission at week 24 (noninferiority) and endoscopic remission at week 48 (superiority) for risankizumab vs ustekinumab in patients with moderately to severely active Crohn’s disease from the SEQUENCE study.

^aITT1H population includes the first ~50% of ITT1 patients.

^bITT1 population includes patients who were randomized to UST or RZB (600 mg IV, 360 mg SC) and received at least 1 dose of study drug. cDifferences adjusted by the stratification factors (number of times the subject failed prior anti-TNF therapy [≤1, >1] and steroid use at baseline [yes, no]). CDAI, Crohn’s disease activity index; ITT, intention-to-treat; IV, intravenous; RZB, risankizumab; SC, subcutaneous; TNF, tumor necrosis factor; UST, ustekinumab.

Adapted from Sands et al. IL-23. Presented at the Advances in Inflammatory Bowel Disease Conference; Orlando, Florida; December 14-16, 2023.¹

The phase 2 GALAXI-1 induction study investigated guselkumab, administered at 3 dose levels, vs placebo in 309 patients with moderately to severely active CD.⁶ Patients in a fifth arm were treated with ustekinumab. Based on clinical remission, the study showed the superiority of guselkumab vs placebo, with similar rates of remission observed at week 12 regardless of the dose of guselkumab. The antip19 antibody yielded a significant improvement in the rate of clinical remission vs placebo in the overall population, in patients who had failed prior biologic therapy, and in patients who had failed prior conventional therapy (P<.05).

IL-23 mediates inflammation in the gut, skin, and entheses, and genome-wide associations identify IL-23 receptor genes as protective in IBD. Inhibition of IL-23 is highly efficacious for patients with CD and UC, and risankizumab was more effective than ustekinumab for biologic-exposed CD. The efficacy and safety profiles of IL-23 blockers make them excellent first-line treatment options for moderateto-severe IBD.

– Stephen B. Hanauer, MD

The phase 2 SERENITY trial evaluated 12 weeks of induction therapy with mirikizumab, administered at 3 dose levels, vs placebo in 291 patients with moderately to severely active CD.⁷ A dose response was observed with the 3 dose levels of mirikizumab based on Simple Endoscopic Score–CD (SES-CD) response and SES-CD remission. The rate of SES-CD response was 43.8% with the highest dose of mirikizumab vs 10.9% with placebo (P<.001), and the rate of SES-CD remission was 20.3% vs 1.3%, respectively (P=.009). The rate of CDAI response was 42.2% with the highest dose of mirikizumab vs 23.4% with placebo (P=.034), and the rate of CDAI remission was also significantly higher with mirikizumab vs with placebo (26.6% vs 9.4%; P=.023).

Anti-p19 therapy has also proven efficacious in the treatment of patients with UC. In the phase 3 LUCENT-1 trial of patients with moderately to severely active UC, the trial met its primary endpoint, demonstrating a rate of clinical remission of 24.2% with mirikizumab vs 13.3% with placebo at week 12 (P=.00006).⁸ Mirikizumab was superior to placebo among patients who were biologic-naive (P<.001) but did not achieve significance among patients who had failed prior biologic therapy (P=.065). However, mirikizumab was superior to placebo as maintenance therapy in both biologic-/tofacitinibnaive patients (51.5% vs 30.7%; P<.001) and in patients who had failed biologic therapy or tofacitinib (46.1% vs 15.6%; P<.001). Guselkumab and risankizumab have also demonstrated superior efficacy as induction monotherapy vs placebo in patients with UC, based on results from the phase 2b QUASAR study and preliminary results from the phase 3 INSPIRE study.^9,10

ABSTRACT SUMMARY Risankizumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomized Phase 3 INSPIRE Study.

The phase 3 INSPIRE study evaluated induction therapy with risankizumab 1200 mg vs placebo in patients with moderately to severely active UC (Abstract S4). The trial met its primary endpoint, demonstrating a superior rate of clinical remission with risankizumab vs placebo at week 12 (20.3% vs 6.2%; P<.00001) in the overall study population. Risankizumab was superior to placebo in all ranked secondary endpoints at week 12, including clinical response based on adapted Mayo score (P<.00001), endoscopic remission (P<.00001), and other secondary endpoints encompassing endoscopic, histologic-endoscopic, and patient-reported outcomes. Risankizumab treatment was generally well tolerated, with safety outcomes that were generally favorable compared with the placebo group.

Intriguingly, the proof-of-concept VEGA study investigated induction therapy with golimumab vs guselkumab monotherapy compared with golimumab plus guselkumab in 214 patients with moderately to severely active UC.¹¹ The combination provides simultaneous targeting of TNF and IL-23. Eligible patients had not received prior therapy with an anti-TNF agent and were refractory or intolerant to conventional therapy. Rates of clinical response were generally similar in all 3 arms, with the exception of golimumab monotherapy vs the combination at week 12 (61% vs 83%; P=.0032). At week 12, golimumab or guselkumab monotherapy yielded similar rates of clinical remission (24%-25%); however, the rate of clinical remission with the 2 drugs combined was 47%—nearly double that of either monotherapy. At week 38, the rate of clinical remission was 21% with golimumab and 31% with guselkumab, whereas the combination of both drugs yielded a clinical remission rate of 38%.