Comparative Analysis of IL-23 Inhibitors

How does risankizumab compare mechanistically and clinically with other IL-23 inhibitors in each indication?
Jun 4, 4:50 PM
I'll search for comparative data on risankizumab versus other IL-23 inhibitors — guselkumab, tildrakizumab, and mirikizumab — across their approved indications (plaque psoriasis, PsA, Crohn's, UC), covering both mechanism and clinical trial outcomes.

Mechanism: all four agents target IL-23 p19 — but not identically

Risankizumab, guselkumab, and tildrakizumab all bind the p19 subunit of IL-23 (avoiding the p40 subunit shared with IL-12, which ustekinumab hits). This selectivity preserves IL-12-driven Th1 responses and the IL-12/IL-23 axis important for immune surveillance. Beyond that broad similarity, the three p19 inhibitors differ substantially in epitope size, affinity, and functional consequence. A detailed structural analysis published in JID Innovations (Daniele et al., 2024) mapped hydrogen-deuterium exchange data onto the IL-23 surface and found that risankizumab and guselkumab have large solvent-accessible epitopes (2,400 Ų and ~2,240 Ų respectively) while tildrakizumab's epitope is much smaller (1,290 Ų). Critically, epitope surface area correlated strongly with both binding affinity and PASI-90 response rates (R² ≈ 0.997 for short-term efficacy). A separately notable molecular difference: guselkumab is a native-Fc IgG1, while risankizumab carries a mutated Fc region — a distinction whose functional significance in vivo remains under investigation. Tildrakizumab also differs in that it does not completely block IL-23 receptor binding, whereas risankizumab and guselkumab both fully prevent IL-23/IL-23Rα interaction. A non-clinical comparative study in mAbs (Zhou et al., 2021) found that risankizumab and guselkumab had ~5-fold higher IL-23 binding affinity than ustekinumab and tildrakizumab, and more potently inhibited Th17 differentiation in vitro, while tildrakizumab had minimal impact on Th17 differentiation in that model. The mechanistic hierarchy, at least preclinically, runs: risankizumab ≈ guselkumab >> tildrakizumab.

Plaque psoriasis: high response rates for all, with risankizumab and guselkumab pulling ahead of tildrakizumab

No direct risankizumab-vs-guselkumab head-to-head RCT exists, so the evidence is indirect. A matching-adjusted indirect comparison (MAIC) of phase 3 trial data (VOYAGE 1/ECLIPSE for guselkumab vs UltIMMa-1/2 for risankizumab) found that guselkumab had a modestly higher mean PASI change at week 4 but the advantage disappeared by week 40, with confidence intervals ruling out any clinically meaningful difference at later timepoints. Real-world Italian cohorts have largely agreed: Ruggiero et al. (2021) in ~70 patients found comparable PASI90 and PASI100 at weeks 28-44, and a larger 150-patient Italian study (Megna et al., 2022) found no significant difference in PASI100 rates (73-85% across all three p19 inhibitors), though guselkumab and risankizumab were slightly faster-acting on palmoplantar lesions than tildrakizumab. The most recent real-world Italian landscape study (Trovato et al., 2026) refines this: risankizumab offers faster and deeper initial responses, while tildrakizumab 200 mg performs particularly well long-term in patients with higher BMI or treatment-resistant disease. A structural biology preprint (posted 2023, peer-reviewed version in JID Innovations 2024) found that PASI-90 response rates align closely with epitope surface area: risankizumab >guselkumab >tildrakizumab >ustekinumab in both short-term and long-term efficacy hierarchies. This mechanistic-to-clinical correlation is one of the cleaner structure-function stories in the class.

The head-to-head that does exist — risankizumab vs ustekinumab — showed risankizumab achieving PASI90 in ~75% vs ~42% for ustekinumab at week 16, a large and consistent difference confirmed across meta-analyses.

Psoriatic arthritis: guselkumab approved, risankizumab approved, tildrakizumab not approved

This is where the agents diverge in their approved indications most clearly. For joint outcomes (ACR20), a network meta-analysis in Rheumatology (Mease et al., 2022) found guselkumab and risankizumab comparable, both roughly on par with sc TNF inhibitors and IL-17A agents for ACR response. For structural progression (modified van der Heijde-Sharp score), guselkumab Q4W was numerically better than risankizumab and most other agents, while guselkumab Q8W was comparable. Guselkumab's PASI performance in PsA patients was notably better than TNF and JAK inhibitors in that analysis. No head-to-head PsA RCT of risankizumab vs guselkumab has been conducted.

Crohn's disease: risankizumab is the only approved targeted IL-23 inhibitor

This is a key differentiator. Risankizumab gained regulatory approval for moderate-to-severe CD in 2022 — guselkumab and tildrakizumab are not approved for CD. The pivotal phase 3 program (ADVANCE/MOTIVATE induction, FORTIFY maintenance) established efficacy, and a landmark phase 3b head-to-head published in the NEJM (Peyrin-Biroulet et al., 2024) compared risankizumab vs ustekinumab in anti-TNF failures: risankizumab was noninferior for clinical remission at week 24 (59% vs 40%) and superior for endoscopic remission at week 48 (32% vs 16%). That endoscopic remission advantage is clinically meaningful and makes this one of the more important trials in the class.

A 2025 meta-analysis of four RCTs covering ~1,800 patients confirmed significant pooled improvements in clinical remission, clinical response, and endoscopic remission, with dose-dependent effects and adverse event rates comparable to placebo. Real-world data from a large Italian cohort (RESOLVE IgIBD, 2025) showed ~58% steroid-free clinical remission at week 12, even in a heavily biologic-experienced population where >50% had failed ustekinumab previously.

Mirikizumab, another p19 inhibitor, is approved for UC but not for CD in most markets, though a preprint NMA and a maintenance-phase MAIC suggest it may outperform risankizumab in CD remission rates at the maintenance phase — with the important caveat that these are cross-trial comparisons and that VIVID-1 (mirikizumab CD trial) had different patient population characteristics than FORTIFY (risankizumab CD).

Ulcerative colitis: risankizumab and mirikizumab both approved (different companies)

Risankizumab received US approval for UC in June 2024. The pivotal JAMA paper (Louis et al., 2024) reported 20% clinical remission at week 12 for induction and ~38-40% at week 52 for maintenance (vs ~6% and ~25% for placebo, respectively). These are solid but not exceptional by modern biologic standards. A MAIC comparing mirikizumab (LUCENT-2) vs risankizumab (COMMAND) maintenance found consistently numerically higher clinical remission rates for mirikizumab (51% vs ~38-40%), though the comparison is methodologically limited by the re-randomized withdrawal study designs in both trials. Whether that numerical difference is clinically meaningful or reflects differences in patient populations is the central unresolved question in the UC space for this class.

The bottom line

Risankizumab occupies a distinctive position: among the p19 inhibitors, it and guselkumab have larger, higher-affinity epitopes that translate to better clinical efficacy than tildrakizumab, particularly for speed of response. Against each other in psoriasis, risankizumab and guselkumab are largely equivalent at later timepoints. In IBD, risankizumab holds an exclusive or near-exclusive niche — it is the only p19 inhibitor fully approved for Crohn's disease with robust phase 3 head-to-head evidence — while the UC space has mirikizumab as a comparably positioned competitor. In PsA, guselkumab may have a modest edge for structural protection. Across indications, all approved p19 inhibitors share favorable safety profiles with no meaningful signal differences, consistent with the class-level avoidance of IL-12 suppression.

This was drawn from one search pass, and the IBD comparative space in particular is moving quickly — further studies comparing agents head-to-head in UC and CD are likely ongoing or recently published.