Risankizumab redefines Crohn’s treatment after ustekinumab failure

Abstract

Conventional Crohn’s disease biologic sequencing typically follows drug class transitions: Anti-tumor necrosis factor, anti-integrin, and anti-cytokine therapies. However, a landmark real-world study by Colwill et al disrupts this paradigm, revealing exceptional efficacy within the cytokine pathway, specifically with risankizumab following ustekinumab. This study asserts these provocative findings demand a critical reappraisal of treatment algorithms, while contextualizing them within the current evidence landscape. It will critically appraise the study’s impressive remission rates and favorable safety profile, contrasting them with alternative switch strategies and exploring the compelling mechanistic rationale for sequential interleukin-23 blockade. The discussion will center on integrating this preliminary evidence into clinical decision-making, advocating for further research to define its place in a new treatment hierarchy.

Key Words: Crohn disease; Ustekinumab; Risankizumab; Interleukin-23; Drug substitution; Treatment failure; Secondary loss of response; Biological therapy

Core Tip: Emerging real-world data indicate that risankizumab may induce high rates of clinical and biomarker remission after ustekinumab failure in Crohn’s disease. These findings challenge the traditional cross-class switching paradigm and suggest potential for sequential, increasingly specific interleukin-23 pathway blockade. While mechanistically plausible, the evidence remains preliminary from single-center studies. Balanced interpretation, validation in larger diverse cohorts, and rigorous cost-effectiveness analyses are needed before revising global treatment algorithms.

TO THE EDITOR

The therapeutic landscape of Crohn’s disease (CD) has been transformed by biologics targeting specific inflammatory pathways. Treatment sequencing remains a key challenge when patients lose response to therapy, either as primary non-response or secondary loss of response (SLOR)[1,2]. Conventional strategies emphasise cross-class switching - for instance, from anti-tumor necrosis factor (TNF) agents to vedolizumab or ustekinumab - based on the principle of targeting distinct immune pathways[3]. Although ustekinumab, an interleukin (IL)-12/23 inhibitor, has demonstrated substantial efficacy, many patients ultimately lose response[4,5]. The question of the optimal next-line therapy after ustekinumab failure remains a significant clinical dilemma.

Emerging evidence for risankizumab

Colwill et al[6] conducted a retrospective cohort study of 51 patients who transitioned from ustekinumab to risankizumab. Results were encouraging: Clinical remission (Harvey-Bradshaw Index ≤ 4) improved from 37.1% at baseline to 94.4% at 9 months, with significant biomarker improvements (C-reactive protein, albumin, faecal calprotectin). Patients with SLOR achieved higher remission rates than primary non-responses. Importantly, no serious adverse events were observed, aligning with prior phase 3 trials of risankizumab[7,8]. While this is the most comprehensive dataset to date, smaller cohorts from other centers have also reported promising outcomes, suggesting this phenomenon may be reproducible[9]. These collective findings indicate risankizumab may provide therapeutic benefit even after ustekinumab failure.

Limitations and cautionary notes

While compelling, these findings must be interpreted cautiously. The study was single-center, retrospective, and limited by a small sample size, which inherently limits the generalizability of its impressive remission rates. The absence of randomization and short follow-up restricts causal inference. Furthermore, the lack of endoscopic outcome data means we cannot assess for transmural healing. Unmeasured confounders, such as differences in baseline disease activity and phenotype, concomitant immunomodulator use, or variations in ustekinumab dosing before the switch, may influence the results. Comparisons with established alternatives such as vedolizumab or anti-TNF therapy were not included, making it challenging to gauge comparative effectiveness. Safety data, though favorable, require longer-term monitoring in this sequence to capture rare adverse events.

Mechanistic rationale

The sequential use of ustekinumab and risankizumab has a plausible and increasingly well-defined biological basis. Ustekinumab blocks the p40 subunit shared by IL-12 and IL-23, whereas risankizumab selectively inhibits the p19 subunit unique to IL-23[10,11]. IL-23 is a master regulator of the Th17 axis, a critical pathway in CD pathogenesis, responsible for stabilizing effector T-cell populations and driving chronic inflammation[12]. It is hypothesized that in a subset of patients, disease activity is predominantly driven by IL-23. In these patients, ustekinumab may provide partial suppression, but more specific and potent inhibition of IL-23 via p19 blockade could overcome this residual inflammation. Furthermore, differences in binding affinity, pharmacokinetics, and the absence of IL-12 inhibition (which may have modest protective effects) further explain risankizumab's efficacy in this context[13]. Nonetheless, this remains a hypothesis requiring further mechanistic and clinical validation.

Clinical and policy implications

Clinically, risankizumab represents a reasonable and increasingly compelling option after ustekinumab failure, particularly in SLOR cases. However, its role should currently be complementary rather than superior to established cross-class strategies until head-to-head data are available. Table 1 provides a comparative summary of switch options after ustekinumab failure, contextualizing the remission rates reported by Colwill et al[6] with historical data for vedolizumab and anti-TNF agents, which typically show lower clinical remission rates in the 20%-40% range over similar follow-up periods[14]. A more detailed comparison of key parameters for these switch strategies is presented in Table 2. Cost and access barriers remain significant concerns. Health technology assessments and rigorous cost-effectiveness studies are urgently needed, as the superior efficacy suggested by this study must be weighed against the considerable drug acquisition costs. This is especially critical in low- and middle-income countries, where broader biologic availability is a primary concern over sequencing nuances. Prospective, head-to-head trials are the definitive next step to compare risankizumab with vedolizumab, anti-TNF agents, or novel therapies in ustekinumab-refractory patients.

Table 1 Comparison of traditional vs emerging paradigms in biologic sequencing for Crohn’s disease.

Feature	Traditional paradigm (cross-class)	Emerging paradigm (intra-class/pathway)
Rationale	Avoid shared mechanisms of failure by targeting a completely different pathway	Leverage deeper, more specific inhibition within a known pathogenic pathway
Example sequence	Anti-TNF → vedolizumab (anti-integrin) → ustekinumab (anti-IL-12/23)	Ustekinumab (anti-IL-12/23 p40) → risankizumab (anti-IL-23 p19)
Key driver	Drug class	Mechanism of action and pathway specificity
Supporting evidence	Extrapolated from trials in biologic-naïve patients; real-world cohort studies	Direct real-world evidence from Colwill et al[6] and others[13] showing high efficacy
Advantage	Theoretically avoids class-specific failure mechanisms	Higher efficacy can be achieved by targeting the core pathway with greater specificity

TNF: Tumor necrosis factor; IL: Interleukin.

Table 2 Comparative context for biologic switch strategies after ustekinumab failure in Crohn’s disease.

Parameter	Risankizumab	Vedolizumab	Anti-TNF
Ref.	Colwill et al[6], 2025	Bressler et al[14], 2021	Allez et al[15], 2010
Study design	Single-center retrospective	Multicenter retrospective	Various retrospective
Sample size (n)	51	78	Approximately 50-100 per cohort
Follow-up	9 months	12 months	6-12 months
Clinical remission rate	94.4% (34/36)	39% (at 12 months)	Approximately 20%-40% (variable)
Biomarker improvement (CRP/FCal)	Significant (P < 0.001)	Modest	Modest to significant
Key strengths	High remission rates; excellent safety profile in this cohort	Distinct gut-selective mechanism; well-established safety	Extensive clinical experience; potential for dose optimization
Key limitations	Single-center; no endoscopic data; potential for selection bias	Lower remission rates in this setting	Immunogenicity; potential for attenuated response in later lines of therapy

TNF: Tumor necrosis factor; CRP: C-reactive protein; FCal: Fecal calprotectin.

CONCLUSION

The real-world findings from Colwill et al[6] highlight risankizumab as an encouraging therapeutic option following ustekinumab failure. The robust clinical and biomarker responses, supported by a sound mechanistic rationale, open the door to reconsidering rigid cross-class sequencing paradigms. However, these results should be regarded as hypothesis-generating rather than practice-changing. Future prospective trials, cost-effectiveness evaluations, and biomarker-driven patient stratification are needed to position risankizumab in CD treatment algorithms firmly and to identify the patients most likely to benefit from this novel sequential approach.