Y-ECCO Literature Review: Krishna Shah
Krishna Shah
Risankizumab versus ustekinumab for moderate-to-severe Crohn’s disease
Peyrin-Biroulet L, Chapman JC, Colombel JF, et al.
N Engl J Med 2024;391:213–23.
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Introduction
The therapeutic landscape for Inflammatory Bowel Disease (IBD) is rapidly evolving, with the introduction of new advanced therapies. Despite these advances, there is an absence of head-to-head clinical trial data to support decision-making regarding the choice and sequencing of drugs – with evidence often being extrapolated from indirect comparisons between single-agent clinical trials or observational studies [1]. This is well highlighted by the fact that there is often a lack of data to support choice of medication after first-line use of anti-tumour necrosis factor (TNF) agents. Ustekinumab is a humanised IgG1 monoclonal antibody that selectively binds to the p40 subunit and was approved for the treatment of Crohn’s Disease (CD) several years ago. Risankizumab, which was approved more recently, is also an IgG1 monoclonal antibody, but it selectively binds to the p19 subunit. Both p19 and p40 are components of the interleukin-23 (IL-23) proinflammatory cytokine, which plays a crucial role in skin, joint and gastrointestinal inflammation [2]. Peyrin-Biroulet and colleagues sought to undertake a direct head-to-head comparison of ustekinumab with risankizumab for patients with CD after failure of anti-TNF therapy.
Methods
The SEQUENCE trial was a phase 3b, multicentre, open-label, randomised controlled trial that aimed to assess the efficacy and safety of risankizumab compared to ustekinumab in patients with moderate-to-severe CD who had experienced either inadequate response or
intolerance to prior anti-TNF medication [3]. The trial population consisted of patients aged 18–80 who had a diagnosis of moderate-to-severely active CD with prior failure of, or unacceptable side effects from, at least one anti-TNF therapy. Disease severity was defined by a Crohn's Disease Activity Index (CDAI) of 220–450 and a Simple Endoscopic Score for Crohn's Disease (SES-CD) of at least 6 for ileocolonic disease or ≥4 for isolated ileal disease. Patients with previous biologic failure to an advanced therapy other than an anti-TNF were also excluded from the trial. Importantly a mandatory glucocorticoid taper was initiated at week 2 for all patients.
Patients were randomised in a 1:1 ratio to receive either risankizumab or ustekinumab. The primary endpoints of the study were clinical remission at week 24 and endoscopic remission at week 48. A non-inferiority assessment was conducted in the first 50% of patients who completed the week 24 assessment to support the continuation of the study, as this trial was designed prior to risankizumab receiving regulatory approval for the treatment of CD. Secondary endpoints included clinical remission at week 48, endoscopic response at weeks 24 and 48, and glucocorticoid-free clinical and endoscopic remission at week 48.
Key findings
A total of 520 patients were randomised and included in the intention-to-treat population: 255 received risankizumab and 265 received ustekinumab. The baseline characteristics were well balanced across the groups, with approximately 25% of patients having previously failed one anti-TNF therapy and 25% taking glucocorticoids at baseline.
The trial demonstrated that risankizumab was non-inferior to ustekinumab with respect to clinical remission at week 24 [58.6% vs 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval (CI) 6.6–30.3]. At week 48, 31.8% (82/255) of patients in the risankizumab group were in endoscopic remission compared to 16.2% (43/265) of patients in the ustekinumab group (adjusted difference 15.6 percentage points; 95% CI 8.4–22.9; p<0.001).
Risankizumab was also superior across all pre-defined secondary endpoints, including clinical remission at week 48 (60.8% vs 40.8%) and glucocorticoid-free endoscopic remission (31.4% vs 15.5%). Additionally, there was a lower rate of serious adverse events with risankizumab than with ustekinumab (10.3% vs 17.4%), including a lower incidence of hospitalisation related to CD.
Discussion
SEQUENCE provides crucial head-to-head data comparing two advanced treatments for the management of patients living with CD. The results demonstrate the superiority of risankizumab over ustekinumab across all primary and secondary outcomes. Importantly, no new safety concerns were identified during the trial. The use of endoscopic remission as a primary outcome underscores the importance of objective outcome measures and the need to prioritise this treatment goal, aligning with the STRIDE II consensus recommendations [4].
These results are also consistent with findings from a head-to-head clinical trial in patients with moderate-to-severe plaque psoriasis, where risankizumab also demonstrated superior efficacy compared to ustekinumab [5]. The selection of ustekinumab as the comparator raises questions about risankizumab’s positioning in the therapeutic hierarchy for CD management. While ustekinumab targets both IL-12 and IL-23, both of which are implicated in pathogenesis of CD, the SEQUENCE trial suggests that IL-12 may be more important for achieving important results for patients, such as improved endoscopic outcomes.
It is important to note that the open-label design is a potential limitation of the trial. Despite blinding of the central endoscopic assessors, this design could still introduce bias in reporting of clinical outcomes. Additionally, as with most clinical trials in CD, SEQUENCE only reported outcomes up to 48 weeks. This highlights an important point in the field generally, namely that there is a need for longer-term follow-up data, particularly to assess the sustainability of these results, long-term safety, prevention of complications and need for surgery.
In addition to long-term follow-up data, real-world studies will be essential to fully understand the efficacy and safety profiles in more diverse, and multiple bio-exposed patient populations. Despite the clinical superiority of risankizumab, it is clear that any translation of these findings to clinical practice will also need to consider cost and most effective allocation of healthcare resources, especially in cost-sensitive healthcare settings. The SEQUENCE trial did not evaluate the cost-effectiveness of risankizumab compared to ustekinumab, and this is likely to be a critical factor in clinical decision-making given the higher cost of risankizumab and the imminent introduction of ustekinumab biosimilar preparations in many countries around the world.
Conclusions
The SEQUENCE trial demonstrated that risankizumab is superior to ustekinumab in treating moderate-to-severely active CD in patients with an inadequate response to at least one prior anti-TNF therapy. The findings suggest that inhibition of p19 may offer a more targeted and effective therapeutic approach. However, while the results are promising, further studies including long-term follow-up, real-world evidence and cost-effectiveness studies are necessary to fully establish the relevant positioning of ustekinumab and risankizumab in the treatment algorithm for patients with CD.
References
- Singh S, Hassan Murad M, Fumery M, et al. Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn’s disease: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2021;6:1002–14.
- Chyuan I-T, Lai J-H. New insights into the IL-12 and IL-23: From a molecular basis to clinical application in immune-mediated inflammation and cancers. Biochem Pharmacol 2020;175:113928.
- Peyrin-Biroulet L, Chapman JC, Colombel J-F, et al. Risankizumab versus ustekinumab for moderate-to-severe Crohn’s disease. N Engl J Med 2024;391:213–23.
- Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): Determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology 2021;160:1570–83.
- Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med 2017;376:1551–60.
Profile
Krishna Shah is an IBD Clinical Research Fellow based at the Royal London Hospital in the United Kingdom. Her research interests include IBD in pregnancy and intestinal ultrasound, in which she is currently training through the International Bowel Ultrasound (IBUS) programme.