SEQUENCEMust knowCD · Head-to-head
Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn's Disease
Peyrin-Biroulet L, et al.
N Engl J Med 2024 · PMID 39018531 (PubMed, opens in a new tab) · doi 10.1056/NEJMoa2314585 (full paper, opens in a new tab)
| Endpoint | Risankizumab | Ustekinumab | Difference |
|---|---|---|---|
| Clinical remission, Week 24 · CDAI below 150 (primary endpoint) | 58.6% | 39.5% | Adjusted difference +18.4 points (95% CI 6.6–30.3); non-inferior |
| Endoscopic remission, Week 48 · SES-CD ≤4 (primary endpoint) | 31.8% (n=255) | 16.2% (n=265) | Adjusted difference +15.6 points (95% CI 8.4–22.9); P<0.001 |
The superiority claim rests on the week-48 endoscopic endpoint; the week-24 test was designed only to show risankizumab was no worse.
Source: Peyrin-Biroulet 2024, abstract. Week-24 remission was analysed in the first 50% of patients; week-48 endoscopic remission in all 520 (255 vs 265). Differences are adjusted.
Structured abstract
BackgroundAfter anti-TNF failure in Crohn's disease, an IL-23 p19 inhibitor (risankizumab) and an IL-12/23 p40 inhibitor (ustekinumab) were both options, but how they compared was unknown.
MethodsPhase 3b, multicentre, open-label, randomised controlled trial with blinded endpoint assessment; 48 weeks. 520 patients. Primary endpoint: Two primary endpoints tested in sequence: clinical remission (CDAI below 150) at week 24 for non-inferiority (margin 10 percentage points, first 50% of patients), then endoscopic remission at week 48 (SES-CD ≤4, a decrease of ≥2 points, and no subscore above 1) for superiority (all patients).
ResultsPrimary result. Week 24 clinical remission 58.6% vs 39.5% (adjusted difference 18.4 percentage points, 95% CI 6.6–30.3; non-inferior). Week 48 endoscopic remission 31.8% vs 16.2% (adjusted difference 15.6 percentage points, 95% CI 8.4–22.9; P<0.001; superior).
Take-homeAfter anti-TNF failure, risankizumab beats ustekinumab for endoscopic remission, so an IL-23 p19 inhibitor is the stronger second-line choice of the two.
| Patients | 520 |
|---|---|
| Population | Adults with moderate-to-severe Crohn's disease (CDAI 220–450 per the trial registration) with inadequate response or unacceptable side effects with one or more anti-TNF agents. 520 patients in the full intention-to-treat efficacy population (527 enrolled per the trial registration). |
| Comparison | Risankizumab vs ustekinumab, both at standard IV induction and SC maintenance doses |
| Drugs | risankizumab, ustekinumab |
| Classes | Anti-IL-23 p19, Anti-IL-12/23 |
| Published | Peyrin-Biroulet L, et al. N Engl J Med 2024;391:213–23. |
Key points
- Risankizumab was non-inferior for clinical remission and superior for endoscopic remission.
- More patients completed all assigned treatment with risankizumab: 90.2% (230/255) vs 72.8% (193/265).
- The incidence of adverse events appeared similar in the two groups.
- Applies to patients who have already failed an anti-TNF, the most common second-line decision in Crohn's disease.
Limitations
- Open-label (endpoint assessment was blinded).
- Industry funded by the maker of risankizumab (AbbVie).
- Ustekinumab dose escalation was not part of the comparison; the trial does not address patients naive to anti-TNF.
Commentary
SEQUENCE is the first head-to-head trial between two drugs that both target IL-23 (ustekinumab blocks the shared p40 subunit of IL-12 and IL-23; risankizumab blocks the IL-23-specific p19 subunit). Its result has made a p19 inhibitor the usual choice over ustekinumab when an anti-TNF has failed.
Other IL-23 p19 inhibitors were also compared with ustekinumab within placebo-controlled trials: VIVID-1 (mirikizumab) and GALAXI-2 and GALAXI-3 (guselkumab). Those comparisons were secondary, so SEQUENCE remains the cleanest head-to-head evidence.
Several ustekinumab biosimilars are marketed in Canada, so drug-plan coverage may influence the choice; the efficacy data favour risankizumab after anti-TNF failure.
Journal club
Design
Phase 3b, multicentre, open-label, randomised controlled trial with blinded endpoint assessment; 48 weeks. 520 patients.
Primary result. Week 24 clinical remission 58.6% vs 39.5% (adjusted difference 18.4 percentage points, 95% CI 6.6–30.3; non-inferior). Week 48 endoscopic remission 31.8% vs 16.2% (adjusted difference 15.6 percentage points, 95% CI 8.4–22.9; P<0.001; superior).
Validity and applicability
- Open-label (endpoint assessment was blinded).
- Industry funded by the maker of risankizumab (AbbVie).
- Ustekinumab dose escalation was not part of the comparison; the trial does not address patients naive to anti-TNF.
Where it sits now
After anti-TNF failure, risankizumab beats ustekinumab for endoscopic remission, so an IL-23 p19 inhibitor is the stronger second-line choice of the two.
- VIVID-1 (2024): Mirikizumab, an IL-23 p19 inhibitor, induces and maintains clinical and endoscopic response in Crohn's disease, including after biologic failure.
- GALAXI-2 and GALAXI-3 (2025): IV guselkumab induction followed by SC maintenance is effective in Crohn's disease and outperformed ustekinumab at week 48 on several endpoints.
- SEAVUE (2022): In biologic-naive moderate-to-severe Crohn's disease, ustekinumab was not superior to adalimumab monotherapy at 1 year and both worked well, so choose by patient factors, safety and preference.
Questions for discussion
- The trial was open-label with blinded endoscopy reading. Which outcomes are most open to bias from the open-label design?
- Ustekinumab dose escalation was not part of the comparison. Does that change how you read the result?
- With lower-cost ustekinumab biosimilars available, when would you still choose ustekinumab after anti-TNF failure?