INSPIRE and COMMANDUC · Induction and maintenance
Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials
Louis E, et al.
JAMA 2024 · PMID 39037800 (PubMed, opens in a new tab) · doi 10.1001/jama.2024.12414 (full paper, opens in a new tab)
| Endpoint | 1200 mg IV | 180 mg SC | 360 mg SC | Placebo | Difference |
|---|---|---|---|---|---|
| Clinical remission, Week 12 · induction (INSPIRE) (primary endpoint) | 20.3% (132/650) | not in this comparison | not in this comparison | 6.2% (20/325) | Adjusted difference 14.0% (95% CI 10.0–18.0); P<0.001 |
| Clinical remission, Week 52 · maintenance (COMMAND) (primary endpoint) | not in this comparison | 40.2% (72/179) | 37.6% (70/186) | 25.1% (46/183) | 180 mg: 16.3% (97.5% CI 6.1–26.6); P<0.001. 360 mg: 14.2% (97.5% CI 4.0–24.5); P=0.002 |
| Clinical remission, Week 12 · no prior advanced-therapy failure (post hoc) | 29.7% | not in this comparison | not in this comparison | 8.4% | Nominal P<0.0001 |
| Clinical remission, Week 12 · prior advanced-therapy failure (post hoc) | 11.4% | not in this comparison | not in this comparison | 4.3% | Nominal P=0.0083 |
Remission was lower after previous advanced-therapy failure in both arms, and so was the gap from placebo.
Source: Louis 2024, abstract (induction and maintenance; maintenance differences use 97.5% CIs). Subgroups: Panaccione 2025, abstract (post hoc analysis, PMID 39804294).
Structured abstract
BackgroundRisankizumab, an IL-23 p19 antibody, was already used in Crohn's disease; its efficacy in UC, including after failure of other advanced therapies, had not been tested in phase 3.
MethodsTwo phase 3, randomised, double-blind, placebo-controlled trials: 12-week IV induction (INSPIRE, 2:1) and 52-week SC randomised-withdrawal maintenance (COMMAND, 1:1:1). 977 patients. Primary endpoint: Clinical remission by adapted Mayo score (stool frequency ≤1 and not above baseline, rectal bleeding 0, endoscopic subscore ≤1 without friability) at week 12 (induction) and week 52 (maintenance).
ResultsPrimary result. Induction: 20.3% (132/650) vs 6.2% (20/325); adjusted difference 14.0% (95% CI 10.0–18.0); P<0.001. Maintenance: 40.2% (180 mg) and 37.6% (360 mg) vs 25.1%; differences 16.3% (97.5% CI 6.1–26.6; P<0.001) and 14.2% (97.5% CI 4.0–24.5; P=0.002).
Take-homeRisankizumab induces and maintains remission in UC, including after advanced-therapy failure, and many week-12 non-responders respond to extended induction.
| Patients | 977 |
|---|---|
| Population | Moderately to severely active UC with intolerance or inadequate response to conventional and/or advanced therapies; about half had prior advanced-therapy failure (503 of 975 analysed in induction; post hoc, PMID 39804294). Maintenance primary analysis: 548 induction responders. |
| Comparison | Risankizumab 1200 mg IV at weeks 0, 4 and 8 vs placebo; responders randomised to 180 mg or 360 mg SC every 8 weeks vs placebo (risankizumab withdrawal) |
| Drugs | risankizumab |
| Classes | Anti-IL-23 (p19) |
| Published | Louis E, et al. JAMA 2024;332:881–97. |
Key points
- Post hoc (PMID 39804294): induction remission was 29.7% vs 8.4% in patients without prior advanced-therapy failure and 11.4% vs 4.3% in those with it.
- Extended induction (PMID 40953785): of 209 week-12 non-responders given 12 more weeks of risankizumab, 50% (1200 mg IV), 56.3% (180 mg SC) and 57.1% (360 mg SC) had a clinical response at week 24.
- Steroid discontinuation by week 52 in patients on steroids at baseline (post hoc, PMID 40168091): 64.9% (180 mg) and 54.2% (360 mg) vs 36.8% with placebo withdrawal.
- No new safety risks were identified.
Limitations
- The maintenance placebo arm is a withdrawal arm (all had received risankizumab induction), so placebo remission stays relatively high (25.1%).
- 360 mg maintenance was not better than 180 mg.
- Subgroup, extended-induction and steroid analyses are post hoc or secondary.
Commentary
Context. INSPIRE and COMMAND made risankizumab, already used in Crohn’s disease, an option in UC. Results by prior advanced-therapy status show the usual pattern: absolute benefit is largest in patients who have not yet failed an advanced therapy.
Related. Other IL-23 p19 antibodies in UC: mirikizumab (LUCENT, PMID 37379135) and guselkumab (QUASAR, PMID 39706209).
Journal club
Design
Two phase 3, randomised, double-blind, placebo-controlled trials: 12-week IV induction (INSPIRE, 2:1) and 52-week SC randomised-withdrawal maintenance (COMMAND, 1:1:1). 977 patients.
Primary result. Induction: 20.3% (132/650) vs 6.2% (20/325); adjusted difference 14.0% (95% CI 10.0–18.0); P<0.001. Maintenance: 40.2% (180 mg) and 37.6% (360 mg) vs 25.1%; differences 16.3% (97.5% CI 6.1–26.6; P<0.001) and 14.2% (97.5% CI 4.0–24.5; P=0.002).
Validity and applicability
- The maintenance placebo arm is a withdrawal arm (all had received risankizumab induction), so placebo remission stays relatively high (25.1%).
- 360 mg maintenance was not better than 180 mg.
- Subgroup, extended-induction and steroid analyses are post hoc or secondary.
Where it sits now
Risankizumab induces and maintains remission in UC, including after advanced-therapy failure, and many week-12 non-responders respond to extended induction.
- ASTRO (2026): Guselkumab can be started with subcutaneous 400 mg injections instead of IV infusions, with clear benefit over placebo by week 12.
- RELIEVE UCCD (UC) (2026): Duvakitug, an anti-TL1A antibody, showed a dose-related remission signal in UC in phase 2b; phase 3 trials will decide its place.
- QUASAR (2025): Guselkumab induces and maintains remission in UC, and the follow-up ASTRO trial showed induction can be given subcutaneously.
- TUSCANY-2 (2025): Afimkibart missed its phase 2b primary endpoint (total Mayo remission), although remission by the modified Mayo score favoured it; anti-TL1A therapy still needs phase 3 proof.
Questions for discussion
- Maintenance placebo patients had all received IV risankizumab. How does carry-over affect a withdrawal arm's 25.1% remission?
- 360 mg was not better than 180 mg. What, if anything, would make you choose the higher dose?
- The advanced-therapy subgroups were post hoc. How should you use them when counselling a patient who has failed two advanced therapies?