ADVANCE and MOTIVATECD · Induction and maintenance
Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials
D'Haens G, et al.
Lancet 2022 · PMID 35644154 (PubMed, opens in a new tab) · doi 10.1016/S0140-6736(22)00467-6 (full paper, opens in a new tab)
| Endpoint | 600 mg | 1200 mg | Placebo | Difference |
|---|---|---|---|---|
| CDAI clinical remission, ADVANCE · week 12 (primary endpoint) | 45% (152/336) | 42% (141/339) | 25% (43/175) | Difference vs placebo: 600 mg 21% (95% CI 12–29); 1200 mg 17% (8–25) |
| Endoscopic response, ADVANCE · week 12 (primary endpoint) | 40% (135/336) | 32% (109/339) | 12% (21/175) | Difference vs placebo: 600 mg 28% (95% CI 21–35); 1200 mg 20% (14–27) |
| CDAI clinical remission, MOTIVATE · week 12 (primary endpoint) | 42% (80/191) | 40% (77/191) | 20% (37/187) | Difference vs placebo: 600 mg 22% (95% CI 13–31); 1200 mg 21% (12–29) |
| Endoscopic response, MOTIVATE · week 12 (primary endpoint) | 29% (55/191) | 34% (65/191) | 11% (21/187) | Difference vs placebo: 600 mg 18% (95% CI 10–25); 1200 mg 23% (15–31) |
1200 mg was no better than 600 mg, which became the induction dose.
Source: D'Haens 2022, abstract (primary analysis populations; clinical remission by CDAI). Differences are adjusted, each dose vs placebo; all P≤0.0001.
Structured abstract
BackgroundMany patients with Crohn's disease do not respond to, or lose response to, anti-TNF and other biologics; selective IL-23 p19 blockade with risankizumab was a new mechanism to test.
MethodsTwo phase 3, randomised, double-masked, placebo-controlled induction trials. 1,549 patients. Primary endpoint: Co-primary at week 12: clinical remission (by CDAI, or by stool frequency and abdominal pain score) and endoscopic response.
ResultsPrimary result. 600 mg vs placebo. ADVANCE: CDAI remission 45% vs 25% (adjusted difference 21%, 95% CI 12–29); endoscopic response 40% vs 12% (28%, 21–35). MOTIVATE: CDAI remission 42% vs 20% (22%, 13–31); endoscopic response 29% vs 11% (18%, 10–25). All co-primary endpoints met for both doses (P≤0.0001).
Take-homeIV risankizumab induction works in both biologic-naive and biologic-experienced Crohn's disease, with endoscopic response rates well above placebo.
| Patients | 1,549 |
|---|---|
| Population | Ages 16–80 with moderately to severely active Crohn's disease. ADVANCE (931 randomised): intolerance or inadequate response to biologics or conventional therapy. MOTIVATE (618 randomised): intolerance or inadequate response to biologics. Primary analysis populations 850 and 569. |
| Comparison | Risankizumab 600 mg or 1200 mg IV vs placebo at weeks 0, 4 and 8 |
| Drugs | risankizumab |
| Classes | Anti-IL-23 p19 |
| Published | D'Haens G, et al. Lancet 2022;399:2015–30. |
Key points
- 1200 mg was not better than 600 mg: ADVANCE CDAI remission 42% and endoscopic response 32%; MOTIVATE 40% and 34%.
- Stool frequency and abdominal pain remission with 600 mg: 43% vs 22% (ADVANCE) and 35% vs 19% (MOTIVATE).
- Treatment-emergent adverse events were similar across groups. Three deaths during induction (two placebo, one risankizumab 1200 mg, judged unrelated).
- Benefit was seen in the biologic-failure population (MOTIVATE) as well as the mixed population (ADVANCE).
Limitations
- 12-week placebo-controlled induction only; maintenance is in FORTIFY.
- Clinical remission was defined differently in the US (CDAI) and non-US (stool frequency and abdominal pain) protocols.
- Industry funded (AbbVie).
Commentary
ADVANCE and MOTIVATE established IV risankizumab 600 mg at weeks 0, 4 and 8 as induction for Crohn’s disease. Maintenance results are in FORTIFY, and the head-to-head comparison with ustekinumab after anti-TNF failure is SEQUENCE.
Later evidence. Patients without a clinical response at week 12 were re-randomised to 12 more weeks of risankizumab (1200 mg IV, or 180 mg or 360 mg SC). By week 24, 62.3% to 76.2% had a stool frequency and abdominal pain clinical response, and 18.0% to 25.1% had endoscopic remission, depending on the regimen (Panaccione R, et al. Clin Gastroenterol Hepatol 2025;23:2012–22; PMID 39909280). These uncontrolled data suggest that week-12 non-response alone need not end a trial of risankizumab.
Journal club
Design
Two phase 3, randomised, double-masked, placebo-controlled induction trials. 1,549 patients.
Primary result. 600 mg vs placebo. ADVANCE: CDAI remission 45% vs 25% (adjusted difference 21%, 95% CI 12–29); endoscopic response 40% vs 12% (28%, 21–35). MOTIVATE: CDAI remission 42% vs 20% (22%, 13–31); endoscopic response 29% vs 11% (18%, 10–25). All co-primary endpoints met for both doses (P≤0.0001).
Validity and applicability
- 12-week placebo-controlled induction only; maintenance is in FORTIFY.
- Clinical remission was defined differently in the US (CDAI) and non-US (stool frequency and abdominal pain) protocols.
- Industry funded (AbbVie).
Where it sits now
IV risankizumab induction works in both biologic-naive and biologic-experienced Crohn's disease, with endoscopic response rates well above placebo.
- FORTIFY (2022): SC risankizumab maintains remission and endoscopic response in Crohn's disease, with 360 mg every 8 weeks giving the most consistent benefit.
- SEQUENCE (2024): 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.
- RELIEVE UCCD (CD) (2026): Duvakitug, an anti-TL1A antibody, gave a dose-related endoscopic response signal in Crohn's disease in phase 2b; phase 3 trials will decide whether TL1A becomes a new Crohn's disease target.
- DIVERSITY (2025): Filgotinib failed its week-10 induction endpoints in Crohn's disease, unlike upadacitinib in its own phase 3 trials, so JAK inhibitors should not be assumed to work equally well in Crohn's disease.
Questions for discussion
- Clinical remission was defined by CDAI in the US and by stool frequency and abdominal pain elsewhere. How do these differ, and why have regulators moved toward patient-reported outcomes?
- Endoscopic response with 600 mg was 40% in ADVANCE but 29% in MOTIVATE. What explains the gap, and how would you set expectations for a patient after two failed biologics?
- Week-12 non-responders could receive more risankizumab. How long would you persist before switching class?