U-EXCEL, U-EXCEED and U-ENDURECD · Induction and maintenance
Upadacitinib Induction and Maintenance Therapy for Crohn's Disease
Loftus EV, et al.
N Engl J Med 2023 · PMID 37224198 (PubMed, opens in a new tab) · doi 10.1056/NEJMoa2212728 (full paper, opens in a new tab)
| Endpoint | 45 mg | 15 mg | 30 mg | Placebo | Difference |
|---|---|---|---|---|---|
| U-EXCEL clinical remission, Week 12 (primary endpoint) | 49.5% | not in this comparison | not in this comparison | 29.1% | P<0.001 |
| U-EXCEL endoscopic response, Week 12 (primary endpoint) | 45.5% | not in this comparison | not in this comparison | 13.1% | P<0.001 |
| U-EXCEED clinical remission, Week 12 · biologic failure (primary endpoint) | 38.9% | not in this comparison | not in this comparison | 21.1% | P<0.001 |
| U-EXCEED endoscopic response, Week 12 · biologic failure (primary endpoint) | 34.6% | not in this comparison | not in this comparison | 3.5% | P<0.001 |
| U-ENDURE clinical remission, Week 52 · induction responders (primary endpoint) | not in this comparison | 37.3% | 47.6% | 15.1% | P<0.001 |
| U-ENDURE endoscopic response, Week 52 · induction responders (primary endpoint) | not in this comparison | 27.6% | 40.1% | 7.3% | P<0.001 |
In both induction trials, the gap over placebo was wider for endoscopic response than for clinical remission, mainly because so few placebo patients had an endoscopic response.
Source: Loftus 2023, abstract. U-EXCEL included conventional- and biologic-failure patients; U-EXCEED only biologic failure. P<0.001 for every comparison with placebo.
Structured abstract
BackgroundCrohn's disease often fails to respond, or stops responding, to biologics. Upadacitinib, an oral selective JAK inhibitor, was tested for induction and maintenance, including after biologic failure.
MethodsTwo phase 3, randomised (2:1), double-blind, placebo-controlled induction trials and a randomised (1:1:1) maintenance trial. 1,021 patients. Primary endpoint: Co-primary at week 12 (induction) and week 52 (maintenance): clinical remission (CDAI below 150) and endoscopic response (SES-CD decrease of more than 50% from induction baseline, or ≥2 points if baseline SES-CD was 4).
ResultsPrimary result. Week 12 clinical remission: 49.5% vs 29.1% (U-EXCEL) and 38.9% vs 21.1% (U-EXCEED); endoscopic response 45.5% vs 13.1% and 34.6% vs 3.5%. Week 52: clinical remission 37.3% (15 mg) and 47.6% (30 mg) vs 15.1%; endoscopic response 27.6% and 40.1% vs 7.3%. P<0.001 for all.
Take-homeOral upadacitinib induces and maintains clinical remission and endoscopic response in Crohn's disease, including after biologic failure, with JAK-class safety issues to monitor.
| Patients | 1,021 |
|---|---|
| Population | Moderate-to-severe Crohn's disease with endoscopic inflammation. U-EXCEL (526 randomised): inadequate response or intolerance to conventional and/or biologic therapy. U-EXCEED (495 randomised): inadequate response or intolerance to biologics. U-ENDURE: 502 induction responders randomised. |
| Comparison | Upadacitinib 45 mg once daily vs placebo for 12 weeks; responders then 15 mg or 30 mg once daily vs placebo for 52 weeks |
| Drugs | upadacitinib |
| Classes | JAK inhibitor |
| Published | Loftus EV, et al. N Engl J Med 2023;388:1966–80. |
Key points
- Herpes zoster was more frequent with 45 mg and 30 mg than with placebo.
- Hepatic disorders and neutropenia were more frequent with 30 mg than with the other maintenance doses.
- Gastrointestinal perforations: 4 patients on 45 mg and 1 each on 30 mg and 15 mg.
- Oral, rapid-onset therapy with large endoscopic effects, including in the biologic-failure population (U-EXCEED).
- 30 mg gave higher week 52 remission and endoscopic response than 15 mg, at the cost of more adverse effects.
Limitations
- Placebo-controlled; no head-to-head comparison with biologics.
- Maintenance used a withdrawal design in induction responders.
- Long-term safety in Crohn's disease (venous thromboembolism, cardiovascular events, malignancy) relies on extension data and other diseases.
- Industry funded (AbbVie).
Commentary
Upadacitinib is the first oral advanced therapy with phase 3 efficacy in Crohn’s disease. Its fast onset and endoscopic effect make it useful in biologic-refractory disease. JAK-inhibitor safety warnings (infection, herpes zoster, venous thromboembolism, major cardiovascular events, malignancy) apply, especially in older adults and people with cardiovascular risk factors; consider recombinant zoster vaccination before starting.
The perforations seen in the trials make it worth checking for penetrating complications before starting.
Journal club
Design
Two phase 3, randomised (2:1), double-blind, placebo-controlled induction trials and a randomised (1:1:1) maintenance trial. 1,021 patients.
Primary result. Week 12 clinical remission: 49.5% vs 29.1% (U-EXCEL) and 38.9% vs 21.1% (U-EXCEED); endoscopic response 45.5% vs 13.1% and 34.6% vs 3.5%. Week 52: clinical remission 37.3% (15 mg) and 47.6% (30 mg) vs 15.1%; endoscopic response 27.6% and 40.1% vs 7.3%. P<0.001 for all.
Validity and applicability
- Placebo-controlled; no head-to-head comparison with biologics.
- Maintenance used a withdrawal design in induction responders.
- Long-term safety in Crohn's disease (venous thromboembolism, cardiovascular events, malignancy) relies on extension data and other diseases.
- Industry funded (AbbVie).
Where it sits now
Oral upadacitinib induces and maintains clinical remission and endoscopic response in Crohn's disease, including after biologic failure, with JAK-class safety issues to monitor.
- 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.
- 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.
- GRAVITI (2025): Guselkumab can be given entirely by subcutaneous injection for both induction and maintenance in Crohn's disease, with no IV infusion needed.
Questions for discussion
- Endoscopic response with placebo was 3.5% in U-EXCEED. Why might placebo endoscopic response be so low in a biologic-failure population?
- Gastrointestinal perforations occurred on upadacitinib. Which patients with Crohn's disease would worry you most, and how would you monitor them?
- 30 mg outperformed 15 mg at week 52 but had more hepatic disorders and neutropenia. How would you choose a maintenance dose?