U-ACHIEVE and U-ACCOMPLISHMust knowUC · Induction and maintenance
Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials
Danese S, et al.
Lancet 2022 · PMID 35644166 (PubMed, opens in a new tab) · doi 10.1016/S0140-6736(22)00581-5 (full paper, opens in a new tab)
| Endpoint | 45 mg | 15 mg | 30 mg | Placebo | Difference |
|---|---|---|---|---|---|
| U-ACHIEVE induction, Week 8 (primary endpoint) | 26% (83/319) | not in this comparison | not in this comparison | 5% (7/154) | Adjusted difference 21.6% (95% CI 15.8–27.4); P<0.0001 |
| U-ACCOMPLISH induction, Week 8 (primary endpoint) | 34% (114/341) | not in this comparison | not in this comparison | 4% (7/174) | Adjusted difference 29.0% (95% CI 23.2–34.7); P<0.0001 |
| U-ACHIEVE maintenance, Week 52 · 8-week responders (primary endpoint) | not in this comparison | 42% (63/148) | 52% (80/154) | 12% (18/149) | 15 mg +30.7% (95% CI 21.7–39.8); 30 mg +39.0% (29.7–48.2); both P<0.0001 |
In maintenance both doses beat placebo; 30 mg was numerically higher, but the two doses were not formally compared.
Source: Danese 2022, abstract. Differences are adjusted. Percentages are as printed (the abstract gives 114/341 as 34%).
Structured abstract
BackgroundMany patients with UC need therapy that works quickly and keeps working. Upadacitinib, an oral selective JAK1 inhibitor, was tested as 8-week induction and 52-week maintenance therapy.
MethodsThree phase 3, multicentre, double-blind, placebo-controlled trials: two replicate 8-week induction trials (2:1) and one 52-week randomised-withdrawal maintenance trial (1:1:1). 996 patients. Primary endpoint: Clinical remission by Adapted Mayo score at week 8 (induction) and week 52 (maintenance).
ResultsPrimary result. U-ACHIEVE induction: 26% vs 5% (adjusted difference 21.6%, 95% CI 15.8–27.4). U-ACCOMPLISH: 34% vs 4% (29.0%, 95% CI 23.2–34.7). Maintenance: 42% (15 mg) and 52% (30 mg) vs 12% (30.7%, 95% CI 21.7–39.8, and 39.0%, 95% CI 29.7–48.2). All P<0.0001.
Take-homeUpadacitinib 45 mg for 8 weeks, then 15 mg or 30 mg daily, gives some of the highest placebo-adjusted remission rates of any UC therapy.
| Patients | 996 |
|---|---|
| Population | Age 16–75 with moderately to severely active UC (Adapted Mayo 5–9, endoscopic subscore 2–3) for at least 90 days. U-ACHIEVE induction 474, U-ACCOMPLISH 522; maintenance primary analysis 451 responders to 8-week upadacitinib 45 mg. |
| Comparison | Upadacitinib 45 mg once daily vs placebo for 8 weeks; responders re-randomised to 15 mg or 30 mg once daily vs placebo |
| Drugs | upadacitinib |
| Classes | JAK inhibitor |
| Published | Danese S, et al. Lancet 2022;399:2113–28. |
Key points
- Both maintenance doses worked; 30 mg gave a numerically higher remission rate (52% vs 42% with 15 mg; the doses were not formally compared).
- Common induction adverse events: acne (5% vs 1% in U-ACHIEVE; 7% vs 2% in U-ACCOMPLISH) and creatine phosphokinase elevation (4% vs 2% in U-ACHIEVE).
- Serious adverse events were less frequent with upadacitinib than placebo in induction (3% vs 6% and 3% vs 5%) and maintenance (7% with 15 mg, 6% with 30 mg, 13% with placebo).
- Cancer, adjudicated major adverse cardiac events and venous thromboembolism were infrequent; no treatment-related deaths.
Limitations
- Placebo-controlled only; no head-to-head comparison with a biologic.
- Maintenance used randomised withdrawal of 8-week responders.
- JAK class safety warnings (from ORAL Surveillance in rheumatoid arthritis) still apply.
Commentary
Why it matters. Upadacitinib is a JAK1-selective inhibitor with rapid onset. In a network meta-analysis of phase 3 trials (PMID 39182898), upadacitinib ranked first for inducing clinical remission and endoscopic improvement in moderate to severe UC.
Choosing the maintenance dose. The trial supports both 15 mg and 30 mg. In practice the lower dose is preferred when it controls the disease, with 30 mg for more refractory or extensive disease, weighed against age and cardiovascular, thrombotic and cancer risk.
Related. OCTAVE (PMID 28467869) for tofacitinib and SELECTION (PMID 34090625) for filgotinib, which is not available in Canada.
Journal club
Design
Three phase 3, multicentre, double-blind, placebo-controlled trials: two replicate 8-week induction trials (2:1) and one 52-week randomised-withdrawal maintenance trial (1:1:1). 996 patients.
Primary result. U-ACHIEVE induction: 26% vs 5% (adjusted difference 21.6%, 95% CI 15.8–27.4). U-ACCOMPLISH: 34% vs 4% (29.0%, 95% CI 23.2–34.7). Maintenance: 42% (15 mg) and 52% (30 mg) vs 12% (30.7%, 95% CI 21.7–39.8, and 39.0%, 95% CI 29.7–48.2). All P<0.0001.
Validity and applicability
- Placebo-controlled only; no head-to-head comparison with a biologic.
- Maintenance used randomised withdrawal of 8-week responders.
- JAK class safety warnings (from ORAL Surveillance in rheumatoid arthritis) still apply.
Where it sits now
Upadacitinib 45 mg for 8 weeks, then 15 mg or 30 mg daily, gives some of the highest placebo-adjusted remission rates of any UC therapy.
- 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
- Both maintenance doses beat placebo. How would you choose between 15 mg and 30 mg, and when would you step down?
- After ORAL Surveillance, which patients would you avoid starting on upadacitinib, and why?
- Placebo-adjusted remission was among the highest of any UC drug. Why are cross-trial comparisons of placebo-adjusted rates still risky?