UNITI-1, UNITI-2 and IM-UNITICD · Induction and maintenance
Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease
Feagan BG, et al.
N Engl J Med 2016 · PMID 27959607 (PubMed, opens in a new tab) · doi 10.1056/NEJMoa1602773 (full paper, opens in a new tab)
| Endpoint | 130 mg IV | About 6 mg/kg IV | 90 mg SC every 8 weeks | 90 mg SC every 12 weeks | Placebo | Difference |
|---|---|---|---|---|---|---|
| UNITI-1: anti-TNF failure, Clinical response, week 6 (primary endpoint) | 34.3% | 33.7% | not in this comparison | not in this comparison | 21.5% | P≤0.003 for both doses vs placebo |
| UNITI-2: conventional therapy failure, Clinical response, week 6 (primary endpoint) | 51.7% | 55.5% | not in this comparison | not in this comparison | 28.7% | P<0.001 for both doses vs placebo |
| IM-UNITI maintenance, Remission, week 44 (primary endpoint) | not in this comparison | not in this comparison | 53.1% | 48.8% | 35.9% | Every 8 weeks P=0.005; every 12 weeks P=0.04 vs placebo |
Response was lower after anti-TNF failure than after conventional therapy failure, with either dose.
Source: Feagan 2016, abstract. The induction and maintenance placebo groups are different patients.
Structured abstract
BackgroundMany patients with Crohn's disease fail or cannot tolerate TNF antagonists. Ustekinumab, an IL-12/23 p40 antibody, was tested as IV induction with and without prior anti-TNF failure, then as subcutaneous maintenance.
MethodsTwo phase 3, randomised, double-blind, placebo-controlled induction trials and a randomised-withdrawal maintenance trial. 1,369 patients. Primary endpoint: Induction: clinical response at week 6 (CDAI decrease ≥100 points or CDAI below 150). Maintenance: remission (CDAI below 150) at week 44.
ResultsPrimary result. Week 6 response, UNITI-1: 34.3% (130 mg) and 33.7% (6 mg/kg) vs 21.5% (P≤0.003). UNITI-2: 51.7% and 55.5% vs 28.7% (P<0.001). Week 44 remission: 53.1% (every 8 weeks) and 48.8% (every 12 weeks) vs 35.9% (P=0.005 and P=0.04).
Take-homeIV ustekinumab induction followed by SC maintenance is effective in Crohn's disease, with larger effects in anti-TNF-naive patients.
| Patients | 1,369 |
|---|---|
| Population | Moderately to severely active Crohn's disease (CDAI 220–450). UNITI-1 (741 patients): primary or secondary non-response or intolerance to TNF antagonists. UNITI-2 (628 patients): failure or intolerance of conventional therapy. IM-UNITI: 397 induction responders randomised. |
| Comparison | IV ustekinumab induction vs placebo, then SC ustekinumab maintenance vs placebo |
| Drugs | ustekinumab |
| Classes | Anti-IL-12/23 |
| Published | Feagan BG, et al. N Engl J Med 2016;375:1946–60. |
Key points
- Response rates were lower in anti-TNF-experienced patients (UNITI-1) than in patients who had failed only conventional therapy (UNITI-2).
- Adverse-event rates were similar across treatment groups within each trial.
- Induction: a single IV dose of 130 mg or about 6 mg/kg. Maintenance: 90 mg SC every 8 or 12 weeks. The weight-based IV dose of about 6 mg/kg followed by 90 mg SC became the standard regimen.
- Ustekinumab later matched adalimumab in biologic-naive patients (SEAVUE) but was beaten by risankizumab after anti-TNF failure (SEQUENCE).
Limitations
- Symptom-based (CDAI) primary endpoints; endoscopic healing was not a primary endpoint.
- Randomised-withdrawal maintenance in induction responders only, so maintenance results apply to patients who respond to induction.
- Industry funded (Janssen).
Commentary
The UNITI program established ustekinumab as the first non-TNF, non-integrin biologic for Crohn’s disease. Ustekinumab biosimilars are now available in Canada, which makes it a lower-cost option.
When response is lost on 90 mg every 8 weeks, REScUE found that shortening to every 4 weeks after IV reinduction was no better than staying on every 8 weeks, and remission rates in both arms were low.
Journal club
Design
Two phase 3, randomised, double-blind, placebo-controlled induction trials and a randomised-withdrawal maintenance trial. 1,369 patients.
Primary result. Week 6 response, UNITI-1: 34.3% (130 mg) and 33.7% (6 mg/kg) vs 21.5% (P≤0.003). UNITI-2: 51.7% and 55.5% vs 28.7% (P<0.001). Week 44 remission: 53.1% (every 8 weeks) and 48.8% (every 12 weeks) vs 35.9% (P=0.005 and P=0.04).
Validity and applicability
- Symptom-based (CDAI) primary endpoints; endoscopic healing was not a primary endpoint.
- Randomised-withdrawal maintenance in induction responders only, so maintenance results apply to patients who respond to induction.
- Industry funded (Janssen).
Where it sits now
IV ustekinumab induction followed by SC maintenance is effective in Crohn's disease, with larger effects in anti-TNF-naive patients.
- REScUE (2026): After secondary loss of response to ustekinumab, IV reinduction plus every-4-week dosing is no better than reinduction plus every-8-week dosing, and few patients regain remission either way.
- 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.
Questions for discussion
- Response was lower after anti-TNF failure (UNITI-1) than after conventional failure (UNITI-2). How does this shape where you place ustekinumab?
- The primary endpoints were CDAI-based. What would endoscopic endpoints have added, and how have later trials such as SEAVUE and SEQUENCE filled the gap?
- Every-8-week maintenance gave numerically higher remission than every 12 weeks. When would you shorten the interval further?