1. In this randomized controlled trial, upadacitinib resulted in higher remission rates for patients with Crohn’s disease compared to a placebo.
2. Overall adverse event rates were similar between upadacitinib and placebo groups.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Crohn’s disease is a chronic inflammatory bowel disease that relapses and is associated with many comorbidities and extra-intestinal symptoms. Although immunomodulatory therapies exist, it is well-established that patients with moderate-to-severe disease experience inadequate symptomatic and endoscopic control. Upadacitinib is an oral Janus kinase inhibitor already approved for treating ulcerative colitis, rheumatoid arthritis, and other rheumatologic conditions. Upadacitinib was previously shown in a phase two trial to result in a higher remission rate compared to a placebo for Crohn’s disease. The current study reported results from two phase three induction trials, followed by a phase three maintenance trial to examine the effects of upadacitinib against a placebo in treating moderate-to-severe Crohn’s disease. Both upadacitinib induction and maintenance therapies resulted in higher rates of clinical remission and endoscopic response compared to placebo. A higher maintenance dose of upadacitinib showed higher response rates. Upadacitinib was associated with higher rates of herpes zoster, hepatic disorders, and neutropenia, alongside small numbers of gastrointestinal perforation. The study was limited by the inability to identify rare adverse events. However, these results demonstrated the superiority of upadacitinib to placebo in treating moderate-to-severe Crohn’s disease.
Click here to read the study in NEJM
In-Depth [randomized controlled trial]: The present study consisted of two phase 3 induction trials (U-EXCEL and U-EXCEED) and one phase three maintenance trial (U-ENDURE) investigating the effects of upadacitinib for Crohn’s disease. Patients between 18 to 75 years of age with moderate-to-severe Crohn’s disease for ≥3 months who had failed conventional/biologic therapies were eligible for inclusion. Patients were prohibited from receiving concomitant biologic therapies and immunosuppressants other than methotrexate or glucocorticoids. For U-EXCEL and U-EXCEED, 526 and 495 patients were randomized 2:1 to receive 45mg upadacitinib or placebo once daily for 12 weeks. Five hundred two patients who had a clinical response to upadacitinib induction were randomized 1:1:1 to receive 15mg upadacitinib, 30mg upadacitinib, or placebo once daily for 52 weeks. The primary outcomes were clinical remission and endoscopic response at 12 and 52 weeks. By 12 weeks, a significantly higher proportion of patients who received 45mg upadacitinib than those receiving placebo achieved clinical remission (U-EXCEL, 49.5% vs. 29.1%; U-EXCEED 38.9% vs. 21.1) and endoscopic response (U-EXCEL 45.5% vs. 13.1%; U-EXCEED 34.6% vs. 3.5%) (p<0.001). By 52 weeks, a higher proportion of patients achieved clinical remission with 15mg upadacitinib (37.3%) and 30mg upadacitinib (47.6%) than with placebo (15.1%), as well as endoscopic response with 15mg upadacitinib (27.6%) and 30mg upadacitinib (40.1%) than with placebo (7.3%) (p<0.001). Although overall rates of adverse events were comparable between all trial groups, herpes zoster infections occurred more frequently with 45mg and 30mg upadacitinib compared to placebo controls. In summary, these results demonstrated the efficacy and safety of upadacitinib in treating moderate-to-severe Crohn’s disease that had failed conventional and biologic therapies.
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