Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease

• Published in: The New England journal of medicine Vol. 388; no. 21; pp. 1966 - 1980
• Main Authors: Loftus, Edward V., Panés, Julian, Lacerda, Ana P., Peyrin-Biroulet, Laurent, D’Haens, Geert, Panaccione, Remo, Reinisch, Walter, Louis, Edouard, Chen, Minhu, Nakase, Hiroshi, Begun, Jakob, Boland, Brigid S., Phillips, Charles, Mohamed, Mohamed-Eslam F., Liu, Jianzhong, Geng, Ziqian, Feng, Tian, Dubcenco, Elena, Colombel, Jean-Frederic
• Format: Journal Article Web Resource
• Language: English
• Published: United States Massachusetts Medical Society 25.05.2023
• Subjects: 4RA0KN46E0 (upadacitinib); Abdomen; Allergy; Arthritis; Clinical trials; Crohn Disease - complications; Crohn Disease - drug therapy; Crohn Disease/complications/drug therapy; Crohn's disease; Endoscopy; FDA approval; Gastroenterology; Gastroenterology & hepatology; Gastroenterology General; Gastroentérologie & hépatologie; Herpes zoster; Herpes Zoster - chemically induced; Herpes Zoster - etiology; Herpes Zoster/chemically induced/etiology; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 3-Ring - administration & dosage; Heterocyclic Compounds, 3-Ring - adverse effects; Heterocyclic Compounds, 3-Ring - therapeutic use; Heterocyclic Compounds, 3-Ring/administration & dosage/adverse effects/therapeutic use; Human health sciences; Humans; Immunodeficiency; Immunology; Induction Chemotherapy - adverse effects; Induction Chemotherapy - methods; Induction Chemotherapy/adverse effects/methods; Induction therapy; Inflammatory Bowel Disease; Janus kinase; Janus Kinase Inhibitors; Janus Kinase Inhibitors - administration & dosage; Janus Kinase Inhibitors - adverse effects; Janus Kinase Inhibitors - therapeutic use; Janus Kinase Inhibitors/administration & dosage/adverse effects/therapeutic use; Laboratories; Maintenance Chemotherapy - adverse effects; Maintenance Chemotherapy - methods; Maintenance Chemotherapy/adverse effects/methods; Neutropenia; Neutropenia - chemically induced; Neutropenia - etiology; Neutropenia/chemically induced/etiology; Pain; Patients; Placebos; Remission; Remission (Medicine); Sciences de la santé humaine; Statistical analysis
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa2212728

Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease. In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]). A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).