Sandborn WJ¹, Feagan BG², Loftus EV Jr³, Peyrin-Biroulet L⁴, Van Assche G⁵, D'Haens G⁶, Schreiber S⁷, Colombel JF⁸, Lewis JD⁹, Ghosh S¹⁰, Armuzzi A¹¹, Scherl E¹², Herfarth H¹³, Vitale L¹⁴, Mohamed MF¹⁴, Othman AA¹⁴, Zhou Q¹⁴, Huang B¹⁴, Thakkar RB¹⁴, Pangan AL¹⁴, Lacerda AP¹⁴, Panes J¹⁵. Gastroenterology. 2020 Feb 7. pii: S0016-5085(20)30167-0. doi: 10.1053/j.gastro.2020.01.047. [Epub ahead of print]

Author information

1 Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.

2 Western University, Robarts Clinical Trials, St. Joseph's Health Care, London, ON, Canada.

3 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

4 Department of Gastroenterology and Inserm U1256 NGERE, University of Lorraine, France, Nancy, France.

5 Department of Gastroenterology and Hepatology, University of Leuven, Leuven, Belgium.

6 Department of Gastroenterology, Amsterdam UMC campus AMC, Amsterdam, Netherlands.

7 Department of Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.

8 Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA.

9 Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

10 University of Birmingham, NIHR Biomedical Research Centre, Birmingham, UK.

11 Presidio Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS Università Cattolica del Sacro Cuore, Rome, Italy.

12 Weill Department of Medicine, New York Presbyterian Hospital Weill Cornell Medicine, New York, NY, USA.

13 Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.

14 AbbVie Inc., North Chicago, IL, USA.

15 Inflammatory Bowel Diseases Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address: JPANES@clinic.cat.

Abstract

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD).

METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily, or 24 mg once daily, and evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%.

RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P<.1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo; endoscopic remission was achieved by 10% (P<.1 vs placebo), 8%, 8% (P<.1 vs placebo), 22% (P<.01 vs placebo), and 14% (P<.05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections versus placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol, compared with patients in the placebo group.

CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients, compared with placebo. Upadacitinib's benefit-risk profile supports further development for treatment of CD. Clinicaltrials.gov ID no: NCT02365649.