Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn’s Disease
Open accessAbstract
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 upadacitinib once daily and were 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 the 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 by 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 vs 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 levels 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, Number: NCT02365649).
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Clinical trials show that selective JAK1 inhibitors such as filgotinib and upadacitinib are more effective than the pan-JAK inhibitor tofacitinib in treating Crohn's disease and ulcerative colitis.
“Importantly, evidences from a set of clinical trials showed that the selective JAK1 inhibitors, such as filgotinib and upadacitinib, are more effective than the pan-JAK inhibitor of tofacitinib in the treatment of Crohn’s disease and ulcerative colitis [104–106].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [104]
The Discussion (page unavailable) reports that upadacitinib was superior to placebo for endoscopic improvement in patients with moderately to severely active Crohn’s disease. It does not establish that upadacitinib or filgotinib is more effective than tofacitinib, or extend that comparison to ulcerative colitis; the References list separate trials but provide no comparative result. (LLM, conf=0.88)
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Research works printed but not linked: 31
- Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn's disease in adults. Am J Gastroenterol 2018;113:481-517.
- Gomollon F, Dignass A, Annese V, et al. European evidence-based consensus on the diagnosis and management of Crohn's disease 2016: part 1: diagnosis and medical management. J Crohns Colitis 2017;11:3- 25.
- Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical re- view on corticosteroids, immunomodulators, and inflix- imab in inflammatory bowel disease. Gastroenterology 2006;130:940-987.
- Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinu- mab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2016;375:1946-1960.
- De Vries LCS, Wildenberg ME, De Jonge WJ, et al. The future of Janus kinase inhibitors in inflammatory bowel disease. J Crohns Colitis 2017;11:885-893.
- Olivera P, Danese S, Peyrin-Biroulet L. JAK inhibition in inflammatory bowel disease. Expert Rev Clin Immunol 2017;13:693-703.
- Sandborn WJ, Ghosh S, Panes J, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. Clin Gastroenterol Hepatol 2014; 12:1485-1493.
- Panes J, Sandborn WJ, Schreiber S, et al. Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. Gut 2017;66:1049-1059.
- Parmentier JM, Voss J, Graff C, et al. In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494). BMC Rheumatol 2018;2:23.
- Aguilar D, Planell N, Panés J, et al. P843 upadacitinib- induced endoscopic improvement is associated with modulation of pathways involved in Crohn's disease path- ogenesis. J Crohns Colitis 2018;12:S542-S543 (suppl 1).
- Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity. Aliment Pharmacol Ther 2015;41:77-86.
- Feagan B, Sandborn WJ, Rutgeerts P, et al. Performance of Crohn's disease clinical trial endpoints based upon different cutoffs for patient reported outcomes or endo- scopic activity: analysis of EXTEND data. Inflamm Bowel Dis 2018;24:932-942.
- Ferrante M, Colombel JF, Sandborn WJ, et al. Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC. Gastroenterology 2013;145:978-986.
- Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics 2005;61:738-748.
- Khan I, Sarker SJ, Hackshaw A. Smaller sample sizes for phase II trials based on exact tests with actual error rates by trading-off their nominal levels of significance and power. Br J Cancer 2012;107:1801-1809.
- Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. The North Amer- ican Crohn's Study Group Investigators. N Engl J Med 1995;332:292-297.
- Klünder B, Mohamed MF, Othman AA. Population pharmacokinetics of upadacitinib in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I and II clinical trials. Clin Pharmacokinet 2018;57:977- 988.
- Mohamed MF, Camp HS, Jiang P, et al. Pharmacoki- netics, safety and tolerability of ABT-494, a novel se- lective JAK 1 inhibitor, in healthy volunteers and subjects with rheumatoid arthritis. Clin Pharmacokinet 2016; 55:1547-1558.
- Klunder B, Mittapalli RK, Mohamed MF, et al. Population pharmacokinetics of upadacitinib using the immediate- release and extended-release formulations in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I-III clinical trials. Clin Pharmacokinet 2019; 58:1045-1058.
- Genovese MC, Smolen JS, Weinblatt ME, et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol 2016;68:2857-2866.
- Kremer JM, Emery P, Camp HS, et al. A phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti- tumor necrosis factor therapy. Arthritis Rheumatol 2016; 68:2867-2877.
- Mohamed MF, Zeng J, Marroum PJ, et al. Pharmacoki- netics of upadacitinib with the clinical regimens of the extended-release formulation utilized in rheumatoid arthritis phase 3 trials. Clin Pharmacol Drug Dev 2019;8:208-216.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as in- duction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723-1736.
- Westhovens R, Taylor PC, Alten R, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in pa- tients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose- finding study (DARWIN 1). Ann Rheum Dis 2017; 76:998-1008.
- Kavanaugh A, Kremer J, Ponce L, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheu- matoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis 2017;76:1009-1019.
- Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and ef- ficacy of tofacitinib, an oral Janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol 2014;41:837-852.
- Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol 2014;66:2675-2684.
- Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011; 13(5):R141.
- Strangfeld A, Richter A, Siegmund B, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treat- ment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis 2017;76:504-510.
- Takeda Pharmaceuticals America, Inc., Deerfield, IL), or natalizumab (Tysabri; Biogen, Cambridge, MA) <8 weeks before baseline. Patients who discontinued ustekinumab (Stelara; Janssen Biotech, Inc., Horsham, PA) <12 weeks before baseline
- Patient who has had surgical bowel resections 2138.e4 Sandborn et al Gastroenterology Vol. 158, No. 8
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“Importantly, evidences from a set of clinical trials showed that the selective JAK1 inhibitors, such as filgotinib and upadacitinib, are more effective than the pan-JAK inhibitor of tofacitinib in the treatment of Crohn’s disease and ulcerative colitis [104–106].”
Background
- Authors
- Sandborn, W. J., Feagan, B. G., Loftus, E. V., Peyrin-Biroulet, L., Van Assche, G., D’Haens, G., Schreiber, S., Colombel, J.-F., Lewis, J. D., Ghosh, S., Armuzzi, A., Scherl, E., Herfarth, H., Vitale, L., Mohamed, M.-E. F., Othman, A. A., Zhou, Q., Huang, B., Thakkar, R. B., Pangan, A. L., Lacerda, A. P., & Panes, J.
- Affiliations
- University of California San Diego (US)
- Western University (CA)
- Mayo Clinic (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- University Hospital Schleswig-Holstein (DE)
- University of Pennsylvania (US)
- University of Birmingham (GB)
- Università Cattolica del Sacro Cuore (IT)
- NewYork–Presbyterian Hospital (US)
- University of North Carolina at Chapel Hill (US)
- AbbVie (United States) (US)
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 158
- Issue
- 8
- Pages
- 2123-2138.e8
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W3004601288
- Cited by
- 322
- References
- 0
- Citations by year
- 2026: 29 · 2025: 57 · 2024: 54 · 2023: 71 · 2022: 49 · 2021: 43 · 2020: 19
- FWCI
- 26.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Gastroenterology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (acceptedVersion, cc-by-nc-nd)
- Lirias (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Meso Scale Diagnostics
- Schering-Plough
- Teva Pharmaceutical Industries
- Celgene
- AbbVie
- National Institutes of Health
- UCB
- National Institute of Diabetes and Digestive and Kidney Diseases
- California Community Foundation
- Vifor Pharma
- Johns Hopkins University
- Tillotts Pharma
- Takeda Pharmaceutical Company
- Janssen Pharmaceuticals
- Nestlé Health Science
- Dr. Falk Pharma
- Atlantic Healthcare
- Eli Lilly and Company
- Boehringer Ingelheim España
- Pfizer
- Genentech
- Ipsen Biopharmaceuticals
- Arrien Pharmaceuticals
- Crohn's and Colitis Foundation of America
- Seres Therapeutics
- Bristol-Myers Squibb
- AstraZeneca España
- Roche España
- Elan
- Shire
- Gilead Sciences
- Biogen
- Johnson and Johnson
- Merck
- Janssen Research and Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- upadacitinib, Crohn's disease, JAK inhibitors, clinical remission, endoscopic remission, maintenance therapy, dose-response relationship, serious infections, adverse events, immunosuppressants, tumor necrosis factor inhibitors, induction period, ileocolonoscopy, drug safety, efficacy
- MeSH terms
- Janus Kinase Inhibitors, Adult, Aged, Colonoscopy, Crohn Disease, Dose-Response Relationship, Drug, Double-Blind Method, Female, Gastrointestinal Agents, Heterocyclic Compounds, 3-Ring, Humans, Male, Middle Aged, Remission Induction, Severity of Illness Index, Time Factors, Treatment Outcome, Young Adult
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