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 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,
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2123-2138.e8 |
| Journal | Gastroenterology |
| Volume | 158 |
| Issue number | 8 |
| DOIs | |
| State | Published - Jun 2020 |
Keywords
- CDAI
- CELEST Trial
- IBD
- JAK Inhibitor
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
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Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease. / Sandborn, William J.; Feagan, Brian G.; Loftus, Edward V. et al.
In: Gastroenterology, Vol. 158, No. 8, 06.2020, p. 2123-2138.e8.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease
AU - Sandborn, William J.
AU - Feagan, Brian G.
AU - Loftus, Edward V.
AU - Peyrin-Biroulet, Laurent
AU - Van Assche, Gert
AU - D'Haens, Geert
AU - Schreiber, Stefan
AU - Colombel, Jean Frederic
AU - Lewis, James D.
AU - Ghosh, Subrata
AU - Armuzzi, Alessandro
AU - Scherl, Ellen
AU - Herfarth, Hans
AU - Vitale, Lauren
AU - Mohamed, Mohamed Eslam F.
AU - Othman, Ahmed A.
AU - Zhou, Qian
AU - Huang, Bidan
AU - Thakkar, Roopal B.
AU - Pangan, Aileen L.
AU - Lacerda, Ana P.
AU - Panes, Julian
N1 - Funding Information: AbbVie and the authors thank the patients who participated in the study and all of the study investigators for their contributions. Larissa Belova, PhD, formerly of AbbVie Inc., and Maria Hovenden, PhD, of ICON plc (North Wales, PA) provided medical writing support, which was funded by AbbVie, in the development of this manuscript. Funding Information: Conflicts of interest The authors disclose the following: William J. Sandborn has received research grants from Atlantic Healthcare Limited, Amgen, Genentech, Gilead Sciences, AbbVie, Janssen, Takeda, Lilly, and Celgene/Receptos; consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene, Celltrion, Conatus, Cosmo, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead Sciences, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pfizer, Precision IBD, Progenity, Prometheus Laboratories, Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, and Vivelix Pharmaceuticals; and holds stock or stock options from BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, and Vimalan Biosciences; in addition, his spouse reports the following: Ophthotech—consultant, stock options; Progenity—consultant, stock; Oppilan Pharma—employee, stock options; Escalier Biosciences—employee, stock options; Precision IBD—employee, stock options; Ventyx Biosciences—employee, stock options; and Vimalan Biosciences—employee, stock options. Brian G. Feagan has received consulting fees from AbbVie, Allergan, ActoGeniX, Albireo, Amgen, AstraZeneca, Atlantic Pharma, Avaxia Biologics Inc, Axcan, Baxter Healthcare Corp, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Centocor, Elan/Biogen, enGene, Ferring, Roche/Genentech, GICare, Gilead, Given Imaging Inc, GlaxoSmithKline, Ironwood, Johnson & Johnson/Janssen, Kyowa Hakko Kirin Co Ltd, Lycera, Lexicon, Lilly, Merck, Mesoblast, Millennium, Nektar, Novartis Novo Nordisk, Prometheus Therapeutics & Diagnostics, Pfizer, Protagonist, Receptos, Salix, Serono, Shire, Sigmoid, Synergy, Takeda, Teva, Tillotts, TiGenix, UCB, Warner-Chilcott, Wyeth, Zealand, and Zyngenia; speaker fees from AbbVie, Johnson & Johnson/Janssen, Takeda, and UCB; financial support for research from AbbVie Inc., Amgen Inc, AstraZeneca/MedImmune Ltd, Atlantic Pharmaceuticals Ltd, Boehringer Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann–La Roche Ltd, Gilead Sciences Inc, GlaxoSmithKline, Janssen Research & Development LLC, Pfizer Inc, Receptos Inc/Celgene International, Sanofi, Santarus Inc, Takeda Development Center Americas Inc, Tillotts Pharma AG, and UCB; and has served as a member of the board of directors of Robarts Clinical Trials, Inc. Edward V. Loftus, Jr, has received consulting fees from AbbVie, UCB, Janssen, Takeda, Celgene, Eli Lilly, Amgen, Pfizer, Celltrion Healthcare, Allergan, Bristol Myers Squibb, Boehringer Ingelheim, Genentech, and Gilead and research support from AbbVie, UCB, Genentech, Janssen, Amgen, Pfizer, Takeda, Robarts Clinical Trials, Gilead, Celgene, Seres Therapeutics, and Medimmune. Laurent Peyrin-Biroulet has received honoraria from AbbVie, Janssen, Genentech, Ferring, Tillotts, Pharmacosmos, Celltrion, Takeda, Boehringer Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestlé, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, Bristol Myers Squibb, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, and Theravance; grants from AbbVie, MSD, and Takeda; and stock options from CTMA. Gert Van Assche has been a consultant for AbbVie, Janssen, Genentech, MSD, Ferring, Protagonist, Takeda, Samsung Bioepis, Pfizer, and TiGenix; been a speaker for AbbVie, MSD, Janssen, Takeda, Ferring, TiGenix, Falk, and Pfizer; served on the advisory board for Takeda, Janssen, MSD, AbbVie, TiGenix, Ferring, and Roche; and received grants and educational support from AbbVie, Janssen, Zealand Pharma, and Pfizer. Geert D'Haens has received consulting and/or lecture fees from AbbVie, ActoGeniX, Boehringer Ingelheim, Centocor, ChemoCentryx, Cosmo Technologies, Elan Pharmaceuticals, enGene, Dr Falk Pharma, Ferring, Galapagos, Giuliani SpA, Given Imaging, GlaxoSmithKline, Janssen Biologics, MSD, Neovacs, Novo Nordisk, Otsuka, PDL BioPharma, Pfizer, Receptos, Salix, SetPoint, Shire Pharmaceuticals, Schering-Plough, Takeda, Tillotts Pharma, UCB Pharma, Versant, and Vifor Pharma; research grants from AbbVie, Janssen, Given Imaging, MSD, Dr Falk Pharma, and PhotoPill; and speaking honoraria from AbbVie, Tillotts, Tramedico, Ferring, MSD, UCB Pharma, Norgine, and Shire. Stefan Schreiber has received consultancy and lecture fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Falk Pharma, Ferring, Genentech/Roche, Gilead, GlaxoSmithKline, I-MAB Biopharma, MSD, Novartis/Sandoz, Pfizer, Shire, Takeda, and UCB. Jean-Frederic Colombel has been a consultant or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Arena Pharmaceuticals, Celgene Corporation, Celltrion, Enterome, Eli Lilly, Ferring Pharmaceuticals, Genentech, Johnson & Johnson, Medimmune, Merck & Co., Nextbiotix, Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Development & Commercialization, Inc, Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, and Theradiag; has been a speaker for AbbVie, Ferring, Takeda, and Celgene Corporation; holds stock options for Intestinal Biotech Development and GENFIT; and has received research grants from AbbVie, Takeda, and Johnson & Johnson. James D. Lewis has received consulting fees from AbbVie, Johnson & Johnson, Janssen Pharmaceuticals, Samsung Bioepis, Takeda, Celgene, Bristol Myers Squibb, and Merck; has served on data and safety monitoring boards for Pfizer, Gilead, Arena Pharmaceuticals, and UCB; has received speaking honoraria from Nestlé Health Science and Bridge Biotherapeutics, Inc; and has received research support from Takeda and Nestlé Health Science. Subrata Ghosh has received consulting fees from Pfizer, Janssen, AbbVie, Bristol Myers Squibb, Receptos, Celgene, Gilead, and Boehringer Ingelheim and speaker fees from AbbVie, Janssen, Takeda, Ferring, Shield, and Falk Pharma. Alessandro Armuzzi has been a consultant or advisory member for AbbVie, Allergan, Amgen, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Mylan, Pfizer, Samsung Bioepis, Sandoz, Sofar, and Takeda; has received lecture fees from AbbVie, Amgen, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, Medtronic, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Otsuka, Pfizer, Samsung Bioepis, Takeda, TiGenix, and Zambon; and has received research funding from MSD, Pfizer, and Takeda. Ellen Scherl has received research and grant support from AbbVie, AstraZeneca, CCF, Janssen Research & Development, Johns Hopkins University, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and New York Crohn's Foundation; has been a consultant/advisory board member for AbbVie, Crohn's and Colitis Foundation of America, Entera Health, Evidera, GI Health Foundation, Janssen, Protagonist Therapeutics, Seres Health, Takeda Pharmaceuticals, and Prime; has been a stock shareholder of Gilead; and has received honoraria from GI Health Foundation for nonbranded speakers bureau, Janssen for nonbranded speakers bureau, and Prime. Hans Herfarth has received consulting fees from Alivio, AMAG, Boehringer Ingelheim, Celltrion, Finch, Gilead, Lycera, Merck, Pfizer, and Seres; and has received research support from Pfizer and Artizan. Lauren Vitale, Mohamed-Eslam F. Mohamed, Qian Zhou, Bidan Huang, Roopal B. Thakkar, Aileen L. Pangan, and Ana P. Lacerda are AbbVie employees and may own AbbVie stock and/or options. Ahmed A. Othman is a former AbbVie employee and may own AbbVie stock and/or options. Julian Panes has received consulting fees from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GlaxoSmithKline, Janssen, MSD, Nestlé, Oppilan, Progenity, Pfizer, Robarts, Roche, Second Genome, Takeda, Theravance, TiGenix, and Topivert; speaker fees from AbbVie, Biogen, Ferring, Janssen, MSD, Shire Pharmaceuticals, Takeda, and Tillotts; and research funding from AbbVie and MSD. Funding This study was funded by AbbVie Inc. Publisher Copyright: © 2020 The Authors
PY - 2020/6
Y1 - 2020/6
N2 - 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,
AB - 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,
KW - CDAI
KW - CELEST Trial
KW - IBD
KW - JAK Inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85085745068&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085745068&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.01.047
DO - 10.1053/j.gastro.2020.01.047
M3 - Article
C2 - 32044319
AN - SCOPUS:85085745068
SN - 0016-5085
VL - 158
SP - 2123-2138.e8
JO - Gastroenterology
JF - Gastroenterology
IS - 8
ER -