Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn's disease (DIVERSITY): a phase 3, double-blind, randomised, placebo-controlled trial.

Autor:	Vermeire S; Department of Gastroenterology and Hepatology, University Hospital Leuven, Leuven, Belgium., Schreiber S; Department of Internal Medicine I, Kiel University, University Hospital Schleswig-Holstein, Kiel, Germany., Rubin DT; Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA., D'Haens G; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, Netherlands., Reinisch W; Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria., Watanabe M; Advanced Research Institute, Tokyo Medical and Dental University, Faculty of Medicine, Juntendo University, Tokyo, Japan., Mehta R; Department of Gastroenterology, Surat Institute of Digestive Sciences Hospital and Research Centre, Surat, India., Roblin X; Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France., Beales I; Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, Norfolk, UK; Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK. Electronic address: i.beales@uea.ac.uk., Gietka P; Department of Gastroenterology and Internal Medicine-National Research Institute, Military Institute of Medicine, Warsaw, Poland., Hibi T; Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan., Hospodarskyy I; Department of Clinical Immunology, Ternopil National Medical University, Ternopil, Ukraine., Ritter T; Department of Research and Education, GI Alliance, Southlake, TX, USA., Genovese MC; Gilead Sciences, Foster City, CA, USA., Kwon P; Gilead Sciences, Foster City, CA, USA., Santermans E; Galapagos NV, Mechelen, Belgium., Le Brun FO; Galapagos, Basel, Switzerland., Barron R; Galapagos, Basel, Switzerland., Masior T; Galapagos, Basel, Switzerland., Danese S; Department of Gastroenterology and Digestive Endoscopy, IRCCS Hospital San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
Jazyk:	angličtina
Zdroj:	The lancet. Gastroenterology & hepatology [Lancet Gastroenterol Hepatol] 2024 Dec 02. Date of Electronic Publication: 2024 Dec 02.
DOI:	10.1016/S2468-1253(24)00272-3
Abstrakt:	Background: There is a need for efficacious therapies for patients with Crohn's disease that are better tolerated and more durable than available treatments. We aimed to evaluate the efficacy and safety of filgotinib, an oral Janus kinase 1 preferential inhibitor, for treating Crohn's disease. Methods: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in 371 centres in 39 countries. Eligible patients were aged 18-75 years with moderately to severely active Crohn's disease for at least 3 months before enrolment. Patients were enrolled into one of two induction studies on the basis of their experience with biological agents (induction study A included biologic-naive and later biologic-experienced patients and induction study B included biologic-experienced patients). In both induction studies, patients were randomly assigned (1:1:1), using an interactive web response system, to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 11 weeks. Patients who received filgotinib and had two-item patient-reported outcome (PRO2) clinical remission or an endoscopic response at week 10 were re-randomised (2:1) to receive their induction dose or placebo orally, once daily to the end of week 58 in the maintenance study. Co-primary endpoints were PRO2 clinical remission and an endoscopic response at week 10 (induction studies) and week 58 (maintenance study). PRO2 clinical remission was defined as an abdominal pain subscore of not more than 1 and a liquid or very soft stool frequency subscore of not more than 3 (from eDiary data) and endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for Crohn's disease from induction baseline (from central reading of endoscopy). For the induction studies, efficacy was assessed in all randomly assigned patients who received at least one dose of study drug. For the maintenance study, efficacy was assessed in all patients from either filgotinib treatment group in the induction studies who reached PRO2 clinical remission or an endoscopic response at week 10, and who were re-randomised and received at least one dose of study drug in the maintenance study. Patients who received placebo throughout the induction and maintenance studies were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of study drug. This trial is complete and is registered with ClinicalTrials.gov, NCT02914561. Findings: Between Oct 31, 2016, and Nov 11, 2022, 2634 patients were screened, of whom 1372 were enrolled (induction study A: n=707, induction study B: n=665, and maintenance study: n=481). There were 346 (49%) women and 358 (51%) men in induction study A, 356 (54%) women and 303 (46%) men in induction study B, and 242 women (51%) and 236 men (49%) in the maintenance study. Significantly more patients had PRO2 clinical remission at week 10 with filgotinib 200 mg than with placebo in induction study B (29·7% vs 17·9%, difference 11·9%; 95% CI 3·7 to 20·2, p=0·0039) but not induction study A (32·9% vs 25·7%, 6·9%; -1·4 to 15·2, p=0·0963); there was no significant difference for endoscopic response (induction study A: 23·9% vs 18·1%, difference 5·5%; 95% CI -2·0 to 12·9, p=0·1365; induction study B: 11·9% vs 11·4%, 0·1%; -6·5 to 6·6, p=0·9797). At week 58, both co-primary endpoints were reported in greater proportions of patients who received filgotinib 200 mg than in those who received placebo (PRO2 clinical remission: 43·8% vs 26·4%, difference 16·8%; 95% CI 2·0 to 31·6, p=0·0382; endoscopic response: 30·4% vs 9·4%, difference 20·6%; 95% CI 8·2 to 33·1, p=0·0038). Co-primary endpoints were not met for filgotinib 100 mg in any study. In the induction studies, the most frequently reported treatment-emergent adverse events (TEAEs; ≥5% of patients in any group) were abdominal pain; arthralgia; an exacerbation, flare, or worsening of Crohn's disease; headache; nasopharyngitis; nausea; and pyrexia. In the maintenance study, the most frequently reported TEAEs (≥5% of patients in any filgotinib or associated placebo group) were those reported in the induction studies (except for headache) and abdominal distension, upper abdominal pain, anaemia, and flatulence. Serious TEAEs were reported in 49 patients in induction study A (18 [8%]) of 222 patients in the filgotinib 200 mg group, 16 [7%] of 245 patients in the filgotinib 100 mg group, and 15 [6%] of 237 patients in the placebo group), 81 patients in induction study B (19 [9%] of 202 patients in the filgotinib 200 mg group, 36 [16%] of 228 patients in the filgotinib 100 mg group, and 26 [11%] of 229 patients in the placebo group), and 49 patients in the maintenance study (13 [11%] of 118 patients in the filgotinib 200 mg-filgotinib 200 mg group, five [9%] of 56 patients in the filgotinib 200 mg-placebo group, 14 [13%] of 104 patients in the filgotinib 100 mg-filgotinib 100 mg group, three [5%] of 55 patients in the filgotinib 100 mg-placebo group, and 14 [10%] of 145 patients in the placebo-placebo group). No deaths were reported during the induction and maintenance studies. Interpretation: Filgotinib 200 mg did not meet the co-primary endpoints of clinical remission and an endoscopic response at week 10, but did meet the co-primary endpoints at week 58. Filgotinib treatment was well tolerated, and no new safety signals were reported. Funding: Galapagos. Competing Interests: Declaration of interests SV reports consulting and/or speaker fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb Therapeutics, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cytoki Pharma, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Materia Prima, Mestag Therapeutics, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Prometheus Biosciences, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma, VectivBio, Ventyx Biosciences, and Zealand Pharma; grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; and participation on a data safety monitoring board for Sanofi. SV is Professor of Medicine at KU Leuven. SS reports consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen Pharmaceuticals, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma, and Ventyx Biosciences. DTR reports consulting fees from AbbVie, AltruBio, Amgen, Avalo Therapeutics, Bristol Myers Squibb, Buhlmann Diagnostics Corp, Chronicles Health, ClostraBio, Connect Biopharma, Cytoki Pharma, Douglas Pharmaceuticals, EcoR1, Eli Lilly, Ferring Pharmaceuticals, Image Analysis Group, InDex Pharmaceuticals, Iterative Health, Janssen Pharmaceuticals, Odyssey Therapeutics, Pfizer, Prometheus Biosciences, Reistone Biopharma, Samsung NeuroLogica, Sangamo Therapeutics, Shanghai Pharma Biotherapeutics USA, Takeda, TISSIUM, and Trellus Health; and grants from Takeda. GD'H reports consulting fees from AbbVie, Alimentiv, AstraZeneca, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly, Galapagos, GSK, Immunic Therapeutics, and Ventyx Biosciences; grants from AbbVie, Eli Lilly, Pfizer, and Takeda; participation on a data safety monitoring board or advisory board for AstraZeneca and Seres Health; and speaker fees from AbbVie, Biogen, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts Pharma. WR reports consulting fees from AbbVie, Amgen, AOP Health (formerly AOP Orphan), Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead Sciences, InDex Pharmaceuticals, Janssen Pharmaceuticals, MEDahead, Microbiotica, Pfizer, and Takeda; participation on an advisory board for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen Pharmaceuticals, and Pfizer; research funding from AbbVie, Janssen Pharmaceuticals, Sandoz, Sanofi, and Takeda; and speaker fees from AbbVie, Celltrion, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, MEDICE, MSD, Pfizer, Roche, Sobi, and Takeda. MW reports consulting fees from AbbVie, EA Pharma, Eli Lilly Japan, Gilead Sciences, and Nippon Boehringer Ingelheim; grants from AbbVie, EA Pharma, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku, Takeda, and Zeria Pharmaceutical; and speaker fees from EA Pharma, Eli Lilly Japan, Gilead Sciences, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Miyarisan, Mochida Pharmaceutical, Takeda, and Zeria Pharmaceutical. XR reports personal fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly, Galapagos, Janssen Pharmaceuticals, MSD, Pfizer, Takeda, and Theradiag. IB reports consulting fees from Galapagos, Gilead Sciences, Janssen Pharmaceuticals, Pfizer, Pharmacosmos, Takeda, and Vifor Pharma. TH reports consulting fees from Aspen Japan, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals, Kissei Pharmaceutical, Nichi-Iko Pharmaceutical, Nippon Kayaku, and Pfizer; and grants from AbbVie, IMRO, Kyorin, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Otsuka Holdings, Takeda, and Zeria Pharmaceutical. IH reports speaker fees from Abbott, GSK, Sandoz, and Takeda. TR reports personal fees from AbbVie, Arena Pharmaceuticals, Eli Lilly, Ferring Pharmaceuticals, Genentech, Gilead Sciences, Gossamer Bio, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Pfizer, Prometheus, and Takeda. MCG was an employee of Gilead Sciences at the time of the work. PK is an employee and shareholder of, and owns stocks or stock options of Gilead Sciences. ES is an employee and shareholder of Galapagos. F-OLB is a former employee and shareholder of Galapagos and an employee of Alfasigma. RB was an employee of Galapagos at the time of the work. TM was an employee of Galapagos at the time of the work, and is now an employee of Ironwood Pharmaceuticals. SD reports consulting fees from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead Sciences, Hospira, Inotrem, Janssen Pharmaceuticals, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor Pharma; and speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals, Mylan, Pfizer, and Takeda. RM and PG report no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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