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Clinical Trial
. 2021 Jun 19;397(10292):2372-2384.
doi: 10.1016/S0140-6736(21)00666-8. Epub 2021 Jun 3.

Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial

Brian G Feagan  1 , Silvio Danese  2 , Edward V Loftus Jr  3 , Séverine Vermeire  4 , Stefan Schreiber  5 , Timothy Ritter  6 , Ronald Fogel  7 , Rajiv Mehta  8 , Sandeep Nijhawan  9 , Radosław Kempiński  10 , Rafał Filip  11 , Ihor Hospodarskyy  12 , Ursula Seidler  13 , Frank Seibold  14 , Ian L P Beales  15 , Hyo Jong Kim  16 , John McNally  17 , Chohee Yun  17 , Sally Zhao  17 , Xiaopeng Liu  17 , Chia-Hsiang Hsueh  17 , Chantal Tasset  18 , Robin Besuyen  18 , Mamoru Watanabe  19 , William J Sandborn  20 , Gerhard Rogler  21 , Toshifumi Hibi  22 , Laurent Peyrin-Biroulet  23
Affiliations
Clinical Trial

Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial

Brian G Feagan et al. Lancet. .

Abstract

Background: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. We assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.

Methods: This phase 2b/3, double-blind, randomised, placebo-controlled trial including two induction studies and one maintenance study was done in 341 study centres in 40 countries. Eligible patients were aged 18-75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumour necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were rerandomised 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary endpoint was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomised patients who received at least one dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomised to any filgotinib treatment group in the induction studies who received at least one dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study 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 the study drug or placebo within each study. This trial is registered with ClinicalTrials.gov, NCT02914522.

Findings: Between Nov 14, 2016, and March 31, 2020, we screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n=277), filgotinib 200 mg (n=245), or placebo (n=137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n=285), filgotinib 200 mg (n=262), or placebo (n=142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n=179) or placebo (n=91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n=202) or placebo (n=99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26·1% vs 15·3%, difference 10·8%; 95% CI 2·1-19·5, p=0·0157; induction study B 11·5% vs 4·2%, 7·2%; 1·6-12·8, p=0·0103). At week 58, 37·2% of patients given filgotinib 200 mg had clinical remission versus 11·2% in the respective placebo group (difference 26·0%, 95% CI 16·0-35·9; p<0·0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23·8% vs 13·5%, 10·4%; 0·0-20·7, p=0·0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 (5·0%) of 562 patients given filgotinib 100 mg, 22 (4·3%) of 507 patients given filgotinib 200 mg, and 13 (4·7%) of 279 patients given placebo. In the maintenance study, serious adverse events were reported in eight (4·5%) of 179 patients given filgotinib 100 mg, seven (7·7%) of 91 patients in the respective placebo group, nine (4·5%) of 202 patients in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment.

Interpretation: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis.

Funding: Gilead Sciences.

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Conflict of interest statement

Declaration of interests BGF reports grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb (BMS), Janssen Biotech/Centocor, Johnson & Johnson (J&J)/Janssen, Pfizer, Receptos, and Takeda; personal fees from Ablynx, Actogenix, AdMIRx, Akebia Therapeutics, Allergan, Atlantic Pharma, Avaxia Biologics, Avir Pharma, Baxter Healthcare Corporation, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Boston Pharmaceuticals, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring, Galapagos, Genentech/Roche, GiCare Pharma, Gilead, Given Imaging, Gossamer Pharma, GSK, Inception IBD, Ironwood, Japan Tobacco Company, Kyowa Kakko Kirin, Lexicon, Lilly, Lycera Biotech, Merck, Mesoblast Pharma, Millennium, Nestles, NextBiotix, Novartis, Novo Nordisk, ParImmune, Progenity, Prometheus Therapeutics & Diagnostics, Protagonist, Qu Biologics, Salix, Shire, Sienna Biologics, Sigmoid Pharma, Synergy Pharma, Teva Pharma, TiGenix, Tillotts, UCB, Vertex, VHsquared, Vivelix Pharma, Wyeth, Zealand, and Zyngenia, outside the submitted work. BGF is Senior Scientific Director at Alimentiv and Professor of Medicine at Western University. SD reports personal fees from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ely Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor outside the submitted work. EVL Jr reports grants and personal fees from Gilead during the conduct of the study; grants from Receptos, Robarts Clinical Trials, and Theravance; grants and personal fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, and Takeda; and personal fees from Allergan, Boehringer Ingelheim, Celltrion Healthcare, Eli Lilly, Iterative Scopes, and Ono Pharma, outside the submitted work. SV reports grants from AbbVie, J&J, Pfizer, and Takeda; and consultancy fees from AbbVie, Arena Pharmaceuticals, Avaxia, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, Hospira, Janssen, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance, and Tillots Pharma, outside the submitted work. SS reports personal fees from AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr Falk Pharma, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda, and Theravance, outside the submitted work. TR reports personal fees from Gilead during the conduct of the study and personal fees from AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda, outside the submitted work. SN reports grants from Gilead Sciences during the conduct of the study. RK reports grants from Janssen and Takeda outside the submitted work. RFi reports grants from Egis and personal fees from AbbVie, Ferring, MSD, and Takeda, outside the submitted work. US reports grants from AbbVie, Abivax, Index Pharmaceuticals, Lilly, Roche-Genentech, and Theravance; grants and personal fees from Takeda; grants, personal fees, and non-financial support from Janssen; and personal fees from Arena Pharmaceuticals, outside the submitted work. FS reports consultancy fees from AbbVie, Janssen, MSD, Pfizer, Takeda and Vifor, outside the submitted work. ILPB reports personal fees from Gilead and Pfizer and personal fees and non-financial support from AbbVie, Janssen, and Takeda, outside the submitted work. HJK reports consultancy fees from Celltrion and speaking fees from Pfizer and Takeda, outside the submitted work. JM, CY, SZ, XL, and C-HH are employees and shareholders of Gilead Sciences. CT is an employee of Galapagos. RB is an employee and shareholder of Galapagos. MW reports grants from Alfresa, Asahi Kasei Medical, Ayumi, Fujirebio, JIMRO, Kaken, Kyorin, Kyowa Hakko Kirin, Miyarisan, and Taiho; grants and personal fees from AbbVie, Astellas, EA, Gilead Sciences, Kissei, Mitsubishi Tanabe, Mochida, Nippon Kayaku, Pfizer Japan, Takeda, and Zeria; and personal fees from Celgene, Celltrion, Eli Lilly Japan, Gilead Sciences, and Janssen, outside the submitted work. WJS reports grants, personal fees, medical writing, and reimbursement of travel expenses from Gilead Sciences, during the conduct of the study; grants and stock options from Allakos; grants and personal fees from AbbVie, Abivax, Alimentiv (previously Robarts Clinical Trials), Arena, Boehringer Ingelheim, Celgene, Genentech/Roche, Gilead Sciences, GSK, Janssen, Eli Lilly, Pfizer, Seres Therapeutics, Shire, Surrozen, Takeda, and Theravance Biopharma; grants, personal fees, and stock and stock options from Prometheus Biosciences; stock and stock options from Ventyx Biosciences and Vimalan Biosciences; personal fees from Admirx, Alfasigma, Alivio Therapeutics, Allergan, Amgen, Applied Molecular Transport, Avexegen Therapeutics, Bausch Health (Salix), Bellatrix Pharmaceuticals, Boston Pharmaceuticals, BMS, Celltrion, Cellularity, Conatus, Cosmo Pharmaceuticals, Equillium, Escalier Biosciences, Ferring, Forbion, Glenmark, Immunic (Vital Therapies), Incyte, Index Pharmaceuticals, Intact Therapeutics, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Otsuka, Pandion Therapeutics, Paul Hastings, Protagonist Therapeutics, Provention Bio, Reistone Biopharma, Ritter Pharmaceuticals, Shanghai Pharma Biotherapeutics, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Thetis Pharmaceuticals, Tigenix, Tillotts Pharma, UCB, Vendata Biosciences, Vivelix Pharmaceuticals, and Zealand; personal fees and stock from Beigene; and personal fees and stock options from Gossamer Bio, Oppilan Pharma, Progenity, Shoreline Biosciences, and Vivreon Biosciences, outside the submitted work. WJS reports that their spouse is a consultant and owns stock options for Iveric Bio and Oppilan Pharma; is an employee with stock and stock options for Prometheus Biosciences; has stock for Progenity; and has stock and stock options for Ventyx Biosciences and Vimalan Biosciences. GR reports personal fees from AbbVie, AstraZeneca, Augurix, BMS, Boehringer, Calypso, Celgene, Dr Falk Pharma, Ferring, Fisher, Genentech, Gilead, Janssen, MSD, Novartis, Pfizer, Phadia, Roche, Takeda, Tillots, UCB, Vifor, Vital Solutions, and Zeller; and grants from AbbVie, Ardeypharm, Augurix, Calypso, Dr Falk Pharma, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillots, UCB, and Zeller, outside the submitted work. TH reports grants from Otuska Holdings; grants and personal fees from AbbVie, IMRO, Kyorin, Mitsubishi-Tanabe, Mochida, Takeda, and Zeria; and personal fees from Aspen Japan, BMS, Celltrion, EA, Eli Lilly, Ferring, Gilead Sciences, Janssen, Kisse Pharmaceutical, Nichi-Iko Pharmaceutical, Nippon Kayaku, and Pfizer, outside the submitted work. LP-B reports personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Boerhinger Ingelheim, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, Index Pharmaceuticals, Inotrem, Janssen, Lilly, MSD, Mylan, Nestle, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Theravance, Tillots, and Vifor; grants from AbbVie, MSD, and Takeda; and stock options with CTMA. All other authors declare no competing interests.

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