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Randomized Controlled Trial
. 2023 Apr 8;401(10383):1159-1171.
doi: 10.1016/S0140-6736(23)00061-2. Epub 2023 Mar 2.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

William J Sandborn  1 , Séverine Vermeire  2 , Laurent Peyrin-Biroulet  3 , Marla C Dubinsky  4 , Julian Panes  5 , Andres Yarur  6 , Timothy Ritter  7 , Filip Baert  8 , Stefan Schreiber  9 , Sheldon Sloan  10 , Fabio Cataldi  10 , Kevin Shan  10 , Christopher J Rabbat  10 , Michael Chiorean  11 , Douglas C Wolf  12 , Bruce E Sands  13 , Geert D'Haens  14 , Silvio Danese  15 , Martina Goetsch  16 , Brian G Feagan  17
Affiliations
Free article
Randomized Controlled Trial

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

William J Sandborn et al. Lancet. .
Free article

Erratum in

  • Department of Error.
    [No authors listed] [No authors listed] Lancet. 2023 Mar 25;401(10381):1000. doi: 10.1016/S0140-6736(23)00586-X. Lancet. 2023. PMID: 36965962 No abstract available.

Abstract

Background: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis.

Methods: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively.

Findings: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported.

Interpretation: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis.

Funding: Arena Pharmaceuticals.

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Conflict of interest statement

Declaration of interests WJS reports research grants from AbbVie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Gilead Sciences, GSK, Janssen, Lilly, Pfizer, Prometheus Laboratories, Seres Therapeutics, Shire Pharmaceuticals, Takeda, and Theravance Biopharma; consulting fees from AbbVie, Abivax, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Allakos, Amgen, Arena Pharmaceuticals, AstraZeneca, Atlantic Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, ClostraBio, Forbion, Galapagos, Genentech (Roche), GSK, Gossamer Bio, Index Pharmaceuticals, Iota Biosciences, Janssen, Lilly, Morphic Therapeutics, Novartis, Oppilan Pharma (now Ventyx Biosciences), Pfizer, Pharm Olam, Polpharma, Progenity, Prometheus Biosciences, Protagonist Therapeutics, PTM Therapeutics, Seres Therapeutics, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Vedanta Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Gastrosciences, Xencor, and Zealand Pharmaceuticals; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (now Ventyx Biosciences), Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Gastrosciences; and is Chief Medical Officer at Ventyx Biosciences. SV reports grants from AbbVie, J&J, Pfizer, Galapagos, and Takeda; and has received consulting or speaking fees from AbbVie, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MRM Health, Mundipharma, MSD, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand Pharma. LP-B reports consulting fees from AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharma, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, and Abivax; grants from Takeda, Fresenius Kabi, and Celltrion; and lecture or speaker fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, and Medac. MCD reports consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health. JP reports consulting fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GSK, Janssen, Mirum, Morphic, Nestle, Origo, Pandion, Progenity, Pfizer, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann; speaker fees from AbbVie, Biogen, Ferring, Janssen, Pfizer, and Takeda; and research funding from AbbVie and Pfizer. AY reports consulting fees from Takeda, Prometheus Labs, Arena Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau fees from Bristol Myers Squibb. TR served on advisory boards or speaker panels for Gilead, AbbVie, Arena Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Gossamer, Intercept, Janssen, Eli Lilly, Pfizer, Prometheus, and Takeda. FB reports grant or research support from AbbVie, Amgen, Janssen, and Takeda; honoraria from AbbVie, Amgen, Arena Pharmaceuticals, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, MSD, Pfizer, Sandoz, and Takeda; and was on speakers bureaus for AbbVie, Arena Pharmaceuticals, Ferring, Galapagos, Janssen, MSD, Pfizer, and Takeda. SSc has been a consultant for AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Fresenius, Galapagos, Genentech, GSK, Gilead, I-MAB Biopharma, Janssen, Lilly, Merck, Novartis-Sandoz, Pfizer, Protagonist, Takeda, and Theravance. FC was a previous employee and stockholder of Arena Pharmaceuticals at the time of research. SSl, KS, CJR, and MG are employees and stockholders of Arena Pharmaceuticals, a wholly-owned subsidiary of Pfizer Inc. MC has been a speaker for AbbVie, Janssen, Medtronic, Pfizer, Bristol Myers Squibb, and Takeda; and has served as a consultant for AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Medtronic, Pfizer, Lilly, Prometheus, and Takeda. DCW has received consulting or speaker honoraria from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Janssen, Lilly, Pfizer, and Takeda. BES reports consulting fees from Abivax, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Entera, Evommune, Galapagos, Genentech, Gilead Sciences, GSK, Gossamer Bio, Index Pharmaceuticals, Inotrem, Innovation Therapeutics, Ironwood Pharmaceuticals, Janssen, Kaleido, Kallyope, Lilly, Miro Bio, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Surrozen, Takeda, Teva, TLL Pharmaceutical, USWM Enterprises, and Viela Bio; speaking fees from Abivax, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; and grant or research support from Janssen. GD has been a consultant for AbbVie, AgomAb, AstraZeneca, AM Pharma, AMT, Arena Pharmaceuticals, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals, Kaleido, Roche, Gilead, GSK, Gossamer Bio, Pfizer, Immunic, J&J, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist; and has received speakers bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, Bristol Myers Squibb, and Takeda. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor; and payment for expert testimony from AbbVie, Amgen, Ferring Pharmaceuticals, Gilead, Janssen, Mylan, Pfizer, and Takeda. BGF has been a consultant for AbbVie, Admirx, AgomAb Therapeutics, Applied Molecular Transport, Arena Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Ferring, Galapagos, Galen Atlantica, Genentech-Roche, Gilead, Gossamer Pharma, GSK, F Hoffmann-La Roche, Janssen, Morphic Therapeutics, OM Pharma, Pandion Therapeutics, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Sanofi, Seres Therapeutics, Surrozen, Takeda, Theravance, TiGenix, Tillotts, and Zealand Pharma; has received speaker bureau fees from AbbVie, Janssen, and Takeda; served on the scientific advisory board for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Bristol Myers Squibb, Genentech, Roche, Janssen, Novartis, Origo BioPharma, Pfizer, Prometheus, Takeda, Tillotts Pharma, Teva, Progenity, Index, and GSK; is a stockholder of Gossamer Pharma; and is an employee of Western University and Alimentiv.

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