Etrolizumab for the Treatment of Ulcerative Colitis and Crohn's Disease: An Overview of the Phase 3 Clinical Program

William J Sandborn, Severine Vermeire, Helen Tyrrell, Azra Hassanali, Stuart Lacey, Swati Tole, Amanda R Tatro, Etrolizumab Global Steering Committee, William J Sandborn, Severine Vermeire, Helen Tyrrell, Azra Hassanali, Stuart Lacey, Swati Tole, Amanda R Tatro, Etrolizumab Global Steering Committee

Abstract

Introduction: Etrolizumab is a next-generation anti-integrin with dual action that targets two pathways of inflammation in the gut. A robust phase 3 clinical program in ulcerative colitis (UC) and Crohn's disease is ongoing and will evaluate the efficacy and safety of etrolizumab in well-defined patient populations in rigorous trials that include direct head-to-head comparisons against approved anti-tumor necrosis factor alpha agents (anti-TNF). The etrolizumab phase 3 clinical program consists of six randomized controlled trials (RCTs; UC: HIBISCUS I and II, GARDENIA, LAUREL, HICKORY; Crohn's disease: BERGAMOT) and two open-label extension trials (OLEs; UC: COTTONWOOD; Crohn's disease: JUNIPER) evaluating patients with moderately to severely active UC or Crohn's disease.

Methods: In the UC RCTs, patients are randomly assigned according to each protocol to receive etrolizumab, adalimumab, infliximab, or placebo. In BERGAMOT, patients are randomly assigned to receive etrolizumab 105 mg, etrolizumab 210 mg, or placebo. The primary outcomes for the UC RCTs are Mayo Clinic score-based clinical response, remission, and clinical remission; for BERGAMOT, the co-primary outcomes are clinical remission (based on abdominal pain and stool frequency) and endoscopic improvement (based on the Simple Endoscopic Score for Crohn's disease). The OLEs will primarily assess long-term efficacy and safety. Secondary and exploratory endpoints include endoscopy, histology, quality of life, and biomarkers at various timepoints.

Discussion: The etrolizumab phase 3 clinical program is the largest and most comprehensive in inflammatory bowel disease, enrolling more than 3000 patients. The program explores both induction and maintenance regimens. HIBISCUS I and II and GARDENIA are among the first head-to-head trials in UC against an anti-TNF and are the first registrational trials making that comparison. This program will also help address unanswered clinical questions on evaluation of treatment effects and treatment selection across a range of patients with varying treatment histories using an extensive repository of patient samples and data.

Trial registration: ClinicalTrials.gov: HIBISCUS I (NCT02163759), HIBISCUS II (NCT02171429), GARDENIA (NCT02136069), LAUREL (NCT02165215), HICKORY (NCT02100696), COTTONWOOD (NCT02118584), BERGAMOT (NCT02394028), JUNIPER (NCT02403323).

Keywords: Anti-integrin; Crohn’s disease; Etrolizumab; Inflammatory bowel disease; Ulcerative colitis.

Figures

Fig. 1
Fig. 1
Etrolizumab dual mechanism of action. IEL intraepithelial lymphocyte, MAdCAM-1 mucosal vascular addressin cell adhesion molecule 1, VCAM-1 vascular cell adhesion molecule 1
Fig. 2
Fig. 2
Ulcerative colitis trial designs. anti-TNF anti-tumor necrosis factor alpha agent, MCS Mayo Clinic score, OLI open-label induction, RB rectal bleeding score. *Patients who achieved a ≥ 3-point decrease and 30% reduction in MCS and ≥ 1-point decrease in RB or an absolute RB of 0 or 1 are randomly assigned to the maintenance arms
Fig. 3
Fig. 3
Crohn’s disease trial designs. *Patients who achieved a ≥ 70-point reduction in Crohn’s disease activity index score from baseline are again randomly assigned to the maintenance arms

References

    1. Stein RB, Hanauer SB. Comparative tolerability of treatments for inflammatory bowel disease. Drug Saf. 2000;23(5):429–448.
    1. Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017;318(17):1679–1686.
    1. Ford AC, Peyrin-Biroulet L. Opportunistic infections with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2013;108(8):1268–1276.
    1. Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201–1214.
    1. Na SY, Moon W. Perspectives on current and novel treatments for inflammatory bowel disease. Gut Liver. 2019;13(6):604–616.
    1. Schreiber S, Peyrin-Biroulet L, Loftus EV, Jr, et al. OP34 VARSITY: A double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis. J Crohns Colitis. 2019;13(suppl_1):S612–S613.
    1. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362(15):1383–1395.
    1. Lamb CA, O'Byrne S, Keir ME, Butcher EC. Gut-selective integrin-targeted therapies for inflammatory bowel disease. J Crohns Colitis. 2018;12:S653–S668.
    1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699–710.
    1. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013;369(8):711–721.
    1. Tew GW, Hackney JA, Gibbons D, et al. Association between response to etrolizumab and expression of integrin αE and granzyme A in colon biopsies of patients with ulcerative colitis. Gastroenterology. 2016;150(2):477–487.e9.
    1. Lamb CA, Mansfield JC, Tew GW, et al. Aeb7 integrin identifies subsets of pro-inflammatory colonic CD4+ T lymphocytes in ulcerative colitis. J Crohns Colitis. 2017;11(5):610–620.
    1. Zundler S, Fischer A, Schillinger D, et al. The alpha4beta1 homing pathway is essential for ileal homing of Crohn's disease effector T cells in vivo. Inflamm Bowel Dis. 2017;23(3):379–391.
    1. Vermeire S, O'Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014;384(9940):309–318.
    1. Williet N, Sandborn WJ, Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;12(8):1246–1256.e6.
    1. European Medicines Agency. Guideline on the development of new medicinal products for the treatment of Crohn’s disease, 15; 2016.
    1. Ichikawa R, Lamb CA, Eastham-Anderson J, et al. Alphae integrin expression is increased in the ileum relative to the colon and unaffected by inflammation. J Crohns Colitis. 2018;12(10):1191–1199.
    1. Higgins PDR, Harding G, Leidy NK, et al. Development and validation of the Crohn's disease patient-reported outcomes signs and symptoms (CD-PRO/SS) diary. J Patient Rep Outcomes. 2017;2(1):24.
    1. Higgins PDR, Harding G, Revicki DA, et al. Development and validation of the ulcerative colitis patient-reported outcomes signs and symptoms (UC-PRO/SS) diary. J Patient Rep Outcomes. 2017;2(1):26.
    1. Peyrin-Biroulet L, Rubin D, Feagan B, et al. Etrolizumab induction therapy improved endoscopic score, patient-reported outcomes, and inflammatory biomarkers in patients with moderate to severe UC who had failed TNF antagonist therapy: results from the HICKORY open-label induction (OLI) trial. Presented at 25th Annual Meeting of the United European Gastroenterology; October 28–November 1, 2017; Barcelona, Spain.
    1. Rubin DT, Feagan BG, Peyrin-Biroulet L, et al. Etrolizumab induction therapy improves histologic outcomes in anti-TNF-failed patients with ulcerative colitis: results from the HICKORY open-label induction cohort. Gastroenterology. 2018;154:S-1366.
    1. Jairath V, Zou G, Parker CE, et al. Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease. Aliment Pharmacol Ther. 2017;45(8):1021–1042.
    1. Sandborn W, Panes J, Jones J, et al. Etrolizumab as induction therapy in moderate to serve Crohn’s disease: results from BERGAMOT cohort 1. United Eur Gastroenterol J. 2017;5(8):1138–1150.
    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(1):77–86.
    1. European Medicines Agency. Letter of support for the development of patient-reported outcomes tools for use as an endpoint in inflammatory bowel disease (IBD) clinical trials. 2019. . Accessed 8 May 2020
    1. Reinisch W, Mishkin DS, Oh YS, et al. P132 Analysis of various central endoscopy reading methodologies in the BERGAMOT exploratory induction cohort evaluating etrolizumab in Crohn’s disease. Presented at 12th Congress of the European Crohns and Colitis Organization; February 15–17, 2017; Barcelona, Spain.
    1. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): Determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9):1324–1338.
    1. Colombel JF, Rutgeerts P, Reinisch W, et al. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011;141(4):1194–1201.
    1. Manginot C, Baumann C, Peyrin-Biroulet L. An endoscopic Mayo score of 0 is associated with a lower risk of colectomy than a score of 1 in ulcerative colitis. Gut. 2015;64(7):1181–1182.
    1. Yzet C, Fumery M, Colombel J-F, et al. OP35 Endoscopic and deep remission at 1 year prevents disease progression in early Crohn’s disease: long-term data from CALM. J Crohns Colitis. 2019;13:S024–S25.
    1. Bryant RV, Burger DC, Delo J, et al. Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6 years of follow-up. Gut. 2016;65(3):408–414.
    1. Christensen B, Hanauer SB, Erlich J, et al. Histologic normalization occurs in ulcerative colitis and is associated with improved clinical outcomes. Clin Gastroenterol Hepatol. 2017;15(10):1557–1564.e1.
    1. Mosli MH, Parker CE, Nelson SA, et al. Histologic scoring indices for evaluation of disease activity in ulcerative colitis. Cochrane Database Syst Rev. 2017;5:CD011256.
    1. Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and validation of the Nancy Histological Index for UC. Gut. 2017;66(1):43–49.
    1. Bryant RV, Winer S, Travis SP, Riddell RH. Systematic review: histological remission in inflammatory bowel disease. Is 'complete' remission the new treatment paradigm? An IOIBD initiative. J Crohns Colitis. 2014;8(12):1582–1597.
    1. Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index for UC. Gut. 2017;66(1):50–58.

Source: PubMed

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