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

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          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).

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          Most cited references24

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          Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis

          The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.
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            Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

            In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease

              Question Is exposure to thiopurines and anti–tumor necrosis factor (TNF) agents, used alone or in combination, associated with an increased risk of lymphoma in patients with inflammatory bowel disease (IBD)? Findings In this cohort study of 189 289 patients with IBD, the risk of incident lymphoma was significantly higher in patients exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy compared with those who were unexposed. The risk was higher in patients exposed to combination therapy compared with thiopurine or anti-TNF monotherapy. Meaning The use of thiopurine monotherapy or anti-TNF monotherapy in patients with IBD was associated with a small but statistically significant increased risk of lymphoma, and this risk was higher with combination therapy than with each of these treatments used alone. Importance An increased risk of lymphoma has been reported among patients receiving thiopurines for inflammatory bowel disease (IBD). The risk of lymphoma associated with anti–tumor necrosis factor (TNF) agents either alone or in combination with thiopurines is uncertain. Objective To assess the risk of lymphoma associated with thiopurines and anti-TNF agents, used alone or in combination, for the management of IBD. Design, Setting, and Participants Nationwide cohort study based on French National Health Insurance databases. Patients aged 18 years or older identified with IBD were included from January 1, 2009, through December 31, 2013, and followed up until December 31, 2015. Exposures At each time of the follow-up, patients were categorized as being exposed to thiopurine monotherapy, anti-TNF monotherapy, or combination therapy, or being unexposed. Main Outcomes and Measures The primary outcome was incident lymphoma. Results Among the 189 289 patients included (54% women; median age, 43 years [interquartile range, 32-56 years]) and followed up for a median of 6.7 years, 123 069 were never exposed during follow-up, 50 405 were exposed to thiopurine monotherapy, 30 294 to anti-TNF monotherapy, and 14 229 to combination therapy. Overall, 336 lymphoma cases occurred: 220 in unexposed patients (incidence rate [IR] per 1000 person-years, 0.26; 95% CI, 0.23-0.29), 70 in patients exposed to thiopurine monotherapy (IR, 0.54; 95% CI, 0.41-0.67), 32 in patients exposed to anti-TNF monotherapy (IR, 0.41; 95% CI, 0.27-0.55), and 14 in patients exposed to combination therapy (IR, 0.95; 95% CI, 0.45-1.45). In a multivariable Cox model, compared with unexposed patients, the risk of lymphoma was higher among those exposed to thiopurine monotherapy (adjusted hazard ratio [aHR], 2.60; 95% CI, 1.96-3.44; P  < .001), anti-TNF monotherapy (aHR, 2.41; 95% CI, 1.60-3.64; P  < .001), or combination therapy (aHR, 6.11; 95% CI, 3.46-10.8; P  < .001). The risk was higher in patients exposed to combination therapy vs those exposed to thiopurine monotherapy (aHR, 2.35; 95% CI, 1.31-4.22; P  < .001) or anti-TNF monotherapy (aHR, 2.53; 95% CI, 1.35-4.77; P  < .001). Conclusions and Relevance Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment. This pharmacoepidemiology study conducted in France assesses the risk of lymphoma associated with thiopurines and anti–tumor necrosis factor agents, used alone or in combination, for treatment of inflammatory bowel disease.
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                Author and article information

                Contributors
                amanda.tatro@roche.com
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                22 May 2020
                22 May 2020
                2020
                : 37
                : 7
                : 3417-3431
                Affiliations
                [1 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, University of California, San Diego, ; La Jolla, CA USA
                [2 ]GRID grid.410569.f, ISNI 0000 0004 0626 3338, University Hospital Leuven, ; Leuven, Belgium
                [3 ]GRID grid.419227.b, Roche Products Limited, ; Welwyn Garden City, UK
                [4 ]GRID grid.417570.0, ISNI 0000 0004 0374 1269, F. Hoffmann-La Roche AG, Global Product Development Medical Affairs, ; 4070 Basel, Switzerland
                Article
                1366
                10.1007/s12325-020-01366-2
                7467434
                32445184
                0b06456e-bea0-446a-bf85-390a9b49cdbb
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 31 January 2020
                Funding
                Funded by: F. Hoffmann-La Roche, Ltd
                Categories
                Study Protocol
                Custom metadata
                © Springer Healthcare Ltd., part of Springer Nature 2020

                anti-integrin,crohn’s disease,etrolizumab,inflammatory bowel disease,ulcerative colitis

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