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The clinical potential of etrolizumab in ulcerative colitis: hypes and hopes.

ABSTRACT: Antiadhesion molecules are effective and safe in patients with ulcerative colitis (UC). Etrolizumab, a monoclonal antibody targeting both ?4?7 and ?E?7, represents a promising therapy for patients with UC, since this novel mechanism of action may be effective in blocking leukocyte recruitment both at the vascular and at the mucosal level. Preliminary studies show that etrolizumab is effective in inducing clinical response and remission, and mucosal healing. Moreover, new predictors of response have recently been identified, opening the way to a tailored therapeutic approach. This review of the literature aims to present and discuss the most recent evidence on etrolizumab in UC, focusing on the clinical implications of the use of etrolizumab in UC.

SUBMITTER: Fiorino G

PROVIDER: S-EPMC4913345 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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The clinical potential of etrolizumab in ulcerative colitis: hypes and hopes.

Fiorino Gionata G Gilardi Daniela D Danese Silvio S

Therapeutic advances in gastroenterology 20160519 4

Antiadhesion molecules are effective and safe in patients with ulcerative colitis (UC). Etrolizumab, a monoclonal antibody targeting both α4β7 and αEβ7, represents a promising therapy for patients with UC, since this novel mechanism of action may be effective in blocking leukocyte recruitment both at the vascular and at the mucosal level. Preliminary studies show that etrolizumab is effective in inducing clinical response and remission, and mucosal healing. Moreover, new predictors of response h ...[more]

PMID: 27366219

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Project description:IntroductionEtrolizumab 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.MethodsIn 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.DiscussionThe 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 registrationClinicalTrials.gov: HIBISCUS I (NCT02163759), HIBISCUS II (NCT02171429), GARDENIA (NCT02136069), LAUREL (NCT02165215), HICKORY (NCT02100696), COTTONWOOD (NCT02118584), BERGAMOT (NCT02394028), JUNIPER (NCT02403323).

Project description:BackgroundChanges in bacterial populations termed "dysbiosis" are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC.Methodology/principal findingsA dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, p?=?0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p<0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR.Conclusions/significanceHelicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.

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The clinical potential of etrolizumab in ulcerative colitis: hypes and hopes.

Publications

The clinical potential of etrolizumab in ulcerative colitis: hypes and hopes.

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