title: The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study.
abstract: OBJECTIVE
  Leucocyte migration to gut mucosa, mediated by integrin binding to mucosal addressin cell adhesion molecule (MAdCAM), is a promising target for therapeutic intervention in inflammatory bowel disease. This first-in-human study of a monoclonal antibody to MAdCAM, PF-00547,659, aimed to explore the safety and preliminary efficacy of this gut-specific mechanism in ulcerative colitis.
  
  
  METHODS
  In this randomised, double-blind placebo-controlled study, 80 patients with active ulcerative colitis received single or multiple (three doses, 4-week intervals) doses of PF-00547,659 0.03-10 mg/kg IV/SC, or placebo. Safety was assessed by adverse events, laboratory tests, and immunogenicity. Exploratory efficacy analyses were based on Mayo score and endoscopic responder rates at weeks 4 and 12. Faecal calprotectin was quantified as a measure of disease activity, and the number of α₄β₇⁺ lymphocytes was measured to demonstrate drug activity.
  
  
  RESULTS
  No obvious drug-related side effects were observed in the PF-00547,659 group, while patient numbers, especially those fully exposed, were small. Overall responder/remission rates at 4 and 12 weeks were 52%/13% and 42%/22%, respectively with combined PF-00547,659 doses compared with 32%/11% and 21%/0%, respectively with placebo. Equivalent endoscopic responder rates were 50% and 42% versus 26% and 29%, respectively. Faecal calprotectin levels decreased to a greater extent with PF-00547,659 than placebo (week 4: 63% vs 18%). Despite variability, there was a trend for an increase in α₄β₇⁺ lymphocytes in patients receiving PF-00547,659.
  
  
  CONCLUSIONS
  The favourable short-term safety profile and preliminary efficacy findings for PF-00547,659 in this first-in-human study pave the way for further investigation in larger trials, to establish the role of PF-00547,659 in ulcerative colitis treatment. Trial Register No: NCT00928681.
authors.affiliation: Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. severine.vermeire@uz.kuleuven.ac.be
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Subrata
authors.initials: S
authors.lastname: Ghosh
authors.forename: Julian
authors.initials: J
authors.lastname: Panes
authors.forename: Jens F
authors.initials: JF
authors.lastname: Dahlerup
authors.forename: Andreas
authors.initials: A
authors.lastname: Luegering
authors.forename: Jana
authors.initials: J
authors.lastname: Sirotiakova
authors.forename: Ulrike
authors.initials: U
authors.lastname: Strauch
authors.forename: Gary
authors.initials: G
authors.lastname: Burgess
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Spanton
authors.forename: Steven W
authors.initials: SW
authors.lastname: Martin
authors.forename: Wojciech
authors.initials: W
authors.lastname: Niezychowski
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules; D003093:Colitis, Ulcerative / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003113:Colonoscopy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006801:Humans; D007111:Immunity, Cellular; D007136:Immunoglobulins / Q000276:immunology* / Q000378:metabolism; D007262:Infusions, Intravenous; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins / Q000276:immunology* / Q000378:metabolism; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; D009088:Mucoproteins