The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study

Gut. 2011 Aug;60(8):1068-75. doi: 10.1136/gut.2010.226548. Epub 2011 Feb 11.

Abstract

Background and aims: 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.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Cell Adhesion / immunology
  • Cell Adhesion Molecules
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / pathology
  • Colitis, Ulcerative / therapy*
  • Colonoscopy
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Humans
  • Immunity, Cellular
  • Immunoglobulins / immunology*
  • Immunoglobulins / metabolism
  • Infusions, Intravenous
  • Lymphocytes / immunology
  • Lymphocytes / pathology
  • Male
  • Middle Aged
  • Mucoproteins / immunology*
  • Mucoproteins / metabolism
  • Remission Induction
  • Retrospective Studies
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Cell Adhesion Molecules
  • Immunoglobulins
  • MADCAM1 protein, human
  • Mucoproteins

Associated data

  • ClinicalTrials.gov/NCT00928681