title: Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study.
abstract: BACKGROUND
  Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS).
  
  
  OBJECTIVE
  Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS.
  
  
  METHODS
  Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo.
  
  
  RESULTS
  Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1-binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.
  
  
  CONCLUSIONS
  CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00726648.
authors.affiliation: Clinical Development, Lycalis s.p.r.l., Brussels, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolf
authors.forename: Jagdev
authors.initials: J
authors.lastname: Sidhu
authors.forename: Christian
authors.initials: C
authors.lastname: Otoul
authors.forename: Dexter L
authors.initials: DL
authors.lastname: Morris
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cnops
authors.forename: Jorg
authors.initials: J
authors.lastname: Taubel
authors.forename: Barbara
authors.initials: B
authors.lastname: Bennett
mesh_terms: D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism*; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009287:Naphthyridines; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D012008:Recurrence; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C584644:CDP323; D039041:Integrin alpha4beta1; D009287:Naphthyridines; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D010649:Phenylalanine