title: A phase 1, randomized, placebo-controlled, dose-escalation study of an anti-IL-13 monoclonal antibody in healthy subjects and mild asthmatics.
abstract: OBJECTIVE
  IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586.
  
  
  METHODS
  In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo.
  
  
  RESULTS
  GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs.
  
  
  CONCLUSIONS
  GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.
authors.affiliation: Nucleus Network, Melbourne, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodsman
authors.forename: Claire
authors.initials: C
authors.lastname: Ashman
authors.forename: Anthony
authors.initials: A
authors.lastname: Cahn
authors.forename: Erika
authors.initials: E
authors.lastname: De Boever
authors.forename: Nicholas
authors.initials: N
authors.lastname: Locantore
authors.forename: Adrian
authors.initials: A
authors.lastname: Serone
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pouliquen
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001249:Asthma / Q000188:drug therapy*; D001944:Breath Tests; D004311:Double-Blind Method; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C582664:GSK679586; D018793:Interleukin-13; D009569:Nitric Oxide