title: Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials.
abstract: BACKGROUND
  Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA.
  
  
  METHODS
  This was a 3-part (Parts A, B and C), multicenter study. Part A and Part B were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of single (Part A) and 3 repeat (Part B) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate (MTX). Part C was a single dose, randomised, single-blind, placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX.
  
  
  RESULTS
  The primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis. In Part A, there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56, 84 and 91. There was also a statistically significant difference in DAS28 between 0.3 mg/kg, 3 mg/kg and 10 mg/kg, as compared to placebo, at Day 84. Although these changes were small and occurred late, they supported progression to Part B and C to determine the therapeutic potential of GSK315234. For Part B, no significant difference was observed between 6 mg/kg and placebo. For Part C, a statistically significant difference in DAS28 was observed at Day 40, Day 84 and Day 100 between the 500 mg subcutaneous group, as compared to placebo. No significant findings were observed at any of the time points for EULAR response criteria, ACR20, ACR50 or ACR70. An exploratory analysis of clinical, pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid.
  
  
  CONCLUSIONS
  Our data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity. Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA.
  
  
  BACKGROUND
  ClinicalTrials.gov no: NCT00674635.
authors.forename: Ernest H
authors.initials: EH
authors.lastname: Choy
authors.forename: Marina
authors.initials: M
authors.lastname: Bendit
authors.forename: Dana
authors.initials: D
authors.lastname: McAleer
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Maria
authors.initials: M
authors.lastname: Feeney
authors.forename: Sara
authors.initials: S
authors.lastname: Brett
authors.forename: Stefano
authors.initials: S
authors.lastname: Zamuner
authors.forename: Andrea
authors.initials: A
authors.lastname: Campanile
authors.forename: John
authors.initials: J
authors.lastname: Toso
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000915:Antibody Affinity / Q000276:immunology; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D053683:Oncostatin M / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology; D016037:Single-Blind Method; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C000590132:GSK315234; D053683:Oncostatin M; D008727:Methotrexate