title: Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study.
abstract: OBJECTIVE
  The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.
  
  
  METHODS
  Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.
  
  
  RESULTS
  Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.
  
  
  CONCLUSIONS
  OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.
  NCT01242488.
authors.affiliation: Division of Immunology and Rheumatology, Stanford University Medical Center, Stanford, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.affiliation: Department of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Furst
authors.affiliation: Houston Institute for Clinical Research, Houston, USA.
authors.forename: Namieta
authors.initials: N
authors.lastname: Janssen
authors.affiliation: Division of Rheumatology, University of South Florida Health, Tampa, Florida, USA.
authors.forename: John
authors.initials: J
authors.lastname: Carter
authors.affiliation: Department of Rheumatology, Southend University Hospital, Westcliff-on-Sea, UK.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Dasgupta
authors.affiliation: UCB Pharma, Raleigh, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Bryson
authors.affiliation: UCB Pharma, Raleigh, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Duncan
authors.affiliation: UCB Pharma, Raleigh, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: Service et Pôle de Rhumatologie, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Durez
authors.affiliation: UCB Pharma, Slough, UK.
authors.forename: Kosmas
authors.initials: K
authors.lastname: Kretsos
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001688:Biological Products / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D017211:Treatment Failure; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C502936:tocilizumab; C000592400:olokizumab
keywords: Autoimmune Diseases; DMARDs (biologic); Disease Activity; Rheumatoid Arthritis