title: The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study.
abstract: OBJECTIVE
  Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX.
  
  
  METHODS
  In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) once-monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24.
  
  
  RESULTS
  In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade.
  
  
  CONCLUSIONS
  In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.affiliation: Swedish Medical Center and University of Washington, Seattle.
authors.forename: Philip
authors.initials: P
authors.lastname: Mease
authors.affiliation: Organización Medica de Investigación, Buenos Aires, Argentina.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mysler
authors.affiliation: Keio University, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Csolnoky Ferenc Hospital, Veszprém, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Drescher
authors.affiliation: Universidad Nacional de Tucuman and Centro Médico Privado de Reumatología, Tucuman, Argentina.
authors.forename: Alberto
authors.initials: A
authors.lastname: Berman
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Jun
authors.initials: J
authors.lastname: Xing
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Moshe
authors.initials: M
authors.lastname: Zilberstein
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Subhashis
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004185:Disability Evaluation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000276:immunology*; D007391:International Cooperation; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015850:Interleukin-6; C000604955:clazakizumab; D008727:Methotrexate