title: Efficacy and Safety of Tabalumab, an Anti-B-Cell-Activating Factor Monoclonal Antibody, in a Heterogeneous Rheumatoid Arthritis Population: Results From a Randomized, Placebo-Controlled, Phase 3 Trial (FLEX-O).
abstract: OBJECTIVE
  The efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor (BAFF), were evaluated in patients with rheumatoid arthritis.
  
  
  METHODS
  In this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered. Efficacy analyses were based on a prespecified subset of patients with 5 or more of 68 tender and 5 or more of 66 swollen joints at baseline (efficacy population, n = 849). The primary efficacy end point was ACR20 (20% improvement in American College of Rheumatology criteria) response at week 24.
  
  
  RESULTS
  At week 24, there were no differences in ACR20 response rates (120/Q4W = 34.4%, 90/Q2W = 33.5%, placebo = 31.5%) or any other measures of efficacy across the treatment groups. Discontinuations due to adverse events (AE) were 3.4%, 2.7%, and 4.0%; incidence of treatment-emergent AEs were 64.1%, 58.2%, and 58.8%, with 23.2%, 25.9%, and 22.0% treatment-emergent infections; and incidence rates of serious AEs were 3.7%, 2.2%, and 2.8% with 1.1%, 0.3%, and 0.7% serious infections in the 120/Q4W, 90/Q2W, and placebo groups, respectively. Three deaths were reported (120/Q4W, n = 2; 90/Q2W, n = 1). Each tabalumab group had significant decreases versus placebo in CD3-CD20 B cells (P ≤ 0.05) and in serum immunoglobulins (P ≤ 0.001).
  
  
  CONCLUSIONS
  Although tabalumab administration resulted in biologic activity, as demonstrated by changes in B cells and immunoglobulins, targeting BAFF-dependent pathways alone is not sufficient to significantly reduce rheumatoid arthritis disease activity.
authors.affiliation: From the *Stanford University Medical Center, Palo Alto, CA; †NYU School of Medicine, New York, NY; ‡Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom; §Private Practice, Memphis, TN; and ∥Eli Lilly and Company, Indianapolis, IN.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Gregg J
authors.initials: GJ
authors.lastname: Silverman
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Gupta
authors.forename: Anne
authors.initials: A
authors.lastname: Gill
authors.forename: Melissa
authors.initials: M
authors.lastname: Veenhuizen
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Komocsar
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Berclaz
authors.forename: Chin
authors.initials: C
authors.lastname: Lee
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053264:B-Cell Activating Factor; C575974:tabalumab