title: Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study.
abstract: OBJECTIVE
  Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.
  
  
  METHODS
  In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.
  
  
  RESULTS
  Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose-related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen.
  
  
  CONCLUSIONS
  Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. p.p.tak@amc.uva.nl
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
authors.forename: R M
authors.initials: RM
authors.lastname: Thurlings
authors.forename: C
authors.initials: C
authors.lastname: Rossier
authors.forename: I
authors.initials: I
authors.lastname: Nestorov
authors.forename: A
authors.initials: A
authors.lastname: Dimic
authors.forename: V
authors.initials: V
authors.lastname: Mircetic
authors.forename: M
authors.initials: M
authors.lastname: Rischmueller
authors.forename: E
authors.initials: E
authors.lastname: Nasonov
authors.forename: E
authors.initials: E
authors.lastname: Shmidt
authors.forename: P
authors.initials: P
authors.lastname: Emery
authors.forename: A
authors.initials: A
authors.lastname: Munafo
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002356:Cartilage / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010919:Placebos; D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein