title: Atacicept in multiple sclerosis (ATAMS): a randomised, placebo-controlled, double-blind, phase 2 trial.
abstract: BACKGROUND
  Depletion of B lymphocytes is associated with suppression of inflammatory activity in multiple sclerosis. We aimed to assess the safety and efficacy of atacicept, a recombinant fusion protein that suppresses B-cell function and antibody production.
  
  
  METHODS
  In this placebo-controlled, double-blind, 36-week, phase 2 trial (ATAMS) in Australia, Canada, Europe, and the USA, patients aged 18-60 years with relapsing multiple sclerosis were randomly assigned via an interactive voice response system in a 1:1:1:1 ratio, stratified by geographical region, to receive weekly subcutaneous injections with atacicept (25, 75, or 150 mg) or placebo. Both patients and study personnel were masked to treatment assignment. The primary endpoint was the change in mean number of gadolinium-enhancing lesions on T1-weighted MRI per patient per scan between weeks 12 and 36. Efficacy endpoints were analysed in the intention-to-treat population. Patients who completed week 36 were eligible to participate in a long-term extension study (ATAMS EXT), consisting of a double-blind phase followed by an open-label phase, for a total study time of up to 5 years. The study was terminated early after the independent data and safety monitoring board noted an increased annualised relapse rate with atacicept. The protocol was subsequently amended to include a 60-week safety follow-up, to allow treatment with approved multiple sclerosis drugs, and to change the primary endpoint to gadolinium-enhancing T1 lesions per scan during the entire double-blind period of ATAMS. Both the trial and the extension are registered with ClinicalTrials.gov, numbers NCT00642902 (ATAMS) and NCT00853762 (ATAMS EXT).
  
  
  RESULTS
  Between April 23, 2008, and early study termination on Sept 11, 2009, 255 patients were randomly assigned: 63 to placebo, 63 to atacicept 25 mg, 64 to 75 mg, and 65 to 150 mg. 90 (35%) patients completed the week 36 treatment visit, 26 (10%) discontinued before study termination (including one who dropped out before receiving study treatment), and 139 (55%) discontinued because of study termination. During the double-blind period of ATAMS, annualised relapse rates were higher in the atacicept groups than in the placebo group (atacicept 25 mg, 0·86, 95% CI 0·43-1·74; 75 mg, 0·79, 0·40-1·58; 150 mg, 0·98, 0·52-1·81; placebo, 0·38, 0·17-0·87). Mean numbers of gadolinium-enhancing T1 lesions per scan were similar in all groups (25 mg, 2·26, 0·97-5·27; 75 mg, 2·30, 1·08-4·92; 150 mg, 2·49, 1·18-5·27; placebo, 3·07, 1·40-6·77). Seven patients (one taking placebo and six atacicept) discontinued treatment because of adverse events. One death occurred in the placebo group. During the safety follow-up, immunoglobulin concentrations and B-cell counts returned towards predose values and annualised relapse rates in the atacicept groups decreased until they were similar to that of the placebo group
  
  
  CONCLUSIONS
  Increased clinical disease activity associated with atacicept suggests that the role of B cells and humoral immunity in multiple sclerosis is complex. For studies that explore therapeutic immunomodulation in multiple sclerosis, rigorous monitoring for negative effects on clinical and MRI outcomes is warranted.
  
  
  BACKGROUND
  Merck Serono (Merck KGaA) and EMD Serono (Merck KGaA).
authors.affiliation: Departments of Neurology and Biomedicine, University Hospital Basel, Basel, Switzerland. Electronic address: ludwig.kappos@usb.ch.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Department of Neurology and Centre for Neuropsychiatry, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: Department of Neurology and Neurosurgery, Russian National Research Medical University, and Moscow Multiple Sclerosis Centre, 11th City Hospital of Moscow, Moscow, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Boyko
authors.affiliation: Medical Image Analysis Centre, University Hospital Basel, Basel, Switzerland.
authors.forename: Ernst Wilhelm
authors.initials: EW
authors.lastname: Radü
authors.affiliation: Biogen Idec, Cambridge, MA, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Mikol
authors.affiliation: Quartz Bio, Geneva, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Lamarine
authors.affiliation: EMD Serono, Billerica, MA, USA.
authors.forename: Yann
authors.initials: Y
authors.lastname: Hyvert
authors.affiliation: Stamford Consultants AG, Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Freudensprung
authors.affiliation: Shire Pharmaceuticals, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Plitz
authors.affiliation: Biogen Idec International, Zug, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: van Beek
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein