title: Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study.
abstract: OBJECTIVE
  Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX).
  
  
  METHODS
  The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated.
  
  
  RESULTS
  Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg.
  
  
  CONCLUSIONS
  Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.
authors.affiliation: Division of Rheumatology, Stanford University, Stanford, California 94304, USA. Genovese@stanford.edu
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Kaine
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Lowenstein
authors.forename: José
authors.initials: J
authors.lastname: Del Giudice
authors.forename: Andrew
authors.initials: A
authors.lastname: Baldassare
authors.forename: Joy
authors.initials: J
authors.lastname: Schechtman
authors.forename: Edward
authors.initials: E
authors.lastname: Fudman
authors.forename: Michael
authors.initials: M
authors.lastname: Kohen
authors.forename: Sheila
authors.initials: S
authors.lastname: Gujrathi
authors.forename: Robert G
authors.initials: RG
authors.lastname: Trapp
authors.forename: Nadera J
authors.initials: NJ
authors.lastname: Sweiss
authors.forename: Greg
authors.initials: G
authors.lastname: Spaniolo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dummer