title: Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine.
abstract: OBJECTIVE
  The P2X(7) purinergic receptor antagonist AZD9056 was evaluated in a phase IIa study and subsequently in a phase IIb study to assess the effects of orally administered AZD9056 on the signs/symptoms of rheumatoid arthritis (RA), with American College of Rheumatology 20% response criteria (ACR20) as the primary outcome.
  
  
  METHODS
  Both studies were randomised, double-blind, placebo-controlled, parallel-group studies in patients with RA receiving methotrexate or sulphasalazine. Phase IIa was an ascending-dose trial in two cohorts (n=75) using AZD9056 administered daily over 4 weeks. Phase IIb included an open-label etanercept treatment group. Patients were randomised to receive treatment for 6 months with 50, 100, 200 or 400 mg AZD9056 (oral, once a day) or matching placebo (oral, once a day), or subcutaneous etanercept (50 mg once a week).
  
  
  RESULTS
  In phase IIa, 65% of AZD9056 recipients at 400 mg/day responded at the ACR20 level compared with 27% of placebo-treated patients. A significant reduction in swollen and tender joint count was observed in the actively treated group compared with placebo, whereas no effect on acute-phase response was observed. Of 385 randomised patients in the phase IIb study, 383 received treatment. AZD9056 (all doses) had no clinically or statistically significant effect on RA relative to placebo as measured by the proportion of patients meeting the ACR20 criteria at 6 months and further supported by secondary end points. In both studies AZD9056 was well tolerated up to 400 mg/day.
  
  
  CONCLUSIONS
  AZD9056 does not have significant efficacy in the treatment of RA, and the P2X(7) receptor does not appear to be a therapeutically useful target in RA.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00520572.
authors.affiliation: The Rebecca MacDonald Centre For Arthritis & Autoimmune Diseases, Mount Sinai Hospital, 60 Murray St, Box 4, Toronto, ON, Canada M5T 3L9. edkeystone@mtsinai.on.ca
authors.forename: Edward C
authors.initials: EC
authors.lastname: Keystone
authors.forename: Millie M
authors.initials: MM
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Layton
authors.forename: Sally
authors.initials: S
authors.lastname: Hollis
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D058920:Purinergic P2X Receptor Antagonists