Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study

Inflamm Bowel Dis. 2015 Oct;21(10):2247-53. doi: 10.1097/MIB.0000000000000514.


Background: AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD.

Methods: We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed.

Results: In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported.

Conclusions: Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / administration & dosage
  • Adamantane / adverse effects
  • Adamantane / analogs & derivatives*
  • Administration, Oral
  • Adult
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Biomarkers / metabolism
  • C-Reactive Protein / metabolism
  • Crohn Disease / drug therapy*
  • Crohn Disease / metabolism
  • Crohn Disease / psychology
  • Double-Blind Method
  • Feces / chemistry
  • Female
  • Humans
  • Leukocyte L1 Antigen Complex / metabolism
  • Male
  • Middle Aged
  • Purinergic P2X Receptor Antagonists / administration & dosage*
  • Purinergic P2X Receptor Antagonists / adverse effects
  • Quality of Life
  • Remission Induction
  • Severity of Illness Index
  • Surveys and Questionnaires
  • Young Adult


  • AZD9056
  • Benzamides
  • Biomarkers
  • Leukocyte L1 Antigen Complex
  • Purinergic P2X Receptor Antagonists
  • C-Reactive Protein
  • Adamantane