Oral P2X7 inhibitor shows promise in treating Crohn's disease symptoms
Phase 2a study data suggest that AZD9056, an oral purinergic receptor P2X7 antagonist, may safely improve symptoms in patients with moderate-to-severe Crohn’s disease.
The P2X7 receptor “is involved in the processing and release of several proinflammatory cytokines linked to the pathogenesis of Crohn’s disease,” Jean-Frédéric Colombel, MD, professor of medicine at the Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, Séverine Vermeire, MD, PhD, from the department of gastroenterology at the Catholic University of Leuven in Belgium, and colleagues wrote. “AZD9056 is a selective oral inhibitor of P2X7 receptor signaling identified through high throughput screening and has been previously studied in patients with rheumatoid arthritis.”
To assess the efficacy and safety of AZD9056 (AstraZeneca) in adults with active Crohn’s disease, Colombel, Vermeire, and colleagues, performed a double-blind study from January 2006 to April 2007, which involved 34 patients with moderate-to-severe active Crohn’s disease who were recruited at 10 centers in five European countries.
Patients were randomly assigned to receive 200-mg oral AZD9056 once per day for 28 days (n = 24) or a matching placebo (n = 10). The primary end-point was change from baseline in Crohn’s Disease Activity Index (CDAI) scores, and clinical remission, clinical response, quality of life improvement, serum C-reactive protein and fecal calprotectin were also evaluated.
Mean CDAI scores changed from 311 at baseline to 242 at day 28 in the treatment arm compared with 262 to 239 in the placebo arm (P = .049). More patients in the treatment arm achieved clinical remission (24% vs. 11%) and response (52% vs. 22%) compared with the placebo arm, but these did not reach statistical significance.
The Mental Component Score of the Short Form 36 was the only quality of life measure that significantly improved in the treatment arm compared with placebo (P = .017). No differences in serum C-reactive protein or fecal calprotectin levels were observed between treatment and placebo arms. The drug was well-tolerated and no serious adverse events were reported.
“The disconnect between improvement in clinical symptoms, particularly abdominal pain, and lack of change in objective markers of inflammation is of concern and has put the further development of AZD9056 for the indication of [Crohn’s disease] on hold,” the researchers wrote. “Nevertheless, the now well-substantiated role of P2X7 in nociception should rekindle the interest in this pathway for modulating pain in gastrointestinal diseases.” – by Adam Leitenberger
Disclosures: This study was funded by AstraZeneca. Colombel reports he has served as consultant, advisory board member, or speaker for AbbVie, AB Science, Amgen, Bristol-Myers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, MedImmune, Merck & Co., Millennium Pharmaceuticals Inc., Neovacs, Nutrition Science Partners Ltd., Pfizer Inc., Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering-Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, TiGenix, UCB Pharma, and Vertex. Vermeire reports she has served as a speaker, a consultant, and an advisory board member for MSD, Takeda, Pfizer, Genentech/Roche and has received research funding from AbbVie, Centocor, and MSD. Please see the full study for a list of all other researchers’ relevant financial disclosures.