Mechanism of action: Purinergic receptor 2X, ligand-gated ion channel 7 (P2X7) Antagonist

Preclinical pharmacology

AZD9056 is a potent antagonist of the human P2X7 receptor with a pA2 for inhibition of agonist-stimulated ethidium bromide release of 8.8 (1.5 nM) in HEK cells expressing the recombinant human P2X7 receptor. AZD9056 inhibits release of pro-inflammatory mediators from isolated human peripheral monocytes (IL-1β and IL-18) and human alveolar macrophages (IL-1β) with IC50 values of 10-13nM and IL-1β release from human synovial cells isolated from the joint tissue of RA patients. AZD9056 demonstrated >100-fold selectivity and specificity compared to both other P2X receptor subtypes and a panel of targets, with the exception of the non-specific sigma receptor (26-fold). AZD9056 has little affinity for P2X7 receptors in rodents; treatment of rats with structural analogues of AZD9056 (e.g., AZ11657312) resulted in a significant reduction in disease severity in the streptococcal cell wall (SCW) model of arthritis, and a delay in the adjuvant-induced arthritis (AA) model.

Safety and tolerability

IAZD9056 has been administered to RA patients (receiving background methotrexate or sulphasalazine) at 50-400 mg, QD for up to 6 months. The most common adverse events were gastrointestinal, dose related, and mainly mild to moderate in severity.

Preclinical safety studies of up to 12 months duration, including pivotal reproductive toxicity studies, have been performed. AZD9056 is considered to be a developmental toxicant (cleft palate abnormalities were observed in rats).

Clinical pharmacology

AZD9056 has been studied in Ph2 clinical trials in RA, COPD, OA and Crohn’s disease patients. No treatment related changes on the primary endpoint of ACR20 comparing AZD9056 (50, 100, 200 and 400mg QD for 6 months) to placebo or Etanercept (50mg once a week) were noted in RA patients receiving background methotrexate or sulphasalazine. In patients with moderate to severe COPD, no significant effects on lung function parameters were noted when comparing AZD9056 (400mg QD for 4 weeks) with placebo. In a 4 week trial in patients with Osteoarthritis (OA), there was no significant effect on pain outcomes. However, a statistically significant decrease in Crohn`s Disease Activity Index (CDAI) from baseline was noted in Crohn’s patients receiving 200mg AZD9056, QD for 4 weeks.

Suitable for and exclusions

Suitable for clinical proposals only and by oral route of administration only. Topical dermatology indications excluded.

The reproductive toxicology package indicates a risk of fetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk-benefit and the use of appropriate highly effective contraception. Administration of AZD9056 to patients with hepatic or renal function that is more than mildly impaired should be avoided until further studies have been done. AZD9056 is a PGP substrate, so caution would be required regarding use with other medicines that are PGP substrates.

Additional information

Gene information from the NCBi

This compound works on the following genes: