Mechanism of action: Chemokine (C-X-C motif) receptor 2 (CXCR2) antagonist
AZD5069 is a potent (IC50 0.79nM), CXCR2 selective (>150-fold less potent at CXCR1 and CCR2b receptors; no effect on C5a, LTB4 or fMLP induced CD11b expression), reversible (but time and temperature dependent) antagonist of the human CXCR2 receptor. Receptor binding potency was found to be similar in cynomolgus monkey, dog, rat and mouse. In functional cellular (neutrophil) studies, AZD5069 inhibited ligand (IL-8 or GRO-α) induced cytosolic calcium increase, CD11b surface expression, adhesion and chemotaxis at concentrations consistent with its binding potency corrected for protein binding (~99%). AZD5069 when administered orally to rats blocked inhaled-LPS induced lung (BAL) and blood neutrophilia-exposures aligned with receptor potency corrected for protein binding.
Proof of target/receptor coverage was demonstrated in healthy volunteer studies by a dose-related response in an ex vivo whole blood GRO-α induced CD11b expression assay and reduction in blood neutrophils. A statistically significant 69% reduction in sputum neutrophils was found in bronchiectasis patients after 80mg BID for 4 weeks. In severe asthmatics, 5, 15 or 45mg BID for 6 months did not reduce the rate of exacerbations nor improve FEV1 or total asthma symptom score. Trough plasma levels at 45mg BID were estimated to provide >96% receptor occupancy based on the whole blood CD11b expression assay.
AZD5069 is partly metabolised via CYP3A4. When co-administered with ketoconazole (a strong inhibitor of CYP3A4) a 2.1-fold increase in AUC and 1.6-fold increase in Cmax were observed, and a correspondingly greater reduction in blood neutrophil counts, than with AZD5069 alone.
Safety and tolerability
AZD5069 has been administered orally to 214 healthy volunteers in single doses up to 200mg and multiple doses up to 100mg BID for 6.5 days. No clinically significant adverse effects have been observed. A reversible reduction in blood neutrophil counts occurs at doses 5.45mg. AZD5069 has also been studied in patients with COPD, bronchiectasis and asthma. In severe asthmatics, 45mg BID (n=161) for up 12 months resulted in a sustained ~25%, reversible on discontinuation of treatment, reduction in blood neutrophils. There was no consistent increase in the rate of infections.
Suitable for and exclusions
Preclinical reprotoxicology data are available and have not identified any specific risks. Women of child-bearing potential using highly effective contraception can be included.
Indications and dosing regimen should consider the potential for and optimization of efficacy compared to the mechanism-based effects on circulating neutrophil counts.
Clinical trials for this compound
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Publications for this compound
Find out more about this compound by reading related publications:
Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite
A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis
The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions
Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist
The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD
Pharmacological Characterization of AZD5069, a Slowly Reversible CXC Chemokine Receptor 2 Antagonist
Gene information from the NCBi
This compound works on the following genes: