AZD5069
Preclinical pharmacology
AZD5069 is a potent, selective reversible (time and temperature dependent) antagonist of the human CXCR2 receptor.
| Potency (IC50) | 0.79nM |
| CXCR2 Selectivity | >150-fold greater than for CXCR1 and CCR2b receptors |
| PPB (%) | 99 |
Receptor binding potency was found to be similar across species including cynomolgus monkey, dog, rat and mouse. In functional in vitro neutrophil assays, 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. Oral administration of AZD5069 to rats blocked inhaled-LPS induced lung (BAL) and blood neutrophilia-exposures aligned with receptor potency (corrected for protein binding).
Clinical pharmacology
Target/receptor coverage was demonstrated in a dose-related response study in an ex vivo whole blood from healthy volunteers measuring 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 partially 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 greater reduction in blood neutrophil counts was observed when compared with patients treated with AZD5069 alone.
Safety and tolerability
AZD5069 has been administered orally to 214 healthy volunteers in single-dose studies up to 200mg and multiple-dose up to 100mg BID for 6.5 days. No clinically significant adverse effects have been observed. A reversible reduction in blood neutrophil counts occurred at 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 reduction in blood neutrophils ~25%, that was reversible on discontinuation of treatment. There was no consistent increase in the observed rate of infections.
Suitable for and exclusions
Preclinical reprotoxicology data 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.
Additional Information
Please note that only proposals in the following therapeutic area will be considered: oncology, respiratory, cardiovascular, renal or metabolic disease; all other disease indications are out-of-scope.
Mechanism of Action
Chemokine (C-X-C motif) receptor 2 (CXCR2) antagonist
Original Therapeutic Area
Other
CNS Penetrant
Unknown
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Uddin M., et al. (2019).
NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma. Front Immunol. Feb 5;10:47. doi: 10.3389/fimmu.2019.00047. PMID: 30804927; PMCID: PMC6370641.
2. Cullberg M., et al. (2018).
Pharmacokinetics of the Oral Selective CXCR2 Antagonist AZD5069: A Summary of Eight Phase I Studies in Healthy Volunteers. Drugs R D. 18(2):149-159. doi:10.1007/s40268-018-0236-x.