Mechanism of action: Neutrophil elastase (NE) inhibitor

Preclinical pharmacology

AZD9668 is a potent, selective and reversible inhibitor of human neutrophil elastase (IC50 at recombinant, plasma, and cell associated as well as explosive NE were 12, 44, and 50nM, respectively). In a panel of 319 other selectivity assays there was no inhibition at concentrations <3μM.  AZD9668 is ~36 to 44 times less potent at the rat, mouse, and dog orthologues. In vivo, AZD9668 prevented acute lung injury (haemorrhage)induced by instillation of human NE with an ED50 of 0.85mg/kg, p.o. (estimated plasma concentration = 2.8nM). In a 4-day cigarette smoke exposure model, AZD9668 dose-dependently reduced both neutrophil numbers and IL-1β levels in bronchoalveolar lavage fluid (maximal inhibitions of 45% and 78%, respectively, at 10mg/kg, p.o.). AZD9668 is a P-gp substrate, not extensively metabolised or plasma protein bound, and primarily excreted via the faeces.

Safety and tolerability

AZD9668 has been administered orally to Caucasian and Japanese healthy volunteers in single doses up to 120mg and multiple doses up to 70mg BID. In Phase 2 studies, AZD9668 (5, 20 and 60mg, BID) were administered for 2, 4, or 12 weeks in patients with COPD, cystic fibrosis, or bronchiectasis. Infrequent (1-3%)elevation in liver enzymes (ALT and/or AST) or bilirubin, has been found in AZD9668 compared to placebo treated subjects. To date >1000 patients have received AZD9668 at up to 60mg BID for up to 12 weeks.

Preclinical studies of up to 12 months duration have been performed.

Clinical pharmacology

In a Phase 1 healthy volunteer study, AZD9668 at doses ≥60mg (equivalent to ~12 x IC50 in plasma) produced a >90% inhibition of zymosan-stimulated neutrophil elastase activity in an ex vivo whole blood assay.

In 28 day Phase 2a studies at 60mg BID, bronchiectasis and CF patients had significantly reduced sputum and plasma inflammatory biomarkers while bronchiectasis patients alone showed improvements in lung function (FEV1 and FVC) and quality of life (SGRQ-C score). In follow-on 12 week Phase 2b studies, there was no significant treatment benefit in COPD patients also treated with tiotropium or budesonide/formoterol, neither were there effects of AZD9668 on lung function in patients with cystic fibrosis.

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.

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

Regarding "Elastase inhibitor AZD9668 treatment prevented progression of experimental abdominal aortic aneurysms"

Feasibility of Computed Tomography in a Multicenter COPD Trial: A Study of the Effect of AZD9668on Structural Airway Changes

Elastase inhibitor AZD9668 treatment prevented progression of experimental abdominal aortic aneurysms

Performance of the EXAcerbations of chronic pulmonary disease tool patient-reported outcome measure in three clinical trials of chronic obstructive pulmonary disease

The potential of neutrophil elastase inhibitors as anti-inflammatory therapies

Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis

Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD

A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium

Neutrophil elastase inhibitors: recent advances in the development of mechanism-based and nonelectrophilic inhibitors

Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD

AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase

Gene information from the NCBi

This compound works on the following genes: