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

Abstract

BACKGROUND:

Neutrophil elastase (NE) is implicated in chronic obstructive pulmonary disease (COPD). AZD9668 is a reversible and selective inhibitor of NE, well tolerated at doses of 60 mg bid during Phase I/IIa development.

METHODS:

This 12-week, randomised, double-blind, placebo-controlled, Phase IIb, trial (NCT01023516), investigated the efficacy and safety of AZD9668 (60 mg bid) versus placebo in patients with symptomatic COPD and a history of exacerbation receiving maintenance budesonide/formoterol. Primary outcome variable: forced expiratory volume in one second (FEV1). Secondary endpoints included: post-bronchodilator FEV1, pre- and post-bronchodilator forced vital capacity, FEV6, forced expiratory flow between 25% and 75% of vital capacity and inspiratory capacity; peak expiratory flow and FEV1 measured at home; EXAcerbations of Chronic pulmonary disease Tool and Breathlessness, Cough and Sputum Scores; St George's respiratory questionnaire for COPD (SGRQ-C) scores; exacerbations; and safety assessments.

RESULTS:

Six hundred and fifteen patients were randomised: placebo (302), AZD9668 60 mg bid (313). AZD9668 showed no effect on lung function: change in mean pre-bronchodilator FEV1 versus placebo was 0.01L (95% confidence interval: -0.03, 0.05; p=0.533). AZD9668 did not significantly improve respiratory signs and symptoms, SGRQ-C score or time to first exacerbation. Adverse events were similar for AZD9668 and placebo.

CONCLUSIONS:

Three months' treatment with AZD9668 did not improve lung function, respiratory signs and symptoms or SGRQ-C score when added to budesonide/formoterol maintenance therapy in patients with COPD. In the absence of definitive biomarkers of short-term disease progression, further research is needed to determine the optimal duration of studies to evaluate NE inhibitors as disease-modifying agents.

• Authors: Piotr Kuna, Martin Jenkins, Christopher D O'Brien, William A Fahy
• Journal: Respiratory medicine (Respir Med) Vol. 106 Issue 4 Pg. 531-9 (Apr 2012) ISSN: 1532-3064 [Electronic] England
• PMID: 22197578 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers
• Bronchodilator Agents
• Drug Combinations
• Ethanolamines
• Glucocorticoids
• Pyridones
• Sulfones
• Budesonide
• N-((5-(methanesulfonyl)pyridin-2-yl)methyl)-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-1,2-dihydropyridine-3-carboxamide
• Leukocyte Elastase
• Formoterol Fumarate

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers (metabolism)
• Bronchodilator Agents (adverse effects, therapeutic use)
• Budesonide (adverse effects, therapeutic use)
• Double-Blind Method
• Drug Combinations
• Drug Therapy, Combination
• Ethanolamines (adverse effects, therapeutic use)
• Female
• Forced Expiratory Volume (drug effects)
• Formoterol Fumarate
• Glucocorticoids (adverse effects, therapeutic use)
• Humans
• Leukocyte Elastase (antagonists & inhibitors)
• Male
• Middle Aged
• Pulmonary Disease, Chronic Obstructive (drug therapy, physiopathology)
• Pyridones (adverse effects, therapeutic use)
• Quality of Life
• Respiratory Mechanics (drug effects)
• Sulfones (adverse effects, therapeutic use)
• Treatment Outcome