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

Eur Respir J. 2012 Oct;40(4):969-76. doi: 10.1183/09031936.00194611. Epub 2012 Jan 20.


The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.

Trial registration: ClinicalTrials.gov NCT00757848.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Biomarkers / metabolism
  • Cell Count
  • Cystic Fibrosis / drug therapy*
  • Female
  • Humans
  • Inflammation Mediators / metabolism
  • Leukocyte Elastase / drug effects
  • Leukocyte Elastase / metabolism
  • Male
  • Neutrophils / drug effects
  • Proteinase Inhibitory Proteins, Secretory / pharmacology
  • Proteinase Inhibitory Proteins, Secretory / therapeutic use*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use*
  • Quality of Life
  • Respiratory Function Tests
  • Sputum / cytology
  • Sputum / metabolism
  • Sulfones / pharmacology
  • Sulfones / therapeutic use*
  • Treatment Outcome


  • Biomarkers
  • Inflammation Mediators
  • Proteinase Inhibitory Proteins, Secretory
  • Pyridones
  • Sulfones
  • 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

Associated data

  • ClinicalTrials.gov/NCT00757848