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

Abstract

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, BronkoTest1 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.

Risk Factors for Bronchiectasis in Children With Cystic Fibrosis

“…The antiinflammatory properties of neutrophil elastase inhibitors are well established, 26 and at least one such agent has shown promise in early trials involving adults with cystic fibrosis. 24 In conclusion, free neutrophil elastase activity in the lung at 3 months of age was associated with increased odds of persistent bronchiectasis at 12 months and at 3 years of age. This observation sets the stage for trials of treatments that target activated neutrophils or inhibit neutrophil elastase activity in order to prevent or delay the onset of bronchiectasis in patients with cystic fibrosis.…”

“…Such therapies are available or are under investigation in clinical trials, [24][25][26] highlighting the relevance of understanding the role that neutrophil elastase may play in disease initiation and progression. Studies of ibuprofen in older children and adults have shown a delayed decrease in lung function and improved maintenance of weight, with these findings attributed to antiinflammatory activity.…”

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores

“…The reason for this is not known; it might be surmised and speculated that AZD9668 (13) is not sufficiently stable, e.g., under sustained oxidative stress conditions. 68 Based on these data, a dose of 60 mg b.i.d. AZD9668 (13) has been orally administered to assess safety and efficacy in CF, BE, and COPD patients.…”

Recent advances in α-1-antitrypsin deficiency-related lung disease

“…The potential to reduce proteolytic lung damage through the use of synthetic NE inhibitors has also been explored. However, the lack of clinical benefit in usual COPD [93] and other conditions such as cystic fibrosis [94] and acute lung injury [95] have meant that trials in A1ATD have not been undertaken.…”