Neutrophil elastase (NE) activity is increased in
bronchiectasis and may play a role in this condition. We wished to determine the effect of
AZD9668, a selective oral inhibitor of NE. Efficacy and safety of
AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with
bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest(®) diary card data; St George's Respiratory Questionnaire for
COPD patients (SGRQ-C); sputum NE activity; inflammatory
biomarker levels;
desmosine levels; adverse events, safety haematology and biochemistry.
AZD9668 levels in plasma and sputum were measured to confirm exposure. Thirty-eight patients were randomised: 16 to placebo and 22 to
AZD9668. There was no change in sputum neutrophils with
AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the
AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of
AZD9668 were also seen in slow vital capacity, plasma
interleukin-8, and post-waking sputum
interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of
AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C.
AZD9668 was well tolerated. In this small signal-searching study, 4 weeks' treatment with
AZD9668 improved lung function in patients with
bronchiectasis and there were trends for reductions in sputum inflammatory
biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in
bronchiectasis.
REGISTRATION: NCT00769119.