BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease. METHODS: This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501. RESULTS: Overall, 94 patients (mean age, 66 years; 53% male) were randomized (n=47 per group), and 82 completed the study (BAY 85-8501, n=37; placebo, n=45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, n=3; placebo, n=1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (P=0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks. CONCLUSIONS: 1mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.
- Watz, H.
- Nagelschmitz, J.
- Kirsten, A.
- Pedersen, F.
- van der Mey, D.
- Schwers, S.
- Bandel, T. J.
- Rabe, K. F.
Keywords
- Aged
- Bronchiectasis/*drug therapy/physiopathology
- Double-Blind Method
- Female
- Humans
- Leukocyte Elastase/*antagonists & inhibitors
- Male
- Middle Aged
- Proteinase Inhibitory Proteins, Secretory/adverse
- effects/pharmacokinetics/*therapeutic use
- Pyrimidinones/adverse effects/pharmacokinetics/*therapeutic use
- Quality of Life
- Sputum/metabolism
- Sulfones/adverse effects/pharmacokinetics/*therapeutic use
- Treatment Outcome
- *Anti-inflammatory
- *Bronchiectasis
- *Neutrophil elastase