Science and Research

Safety and efficacy of the human neutrophil elastase inhibitor BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis: A randomized controlled trial

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
Publication details
DOI: 10.1016/j.pupt.2019.03.009
Journal: Pulmonary pharmacology & therapeutics
Pages: 86-93 
Work Type: Original
Location: ARCN
Disease Area: AA, COPD
Partner / Member: Ghd
Access-Number: 30917927
See publication on PubMed

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