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

Abstract

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 1 mg 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:

1 mg 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.

• Authors: Henrik Watz, Johannes Nagelschmitz, Anne Kirsten, Frauke Pedersen, Dorina van der Mey, Stephan Schwers, Tiemo-Joerg Bandel, Klaus F Rabe
• Journal: Pulmonary pharmacology & therapeutics (Pulm Pharmacol Ther) Vol. 56 Pg. 86-93 (06 2019) ISSN: 1522-9629 [Electronic] England
• PMID: 30917927 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• BAY 85-8501
• Proteinase Inhibitory Proteins, Secretory
• Pyrimidinones
• Sulfones
• ELANE protein, human
• Leukocyte Elastase

Topics

• 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