Henrik Watz1, Johannes Nagelschmitz2, Anne Kirsten3, Frauke Pedersen4, Dorina van der Mey5, Stephan Schwers6, Tiemo-Joerg Bandel7, Klaus F Rabe8. 1. Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Wöhrendamm 80, 22927, Grosshansdorf, Germany. Electronic address: h.watz@pulmoresearch.de. 2. Bayer AG, Aprather Weg 18a, D-42113, Wuppertal, Germany. Electronic address: johannes.nagelschmitz@bayer.com. 3. Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Wöhrendamm 80, 22927, Grosshansdorf, Germany. Electronic address: a.kirsten@pulmoresearch.de. 4. Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Wöhrendamm 80, 22927, Grosshansdorf, Germany. Electronic address: f.pedersen@pulmoresearch.de. 5. Bayer AG, Aprather Weg 18a, D-42113, Wuppertal, Germany. Electronic address: dorina.vandermey@bayer.com. 6. Bayer AG, Aprather Weg 18a, D-42113, Wuppertal, Germany. Electronic address: stephan.schwers@bayer.com. 7. Bayer AG, Aprather Weg 18a, D-42113, Wuppertal, Germany. Electronic address: tiemo-joerg.bandel@bayer.com. 8. LungenClinic Grosshansdorf, Airway Research Centre North (ARCN), German Centre for Lung Research (DZL), Wöhrendamm 80, 22927, Grosshansdorf, Germany. Electronic address: k.f.rabe@lungenclinic.de.
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.
RCT Entities:
BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Humanneutrophil 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: Martina Oriano; Francesco Amati; Andrea Gramegna; Anthony De Soyza; Marco Mantero; Oriol Sibila; Sanjay H Chotirmall; Antonio Voza; Paola Marchisio; Francesco Blasi; Stefano Aliberti Journal: Int J Mol Sci Date: 2021-06-01 Impact factor: 5.923
Authors: Michael C McKelvey; Ryan Brown; Sinéad Ryan; Marcus A Mall; Sinéad Weldon; Clifford C Taggart Journal: Int J Mol Sci Date: 2021-05-09 Impact factor: 5.923