The novel elastase inhibitor BAY 85-8501 provides a new approach in the treatment of pulmonary diseases

Human neutrophil elastase (HNE) is a key mediator of tissue remodeling and inflammation. An excess of HNE activity has been implicated in the pathogenesis of inflammatory pulmonary diseases like bronchiectasis (BE), COPD and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic target. This is the first disclosure of BAY 85-8501, a novel, highly selective and reversible HNE inhibitor with picomolar activity, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models (protease-induced acute lung injury model in mice, minimal effective dose 0.01 mg/kg po). After single dose studies the drug candidate was evaluated in a multiple dose (MD) study in 26 healthy male subjects (0.3 - 1 mg as tablets once daily over 14 days). All treatments were safe and well tolerated without serious or severe adverse events and all clinical safety and laboratory parameters were in the normal range. Drug half-life allows once daily dosing. Evaluation of HNE inhibition after MD in an ex-vivo zymosan whole blood challenge assay (eliciting sterile inflammation) showed up to 90 % target inhibition at trough (24 h). Biomarker evaluation in BE patients revealed that significant HNE activity in sputum could be detected and this might be used for stratification of patients for HNE inhibitor treatment. Conclusion: BAY 85-8501 is a promising candidate for evaluation as chronic anti-inflammatory treatment in patients with bronchiectasis. A Phase 2 study is currently conducted (ClinicalTrials.gov ID NCT01818544).