The novel elastase inhibitor BAY 85-8501: First-in-man study to evaluate safety, tolerability and pharmacokinetics in healthy male subjects

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, e.g. bronchiectasis (BE), COPD, and pulmonary hypertension. HNE inhibitors could potentially restore the protease/anti-protease balance in these diseases providing a new therapeutic target. BAY 85-8501 is a novel, selective and reversible HNE inhibitor with activity in the picomolar concentration range, which reveals target inhibition in the lung and ameliorates pulmonary inflammation in preclinical models. This First-in-Man study evaluated BAY 85-8501 in a Single-Dose-Escalation (SDE) design with 0.05, 0.1, 0.2, 0.5 or 1.0 mg as oral liquid formulation in 37 healthy male subjects (27 active, 10 placebo). The single dose treatments were safe and well tolerated without serious or severe adverse events and without any hints for mode of action or drug substance related adverse effects. All clinical safety parameters (BP, HR, ECG) and clinical laboratory parameters were in the normal range for single doses up to 1 mg. Drug absorption was fast, max. concentration (C) reached after 1 h, mean drug half-life was up to 145 - 175 h, allowing once daily dosing. Max. C and Area under Curve (0-24) increased in a dose-proportional way. Renal elimination of the unchanged drug is a minor pathway of elimination ( 4%). SDE up to 1 mg BAY 85-8501 was safe and well tolerated with pharmacokinetics that allow once daily dosing. Drug candidate is adequate for further clinical evaluation in studies in chronic anti-inflammatory treatment of lung diseases.