CHI25243, a novel potent inhaled inhibitor of neutrophil elastase for the treatment of bronchiectasis and other chronic inflammatory lung disease

Neutrophil elastase (NE) is a key proteolytic enzyme implicated in the pathogenesis and progression of chronic neutrophil-driven inflammatory lung diseases, including bronchiectasis, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). A number of clinical observations indicate that targeting NE might be beneficial for treating such inflammatory lung diseases. Here we studied the pharmacological profile of CHI25243, a novel inhaled NE inhibitor designed for inhaled treatment of neutrophil-driven inflammatory lung diseases such as bronchiectasis.

In in vitro assays, CHI25243 shows a high potency in inhibiting human NE (IC50 = 0.2nM) conserved across species (rat, IC50 = 4.1nM; dog, IC50 = 7.9nM; cynomolgus monkey, IC50 = 2.3nM), with a significant selectivity (more than 100-fold) toward NE compared to other serine proteases. The in vivo effect of CHI25243 in inhibiting NE in the lungs was assessed in two rat models: human NE-induced lung injury and LPS-fMLP models. When administered intratracheally (i.t.), CHI25243 prevents human NE-induced lung injury, measured as lung haemorrhage with an ED50 of 74 µg/kg, while in the LPS/fMLP model CHI25243 significantly reduces endogenous elastase activity at 3 µg/kg reaching a maximal effect at 300 µg/kg. The protective effect observed with CHI25243 in the LPS-fMLP model is maintained up to 24h post-treatment, with 30 µg/kg being the minimum dose providing 24h efficacy. In addition, CHI25243 was tested in the rat lung infection model which mimicks the persistent Pseudomonas aeruginosa infection experienced by patients with CF and bronchiectasis. Here, when administered i.t. for 7 days, CHI25243 significantly reduces both lung tissue infection and inflammation with a MED between 30 and 100 µg/kg.

CHI25243 is a novel, potent and selective inhaled NE inhibitor, which shows target inhibition in the lung and is capable of inhibiting both pulmonary inflammation and infection in various preclinical animal models, suggesting the potential for the treatment of bronchiectasis and other chronic inflammatory lung diseases.