Pharmacological characterization of CHF6162, a novel long acting inhaled corticosteroid for the treatment of asthma

Inhaled corticosteroids (ICS) are the mainstay of asthma therapy. We report here the characterization of CHF6162, a novel ICS, in comparison with budesonide and fluticasone furoate (FF). CHF6162 showed sub-nanomolar potency in inducing glucocorticoid receptor nuclear translocation and in eliciting anti-inflammatory effects such as inhibition of NO, IL-8 and TNFα release in different cell-based assay and in trans-activating steroid-responsive gene GILZ. Pharmacokinetic properties of CHF6162 were tuned to obtain high lung retention (11h), high intrinsic clearance (20ml/min/106 cell) and low oral bioavailability (about 10%), to minimize systemic exposure and reduce systemically driven adverse effects. In the rat model of ovalbumin-induced pulmonary inflammation, intratracheal administration of CHF6162 (0.003-0.1µmol/kg), FF (0.01-1µmol/kg) and budesonide (0.01-1µmol/kg) dose-dependently and significantly inhibited influx of total white cells, eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage (BAL). Potency ranking for inhibition of eosinophil recruitment was CHF6162 (ED50=0.0041µmol/kg)>FF (ED50=0.059µmol/kg) >budesonide (ED50=0.11µmol/kg). The duration of action of CHF6162 was compared to that of FF and budesonide by administering the ED75 dose 24 h before ovalbumin challenge: both CHF6162 and FF, but not budesonide, retained a significant anti-inflammatory activity at 24 h. In conclusion, CHF6162 is a novel long-acting and highly effective ICS with low systemic exposure predictive of a good safety profile. These features make CHF6162 a potential candidate to be progressed into clinical trials