Abstract
There are now compelling data to support the hypothesis that CF lung disease results from a failure of innate host defence mechanisms as a consequence of airway mucosal dehydration. The regulation of airway surface liquid (ASL) volume through the coordinated activity of ion channels and transporters in the airway epithelium is crucial to the effectiveness of mucus clearance by both mucociliary and cough clearance mechanisms. In the simplest pathophysiological paradigm for CF the absence or reduction of functional CFTR at the apical membrane of ciliated airway epithelial cells results in an imbalance of CFTR-mediated Cl- secretion and ENaC (epithelial sodium channel)-mediated Na+ absorption resulting in a net loss of fluid from airway surfaces. Approaches to normalize this imbalance and restore fluid to the airway mucosa are predicted to improve mucus clearance and thereby positively impact upon lung health in CF. One approach to restore hydration to the airway mucosa is to attenuate ENaC function, thereby blocking Na+ and fluid reabsorption. Early studies failed to demonstrate a robust clinical benefit of inhaled amiloride, a low potency ENaC blocker, in the CF lung. It has been proposed that the lack of clinical efficacy observed with amiloride was as a consequence of its low potency, short duration of action in the airway and the dose limiting side effect of hyperkalaemia. Novel ENaC blockers that demonstrate a long duration of action in the airway and that are safe, may therefore represent a novel therapeutic opportunity for the treatment of CF lung disease. An approach taken by Novartis, has been to design ENaC blockers specifically for inhaled dosing by dry powder delivery. Drug candidates will be described that exemplify the design strategy adopted to achieve both a potent and sustained activity in the lung together with a reduced potential to induce the mechanism-based side effect of hyperkalaemia, in pre-clinical models.