Denufosol: A review of studies with inhaled P2Y2 agonists that led to Phase 3

Among the most promising of the new therapies being developed for the treatment of Cystic Fibrosis (CF) are those targeted at increasing mucosal hydration on the surface of the airways. One of these therapies, P2Y(2) receptor agonists, bypasses the defective CFTR chloride channel, and activates an alternative chloride channel. This activation results in an increase in airway surface epithelial hydration, and through these actions and effects on cilia beat frequency, increases mucociliary clearance. The pharmacology of P2Y(2) agonists has been confirmed in several preclinical and clinical studies. Denufosol tetrasodium is a novel second-generation, metabolically stable, selective P2Y(2) receptor agonist currently in Phase 3 clinical development. In radiolabelled deposition studies of P2Y(2) agonists in healthy non-smokers and smokers, approximately 7 mg of a 40-mg nebulizer (PARI LC Star) load was deposited in the lungs. In a pharmacokinetic study in healthy volunteers, very limited systemic exposure was observed when doses of 200 mg of denufosol were nebulized. Thus, it appears that high concentrations of denufosol can be achieved in the airways with very low systemic absorption. Denufosol has been generally well-tolerated in healthy volunteers and patients with CF. The most common adverse events were in the respiratory system, with cough having the highest frequency. Doses of 20-60 mg have been evaluated in Phase 2 trials of up to 28 days duration, and superiority relative to placebo on FEVI has been observed in patients with relatively normal lung function (FEVI greater than or equal to 75% of predicted). The first Phase 3 trial is a comparison of denufosol 60 mg and placebo in 350 patients with CF with FEVI at study entry greater than or equal to 75% of predicted. (C) 2007 Elsevier Ltd. All rights reserved.