Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator.

Background Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β2-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma. Methods This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50-2100 μg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1 s (FEV1) for each treatment period. Results Sixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache (n = 10, 62.5%) and nasopharyngitis (n = 7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5 min post-dose). Doses ≥200 μg resulted in improvements in trough FEV1 (mean change from baseline range 0.186-0.463 L) with sustained bronchodilation for 24-36 h. Plasma concentrations increased in a dose-proportional manner, peaking ~ 1 h post-dose, with a derived terminal elimination half-life of 15.96-23.10 h. Conclusions In this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36 h. Trial registration ClinicalTrials.gov; No.: NCT02573155.