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

Abstract

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.

Keywords: Asthma; Bronchodilator; MABA, dual-pharmacology muscarinic receptor antagonist β2-adrenoceptor agonist; Pharmacokinetics; Safety.

Conflict of interest statement

EJ, CA, UW-H, BS, and IP are employees of AstraZeneca and may own stock or stock options. MA is an employee of PAREXEL. AstraZeneca contracted PAREXEL for the conduct of this study. CV, HP, MJB, and AA were employees of AstraZeneca at the time the study was conducted. CV is a current employee of PAREXEL. HP is a current employee of Allergy Therapeutics, MJB is a current employee of InsudPharma, and AA is a current employee of Eloxx Pharmaceuticals.

Figures

Fig. 1

Patient disposition and flow

Fig. 2

Mean (SD) change from baseline in (a) heart rate and (b) QTcF at each timepoint over 12 h post-dose (safety population). bpm = beats per minute; QTcF = QT interval corrected for heart rate using the Fridericia formula; SD = standard deviation

Fig. 3

Mean (95% CI) change from baseline in a) trough and b) peak FEV1 (per protocol population). CI = confidence interval; FEV1 = forced expiratory volume in 1 s

Fig. 4

Geometric mean (SD) navafenterol plasma concentration at each timepoint over 36 h post-dose (pharmacokinetics population). Data are shown on a semi-logarithmic scale. For error bars, the geometric mean SD is displayed as exponential (arithmetic mean of the natural log-transformed variable ± arithmetic SD of the natural log-transformed variable). SD = standard deviation