Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies

Abstract

Background: Navafenterol (AZD8871) is a novel, long-acting, dual-pharmacology (muscarinic receptor antagonist and β2-adrenoceptor agonist) molecule in development for chronic obstructive pulmonary disease and asthma.

Methods: These two phase I, randomised, single-blind, multiple-ascending-dose studies evaluated inhaled navafenterol and placebo (3:1 ratio) in healthy, male, non-Japanese (study A; NCT02814656) and Japanese (study B; NCT03159442) volunteers. In each study, volunteers were dosed in three cohorts, allowing gradual dose escalation from 300 μg to 600 μg to 900 μg. The primary objective was to investigate the safety and tolerability of navafenterol at steady state. Pharmacokinetics were also assessed.

Results: Twenty-four volunteers completed each study (navafenterol, n = 6; placebo, n = 2 in each cohort). There were no deaths, serious adverse events (AEs) or treatment-emergent AEs (TEAEs) leading to discontinuation of navafenterol. The most frequent TEAEs were vessel puncture-site bruise (placebo, n = 2; navafenterol 900 μg; n = 3) in study A and diarrhoea (placebo, n = 1; navafenterol 300 μg, n = 2; navafenterol 900 μg, n = 3) in study B. No dose-response relationship was observed for TEAEs. There was a dose-dependent increase in mean heart rate on day 16 in both studies. The pharmacokinetics of navafenterol were similar between non-Japanese and Japanese volunteers.

Conclusions: Multiple ascending doses of navafenterol were well-tolerated and the safety and pharmacokinetics of navafenterol were similar in non-Japanese and Japanese volunteers. The findings support navafenterol clinical development.

Trial registration: ClinicalTrials.gov ; Nos.: NCT02814656 and NCT03159442; URL: www.clinicaltrials.gov .

Keywords: Bronchodilator; COPD; Dual-pharmacology muscarinic receptor antagonist β2-adrenoceptor agonist; MABA; Pharmacokinetics; Safety.

Conflict of interest statement

VB was an employee of AstraZeneca at the time these studies were conducted and is now a current employee of IQVIA. LJ, UW-H, CA, BS, AL and IP are employees of AstraZeneca, and may own stock or stock options. AA was an employee of AstraZeneca at the time these studies were conducted and is now a current employee of Eloxx Pharmaceuticals. M-PM was a contractor to AstraZeneca at the time these studies were conducted. MA is an employee of PAREXEL. AstraZeneca provided funding to PAREXEL for the conduct of these studies.

Figures

Fig. 1

Study design for (a) study A and (b) study B

Fig. 2

Patient disposition and flow in (a) study A and (b) study B. PK = pharmacokinetic; PP = per protocol. aOne volunteer withdrew prior to the first dose and was replaced by a reserve volunteer as per the protocol

Fig. 3

Mean change from baseline on day 16 (safety population) in glucose i-STAT concentration in (a) study A and (b) study B, and mean change from baseline in potassium i-STAT concentration in (c) study A and (d) study B. SD = standard deviation

Fig. 4

Mean change from baseline in heart rate over time at day 16 (safety population) in (a) study A and (b) study B. aexcept for navafenterol 600 μg at 12 h post dose on day 16, n = 5. bpm = beats per minute; SD = standard deviation

Fig. 5

Geometric mean plasma concentration-time profiles of navafenterol (pharmacokinetic population) on days 1 and 16 in (a) study A and (b) study B, and pre-dose concentrations from days 6 to 16 in (c) study A and (d) study B. Note that a longer sampling scheme was used in study B (samples collected up to 336 h following the last dose) than in study A (samples collected up to 96 h following the last dose). SD = geometric standard deviation