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Abstract Background Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. Methods This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 2. Safety and tolerability were monitored throughout. Results Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P

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

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 .