Journal Article

Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, long-acting, dual-pharmacology bronchodilator

Lei, Alejhandra, Seoane, Beatriz, Aggarwal, Ajay, Balaguer, Victor, Villarroel, Cristina, Astbury, Carol, Jimenez, Eulalia, Wählby-Hamrén, Ulrika, Psallidas, Ioannis, Singh, Dave

2020

Overview

Background Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β 2− 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 (FEV 1 ) 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 FEV 1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P  < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065–0.069 L, both P  < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4–37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%). Conclusions Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. Trial registry ClinicalTrials.gov ; No.: NCT02573155 ; URL: www.clinicaltrials.gov . Registered 9th October, 2015.

• Publisher: BioMed Central,Nature Publishing Group,BMC
• Subject: Acetylcholine receptors (muscarinic) / Administration, Inhalation / Adrenergic beta-2 Receptor Agonists - administration & dosage / Adrenergic beta-2 Receptor Agonists - adverse effects / Adrenergic beta-2 Receptor Agonists - pharmacokinetics / Aged / Agonists / Bronchoconstriction - drug effects / Bronchodilation / Bronchodilator / Bronchodilator Agents - administration & dosage / Bronchodilator Agents - adverse effects / Bronchodilator Agents - pharmacokinetics / Bronchodilators / Chronic obstructive pulmonary disease / Comparators / Confidence intervals / COPD / Cross-Over Studies / Double-Blind Method / Double-blind studies / Drug dosages / Dual-pharmacology muscarinic receptor antagonist β2-adrenoceptor agonist / England / Female / Forced Expiratory Volume / Humans / Informed consent / Laboratories / Least squares / Lung - drug effects / Lung - physiopathology / Lung diseases / MABA / Male / Medicine / Medicine & Public Health / Middle Aged / Muscarinic Antagonists - administration & dosage / Muscarinic Antagonists - adverse effects / Muscarinic Antagonists - pharmacokinetics / Obstructive lung disease / Patients / Pharmacodynamics / Pharmacokinetics / Pharmacology / Pneumology/Respiratory System / Pulmonary Disease, Chronic Obstructive - diagnosis / Pulmonary Disease, Chronic Obstructive - drug therapy / Pulmonary Disease, Chronic Obstructive - physiopathology / Quinolines - administration & dosage / Quinolines - adverse effects / Quinolines - pharmacokinetics / Recovery of Function / Safety / Statistical analysis / Thoracic surgery / Treatment Outcome / Triazoles - administration & dosage / Triazoles - adverse effects / Triazoles - pharmacokinetics / Vital Capacity