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.
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 < .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.
['Singh|Dave|D|', 'Balaguer|Victor|V|', 'Astbury|Carol|C|', 'Wählby-Hamrén|Ulrika|U|', 'Jimenez|Eulalia|E|', 'Seoane|Beatriz|B|', 'Villarroel|Cristina|C|', 'Lei|Alejhandra|A|', 'Aggarwal|Ajay|A|', 'Psallidas|Ioannis|I|']
D000280:Administration, Inhalation D058666:Adrenergic beta-2 Receptor Agonists D000368:Aged D016084:Bronchoconstriction D001993:Bronchodilator Agents D018592:Cross-Over Studies D004311:Double-Blind Method D004739:England D005260:Female D005541:Forced Expiratory Volume D006801:Humans D008168:Lung D008297:Male D008875:Middle Aged D018727:Muscarinic Antagonists D029424:Pulmonary Disease, Chronic Obstructive D011804:Quinolines D020127:Recovery of Function D016896:Treatment Outcome D014230:Triazoles D014797:Vital Capacity
COPD Safety Bronchodilator MABA Dual-pharmacology muscarinic receptor antagonist β2-adrenoceptor agonist Pharmacokinetics