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

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 < .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.

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

Conflict of interest statement

D. S. has received sponsorship to attend international meetings, honoraria for lecturing or attending advisory boards, and research grants from various pharmaceutical companies including Apellis, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Skypharma, Teva, Therevance, and Verona. V. B., C. A., U. W. H., L. J., B. S., A. L., and I. P. are employees of AstraZeneca and may own stock or stock options. C. V. and A. A. were employees of AstraZeneca at the time the study was conducted. C. V. is a current employee of PAREXEL. A. A. is a current employee of Eloxx Pharmaceuticals.

Figures

Fig. 1

Patient disposition and flow. AE = adverse event; PK = pharmacokinetic. aFive patients discontinued due to treatment emergent AEs leading to study drug discontinuation, 1 patient withdrew due to a treatment emergent AE during the washout period, and 1 withdrew due to a non-treatment-emergent AE; bpatient had a positive drug screen test for cocaine; cpatient did not meet stability/variability criteria

Fig. 2

Study design. TP = treatment period. aThe figure shows an example of the washout timings for one patient. The washout period was 10 to 21 days following navafenterol or placebo, and 7 to 21 days following the active comparators indacaterol and tiotropium. Therefore the length of each washout period depended on the patient’s randomization sequence. One exception per patient of up to 28 days was considered acceptable; bdays following administration of last dose

Fig. 3

Placebo-corrected mean change from baseline in a trough FEV1 at day 2 and b normalized FEV1 AUC0–24 (per protocol population). Data are LS means ± standard error. AUC0–24 = area under the curve from 0 to 24 h post-dose; FEV1 = forced expiratory volume in 1 s; LS = least squares. *P < .0001 vs placebo

Fig. 4

Mean change from baseline in FEV1 over 36 h (per protocol population). Data are LS means ± standard error. The number of patients exposed to each treatment differed from the number of non − missing observations for navafenterol 1800 μg (at 45 min and 2 h; both n = 30) and placebo (at 12 and 14 h; n = 31 and n = 30, respectively). FEV1 = forced expiratory volume in 1 s; LS = least squares

Fig. 5

Mean change from baseline in QTcF over time (safety population). Data are LS means ± standard error. QTcF = QT interval corrected for heart rate using the Fridericia formula; LS = least squares