Abediterol, a novel long-acting β2-agonist: bronchodilation, safety, tolerability and pharmacokinetic results from a single-dose, dose-ranging, active-comparator study in patients with COPD

Abstract

Background: Abediterol is a novel, once-daily long-acting β2-agonist in development for the treatment of chronic obstructive pulmonary disease (COPD) and asthma in combination with an anti-inflammatory agent. This Phase IIa, randomised, double-blind, crossover study investigated the bronchodilation, safety, tolerability and pharmacokinetics of abediterol in patients with moderate to severe COPD.

Methods: Seventy patients (aged ≥40 years, Global initiative for chronic Obstructive Lung Disease Stage II/III) were randomised (1:1:1:1:1:1) to single doses of abediterol 0.625, 2.5, 5 or 10 μg, indacaterol 150 μg or placebo. Spirometry was performed up to 36 h post-dose. Pharmacokinetics were assessed in a subset of patients (N = 20). Safety and tolerability were evaluated throughout the study.

Results: Abediterol (all doses) significantly improved change from baseline in trough forced expiratory volume in 1 s (FEV1) compared with placebo (0.102, 0.203, 0.233 and 0.259 L for abediterol 0.625, 2.5, 5 and 10 μg, respectively; all p < 0.0001; primary endpoint). Abediterol 2.5, 5 and 10 μg significantly improved trough FEV1 compared with indacaterol 150 μg (0.092, 0.122 and 0.148 L, respectively; all p < 0.0001). Improvements in bronchodilation were maintained at all time points post-dose versus placebo (all abediterol doses) and from 15 or 30 min post-dose versus indacaterol 150 μg with abediterol 2.5, 5 and 10 μg (all p < 0.05). Abediterol had low systemic exposure; incidence of treatment-emergent adverse events was similar between treatment groups.

Conclusions: All doses of abediterol (0.625-10 μg) provided clinically and statistically significant, dose-dependent improvements in bronchodilation versus placebo, and abediterol 2.5, 5 and 10 μg gave significant improvements versus indacaterol. All doses of abediterol were safe and well tolerated in patients with COPD.

Trial registration: Clinicaltrials.gov NCT01425814 . Registered 29 August 2011.

Keywords: Bronchodilation; COPD; Chronic respiratory disease; LABA.

Figures

Fig. 1

Study design

Fig. 2

Patient disposition

Fig. 3

Change from baseline in trough FEV1 at Day 2 (per-protocol population). ****p < 0.0001 vs placebo; ††††p < 0.0001 vs indacaterol. Data reported as LS mean difference from placebo (ANCOVA) ± SE. ANCOVA, analysis of covariance; FEV1, forced expiratory volume in 1 s; LS, least squares; SE, standard error

Fig. 4

a Change from baseline in FEV1 over time. Data reported as LS mean ± SE; p < 0.05 abediterol (all doses) vs placebo, all time points; p < 0.05 abediterol 2.5–10 μg vs indacaterol, all time points from 0.5 h post-dose. b Placebo-subtracted change from baseline in FEV1 AUC0–24. c Placebo-subtracted change from baseline in peak FEV1 (per-protocol population). ap < 0.05 abediterol (all doses) vs placebo, all time points; p < 0.05 abediterol 2.5–10 μg vs indacaterol, all time points from 0.5 h post-dose. Data reported as LS means with 95 % CIs (ANCOVA). b ****p < 0.0001 vs placebo; ††††p < 0.0001 vs indacaterol. Data reported as LS mean difference from placebo (ANCOVA) ± SE. c ****p < 0.0001 vs placebo, ††††p < 0.0001 vs indacaterol. Data reported as LS mean difference from placebo (ANCOVA) ± SE. ANCOVA, analysis of covariance; AUC0-24/24, area under the curve over the 24 h period immediately after morning IMP administration; CI, confidence interval; FEV1, forced expiratory volume in 1 s; IMP, investigational medicinal product; LS, least squares; SE, standard error

Fig. 5

Change from baseline in inspiratory capacity versus placebo and indacaterol (ITT population). Data reported as LS mean difference ± 95 % CI. ***p < 0.001 vs placebo; †p < 0.05 vs indacaterol; ††p < 0.01 vs indacaterol. CI, confidence interval; LS, least squares

Fig. 6

Plasma concentration of abediterol over time (PK population). Data reported as mean ± SD. PK, pharmacokinetic; SD, standard deviation