Beier et al. BMC Pulmonary Medicine (2016) 16:102 DOI 10.1186/s12890-016-0266-5 RESEARCH ARTICLE Open Access 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 Jutta Beier1*, Helena Pujol2, Beatriz Seoane2, Eulalia Jimenez2, Carol Astbury2, Eric Massana3, Sandrine Ruiz2 and Gonzalo de Miquel2 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 μgorplacebo.Spirometry was performed up to 36 h post-dose. Pharmacokinetics were assessed in a subset of patients (N =20).Safetyand 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 μgwithabediterol2.5,5and10μg(allp < 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: COPD, LABA, Bronchodilation, Chronic respiratory disease * Correspondence: [email protected] 1insaf Respiratory Research Institute, Biebricher Allee 34, 65187 Wiesbaden, Germany Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Beier et al. BMC Pulmonary Medicine (2016) 16:102 Page 2 of 13 Background moderate to severe COPD. In addition to the evaluation Inhaled bronchodilator medications – anticholinergics of standard bronchodilation parameters such as forced and β2-agonists – are central to the symptomatic treat- expiratory volume in 1 s (FEV1) and forced vital capacity ment of chronic obstructive pulmonary disease (COPD) (FVC), inspiratory capacity (IC) was also investigated as [1]. Two classes of long-acting bronchodilators are cur- an indirect measure of hyperinflation, a key aspect of rently available: (1) long-acting muscarinic antagonists COPD which causes dyspnoea, limits exercise capacity (LAMAs), i.e. tiotropium, glycopyrrolate and umeclidi- and contributes to reduced quality of life [21–23]. nium (all once-daily [QD] administration), and aclidinium bromide (twice-daily [BID] administration); and (2) long- Methods acting β2-agonists (LABAs), which include formoterol Patients BID, salmeterol BID, indacaterol QD and olodaterol QD. Male and female patients aged ≥40 years with a smoking In addition, four LABA/LAMA combinations have re- history ≥10 pack-years and moderate to severe clinically cently become available for the management of COPD, stable COPD were eligible for inclusion in the study. Pa- namely QD indacaterol/glycopyrrolate (QVA149), vilan- tients had post-salbutamol FEV1 ≥30 % and <80 % of the terol/umeclidinium, tiotropium/olodaterol and twice-daily predicted normal value (based on European Community aclidinium/formoterol [2–5]. for Steel and Coal predicted values) and post-salbutamol Long-acting bronchodilators are currently the main- FEV1/FVC ratio <70 %. Exclusion criteria included asthma stay of maintenance therapy for patients with moderate (as defined by the Global Initiative for Asthma [24]); to severe COPD [1, 6]. However, the addition of inhaled oxygen therapy for ≥15 h/day; respiratory tract infec- corticosteroids (ICS) may be of benefit to some patients, tion or COPD exacerbation within 6 weeks of the particularly those with a history of exacerbations and screening visit; hospitalisation for COPD exacerbation more severe disease, as recommended in the Global ini- ≤3 months before screening; body mass index ≥40 kg/m2; tiative for chronic Obstructive Lung Disease (GOLD) hypertension (≥160/100 mmHg) or resting heart rate guidelines [6, 7]. Combination therapies including both a ≥100 bpm at screening; and any clinically significant LABA and an ICS in a single inhaler are more effective respiratory or cardiovascular condition. Patients with at reducing the frequency of moderate to severe exacer- QT values at screening of ≥500 ms or QT interval bations than either drug administered individually [1, 6]. corrected using Bazett’s formula values >450 (male) Abediterol is a new LABA being developed as a com- or >470 (female) ms were excluded. Patients with a bination therapy with an anti-inflammatory agent for the known hypersensitivity to β2-adrenergic agonists, in- treatment of both asthma and COPD [1, 8]. As a new haled medication or drugs chemically related to abe- chemical entity, studies of abediterol as monotherapy diterol were also excluded. have been conducted to establish its clinical efficacy and Concomitant use of anticholinergic agents, short- safety profile [9–15]. In vitro pre-clinical studies with acting β2-agonists (except inhaled salbutamol as relief human β2-adrenoreceptor over-expressing cells in iso- medication), LABAs, methylxanthines, cromolyn so- lated guinea pig tissues and in vivo animal models have dium, nedocromil, leukotriene modifiers, non-selective demonstrated that abediterol displays superior broncho- β1-blocking agents (selective β1-agents were permitted dilatory potency and similar or superior selectivity for if stable ≥4 weeks prior to screening), roflumilast or β2-adrenoreceptors over β1-adrenoreceptors compared β2-antagonists (including eye drops) was not permitted with formoterol, indacaterol, salmeterol, vilanterol and during the study. Prohibited concomitant medications olodaterol. In vivo models have also confirmed that abe- were to be withdrawn before the patient entered the study diterol has a duration of action similar or superior to and discontinued prior to screening as follows: long-acting LABA reference compounds, whilst demonstrating a re- inhaled anticholinergic agents, ≥72 h; short-acting inhaled duced effect on heart rate [9, 16–19]. In early-phase anticholinergic agents, ≥12 h; other oral, intranasal or clinical trials, abediterol was associated with rapid and parenteral anticholinergic agents, ≥72 h; oral short-acting sustained improvements in bronchodilation compared β2-agonists, ≥24 h; inhaled long-acting β2-agonists, 48 h; with placebo, and doses ≤10 μg were found to be safe continuous oral or parenteral corticosteroids, ≥4 weeks; and well tolerated in healthy subjects and patients with short-term oral or parenteral corticosteroids to treat exac- asthma or COPD, with a safety profile consistent with erbations, ≥6 weeks (or 3 months if exacerbation led to that expected for the drug class [12, 14, 15, 20]. hospitalisation); methylxanthines, ≥48 h; cromolyn so- Here, we report the results of a Phase IIa single-dose dium or nedocromil, ≥5 days; leukotriene modifiers, study designed to investigate the bronchodilation, safety, ≥48 h; non-selective β1 blocking agents, ≥2weeks;any tolerability and pharmacokinetics (PK) of four doses of over-the-counter medicinal product or herbal product abediterol (0.625, 2.5, 5 and 10 μg) compared with pla- which could have had an effect on any efficacy or cebo and with indacaterol 150 μg in patients with safety assessment, ≥36 h, except paracetamol; any Beier et al. BMC Pulmonary Medicine (2016) 16:102 Page 3 of 13 other investigational drug ≥1 month or the equivalent The study complied with the declaration of Helsinki and of 6 half-lives of the treatment; roflumilast, ≥1 week. the International Conference on Harmonisation and Good Oral corticosteroids were permitted if used at stable Clinical Practice guidelines. The protocol was approved by doses equivalent to ≤10 mg/day of prednisone. ICS an independent ethics committee (Ethikkommission der, were allowed if stable ≥4 weeks prior to screening and Landesärztekammer Hessen, Im Vogelsgesang