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Abediterol is a once-daily, long-acting β 2 -adrenergic agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. We assessed the efficacy, safety, and tolerability of three dose levels of abediterol, given once daily for 7 days in patients with stable, persistent asthma. This was an ascending-dose, three-period incomplete crossover study design investigating three dose levels of abediterol versus placebo (EudraCT No. 2008-003732-38). Twenty-eight male patients (25-59 years) were randomized to one of four treatment sequences (1:1:1:1). Follow-up was 7 days after final treatment. Spirometry was performed regularly up to 24 h postdose Day 1, up to 36 h postdose Day 7, and at follow-up. Vital signs, 12-lead electrocardiogram, and clinical laboratory tests were recorded throughout. Abediterol 2.5, 5, and 10 μg provided clinically and statistically significant improvements from baseline (predose, Day 1) in trough forced expiratory volume in 1 sec (FEV 1 ) versus placebo on Day 7 (primary endpoint) of 334, 365, and 294 mL, respectively (all P < 0.01), and peak FEV 1 versus placebo on Day 7 of 364 (P < 0.001), 403 (P < 0.001), and 375 mL (P < 0.01), respectively. Days 1 and 7 area under the curve (AUC) parameters within each abediterol group were similar for AUC 0-6 , AUC 0-12 , AUC 0-24 , and AUC 12-24 , with dose-dependent effects observed on Day 1. Abediterol (2.5-10 μg) demonstrated a good safety and tolerability profile. Abediterol 2.5, 5, and 10 μg once daily achieved statistically and clinically significant improvements in pulmonary function versus placebo over 7 days and demonstrated a safety and tolerability profile comparable with placebo., (© 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

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.

Here we report the results of a first-in-human study to evaluate the safety, tolerability pharmacokinetics, and pharmacodynamics of abediterol, a new β2 -adrenergic agonist. Forty-eight healthy males aged 18-45 years received abediterol doses of 5, 10, 25, or 50 µg, or placebo. Safety and tolerability assessments included adverse event reporting, pulse and blood pressure monitoring, 12-lead electrocardiograms, laboratory tests, and physical examination. Pharmacodynamic assessments included whole body plethysmography to determine the bronchodilatory effect by means of airway conductance and resistance. Blood and urine samples were obtained for pharmacokinetic analyses. Abediterol showed an overall good safety and tolerability profile in the dose range tested, consistent with the expected characteristics of a β2 -adrenergic agonist. A dose-dependent increase of systemic treatment-emergent adverse events was observed, the most frequent being palpitations, tremor, nausea, and asthenia; most were mild in intensity and resolved without the need for intervention. Improvements in airway conductance (increase) and resistance (decrease) were greater for all doses of abediterol tested compared with placebo at all time-points up to 36 hours. This first-in-human study suggests a potent, rapid, and sustained bronchodilatory effect of abediterol in healthy male subjects. Lower doses are currently under investigation in patients with asthma and in patients with COPD., (© 2014, The American College of Clinical Pharmacology.)

Background: Long-acting β2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 μg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma., Methods: This was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 μg, salbutamol 400 μg, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV1). Additional endpoints included trough FEV1, normalized area under the FEV1 curve (FEV1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC)., Results: Abediterol produced dose-dependent improvements in peak FEV1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001 all doses). Abediterol 0.625, 1.25, and 2.5 μg had similar magnitude of peak FEV1 effect to salbutamol. Dose-dependent changes from baseline in trough FEV1 versus placebo were 0.219 (95% CI 0.136, 0.302) to 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001). All abediterol doses achieved significant improvements versus placebo in FEV1 AUC 0-6, 0-12, and 0-24 h, and peak and trough FVC (p < 0.05). Less than 10% of patients experienced treatment-related adverse events for each dose of abediterol; most were mild to moderate in intensity and the most common were headache and nasopharyngitis. There were no clinically relevant changes in heart rate., Conclusions: Abediterol 0.625-2.5 μg provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in patients with asthma, with a peak effect similar to salbutamol and duration of action compatible with once-daily dosing. All doses of abediterol were well tolerated.

The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU) or the EXAcerbations of Chronic pulmonary disease Tool (EXACT) were compared prospectively in a 24-week, phase III trial (ATTAIN). Patients with moderate-to-severe chronic obstructive pulmonary disease received twice-daily aclidinium 200 μg, aclidinium 400 μg or placebo. All HCRU events were reported to physicians. "EXACT-identified" events were categorised as "EXACT-reported" (detected by EXACT and reported to the physician) and "EXACT-unreported" (detected but not reported). Health status was measured using the St George's Respiratory Questionnaire (SGRQ). Annualised EXACT-identified event rates were higher in all study arms (placebo 1.39, aclidinium 200 μg 1.00 and aclidinium 400 μg 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 μg 0.43 and aclidinium 400 μg 0.40 per patient per year). Concordance between methods was low (kappa 0.16). Aclidinium reduced EXACT-identified events (rate ratio versus placebo: aclidinium 200 μg 0.72 and aclidinium 400 μg 0.71; both p<0.05); HCRU events were similarly reduced. At week 24, SGRQ scores improved (-6.6 versus baseline) in patients with no event during weeks 1-12; improvements were significantly smaller in patients with HCRU events (-3.4; p=0.036) or EXACT-unreported events (-3.0; p=0.002). Unreported events were more frequent than reported events. Both had similar negative impact on health status. Aclidinium reduced the frequency of both types of event., (©ERS 2014.)

Background: Abediterol (LAS100977) is a novel, long-acting β2-agonist, in development for the once-daily treatment of asthma in combination with mometasone. Here we report the results of a Phase IIa trial of single doses of abediterol added to ongoing maintenance therapy (inhaled corticosteroids) in patients with persistent mild-to-moderate asthma., Methods: This was a randomised, double-blind, placebo- and active-comparator-controlled, five-way crossover study. Male patients (18-70 years) with a clinical diagnosis of persistent asthma received abediterol (5, 10 and 25 μg), salmeterol and placebo, on top of ongoing maintenance therapy. Lung function was determined using spirometry and whole body plethysmography. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) after a single dose., Results: All three abediterol doses induced statistically significant increases in trough FEV1 vs placebo and salmeterol. Improvements in other lung function parameters were also statistically significantly greater with all abediterol doses vs both placebo (p < 0.0001) and salmeterol (p < 0.05) than the first assessment at 5 min post-dose. These improvements were sustained to 36 h post-dose. The profile of treatment-emergent adverse events judged as related to abediterol was consistent with that seen after adrenergic stimulation and occurred exclusively in patients who received abediterol 10 μg or 25 μg., Conclusions: This first-in-patient study revealed the potent, rapid and long-acting bronchodilatory effect of abediterol in patients with persistent mild-to-moderate asthma together with an overall good safety and tolerability profile. Further studies are now underway to establish the optimal efficacy-safety-tolerability profile for this compound., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV(1)) at week 24. Other end-points included peak FEV(1), health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI). Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV(1) (99 and 128 mL; both p<0.0001) and peak FEV(1) (185 and 209 mL; both p<0.0001). Peak FEV(1) improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo. Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.

Systemic exposure to anticholinergics used for chronic obstructive pulmonary disease (COPD) may lead to side effects. This study assessed safety, tolerability, and pharmacokinetics of multiple doses of aclidinium bromide, a novel, long-acting antimuscarinic. Sixteen healthy participants received aclidinium bromide 200, 400, or 800 microg or placebo by dry-powder inhaler for 5 days, with > or =7 days washout. Aclidinium bromide and metabolite pharmacokinetics were assessed. Aclidinium bromide plasma levels were below the lower limit of quantification (LLOQ: 0.05 ng/mL) after 200 microg and in most participants after 400 microg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC(0-t) and C(max) at steady state were, respectively, 0.08 ng.h/mL and 0.12 ng/mL (aclidinium bromide), 0.40 ng.h/mL and 0.14 ng/mL (alcohol metabolite), and 13.47 ng.h/mL and 2.26 ng/mL (acid metabolite). The t(max) for aclidinium bromide 800 microg was 15 minutes (first kinetic time point). Adverse event frequency was comparable between treatment groups and placebo. The most commonly reported adverse events, probably treatment related, were coughing (n = 2) and dysphagia (n = 1); 94% of adverse events were mild. These data suggest a low systemic bioavailability and favorable safety profile for aclidinium bromide with repeated dosing for COPD.

Background: Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). A next-generation multidose dry powder inhaler will be used for the delivery of aclidinium bromide., Objectives: To quantify whole lung deposition and regional lung deposition of aclidinium delivered by a multidose dry powder inhaler (Genuair) in healthy subjects., Methods: A single dose (200 microg) of aclidinium bromide, radiolabelled with (99m)Tc, was administered from the multidose dry powder inhaler at a targeted peak inspiratory flow rate (PIFR) of 90 litres/min in 12 healthy males (18-63 years). Gamma scintigraphy was used to quantify drug deposition in the lungs and oropharynx, as well as amounts retained in the inhaler and exhaled. The quantities of drug deposited in 6 concentric regions within the lungs were also determined., Results: The mean (+/- SD) PIFR was 79.0 +/- 9.4 litres/min. The mean (+/- SD) percentages of the metered dose deposited in the whole lung and oropharynx were 30.1 +/- 7.3 and 54.7 +/- 7.2%, respectively. Deposition of aclidinium occurred in all 6 lung zones, but was highest in the most central zone., Conclusions: These results demonstrated that the multidose dry powder inhaler delivered aclidinium efficiently to the lungs. The whole lung deposition seen in this study is an indication of the likely whole lung deposition in COPD patients who inhale with similar PIFRs; however, further studies in patients are required to confirm this., ((c) 2009 S. Karger AG, Basel.)

Background: Several clinical and experimental lines of evidence suggest that leucotriene B4 (LTB4), an arachidonic acid derivative with potent proinflammatory properties, plays a key role in the pathophysiology of rheumatoid arthritis (RA)., Objective: To evaluate the efficacy and safety of BIIL 284, an oral long-acting LTB4 receptor antagonist, as monotherapy for the treatment of patients with active RA., Methods: This was a multi-centre, randomised, double-blind, placebo-controlled trial of patients with active RA of 3 months' duration. A total of 342 patients were randomised to receive 5 mg, 25 mg or 75 mg of BIIL 284 or placebo. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR) 20., Results: Although a higher percentage of ACR 20 responders was observed in the groups treated with 25 mg and 75 mg of BIIL 284 compared with those treated with placebo, no statistically significant differences were found between any of the three active treatment groups compared with the placebo group with regard to the primary or secondary end points. All trial treatments were safe and well tolerated., Conclusions: This clinical trial demonstrates that treatment of patients with active RA with a potent oral long-acting LTB4 receptor antagonist produced only modest improvements in disease activity. The results of this trial support the conclusion that LTB4 is not a major contributor to the inflammatory process in RA.