Gonzalo de Miquel

Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study

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 (FEV1) at week 24. Other end-points included peak FEV1, health status (St Georges 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 FEV1 (99 and 128 mL; both p<0.0001) and peak FEV1 (185 and 209 mL; both p<0.0001). Peak FEV1 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.

Safety and Pharmacokinetics of Multiple Doses of Aclidinium Bromide, a Novel Long‐Acting Muscarinic Antagonist for the Treatment of Chronic Obstructive Pulmonary Disease, in Healthy Participants

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 μg or placebo by dry‐powder inhaler for 5 days, with ≥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 μg and in most participants after 400 μg. Plasma levels in all participants were below the LLOQ at all doses, including the highest dose, beyond 1 hour postdose. AUC0‐t and Cmax 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 tmax for aclidinium bromide 800 μg 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.

Characterisation and impact of reported and unreported exacerbations: results from ATTAIN

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 &mgr;g, aclidinium 400 &mgr;g 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 &mgr;g 1.00 and aclidinium 400 &mgr;g 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 &mgr;g 0.43 and aclidinium 400 &mgr;g 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 &mgr;g 0.72 and aclidinium 400 &mgr;g 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. There are twice as many unreported exacerbation events as reported events; both have similar impact on health status http://ow.ly/AwJVf

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of abediterol (LAS100977), a novel long-acting Β2-agonist

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.

A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study.

BackgroundLong-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.MethodsThis 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).ResultsAbediterol 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.ConclusionsAbediterol 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.