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The efficacy and safety of aclidinium bromide, with particular focus on data that assess its effect on two key goals of COPD treatment – symptom improvement and exacerbation reduction – are discussed
Paul Jones PhD FRCP
St George’s, University of London, London, UK
Chronic obstructive pulmonary disease (COPD) affects an estimated three million people in the UK, of whom approximately 900,000 are diagnosed.(1)
It is most frequently caused by smoking, although other factors such as exposure to occupational and environmental hazards may also contribute. COPD is a chronic condition characterised by airflow obstruction that is not fully reversible, often resulting in symptoms of breathlessness on exercise, chronic cough, sputum production and wheeze. Although COPD is progressive in the long term, patients usually do not experience rapid deterioration although acute exacerbations, defined as a sustained worsening of symptoms beyond normal day-to-day variations, occur often.
The airflow obstruction present in COPD is caused by chronic inflammation and parenchymal damage, which is irreversible. None of the currently available treatments are proven conclusively to arrest or slow the long-term decline in lung function.(2) Therefore, the goals of COPD treatment focus on providing patients with symptom relief, improvements in health status and exercise tolerance and a reduction in the frequency and severity of exacerbations.(1,2) Inhaled bronchodilator therapy is the cornerstone of pharmacological treatment, largely with long-acting anticholinergics and β2-agonists.
Anticholinergic therapy is recommended as a first choice in patients with significant symptoms and less frequent exacerbations and in combination with inhaled corticosteroids in patients with significant symptoms and more frequent exacerbations.(2) A study-level meta-analysis has shown that improvements in lung function, as measured by mean trough forced expiratory volume in one second (FEV1), are associated with improvements in health status.(3) This article will describe the efficacy and safety of aclidinium bromide, focusing on data from patient-reported outcomes tools which assess the effect of aclidinium on two of the key goals of COPD treatment – improvement of symptoms and reduction of exacerbations.
Aclidinium bromide
Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist that has been developed for the treatment of COPD. In July 2012, aclidinium 400µg twice daily (BID) was approved as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD in the European Union and for the long-term maintenance treatment of bronchospasm associated with COPD in the US.
Improvements in lung function
Two pivotal phase III clinical trials, ACCORD COPD I4 and ATTAIN,(5) have been conducted for aclidinium in patients with moderate to severe COPD. Both were placebo-controlled and investigated aclidinium 200 and 400µg BID in patients with moderate to severe COPD. In ACCORD COPD I, patients treated with aclidinium 200µg and 400µg BID achieved significant improvements from baseline at Week 12 in both mean trough FEV1 (the primary endpoint of the study) of: 86ml and 124ml versus placebo, respectively; p≤0.0001. Peak FEV1 also improved; 146ml and 192ml versus placebo, respectively; p≤0.0001. Similarly, in ATTAIN, at week 24 improvements in trough FEV1 were 99ml and 128ml for the 200μg and 400μg BID doses, respectively (p<0.0001). The improvements in lung function were seen from week 1 onwards, and maintained throughout both studies.
These data are supported by pooled analyses of ACCORD COPD I and ATTAIN, which show that the improvements in lung function were clinically significant, with the improvement in trough FEV1 achieved with aclidinium 400µg BID (112ml at week 12) above the level usually judged to be clinically meaningful (>100ml) and greater than that achieved with the 200µg BID dose.(6)
Effect on symptoms
In both the ACCORD COPD I and ATTAIN trials, symptoms of COPD were assessed using the Transition Dyspnoea Index (TDI).7 Patients also completed a daily electronic diary, recording their COPD symptoms in the early morning and at night. The ATTAIN trial also used the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) to capture changes in patients’ symptoms as well as exacerbations.(8)
In ACCORD COPD I,4 patients treated with aclidinium consistently experienced significant improvements in symptom scores. Both doses of aclidinium improved TDI scores compared with placebo, with treatment differences from placebo of 0.9 and 1.0 at Week 12 for aclidinium 200µg and 400µg BID, respectively (p<0.01 for both). The percentage of patients achieving a clinically meaningful improvement in TDI (≥1 unit9) ranged from 48% for aclidinium 400µg BID at week 12 to 55% for aclidinium 200µg BID at week 4, compared with 31–34% for placebo (p<0.05 for all versus placebo based on odds ratios). Night-time symptoms, including breathlessness, cough, sputum production and wheezing, were significantly reduced in patients treated with aclidinium compared with placebo, as were the severity of breathlessness in the morning and the impact of breathlessness on early‑morning activities (p<0.05 for all measures).
The ATTAIN trial(5) showed similar improvements at week 24 in TDI score (treatment difference from placebo of 0.6 (p<0.05) and 1.0 (p<0.001) for aclidinium 200µg and 400µg BID, respectively) with significantly more patients treated with aclidinium achieving a clinically meaningful improvement compared with placebo (53.3% (p<0.05) and 56.9% (p<0.01) for aclidinium 200µg and 400µg BID, respectively versus 45.5% for placebo). In addition, aclidinium significantly reduced EXACT-Respiratory Symptoms scores versus placebo for breathlessness (p≤0.0001 for both doses), chest symptoms (p≤0.01 for both doses), and cough and sputum (p≤0.03 for both doses), and reduced the incidence of night-time and early- morning symptoms (p<0.01).10
Health status and exercise tolerance
In the clinical trial programme, changes in health status were measured using the St George’s Respiratory Questionnaire (SGRQ).(11) In ACCORD COPD I,(4) SGRQ total scores were significantly improved from baseline at all visits compared with placebo and a greater proportion of patients receiving aclidinium achieved a clinically meaningful improvement of a ≥four-point decrease from baseline.(12) At week 12, the treatment difference in total score was –2.7 and –2.5 for aclidinium 200µg and 400µg BID, respectively (p<0.05 for both). The ATTAIN trial5 reported significant improvements in SGRQ score; at week 24 the mean improvement over placebo was –3.8 and –4.6 for aclidinium 200µg and 400µg BID, respectively (p<0.001), with significantly more patients having a clinically significant improvement (56.0% and 57.3% for aclidinium 200µg and 400µg BID, respectively, versus 41.0% for placebo, p<0.001 for both).
There are no data on the effect of aclidinium 400µg BID on exercise tolerance. A phase II study in 181 patients with moderate-to-severe COPD13 demonstrated that patients receiving aclidinium 200µg once daily had significantly improved exercise endurance time from day 1 (treatment difference in endurance time of 143 seconds; p<0.001) and throughout the six weeks of treatment (treatment difference in endurance time at week 6 of 116 seconds; p<0.05). A phase III, double-blind, randomised, crossover study comparing the effects of aclidinium 400µg BID with placebo on measures of exercise endurance and physical activity (NCT01471171) has recently completed, with results expected later this year.
Exacerbations
Neither the ACCORD COPD I trial nor the ATTAIN trial was designed or powered to evaluate exacerbations as an endpoint, so the study populations were not enriched with patients with a history of exacerbations. Nonetheless, exacerbations were assessed in these trials as episodes of increased Healthcare Resource Utilisation (HCRU) – episodes of increased symptoms on ≥two consecutive days that require a change in treatment. Using the HCRU definition of a moderate or severe exacerbation (those requiring treatment with antibiotics ± systemic corticosteroids ± hospitalisation), a numerical, but not statistically significant, reduction was observed in the rate of moderate or severe exacerbations in both studies individually.(4,5) When data from both studies were pooled, the reduction in the rate of moderate or severe exacerbations was significant for aclidinium 400µg BID compared with placebo (0.31 versus 0.44; rate ratio 0.71; p=0.01).(14)
Safety and tolerability
Preclinical studies have shown that aclidinium exhibits potent and selective inhibition of human muscarinic receptors, with a long residence time at M3 receptors and a shorter residence time on M2 receptors.(15) M3 receptors, expressed on bronchial smooth muscle, are primarily responsible for smooth muscle contraction. M2 receptors promote bronchodilation through the parasympathetic nervous system, but they are also responsible for cardiac side effects.
Inhaled aclidinium is poorly absorbed from the lungs, and any aclidinium that does reach the systemic circulation is rapidly hydrolysed (estimated half-life of approximately 2.4 minutes) into two inactive metabolites.(16,17) The combination of selectivity for the M3 receptor, low systemic exposure and rapid metabolism results in a low propensity for drug–drug interactions and the potential for a favourable safety profile. This potential was realised in both the ACCORD COPD I and ATTAIN trials, both of which reported overall incidences of adverse events (AEs) that were comparable between aclidinium and placebo.(4,5)
A pooled analysis of data from ACCORD COPD I, ATTAIN and ACCORD COPD II suggests that aclidinium is not associated with an increase in the incidence of major adverse cardiovascular events (MACE), with the incidence of total MACE (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) in the aclidinium group being half of that in the placebo group (0.3% versus 0.6%).(18)
Genuair® inhaler
In respiratory diseases, inhaler design is of key importance because efficacious drugs need to be delivered reliably to the correct areas of the lungs. In addition, patients’ ability and willingness to use their inhaler has a significant influence on adherence to prescribed therapy and, therefore, clinical outcomes. Aclidinium is a dry powder formulation delivered via the novel, breath-actuated, multidose, dry powder Genuair®/PressairTM inhaler (Figure 1).
The Genuair® is simple to use and has a number of important features, including: a control window that changes from red to green to indicate that the device is ready to use; an audible click once the dose has been delivered successfully; and an indicator to track the number of remaining doses, to ensure consistent dose delivery. In a phase III, two-week crossover study,(19) patients made fewer critical errors (those that reduce or prevent appropriate drug delivery to the lungs) with Genuair® compared with HandiHaler® (10.5% versus 26.7%; p<0.0001).
After two weeks of daily use, 79.1% of patients preferred Genuair® to HandiHaler® (p<0.0001) and a greater proportion reported that they were ‘very satisfied’ or ‘satisfied’ (54.8% and 31.7%, respectively) with Genuair® compared with HandiHaler® (19.0% and 39.0%, respectively). Similar results have been reported in studies comparing the Genuair® inhaler with other dry powder devices for COPD, including the Diskus®, Respimat® and Aerolizer® inhalers.(20,21)
Conclusions
The ACCORD COPD I and ATTAIN trials have demonstrated that aclidinium is an effective treatment for COPD, providing sustained and clinically meaningful improvements in lung function and COPD symptoms which result in improvements in health-related quality of life. Pooled data suggest that aclidinium reduces exacerbations, and phase II data (using a lower once-daily dose) suggest that it may improve exercise endurance and physical activity. Importantly, aclidinium has a favourable safety profile, with a low incidence of AEs and cardiovascular AEs.
The Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) 2011 strategy document()2 suggests that the first-choice treatment for patients with symptomatic COPD should be a long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). In the UK, the National Institute for Health and Clinical Excellence (NICE) clinical guideline 101 for COPD1 suggests a LABA or LAMA for patients with stable COPD who remain symptomatic or have exacerbations despite using short-acting bronchodilators. The clinical trial evidence strongly suggests that aclidinium can be prescribed as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD whenever NICE or GOLD guidelines recommend a LAMA.
Acknowledgements
Genuair®/PressairTM are registered trademarks of Almirall S.A., Barcelona, Spain, for use within the European Union as Genuair® and within the US as PressairTM.
The author and his institution have received consulting and lecture fees from Almirall S.A. in association with the aclidinium development programme, but no fees for the writing of this paper.
We thank Sarah Feaver, PhD, from Complete Medical Communications who provided medical writing support funded by Almirall S.A., Barcelona, Spain. Almirall S.A. undertook a review of the final draft of the manuscript for scientific accuracy.
Key points
- Aclidinium 400μg twice daily (BID) is a long-acting muscarinic antagonist that significantly improves lung function over 24 hours in patients with moderate to severe COPD.
- Aclidinium 400μg BID produces clinically significant improvements in breathlessness and other symptoms of COPD.
- Aclidinium 400μg BID improves health status and may improve exercise endurance.
- Pooled analysis of phase III data shows that aclidinium 400μg BID significantly reduces exacerbation frequency.
- Aclidinium is rapidly cleared from plasma, resulting in a low systemic exposure and a low propensity to induce anticholinergic and cardiac adverse events. The approved dose is well tolerated with an adverse-event profile similar to that of placebo.
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