Aclidinium bromide/formoterol fixed-dose combination therapy for COPD: the evidence to date

Abstract

The quest for the right combination of bronchodilators with different mechanisms of action such as long-acting muscarinic antagonists and long-acting β-agonists in the management of stable moderate-to-severe chronic obstructive pulmonary disease (COPD) is a topic of intense research activity currently, given the rising morbidity and mortality due to this disease. The fixed-dose combination of aclidinium bromide and formoterol fumarate in a single inhaler seems to offer superior advantages over either drugs given alone or as separate inhalers concurrently. Since the fixed-dose combination needs to be given twice daily, it is likely to achieve control of symptoms most crucial to the quality of life in COPD, namely, the morning hours. This is reflected in significant trough FEV1 (forced expiratory volume in 1 second) improvements after the dose. This paper reviews the various studies related to this combination put in the perspective of its safety and efficacy and potential benefits over other therapeutic options. However, there is a dearth of data on the long-term safety and efficacy in terms of improvement in lung function. This combination could emerge as an excellent option in the management of stable COPD if data on exacerbation rates and patient-reported outcomes become available from longer-term studies. Moreover, we need some more studies to define the ideal phenotype of COPD best suited for the use of this combination.

Keywords: COPD; aclidinium; bronchodilators; combination therapy; formoterol; lung function.

Figure 1

Onset of action of aclidinium, ipratropium, and tiotropium in isolated guinea pig trachea. Notes: Contraction was induced with 10 μM carbachol and allowed to plateau before the addition of antagonists. Onset was defined as the time from antagonist addition to achieve inhibition of 50% (t_1/2) or 100% (t_max) of the contraction. Data are reported as mean ± SE; n=5–7. ***P<0.001 compared with first observational time point. Copyright © 2009. Reproduced from The American Society for Pharmacology and Experimental Therapeutics. Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331(2):740–751. Abbreviation: SE, standard error.

Figure 2

Effect of aclidinium and tiotropium on heart rate in conscious beagle dogs. Notes: Animals were anesthetized in order to deliver the nebulized compounds or vehicle and were allowed to regain consciousness. The effect on heart rate of a dose 100 times higher than that used to achieve submaximal bronchodilation was assessed continuously up to 6 hours and expressed as a percentage change from baseline heart rate. Data are reported as mean ± SE; n=4 for aclidinium and tiotropium; n=3 for vehicle. *P<0.05, **P<0.01, ***P<0.001 compared with vehicle; ^†P<0.05, ^††P<0.01, †††P<0.001 compared with tiotropium. Copyright © 2009. Reproduced from The American Society for Pharmacology and Experimental Therapeutics. Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331(2):740–751. Abbreviation: SE, standard error.

Figure 3

Mean (± SE) changes in sG_aw (%) over 24 hours as a percentage of baseline value. Notes: Placebo (Image), 50 mg aclidinium bromide (Image), 300 mg aclidinium bromide (Image), 600 mg aclidinium bromide (Image). © 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society. Reproduced from Schelfhout VJ, Ferrer P, Jansat JM, et al. Activity of aclidinium bro mide, a new long-acting muscarinic antagonist: a phase I study. Br J Clin Pharmacol. 2010;69(5):458–464. Abbreviations: sG_aw, specific airway conductance; SE, standard error.

Figure 4

Mean changes from baseline in FEV₁ 0–3 hours (A) on day 1 and (B) at week 24. Notes: Analyses were based on a mixed model for repeated measures. *P<0.05 vs placebo; ^†P<0.05 vs aclidinium and placebo; ^§P<0.05 vs aclidinium, formoterol, and placebo; ^¥P<0.05 vs aclidinium/formoterol FDC 400/6 μg and placebo. No significant differences between the two FDCs at any time point. Reproduced from D’Urzo AD, Rennard SI, Kerwin EM, Mergel V, Leselbaum AR, Caracta CF; AUGMENT COPD Study Investigators. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15(1):123. Abbreviations: ACL, aclidinium; FOR, formoterol; LS, least squares; FEV₁, forced expiratory volume in 1 second; FDCs, fixed-dose combinations; ACL400/FOR12 FDC, FDC of aclidinium 400 μg and formoterol 12 μg; ACL400/FOR6 FDC, FDC of aclidinium 400 μg and formoterol 6 μg.

Figure 5

Improvement in TDI focal score at 24 weeks (ITT population). Notes: Data are presented as least squares means (SE). ***P<0.001 vs placebo. Reproduced from Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med. 2014;14:178. http://creativecommons.org/licenses/by/4.0/. Abbreviations: FDC, aclidinium/formoterol fixed-dose combination; ITT, intent-to-treat; MCID, minimum clinically important difference; SE, standard error; TDI, Transition Dyspnea Index.