Overview of the Efficacy of the Fixed Combination Aclidinium-Bromide/Formoterol-Fumarate in the Maintenance Treatment of COPD
Fixed combination inhalation medications have become the cornerstone of pharmacotherapy for moderate to severe chronic obstructive pulmonary disease (COPD). American authors have published an overview of study results evaluating the efficacy and safety of one of the newest fixed combinations of LABA/LAMA, aclidinium-bromide and formoterol-fumarate (AB/FF), in the maintenance treatment of COPD compared to placebo or other medications. These clinical studies investigated the extent to which regular use of this fixed combination alleviates COPD symptoms, improves lung function, reduces the incidence of exacerbations, and increases exercise tolerance.
Current Recommendations in the Treatment of COPD
Current standards of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend the combination of 2 long-acting bronchodilators with different mechanisms of action for the maintenance treatment of COPD. Combined inhalation therapy can lead to greater bronchodilation without increasing the risk of side effects. The convenient use of fixed combinations increases patient compliance with the treatment. Numerous studies with these combinations have demonstrated improvements in lung function, reductions in the severity and frequency of COPD exacerbations, alleviation of symptoms, and increased exercise tolerance.
Mechanism of Action
Aclidinium-bromide is a long-acting muscarinic receptor antagonist (LAMA) with affinity for the M1–5 subtypes. In the treatment of COPD, the effect on the M3 receptor is critical. It induces bronchodilation and a decrease in bronchial secretion.
Formoterol-fumarate is a long-acting selective agonist of β2-adrenergic receptors (LABA), which acts in the lungs to relax the smooth muscle of the bronchial walls and induce bronchodilation.
Efficacy
Studies of phase III ACLIFORM, AUGMENT, and AMPLIFY are significant in terms of the proven efficacy of AB/FF.
The first two were 6-month multicenter randomized double-blind studies that compared the fixed combination of AB/FF with placebo and monotherapy with the individual components of the combination. They included patients over 40 years old with COPD (FEV1/FVC < 70% and FEV1 < 80% predicted value after administration of a bronchodilator) who were randomized to receive AB/FF 400/12 µg or 400/6 µg, AB 400 µg, FF 12 µg, or placebo twice daily. In the ACLIFORM study, after 24 weeks of treatment, there was greater improvement in FEV1 1 hour after morning dosing of AB/FF in both doses compared to placebo (p < 0.001) and monotherapy with the individual components (p < 0.001). Similarly, in the AUGMENT study, the fixed combination showed significant improvement in FEV1 1 hour after dosing compared to AB alone, FF alone, or placebo (p < 0.01).
The 6-month double-blind AMPLIFY study with a placebo look-alike, which was also conducted in the Czech Republic, evaluated the efficacy and safety of AB/FF at a dose of 400/12 µg twice daily compared to monotherapy with AB 400 µg twice daily, FF 12 µg, and tiotropium (TIO) 18 µg once daily. All comparisons showed statistically significant greater improvement in FEV1 1 hour after dosing with the fixed combination (all p < 0.0001). The fixed combination also led to significantly greater improvement in FEV1 before the morning dose compared to FF monotherapy (p < 0.001).
The results of these studies also showed an increase in exercise tolerance with AB/FF treatment, significantly prolonging exercise time compared to placebo (p < 0.01) and reducing the proportion of inactive individuals (p < 0.0001). Patients with the fixed combination AB/FF 400/12 µg also showed a significant reduction in the incidence of moderate to severe exacerbations compared to placebo (p < 0.01) and AB monotherapy (p < 0.05), as well as a delay in the time to first exacerbation.
Safety Profile
Adverse events during treatment included diarrhea, headaches, lower urinary tract infections, dizziness, and anxiety. In the ACLIFORM study, adverse events occurred in < 3% of patients except for headaches, which were reported by 7–11% of patients. In the AUGMENT study, adverse events were mild to moderate in severity and most commonly involved nasopharyngitis. The incidence of serious adverse events was low. The most common pneumonia occurred in 3 patients with AB/FF and in 2 patients with AB.
Conclusion
The long-term efficacy and safety of the fixed inhalation combination of aclidinium-bromide/formoterol-fumarate has been demonstrated in all the above studies. Adverse events were predictable and their incidence was similar to other fixed LAMA/LABA combinations.
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Source: Haley R., Gupta N., Sethi S. Aclidinium bromide and formoterol fumarate for the maintenance treatment of chronic obstructive pulmonary disease. Expert Rev Clin Pharmacol 2020; 13 (2): 103–113, doi: 10.1080/17512433.2020.1717334.
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