CHICAGO – A fixed-dose combination of aclidinium bromide and formoterol fumarate improved lung function better than either drug alone without increasing toxicity in patients with moderate to severe chronic obstructive pulmonary disease in the phase III AUGMENT trial.
Aclidinium bromide (Tudorza Pressair) 400 mcg twice daily is a long-acting muscarinic antagonist (LAMA) approved in 2012 for the long-term maintenance treatment of COPD-associated bronchospasm. Formoterol fumarate (Foradil Aerolizer), a long-acting beta2-agonist (LABA), is also used in COPD to control symptoms and prevent wheezing.
Several fixed-dose LABA/LAMA combinations are in development, but none have been approved in COPD.
Patrice Wendling/IMNG Medical Media
Dr. Anthony D'Urzo
Combining two agents with different mechanisms of action is often recommended for improved bronchodilation, patient compliance, and cost-effectiveness in patients with COPD, Dr. Anthony D’Urzo said during a late-breaking abstract session at the annual meeting of the American College of Chest Physicians.
AUGMENT investigators (Chest 2013;144[4 MeetingAbstracts]:1025A) evenly randomized 1,692 patients with moderate to severe COPD to one of five twice-daily, metered-dose inhaler treatments: aclidinium 400 mcg plus formoterol 6 mcg or 12 mcg, aclidinium 400 mcg monotherapy, formoterol 12 mcg monotherapy, or placebo. Mean prebronchodilator forced expiratory volume in 1 second (FEV1) was 1.36 mL, and the mean age of the patients was 64 years. About half of the patients were current smokers, an intentional choice to reflect daily clinical practice, he said.
At week 24, the low- and high-dose formoterol combinations significantly increased FEV1 1 hour after morning dosing by 87 mL and 108 mL, respectively, compared with aclidinium alone (both P < .0001), said Dr. D’Urzo, director of the Primary Care Lung Clinic, University of Toronto.
Specifically, peak FEV1 increased by 176 mL with aclidinium alone, 201 mL with formoterol alone, 263 mL with the low-dose combination, and 284 mL with the high-dose combination, and decreased by 37 mL with placebo.
The low- and high-dose formoterol combinations also increased the coprimary endpoint of morning predose (trough) FEV1 at week 24 by 45 mL and 26 mL, respectively, compared with formoterol alone, but the increase was significant only for the higher-dose combination (P = .010), he said.
Specifically, trough FEV1 increased by 102 mL with aclidinium alone, 85 mL with formoterol alone, 111 mL with the low-dose combination, and 130 mL with the high-dose combination, and decreased by 35 mL with placebo.
Session comoderator Dr. Andrew Berman, division director of pulmonary and critical care medicine at Rutgers New Jersey Medical School in Newark, said targeting two different receptors clearly increases the degree of bronchodilation, but he questioned what the combined mechanism of action is and whether there’s perhaps a negative effect when combining two drugs since most clinicians would agree there’s only so much the airways can dilate.
Dr. D’Urzo said the combined mechanism is uncertain, but that there is evidence which suggests that beta2-agonists may augment the bronchial smooth muscle relaxation that is directly induced by muscarinic antagonists via a mechanism that decreases the release of acetylcholine via a modulation of cholinergic neurotransmission.
Adverse events leading to treatment discontinuation were similar across treatment arms, as were serious adverse events reported in 5.7% of patients on the high-dose combination, 5.4% on the low-dose combination, 5% on aclidinium alone, 4.5% on formoterol alone, and 3.6% on placebo. Three deaths occurred in the aclidinium monotherapy arm and one each in the high-dose formoterol combination and formoterol monotherapy arms, but none were thought related to treatment, he said.
Positive results have been reported from a second clinical trial, but codevelopers Forest Laboratories and Almirall announced in August that the New Drug Application submission planned for late 2013 was being delayed in order to resolve concerns raised by the Food and Drug Administration related to "chemistry, manufacturing, and control specifications associated with the combination formula." Forest is preparing a "robust package to address the FDA’s concerns" and is hoping to meet with its officials in early 2014, Forest R&D president Marco Taglietti said during an October earnings conference call.
Dr. D’Urzo reported having financial ties with several drug firms, including study sponsor Forest Research Institute; two coauthors are Forest employees.