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An FDA advisory panel voted 12-2 to recommend approval of aclidinium bromide (Forest Laboratories and Almirall SA) 400 µg twice daily for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.
An FDA advisory panel voted 12-2 to recommend approval of aclidinium bromide (Forest Laboratories and Almirall SA) 400 µg twice daily for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
The Pulmonary-Allergy Drugs Advisory Committee convened February 23 to discuss the efficacy data and safety profile of the drug at the 400 µg, twice-daily dose level for the proposed indication. The FDA isn't required to follow the recommendations of its advisory committees, but it often does.
Aclidinium is an experimental inhaled therapy, which belongs to the anticholinergic drug class. It is an M3 muscarinic antagonist, which acts on the M3 receptor to relieve bronchospasm.
“Common anticholinergic adverse effects include dry mouth, constipation, and urinary retention. More recently, safety concerns regarding increased risk of stroke, cardiovascular death, and myocardial infarction (MI) associated with inhaled anticholinergic use have been raised following a meta-analysis of 17 clinical trials in COPD,” Susan Limb, MD, medical team leader, Division of Pulmonary, Allergy, and Rheumatology Products, CDER, FDA, stated in the introductory memo for the FDA Briefing Package.
The panel review included data for 3 multicenter, randomized, double-blind, placebo-controlled safety and efficacy trials, which compared aclidinium 400 µg twice a day, aclidinium 200 µg twice a day, and placebo for 12 or 24 weeks in patients with stable, moderate to severe COPD as well as 2 open-label extension trials, according to the briefing material.
The primary efficacy end point was considered to be the change from baseline in morning trough FEV1 at week 12 or week 24, and all 3 efficacy trials demonstrated a statistically significant increase from baseline morning trough FEV1 compared to placebo at week 12 or 24. The effect size for the 400-µg dose ranged from 72 mL to 124 mL at week 12. Although the magnitude of the treatment difference was smaller, the 200-µg dose also demonstrated a significant difference from placebo.
Researchers also noted decreases in total symptom scores on St. George’s Respiratory Questionnaire for patients treated with aclidinium compared to placebo, which were assessed as another efficacy variable.
Indicative of efficacy, researchers also assessed use of daily rescue medication which appeared to decrease by a mean of -1.2 puffs per day for those patients taking aclidinium 400 µg compared with -0.9 puffs per day for those patients taking aclidinium 200 µg and -0.3 puffs per day for those taking placebo in 1 trial.
Safety data show a total of 17 deaths. In the placebo-controlled trials, 4 deaths were reported in the group of patients taking aclidinium 400 µg and 2 deaths were reported in the group of patients taking aclidinium 200 µg. In the long-term safety trials, 6 deaths were reported in the group of patients taking aclidinium 400 µg and 3 were reported in the 200-µg group.
Of particular interest were those deaths attributed to a cardiovascular event or cardiorespiratory arrest. Although low, 4 of the 10 deaths that occurred in the aclidinium 400-µg group were due to cardiac arrest and 1 was due to acute cardiac failure. In the 200-µg group 1 death occurred due to MI. No cardiovascular-related deaths occurred in the placebo group.
The panel agreed that a post-marketing study should be conducted to determine the risk of cardiovascular side effects.