SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel on Feb. 23 recommended that aclidinium bromide, an inhaled long-acting anticholinergic bronchodilator, should be approved as a treatment for chronic obstructive pulmonary disease, with a postmarketing study that evaluates the cardiovascular safety of the drug.
The FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 12 to 2 that the efficacy and safety data from clinical trials provided "substantial evidence" to support approval of aclidinium, at a dose of 400 mcg twice a day administered in a breath-actuated dry powder inhaler, for the long-term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema.
The panel unanimously agreed that the data in the clinical trials presented by the manufacturer provided evidence that this dose provided a clinically meaningful benefit in patients, citing the significant increases in trough forced expiratory volume in 1 second (FEV1) from baseline (the primary efficacy end point) among those treated with 400 mcg twice a day, compared with those on placebo after 12 weeks of treatment in clinical studies. Some panelists pointed out that there was also some evidence of improvements in COPD exacerbations and in patient-reported symptoms on a patient questionnaire, which were secondary end points.
If approved, it will be the second long-acting inhaled anticholinergic agent for COPD on the U.S. market, following tiotropium bromide (Spiriva HandiHaler), approved for COPD in 2004, but taken once a day. Ipratropium bromide, a short-acting inhaled anticholinergic, was approved in 1986 for COPD.
Clinical data presented by the manufacturer Forest Laboratories Inc., included two pivotal 12-week studies of almost 1,400 outpatients, most of whom were white and had stable moderate to severe COPD (mean age about 64 years). Patients received 400 mcg or 200 mcg of aclidinium twice a day or placebo. About half were still smoking; people with clinically significant cardiovascular disease were excluded. They were allowed to continue treatment with short-acting bronchodilators, inhaled corticosteroids, long-acting theophylline, oxygen for 15 hours or less, and stable-dose prednisone.
Overall, cardiovascular events were not common and were evenly distributed among the treatment arms, according to the company. This included the overall rates of major adverse cardiac events (MACE), although there were some small differences in the individual components of this score, a combination of CV deaths, nonfatal myocardial infarction, and nonfatal strokes. (There were two CV deaths among those aclidinium, and no deaths among those on placebo.) The rate of anticholinergic effects was low, which the company said might be due to low systemic exposure to the drug.
Cardiovascular safety of the drug is an issue because of some concerns raised by data on other inhaled anticholinergics over the past several years.
The panel voted 10 to 3 with 1 abstention that that the safety had been adequately evaluated. But panelists, including those who supported approval, still had concerns about cardiovascular safety and recommended that these concerns should be evaluated further in a postmarketing study.
The company plans to conduct a double-blind, randomized parallel postmarketing 3-year study of 4,000 patients with COPD, with a history of COPD exacerbations during the previous year, randomized to 400 mcg aclidinium or placebo plus standard of care, which will compare rates of moderate to severe COPD exacerbations within the first year.
The primary safety end point will be time to first MACE event; the study will also evaluate the rates of other serious cardiac events, conduction disorders and cerebrovascular disorders.
The FDA’s deadline for making an approval decision is April 23. If approved, Forest plans to market it as "Tudorza Pressair."
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.