WASHINGTON -- The FDA has approved aclidinium bromide (Tudorza Pressair) for long-term treatment of bronchospasm associated with chronic o...
Aclidinium bromide, distributed by Forest Laboratories subsidiary Forest Pharmaceuticals, is a dry powder inhaler used twice daily. It is a newer type of anticholinergic known as a long-acting M3 muscarinic antagonist.
One other drug, tiotropium bromide (Spiriva HandiHaler), is also a long-acting muscarinic antagonist used for bronchospasm treatment; it came on the market in 2004. Other drugs used to treat COPD include long-acting beta agonists such as fluticasone (Advair), formoterol (Foradil), and budesonide/formoterol (Symbicort).
"COPD is a serious disease that gets worse over time," Curtis Rosebraugh, MD, MPH, of the FDA's Center for Drug Evaluation and Research, said in a statement. "The availability of long-term maintenance drugs for COPD provides additional treatment options for the millions of people who suffer with this debilitating disease."
An FDA advisory committee voted 12-2 in February to recommend approval of the drug but called for postmarketing studies to determine the risk of cardiovascular side effects with its use.
"What's really needed is a pragmatic trial where the number of exclusions are kept to a minimum," such as exclusions for patients with cardiovascular disease, said committee member David Au, MD, of the VA Puget Sound Health Care System in Seattle, who voted in favor of approval.
The clinical trial program for aclidinium included two crossover trials to evaluate the nominal dose and dosing frequency, and three safety and efficacy trials, according to an FDA review of the trial program. All three of the efficacy trials were randomized, placebo-controlled trials that included double-blind treatment periods of either 12 or 24 weeks. Patients who were enrolled in the two 12-week trials were then given the option of rolling over into an open-label extension trial.
All three safety and efficacy trials compared aclidinium 400 mcg BID and aclidinium 200 mcg BID with placebo in patients with stable, moderate to severe COPD.
In all three trials, aclidinium demonstrated a statistically significant increase from baseline morning trough forced expiratory volume in one second (FEV1) compared with placebo at week 12 or 24. The effect size for the 400-mcg dose ranged from 72 mL to 124 mL at week 12.
The smaller, 200-mcg dose also showed a significant difference from placebo, but the magnitude of the effect was smaller.
Looking specifically at major adverse cardiac events (MACE), the investigators found that such events occurred in 0.3% of patients in each of the treatment arms versus 0.6% of patients on placebo. In the long-term safety trials, the rates were 2.1% in the 400-mcg group versus 1.8% in the 200-mcg group.
Of particular interest were the cardiovascular deaths in the study, said FDA reviewer Jennifer Rodriguez Pippin, MD, during the February meeting. She called it "notable" that both of the cardiovascular deaths in the placebo-controlled trials were among patients taking the study drug, while none occurred in the placebo group.
Committee member Paul Greenberger, MD, of Northwestern University in Chicago, said another issue with the study population is that "there's a risk of continued smoking on disease and cardiovascular outcomes in this population." He noted that at least 50% of patients continued to smoke during the trials. "This has to be considered if you're going to separate out the effects of one more year of smoking versus a potential effect from the medication."
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