FDA Panel Recommends Twice-Daily Aclidinium for COPD

Troy Brown

February 24, 2012

February 24, 2012 — The US Food and Drug Administration's (FDA's) Pulmonary-Allergy Drugs Advisory Committee voted 12 to 2 in favor of approving aclidinium bromide (Forest Labs) 400 μg twice daily for the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Aclidinium bromide is a long-acting inhaled muscarinic receptor agonist that acts primarily on the M3 receptor to relieve bronchospasm.

Two studies (study 33 and study 34) have compared the efficacy and safety of 200 μg aclidinium bromide twice daily vs 400 μg twice daily vs placebo.

In study 33, both doses of aclidinium bromide resulted in statistically significant improvement in quality of life, as measured by the St. George's Respiratory Questionnaire, when compared with placebo.

In both study 33 and study 34, the 400-μg dose was associated with improvements that were clinically meaningful (≥4 units on the St. George's Respiratory Questionnaire).

Both doses were associated with a clinically significant reduction in breathlessness, as measured by the Transition Dyspnea Index (TDI).

Statistically significant improvement in TDI focal scores from baseline to week 12 was found in study 33 in the aclidinium bromide 400-μg group vs the placebo group, and study 34 revealed statistically significant improvements from baseline to week 12 and week 24 in the aclidinium bromide 400-μg group.

Both studies showed that overall rescue medication use was reduced to a statistically significant amount at week 12 with the 400-μg dose compared with placebo.

Systemic anticholinergic effects occurred infrequently. Investigators found no dose-related differences for treatment-emergent adverse events, serious adverse events, adverse events leading to dropout, or adverse events of special interest. Treatment-emergent adverse events were similar between both doses and placebo.

In an all-day meeting, the committee discussed the results of these studies.

Tiotropium bromide (Spiriva, Pfizer) is currently the only long-acting muscarinic antagonist for COPD treatment approved by the FDA.

"I think the company has been vigilant in trying to do the appropriate dose–response relationship studies. They have come up with a dose that appears to be efficacious. I am aware that the studies weren't powered to look for COPD exacerbation data, but I would encourage the company to continue to gather these results," said Paula Carvalho, MD, professor of medicine, Division of Pulmonary and Critical Care Medicine at the University of Washington in Seattle.

The committee voted unanimously that the efficacy data provide substantial evidence of a clinically meaningful benefit from the medication.

When asked whether the safety of aclidinium has been adequately assessed, 10 members voted yes, 3 voted no, and 1 member abstained.

Explaining her "no" vote, Judith Voynow, MD, from Pediatric Pulmonary and Sleep Medicine at Duke University Medical Center in Durham, North Carolina, said, "I felt that there was still too much uncertainty. The 'no' vote was in the context of benefit associated with risk."

Noting that the study excluded patients with acute cardiovascular disease, Dr. Voynow explained, "I would be concerned about administering this drug to someone with underlying cardiovascular disease. I'm not sure the benefit would outweigh that risk."

David Au, MD, acting director of Northwest Health Services Research and Development Center of Excellence VA, Puget Sound Health Care System, Seattle Division in Seattle, said he voted yes, with a little reluctance. "The preponderance of evidence suggests its safety. I do think that it would be better to have a longer duration and more inclusive criteria to truly understand its broad application.

Efficacy

The committee was asked to discuss the efficacy data for the bronchodilator effect of aclidinium and the effect of aclidinium bromide on other efficacy endpoints.

"I believe that the bronchodilator efficacy data are pretty robust, seen in each of the trials.... There is some bronchodilator effect seen even at reduced doses, so there's a physiologic basis for the bronchodilator efficacy," said William Calhoun, MD, Henry Renfert Jr MD Professor and Vice Chair for Research, Department of Internal Medicine, University of Texas Medical Branch, Galveston.

"The responder analysis is helpful in that it demonstrates that about twice as many people have significant bronchodilator response than in the placebo group, so that's a meaningful change to me," he said.

Safety Profile

The panel was also asked to discuss the overall safety profile of aclidinium, given the size of the safety database and the duration of exposure.

There was an increased number of deaths overall in patients who received aclidinium 400 µg.

A total of 17 patients died during these studies: 8 deaths occurred in the placebo-controlled trials (4 deaths in the aclidinium 400 µg group, 2 deaths in the aclidinium 200 µg group, and 2 deaths in the placebo group), and 9 deaths occurred in the long-term trials (6 deaths in the aclidinium 400 µg group and 3 deaths in the 200 µg group).

The researchers were particularly concerned about deaths from cardiovascular events or cardiorespiratory arrest. Of the 10 patients who died in the aclidinium 400 µg group, 4 died from cardiac arrest and 1 died from acute cardiac failure. Only 1 patient in the 200-µg group died from myocardial infarction, and no patients in the placebo group died from cardiovascular causes.

Several panel members pointed out that a substantial number of patients with COPD have preexisting cardiovascular disease or risk factors such as hypertension or diabetes, so cardiovascular events are particularly worrisome.

Because serious adverse events were uncommon, larger studies would be needed, they said.

"It would be great if the database were bigger, because rare events require larger databases and longer periods of time in order to accurately assess the magnitude of the risk," said Dr. Calhoun.

“I voted yes, with one caveat: I counted about 64 weeks of exposure in the carryover patients, and that appears to be an adequate amount of time," he said. "But again, the patients that I will be prescribing this drug to in the future are going to have heart disease, and I would need to have that data in the future.”

A significant number of patients continue to smoke after COPD diagnosis, noted Paul Greenberger, MD, professor of medicine at the Northwestern University Feinberg School of Medicine in Chicago, Illinois. "At least 15% or more are continuing to smoke during the study," he said. For this reason, it will be necessary to collect more data on which patients continue to smoke during treatment

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