FDA approves aclidinium bromide inhalation powder to treat COPD

FDA has approved aclidinium bromide inhalation powder (Tudorza Pressair, Forest Pharmaceuticals) for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Aclidinium bromide inhalation powder, which is used twice daily, is a long-acting antimuscarinic agent that helps muscles around the large airways of the lungs stay relaxed to improve airflow.

COPD is a common, progressive, and debilitating lung disease characterized by persistent airflow limitation that makes it hard to breathe; it is currently the third leading cause of mortality in the United States. Characteristic symptoms include breathlessness, excessive production of sputum, and a chronic cough.

“The Global Initiative for Chronic Obstructive Lung Disease 2011 guidelines recommend long-acting anticholinergics as a first-line therapy for a broad range of COPD patients with moderate to very severe disease,” Professor Richard Casaburi, MD, associate chief for research in the Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, said in a press release. “Tudorza will be a valuable anticholinergic option in the clinical armamentarium available to manage this serious disease.”

The clinical development program of aclidinium bromide inhalation powder included a dose-ranging trial and three confirmatory pivotal trials. The two 12-week and one 24-week pivotal placebo-controlled trials evaluated the efficacy and safety of aclidinium bromide 400 µg twice daily in 1,276 patients. Patients enrolled in these trials had a clinical diagnosis of COPD, were aged 40 years or older, had a smoking history of at least 10 pack-years, a forced expiratory volume in 1 second (FEV₁) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV₁ over forced vital capacity (FEV₁/FVC) of less than 0.7.

In all three pivotal trials, aclidinium bromide inhalation powder demonstrated statistically significant improvements in bronchodilation, as measured by change from baseline in morning pre-dose trough FEV1 at 12 weeks (the primary end point) compared to placebo. The mean 12-week pre-dose FEV₁ improvements versus placebo were 0.12 L, 0.07 L, and 0.11 L in the three trials, with a 24-week improvement of 0.13 L in the 6-month trial. Mean peak improvements in lung function (FEV₁) assessed after the first dose of aclidinium bromide were similar to those observed at week 12 in each study. Aclidinium bromide had a low incidence of side effects in these trials.

The most common adverse reactions that occurred in the aclidinium bromide group with a frequency of greater than or equal to 3% and exceeding placebo were headache (6.6% vs 5.0%), nasopharyngitis (5.5% vs 3.9%), and cough (3.0% vs 2.2%). Three long-term safety studies, evaluating 891 patients treated with aclidinium bromide 400 µg twice daily for 40 to 52 weeks reported similar adverse events, with no new safety findings compared to the placebo-controlled trials.

Additionally, serial spirometric evaluations of FEV₁ were performed over 12 hours in a subset of patients in the three pivotal trials. Improvement of lung function with aclidinium bromide versus placebo was achieved for the first 12 hours on day 1 and was consistent over the 3- or 6-month treatment period evaluated.

In two of the three trials, patients treated with aclidinium bromide also used less daily rescue albuterol compared to placebo-treated patients.Tudorza is administered using a multiple-dose dry powder inhaler, Pressair, which delivers 60 doses of aclidinium bromide powder for inhalation. The Pressair inhaler has a colored control window and audible “click,” which confirm successful inhalation of the dose and a dose indicator to let patients know how many doses remain in the inhaler.

“Aclidinium bromide is another antimuscarinic antagonist that appears to offer a positive therapeutic response when compared to tiotropium and ipratropium,” said Formulary advisor James M. Wooten, PharmD, associate professor, department of medicine, section of clinical pharmacology, University of Missouri-Kansas City. “The pharmacology of the drug is unique in that it may have a longer duration of effect on the M1 receptor thus prolonging the therapeutic response. Whether it is a better option than the other available antimuscarinic agents [tiotropium and ipratropium] remains to be seen.”

Forest expects aclidinium bromide inhalation powder to be available to wholesalers in the fourth calendar quarter of 2012.