FDA panel backs bronchodilator combo for COPD, with precautions

SILVER SPRING, MD. – A fixed-dose combination of umeclidinium bromide, a new long-acting antimuscarinic agent (LAMA), and vilanterol, a relatively new long-acting beta agonist (LABA), in an inhaled powder formulation, should be approved for treatment of chronic obstructive pulmonary disease, with a recommendation for a postmarketing safety study, according to the majority of a Food and Drug Administration advisory panel.

At a meeting on Sept. 10, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 11-2 that the safety and efficacy data on the combined treatment, administered once a day, supported approval for the proposed indication: the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. The daily dose is 62.5 mcg of umeclidinium and 25 mcg of vilanterol (UMEC/VI 62.5/25), provided in one inhalation.

In another vote, the panel unanimously agreed that treatment with UMEC/VI 62.5/25 provided clinically meaningful benefits for this indication, based on the clinical trial results provided by GlaxoSmithKline. However, all the panelists were concerned about potential safety issues in patients with severe heart disease. There was also concern over the generalizability of the use of the combination because of a cardiovascular safety signal in the studies and the types of patients excluded in the research.

Those voting in favor of approval recommended a postmarketing study to evaluate the safety signal further, and a statement in the precautions and warnings section of the label about possible risks. The two panelists voting against approval said that the study should be done before approval.

If approved, this would be the first LAMA/LABA combination product to become available in the United States. Umeclidinium is not yet available in any product, although the FDA is currently reviewing the 62.5-mcg dose as monotherapy. Vilanterol is available only as the LABA component in Breo Ellipta, the combination of vilanterol with the inhaled corticosteroid fluticasone, which was approved in May 2013 for COPD. The same device is used to deliver UMEC/VI 62.5/25, which, if approved, will be marketed as Anoro Ellipta, by GSK and Theravance.

Research details

The four main safety and efficacy studies compared two doses of umeclidinium (125 mcg and 62.5 mcg) combined with 25 mcg of vilanterol to the separate components alone and to placebo (in two studies) or to the approved long-acting antimuscarinic agent tiotropium (two studies) in about 4,700 patients – most of whom were male and white – with moderate to severe COPD. Their mean age was 63 years, almost half were still smoking, and almost 30% had had at least one exacerbation during the previous year that required treatment with corticosteroids and/or antibiotics; about 10% said they had been hospitalized for an exacerbation during the previous year (25% were enrolled in the United States).

In the two placebo-controlled studies, the combination and the two separate components (UMEC and vilanterol) were associated with statistically significant improvements in mean trough forced expiratory volume in 1 second (FEV₁) from baseline at 24 weeks (the primary endpoint), compared with placebo. Improvements were also statistically significant for the two combinations over the individual components. In the active controlled study, the two combinations showed improvements in trough FEV₁ that were superior to vilanterol alone and to tiotropium alone. The results with the higher dose of umeclidinium and vilanterol were similar to the 62.5-mcg dose, the proposed dose for approval.

The mortality rate and nonfatal serious adverse events were even in the treatment arms, in the four primary efficacy studies, and in long-term safety studies, and adverse events were consistent with those associated with the LAMAs and LABAs, according to GSK. The total number of cardiovascular-related events was fairly low in the safety database that included the four main studies and a long-term safety study. But there were numerical imbalances in ischemia-related events in the primary efficacy studies that were not seen in the long-term safety study, an issue raised by the FDA, although the overall number of events was low, according to the agency.

Panelists raised several safety issues, including the generalizability of the cardiac safety data to patients with more severe cardiac disease, because of exclusion criteria that may have eliminated these patients.

The panel chair, Dr. David Jacoby, professor of medicine in the division of pulmonary and critical care medicine at Oregon Health and Science University, Portland, supported approval but recommended that safety should be studied further in patients with COPD who have more severe cardiac disease.

Also voting for approval, Dr. Nizar Jarjour, professor and head of the section of allergy, pulmonary, and critical care at the University of Wisconsin, Madison, said the data indicated that the product was reasonably safe. But if it were to be used outside the parameters studied in the trials, such as for patients with recent exacerbations of COPD, or severe heart disease, he said he have would "no real confidence" that it would have the same safety profile as seen in the trials.