Clinical Context

A new combination inhaler for use in chronic obstructive pulmonary disease (COPD), referred to by some as the "son of Advair," contains the synthetic inhaled corticosteroid fluticasone furoate and the long-acting beta2-adrenergic agonist vilanterol trifenatate. The US Food and Drug Administration (FDA) has approved it as Breo Ellipta, and it will also be marketed in Europe as Relvar Ellipta.

Unlike Advair Diskus, the new inhaler has once-daily dosing, which should improve compliance. The inhaler design provides "consistent dosing even in patients with severe lung function impairment," according to the manufacturer.

Study Synopsis and Perspective

The FDA gave the marketing nod to a novel once-daily inhaled therapy for the treatment of COPD.

The product is a combination of the synthetic inhaled corticosteroid fluticasone furoate and the long-acting beta2-adrenergic agonist vilanterol trifenatate that some have hailed as the "son of Advair" (fluticasone propionate and salmeterol). The drug manufacturer has announced that the new product will be called Breo Ellipta in the United States and Relvar Ellipta in Europe.

In contrast to Advair Diskus, which is dosed twice daily, the new once-daily inhaler contains a different, reputedly more stable side-chain variant of fluticasone, with vilanterol in place of salmeterol. The drugs are delivered via a dry powder inhaler containing 2 blister strips, each containing 30 doses of fluticasone or vilanterol. The manufacturer claims that the inhaler design provides "consistent dosing even in patients with severe lung function impairment."

On April 17, the Pulmonary-Allergy Drugs Advisory Committee to the FDA voted 9 to 4 to recommend approval of fluticasone furoate/vilanterol trifenatate 100/25 μg as a once-daily inhaled treatment for reduction of COPD exacerbations, and 12 to 1 to support approval of the combination for the long-term maintenance treatment of airflow obstruction in COPD.

Questions Still Exist

There is some question, however, about whether the improvements in airway obstruction seen in the manufacturer-conducted trials submitted for approval came from the corticosteroid or the long-acting beta2-adrenergic agonist component of the combination. According to FDA's summary minutes of the April 17 panel meeting, one member said that "there were no statistically robust data to support the contribution of FF [fluticasone furoate] component to the combination in either lung function trial."

An investigator for 2 double-blinded group trials, however, tells Medscape Medical News that compared with vilanterol alone, fluticasone furoate with vilanterol trifenatate was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbations.

In addition, the once-daily dosing may help to improve compliance, said Nicola A. Hanania, MD, associate professor of medicine in the Section of Pulmonary Medicine and director of the Asthma/COPD Clinical Research Center at Baylor College of Medicine in Houston, Texas.

"Fluticasone furoate has been shown to have a longer effect than fluticasone propionate, even though both are fluticasone, and that's why they were able to show that it's a once-a-day drug," he said. "Vilanterol, as well, has once-a-day activity compared to salmeterol, which is a very weak agonist."

In these 2 studies, investigators saw an increased risk for pneumonia among patients receiving the combination, and there were 8 pneumonia deaths among the 3255 patients enrolled in the trials. All of the deaths occurred in patients receiving various fluticasone/vilanterol combinations; none occurred in patients receiving vilanterol alone.

At the FDA panel hearing in April, some panel members noted that the inhaler did not appear to be associated with cardiovascular, potassium, or tremor safety signals and that adverse event testing appeared adequate.

However, there were also concerns about the increased risks for pneumonia, fracture, and ocular adverse events such as elevated intraocular pressure. Some of the 5 members who voted "no" on the question of adequate evidence for safety said the risks from the therapy might outweigh the benefits in patients with mild COPD.

The FDA does warn that the new fluticasone/vilanterol combination may cause serious adverse effects, including increased risks for pneumonia and bone fractures. The most common adverse effects seen among patients using the combination included nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.

The medication carries a boxed warning that long-acting beta2-adrenergic agonists increase the risk for asthma-related death. The safety and efficacy of the new combination inhaler in patients with asthma have not been established, and it is not approved for the treatment of asthma, according to the FDA.

There is also a patient medication guide with instructions for use and information about the potential risks of taking the drug. The new fluticasone/vilanterol combination should not be used as a rescue therapy to treat sudden breathing problems (acute bronchospasm) and is not recommended for people younger than 18 years.

The cost of the therapy was not known at this time, but given that it is a new drug formulation in a novel inhaler design, there is likely to be a price premium compared with other therapies, Dr. Hanania said.

"We've had quite a bit of advancement in COPD pharmacotherapy in the last 10 years, which is really good because there is an unmet need. But one of the problems is they are costly, and people who can't afford it go back to their regular rescue medications," he said.

More information on the new combination drug is available on the FDA Web site, along with labeling information.

The studies submitted to the FDA were funded by GlaxoSmithKline. Baylor College of Medicine has received research support from the company.

Clinical Implications

• The FDA has approved a novel, once-daily, combination inhaled therapy for treatment of COPD. It contains a side-chain variant of fluticasone that is thought to be more stable, and vilanterol, a long-acting beta2-adrenergic agonist, delivered via a dry powder inhaler. Approved indications are for reduction of COPD exacerbations and for long-term maintenance treatment of airflow obstruction.
• In the trials underlying approval, the new combination inhaler was associated with improvements in airway obstruction. However, it was unclear whether fluticasone or vilanterol caused these improvements. In 2 double-blinded group trials, the combination vs vilanterol alone led to a reduced rate of moderate and severe COPD exacerbations in patients with a history of exacerbations.
• Clinical trials showed an increased risk for pneumonia among patients receiving the new fluticasone/vilanterol combination. FDA concerns also include increased risks for fracture, elevated intraocular pressure, and other ocular adverse events. The most common adverse effects include nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.

CME Test