The FDA's Pulmonary-Allergy Drugs Advisory Committee gave its blessing to inhaled Breo (fluticasone furoate [FF]/vilanterol [VI]), the combination corticosteroid and long-acting beta2 agonist (LABA) for chronic obstructive pulmonary disease (COPD) from GlaxoSmithKline plc and Theravance Inc., though voting across several categories was mixed.

For the compound as a maintenance therapy, the panel's vote was 9-4 in favor. As a treatment to reduce COPD exacerbations, the tally came out the same, but one member said he meant to cast his electronic ballot against approval, and hit the wrong button. John Connett, professor of biostatistics at the University of Minnesota School of Public Health in Minneapolis, said he wanted to remain consistent with his previous vote on exacerbations, which he regarded as "still not a settled issue."

Leading up to that balloting were votes 12-1 in favor of Breo's efficacy as a maintenance therapy, 8-5 in favor of efficacy against exacerbations and 10-3 positive for safety in the proposed indications.

Kathryn Blake, senior research scientist at Nemours Children's Clinic in Jacksonville, Fla., questioned the context of the voting. "When we're looking at the safety of this drug, how much should we take into consideration its comparability with what's already on the market? Should we hold a drug that we're looking at now [to] a different standard?"

An FDA representative noted there was no comparative safety requirement. Blake ended up favoring approval, though she "encourage[d] GSK to continue to look at the phenotypic and even genotypic variables that might predispose patients to some of the adverse effects, and to make their data available to other investigators who will look at this important issue."

Paula Carvalho, professor of medicine at the University of Washington in Seattle, voted against recommending approval. "I actually was more impressed on the data with vilanterol alone," she said. FF, the other drug in the combo, is marketed by London-based GSK for allergic rhinitis as Veramyst in the U.S. and as Avamys elsewhere. The FDA approved FF, delivered in mist form by way of a device, in 2007.

James Stoller, professor of medicine at the Education Institute of Cleveland Clinic, wanted the labeling of Breo to distinguish such conditions as bronchitis and emphysema from COPD, something which "can actually not be characterized by the nature of the data that we have on these patients."

He said that "the specific language of the indication to subsume both would strike me as ambitious, given the data we've been shown," though Stoller acknowledged, "it's a splitting-hairs argument, and I have every confidence that if this sample looks like every other patient population in COPD, they're likely both in there."

Still, he added, with "some of the analytic details regarding safety and efficacy, my preference would have been to see a little more robustly analyzed," separating cases of pneumonia better from cases of COPD exacerbation.

Briefing documents ahead of the adcom's meeting had created a mixed picture, citing inconsistent data with Breo but drawing remarks from analysts that suggested the scenario was not as bad as it might have been for the drug's sponsors. (See BioWorld Today, April 16, 3013.)

Leerink Swann analyst Howard Liang was especially upbeat ahead of the meeting, and wrote in a research report that the documents "include endorsement of the dose selection, and lack of safety surprises and apparently modest concern on pneumonia deaths" – good news for the sponsors. Along with "strong positive implications," the FDA opinion "essentially eliminates the worse-case scenario that [the] dose selection of VI is questioned," Liang wrote.

Any trouble at the agency with Breo, Liang pointed out, might have implications for GSK and South San Francisco-based Theravance's other candidates in their partnership for COPD, such as Anoro (umeclidinium bromide/VI), a combination of a long-acting muscarinic beta2 agonist and the LABA product. The FDA is expected to decide about Anoro in December. The companies' deal dates back about a decade. (See BioWorld Today, Jan. 7, 2003.)

As expected, an issue at Wednesday's panel had to do with the benefit vs. risk of adding FF to VI, given that some experts question the use of an inhaled steroid to treat COPD. Some talk focused on the efficacy with Breo's FF/VI at 100/25 mcg once daily, compared to VI 25 mcg alone. The panel seemed skeptical about adverse events such as pneumonia.

Rodney Mullins, national director of Public Health Consultants in Duluth, Ga., was among those voting against approval, on the basis of pneumonia and cardiovascular risk. He cited the high dropout rate. "I do have some safety concerns about this particular therapy, because I believe the toxicity over a long period of time is going to cause continued exacerbations, as it did in the clinical trials," Mullins said.

Theravance's shares (NASDAQ:THRX) halted trading for the day of the panel meeting. The stock was up 18 percent in after-hours trading.