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Brand new ‘Toy’? Theravance, GSK: Breo positive in asthma

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By Randy Osborne
Staff Writer

Positive Phase III data with Breo Ellipta in asthma reported by Theravance Inc. and partner Glaxosmithkline plc (GSK) could let them join two major competitors in the field, but with a once-a-day rather than twice-a-day, therapy, which is already approved for chronic obstructive pulmonary disorder (COPD).

And this could make a big difference in the market, if the findings of an oft-cited study by Edmond Toy, with the Analysis Group in Denver, hold true. Toy found that the less-frequent dosing is especially important in patients with COPD, and “in this particular category, improved compliance is correlated with better patient outcomes,” said Michael Aguiar, head of investor relations for Theravance.

A 990-patient Phase III trial with the inhaled corticosteroid (ICS) fluticasone furoate (FF) and vilanterol (VI) combo, which make up Breo, found that the compound improved expiratory volume to a statistically significant degree, and the new data will inform a regulatory filing in the U.S., the companies said.

It was the long-acting beta2 agonist (LABA) VI that led to the boxed warning, which notes that data from a large, placebo-controlled study in the U.S. showed an increase in asthma-related deaths in patients receiving the LABA salmeterol plus the usual asthma drugs, so the results were considered a class effect of LABAs. Breo won approval earlier this year. (See BioWorld Today, May 13, 2013.)

But the same warnings appear on the marketed COPD/asthma products Symbicort (formoterol and budesonide, Astrazeneca plc), Advair (fluticasone/salmeterol, Glaxosmithkline plc), and Dulera (mometasone furoate/formoterol fumarate), Aguiar pointed out.

“My guess is that the black-box warning would probably stay” on Breo, if it’s approved for asthma, he told BioWorld Today, but this matters less than the once-per-day dosing advantage.

The Breo formulation was cleared in the European Union last month for COPD and asthma. Health Canada cleared it as July for COPD, but not asthma. In September 2013, the Japanese Ministry of Health, Labor and Welfare approved FF/VI 100/25 mcg and 200/25 mcg for the treatment of bronchial asthma under the trade name Relvar Ellipta. And in October, the Mexican regulatory authority approved Relvar Ellipta 100/25 mcg and 200/25 mcg for the treatment of COPD and asthma.

“There was some additional work that we felt we needed to do, from an FDA perspective,” for the asthma label, Aguiar said. “This is a fairly important study for us.”

The trial was a 12-week, double-blind, parallel group, multicenter experiment testing FF/VI at 200/25 mcg, 100/25 mcg, and FF 100 mcg inhalation powder, enrolling patients with moderate to severe persistent asthma.

Patients were randomized to one of the three treatments taken once daily in the evening. The primary endpoint was weighted mean serial forced expiratory volume in one second (FEV1) at the end of the 12-week treatment period. The primary comparison was FF/VI 100/25 mcg (the Breo dose) vs. FF 100 mcg. Of particular interest, Aguiar said, was the Breo dose as compared with the FF alone.

In FEV1, FF/VI 100/25 mcg turned up a statistically significant improvement in lung function compared with FF 100 mcg (108 ml, 95 percent CI 45, 171 p < 0.001) at the end of the treatment period. In patients getting FF/VI 200/25 mcg, an added improvement of 24 ml (95 percent CI -37, 86) was observed when compared with the Breo dose.

The most common reported side effects across all treatment arms included headache, nasopharyngitis, upper respiratory tract infection and influenza. The incidences of any on-treatment serious adverse events across all treatment arms were similar (FF 100 mcg < 1 percent, FF/VI 100/25 mcg 1 percent, FF/VI 200/25 mcg < 1 percent).

The drug’s path to market in the U.S. for COPD has not been without suspense. It was ultimately cleared by U.S. regulators for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema, as well as for reducing COPD exacerbations.

But a month before that, the FDA’s Pulmonary-Allergy Drugs Advisory Committee struggled with its decision. As a maintenance therapy, Breo gained the panel’s vote of 9-4 in favor to recommend marketing clearance.

As a treatment to reduce COPD exacerbations, the tally ended up identical, though one member said he hit the wrong button and meant to vote no. Balloting by the adcom totaled 12-1 in favor of Breo’s efficacy as a maintenance therapy, 8-5 in favor of efficacy for exacerbations and 10-3 positive for safety. (See BioWorld Today, April 18, 2013.)

In LAMA/LABA, LITTLE ‘BREATHING ROOM’

Whether the Breo hitch augurs trouble for other compounds in the alliance between London-based GSK and Theravance, of South San Francisco, is unclear, though Leerink Swann analyst Howard Liang, in an April research report, worried over the fate of Anoro (umeclidinium bromide/VI), adding to the LABA a long-acting muscarinic antagonist (LAMA) for COPD. The FDA’s advisory panel has given its nod, and the agency is expected to decide about Anoro in December. The companies’ deal dates back about a decade. (See BioWorld Today, Jan. 7, 2003, and Sept. 11, 2013.)

But the Breo formulation against asthma has taken center stage more recently, as have LAMA/LABA pairings in COPD. PT003 was developed by London-based Astrazeneca plc and Pearl Therapeutics Inc., of Redwood City, Calif. In May, Pearl launched the Phase III trial with glycopyrrolate/formoterol fumarate, having raised $65 million in a Series D round the previous November to fund the experiment. (See BioWorld Today, Nov. 14, 2012, and May 15, 2013.)

A race is under way in LAMA/LABA for COPD between New York-based Forest Laboratories Inc. (with Spanish partner Almirall SA) and Novartis AG, of Basel, Switzerland. Forest/Almirall’s August delay in submitting a new drug application (NDA), originally planned for the first quarter of this year, pushed the duo back. The falter came after a pre-new drug application meeting with the FDA, and the issues to resolve had to do with chemistry, manufacturing and control specification. Leerink Swann analyst Seamus Fernandez, in a research report, projected a one-year holdup. (See BioWorld Today, Aug. 16, 2013.)

Forest/Almirall’s aclidinium bromide product (branded Tudorza and Eklira) is already on the market for maintenance treatment of COPD in the U.S. and Europe, as is FF; the new drug brings them together. If it’s stalled for as long as Fernandez predicted, then the filing would fall right around the estimated time when Novartis goes to the FDA with the LAMA/LABA candidate QVA149 (indacaterol maleate and glycopyrronium bromide), partnered with Sosei Group Corp., of Tokyo.

QVA149 met its primary endpoint in a fifth Phase III trial in more than 2,000 subjects, showing statistically significant reduction in moderate to severe exacerbations of COPD compared to patients treated with glycopyrronium 50 mg alone, and a regulatory filing for next year is said to be on track.