Pearl Therapeutics Inc. launched its much-anticipated Phase III (PINNACLE) trial of PT003, a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered by pressurized hydrofluoroalkane, in chronic obstructive pulmonary disease (COPD).

The Redwood City, Calif.-based company raised $65 million in a Series D financing in November to support the trial. (See BioWorld Today, Nov. 14, 2012.)

The product is a combination of a long-acting muscarinic antagonist (LAMA), glycopyrrolate, and a long-acting beta-2 agonist (LABA), formoterol fumarate, a pair of medicines believed to have great potential for COPD in combination.

Colin Reisner, chief medical officer for Pearl, told BioWorld Today that the company completed its dose-ranging studies at the end of 2012 and has had discussions with the European Medicines Agency, Health Canada and the FDA, including an end-of-Phase-II meeting with the FDA.

"We got agreement on the dose of each individual component and combination as well as the overall program," Reisner said.

Pearl has been rapidly gearing up for the Phase III trial since it concluded the end-of-Phase-II meeting. It has set up more than 260 trial sites in the U.S., Australia and New Zealand.

The PINNACLE study will enroll more than 2,700 subjects, comparing efficacy of a single dose of PT003 to that of its components and placebo. In one trial, open-label tiotropium will serve as active control.

The trial will assess efficacy through improvement in forced expiratory volume in one second (FEV1). Other endpoints will also be used to support regulatory requirements in some regions.

Study participants will be able to continue treatment in a 28-week extension study, for additional assessment of safety. Enrollment is expected to be complete in mid-2014.

Pearl reported Phase IIb results in 2011 that showed a statistically significant improvement in FEV1 of 47 percent over Foradil (formoterol, Novartis AG) and 49 percent over Spiriva (tiotroprium, Pfizer Inc./Boehringer Ingelheim GmbH) after one week of dosing (p < 0.0001 for both comparisons).

A combination LAMA/LABA inhaler is a logical development since standard treatment of COPD begins with a product like Spiriva, and then advances to combination treatment, such as Spiriva plus Symbicort (formoterol and budesonide, AstraZeneca plc) or Advair (fluticasone/salmeterol, GlaxoSmithKline plc). A combination LAMA/LABA inhaler would fill a niche in the treatment plan, but so far is not available on the market.

The difficulty in developing a LAMA/LABA inhaler is that in metered-dose inhalers, the products are unstable in the low microgram dose range.

"With our formulation," Reisner said, "the suspension of porous particles tends to stabilize the formulation even at very low dose levels."

Pearl's Series D financing, provided by Vatera Capital, along with 5AM Ventures, Clarus Ventures and New Leaf Venture Partners, will largely support the Phase III studies.

"We haven't decided how we're going to get to the end," said Pearl CEO Chuck Bramlage. "Some of our investors are interested in going the distance, and we have some business development opportunities. . . . You'll probably be hearing more from us in a couple months on that."

Reisner noted one positive piece of news for Phase III development was that Pearl has received approval from the FDA, EMA and Health Canada to go forward based on the dose strength used in Phase II, rather than taking two or more doses forward into Phase III.

The company did a thorough dose-ranging study on glycopyrrholate, which Reisner said has been "incredibly difficult" in terms of nailing down the dose response appropriately in the past.

"We were able to evaluate the product down into the nanogram range," Reisner said. Having fully characterized the dose-response profile, the company has a single dose of its LAMA, a single dose of its LABA and one dose of the combination product. "We're the only company to do that in Phase III. Every other company has taken two doses forward."

The market for COPD is estimated at more than $8 billion and growing, and companies like GlaxoSmithKline plc, Boehringer Ingelheim, Merck & Co. Inc., Pfizer Inc., Novartis and AstraZeneca have products in that space.

Spiriva is the leading LAMA on the market with Foradil as the top-selling LABA.

The GOLD Guidelines for treatment of COPD patients who need more than one medication call for use of a once-daily LAMA, like Spiriva, plus a twice-daily LABA, such as formoterol or salmeterol. Alternately, some physicians prescribe an inhaled corticosteroid with a LABA.

Sosei Group Corp., of Tokyo, is developing a LABA/LAMA combo product, QVA149 (indacaterol maleate/glycopyrronium bromide). Sosei and its partner Novartis reported that the drug 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 glycophyrronium 50 mg. That product is on schedule for U.S. registration review in 2014.

Anoro Ellipta, a LAMA/LABA combo product from the collaboration between GSK and Theravance Inc. – recently approved Breo Ellipta, a combination LABA and inhaled corticosteroid, emerged from that same alliance – is currently under FDA review, with a Dec. 18 PDUFA date. (See BioWorld Today, May 13, 2013.)