Sunovion Pharmaceuticals Inc. moved its nebulized long-acting muscarinic antagonist (LAMA) into phase III development by opening the final two studies in a pivotal program that will collectively enroll approximately 2,340 adults with moderate to very severe chronic obstructive pulmonary disease (COPD).

The Marlborough, Mass.-based company, a wholly owned subsidiary of Japan's Sumitomo Dainippon Pharma Co. Ltd., is investigating SUN-101 (glycopyrrolate), an inhaled formulation based on approved pharmaceutical product, delivered through an investigational nebulizer system known as Eflow (SUN-101/Eflow) for the twice-daily maintenance treatment of bronchoconstriction in patients with COPD, including those with chronic bronchitis and emphysema.

The program came to Sunovion through its 2012 buyout of Elevation Pharmaceuticals Inc., which took the drug/device combo through phase IIb development using a nebulizer developed by and licensed from Pari Pharma GmbH, of Grafelfing, Germany. SUN-101/Eflow represents the first nebulized LAMA to move into phase III development, according to Alistair Wheeler, Sunovion's vice president of clinical development and medical affairs.

Elevation's strategy was to target a specific subpopulation of COPD patients whose symptoms are not well controlled with dry powder or metered-dose inhalers – mainly those who are older and sicker – with a nebulizer-based formulation of glycopyrrolate. By turning the solution into a mist using the Eflow nebulizer – a portable device based on a vibrating membrane – those patients could receive a full dose of drug in about two minutes. In contrast, a standard jet nebulizer requires up to 10 minutes to deliver a full dose.

"The current use of nebulizers is limited, to some extent, by the practical use of the device in terms of portability and convenience factors, which include noise and duration," Wheeler told BioWorld Today. "The reason we acquired Elevation was that the Eflow device offers more rapid administration than a conventional nebulizer, and it is silent – not just quiet, but silent – which is a big advantage."

The technology developed by Elevation, which now operates as Sunovion subsidiary Respiratory Development Inc., also enables better control of droplet size for optimal distribution to the lung.

TAKING ON HANDHELD LAMA/LABAS

Sunovion snagged San Diego-based Elevation shortly after data from the first phase IIb trial, known as GOLDEN-1 (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer), were reported, paying $100 million up front and up to $300 million in development and commercial milestone payments. (See BioWorld Today, Aug. 31, 2012.)

Sunovion completed the phase II program, which established twice-daily dosing as the optimum schedule. The company reported positive efficacy and safety data last year at the American College of Chest Physicians (CHEST) annual meeting in Austin, Texas.

The company also held its end-of-phase II meeting with the FDA to discuss the findings and design of the pivotal program. The 12-week, randomized, double-blind, placebo-controlled GOLDEN-3 and GOLDEN-4 safety and efficacy studies are expected to enroll approximately 645 people each across approximately 50 U.S. sites, comparing twice-daily SUN-101/Eflow 25 mcg and 50 mcg with placebo.

Multiple dose levels were not required but those help Sunovion "to be certain that we got it right" and to provide a higher comfort level with the FDA in reviewing a LAMA product, Wheeler said.

The primary endpoint from both studies is change from baseline in trough forced expiratory volume in 1 second (FEV1) at week 12. Secondary endpoints include standardized change from baseline at week 12 in FEV1 area under the curve, change from baseline in trough forced vital capacity at week 12, change from baseline in health status measured by St. George's Respiratory Questionnaire and change in rescue medication use. Safety will be assessed by the number of treatment-emergent adverse events (AEs), serious AEs or major adverse cardiac events (MACEs) and the number and percentage of study participants who discontinue the study due to treatment-related AEs.

GOLDEN-5, an open-label, 48-week long-term safety study that began enrollment in October 2014, is comparing 50 mcg of SUN-101/Eflow delivered twice-daily and Spiriva (tiotroprium, Pfizer Inc./Boehringer Ingelheim GmbH) 18 mcg delivered once-daily by the Handihaler device. The randomized, open-label, active-controlled, parallel-group trial is expected to enroll approximately 1,050 people with COPD at 150 sites in the U.S. and Europe. Primary safety endpoints are the number and percentage of study participants with treatment-emergent AEs and treatment-emergent serious AEs and the number and percentage of study participants who discontinue the study due to treatment-emergent AEs. Secondary endpoints are mean change from baseline over 48 weeks in trough FEV1 for all subjects and number and percentage of subjects with MACE.

Although the FDA has allowed companies to move similar COPD products through pivotal safety studies with a placebo control or no control, Sunovion opted for an active control to provide a more granular level of safety and efficacy data to the FDA, according to Wheeler.

"The program is relatively cookie-cutter," he said.

The company expects to have top-line data from GOLDEN-3 and GOLDEN-4 early next year, followed by the long-term safety data. The complete data package could be ready to present as early as the CHEST 2016 meeting, although "we have not yet put the detail into our plans for publicizing" the findings, Wheeler said.

Sunovion plans to file first with the FDA, where SUN-101 could be the first LAMA delivered via nebulizer approved by the agency. But the potential market opportunity is much larger than simply cannibalizing other nebulizer therapies, Wheeler insisted, noting that many patients on LAMA monotherapy and the increasingly popular combination of LAMA with a long-acting beta2 agonist (LABA) are searching for better therapies.

"The more severe population is the core of any nebulized therapy," he conceded, "but Elevation would not have started EP-101 – and we would not have acquired it and made it SUN-101 – if there were no advantages above and beyond nebulized therapy. We see it as another treatment option for patients who have a less than optimal response to handheld therapy."

In 2013, the FDA approved Anoro Ellipta (vilanterol plus umeclidinium bromide, Glaxosmithkline plc/Theravance Inc.) as the first once-daily product in the U.S. to combine two long-acting bronchodilators in a single inhaler for the maintenance treatment of COPD, raising the bar in treating the serious chronic condition. (See BioWorld Today, Dec. 19, 2013.)

But many COPD patients use the LAMA/LABA and other handheld devices without deriving optimal clinical benefit because they won't commit to the inconvenience of a nebulizer – usually a static piece of equipment powered by a noisy compressor. No one knows that better than Sunovion, which is a market leader in the nebulized space with Brovana (arformoterol tartrate) and legacy product Xopenex inhalation solution.

"People see themselves as being attached to a machine," Wheeler said. "They see them as too heavy and too bulky to take with them for a weekend. There's an emotional speed bump they have to cross."

The SUN-101/Eflow combo, which can be placed in a pocket or purse, "will be acceptable to a portion of that population," he added. "I think people will be more willing to take a look."