The experimental therapy SUN-101/eFlow is a combination of glycopyrrolate, an agent used to reduce secretions in the mouth, throat, airway, and stomach named SUN-101, and eFlow, which is an innovative nebulizer closed system for the long-term, maintenance treatment of airflow obstruction in people with moderate-to-very severe COPD.
Sunovion Pharmaceuticals announced the filing acceptance of a New Drug Application (NDA) by the U.S. Food and Drug Administration (FDA) for this treatment in October 2016. If approved, SUN-101/eFlow would be the first available nebulized long-acting muscarinic antagonist for adults with COPD. The expected action date by the FDA under the Prescription Drug User Fee Act (PDUFA) is May 29, 2017.
The NDA submission was based on data from the GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) program that comprised three randomized Phase 3 clinical trials — GOLDEN 3 (NCT02347761), GOLDEN 4 (NCT02347774), and GOLDEN 5 (NCT02276222) — evaluating the effectiveness and safety of the SUN-101/eFlow system.
How SUN-101/eFlow treatment for COPD works
SUN-101’s key ingredient is glycopyrrolate, a long-acting muscarinic antagonist (LAMA) bronchodilator that connects to the muscarinic receptor subtypes M1 to M5. The M3 receptors are located in the muscles of the bronchi (or airways in the respiratory tract that conducts air into the lungs) and are responsible for their constriction.
The eFlow is an advanced, handheld nebulizer that was developed by PARI Pharma and optimized for SUN-101 as a closed delivery system.
The SUN-101/eFlow development program, GOLDEN, included seven studies in total.
The Phase 2 GOLDEN-1 study (NCT01426009) aimed at determining the steady-state efficacy and dose response profile of four doses (25, 50, 100, and 200 µg) of SUN-101, and assess their safety and pharmacokinetic profile compared to placebo and two drugs of reference (tiotropium and ipratropium, administered through a Handihaler DPI device). All once-daily doses of SUN-101 were well-tolerated, with a similar number of adverse events, and all demonstrated dose-related and significant improvements in lung function measured as FEV1 (or forced expiratory volume 1, the amount of air a person can forcibly exhale in one second) at the end of the study (day 7) compared to placebo. The results were reported in an article published in the European Respiratory Journal in 2012.
The GOLDEN-2 Phase 2 study (NCT1706536) compared the efficacy and safety of different doses of SUN-101 with placebo in patients with moderate-to-severe COPD. Results showed that SUN-101 demonstrated the rapid onset (five minutes or less) of dose-related bronchodilation following a single-dose administration (between 12.5–400 μg) and produced clinically meaningful improvements in lung function measured as FEV1 that were maintained over a 24-hour period at all doses above 50 μg. The treatment’s safety profile was also seen to be similar to tiotropium, according to a report published in the International Journal of Chronic Obstructive Pulmonary Disease in 2016.
GOLDEN-3 and GOLDEN-4 were Phase 3, 12-week-long studies that compared SUN-101/eFlow with placebo in adults with moderate-to-very severe COPD, given twice a day at 25 or 50 mcg with placebo. The primary objective of these trials was the change in lung function at week 12, as measured by trough FEV1. Secondary objectives included a standardized change from baseline in FEV area under the curve (AUC), change from baseline in trough FVC, change from baseline in health status measured by St. George’s Respiratory Questionnaire, and change in rescue medication use. Safety was assessed by the number of treatment-emergent adverse events, serious adverse events, or major adverse cardiac events, and the number and percentage of study participants who discontinued the study due to treatment-emergent adverse events. People already using an effective long-acting bronchodilator therapy, and those with very severe disease (post-bronchodilator FEV1 of less than 80% of predicted normal, or FEV1/FVC ratio of less than 0.70) and co-existing cardiovascular illness were included in both studies.
The company reported in April 2016 that both GOLDEN 3 and GOLDEN 4 trials met their primary endpoints, finding with statistically significant changes from baseline in FEV1 observed for both the 25 mcg and 50 mcg dose of SUN-101/eFlow, compared to placebo. The treatment was well tolerated with no major adverse events reported.
The GOLDEN-5 study was a long-term (48-week) open-label safety study, with 1,087 moderate-to-very severe COPD patients receiving one of two treatments: SUN-101 at 50mcg twice daily or tiotropium at 18 mcg once daily. The primary objectives were the number and percentage of patients with treatment-emergent adverse events, serious events, and the number and percentage of participants who discontinued the study due to treatment-emergent events. Secondary objectives were the mean change from baseline over 48 weeks in trough FEV1, and the number and percentage of participants with major adverse cardiac events.
Results showed that SUN-101/eFlow was well-tolerated as a twice-daily maintenance therapy for bronchoconstriction, with a similar overall incidence of adverse events to standard of care. The incidence of major adverse cardiovascular events was similar to tiotropium.
GOLDEN-6 (NCT02038829) compared different SUN-101 doses (3, 6.25, 12.5, and 50 mcg) to Tudorza in COPD patients, ages 40 to 65, and GOLDEN-7 (NCT02512302) determined the amount of glycopyrrolate absorbed in the lungs, using the eFlow nebulizer compared to Seebri Breezhaler (glycopyrronium).
Sunovion will present results from these Phase 3 efficacy and safety studies at the American Thoracic Society 2017 International Conference (ATS 2017), in Washington, D.C., May 19–24.
The seven poster presentations will include data that demonstrate the safety and efficacy of SUN-101/eFlow, as well as data from a patient survey showing satisfaction with the eFlow device.
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