Cardiovascular Safety and Efficacy of Nebulized Glycopyrrolate/eFlow CS in Phase 3 Trials of Patients With Moderate to Very Severe COPD

Abstract

SESSION TITLE: COPD 2 SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, November 1, 2017 at 01:30 PM - 02:30 PM PURPOSE: The GOLDEN Phase 3 studies in subjects with moderate-to-very-severe COPD assessed the efficacy and safety of a novel, nebulized glycopyrrolate (GLY) and were prospectively designed to include subjects with cardiovascular (CV) risk factors. METHODS: In two 12-week and one 48-week study, 2379 subjects were stratified by CV risk (high vs low) and randomized to placebo, GLY 25 or 50 mcg twice daily, or tiotropium (TIO; 18 mcg once daily). Safety, lung function, patient-reported outcomes and exacerbations were assessed by CV risk subgroup. RESULTS: Across studies, 1526 subjects were at high CV risk and 853 were at low CV risk. At week 12, the incidence of adverse events leading to discontinuation was similar in high and low CV risk subgroups and lower in GLY 25 and 50 mcg groups (high: 6.2% and 3.6%; low: 3.2% and 4.5%) than placebo (high: 9.0%; low: 9.9%). In the 48-week study, discontinuations were higher for GLY (high: 10.7%; low: 8.7%) vs TIO (3.7%; 1.2%, respectively), partly due to increased cough and COPD event rates. CV events of special interest were low in both CV risk subgroups, and generally similar between treatments at 12 weeks (high: placebo, 3.6%; GLY 25 mcg, 1.1%; GLY 50 mcg, 2.2%; low: 0.7%; 2.6%; 1.9%, respectively). Incidences at 48 weeks were similar in the high CV risk group and numerically higher for TIO than GLY in the low CV risk subgroup, particularly for arrhythmias (high: GLY, 5.0%; TIO, 5.1%; low: GLY, 2.3%; TIO, 4.1%). Major adverse cardiac events (MACE) occurred more frequently with placebo in the high CV risk subgroup at 12 weeks (incidence rate [IR] for high vs low: placebo, 25.1 vs 0; GLY 25 mcg, 0 vs 0; GLY 50 mcg, 24.3 vs 21.6). At 48 weeks, IR for MACE were higher for TIO than GLY (high vs low: GLY, 6.7 vs 6.0; TIO 24.3 vs 13.6). GLY led to statistically significant, clinically important improvements in trough forced expiratory volume in 1 second (FEV1) in high and low CV risk subgroups at week 12 vs placebo (25 mcg, 95 and 97 mL; 50 mcg, 99 and 113 mL, respectively, p<0.001). The overall change from baseline in trough FEV1 was similar across CV risk subgroups for GLY (100 and 94 mL) and TIO (84 and 107 mL) over 48 weeks’ treatment. At week 12, in both subgroups, GLY produced statistically significant improvements (p<0.05) vs placebo in St George’s Respiratory Questionnaire (SGRQ) and the proportion of GLY responders was consistently higher than placebo. Over 48 weeks, change from baseline in SGRQ was higher for GLY vs TIO in the high CV risk subgroup, as was the proportion of GLY SGRQ responders at 48 weeks (47% vs 39%). Change and response for the low risk group was numerically higher for TIO than GLY. Exacerbation rates were similar across all treatment groups and most exacerbations were moderate in severity in both subgroups after 12 and 48 weeks. CONCLUSIONS: Nebulized GLY had an acceptable safety/tolerability profile and improved lung function and patient-reported outcomes in subjects with COPD and CV risk factors for up to 48 weeks. CLINICAL IMPLICATIONS: Nebulized GLY is well tolerated and effective and provides a novel treatment option in patients who may require or benefit from nebulized long-acting muscarinic antagonist therapy. DISCLOSURE: Gary Ferguson: Grant monies (from industry related sources): Sunovion Pharmaceuticals Inc., Grant monies (from industry related sources): Boehringer Ingelheim, Other: Sunovion Pharmaceuticals Inc., Other: Boehringer Ingelheim Robert Tosiello: Employee: Sunovion Pharmaceuticals Inc. Thomas Goodin: Employee: Sunovion Pharmaceuticals Inc. Abstract describes analysis from Phase 3 trials of nebulized glycopyrrolate in COPD (not currently approved)