The Effect of Concurrent Bronchodilator Therapy on the Efficacy and Safety of a Novel, Nebulized Glycopyrrolate in Phase 3 Studies in Subjects With Moderate to Very Severe COPD

Abstract

SESSION TITLE: COPD: Advances in Pharmacotherapy SESSION TYPE: Original Investigation Slide PRESENTED ON: Tuesday, October 31, 2017 at 11:00 AM - 12:15 PM PURPOSE: The GOLDEN Phase 3 studies assessed the efficacy and safety of a novel, nebulized glycopyrrolate (GLY) for up to 48 weeks, and included subjects on stable doses of long-acting β2-agonists (LABA) ± inhaled corticosteroids (ICS) who continued background therapy over the treatment period. METHODS: In two 12-week placebo-controlled studies and one 48-week active-controlled study, 2379 subjects were stratified by background LABA±ICS (LABA-yes [n=861] vs LABA-no [n=1518]) and randomized to placebo, GLY 25 or 50 mcg twice daily (BID) via an investigational eFlow Closed System nebulizer (PARI Pharma, Germany), or tiotropium (TIO; 18 mcg once daily). Lung function, patient-reported outcomes, exacerbations and safety were assessed in the LABA subgroups. Statistical methodology included mixed-model repeated measures, analysis of covariance and descriptive safety data. RESULTS: GLY 25 and 50 mcg BID produced statistically significant and clinically important improvements vs placebo in trough forced expiratory volume in 1 second (FEV1; 92-110 mL, p<0.001) in LABA subgroups at week 12. The overall change from baseline in trough FEV1 was similar for GLY 50 mcg BID and TIO (92-106 mL) in both LABA subgroups at week 48. At 12 weeks, GLY produced statistically significant improvements in SGRQ in LABA subgroups (-2.073 to -3.888 vs placebo, p<0.05), and the proportion of SGRQ responders was consistently higher with GLY 25 and 50 mcg BID (LABA-yes: 48.3%, 43.4%; LABA-no: 46.1%, 40.9%) than placebo (yes: 24.8%; no: 38.7%). Over 48 weeks, change from baseline SGRQ in the LABA-yes subgroup was -5.190 for GLY and -3.094 for TIO, and -4.368 and -4.821, respectively, in the LABA-no subgroup. The proportion of GLY SGRQ responders was higher in the LABA-yes (53.7% vs 41.1% TIO) and similar to TIO in the LABA-no (42.6% vs 48.8% TIO) subgroups after 48 weeks. Exacerbation rates were generally similar across treatments and most were moderate in severity in both LABA subgroups after 12 and 48 weeks. The incidence of adverse events leading to discontinuation was similar in the LABA subgroups and less frequent in the GLY groups compared to placebo at 12 weeks. There was a higher discontinuation rate in the GLY LABA subgroups, with higher overall cough and COPD incidence rates (IRs) vs TIO. Cardiovascular events of special interest were more frequent in the LABA-no subgroup with generally similar IRs between treatments in LABA subgroups at 12 and 48 weeks. At 12 weeks, there were two major adverse cardiac events (MACE; IR per thousand patient-years=23.6) in the placebo LABA-no group and three MACE (IR=33.9) in the GLY 50 mcg BID LABA-no group. The MACE IRs in the TIO group were numerically higher than GLY in both LABA subgroups at 48 weeks. CONCLUSIONS: Nebulized GLY improved lung function and patient-reported outcomes with an acceptable safety/tolerability profile in subjects with COPD, with and without background LABA±ICS, for up to 48 weeks. CLINICAL IMPLICATIONS: Nebulized GLY is well tolerated and effective when administered with or without concurrent bronchodilator therapy and provides a novel treatment option for patients who may require or benefit from nebulized LAMA therapy. DISCLOSURE: Edward Kerwin: Consultant fee, speaker bureau, advisory committee, etc.: Sunovion Robert Tosiello: Employee: Sunovion Pharmaceuticals Inc. Barry Price: 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)