Bronchodilator Efficacy Of Extrafine Glycopyrronium Bromide: The Glyco 2 Study

An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 mu g versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 mu g twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 mu g once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 mu g. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV1) area under the curve (AUC(0-12h)) and peak FEV1, with a trend toward greater efficacy with higher GB dose. All adverse events were mild-moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose-response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV1 on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 mu g BID, respectively (all P<0.001). GB 25 and 50 mu g BID were superior (P<0.05) to GB 12.5 mu g BID for pre-dose morning FEV1 on Day 8. For this endpoint, GB 25 and 50 mu g BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV1 peak and AUC0-12h with all GB doses and placebo (all P<0.001). All adverse events were mild-moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 mu g BID is the optimal dose in patients with COPD.