Sustained efficacy of multiple doses of extrafine glycopyrronium bromide in COPD patients

Background: CHF 5259 is a twice daily inhaled long-acting muscarinic antagonist (glycopyrronium bromide, GB) in development in an extrafine fixed dose combination with beclomethasone dipropionate plus formoterol (Foster®) in a metered dose inhaler for the treatment of COPD Methods: This study was a randomized, double-blind, placebo-controlled, 4-period, 4-treatment, repeated dose cross-over design followed by an open-label extension period with tiotropium, to evaluate the bronchodilator effect and to assess the safety and tolerability of repeated doses of extrafine GB via a pressurised metered dose inhaler (pMDI). The study comprised a total of five 8-day repeated-dose periods, separated by a 7-day wash-out period. In the first four periods, the patients were administered GB (3 dose levels: 12.5, 25, and 50 μg twice a day) or placebo according to a cross-over design. The fifth period was an open-label period with tiotropium (18 μg once a day). The primary endpoint was to evaluate the trough FEV1 at 12 h post-dose on Day 7. Other lung function parameters were evaluated as well as the safety, tolerability and the pharmacokinetic (PK) profile of GB at steady state. Results Thirty eight COPD patients were randomized (mean age: 57.5 years, mean baseline FEV1: 52% of the predicted normal value). For the primary endpoint (trough FEV1 12 h post-dose on Day 7) GB (at all dose levels) showed highly significant improvements (mean difference >110 ml, p<0.001) versus placebo. All doses of GB were superior to placebo for peak FEV1, AUC 0-12h on Day 7 and pre-dose FEV1 on Day 8 (p<0.001). In the comparison between GB dose levels, a statistically significantly higher peak FEV1 was reached for GB 50 μg compared to GB 25 μg (p < 0.05). Both GB doses of 50 and 100 μg were statistically superior to GB 25 μg in pre-dose FEV1 on Day 8 (p< 0.05). In general, the improvement at 50 μg and 100 μg GB doses was similar to tiotropium, , although the improvement of pre-dose FEV1 at Day 8 was statistically significantly greater than with tiotropium (p<0.05). Conclusion: Multiple dose administration in moderate to severe COPD patients of extrafine GB up to 100 μg for 8 days provided clinically meaningful effect with overall efficacy similar to tiotropium. GB is well tolerated in moderate to severe COPD patients. (Table Presented).