Dose-Related Efficacy of GSK573719: A Long-Acting Muscarinic Receptor Antagonist (LAMA) With Sustained 24-Hour Activity in COPD

Abstract

PURPOSE: This was a phase IIb dose-ranging study for GSK573719, an inhaled LAMA with sustained 24-hour activity under development as a once-daily therapy alone and in combination with the long-acting beta2 agonist vilanterol for the treatment of COPD. The study objectives were to evaluate the efficacy, dose response, safety and pharmacokinetics of GSK573719 in patients with COPD. METHODS: This was a multicenter, randomized, double-blind, double-dummy, placebo-controlled, three-way cross-over, incomplete block study evaluating five doses of GSK573719 administered once daily (62.5-1000mcg) and three doses twice daily (62.5-250mcg) via a novel single-step activation dry powder inhaler in patients (N=176) with COPD (FEV1 > 35 and < 70% predicted). Tiotropium (18mcg, open-label) was an active control. The primary endpoint was morning trough FEV1 after 14 days of treatment. RESULTS: All doses of GSK573719 significantly increased trough FEV1 at Day 15 with improvements ranging from 95-186mL over placebo (p < 0.006) with oncedaily dosing and from 79-172mL with twice-daily dosing (p < 0.03). A 105mL increase was observed for tiotropium. All once-daily doses of GSK573719 significantly (p<0.001) increased 0-24 hour weighted mean FEV1 at Day 14 by 131 -143mL over placebo, similar to increases with twice-daily dosing (120-142mL) and tiotropium (127mL). All doses of GSK573719 significantly reduced rescue albuterol use, except 62.5mcg and 1000mcg once daily. Across all doses, plasma Cmax on Day 14 occurred at a median tmax of 5-15 minutes; steady-state was achieved by Day 7. No correlations between Cmax and heart rate were observed. GSK573719 was well tolerated at all doses, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters. CONCLUSIONS: Once-daily dosing with GSK573719 in patients with COPD provides clinically significant and sustained improvement in lung function over 24 hours with similar efficacy to twice-daily dosing. CLINICAL IMPLICATIONS: Further development of GSK573719 may provide an alternative to currently available long-acting bronchodilators for the treatment of COPD.