Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD

GSK961081 is an inhaled bi-functional molecule with both muscarinic antagonism and β2-agonism (MABA) properties. This randomised, double-blind, double-dummy, crossover study evaluated 14 days treatment with the MABA GSK961081 400 μg and 1200 μg once daily and tiotropium 18 μg once daily plus salmeterol 50 μg twice daily (TIO + SAL), versus placebo in 50 patients with moderate COPD. The primary endpoint was forced expiratory volume in 1 s (FEV1) at 24 h on Days 1 and 14. MABA 400 (n = 29), MABA 1200 (n = 32) and TIO + SAL (n = 41) resulted in significant increases in FEV1 over 24 h. Mean (95% CI) 24 h trough FEV1 (L) values relative to placebo (n = 43) were, for Day 1, MABA 400: 0.141 (0.060, 0.222); MABA 1200: 0.184 (0.105, 0.263); TIO + SAL: 0.162 (0.092, 0.231); for Day 14, MABA 400: 0.115 (0.024, 0.205); MABA 1200: 0.168 (0.080, 0.255); TIO + SAL: 0.103 (0.026, 0.180). Onset of bronchodilation was faster for both MABA doses versus TIO + SAL. No clinically relevant systemic pharmacodynamic effects were observed. Adverse events were similar across groups; however tremor (n = 2, MABA 1200), dysgeusia (n = 2, MABA 1200; n = 2, MABA 400) and dry mouth (n = 1, MABA 1200) were reported after GSK961081 only. GSK961081 demonstrated sustained bronchodilation similar to TIO + SAL, but with a more rapid onset, and was well tolerated at the tested doses.