A randomized placebo controlled trial of AZD8999 (LAS190792) a novel dual acting bronchodilator in asthmatics

AZD8999 is an inhaled long-acting, dual muscarinic antagonist/β 2 adrenoceptor agonist (MABA) under development for the treatment of COPD and asthma. This was an ascending-dose first in man trial, designed to test safety, tolerability, pharmacokinetics and pharmacodynamics (bronchodilation) of AZD8999. Male, mild asthma patients 18-70 years were included. It was an interweaving cohort design; two alternating cohorts of 8 patients (6 active 2 placebo) progressively received increasing single doses of AZD8999 from 5-400 µg. 17 patients were randomized and 16 completed. All 6 doses were safe and well tolerated and no stopping criteria were met. Dosing was escalated to stay below pre-specified human exposure limits and the maximum tolerated dose was not reached. Overall, the most frequently reported adverse event was headache, experienced by 29.4% patients. There was 1 serious adverse event, not casually related to treatment and not leading to discontinuation. An improvement in the trough FEV 1 change from baseline was observed for all doses of AZD8999 ≥20 µg with a clinically meaningful response occurring at all doses ≥50 µg (mean change from baseline range 0.371-0.599 L). Bronchodilation was sustained over the 36 hour observation period following AZD8999 doses ≥20 µg. Concentrations were below the limit of quantification ( In conclusion, AZD8999 was safe, well tolerated and showed clinically-meaningful and sustained bronchodilation at doses of 50 µg and above.