A randomized placebo controlled trial of AZD8871 a novel dual acting bronchodilator in asthmatics

Abstract

AZD8871 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 AZD8871. Mild asthma patients aged 18 to 70 years (males only) were included. It was an interweaving cohort design, two alternating cohorts of 8 patients (6 active 2 placebo) progressively received increasing single doses of AZD8871 from 50-2100 µg. 16 patients were randomized and 15 completed. All 6 doses were safe and well tolerated; there were no serious adverse events (AEs) 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. AEs reported by the highest number of patients were headache (10, 62.5%) and nasopharyngitis (7, 43.8%). No positive dose-response was observed with any specific treatment emergent AE. AZD8871 had a quick onset of action and a clear, dose ordered bronchodilator response. A sustained effect was observed over 24-36 hours following AZD8871 doses ≥200 µg. An improvement in trough FEV 1 change from baseline was observed for all doses with a clinically meaningful response occurring at all doses ≥200 µg (mean change from baseline range 0.218-0.463 L). AZD8871 plasma AUC and Cmax increased in a dose proportional manner. Peak plasma concentrations were achieved at 1 hour post dose. Mean derived terminal half-life was ~ 19 hours (calculated over a time period of 36 hours). In conclusion, AZD8871 was safe, well tolerated and showed sustained bronchodilation at doses 200-2100 µg.