Abstract
BackgroundNavafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD.MethodsThis was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 2. Safety and tolerability were monitored throughout.ResultsThirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065–0.069 L, both P < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4–37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%).ConclusionsBoth doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised.Trial registryClinicalTrials.gov; No.: NCT02573155; URL: www.clinicaltrials.gov. Registered 9th October, 2015.
Highlights
Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD)
Whilst bronchodilator monotherapy is recommended for treatment initiation in many patients with COPD [1], there is considerable evidence that the combination of a long-acting muscarinic receptor antagonist (LAMA) with a long-acting β2-agonist (LABA) offers additional benefits over monotherapy [2, 3]
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommends a combination of a LAMA and Long-acting β2-adrenoceptor agonist (LABA) for treatment escalation, or initiation, in patients with greater symptom burden or exacerbation risk [1]
Summary
Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). Whilst bronchodilator monotherapy is recommended for treatment initiation in many patients with COPD [1], there is considerable evidence that the combination of a long-acting muscarinic receptor antagonist (LAMA) with a long-acting β2-agonist (LABA) offers additional benefits over monotherapy [2, 3]. The development of dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecules offers a new approach to the treatment of COPD [4]. These molecules combine two mechanisms of action within a single entity, offering potential advantages such as the delivery of a fixed ratio of LAMA/LABA activity into each lung region, simplification of technical and clinical development, and the potential for additive or synergistic bronchodilation over either entity alone [4, 5]. Its pharmacological profile has been extensively studied in preclinical investigations in vitro and in vivo, and these investigations have confirmed its dual action at β2- and muscarinic receptors [6]
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