The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD

Abstract

BackgroundNavafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and beta agonist (MABA), being developed for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD.MethodsThis phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol [UMEC/VI]; 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough FEV1 on day 15. Secondary endpoints included: change from baseline in peak FEV1; change from baseline in breathlessness, cough and sputum scale (BCSS); change from baseline in COPD assessment tool (CAT); adverse events; and pharmacokinetics.ResultsSeventy-three participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares [LS] mean difference 0.202 L; p<0.0001). There was no significant difference in FEV1 between navafenterol and UMEC/VI (LS mean difference −0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period.ConclusionOnce-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.

The future of inhalation therapy in chronic obstructive pulmonary disease

“…Navafenterol or AZD8871/LAS191351 at a dose of 400 ​μg caused significant and sustained bronchodilation that was superior to that induced by placebo, and at a dose of 1800 ​μg was more effective than 150 ​μg indacaterol or 18 ​μg tiotropium, without eliciting the occurrence of adverse events ( Singh et al., 2020a ). Furthermore, at a dose of 600 ​μg once daily it provoked FEV 1 changes in patients with COPD similar to those observed with umeclidinium/vilanterol 62.5/25 ​μg once daily ( Singh et al., 2021 ). CHF6366 is another interesting MABA.…”

Contemporary Concise Review 2022: Chronic obstructive pulmonary disease

“…Although there were small significant changes in lung function in the BD group, health status was unaffected 51 . By contrast, combining long‐acting beta‐agonist and anti‐muscarinic properties in a single molecule is now possible and the novel compound navafenterol proved to be at least as effective as the dual BD combinations in reducing symptoms and improving lung function 52 …”

Pathophysiology, Therapeutic Targets, and Future Therapeutic Alternatives in COPD: Focus on the Importance of the Cholinergic System

“…A phase II study has demonstrated lung function improvements compared with placebo with an acceptable tolerability profile in patients treated with inhaled batefenterol plus fluticasone once daily [ 78 ]. Navafenterol (AZD8871) is a MABA that has undergone a phase IIa three-way crossover study that compared 2 weeks’ treatment with inhaled navafenterol, inhaled umeclidinium plus vilanterol, and placebo [ 79 ]. Navafenterol was well tolerated and demonstrated significant improvements in trough FEV 1 versus placebo (mean difference 0.202 L; p < 0.0001); no significant difference versus umeclidinium plus vilanterol was observed [ 79 ].…”

“…Navafenterol (AZD8871) is a MABA that has undergone a phase IIa three-way crossover study that compared 2 weeks’ treatment with inhaled navafenterol, inhaled umeclidinium plus vilanterol, and placebo [ 79 ]. Navafenterol was well tolerated and demonstrated significant improvements in trough FEV 1 versus placebo (mean difference 0.202 L; p < 0.0001); no significant difference versus umeclidinium plus vilanterol was observed [ 79 ]. It is currently unclear if clinical development of batefenterol or navafenterol will proceed further.…”