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

Dave Singh, Jutta Beier, Carol Astbury, Maria G Belvisi, Carla A Da Silva, Alexandra Jauhiainen, Eulalia Jimenez, Alejhandra Lei, Sofia Necander, Jaclyn A Smith, Ulrika Wählby Hamrén, Wenjing Xin, Ioannis Psallidas, Dave Singh, Jutta Beier, Carol Astbury, Maria G Belvisi, Carla A Da Silva, Alexandra Jauhiainen, Eulalia Jimenez, Alejhandra Lei, Sofia Necander, Jaclyn A Smith, Ulrika Wählby Hamrén, Wenjing Xin, Ioannis Psallidas

Abstract

Background: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and β-agonist, developed for the treatment of 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.

Methods: This 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 forced expiratory volume in 1 s (FEV1) on day 15. Secondary end-points 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.

Results: 73 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.

Conclusion: Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.

Conflict of interest statement

Conflict of interest: D. Singh has received grants and personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Behring, Epiendo, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Sanofi, Teva, Theravance and Verona, and personal fees from Cipla, Genentech and Peptinnovate. J. Beier has received consultation fees from AstraZeneca, Berlin Chemie/Menarini, Chiesi and Pohl-Boskamp, and participated in scientific advisory boards that were funded by AstraZeneca and Chiesi. C. Astbury, M.G. Belvisi, C.A. Da Silva, A. Jauhiainen, E. Jimenez, A. Lei, S. Necander, U. Wählby Hamrén, W. Xin and I. Psallidas are employees of AstraZeneca and may hold stock or stock options. The VitaloJAK algorithm has been licensed by Manchester University Foundation Trust (MFT) and the University of Manchester to Vitalograph Ltd and Vitalograph Ireland (Ltd); MFT receives royalties which may be shared with the clinical division in which J.A. Smith works, and J.A. Smith has received personal fees from AstraZeneca.

Copyright ©The authors 2022.

Figures

FIGURE 1
FIGURE 1
a) Study design; b) patient disposition. UMEC/VI: umeclidinium/vilanterol; FEV1: forced expiratory volume in 1 s; AE: adverse event.
FIGURE 2
FIGURE 2
a) Least squares (LS) mean change from baseline in trough forced expiratory volume in 1 s (FEV1) at day 15. b) LS mean change from baseline in peak FEV1 at day 14. UMEC/VI: umeclidinium/vilanterol.
FIGURE 3
FIGURE 3
Forced expiratory volume in 1 s (FEV1) over 24 h on day 1 and day 14. LS: least-squares; UMEC/VI: umeclidinium/vilanterol. *: p<0.05, significant difference between navafenterol and UMEC/VI.
FIGURE 4
FIGURE 4
Effect of treatment on the symptoms of COPD, as measured by a) the COPD Assessment Tool (CAT) and b) the Breathlessness, Cough and Sputum Scale (BCSS). LS: least-squares; UMEC/VI: umeclidinium/vilanterol.
FIGURE 5
FIGURE 5
Relative change from baseline (geometric mean (Gmean) ratios) in objective cough count for day 14 over a) 0–4 h post-dose, b) 0–12 h post-dose and c) 0–24 h post-dose. UMEC/VI: umeclidinium/vilanterol.

References

    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) . Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease. Date last updated: 2020. Date last accessed: 10 July 2021.
    1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3: e442. doi:10.1371/journal.pmed.0030442
    1. Rennard SI, Drummond MB. Early chronic obstructive pulmonary disease: definition, assessment, and prevention. Lancet 2015; 385: 1778. doi:10.1016/S0140-6736(15)60647-X.
    1. Miravitlles M, Ribera A. Understanding the impact of symptoms on the burden of COPD. Respir Res 2017; 18: 67. doi:10.1186/s12931-017-0548-3
    1. Cook N, Gey J, Oezel B, et al. . Impact of cough and mucus on COPD patients: primary insights from an exploratory study with an online patient community. Int J Chron Obstruct Pulmon Dis 2019; 14: 1365–1376. doi:10.2147/COPD.S202580
    1. Ray R, Tombs L, Naya I, et al. . Efficacy and safety of the dual bronchodilator combination umeclidinium/vilanterol in COPD by age and airflow limitation severity: a pooled post hoc analysis of seven clinical trials. Pulm Pharmacol Ther 2019; 57: 101802. doi:10.1016/j.pupt.2019.101802
    1. Maltais F, Bjermer L, Kerwin EM, et al. . Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial. Respir Res 2019; 20: 238. doi:10.1186/s12931-019-1193-9
    1. Calzetta L, Matera MG, Rogliani P, et al. . Dual LABA/LAMA bronchodilators in chronic obstructive pulmonary disease: why, when, and how. Expert Rev Respir Med 2018; 12: 261–264. doi:10.1080/17476348.2018.1442216
    1. Cazzola M, Lopez-Campos JL, Puente-Maestu L. The MABA approach: a new option to improve bronchodilator therapy. Eur Respir J 2013; 42: 885–887. doi:10.1183/09031936.00067013
    1. Matera MG, Page CP, Calzetta L, et al. . Pharmacology and therapeutics of bronchodilators revisited. Pharmacol Rev 2020; 72: 218–252. doi:10.1124/pr.119.018150
    1. Aparici M, Carcasona C, Ramos I, et al. . Pharmacological profile of AZD8871 (LAS191351), a novel inhaled dual M3 receptor antagonist/β2-adrenoceptor agonist molecule with long-lasting effects and favorable safety profile. J Pharmacol Exp Ther 2019; 370: 127–136. doi:10.1124/jpet.118.255620
    1. Singh D, Balaguer V, Astbury C, et al. . Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, long-acting, dual-pharmacology bronchodilator. Respir Res 2020; 21: 102. doi:10.1186/s12931-020-01347-7
    1. Singh D, Fuhr R, Jimenez L, et al. . A randomized trial of dual-acting bronchodilator AZD8871 for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2019; 199: 1282–1284. doi:10.1164/rccm.201812-2345LE
    1. Smith J, Woodcock A. Cough and its importance in COPD. Int J Chron Obstruct Pulmon Dis 2006; 1: 305–314. doi:10.2147/copd.2006.1.3.305
    1. CONSORT . CONSORT 2010 Checklist of Information to Include When Reporting a Randomised Trial. Available from: Date last updated: 2010. Date last accessed: 2 June 2021.
    1. DeVries R, Kriebel D, Sama S. Validation of the breathlessness, cough and sputum scale to predict COPD exacerbation. NPJ Prim Care Respir Med 2016; 26: 16083. doi:10.1038/npjpcrm.2016.83
    1. Leidy NK, Rennard SI, Schmier J, et al. . The breathlessness, cough, and sputum scale: the development of empirically based guidelines for interpretation. Chest 2003; 124: 2182–2191. doi:10.1378/chest.124.6.2182
    1. Jones PW, Harding G, Berry P, et al. . Development and first validation of the COPD Assessment Test. Eur Respir J 2009; 34: 648–654. doi:10.1183/09031936.00102509
    1. Smith JA, Holt K, Dockry R, et al. . Performance of a digital signal processing algorithm for the accurate quantification of cough frequency. Eur Respir J 2021; 58: 2004271.10.1183/13993003.04271-2020
    1. Spinou A, Birring SS. An update on measurement and monitoring of cough: what are the important study endpoints? J Thorac Dis 2014; 6: S728–S734.
    1. Lodhi S, Smith JA, Satia I, et al. . Cough rhythms in asthma: potential implication for management. J Allergy Clin Immunol Pract 2019; 7: 2024–2027. doi:10.1016/j.jaip.2018.12.020
    1. Cazzola M, Hanania NA, MacNee W, et al. . A review of the most common patient-reported outcomes in COPD – revisiting current knowledge and estimating future challenges. Int J Chron Obstruct Pulmon Dis 2015; 10: 725–738. doi:10.2147/COPD.S77368
    1. Smith J, Owen E, Earis J, et al. . Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol 2006; 117: 831–835. doi:10.1016/j.jaci.2005.09.055
    1. Smith J, Owen E, Earis J, et al. . Cough in COPD: correlation of objective monitoring with cough challenge and subjective assessments. Chest 2006; 130: 379–385. doi:10.1016/S0012-3692(15)51851-5
    1. Marsden PA, Satia I, Ibrahim B, et al. . Objective cough frequency, airway inflammation, and disease control in asthma. Chest 2016; 149: 1460–1466. doi:10.1016/j.chest.2016.02.676
    1. Satia I, Watson R, Scime T, et al. . Allergen challenge increases capsaicin-evoked cough responses in patients with allergic asthma. J Allergy Clin Immunol 2019; 144: 788–795. doi:10.1016/j.jaci.2018.11.050
    1. Sumner H, Woodcock A, Kolsum U, et al. . Predictors of objective cough frequency in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187: 943–949. doi:10.1164/rccm.201211-2000OC
    1. Nguyen AM, Muccino D, Birring S, et al. . Defining minimal clinically important differences (MCID) in chronic cough: analyses of objective cough counts from a phase 2 randomized controlled trial. J Allergy Clin Immunol 2019; 143: Suppl., AB169. doi:10.1016/j.jaci.2018.10.047
    1. Müller V, Gálffy G, Orosz M, et al. . Characteristics of reversible and nonreversible COPD and asthma and COPD overlap syndrome patients: an analysis of salbutamol Easyhaler data. Int J Chron Obstruct Pulmon Dis 2016; 11: 93–101.
    1. Maleki-Yazdi MR, Kaelin T, Richard N, et al. . Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med 2014; 108: 1752–1760. doi:10.1016/j.rmed.2014.10.002
    1. Donohue JF, Niewoehner D, Brooks J, et al. . Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res 2014; 15: 78. doi:10.1186/1465-9921-15-78
    1. Vogelmeier C, Paggiaro PL, Dorca J, et al. . Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. Eur Respir J 2016; 48: 1030–1039. doi:10.1183/13993003.00216-2016
    1. Ora J, Coppola A, Cazzola M, et al. . Long-acting muscarinic antagonists under investigational to treat chronic obstructive pulmonary disease. J Exp Pharmacol 2020; 12: 559–574. doi:10.2147/JEP.S259330
    1. Crim C, Gotfried M, Spangenthal S, et al. . A randomized, controlled, repeat-dose study of batefenterol/fluticasone furoate compared with placebo in the treatment of COPD. BMC Pulm Med 2020; 20: 119. doi:10.1186/s12890-020-1153-7

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