The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease

References

• Global strategy for the diagnosis, management and prevention of COPD, global initiative for chronic obstructive lung disease (GOLD) 2017. [Internet]. 2017. [cited 2017 Nov 15]. Available from: http://goldcopd.org.
   Google Scholar
• Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J. 2006;27(2):397–412.
   PubMed Web of Science ®Google Scholar
• Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442.
   PubMed Web of Science ®Google Scholar
• Montuschi P, Ciabattoni G. Bronchodilating drugs for chronic obstructive pulmonary disease: current status and future trends. J Med Chem. 2015;58(10):4131–4164.
   PubMed Web of Science ®Google Scholar
• Dal Negro RW, Bonadiman L, Micheletto C, et al. Changes of clinical outcomes and health care resources in moderate and in severe COPD treated uniquely with tiotropium 18 mcg od for twenty-four months. Pulm Pharmacol Ther. 2011;24(4):373–376.
   PubMed Web of Science ®Google Scholar
• Gavalda A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther. 2009;331(2):740–751.
   PubMed Web of Science ®Google Scholar
• Prat M, Fernández D, Buil MA, et al. Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)ace. J Med Chem. 2009;52(16):5076–5092.
   PubMed Web of Science ®Google Scholar
• Sentellas S, Ramos I, Albertí J, et al. Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: in vitro plasma inactivation and pharmacological activity of its main metabolites. Eur J Pharm Sci. 2010;39(5):283–290.
   PubMed Web of Science ®Google Scholar
• Milara J, Serrano A, Peiró T, et al. Aclidinium inhibits human lung fibroblast to myofibroblast transition. Thorax. 2012;67(3):229–337.
   PubMed Web of Science ®Google Scholar
• Milara J, Serrano A, Peiró T, et al. Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition. Eur Respir. J. 2013;41(6):1264–1274.
   PubMed Web of Science ®Google Scholar
• Domínguez-Fandos D, Ferrer E, Puig-Pey R, et al. Effects of aclidinium bromide in a cigarette smoke-exposed guinea pig model of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2014;50:337–346.
   PubMed Web of Science ®Google Scholar
• Cortijo J, Mata M, Milara J, et al. Aclidinium inhibits cholinergic and tobacco smoke-induced MUC5AC in human airways. Eur Respir J. 2011;37:2.
   Web of Science ®Google Scholar
• Bretaris Genuair, INN-aclidinium bromide - European medicines agency - Summary of product characteristics [internet]. 2012 [cited 2017 Nov 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002706/WC500132732.pdf
   Google Scholar
• Duaklir, INN-aclidinium and formoterol - European medicines agency - Summary of product characteristics [internet]. 2014 [cited 2017 Nov 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003745/WC500178413.pdf
   Google Scholar
• Spiriva Handihaler - Summary of product characteristics [internet]. 2015 [cited 2017 Nov 15]. Available from: https://www.medicines.org.uk/emc/medicine/10039
   Google Scholar
• Spiriva Respimat - Summary of product characteristics [internet]. 2016 [cited 2017 Nov 15]. Available from: http://www.medicines.org.uk/emc/medicine/20134/SPC
   Google Scholar
• Spiolto Respimat - Summary of product characteristics [internet]. 2017 [cited 2017 Nov 15]. Available from: https://www.medicines.org.uk/emc/medicine/30495
   Google Scholar
• Seebri Breezhaler - European medicines agency - Summary of product characteristics [internet]. 2012 [cited 2017 Nov 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002430/WC500133769.pdf
   Google Scholar
• Ultibro Breezhaler - European medicines agency - Summary of product characteristics [internet]. 2013 [cited 2017 Nov 15]. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002679/WC500151255.pdf
   Google Scholar
• Incruse Ellipta - European medicines agency - Summary of product characteristics [internet]. 2014 [cited 2017 Nov 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002809/WC500167430.pdf
   Google Scholar
• Anoro Ellipta - Incruse Ellipta - European medicines agency - Summary of product characteristics [internet]. 2014 [cited 2017 Nov 15]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002751/WC500168424.pdf
   Google Scholar
• Belmonte KE. Cholinergic pathways in the lungs and anticholinergic therapy for chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(4):297–304.
   PubMedGoogle Scholar
• Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998;50(2):279–290.
   PubMed Web of Science ®Google Scholar
• van Koppen CJ, Blankesteijn WM, Klaassen AB, et al. Autoradiographic visualization of muscarinic receptors in pulmonary nerves and ganglia. Neurosci Lett. 1987;83(3):237–240.
   PubMed Web of Science ®Google Scholar
• Eglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev. 1996;48(4):531–565.
   PubMed Web of Science ®Google Scholar
• Gosens R, Zaagsma J, Meurs H, et al. Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res. 2006;7(1):73.
   PubMedGoogle Scholar
• Paredes-Gamero EJ, Medeiros VP, Farias EHC, et al. Heparin induces rat aorta relaxation via integrin-dependent activation of muscarinic M3 receptors. Hypertension. 2010;56(4):713–721.
   PubMed Web of Science ®Google Scholar
• Villetti G, Pastore F, Bergamaschi M, et al. Bronchodilator activity of (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino] carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407), a potent, long-acting, and selective muscarinic M3 receptor antagonist. J Pharmacol Exp Ther. 2010;335(3):622–635.
   PubMed Web of Science ®Google Scholar
• Scullion JE. The development of anticholinergics in the management of COPD. Int J Chron Obstruct Pulmon Dis. 2007;2(1):33–40.
   PubMedGoogle Scholar
• Barnes PJ. Bronchodilators: basic pharmacology. In: Chronic obstructive pulmonary disease. Calverley PMA, Pride NB (eds). Boston (MA): Springer US; 1995. p. 391–417.
   Google Scholar
• Melani AS. Long-acting muscarinic antagonists. Expert Rev Clin Pharmacol. 2015;8(4):479–501.
   PubMed Web of Science ®Google Scholar
• Kesten S, Jara M, Wentworth C, et al. Pooled clinical trial analysis of tiotropium safety. Chest. 2006;130(6):1695–1703.
   PubMed Web of Science ®Google Scholar
• Hanania NA, Lareau SC, Yawn BP. Safety of inhaled long-acting anti-muscarinic agents in COPD. Postgrad Med. 2017;129(5):500–512.
   PubMed Web of Science ®Google Scholar
• Cereda E, Ezhaya A, Gil Quintero M, et al. Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads. J Med Chem. 1990;33(8):2108–2113.
   PubMed Web of Science ®Google Scholar
• Doods HN. Selective muscarinic antagonists as bronchodilators. Agents Actions Suppl. 1991;34:117–130.
   PubMedGoogle Scholar
• Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J. 2012;40(4):830–836.
   PubMed Web of Science ®Google Scholar
• Kerwin EM, D’Urzo AD, Gelb AF, et al. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD. 2012;9(2):90–101.
   PubMedGoogle Scholar
• D’Urzo A, Kerwin E, Rennard S, et al. One-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPD. COPD. 2013;10(4):500–510.
   PubMedGoogle Scholar
• Rennard SI, Scanlon PD, Ferguson GT, et al. ACCORD COPD II: A randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patients. Clin Drug Investig. 2013;33(12):893–904.
   PubMed Web of Science ®Google Scholar
• Casarosa P, Bouyssou T, Germeyer S, et al. Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs. J Pharmacol Exp Ther. 2009;330(2):660–668.
   PubMed Web of Science ®Google Scholar
• Gavaldà A, Ramos I, Carcasona C, et al. The in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide. Pulm Pharmacol Ther. 2014;28(2):114–121.
   PubMed Web of Science ®Google Scholar
• Pera T, Zuidhof A, Valadas J, et al. Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD. Eur Respir J. 2011;38(4):789–796.
   PubMed Web of Science ®Google Scholar
• Jansat JM, Lamarca R, Garcia Gil E, et al. Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Int J Clin Pharmacol Ther. 2009;47(7):460–468.
   PubMed Web of Science ®Google Scholar
• Alberti J, Martinet A, Sentellas S, et al. Identification of the human enzymes responsible for the enzymatic hydrolysis of aclidinium bromide. Drug Metab Dispos. 2010;38(7):1202–1210.
   PubMed Web of Science ®Google Scholar
• Jansat JM, Lamarca R, de Miquel G, et al. Safety and pharmacokinetics of multiple doses of aclidinium bromide, a novel long-acting muscarinic antagonist for the treatment of chronic obstructive pulmonary disease, in healthy participants. J Clin Pharmacol. 2009;49(10):1239–1246.
   PubMed Web of Science ®Google Scholar
• Ortiz S, Flach S, Ho J, et al. Mass balance and metabolism of aclidinium bromide following intravenous administration of [14C]-aclidinium bromide in healthy subjects. Biopharm Drug Dispos. 2012;33(1):39–45.
   PubMed Web of Science ®Google Scholar
• Newman SP, Sutton DJ, Segarra R, et al. Lung deposition of aclidinium bromide from Genuair, a multidose dry powder inhaler. Respiration. 2009;78(3):322–328.
   PubMed Web of Science ®Google Scholar
• Schelfhout VJ, Ferrer P, Jansat JM, et al. Activity of aclidinium bromide, a new long-acting muscarinic antagonist: a phase I study. Br J Clin Pharmacol. 2010;69(5):458–464.
   PubMed Web of Science ®Google Scholar
• Lasseter K, Dilzer S, Jansat JM, et al. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers. Pulm Pharmacol Ther. 2012;25(2):193–199.
   PubMed Web of Science ®Google Scholar
• Hohlfeld JM, Sharma A, van Noord JA, et al. Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease. J Clin Pharmacol. 2014;54(4):405–414.
   PubMed Web of Science ®Google Scholar
• Schmid K, Pascual S, Gil EG, et al. Pharmacokinetics and safety of aclidinium bromide, a muscarinic antagonist, in adults with normal or impaired renal function: a phase I, open-label, single-dose clinical trial. Clin Ther. 2010;32(10):1798–1812.
   PubMed Web of Science ®Google Scholar
• Lasseter KC, Aubets J, Chuecos F, et al. Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects. J Clin Pharmacol. 2011;51(6):923–932.
   PubMed Web of Science ®Google Scholar
• de la Motte S, Beier J, Schmid K, et al. Pharmacokinetics and safety of aclidinium bromide in younger and elderly patients with chronic obstructive pulmonary disease. Int J Clin Pharmacol Ther. 2012;50(6):403–412.
   PubMed Web of Science ®Google Scholar
• Vestbo J, Vogelmeier C, Creemers J, et al. Onset of effect of aclidinium, a novel, long-acting muscarinic antagonist, in patients with COPD. COPD. 2010;7(5):331–336.
   PubMedGoogle Scholar
• Joos GF, Schelfhout VJ, Pauwels RA, et al. Bronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patients. Respir Med. 2010;104(6):865–872.
   PubMed Web of Science ®Google Scholar
• Chanez P, Burge PS, Dahl R, et al. Aclidinium bromide provides long-acting bronchodilation in patients with COPD. Pulm Pharmacol Ther. 2010;23(1):15–21.
   PubMed Web of Science ®Google Scholar
• Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest. 2012;141(3):745–752.
   PubMed Web of Science ®Google Scholar
• Singh D, Magnussen H, Kirsten A, et al. A randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patients. Pulm Pharmacol Ther. 2012;25(3):248–253.
   PubMed Web of Science ®Google Scholar
• Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res. 2011;12(1):55.
   PubMed Web of Science ®Google Scholar
• Maltais F, Celli B, Casaburi R, et al. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med. 2011;105(4):580–587.
   PubMed Web of Science ®Google Scholar
• Beeh KM, Watz H, Puente-Maestu L, et al. Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: randomized, placebo-controlled, crossover trial. BMC Pulm Med. 2014;14:209.
   PubMed Web of Science ®Google Scholar
• Gelb AF, Tashkin DP, Make BJ, et al. Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Respir Med. 2013;107(12):1957–1965.
   PubMed Web of Science ®Google Scholar
• Beier J, Kirsten A-M, Mróz R, et al. Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled phase IIIb study. COPD. 2013;10(4):511–522.
   PubMedGoogle Scholar
• Marth K, Schuller E, Pohl W. Improvements in patient-reported outcomes: a prospective, non-interventional study with aclidinium bromide for treatment of COPD. Respir Med. 2015;109(5):616–624.
   PubMed Web of Science ®Google Scholar
• Beier J, Mroz R, Kirsten AM, et al. Improvement in 24-hour bronchodilation and symptom control with aclidinium bromide versus tiotropium and placebo in symptomatic patients with COPD: post hoc analysis of a phase IIIb study. Int J COPD. 2017;12:1731–1740.
   Google Scholar
• Chapman KR, Beck E, Alcaide D, et al. Overall and cardiovascular safety of aclidinium bromide in patients with COPD: a pooled analysis of six phase III, placebo- controlled, randomized studies. Chronic Obstr Pulm Dis. 2015;3(1):435–445.
   PubMed Web of Science ®Google Scholar
• McGarvey L, Morice AH, Smith JA, et al. Effect of aclidinium bromide on cough and sputum symptoms in moderate-to-severe COPD in three phase III trials. BMJ Open Respir Res. 2016;3(1):e000148.
   PubMed Web of Science ®Google Scholar
• Wang J, Jin D, Zuo P, et al. Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology. 2011;16(2):350–358.
   PubMed Web of Science ®Google Scholar
• Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med. 2014;14(1):178.
   PubMed Web of Science ®Google Scholar
• D’Urzo AD, Rennard SI, Kerwin EM, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15(1):123.
   PubMed Web of Science ®Google Scholar
• 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(4):1030–1039.
   PubMed Web of Science ®Google Scholar
• Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015;16:92.
   PubMed Web of Science ®Google Scholar
• Miravitlles M, Chapman KR, Chuecos F, et al. The efficacy of aclidinium/formoterol on lung function and symptoms in patients with COPD categorized by symptom status: a pooled analysis. Int J COPD. 2016;11(1):2041–2052.
   Google Scholar
• Donohue JF, Soong W, Wu X, et al. Long-term safety of aclidinium bromide/formoterol fumarate fixed-dose combination: results of a randomized 1-year trial in patients with COPD. Respir Med. 2016;116:41–48.
   PubMed Web of Science ®Google Scholar
• D’Urzo A, Rennard S, Kerwin E, et al. A randomised double-blind, placebo-controlled, long-term extension study of the efficacy, safety and tolerability of fixed-dose combinations of aclidinium/formoterol or monotherapy in the treatment of chronic obstructive pulmonary disease. Respir Med. 2017;125:39–48.
   PubMed Web of Science ®Google Scholar
• Singh D, D’Urzo AD, Chuecos F, et al. Reduction in clinically important deterioration in chronic obstructive pulmonary disease with aclidinium/formoterol. Respir Res. 2017;18(1):106.
   PubMed Web of Science ®Google Scholar
• Ramos M, Haughney J, Henry N, et al. Cost versus utility of aclidinium bromide 400 µg plus formoterol fumarate dihydrate 12 µg compared to aclidinium bromide 400 µg alone in the management of moderate-to-severe COPD. Clin Outcomes Res. 2016;8:445–456.
   PubMed Web of Science ®Google Scholar
• Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;9(9):CD010509.
   Google Scholar
• Oba Y, Lone NA. Comparative efficacy of long-acting muscarinic antagonists in preventing COPD exacerbations: A network meta-analysis and meta-regression. Ther Adv Respir Dis. 2015;9(1):3–15.
   PubMed Web of Science ®Google Scholar
• Dong YH, Lin HH, Shau WY, et al. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48–56.
   PubMed Web of Science ®Google Scholar
• Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491–1501.
   PubMed Web of Science ®Google Scholar
• Marsh K, Zaiser E, Orfanos P, et al. Evaluation of COPD treatments: a multicriteria decision analysis of aclidinium and tiotropium in the United States. Value Heal. 2017;20(1):132–140.
   PubMed Web of Science ®Google Scholar
• Montuschi P, Malerba M, Macis G, et al. Triple inhaled therapy for chronic obstructive pulmonary disease. Drug Discov Today. 2016;21(11):1820–1827.
   PubMed Web of Science ®Google Scholar