Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD

References

• Matera MG, Page C, Cazzola M. PDE inhibitors currently in early clinical trials for the treatment of asthma. Expert Opin Investig Drugs. 2014;23(9):1267–1275.
   PubMed Web of Science ®Google Scholar
• Matera MG, Rogliani P, Calzetta L, et al. Phosphodiesterase inhibitors for chronic obstructive pulmonary disease: what does the future hold? Drugs. 2014;74(17):1983–1992.
   PubMed Web of Science ®Google Scholar
• Abusnina A, Lugnier C. Therapeutic potentials of natural compounds acting on cyclic nucleotide phosphodiesterase families. Cell Signal. 2017;39:55–65.
   PubMed Web of Science ®Google Scholar
• Fertig BA, Baillie GS. PDE4-mediated cAMP signalling. J Cardiovasc Dev Dis. 2018;5:8.
   Web of Science ®Google Scholar
• Abbott-Banner KH, Page CP. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases. Basic Clin Pharmacol Toxicol. 2014;114(5):365–376.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Calzetta L, Rogliani P, et al. The discovery of roflumilast for the treatment of chronic obstructive pulmonary disease. Expert Opin Drug Discov. 2016;11(7):733–744.
   PubMed Web of Science ®Google Scholar
• Rogliani P, Calzetta L, Cazzola M, et al. Drug safety evaluation of roflumilast for the treatment of COPD: a meta-analysis. Expert Opin Drug Saf. 2016;15(8):1133–1146.
   PubMed Web of Science ®Google Scholar
• Brescia M, Zaccolo M. Modulation of compartmentalised cyclic nucleotide signalling via local inhibition of phosphodiesterase activity. Int J Mol Sci. 2016;17(10):1672.
   PubMed Web of Science ®Google Scholar
• Page CP. Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol. 2014;165(3):152–164.
   PubMed Web of Science ®Google Scholar
• Spina D, Page CP. Xanthines and phosphodiesterase inhibitors. Handb Exp Pharmacol. 2017;237:63–91.
   PubMedGoogle Scholar
• Page C, Cazzola M. Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease. Eur Respir J. 2014;44(2):475–482.
   PubMed Web of Science ®Google Scholar
• Page C, Cazzola M. Bifunctional drugs for the treatment of respiratory diseases. Handb Exp Pharmacol. 2017;237:197–212.
   PubMedGoogle Scholar
• Giembycz MA, Maurice DH. Cyclic nucleotide-based therapeutics for chronic obstructive pulmonary disease. Curr Opin Pharmacol. 2014;16:89–107.
   PubMed Web of Science ®Google Scholar
• Beute J, Manganiello V, Klein JA. Phosphodiesterase 3 and 4 inhibition: facing a bright future in asthma control. In HKG H, CHS T, editors. Asthma diagnosis and management - approach based on phenotype and endotype. IntechOpen; 2018. DOI:10.5772/intechopen.74309
   Google Scholar
• Matera MG, Page CP, Cazzola M. Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol Sci. 2011;32(8):495–506.
   PubMed Web of Science ®Google Scholar
• Banner KH, Press NJ. Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol. 2009;157(6):892–906.
   PubMed Web of Science ®Google Scholar
• Brunnée T, Engelstätter R, Steinijans VW, et al. Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. Eur Respir J. 1992;5(8):982–985.
   PubMed Web of Science ®Google Scholar
• Foster RW, Rakshi K, Carpenter JR, et al. Trials of the bronchodilator activity of the isoenzyme-selective phosphodiesterase inhibitor AH 21-132 in healthy volunteers during a methacholine challenge test. Br J Clin Pharmacol. 1992;34(6):527–534.
   PubMed Web of Science ®Google Scholar
• Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2002;24(3):159–184.
   PubMedGoogle Scholar
• Ochiai K, Takita S, Kojima A, et al. Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. Bioorg Med Chem Lett. 2013;23(1):375–381.
   PubMed Web of Science ®Google Scholar
• Cazzola M, Page C, Calzetta L, et al. Ensifentrine (RPL554): an inhaled ‘bifunctional’ dual PDE3/4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease. Pharm Pat Anal. 2018;7(6):249–257.
   PubMed Web of Science ®Google Scholar
• Drug Approvals International. RPL 554. [cited 2019 Jun 27] . Available from: http://drugapprovalsint.com/rpl-554/
   Google Scholar
• Spina D, Ferlenga P, Biasini I, et al. The effect duration of selective phosphodiesterase inhibitors in the guinea pig. Life Sci. 1998;62(11):953–965.
   PubMed Web of Science ®Google Scholar
• Boswell-Smith V, Spina D, Oxford AW, et al. The pharmacology of two novel long-acting phosphodiesterase 3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(n-carbamoyl-2-aminoethyl)-3,4,6, 7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquino lin-4-one]. J Pharmacol Exp Ther. 2006;318(2):840–848.
   PubMed Web of Science ®Google Scholar
• Venkatasamy R, Spina D. Novel relaxant effects of RPL554 on guinea pig tracheal smooth muscle contractility. Br J Pharmacol. 2016;173(15):2335–2351.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Page CP, Spina D, et al. Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J Pharmacol Exp Ther. 2013;346(3):414–423.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Cazzola M, Page CP, et al. Long-lasting interaction study between RPL554 and glycopyrronium bromide on human isolated bronchi (abstract). Eur Respir J. 2014;44:P3334.
   Google Scholar
• Calzetta L, Cazzola M, Page CP, et al. Pharmacological characterization of the interaction between the dual phosphodiesterase (PDE) 3/4 inhibitor RPL554 and glycopyrronium on human isolated bronchi and small airways. Pulm Pharmacol Ther. 2015;32:15–23.
   PubMed Web of Science ®Google Scholar
• Turner MJ, Matthes E, Billet A, et al. The dual phosphodiesterase 3 and 4 inhibitor RPL554 stimulates CFTR and ciliary beating in primary cultures of bronchial epithelia. Am J Physiol Lung Cell Mol Physiol. 2016;310(1):L59–70.
   PubMed Web of Science ®Google Scholar
• Turner M, Thomas D, Hanrahan JW. The dual phosphodiesterase 3/4 inhibitor, RPL554, stimulates rare Class III and IV CFTR mutants (abstract). Pediatr Pulmonol. 2018;53(S2):150.
   Google Scholar
• Franciosi LG, Diamant Z, Banner KH, et al. Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials. Lancet Respir Med. 2013;1(9):714–727.
   PubMed Web of Science ®Google Scholar
• Singh D, Abbott-Banner KH, Reid F, et al. A phase I, randomised, double blind, placebo controlled, study to assess the safety, tolerability and pharmacokinetics of single inhaled doses of the dual phosphodiesterase 3/4 (PDE3/4) inhibitor RPL554 administered by nebuliser to healthy male subjects (abstract). Am J Respir Crit Care Med. 2016;193:A6839.
   Web of Science ®Google Scholar
• Newman KB, Armstrong M, Maurer BT, et al. Low oral bioavailability of RPL554, a first-in-class dual PDE3/4 inhibitor, demonstrates that its nebulized, inhaled formulation is appropriate for delivering optimal pulmonary dose (abstract). Am J Respir Crit Care Med. 2018;197:A3022.
   Web of Science ®Google Scholar
• Bjermer L, Abbott-Banner K, Newman K. Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma. Pulm Pharmacol Ther. 2019;58:101814.
   PubMed Web of Science ®Google Scholar
• Eneje OJ, Maurer B, Newman K, et al. A single dose of a novel nebulised PDE3/4 inhibitor RPL554 increased FEV1 in patients with cystic fibrosis and demonstrated a reproducible pharmacokinetic profile (abstract). Pediatr Pulmonol. 2018;53(S2):228.
   Google Scholar
• Franciosi L, Diamant Z, Morelli N, et al. A combined phase I/IIa study of the safety, bronchodilator and bronchoprotective effects of nebulized RPL554, a dual PDE3/4-inhibitor, in healthy subjects and asthmatics (abstract). Clin Transl Allergy. 2013;3(Suppl 1):O13.
   PubMedGoogle Scholar
• Singh D, Abbott-Banner K, Newman K. RPL554, an inhaled PDE3/4 inhibitor, causes profound and sustained bronchodilation in healthy volunteers and COPD patients (abstract). Eur Respir J. 2016;48:PA4052.
   Web of Science ®Google Scholar
• Singh D, Abbott-Banner K, Bengtsson T, et al. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018;52(5):1801074.
   PubMed Web of Science ®Google Scholar
• Maurer B, Singh D, Martinez F, et al. RPL554, a first-in-class dual PDE3/4 inhibitor, causes significant bronchodilation and symptom relief; a Phase 2b COPD study (abstract). Eur Respir J. 2018;52(suppl62):OA1940.
   Google Scholar
• Singh D, Maurer BT, Martinez FJ, et al. RPL554 (dual PDE3/4 enzyme inhibitor): baseline airway reversibility impacts immediate bronchodilation, in contrast to progressive symptom improvement (abstract). Am J Respir Crit Care Med. 2019;199:A3846.
   Web of Science ®Google Scholar
• Cazzola M, Page C. An inhaled “bifunctional” dual PDE3/4 inhibitor provides additional short-term improvements in lung function compared to existing classes of bronchodilator: implications for future treatment of COPD. Eur Respir J. 2018;52(5):1801675.
   PubMed Web of Science ®Google Scholar
• Pharma V. The search for better respiratory therapies. The goal for Verona Pharma is to build a strong clinical R&D pipeline to target debilitating respiratory diseases. [cited 2019 Aug 15]. Available from: http://www.veronapharma.com/our-science/
   Google Scholar
• Zuo H, Cattani-Cavalieri I, Musheshe N, et al. Phosphodiesterases as therapeutic targets for respiratory diseases. Pharmacol Ther. 2019;197:225–242.
   PubMed Web of Science ®Google Scholar
• Kleinjan A, Beute J, Ganesh K, et al. Targeting PDE3 abrogates the hallmarks of asthma in asthma models (abstract). Eur Respir J. 2018;52:PA3948.
   Web of Science ®Google Scholar
• Beute J, Lukkes M, Koekoek EP, et al. A pathophysiological role of PDE3 in allergic airway inflammation. JCI Insight. 2018;3(2):94888.
   PubMed Web of Science ®Google Scholar
• Nony P, Boissel JP, Lievre M, et al. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients: a meta-analysis. Eur J Clin Pharmacol. 1994;46(3):191–196.
   PubMed Web of Science ®Google Scholar
• Packer M, Carver J, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure.The PROMISE Study Research Group. N Engl J Med. 1991;325(21):1468–1475.
   PubMed Web of Science ®Google Scholar
• Roe AT, Frisk M, Louch WE. Targeting cardiomyocyte Ca2+ homeostasis in heart failure. Curr Pharm Des. 2015;21(4):431–448.
   PubMed Web of Science ®Google Scholar
• Page C, Pitchford S, Spina D. Development of new drugs for the treatment of respiratory diseases: from concept to the clinic. J Drug Deliv Sci. 2011;21(4):347–352.
   Web of Science ®Google Scholar