Ensifentrine (RPL554): an inhaled ‘bifunctional’ dual PDE3/4 inhibitor for the treatment of asthma and chronic obstructive pulmonary disease
Abstract
Ensifentrine (RPL554), an inhaled ‘bifunctional’ dual phosphodiesterase 3/4 inhibitor that exhibits both bronchodilator and anti-inflammatory activities, provides a new option in the treatment of chronic obstructive pulmonary disease (COPD) and other inflammatory airway diseases that are under clinical development. Ensifentrine appears to be initially under development for the treatment of COPD although it is not yet clear whether it should be understood as an add-on therapy in patients for the treatment of acute exacerbations of COPD or for the regular maintenance treatment of patients either alone, or on top of existing drug classes.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Are phosphodiesterase 4 inhibitors just more theophylline? J. Allergy. Clin. Immunol. 117(6), 1237–1243 (2006).
- 2 . Xanthines and phosphodiesterase inhibitors. Handb. Exp. Pharmacol. 237, 63–91 (2017).
- 3 The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C(4)-induced contractions in passively sensitized human airways. Br. J. Pharmacol. 131(8), 1607–1618 (2000).
- 4 . A major functional role for phosphodiesterase 4D5 in human airway smooth muscle cells. Am. J. Respir. Cell Mol. Biol. 38(1), 1–7 (2008).
- 5 . Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases. Basic Clin. Pharmacol. Toxicol. 114(5), 365–376 (2014).
- 6 A pathophysiological role of PDE3 in allergic airway inflammation. JCI Insight 3(2), e94888 (2018).
- 7 . Phosphodiesterase expression in human epithelial cells. Am. J. Physiol. 275(4 Pt 1), L694–L700 (1998).
- 8 . Oxidative stress-induced glucocorticoid resistance is prevented by dual PDE3/4 inhibition in human alveolar macrophages. Clin. Exp. Allergy 41(4), 535–546 (2011).
- 9 . Modulation of spasmogen-stimulated Ins(1,4,5)P3 generation and functional responses by selective inhibitors of types 3 and 4 phosphodiesterase in airways smooth muscle. Br. J. Pharmacol. 124(1), 47–54 (1998).
- 10 . Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br. J. Pharmacol. 157(6), 892–906 (2009).
- 11 . Bifunctional drugs for the treatment of respiratory diseases. Handb. Exp. Pharmacol. 237, 197–212 (2017).
- 12 . Novel bronchodilators for the treatment of chronic obstructive pulmonary disease. Trends Pharmacol. Sci. 32(8), 495–506 (2011).
- 13 . Phosphodiesterase 4-dependent regulation of cyclic AMP levels and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes. Eur. J. Pharmacol. 367(2–3), 343–350 (1999).
- 14 . 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]isoquinolin-4-one]. J. Pharmacol. Exp. Ther. 318(2), 840–848 (2006). • Fundamental article that illustrates the preclinical development of RPL554.
- 15 The effect duration of selective phosphodiesterase inhibitors in the guinea pig. Life Sci. 62(11), 953–965 (1998).
- 16 . Pharmacodynamische effekte oraler Einzeldosen des vasodilators HL 725 an gesunden mannlichen Probanden. In: Miehlke K (Ed.). Verhandlungen der Deutschen Gesellschaft für innere Medizin: 90. Kongress. Springer, Berlin u.a (1984).
- 17 Dynamic activation of cystic fibrosis transmembrane conductance regulator by type 3 and type 4D phosphodiesterase inhibitors. J. Pharmacol. Exp. Ther. 314(2), 846–854 (2005).
- 18 Effect of the mixed phosphodiesterase 3/4 inhibitor RPL554 on human isolated bronchial smooth muscle tone. J. Pharmacol. Exp. Ther. 346(3), 414–423 (2013). •• Demonstrates that RPL554 relaxes human bronchi and that it can interact with a muscarinic receptor antagonist to produce a synergistic inhibition of airway smooth muscle tone.
- 19 . 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. 32, 15–23 (2015). • RPL554 and glycopyrronium demonstrated a synergistic interaction in relaxing both human medium and small isolated bronchi, in terms of peak relaxation and an extended duration of action, suggesting that this combination may have a beneficial role in the treatment of asthma or chronic obstructive pulmonary disease (COPD).
- 20 . Novel relaxant effects of RPL554 on guinea pig tracheal smooth muscle contractility. Br. J. Pharmacol. 173(15), 2335–2351 (2016).
- 21 . RPL554, a dual phosphodiesterase (PDE) 3/4 inhibitor acts synergistically with muscarinic receptor antagonists and beta-adrenoceptor agonists to produce bronchodilation in vivo. Am. J. Respir. Crit. Care Med. 189, A4218 (2014).
- 22 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. 310(1), L59–L70 (2016).
- 23 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. 1(9), 714–727 (2013). • A preliminary study documenting that inhaled RPL554 is an effective and well-tolerated bronchodilator, bronchoprotector and anti-inflammatory drug in asthma and COPD.
- 24 . A Phase I, randomised, double blind, placebo controlled, study to assess the safety, tolerability and pharmacokinetics of multiple inhaled doses of RPL554 administered by nebuliser to healthy male subjects and stable COPD patients. Am. J. Respir. Crit. Care Med. 193, A6838 (2016). • An interesting study that documents the value of using RPL554 as an add-on drug in the treatment of COPD.
- 25 . RPL554, an inhaled PDE3/4 inhibitor, causes comparable bronchodilation to high dose nebulised salbutamol in asthmatics with fewer systemic effects. Eur. Respir. J. 48, PA4905 (2016).
- 26 . Verona's RPL554 improves lung function in CF trial (2018). www.pharmatimes.com/news/veronas_rpl554_improves_lung_function_in_cf_trial_1225272.
- 27 . 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. Am. J. Respir. Crit. Care Med. 197, A3022 (2018).
- 28 . RPL554, an inhaled PDE3/4 inhibitor, causes profound and sustained bronchodilation in healthy volunteers and COPD patients. Eur. Respir. J. 48, PA4052 (2016).
- 29 . The novel inhaled dual PDE3/4 inhibitor RPL554 produces significant additional improvements in lung function when administered on top of existing standard of care in COPD patients. Eur. Respir. J. 48, OA1970 (2016).
- 30 . RPL554, a first-in-class dual PDE3/4 inhibitor, causes rapid additional bronchodilation when dosed with tiotropium in COPD patients. Am. J. Respir. Crit. Care Med. 197, A4227 (2018).
- 31 . Verona's RPL554 seems to improve COPD lung function, trial results show (2018). https://copdnewstoday.com/2018/04/03/verona-rpl554-improves-copd-lung-function-phase-2-trial/.
- 32 Anonymous. Verona Pharma begins Phase ll trial of RPL554 for COPD (2018). www.drugdevelopment-technology.com/news/verona-pharma-begins-phase-ll-trial-rpl554-copd/.
- 33 Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62(12), 1081–1087 (2007).
- 34 . Roflumilast for asthma: efficacy findings in mechanism of action studies. Pulm. Pharmacol. Ther. 35(Suppl.), S4–S10 (2015).
- 35 A novel model-based approach for dose determination of glycopyrronium bromide in COPD. BMC Pulm. Med. 12, 74 (2012).
- 36 . Muscarinic receptor antagonists. Handb. Exp. Pharmacol. 237, 41–62 (2017).
- 37 . Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur. Respir. J. 19(4), 639–644 (2002).
- 38 Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthma versus controls. Eur. Respir. J. 42(3), 662–670 (2013).