The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD

Dave Singh, Katharine Abbott-Banner, Thomas Bengtsson, Kenneth Newman, Dave Singh, Katharine Abbott-Banner, Thomas Bengtsson, Kenneth Newman

Abstract

We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo. Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days. Forced expiratory volume in 1 s (FEV1), lung volumes and specific airway conductance (sG aw) were measured.In study 1, peak FEV1 change compared with placebo was similar with RPL554, ipratropium and salbutamol (mean 223, 199 and 187 mL, respectively). The peak FEV1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL; p<0.0001) and RPL554+salbutamol versus salbutamol (mean difference 108 mL; p<0.0001). In study 2 (day 3), both RPL554 doses caused greater peak FEV1 effects than placebo. The average FEV1 (0-12 h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL; p=0.0009). In both studies, lung volumes and sG aw showed greater RPL554 combination treatment effects versus monotherapy.RPL554 combined with standard bronchodilators caused additional bronchodilation and hyperinflation reduction.

Trial registration: ClinicalTrials.gov NCT02542254 NCT03028142.

Conflict of interest statement

Conflict of interest: D. Singh reports receiving personal fees from Verona during the conduct of the study; and personal fees from Apellis, Cipla, Genentech, Peptinnovate and Skyepharma, and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Menarini, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Therevance and Verona, outside the submitted work. Conflict of interest: K. Abbott-Banner has nothing to disclose. Conflict of interest: T. Bengtsson reports receiving personal fees for statistical consultancy from Verona Pharma plc during the conduct of the study and outside the submitted work. Conflict of interest: K. Newman was previously an employee of Verona Pharma.

Copyright ©ERS 2018.

Figures

FIGURE 1
FIGURE 1
Overview of study designs. a) Study 1 randomised treatments (A–F): RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo. b) Study 2 randomised treatments (A–C): tiotropium (18 µg) once daily and RPL554 (6 mg) twice daily, tiotropium (18 µg) once daily and RPL554 (1.5 mg) twice daily or tiotropium (18 µg) once daily and placebo twice daily.
FIGURE 2
FIGURE 2
Study 1: forced expiratory volume in 1 s (FEV1) changes caused by RPL554 (6 mg), salbutamol (200 µg) and ipratropium (40 µg) alone and in combination (single doses). a) Peak FEV1 and b) average FEV1(0–8 h). Data are presented as mean±sem. **: p<0.01.
FIGURE 3
FIGURE 3
Study 1: a) Residual volume (RV) and b) specific airway conductance (sGaw) changes caused by RPL554 (6 mg), salbutamol (200 µg) and ipratropium (40 µg) alone and in combination (single doses). Data are presented as mean±sem. *: p<0.05; **: p<0.01.
FIGURE 4
FIGURE 4
Study 2: lung function (forced expiratory volume in 1 s (FEV1)) on day 3. a) FEV1 change from baseline (pre-dose on day 1). b) Peak FEV1 change from baseline (pre-dose on day 1) caused by tiotropium (18 µg), tiotropium (18 µg)+RPL554 (1.5 mg) and tiotropium (18 µg)+RPL554 (6 mg). c) Average FEV1(0–12 h) change from baseline (pre-dose on day 1) caused by tiotropium (18 µg), tiotropium (18 µg)+RPL554 (1.5 mg) and tiotropium (18 µg)+RPL554 (6 mg). Data are presented as mean±sem. **: p<0.01.
FIGURE 5
FIGURE 5
Study 2: a) Residual volume (RV) and b) specific airway conductance (sGaw) changes on day 3 caused by tiotropium (18 µg), tiotropium (18 µg)+RPL554 (1.5 mg) and tiotropium (18 µg)+RPL554 (6 mg). The change from baseline (pre-dose on day 1) is shown. Data are presented as mean±sem. **: p<0.01.

References

    1. 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]isoquinolin-4-one]. J Pharmacol Exp Ther 2006; 318: 840–848.
    1. 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: 714–727.
    1. de Boer J, Philpott AJ, van Amsterdam RG, et al. . Human bronchial cyclic nucleotide phosphodiesterase isoenzymes: biochemical and pharmacological analysis using selective inhibitors. Br J Pharmacol 1992; 106: 1028–1034.
    1. Bardin PG, Dorward MA, Lampe FC, et al. . Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol 1998; 45: 387–391.
    1. Myou S, Fujimura M, Kamio Y, et al. . Bronchodilator effect of inhaled olprinone, a phosphodiesterase 3 inhibitor, in asthmatic patients. Am J Respir Crit Care Med 1999; 160: 817–820.
    1. Page CP, Spina D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Handb Exp Pharmacol 2011: 391–414.
    1. Banner KH, Press NJ. Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease. Br J Pharmacol 2009; 157: 892–906.
    1. 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: 365–376.
    1. 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.
    1. 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: 414–423.
    1. Singh D, Banner K, Newman K. RPL554, an inhaled PDE3/4 inhibitor, causes profound and sustained bronchodilation in healthy volunteers and COPD patients. Eur Respir J 2016; 48: PA4052.
    1. Miller MR, Hankinson J, Brusasco V, et al. . Standardisation of spirometry. Eur Respir J 2005; 26: 319–338.
    1. Quanjer PH, Tammeling GJ, Cotes JE, et al. . Lung volumes and forced ventilatory flows. Eur Respir J 1993; 6: Suppl. 16, 5–40.
    1. Langer D, Ciavaglia CE, Neder JA, et al. . Lung hyperinflation in chronic obstructive pulmonary disease: mechanisms, clinical implications and treatment. Expert Rev Respir Med 2014; 8: 731–749.
    1. Venkatasamy R, Spina D. Novel relaxant effects of RPL554 on guinea pig tracheal smooth muscle contractility. Br J Pharmacol 2016; 173: 2335–2351.
    1. Naline E, Qian Y, Advenier C, et al. . Effects of RP 73401, a novel, potent and selective phosphodiesterase type 4 inhibitor, on contractility of human, isolated bronchial muscle. Br J Pharmacol 1996; 118: 1939–1944.
    1. Schmidt DT, Watson N, Dent G, et al. . The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C4-induced contractions in passively sensitized human airways. Br J Pharmacol 2000; 131: 1607–1618.
    1. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. . Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374: 695–703.
    1. Rennard SI, Calverley PM, Goehring UM, et al. . Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011; 12: 18.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren