Verona Pharma: ATS Sunday poster presentations

Verona Pharma plc (AIM: VRP), the drug development company focused on “first-in-class” medicines to treat respiratory diseases, today announces that two posters were presented on Sunday 19 May as part of the scientific programme at American Thoracic Society (ATS) International Conference, Philadelphia, USA, 17-22 May 2013. The abstracts for these two posters are reproduced below.

[Poster Board # F79] RPL554, A Dual Phosphodiesterase 3/4 Inhibitor, Relaxes Human Bronchi And Acts Synergistically With Muscarinic Receptor Antagonists, [Publication Page: A1495]

M.G. Matera, MD, PhD1, L. Calzetta, DVM, Mphil, PhD2, D. Spina, Ph.D3, C. Page, PhD3, F. Facciolo, MD2, M. Cazzola, MD2

1Naples/IT, 2Rome/IT, 3London/UK

Rationale: Phosphodiesterases (PDEs) hydrolyse second messengers such as cAMP and cGMP that regulate cellular processes in the release of inflammatory mediators and in airway smooth muscle (ASM) relaxation. Selective PDE4 inhibitors are anti-inflammatory in the lung, but have little or no bronchodilation. Selective PDE3 inhibitors on the other hand do produce significant bronchodilation in asthmatics. Thus, combining anti-inflammatory actions and bronchodilation into a single molecule may be clinically beneficial. In the present study, RPL554, a dual PDE3/PDE4 inhibitor, was investigated on the ASM tone, including its potential synergy with a muscarinic receptor antagonist and a β2-agonist.

Methods: Human isolated airways were used to evaluate RPL554 on the contractile response induced by electrical field stimulation (EFS), acetylcholine (ACh) or histamine (HIS) in passively sensitized tissues. Berenbaum and Bliss Independence (BI) methods were used to investigate the synergistic interaction of RPL554 plus atropine or salbutamol. All values are expressed as mean±SEM for n=5 and a Student’s t test used to test statistical significance (p<0.05).

Results: RPL554 inhibited the contraction induced by EFS (Emax: -91.33±3.37%, p<0.001), relaxed bronchi pre-contracted with ACh (Emax: -94.62±2.63%, pD2: 4.84±0.12, p<0.001) and abolished (P<0.001) the contraction induced by HIS in sensitized tissues, compared with control bronchi. Berenbaum and BI analyses suggested a synergistic interaction between RPL554 and atropine (BI delta: 0.54±0.09; Interaction Index: 0.09±0.07) and a weak synergism between RPL554 and salbutamol (BI delta: 0.29±0.11; Interaction Index: 0.25±0.06). The interaction between low concentrations of RPL554 (10nM and 100nM) induced significant synergistic relaxation in the presence of atropine (10nM: 44.30±13.35%, p<0.05; 100nM: 67.63±6.34%, p<0.01) compared to that expected in bronchi pre-contracted with ACh (10nM: 6.61±1.83%; 100nM: 19.77±8.84%), but not for RPL554 plus salbutamol (p>0.05).

Conclusions: RPL554 relaxes human bronchi and acts synergistically with a muscarinic receptor antagonist on ASM tone, suggesting that when given alone or in combination, it may be an important novel treatment for airway diseases.

Am J Respir Crit Care Med 187;2013:A1495

Poster Board # F81] Safety And Bronchodilator Effects Of Nebulized RPL554, A Novel Dual PDE3/4 Inhibitor In COPD, [Publication Page: A1497]

M. Cazzola, MD1, L. Calzetta, DVM, Mphil, PhD1, A. Segreti, MD1, P. Rogliani, MD1, C. Page, PhD2

1Rome/IT, 2London/UK

Rationale: RPL554 is a novel inhaled dual phosphodiesterase (PDE) 3 and 4 inhibitor that has been shown to produce bronchodilation in humans as well as anti-inflammatory effects in the lung in preclinical models. The aim of this Phase IIa clinical trial was to evaluate the safety and effectiveness of nebulised RPL554 as a bronchodilator in mild-to-moderate COPD patients.

Methods: This single blind, randomized crossover study evaluated the safety and effect of a single dose of RPL554 (0.018 mg/kg) on FEV1 compared to a placebo vehicle (citrate phosphate buffer, pH 3.2) in 12 male COPD patients. The subjects were not allowed to use long or short acting β2-agonists or muscarinic receptor antagonists 24 hours before the study days. After the administration of the study medication (either RPL554 or placebo by inhalation using a standard nebuliser and a nasal/oral mask for 10 minutes), the tolerability and bronchodilator effects were assessed repeatedly over an 8 hour period. The washout period was at least 48 hours and maximal 1 week. All values are expressed as mean±SEM with analysis of variance (ANOVA) used to assess statistical differences between treatments (p<0.05).

Results: RPL554 was well-tolerated by all COPD patients. There were no changes observed in standing and sitting blood pressures or sitting heart rate. However, RPL554 did produce a modest, but significant increase in standing heart rate at 5 hours post-administration when compared to placebo (81±4 bpm versus 73±2 bpm, respectively, p<0.01). RPL554 significantly improved lung function as expressed by the changes in FEV1 from baseline values (p<0.001). RPL554 produced the maximal bronchodilator effect (+194±46 mL and +17±5 % versus baseline values) at 60 minutes post-administration. The difference in mean FEV1 between the RPL554- and placebo-treated groups were greater than +5% at every time point studied. At 8 hours after administration, RPL554 still produced a +7±3% larger FEV1 response than the placebo group.

Conclusion: This clinical trial demonstrated that RPL554 is well tolerated and produces a substantial bronchodilation when inhaled by these mild-to-moderate COPD patients.

Am J Respir Crit Care Med 187;2013:A1497