VRP Verona Pharma Plc

Verona Pharma plc

("Verona Pharma" or the "Company")

Data demonstrating PDE3/4 inhibitor RPL554 enhances CTFR-dependent currents in cystic fibrosis airway epithelia

 Poster presented at North American Cystic Fibrosis Conference, USA

8 October 2015, Cardiff – Verona Pharma plc (AIM: VRP.L), the drug development company focused on first-in-class medicines to treat respiratory diseases, announces that a poster will be presented later today at the North American Cystic Fibrosis Conference in Phoenix, Arizona, USA, 8-10 October 2015.

Poster number 231, entitled: “The Dual Phosphodiesterase 3 and 4 Inhibitor, RPL554, Enhances Forskolin-Stimulated, CTFR-Dependent Currents in Cystic Fibrosis Airway Epithelia” investigated the effect of RPL554, an inhaled dual PDE3/4 inhibitor, on the Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel that is mutated in Cystic Fibrosis (CF).

In a preclinical model, RPL554 was shown to have CFTR-stimulatory properties and that CFTR activation by RPL554 is mediated by its inhibition of PDE4 in cells from CF patients with the R117H/F508del mutation. The data reported suggest that CFTR activation may contribute to the action of inhaled RPL554 in chronic obstructive pulmonary disease (COPD) and asthma, and further support the concept that RPL554 may be an attractive novel therapeutic option for the treatment of CF, an orphan disease with about 70,000 people afflicted worldwide. This work was partly funded through the Venture and Innovation Award which Verona Pharma received from the UK CF Trust in November 2014. This poster also extends the work presented at the 2014 North American Cystic Fibrosis Conference in Atlanta, Georgia, USA, announced in a press release on 29 September 2014.

Verona Pharma's lead drug, RPL554, is a first-in-class drug currently in Phase II trials as a nebulised treatment for acute exacerbations of COPD in the hospital setting.  

The full abstract for this poster is reproduced below.

THE DUAL PHOSPHODIESTERASE 3 AND 4 INHIBITOR, RPL554 ENHANCES FORSKOLIN-STIMULATED, CFTR-DEPENDENT CURRENTS IN CYSTIC FIBROSIS AIRWAY EPITHELIA

Mark J. Turner¹, Elizabeth Matthes¹, Kathy Abbott-Banner², Scott H. Randell³ and John W. Hanrahan¹

¹ Dept. of Physiology, McGill University, Montréal, Canada

² Verona Pharma plc, London UK

³ UNC Chapel Hill, Chapel Hill NC

Efficient spatial and temporal regulation of cAMP is required for cell signal transduction by protein kinase A (PKA) and the exchange protein directly activated by cyclic AMP (EPAC). The enzymes responsible for degrading cAMP are the cyclic nucleotide phosphodiesterases (PDEs), of which at least 11 different isoforms have been identified in humans. The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is the PKA-activated anion channel that is mutated in Cystic Fibrosis (CF). Inhibitors of both PDE3 and PDE4 have been shown to elevate intracellular cAMP and activate CFTR in various airway epithelial models, suggesting they could serve as potential therapeutic targets for CF. Using qPCR, of the 7 PDEs surveyed, we found PDE4D to be the most highly expressed isoform in CFBE-WT and CFBE-F508del cells, contributing ~64% of the total PDE expression in both cell lines (n=3). Relatively high levels of PDE7A (11.1 ± 2.6% of the total in WT cells and 7.5 ± 0.7% in ?F-508 cells; n=4; p>0.05) and PDE8A (27.2 ± 4.7% in WT cells and 18.1 ± 1.2% in F508del cells; n=3; p<0.01) were also observed, suggesting they may also contribute to CFTR regulation. RPL554, a dual PDE3/4 inhibitor in Ph2a clinical trials, is a "first-in-class" inhaled treatment for respiratory diseases and has been shown to have significant bronchodilator and anti-inflammatory (including anti-neutrophilic) activity in humans (Franciosi, L.G., et al., Lancet Respir Med, 2013. 1(9) 714-727). RPL554 caused a dose-dependent increase in CFTR-dependent short circuit current (Isc) across CFBE-WT cells, with 10?M RPL554 eliciting 65.9 ± 4.5% (n=3) of the maximal forskolin response. Similar results were also obtained with primary WT human bronchial epithelial cells. To determine if the RPL554 stimulation was mediated by inhibition of PDE3 or PDE4 in primary human bronchial epithelial cells (HBEs), and whether PDE inhibition was able to activate CFTR in CF airway epithelia, the specific PDE inhibitors Milrinone (PDE3) and Rolipram (PDE4) were tested on HBEs from three R117H/F508del CF patients. Forskolin (2?M) increased Isc by 1.43 ± 0.11?A cm-2 (n=16), which was enhanced to 2.06 ± 0.19?A cm-2 in cells that had been pre-treated with Lumacaftor for 24 h (p<0.01; n=15) demonstrating Lumacaftor was able to act as a corrector in these cells. The acute addition of Rolipram, RPL554, and Rolipram + Milrinone (without Lumacaftor pre-treatment) increased forskolin-stimulated Isc by 0.92 ± 0.17?A cm-2 (p<0.01; n=5), 0.92 ± 0.19?A cm-2 (p<0.05; n=8) and 0.64 ± 0.14?A cm-2 (p<0.05; n=9), respectively. No increase was induced by Milrinone alone (Isc increased by -0.03 ± 0.10?A cm-2; n=5). The similar magnitude of the response caused by Rolipram and RPL554, together with the absence of an effect of Milrinone, suggests that the CFTR activation by RPL554 is mediated by inhibition of PDE4. These data suggest that CFTR activation may contribute to the action of inhaled RPL554 in COPD and asthma and further support the concept that RPL554 may be an attractive novel therapeutic option for the treatment of CF.

Work supported by a Venture and Innovation Award from the UK CF Trust.

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Notes to Editors

About Verona Pharma plc

Verona Pharma plc is a UK-based clinical stage biopharmaceutical company focused on the development of innovative prescription medicines to treat respiratory diseases with significant unmet medical needs, such as chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. 

Verona Pharma's lead drug, RPL554, is a first-in-class drug currently in Phase II trials as a nebulised treatment for acute exacerbations of COPD in the hospital setting.  The drug is a dual phosphodiesterase (PDE) 3/4 inhibitor and therefore has both bronchodilator and anti-inflammatory effects, which are essential to the improvement of patients with COPD and asthma. 

Verona Pharma is also building a broader portfolio of RPL554-containing products to maximise its benefit to patients and its value.  This includes the very significant markets for COPD and asthma maintenance therapy.  The Company is also exploring the potential of the drug in different diseases, such as cystic fibrosis, where it is in pre-clinical testing and has received a Venture and Innovation Award from the Cystic Fibrosis Trust.