Verona Pharma PLC RPL554 data presented at North American CF Conference

 
TIDMVRP 
 
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. 
 
                                    -Ends- 
 
For further information please contact: 
 
Verona Pharma plc                      Tel: +44 (0)20 3283 4200 
 
Jan-Anders Karlsson, Chief Executive 
Officer 
 
N+1 Singer                             Tel: +44 (0)20 7496 3000 
 
Aubrey Powell / Jen Boorer 
 
FTI Consulting                         Tel: +44 (0)20 3727 1000 
 
Simon Conway / Stephanie Cuthbert / 
Natalie Garland-Collins 
 
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. 
 
 
 
END
(END) Dow Jones Newswires
October 08, 2015 06:30 ET (10:30 GMT)
Verona Pharma (LSE:VRP)
Historical Stock Chart
From Jun 2024 to Jul 2024