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Verona Pharma Data Highlighting Synergistic Action Of Novel Dual PDE3/4 Inhibitor RPL554 With Muscarinic Receptor Antagonists And Beta-Adrenoceptor Agonists In Reversing Bronchoconstriction Presented At American Thoracic Society International Conference



5/21/2014 10:53:36 AM

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Verona Pharma plc (AIM: VRP), the drug development company focused on “first-in-class” medicines to treat respiratory diseases, today announces that a poster was presented on Tuesday 20 May as part of the scientific programme at American Thoracic Society (ATS) International Conference, San Diego, USA, 16-21 May 2014. The abstract for this poster is reproduced below.

[Poster Board # A52] RPL554, A Dual Phosphodiesterase (PDE) 3/4 Inhibitor Acts Synergistically With Muscarinic Receptor Antagonists And Beta-Adrenoceptor Agonists To Produce Bronchodilation In Vivo, [Publication Number: A4218]

S. Keir, PhD, C. Page, PhD

Introduction: RPL554 is a novel PDE3/4 inhibitor in development for the treatment of respiratory diseases, including asthma and COPD. We have recently reported that RPL554 induces a synergistic interaction with muscarinic antagonists in isolated human bronchi (Calzetta et al, 2013). This study investigates the ability of RPL554 to reverse the bronchoconstriction induced by bombesin and potential synergistic effects when RPL554 is administered in combination with atropine or salbutamol.

Methods: Guinea pigs were anaesthetised and ventilated. Bronchoconstriction was induced by the intravenous administration of bombesin (2µg/ml; 5 ml/hr). Bronchodilation was induced by the iv. administration of RPL554 alone at various doses, or in combination with sub maximal doses of atropine (2µg/kg) or salbutamol (20µg/kg), doses selected following studies generating a dose-response curve for both atropine and salbutamol to select a dose resulting in approximately 20% reduction in airways obstruction. Total lung resistance (RL) and mean arterial blood pressure were measured. Data are expressed as % reduction in bronchoconstriction or blood pressure.

Results: RPL554 caused a dose-dependent relaxation of guinea pig airways from 10-80µg/kg. In combination with 2µg/kg atropine (a dose that caused 22.3 + 4.9 % reduction in RL), a submaximal dose of RPL554 (20µg/kg) caused a greater relaxation of the airways than this dose of RPL554 administered alone. Furthermore, in combination with 20µg/kg salbutamol (a dose that caused 34.2 + 11.1 % reduction in RL), RPL554 also resulted in greater relaxation of the airways (Table 1). The iv. administration of 20µg/kg RPL554 caused a reduction in mean arterial blood pressure, a response which was not potentiated when co-administered with either (control: 37.3 + 6.7%, + 2µg/kg atropine: 35.3 + 4.3 %; + 20µg/kg salbutamol: 23.3 + 13.0%).

Conclusions: Our results provide further evidence that RPL554 is an effective bronchodilator, when combined with either the muscarinic receptor antagonist atropine or the ß2-adrenoceptor agonist salbutamol has synergistic activities as a bronchodilator, but does not interact with the drug classes on blood pressure.

Given the recent report that RPL554 is an effective bronchodilator in subjects with asthma or COPD (Francioisi et al, 2013), our results suggest that this drug could provide additional clinical benefit when administered with other bronchodilators.

Calzetta et al. 2013 J. Pharm. Exp. Ther. 346:414-423

Francioisi et al. 2013 AJRCCM 187:A3875

For further information please contact:

Verona Pharma plc Tel: 020 7863 3300
Clive Page, Chairman
Jan-Anders Karlsson, CEO

WH Ireland Limited Tel: 020 7220 1666
Chris Fielding
Nick Field

FTI Consulting Tel: 020 3727 1000
Julia Phillips
Simon Conway
Victoria Foster Mitchell

About Verona Pharma plc
Verona Pharma is developing first-in-class drugs to treat respiratory disease, such as COPD, asthma and chronic, severe cough. The Company has three drug programmes, two of which are in Phase II. The lead programme, RPL554, is an innovative dual phosphodiesterase (PDE) 3 and 4 inhibitor with both bronchodilator and anti-inflammatory properties. VRP700 is an innovative product for suppressing chronic, severe cough in patients with underlying lung disease. In its third programme, Verona Pharma is investigating novel anti-inflammatory molecules, called NAIPs, for a wide range of respiratory and inflammatory diseases.

About RPL554 for the treatment of COPD and Asthma
Verona’s lead drug, RPL554, is a dual phosphodiesterase (PDE) 3 and 4 inhibitor being developed as a novel treatment for chronic obstructive airways disease such as COPD and asthma with bronchodilator and anti-inflammatory effects. Both effects are essential to improve symptoms in patients with COPD or asthma. RPL554 is currently in phase II for both diseases.

COPD is a chronic lung disease with significant unmet need for which current treatment is far from optimal, as it often has unwanted side-effects and/or limited effectiveness. COPD is most commonly characterised by fixed airflow obstruction and chronic airways inflammation resulting from exposure to irritants like tobacco smoke. Asthma, which remains one of the most common chronic diseases in the world, is characterised by recurrent breathing problems and symptoms such as breathlessness, wheezing, chest tightness, and coughing. The market for COPD and asthma drugs is estimated to be £20 billion [source: visiongain].

About VRP700 for the treatment of Cough
VRP700 is Verona Pharma's lead drug compound for the treatment of cough, having a novel mechanism of action involving the suppression of cough initiating signals originating from cough sensory nerve endings located in the lungs. A clinical trial completed at the University of Florence, Italy in September 2011 clearly demonstrated significant anti-tussive effects with nebulised VRP700 in hospitalized patients with chronic severe cough.

Cough can be a very debilitating comorbidity reported by patients, especially those with respiratory conditions such as asthma, COPD, lung cancer, interstitial lung disease, fibrosis or lung infections. It is a neglected symptom which is often self-medicated. Consumer spending on OTC medications, including those for cough, grew by 10% over 2005-10, to reach GBP532 million [source: Mintel]. However, there is very little clinical evidence for such OTC cough medications being really effective and it is widely recognised by the medical community that there is a large need for more effective drugs to control and prevent pathologically induced coughing.

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