ATS Sunday Poster Presentations

VERONA PHARMA PLC - ATS Sunday Poster Presentations

PR Newswire

London, May 20

Clinical and pre-clinical data highlighting the significant bronchodilator

activity of novel dual PDE3/4 inhibitor RPL554 presented at ATS international

Verona Pharma plc (AIM: VRP), the drug development company focused on"first-in-class" medicines to treat respiratory diseases, today announces thattwo posters were presented on Sunday 19 May as part of the scientific programmeat 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, RelaxesHuman 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 cAMPand cGMP that regulate cellular processes in the release of inflammatorymediators and in airway smooth muscle (ASM) relaxation. Selective PDE4inhibitors are anti-inflammatory in the lung, but have little or nobronchodilation. Selective PDE3 inhibitors on the other hand do producesignificant bronchodilation in asthmatics. Thus, combining anti-inflammatoryactions and bronchodilation into a single molecule may be clinicallybeneficial. In the present study, RPL554, a dual PDE3/PDE4 inhibitor, wasinvestigated on the ASM tone, including its potential synergy with a muscarinicreceptor antagonist and a β2-agonist.

Methods: Human isolated airways were used to evaluate RPL554 on the contractileresponse induced by electrical field stimulation (EFS), acetylcholine (ACh) orhistamine (HIS) in passively sensitized tissues. Berenbaum and BlissIndependence (BI) methods were used to investigate the synergistic interactionof RPL554 plus atropine or salbutamol. All values are expressed as mean±SEM forn=5 and a Student's t test used to test statistical significance (p

Results: RPL554 inhibited the contraction induced by EFS (Emax: -91.33±3.37%, p0.05).

Conclusions: RPL554 relaxes human bronchi and acts synergistically with amuscarinic receptor antagonist on ASM tone, suggesting that when given alone orin 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, ANovel 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 4inhibitor that has been shown to produce bronchodilation in humans as well asanti-inflammatory effects in the lung in preclinical models. The aim of thisPhase IIa clinical trial was to evaluate the safety and effectiveness ofnebulised RPL554 as a bronchodilator in mild-to-moderate COPD patients.

Methods: This single blind, randomized crossover study evaluated the safety andeffect of a single dose of RPL554 (0.018 mg/kg) on FEV1 compared to a placebovehicle (citrate phosphate buffer, pH 3.2) in 12 male COPD patients. Thesubjects were not allowed to use long or short acting β2-agonists or muscarinicreceptor antagonists 24 hours before the study days. After the administrationof the study medication (either RPL554 or placebo by inhalation using astandard nebuliser and a nasal/oral mask for 10 minutes), the tolerability andbronchodilator effects were assessed repeatedly over an 8 hour period. Thewashout period was at least 48 hours and maximal 1 week. All values areexpressed as mean±SEM with analysis of variance (ANOVA) used to assessstatistical differences between treatments (p

Results: RPL554 was well-tolerated by all COPD patients. There were no changesobserved in standing and sitting blood pressures or sitting heart rate.However, RPL554 did produce a modest, but significant increase in standingheart rate at 5 hours post-administration when compared to placebo (81±4 bpmversus 73±2 bpm, respectively, p

Conclusion: This clinical trial demonstrated that RPL554 is well tolerated andproduces a substantial bronchodilation when inhaled by these mild-to-moderateCOPD patients.

Am J Respir Crit Care Med 187;2013:A1497

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Verona Pharma is developing first-in-class drugs to treat respiratory disease,such as COPD, asthma and chronic, severe cough. The Company has three drugprogrammes, two of which are in Phase II. The lead programme, RPL554, is aninnovative dual phosphodiesterase (PDE) 3 and 4 inhibitor with bothbronchodilator and anti-inflammatory properties. VRP700 is an innovativeproduct for suppressing chronic, severe cough in patients with underlying lungdisease. In its third programme, Verona Pharma is investigating novelanti-inflammatory molecules, called NAIPs, for a wide range of respiratory andinflammatory diseases.

About RPL554 for the treatment of COPD and Asthma

Verona's lead drug, RPL554, is a dual phosphodiesterase (PDE) 3 and 4 inhibitorbeing developed as a novel treatment for chronic obstructive airways diseasesuch as COPD and asthma with bronchodilator and anti-inflammatory effects. Botheffects 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 currenttreatment is far from optimal, as it often has unwanted side-effects and/orlimited effectiveness. COPD is most commonly characterised by fixed airflowobstruction and chronic airways inflammation resulting from exposure toirritants like tobacco smoke. Asthma, which remains one of the most commonchronic diseases in the world, is characterised by recurrent breathing problemsand 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, havinga novel mechanism of action involving the suppression of cough initiatingsignals originating from cough sensory nerve endings located in the lungs. Aclinical trial completed at the University of Florence, Italy in September 2011clearly demonstrated significant anti-tussive effects with nebulised VRP700 inhospitalized patients with chronic severe cough.

Cough can be a very debilitating comorbidity reported by patients, especiallythose with respiratory conditions such as asthma, COPD, lung cancer,interstitial lung disease, fibrosis or lung infections. It is a neglectedsymptom 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 OTCcough medications being really effective and it is widely recognised by themedical community that there is a large need for more effective drugs tocontrol and prevent pathologically induced coughing.