Interim results from new RPL554 trial

Verona Pharma plc ("Verona Pharma" or the "Company") Interim results from new RPL554 trial demonstrates excellent drug tolerability even at highest dose Single ascending dose study in 50 healthy volunteers up to a dose that was 16 times greater than the previously used bronchodilator dose Well tolerated without an effect oncardio-vascular parameters and without nausea or vomiting at any dose Results support twice daily dosing with this new formulation of RPL554 23 March 2015, Cardiff - Verona Pharma plc (AIM: VRP.L), the drug developmentcompany focused on first-in-class medicines to treat respiratory diseases,today announces encouraging interim results from the first part of a 120subject Phase I/II clinical trial with RPL554, using a new proprietarynebulised formulation. RPL554 is a novel PDE3/4 inhibitor, which is currentlyin development as a nebulised treatment for acute exacerbations in COPDpatients in a hospital or home-care setting. The trial is being performed at the Medicines Evaluation Unit in Manchester bylead investigator Professor Dave Singh. In the first part of this study, which was successfully completed ahead ofschedule, 50 healthy volunteers were enrolled in a single ascending dose studywith the new drug formulation. Five dose levels were tested with thepre-specified highest dose being approximately16 times greater than the dosetested in earlier reported clinical studies, using the previous formulation ofRPL554. The results from this study showed that the drug was well tolerated across alldoses and no maximum tolerated dose could be defined. Importantly, there wereno changes in subjects' cardiovascular parameters and there was completeabsence of nausea or vomiting at all doses. Pharmacokinetic data showed lower peak plasma levels of the drug and a plasmahalf-life of 11-12hr, significantly longer than that of historically publisheddata of similar doses, using the previous formulation. This suggests that thenew formulation results in a longer residence time for RPL554 in the lung andslower release into the blood stream. Pulmonary residence time is an importantfactor in determining duration of effect.1 These results support the potentialfor RPL554 to be a drug administered twice-a-day and this will be furtherverified in the second part of the trial, which is now being initiated. In the next part of the study, multiple ascending doses given for fiveconsecutive days will be investigated in both healthy volunteers and patientswith chronic obstructive pulmonary disease (COPD). The primary objective ofthis study is to further confirm safety and tolerability, as well as toinvestigate bronchodilation in COPD patients. In studies with the previousformulation, RPL554 generated significant bronchodilation that appeared to beat least similar in effect size to that seen with salbutamol,2 a commonly useddrug in the treatment of COPD. Results from this new study are expected to beavailable in the second half of 2015. Dr Ken Newman, Chief Medical Officer of Verona Pharma,commented: "These initial results are very encouraging and confirm that the newformulation of RPL554 has excellenttolerabilityand hasa significantlyimprovedprofile in comparison to the previous formulation. This has alloweddoses ofRPL554 to be assessed that are many multiples higher than doses tested in theclinic to datethat have already demonstrated a robust bronchodilator effect.Itis important to note that even at the highest dosenow evaluated we have seen noimpact on subjects' cardiovascular parameters. No vomitingor evidence of nauseahas been reported. Additionally, the initial pharmacokinetic data suggestsaprofile that we tentatively believe could make RPL554 amenabletotwice-a-daydosing.We look forward to reporting data from the second part ofthis trial in the second halfof 2015,which we expect will confirm thepotentbronchodilatorpotentialof thisdrug in COPD patients." Dr Jan-Anders Karlsson, Chief Executive Officerof Verona Pharma, said: "We are very excited by this first set of clinical data generated with our newproprietary formulation for nebulised RPL554,which is consistent with theexpected profile based on preclinical studies. We have already demonstrated inearlier trials that RPL554 has the unique ability to combine potentbronchodilation with broad anti-inflammatory activity in a single molecule. Thestudies we are now commencing, thanks to the excellent tolerability of our newformulation, will allow us to assess markedly higher doses of the drug thanthose used in our studies in COPD patients to date and seeks to maximise theclinical impact of the drug. We look forward to reporting datafrom thisimportant clinical study later in the course of2015. "We are initially developing nebulised RPL554 as a treatment for acuteexacerbations in COPD,where we believe it has significant marketpotential.Wecontinue to believe that the emerging profile of RPL554suggeststhat it could potentially become an important addition to available treatmentoptionsboth as a monotherapy and, as a result of its unique mechanism ofaction, as a combination partner for existing drugs for COPD." Phase I and Phase II proof of concept studies with RPL554 in its previousnebulised formulation were successfully conducted in over 100 subjects. Resultscollectively showed that the drug is a very potent bronchodilator with theability to elicit a unique anti-inflammatory response. At the doses previouslytested, RPL554 had a benign side effect profile, which compared favourably withexisting standard treatments. The original nebulised formulation of the drugused in these initial studies was devised to provide proof-of-concept data,before developing the new formulation suitable for commercial scale-up. It is expected that the new formulation of RPL554 will result in asignificantly improved therapeutic index in patients, implying that they shouldbe able to inhale higher doses with prolonged effect, offering potential forimprovements in convenience and compliance, as well as health economic benefit.In addition, the commercial viability of the new formulation is underlined bysignificantly improved stability compared to the previous formulation. -Ends For further information please contact: Verona Pharma plc Tel: +44 (0) 20 3283 4200Jan-Anders Karlsson, Chief Executive Officer N+1 Singer Tel: +44 (0)20 7496 3000Aubrey Powell / Jen Boorer FTI Consulting Tel: +44 (0)20 3727 1000Julia Phillips / Simon Conway Notes to Editors About Verona Pharma plc Verona Pharma plc is a UK-based clinical stage biopharmaceutical companyfocused on the development of innovative prescription medicines to treatrespiratory diseases with significant unmet medical needs, such as chronicobstructive pulmonary disease (COPD), asthma and cystic fibrosis. Verona Pharma's lead drug, RPL554, is a first-in-class drug currently in PhaseII trials as a nebulised treatment for acute exacerbations of COPD in thehospital setting. The drug is a dual phosphodiesterase (PDE) 3/4 inhibitor andtherefore has both bronchodilator and anti-inflammatory effects, which areessential to the improvement of patients with COPD and asthma. Verona Pharma is also building a broader portfolio of RPL554-containingproducts to maximise its benefit to patients and its value. This includes thevery significant markets for COPD and asthma maintenance therapy. The Companyis also exploring the potential of the drug in different diseases, such ascystic fibrosis, where it is in pre-clinical testing and has recently receiveda Venture and Innovation Award from the Cystic Fibrosis Trust. About The Medicines Evaluation Unit The Medicines Evaluation Unit ("MEU") is one of the UK's leading contractresearch organisations, working in collaboration with the University Hospitalof South Manchester. The MEU specialises in performing clinical trials (fromPhase I through to IV) in respiratory/inflammatory medicine and related areas.The MEU has an outstanding reputation for performing high quality clinicalresearch complying with UK Clinical Trials legislation and EU Directives andholds MHRA Phase I accreditation. About Chronic Obstructive Pulmonary Disease (COPD) Sixty-five million people worldwide suffer from moderate to severe COPD and theWorld Health Organisation (WHO) expects COPD to be the 3rd leading cause ofdeath globally by 2020. It is the only major chronic disease with increasingmortality. Currently available drugs are aimed at long-term maintenancetherapy, with the market dominated by large pharma. Despite the wideavailability of these therapies, COPD patients suffer acute periods ofworsening symptoms (exacerbations), which cause, in the US alone, some 1.5million A&E visits, 726,000 hospitalisations and 120,000 deaths per annum. Bronchodilating therapy is considered to be the standard of care, and agentscan be administered via handheld devices such as metered dose inhaler (MDI),dry powder inhaler (DPI) and by nebulisers. The nebulised bronchodilator marketwas worth about $1 billion in 2014 in the US.3 RPL554 is being developed byVerona Pharma as an add-on therapy to the "Standard of Care" with theobjectives of providing rapid and pronounced improvement in lung function,reduced symptoms and both shortened duration of hospital stays and reducedre-admission rates 30 days after discharge from hospital. Studies to date onRPL554 have demonstrated that it has a strongly differentiated 3-way mode ofaction, being: (1) bronchodilation (the relaxation of smooth muscle in theairway); (2) anti-inflammatory effects on cells and (3) ion channel activationin epithelial cells, with increased mucociliary clearance of the airway. 1 Olsson et al, in bvgH.D.C. Smyth and A.J. Hickey (eds.), Controlled PulmonaryDrug Delivery, 21 Advances in Delivery Science and Technology, DOI 10.1007/978-1-4419-9745-6_2, © Controlled Release Society 2011 2 Franciosi, L.G., et al., Efficacy and safety of RPL554, a dual PDE3 and PDE4inhibitor, in healthy volunteers and in patients with asthma or chronicobstructive pulmonary disease: findings from four clinical trials. LancetRespir Med, 2013. 1(9): p. 714-27.

3 IMS Consulting Group market research 2014