The goal for Verona Pharma is to build a strong clinical R&D pipeline to target debilitating respiratory diseases.
Our breakthrough lead product, RPL554, is first-in-class. It offers a unique, dual mechanism of action unlike any other type of drug currently available or in development for respiratory diseases. Uniquely, it combines bronchodilator and anti-inflammatory properties in one compound and has the potential to benefit patients not satisfactorily treated with existing medicines. It has secured the Company Venture and Innovation awards from the Cystic Fibrosis Trust, UK, to continue its study in models of cystic fibrosis. The funds from these awards have enabled us to demonstrate that in addition to its bronchodilator and anti-inflammatory properties, RPL554 also activates CFTR, the protein behind the genetic defect in cystic fibrosis. This is just part of the process of building a strong clinical R&D pipeline for more breakthrough, first-in-class drugs to treat respiratory diseases.
|Pre-clinical||Phase 1||Phase 2||Phase 3|
|Maintenance treatment COPD||Nebulizer|
|Acute treatment COPD||Nebulizer|
|Maintenance treatment COPD||DPI/MDI|
|Treatment of asthma*||DPI/MDI|
*Treatment of asthma is a future potential indication and will most likely be pursued together with a larger pharma partner
RPL554 is a first-in-class inhaled drug in development to treat respiratory diseases with significant unmet medical needs such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) and potentially asthma and other respiratory diseases.
RPL554 is currently being developed in a nebulized formulation for the maintenance treatment of COPD patients and as a treatment for CF. It is also being developed as an add-on therapy to commonly used therapies for the treatment of acute exacerbations of COPD in the hospital setting. It has the potential to substantially improve lung function and quality of life of patients not satisfactorily treated with existing drugs.
We are also developing dry powder inhaler (DPI) and metered dose inhaler (MDI) formulations of RPL554 for maintenance treatment of COPD and may develop these formulations for asthma and other respiratory diseases.
Ensifentrine is a dual inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) enzymes. This dual inhibition enables it to combine bronchodilator and anti-inflammatory properties in one compound, differentiating it from existing drug classes used to treat COPD, including corticosteroids, beta2-agonists and anti-muscarinics.
Ensifentrine also activates the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which is beneficial in reducing mucous viscosity and improving mucociliary clearance, thereby potentially also making it an attractive therapy for the treatment of CF.
Previous attempts to develop PDE4 inhibitors for COPD, asthma and other indications have been limited by side effects, particularly those centered on the gastrointestinal system, such as nausea, vomiting and weight loss. Ensifentrine is designed to maximize effectiveness and reduce adverse events by:
relying on a chemical structure that is distinct from other PDE4 inhibitors to avoid gastrointestinal and other side effects typically associated with PDE4 inhibition;
having high selectivity for PDE3 and PDE4 over other enzymes and receptors to minimize off-target effects;
enabling delivery directly to the lung by inhalation, thereby maximizing pulmonary exposure to RPL554 while minimizing systemic distribution and potential adverse events.
By acting as an inhaled, dual inhibitor of PDE3 and PDE4 and stimulating the CFTR, we believe that ensifentrine has the potential to be a more effective and better tolerated treatment of COPD than existing standalone PDE4 inhibitors. We also believe these properties give ensifentrine broad potential applicability in the treatment of other respiratory diseases, including CF.
Targeting unmet needs
384m people worldwide suffer from COPD and 37 years is the median life expectancy of CF patients
Read more about COPD and CF in the unmet needs section of this website
Basic & Clinical Pharmacology & Toxicology
Peer-reviewed publication on dual PDE3/4 inhibitors as novel treatments for COPD
The Lancet Respiratory Medicine
Peer-reviewed paper in the Lancet's highly-respected medication journal
To date ensifentrine has been studied in twelve Phase 1 and 2 clinical trials involving over 800 human subjects
These studies have shown clinically meaningful and statistically significant improvements in lung function versus bronchodilator drugs. Ensifentrine has also demonstrated anti-inflammatory effects in clinical trials, which we believe provide a differentiated anti-inflammatory profile. Ensifentrine has been well tolerated in each of the clinical trials with a favourable safety profile.
The initial proof-of-concept inhaled formulation of ensifentrine was studied in five clinical trials involving 105 human subjects, where it demonstrated bronchodilator, bronchoprotective and potent anti-inflammatory effects. It was also well tolerated (especially with respect to cardiovascular and gastrointestinal effects). The results for these studies were published in the Lancet Respiratory Medicine in 2013.
Based on this positive early data, in 2014, we developed a new, proprietary nebulized formulation for our ongoing development programs. This formulation was designed to have a broader dose range, improved PK profile and dosing regime and neutral pH.
In this formulation, ensifentrine has been studied in seven Phase 1 and 2 trials, involving 695 subjects. RPL554 has been demonstrated to produce a large and sustained improvement in lung function in COPD patients and a significant improvement in COPD symptoms. When inhaled on top of standard doses of frequently used short- and long-acting bronchodilators, RPL554 produced a statistically significant (P≤0.001) and a clinically meaningful additional (>50%) bronchodilator response. Ensifentrine has also been shown to be well tolerated at all dose levels.
A summary of these seven trials can be found here. For the results of these seven trials, please see our announcements:
Ongoing clinical development
Verona Pharma is currently undertaking a comprehensive Phase 2 clinical trial programme for the development of ensifentrine as a maintenance treatment of COPD with nebulized and inhaled formulations. We have already demonstrated that ensifentrine is an effective add-on to treatment with both single bronchodilators and dual bronchodilators. We expect to start pivotal Phase 3 clinical trials in late 2019.
We have also conducted a positive Phase 2a study evaluating the potential of ensifentrine as a treatment for cystic fibrosis (CF), and are investigating a proof-of-concept clinical trial for the proposed development of ensifentrine as an anti-inflammatory treatment in this indication. The Company has received two Venture and Innovation Awards from the UK Cystic Fibrosis Trust to support its CF studies.
We believe that ensifentrine’s properties as an inhaled, dual inhibitor of PDE3 and PDE4 also give it broad potential applicability in the treatment of asthma and other respiratory diseases.
A truly worthwhile objective. We believe ensifentrine has the potential to be the first novel class of bronchodilator in over forty years, and the first therapy for the treatment of respiratory diseases that acts as both a bronchodilator and anti-inflammatory agent in a single compound.
New medicines for COPD have become more accessible, and convenient for the patient, but with little prospect of substantially improving the current management and treatment of this serious disease. Of the patients treated with dual bronchodilator (LAMA/LABA) and triple therapy (LAMA/LABA/ICS), research suggests that up to 40% (approximately 800,000 patients in the US alone) are uncontrolled, remaining symptomatic and at an increased risk of exacerbations. Furthermore, novel anti-inflammatory therapies are required, as current treatments such as ICS and PDE4 inhibitors are either effective only in specific subsets of exacerbating COPD patients or are associated with distressing side effects which can reduce treatment compliance. In the US approximately 2.2 million COPD patients are treated with LABA/ICS therapy. We have already demonstrated that ensifentrine is a very effective addition to single bronchodilators and we believe it is well placed to potentially meet the need for a safe and effective dual bronchodilator/anti-inflammatory treatment regimen as an add-on to existing dual and triple therapies.
|The short-term bronchodilator effects of the dual PDE3 and PDE4 inhibitor RPL554 in COPD||David Singh, Katharine Abbot-Banner, Thomas Bergtsson, Kenneth Newman||Eur. Respir. J. 2018||Link|
|Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials.||Lui.G Franciosi, PhD, Prof. Zuzana Diamant, MD, Katharine H Banner, PhD, Rob Zuiker, MD, Nicoletta Morelli, MD Ingrid Kamerling, PhD, Marieke L. de Kam MSc, Prof. Jacobus Burggraaf, MD, Prof. Adam.F.Cohen, MD Prof. Mario Cazzola, Et al.||The Lancet Respiratory Medicine, October 25, 2013, http://dx.doi.org/10.1016/S2213- 2600(13)70187-5||Link|
|Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases||Katharine H. Abbott-Banner and Clive P. Page||Journal Reference: Basic & Clinical Pharmacology & Toxicology Doi: 10.1111/bcpt.12209||Link|
|A combined Phase I/IIa study of the safety, bronchodilator and bronchoprotective effects of nebulized RPL554, a dual PDE3/4 inhibitor, in healthy subjects and asthmatics.||Franciosi L, Diamant Z, Morelli N, de Kam M, Cohen A, Walker M, Page CP.||Clin Transl Allergy. 2013; 3(Suppl 1): O13||Link|
|Safety and bronchodilator effects of nebulized RPL554, a novel dual PDE3/4 inhibitor in COPD.||Cazzola M, Calzetta L, Segreti A, Rogliani P, Page CP.||Am J Respir Crit Care Med. 2013; 187:A1497||Link|
|RPL554, a dual phosphodiesterase 3/4 inhibitor, relaxes human brochi and acts synergistically with muscarinic receptor antagonists.||Matera MG, Calzetta L, Spina D, Page CP, Facciolo F, Cazzola M.||Am J Respir Crit Care Med. 2013; 187:A1495||Link|
|RPL554, a a dual PDE3/4 inhibitor, is well tolerated and maintains bronchodilator activity when administered by inhalation to mild to moderate allergic asthmatics on 6 consecutive days.||Franciosi L, Zuiker R, Kamerling IM, Burgraaf J, Cohen A, Walker M, Page CP.||Am J Respir Crit Care Med. 2013; 187:A3875||Link|
|Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease.||Banner KH, Press NJ.||British J Pharmacol. 2009; 157(6): 892-906||Link|
|Pharmacology and therapeutics of bronchodilators.||Cazzola M, Page CP, Calzetta L, Matera MG.||Pharmacol Rev. 2012 Jul;64(3):450-504. Epub 2012 May 18.||Link|
|Non-anticoagulant effects of heparin: an overview.||Lever R, Page CP.||Handb Exp Pharmacol. 2012;(207):281-305.||Link|
Verona Pharma has a Clinical and Scientific Advisory Board (CSAB) of key opinion leaders in the fields of chronic obstructive pulmonary disease (COPD) to help guide and inform the future clinical development of Verona Pharma’s lead drug candidate, RPL554. Our CSAB includes the following members:
Gerard Criner, MD, is Chair and Professor of Thoracic Medicine and Surgery at Lewis Katz School of Medicine at Temple University in Philadelphia, PA, where he also obtained his medical degree in 1989. Dr. Criner completed his internship and residency in internal medicine at Temple University Hospital, and his fellowship in pulmonary and critical care medicine at Boston University School of Medicine in Boston, MA.
Dr. Criner is committee member of the Intensive Care Unit Committee at Temple University Hospital and executive director of Philadelphia Critical Care Society. He also serves on the board of directors for the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and acts as Chairman for the ACCP guidelines on the prevention of acute exacerbations in COPD. As a principal investigator, Dr. Criner has received extensive research funding and has conducted several clinical trials in pulmonary disease. Dr. Criner’s primary research focuses on advanced lung conditions, including COPD, emphysema, pulmonary fibrosis, pulmonary hypertension, and respiratory failure. Dr. Criner has published over 300 scientific papers, reviews, and book chapters, with numerous research articles in peer-reviewed journals including New England Journal of Medicine, American Journal of Respiratory and Critical Care Medicine (AJRCCM), Chest and Lancet Respiratory Medicine. He serves on the editorial review board of Advances for Respiratory Care Managers and AJRCCM. Dr. Criner has lectured nationally and internationally at numerous scientific meetings and congresses.
Prof. Fabbri received his doctorate in Medicine and Surgery from the University of Padua in 1972 (110/110 summa cum laude), Board in Occupational Medicine from the University of Padua on 1975 (70/70 summa cum laude) and Board on Respiratory Medicine from the University of Bologna on 1978 (70/70 summa cum laude).
He has been a Visiting Research Fellow at the Department of Respiratory Diseases of Tulane University and at the Cardiovascular Research Institute at the University of California, San Francisco, USA. He has served as Editor of the European Respiratory Review and of the European Respiratory Monograph and as Associate Editor of the American Journal of Respiratory and Critical Care Medicine. From 2004 he is Associate Editor of the European Respiratory Journal, from 2010 of the European Journal of Clinical Investigation and from 2012 of The Lancet Respiratory Medicine.
Prof. Fabbri leads a multicentre research group carrying on clinical trials on the role of inflammation in asthma and chronic obstructive pulmonary diseases. He has published more than 300 papers in extenso in peer-reviewed journals. He was member of the Executive Committee of the Global Initiative on Asthma (GINA) from 1990 to 2001; member of the Scientific Committee of the Global Initiative on Obstructive Lung Disease (GOLD) from 1997 to 2005 and from 2009 to date; Chairman of the Scientific Committee of the Global Initiative on Obstructive Lung Disease (GOLD) from 2001 to 2004; member of the Workshop Panel of the Global Initiative on Obstructive Lung Disease (GOLD) from 2001 to 2005; and Chairman of the Executive Committee of the Global Initiative on Obstructive Lung Disease (GOLD) from 2004 to September 2005.
Prof. Fabbri was elected vice-president of the ERS in September 2005, with mandate to become President Elect (2006-7), President (2007-8), and Past president (2008-9).
Dr. Ferguson is a graduate of the University of Washington School of Medicine. He received his postgraduate training at the University of Washington and then at the University of Colorado Health Sciences Centers, specializing in pulmonary and critical care medicine. After completing a research fellowship at National Jewish Center for Immunology and Respiratory Medicine, Dr. Ferguson joined the faculty of the University of Colorado and National Jewish Medical Center as Director of the Emphysema/COPD program. He continued his academic career at Wayne State University School of Medicine.
Dr. Ferguson is currently Director of the Pulmonary Research Institute of Southeast Michigan, Clinical Professor of Medicine at Michigan State University and Director of Pulmonary Research at St John’s/Providence Medical Center. He is board certified in Internal Medicine, Pulmonary Medicine and Critical Care Medicine and is a Fellow of the American College of Chest Physicians. He has repeatedly been selected to America’s Best Doctors.
Dr. Ferguson’s research interests focus predominantly on airways diseases, primarily COPD and asthma. He is published extensively in peer review journals and textbooks and has lectured nationally and internationally in his fields of interest. He is on the editorial board of the journal J COPD Foundation and regularly reviews research for several journals and for national granting agencies.
Professor Rabe has been active in various fields of respiratory medicine worldwide. His current scientific interests are related to large clinical trials in COPD and asthma, the mechanisms of airway inflammation and the endoscopic staging of lung cancer. Professor Rabe has been involved in many major COPD trials, including the pivotal roflumilast studies. Professor Rabe is Past President of ERS and currently serves as Vice Chairman of the German Center for Lung Research. He is the current President of the German Chest Society and a member of the British Pharmacological Society and the American Thoracic Society. He has served on committees for both the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Professor Rabe was the first European Associate Editor of the American Journal of Respiratory and Critical Care Medicine, and is past Chief Editor of the European Respiratory Journal. He is currently an editorial board member for several scientific journals.
Professor Singh graduated from Cambridge University and trained in clinical pharmacology and respiratory medicine in Manchester, including postgraduate research. His research interest is the development of new drugs for asthma and COPD, involving clinical trials, biomarker studies and basic mechanisms. He has over 200 publications in peer reviewed journals, and is a member of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Science Committee. He is a professor of clinical pharmacology and respiratory medicine at the University of Manchester, and the medical director of the Medicines Evaluation Unit, which performs both early and late phase clinical trials.
Wisia Wedzicha is Professor of Respiratory Medicine and Head of the Airways Division at the National Heart and Lung Institute, Imperial College, UK. She qualified from Somerville College, Oxford University and St Bartholomew’s Hospital Medical College, University of London. She was elected as Fellow of the Academy of Medical Sciences (FMedSci) in 2013 and is a National Institute of Health Research (NIHR) Senior Investigator. She received the Helmholtz International Fellow Award in 2014 and she delivered the Samuel Gee lecture at the Royal College of Physicians in 2016.
Professor Wedzicha has a major interest in the causes, mechanisms, impact and prevention of COPD exacerbations, and in the role of bacterial and viral infection in COPD exacerbations. She directs an active research group specialising in COPD exacerbations, and has published extensively on this topic.
Professor Wedzicha chaired the English Department of the Health Home Oxygen Clinical User Group, and was a member of the Guideline Development Group for the revision of the National Institute for Healthcare and Clinical Excellence COPD Guidelines. She was a member of the Programme Board for the COPD National Clinical Strategy.
Professor Wedzicha was Editor-in-Chief of Thorax from 2002 to 2010, and is a member of the BioMed Central advisory board. She is currently Editor in Chief for the American Journal of Respiratory and Critical Care Medicine. In addition, she is on the editorial boards of a number of international journals. She was the Lancet Ombudsman till 2014, Publications Director for the European Respiratory Society (ERS) and has also previously been ERS Guidelines Director.