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|
|Treatment of acute 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.
RPL554 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.
RPL554 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. RPL554 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 RPL554while 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 RPL554 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 RPL554 broad potential applicability in the treatment of other respiratory diseases, including CF.
Realising multiple value creation opportunities with a unique respiratory product RPL554
27 June 2016
The Lancet Respiratory Medicine
Peer-reviewed paper in the Lancet's highly-respected medication journal
Targeting unmet needs
210m people worldwide suffer from COPD and 37 years is the median life expectancy of CF patients
To date RPL554 has been studied in eight Phase 1 and 2a clinical trials in over 280 human subjects
These studies have shown clinically meaningful and statistically significant improvements in lung function versus bronchodilator drugs. RPL544 has also demonstrated anti-inflammatory effects in clinical trials, which we believe provide a differentiated anti-inflammatory profile. RPL554 has been wellhen RPL554 is used as both a single agent and as an add-on therapy with currently marketed tolerated in each of the clinical trials and has not been observed to result in the gastrointestinal or other side effects commonly associated with PDE4 inhibitors.
The initial proof-of-concept inhaled formulation of RPL554 was studied in five clinical trials in 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, RPL554 has been confirmed in three Phase 1 and 2a trials, in over 170 subjects, to be well tolerated at all dose levels and to cause a pronounced improvement in lung function in COPD patients. When inhaled on top of standard doses of commonly used bronchodilators, RPL554 produced a statistically significant (P≤0.001) and a clinically meaningful additional (>50%) bronchodilator response.
For the results of these three trials, please see our announcements:
Ongoing clinical development
Verona Pharma is currently planning a comprehensive Phase 2 clinical trial programme for nebulized RPL554 as a potential maintenance treatment of COPD and as an add-on therapy to bronchodilators and other commonly used therapies for the treatment of hospitalized patients with acute exacerbations of COPD.
We are also planning clinical studies to evaluate the potential of RPL554 as a treatment for cystic fibrosis. The Company has received two Venture and Innovation Awards from the UK Cystic Fibrosis Trust to support its CF studies.
A truly worthwhile objective. We believe RPL554 has the potential to be the first novel type of bronchodilator in over forty years.
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.