Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to chronic respiratory diseases?
There are many different chronic respiratory diseases. Verona Pharma is mainly focused on two diseases: asthma and COPD.
Asthma is a very common disease and unfortunately it has been increasing in prevalence in developed countries. This is the same with COPD; however, there may be different reasons for this.
There are big questions over whether we are treating asthma patients in the right way and if there is anything we can do, to not only treat symptoms, but actually change the course of the disease.
COPD is a rather different disease, it is seen as a smoker’s disease, but this is a very simplistic statement as non-smokers can also develop the disease. COPD is an umbrella for a couple of different sub-types of respiratory disease. At present, it is not fully understood how several of these sub-types differ from another. COPD presents problems because, like asthma, you have narrow airways combined with inflammation. COPD differs from asthma because there is a decline in lung function over time.
Once you have developed COPD, it naturally progresses due to a loss of lung function. Gradually you lose your capacity to breathe. Asthma is a very different type of disease to COPD; however, the same types of treatments are used to some extent.
What treatments are currently available for these diseases?
For moderate and severe asthma, treatments such as inhaled steroids, which have anti-inflammatory activities, are used to control the disease. Long-acting beta2-agonists which are bronchodilators are also used. Ideally, these should be given together to ensure patients benefit from both effects – bronchodilation and anti-inflammation and prevent the disease from worsening. Other treatments are short acting beta2- agonists, anti-muscarinic drugs and leukotriene antagonists.
Sometimes bronchodilators are used to treat mild to moderate asthma, as and when they are needed. This means that patients may only need to use them when they are exercising for example. Unfortunately, none of these treatments cure the underlying disease.
For many years pharmaceutical industry and academia have been looking for more powerful and effective treatments. The mainstay therapies are basically working via the same mechanisms as those already being used in the 80s and 90s. Inhaled beta2-agonists, for example, were first introduced back in 1968.
The biggest improvement has been a more effective treatment for day and night, better protecting the patient from symptoms of the disease. The drawback to this treatment is the concern that a once or twice a day long-acting bronchodilator may mask the underlying deterioration of the disease. If taking a once or twice daily bronchodilator is essential, then it should be taken with an inhaled steroid. This will prevent the inflammation from getting worse. Bronchodilation alone may make the patient feel good, but it does not treat the underlying inflammation. This results in the disease progressing even though the patient feels that they can breathe.
While asthma and COPD are different diseases of the lungs, they are treated with similar medicines; bronchodilators to open the airways and improve breathing, and steroids to control inflammation. However, inhaled steroids are not considered as effective as in asthmatics. COPD sufferers also get more infections and there is more sputum production so antibiotics are used much more.
What are Verona Pharma’s aims with regards to developing treatments for these diseases?
Our ambition is to develop new types of treatments that can improve patients with these diseases. There are two parts to this:
- Narrowing airways and bronchospasm – we still think there is room for better and more effective bronchodilators, especially those which work via a different mechanism of action. Today we use a beta-agonist or an anti-muscarinic. We’ve had these types of medicines for almost 50 years. I think it is important to find new ways of opening the airways for patients when they are really unwell. As a stand-alone treatment or in combination with existing drugs, this would be helpful to patients.
- Underlying inflammation – we would like to treat this. In severe and moderate asthma patients and COPD patients the inflammation leads to exacerbations or acute, severe attacks of the disease. We would also like to find more effective methods of treatment to what is currently available.
Please could you tell us a little bit about your lead drug compound?
Our lead compound is RPL554. It was in-licensed by the founders of the company – Professor Clive Page and Professor Michael Walker. This drug was originally created by Sir David Jack who developed many medicines whilst at Glaxo, such as the beta-agonists and the inhaled steroids. He was the father to many of those therapies.
When Sir David Jack retired from Glaxo, he started other projects. He wanted to find a compound that was a bronchodilator but also had anti-inflammatory properties. At present, there are no compounds which have both actions, they are either bronchodilators or anti-inflammatory.
Our ambition was to find a compound that had both activities in one molecule. We believe that our compound RPL554 has both these properties and if the clinical data supports this, it will be a first-in-class product.
RPL554 has been described as a novel long acting inhibitor of both phosphodiesterase 3 and phosphodiesterase 4 enzymes. What role do these enzymes play in chronic respiratory diseases?
These enzymes are present in many cells in the body, especially in the airways. There are 11 families of phosophodiesterase enzymes in the body.
The phosophodiesterase-3 enzyme is a protein that is commonly involved in smooth muscle and other cells. We have found that if you stimulate or inhibit this enzyme then you affect the tone of the airway muscle. An inhibitor produces bronchodilation, or relaxation of the airways.
Phosphodiesterase-4 is an enzyme that is present in many inflammatory cells.
By working on both enzymes at the same time, we hope to be able to both produce a bronchodilator response, to make it easier for patients to breath, but also target inflammation, to prevent the worsening of the disease by decreasing the inflammatory process. This would help reduce acute attacks of asthma or COPD.
How was RPL554 developed?
We decided to develop this product as an inhaled drug through an aerosol, so patients would breathe it in. We think that this is a particularly good method, as we want to be able deliver the drug straight to the target organ, which in our case, are the lungs. We do not want the drug to be dispersed too widely in the body.
The compound was discovered by Sir David Jack, but at an early stage, in pre-clinical development, it was taken up by Verona Pharma, who has then developed it. We are now conducting phase I and phase II clinical trials.
We have done the first studies in human subjects and in patients. We have found RPL554 to be well tolerated and effective as a bronchodilator in asthma and COPD patients.
What stage of development is RPL554 at?
We are now doing Phase IIa trials.
What impact do you hope RPL554 will have?
We have now progressed from healthy volunteers, to patients. We have demonstrated that RPL554 is a bronchodilator and we are testing it in inflammation. It is early days, but in my mind, it is a very important discovery.
The mechanism of action of the product acts via a different pathway to other drugs to the currently available beta2-agonists and the anti-muscarinics to relax the airways. We believe it is a first-in-class compound; there is nothing like it on the market.
I think that RPL554 is very important for a number of reasons.
Firstly, it could have a major impact on patients that are not well-treated with the existing treatments.
It is also possible that the drug will have an add-on effect, which means it can be used in combination with other products. Therefore, we may be able to provide a better overall bronchodilator effect, so patients feel better, can do more exercise and have an improved quality of life.
Finally, we believe it may have anti-inflammatory effects that may be able to prevent exacerbations, or attacks and worsening of asthma in certain situations. If this is shown to be true, the drug would be the first in a new class of compounds and treatments for asthma and COPD with features unique to it
What other drugs does Verona Pharma have in the pipeline?
RPL554 is in phase IIa. We have another compound which is also at the same stage. It is called the VRP700 and is an anti-cough compound. We are not intending to develop a drug to treat patients or children with the flu cough, or a bacterial infection cough. We are looking at patients with very severe chronic cough which can be quite common in a number of diseases.
Severe chronic cough occurs, for example, in interstitial lung disease. There are quite a few different diseases within this category. The main feature these diseases have in common is that they change the structure of the lungs, so they become more rigid and less inhaled oxygen reaches the blood. As the lung structure deteriorates in these patients, they have a much lower capacity to breathe and to oxygenate the blood. Consequently, it is an end-stage life disease.
You may have heard of pulmonary fibrosis, which is one of these groups of diseases. It has a survival time of roughly between two to five years or so. It involves a constant deterioration of lung function, and unfortunately the patient will die.
There is no good treatment for this disease. One of the severe symptoms of these patients is that they have a chronic severe cough. That means their cough may be 10 or 20 times every hour they are awake. You can imagine that this makes it extremely difficult for them to function and even to go out and socialize.
There is no treatment for this symptom, only opioid drugs have some small effects such as high doses of codeine, but this is not really used and has lots of side effects.
Our treatment again is an inhaled compound. We have done one study in Italy in a group of patients. We found that our compound has very positive effects in reducing coughing.
What plans does Verona Pharma have for the future?
The immediate plans are to continue to develop these compounds so that we understand how they work and if they are indeed likely to have the chance to go all the way to the market. We want to develop compounds up to proof of concept, which basically means that you understand the compound and you are ready to take it into Phase III and full development. At that point in time we will look for a partner that can help us develop and commercialize the compounds.
We plan to build a pipeline of compounds that are first-in-class, where there is less competition, and it should be for patients with severe disease, where there really is an unmet medical need. We focus on respiratory diseases where our compounds can make a real difference to patients.
How do you think the future of treatments for chronic respiratory diseases will progress?
Historically, there has been limited progress in the sense that we have not found any way to change the course of the disease. This is unfortunately the same for both patients with asthma and COPD. We have found drugs that can improve symptoms and prevent acute attacks of the disease, but there is currently no cure.
I think the reason for this is that we don’t fully understand the diseases. In both asthma, and especially COPD, there are a number of sub-sets, or phenotypes, of diseases. These different patient categories seem to need partly different treatments. We have taken a broad-brush approach, but we need to understand these different types of patients better, so that we can treat those that benefit the most.
For patients with mild to moderate asthma especially, available drugs can be quite effective. The patents for these older drugs will soon expire. This will change the dynamics in the market place. There is an expectation that patients are taken off of more expensive proprietary medicines on to generic compounds that may or may not work as well, but will certainly be cheaper for the health care system.
This means that there will probably be less innovation for patients with milder disease as the healthcare system will control the condition with generic drugs. The innovation will be focused much more on the severe end of the disease, where there is an unmet medical need. This is not a bad thing, but it will certainly change the way we look at the disease. It will mean that people focus much more on finding sub-sets of patients that actually will benefit from new types of treatment.
Verona Pharma wants to contribute to this development and discover novel drugs for sub-sets of patients with higher unmet medical need.
Would you like to make any further comments?
I have been with Verona Pharma for only a short time. I started on 1st June. I have been reviewing the progress of the compounds and the strategy. Together with the team and Board we are taking a fresh look at our activities and will focus more on high value projects and identify ways of moving the potential drugs forward as fast as possible towards the market. It is important to prepare for not only approval of new drugs but also for marketability and reimbursement whilst in the marketplace. This will create new drugs for patients with severe disease and value for shareholders in Verona Pharma.
Where can readers find more information?
They can find more information at:-
About Jan-Anders Karlsson, CEO of Verona Pharma
Dr Karlsson has broad pharmaceutical and biotechnology R&D and corporate experience. He was formerly the CEO at S*BIO, a Singapore and US based biotechnology company focused on the discovery and development of novel small molecule anti-cancer drugs.
Before S*BIO, Dr Karlsson was Executive Vice President of Pharma Global Research at Bayer Healthcare after holding senior leadership positions at Rhone-Poulenc Rorer (now Sanofi) and Astra (now AstraZeneca).