Transforming Drug Discovery

Dr Chas Bountra, the Chairman of the marcus evans Discovery Summit 2010 shares his recommendations for drug discovery acceleration across Europe.

Interview with: Dr Chas Bountra, Chief Scientist, University of Oxford – Structural Genomics Consortium


Cannes, France, February 18, 2010 - FOR IMMEDIATE RELEASE

Drug discovery requires a lot of time, effort, brain power and money. At the moment a lot of that is being wasted as pharmaceutical companies often work secretly doing the same experiments with ridiculously low success rates. Dr Chas Bountra, Chief Scientist at the University of Oxford’s Structural Genomics Consortium (SGC) is working towards transforming this status quo. The Chairman of the marcus evans Discovery Summit 2010, taking place in France, 22 – 24 March, has joined forces with scientists from across the world and is making all the SGC data publicly available, to reduce the duplication of experiments. Here he shares his vision of the drug discovery future and his ideas on accelerating the discovery process.

What are the main issues facing drug discovery chief scientific officers?

Dr Chas Bountra: The biggest challenge for chief scientific officers at the moment is target identification and validation. For many years now, the industry has taken new targets, ran high throughput screens, come up with lead molecules, optimised them into clinical candidates, taken them into phase one, and at phase two discovered that they do not work. The attrition rate for novel targets is around 90 per cent, and may be even higher in some therapeutic areas. This is killing our industry and we absolutely cannot continue in this manner.

There are multiple reasons why the rate is so high – in many disease areas, our understanding of the pathways contributing to disease and its symptoms, is pretty poor. We do not know the most important pathways, or the most important targets on those pathways. I am also not convinced that the pre-clinical models we use in drug discovery are predictive of what happens in patients – a lot of the pre-clinical in vivo models are not models of the disease, but simply models of a pathway we believe to play a role in disease, and at best are pharmacodynamic models. Frankly, I do not think we will ever have “disease” models for many diseases, such as Alzheimer’s, depression or neuropathic pain. These models simply give us a bit of confidence to carry on to the next step. Just because they work in an animal model, does not mean that they will work in patients. History has repeatedly demonstrated this.

With drugs that are already out there, we often do not know how or where they are working. Drugs often have multiple activities. If we do not know how or where or in which patients existing drugs are working, how can we design better ones? Regulators and patients are looking for drugs that are absolutely clean, with no side effects whatsoever. This is a tough hurdle - scientifically I believe it is impossible. We have to balance risk against the benefits. At best we can strive for a molecule which will have some beneficial effects at a certain dose, but at a slightly higher dose, it is likely to have some side effects, in at least a sub-set of patients.

What attrition rate reduction strategies would you recommend?

Dr Chas Bountra: In some disease areas we have to take the long-term perspective. We are not going to be able to treat some of these diseases tomorrow or next year, so for these we need to try to understand the disease, patient heterogeneity and identify pathways and subsequently targets which will have a much greater chance of working in the clinic. Pharmaceutical companies need to create value for shareholders and take drugs to the market quickly; long-term disease understanding has to take place in academia.

We also need to do more functional studies in human disease tissue. I aim to put molecules or probes we generate in SGC into human disease tissue to see what happens – this I believe is the best way forward for dissecting disease pathways and identifying the role of new proteins on these pathways i.e. target discovery. We now better appreciate the limitations of recombinant systems, species differences, and differences in pharmacology between normal and disease tissues. We can also learn a lot from clinical genetic and epidemiology studies.

Many targets are members of large protein families. We should not simply take the first target identified in a report and assume it will work in the clinic. Other targets within that same group could work better. In the past two decades, I believe we have been seduced by single molecular targets - in the absence of an understanding of disease signalling cascades, this has often meant working on redundant or late stage targets. We know from clinical trials that most chronic diseases are treated with molecules with multiple pharmacological activities, so they hit multiple targets, or are treated with a combination of drugs. Chronic disease is complex and unlikely to be treated by drugs that just hit one protein, unless we can determine those proteins or targets that are very early in disease pathophysiology. We need to therefore identify molecules that have multiple activities or targets that are early in pathophysiology. This is not easy to do, but it is absolutely the way forward.

What are some of the scientific areas or technologies worth following?

Dr Chas Bountra: I am very excited about the future of epigenetics. At Oxford, we are putting a lot of resources into identifying molecules that will hit epigenetic proteins i.e. proteins that modify chromatin. If a chemical modification of DNA or histone proteins alters the transcription of several genes which lead to a chronic disease, then modulation of the protein producing that modification should lead to treatments for that disease and potentially a disease modifying agent. It is a new area of science, and together with some other academic groups, we are investing a lot of effort and resources. It is going to be a very exciting area to watch.

Also very important is bioinformatics. We are in an era where we generate masses of data, but we need to be able to sift out the data that is misleading or of low quality. A colleague of mine from a major pharmaceutical company once said, “We are brilliant at generating data, but we are not very good at creating knowledge”. He is absolutely right. I wish we could pool data from large Genome-Wide Association Studies, epidemiology studies, RNAi screens, and so on, to identify pathways or targets that based on large cohorts are believed to be important in clinical disease pathways.

What are your thoughts on partnerships and collaborations in this industry?

Dr Chas Bountra: All the data we generate is placed in the public domain, without any intellectual property protection. We share all our know-how, reagents, etc. This is a brilliant way of working with the very best people, and accelerating the drug discovery process. At the moment, there is massive duplication. Many pharmaceutical companies are working on the same targets, and years later, we still do not know whether those targets work! Everyone is doing the same experiments in secret as they are competing against each other and we know from previous experience that 90 per cent of these targets will not work in phase two. That is a lot of effort, money, resources and brain power wasted. In addition, unnecessarily testing drugs in people surely cannot be right. We are exploring ways in which public and private sectors can work together to do more clinical Proof of Concept studies on novel targets, pre-competitively. If we can achieve this, then I am convinced this will be in the interest of patients, society and industry. The fact is we cannot allow current modus operandi to continue. In 30 or 40 years, some economies will be unable to cope with the cost of caring for Alzheimer’s, Parkinson’s and stroke patients. We urgently need to come up with better treatments. We have to do something radical and brave.


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About the Discovery Summit 2010

This unique forum will take place at The Majestic Barrire, Cannes, 22 - 24 March 2010. Offering much more than any conference, seminar or trade show, this exclusive meeting will bring together esteemed industry thought leaders and solution providers to a highly focused and interactive networking event. The summit includes presentations on revolutionising R&D, effective growth strategies and reducing attrition.

For more information please send an email to info@marcusevanscy.com or visit the event website at http://www.discovery-summit.com/ChasBountraInterview

Please note that the summit is a closed business event and the number of participants strictly limited.

About marcus evans Summits

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