The genetic advantage

Allen Roses tells NGP how pharmacogenetics can help cut the size and cost of clinical trials.

“106,000 deaths and 2.2 million serious events are caused by adverse drug reactions in the US each year”
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NGP. Why is it hard to predict a patient’s response during the development of a new drug?
Allen Roses. One never knows how one is going to respond to an external chemical given to the body. What is made harder is if you don’t study it when it occurs, and most people have not done so because it was prohibitive and there was no way of really doing so in the past, but now you can apply pharmacogenetic technology during the development period. As a result of this, when an adverse event occurs, there are now ways of finding the genetic markers that are associated with those people who will respond or those people who will may get an adverse effect.

NGP. What effects will multi-gene studies have on the discovery and the drug development?
AR. When we’re working on a drug that’s in a particular therapeutic area, we can use candidate gene lists that have to do with either the disease and what we think we know about the disease, or the mechanism of the molecule that we are providing, which we would know about. These could be helpful in terms of focus on efficacy effects that we would see in using the drug. The drug is used in a trial that contains a certain percentage of people that have the clinical endpoints. The initial candidate gene lists that we would use – which actually are polymorphisms, or variances, within the candidate genes or around the candidate genes – those would be the first things we would study. And about 80 percent of the time, we achieve reasonable data.

NGP. Why is pharmacogenetics expanding in the industry?
AR. There are a couple of reasons. The industry is contracting because it has been operating on the overall ‘one size fits all’ concept. We’re going to make a drug, everybody’s going to take it at the dose at which we put it out there. With all the failures of proof of concept – the inability to show efficacy with many, many molecules – and with the safety problems that are associated with many molecules, drugs have come under both public and newspaper/journalistic attack for being unsafe and for not working. But the real driving reason for all this is always the finances, and it isn’t as important that you get your drug registered, although that certainly is important, what’s critically important is to get it reimbursed.

Pharmacogenetics can identify the people in advance who will respond to the drug once it’s on the market because of studies that were done during development – companion diagnostics. The insurer or the national health service, or whoever’s making these decisions, can estimate what the cost of the drug will be if given to those people with predicted responses, and not given to those people who don’t have a predicted response.

There is a very different approach in Europe than in the US. In the US, the government or a government agency doesn’t make the decisions; they’re made by panoply of large healthcare providers. Pharmacogenetics can provide value to the drug at a reasonable cost by identifying people who will respond that the drug can be reimbursed, protecting the drug against adverse events by developing prognostic or diagnostic markers and identifying people who might have adverse events.

NGP. What is the importance of an efficient collaboration between industry and academia in regards to collection of pharmacogenetic data?
AR. There are two ways of looking at this: a pharmacogenetic study, in a single study, can be done in a general university. Usually this isn’t done until after the drug is on the market, before they can have access to it, and is usually looking at adverse events, which are all a negative influence as far as drug companies are concerned.

We’ve established a series of external companies, small, which are called the Blue Wine Group, after the Duke Blue Devils mascot. The Duke Wine Group has three companies: one of them is Cabernet, and Cabernet Pharmaceuticals has a strictly laser focus on pharmacogenetic consultation and project management for large pharma. This is how I spend 20 percent of my consultation time at Duke. We’re not getting anything out of it except keeping these studies going and allowing them to achieve a better chance of getting proof of concept, and a better chance of keeping their drugs on the market and providing new drugs, all of which they totally own.

However, because we’re creating companion diagnostics for them and their drugs, we also have the opportunity to commercialise those companion diagnostics. Therefore, a second company, called Shiraz Pharmaceuticals, is in charge of making the arrangements and taking care of all the things the drug company doesn’t want to, or doesn’t have the expertise in-house to do, to commercialise those companion diagnostics.

In the case of Shiraz Pharmaceuticals, it’s part of Dean Drug Discovery: it has a relationship with the Dean Drug Discovery research institute that we have, which is called the Dean Drug Discovery Institute. Any milestone in royalties that are collected by Shiraz, 80 percent will be paid to Duke University. So it becomes a source of income for Duke, and it also becomes an automatic thought process about, if we have some IP that’s developed inside the university, maybe we should go to Shiraz to see about commercialisation.

We get commercialisable IP from private individuals, from Duke and other universities, and as time goes on from the companies with whom we have contracts for the development of companion diagnostics. That then allows people within the university to understand how the market for drugs actually works, and it also shows them ways that we can share in technology, not as a one-off but with defined expertise. That defined expertise is being developed transferred in educational programs, both to the Fuqua School of Business and to the Duke Medical School.

The third company that’s been started is a company called Zinfandel Pharmaceuticals, so they’re all red wines. Zinfandel Pharmaceuticals is preparing to do a prevention clinical trial study with Alzheimer’s disease. It’s taking IP that was developed for diagnostic purposes to predict who will develop Alzheimer’s disease at what particular age, so we can take an epidemiological population between ages 62 and 87 and predict a high-risk group versus a low-risk group.

Then we would design and register our study with the regulators using pharmacogenetics to identify the high risks during the course of the study of the people who would go from normal to the development of Alzheimer’s disease. Instead of needing hundreds of thousands of people to do that kind of study, you can do it with much lower numbers, if it works.

We will partner with major pharmaceutical companies who have a molecule that we are interested in. We’re designing the preliminary studies with several epidemiological populations across the world to see how fast we could recruit people who are virtually or seemingly normal between the ages of 62 and 87. At the time the study would be ready to start, probably in late 2010 or early 2011, we would already have names of people who have said they would be interested in participating and get a very, very fast start to the study.

Allen Roses is Jefferson Pilot Professor of Neurobiology at Duke University and CEO of Cabernet Pharmaceuticals, Inc. He also serves in several capacities at Duke University: as Jefferson-Pilot Professor of Neurobiology and Genetics, as Professor of Medicine (Neurology) as Director of the Deane Drug Discovery Institute, and as Senior Scholar at the Fuqua School of Business. He recently returned to Duke after a decade-long career as a Senior Vice President at GlaxoSmithKline.