TR: So genes involved in common diseases are under evolutionary selection. How does that affect drug discovery?
KS: These variants almost always impact [the normal] physiological function of a gene. It’s not like a mutation that makes a dysfunctional [gene product], such as cystic fibrosis or sickle cell anemia. These are examples of accidents in evolution, which are difficult therapeutic challenges. It’s very difficult to replace an abnormal gene product. It’s easier to design a molecule to turn up or down the normal physiological function of a biochemical pathway.
TR: These principles seemed to have worked for deCode’s drug discovery program – the company is set to begin its first round of late-stage clinical trials for a drug to prevent heart attack.
KS: Yes. We isolated a genetic variant that doubles risk of a myocardial infarction [heart attack.] The variant increases production of leukotriene B4, an important inflammatory mediator.
We found that pharma companies had already developed several inhibitors of the protein made by the disease gene, which had been shelved [because they weren’t effective for the application for which they had been developed.] We licensed a compound from Bayer and found that it can down regulate leukotriene B4 to below normal levels in people at risk. We are now starting phase III trials to show that this decreases the risk of heart attack.
We have also found that people who have had a heart attack but do not have the at-risk variants also have up-regulated leukotriene B4. That means we can use the same measure to control genetic and environmental risk.
TR: You also have a substantial benefit when it comes to clinical trials – a built-in way to determine who is most likely to respond to the drug.
KS: You can use genetics as a marker of where people fall on the disease spectrum. Then you can find high-risk people and recruit them into the trial. It’s likely that a clinical trial in that population will be a more sensitive measure of the [effectiveness of the drug.]
We are focusing the clinical trials of [our heart attack drug] largely on African Americans with the gene variation, partly because the need is greatest and partly because it’s the best thing to do in terms of trial design. We are also about to start a phase II trial of a drug for a peripheral artery disease, which will focus on people at risk from the specific pathway [that we identified in genetic studies.]
TR: DeCode has traditionally been known as a genomics company. Has your focus shifted from gene discovery to drug discovery?
KS: The goal of the company is to discover drugs and bring them to market. We are still using genetics – it is a prerequisite for everything we do. It gives us much better drug targets and helps us to go much more swiftly from drug discovery to [late-stage] clinical trials. Traditional drug development companies start with an unproven hypothesis that they don’t know is correct. We start with an observation, so we have proof of concept from the beginning.
TR: When deCode was first starting out, several other genomics companies were also in the game. But they eventually died out or shifted focus. Now you predict more companies will move back into this field?
KS: Back when we started, there were 25 similar companies – but they all changed focus because they could not find disease genes. Genetics is a resource based on people. We were successful because we based our company on a population (see “Translating Iceland’s Genes into Medicine”).
Once genome association technology is refined, it will become easier to find disease genes. Within a relatively short time, there will be many more programs like this.
Companies like GlaxoSmithKline will begin to use genome wide association studies to find targets and to design clinical trials. But my prediction is that many people will have difficulty handling the amount of information [generated by these studies.]