DeCode has recently shed some light on its plans for drugs and diagnostics, and the company seems to be aiming for the nearest thing to pharmacogenomics with its products for heart attack.
Of the three areas for which DeCode and partner Illumina are developing genetic diagnostics, myocardial infarction is at the top of the list. "We're prioritizing [myocardial infarction], since that also allows us to prepare the market, so to speak, with a test that would already be out there for tagging patients who would most likely benefit from our drug, even before the drug is launched," said Jeff Gulcher, DeCode's CSO, last week at the Jeffries Life Sciences Conference in New York. DeCode and Illumina are also working on diagnostics in type-2 diabetes and breast cancer.
But instead of predicting which patients will respond to its cardiovascular compounds, DeCode wants to identify patients who are most in need of two of its drugs, in part by using genetic risk scoring. The two drugs, DG031 and DG051, will be the first inhibitors of the leukotriene B4 pathway if they survive clinical trials and regulatory approval.
Illumina and DeCode agreed in May to develop a heart attack risk diagnostic for genotypes of leukotriene A4 hydrolase, and DeCode sees potential for a similar diagnostic that uses genotypes of 5-lipoxygenase activating protein, according to slides Gulcher presented earlier last week at DeCode's annual R&D event in Reykjavik, Iceland. LTA4H is the target for DG051, for which DeCode last week filed an investigational new drug application with the US Food and Drug Administration to begin phase I clinical trials. The other diagnostic target, FLAP, is the target of DG031, which the company began testing in phase 3 clinical trials in May.
Tightening its grip on the leukotriene pathway, the Iceland-based drug maker is also "exploring options to develop a commercial assay for LTB4," the pathway's final metabolite, which DeCode has linked to increased heart attack risk, according to slides from a presentation given last week by David Hartman, senior vice president of product development.
Although Gulcher's presentation materials listed FLAP and LTA4H testing as one of four "major potential diagnostics," it was not clear whether Illumina will be working to include FLAP interrogation with its current LTA4H diagnostic project. Illumina did not return calls requesting comment.
DeCode did not respond to several calls before press time.
A recent report by the American Heart Association shows there were 865,000 new and recurrent myocardial infarctions in the United States each year between 1987 and 2002. This year, the AHA estimates that more than 700,000 Americans, or about 3.5 percent of the population, will have a heart attack.
There is currently no test to determine a patient's risk of developing MI due to genetic predisposition. "The [example] of a heart attack in a mother or father [of the patient] gives you somewhere between a 30 percent and a 50 percent increase in cardiac risk," Richard Stein, a spokesperson for the American Heart Association and director of preventive cardiology at Beth Israel Hospital in New York told Pharmacogenomics Reporter in May. "Certainly smoking, obesity, sedentary behavior - nurture, as opposed to nature, phenomena - still obviously play a major role in development of atherosclerosis, but clearly we take what is a very crude tool now to assess risk, in terms of family history or ethnic origins, which really are primitive ways of looking at genealogy," he said.
"We have additional markers that we can work with other groups as well."
Asked at the Jeffries event how the leukotriene pathway might contribute directly to increased heart attack risk, Gulcher laid out some of DeCode's findings. "We find that LTB4 is elevated in [heart attack] patients, so the question then is, 'What can LTB4 or even an elevation in enzyme do to the vasculature?'" Gulcher asked. "There have been a variety of animal studies by ourselves and others where it has been demonstrated that mutations in these genes affect atherogenesis — if you dampen down the function of one of these genes in the pathway, then you have protection against atherosclerosis."
The company has also observed a decreased progression of atherosclerosis in animals given DG031, "once again supporting the notion that this inflammation or this elevation in enzyme activity is causing — or at least leading to increased — atherosclerosis, but not being secondary to this increase in atherosclerosis," Gulcher said. Plaques that appear more unstable or that have high inflammation tend to have higher levels of both RNA and protein for FLAP and LTA4H, he said.
Other Dx Plans
DeCode currently has four potential diagnostic programs, but has only disclosed plans to develop three of them with Illumina. "We're working on three major programs with Illumina," said Gulcher last week at the Jeffries event. "The idea is to launch genetic markers for myocardial infarction prediction, type-2 diabetes, and breast cancer," he said. "We have additional markers that we can work with other groups as well."
It was not clear what marker or groups Gulcher was referring to, but it seems the company is also considering developing tests with other companies.
DeCode's fourth diagnostic, for prostate cancer, will seek polymorphisms in the AW gene to distinguish aggressive and benign prostate cancer, according to Gulcher. DeCode identified the gene as linked to aggressive cancer, but its function is unknown. The firm believes the market for its prostate test includes all of the two million men in the United States who take a prostate serum antigen test every year when they turn 40, plus a large "catch-up" market and the approximately 200,000 men who are diagnosed with prostate malignancies every year.
With the other three tests, both companies will perform validation using Illumina's BeadLab platforms. "It is co-development such that they'll be the marketing lead and manufacturing lead, and we'll split 50 percent of the operating profits," Gulcher said.