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Perlegen May Soon Have Dx That Identifies Patients at Risk for SAE Following Avandia

Perlegen may be close to developing a test that can identify patients at risk of experiencing heart failure after taking GlaxoSmithKline’s popular type 2 diabetic drug Avandia.
The Mountain View, Calif.-based company announced last month that it has collected more than 3,000 DNA samples from diabetic patients treated with two popular insulin-sensitizing thiazolidinediones, GlaxoSmithKline’s Avandia and Takeda’s Actos, to analyze the genetic variability associated with adverse events tied to this class of medications.
“Results of these analyses may help to direct patients to the drug that is most appropriate for their use, and may provide researchers with important new targets or pathways for drug discovery and development,” the company said in a release.
Although the company is keeping a tight lid on the details surrounding the study or any technology that may be developed out of the emerging data, in an interview with Pharmacogenomics Reporter last week, Perlegen Chief Corporate Development Officer Rob Middlebrook revealed that the goal of the study is to ultimately develop a diagnostic that can aid physicians with treatment protocols for type 2 diabetes.
“We won’t talk about what it is we’re exactly doing. What I can say is we collected a large number of samples. We have conducted some genetic research so far. We did identify some significant associations with the samples,” Middlebrook said. The company expects to continue additional research for a majority of this year. 
If Perlegen identifies genetic variations that predict response to TZDs like Actos and Avandia, then the company will move ahead with diagnostic development plans. The potential diagnostic that Perlegen would develop would be used in conjunction with a specific TZD to determine the appropriate treatment for patients with type 2 diabetes and be able to cut the adverse reaction rate by half, the company hopes.
“These are not black-and-white tests, but if we can reduce the incidence of an adverse effect by, for instance, 50 percent or more, then it’s our view that that would have real clinical utility for health care practitioners,” Middlebrook said.
The controversy over Avandia was sparked by a May 2007 New England Journal of Medicine study by Cleveland Clinic cardiologist Steven Nissen. In the study, Nissen reviewed 42 patient trials of Avandia, also known as rosiglitazone, and found the popular drug was associated with a 43-percent increase in heart attacks and possibly a 64-percent increase in cardiovascular death.
“Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance,” Nissen concluded in the paper.
He acknowledged the study was limited by a lack of access to original source data. “Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes,” he added.
Despite GSK’s vociferous challenges to Nissen’s analysis, on June 6 the FDA requested that a black box warning about congestive heart failure be placed on Avandia and Actos’ label. GSK is also conducting two long-term diabetes studies that promise to provide additional information about Avandia’s association with increased cardiovascular risks. The results from these studies are expected in 2009.
With the class-action litigation surrounding Merck’s Vioxx as a backdrop, GSK’s stock lost around 10 percent of its value since Nissen’s NEJM article appeared.
Perlegen maintains that the row over Avandia and Actos did not precipitate its interest in developing a genetic test to guide diabetes treatment with TZDs. However, the company did acknowledge in a statement that a black box warning in new labeling “may significantly impact the use of these agents.”
“In general, the nature of the drug responses we look at are those where we view there to be a critical unmet medical need. Certainly, in the case of TZDs, there has been an incidence of adverse effects that is a concern,” Middlebrook said. “Our view is that these drugs are appropriate candidates for genetic targeting.”
Certainly, the controversy does highlight a significant unmet need for a diagnostic in a large and profitable market. Perlegen estimates that approximately 200 million people worldwide have type 2 diabetes, including close to 20 million in the United States.

“These are not black-and-white tests but if we can reduce the incidence of an adverse effect by, for instance, 50 percent or more, then it’s our view that that would have real clinical utility for health care practitioners.”

Capturing a significant portion of this market, GSK’s product had reached blockbuster status. During the quarter ended March 31, GSK’s worldwide sales for Avandia grew 19 percent to $838 million from the year ago period. In 2006, the drug netted GSK $3.3 billion in global sales, a 25-percent increase from the previous year.
Although Perlegen has genetic research collaborations with several large pharma and biotech companies, including Genentech, Pfizer, Merck, and even GSK, the company said it is pursuing the TZD diagnostic project alone. The company has licensed its own Phase III-ready TZD from Mitsubishi Pharma.
The company’s early results “demonstrated a significant genetic component to the adverse effect profile of these TZDs,” said David Cox, Perlegen's chief scientific officer, in a statement. "Through our analysis of this valuable sample set, using both genotyping and sequencing technologies, we hope to provide patients and physicians with critical decision-making information, while revealing biological insights that will enable the discovery of safer medicines."
According to Middlebrook, the company is utilizing a combination of proprietary methods and third-party genetic analysis tools in clinical studies. Ultimately, any potential assay developed from Perlegen’s research could be based on a number of platforms depending on the specific genetic variations the company identifies.
Although Middlebrook would not reveal details regarding the specific genetic associations Perlegen has discovered, he did note that the edema some patients on TZDs experience may be an important signal to uncovering the genetic underpinnings for the cardiovascular risk associated with these drugs.
Avandia’s label warns patients against the risk of cardiac failure and other cardiac effects (including CHF), weight gain, hypoglycemia, fractures, hepatic events, ovulation in post-menopausal women, and edema.
Middlebrook noted that TZDs have been a third-line therapy, after treatment with metformins and sulfonylurias, due to the increased risk of edema associated with the class. Between 8 percent and 15 percent of diabetes patients of TZDs can experience edema, Middlebrook said.
“The adverse effects profile of the TZDs includes a range of potential AEs. The one that historically physicians have focused the most on has been the edema and there may well be a correlation between the edema and the cardiovascular risks,” Middlebrook said. “As far as the specific types of genetic analysis we’re doing, there I’m afraid I can’t speak to the different phenotypes that we’re looking at.”

The company expects to take any potential predictive assay that emerges from this research through the FDA regulatory process. 

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