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With 1,000 Enrolled, Iverson Hoping to Report First Warfarin PGx Study Outcomes Data by End of 2015

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This article has been updated from an earlier version with additional information about the design and size of the WARFARIN trial. Additionally, Iverson has further clarified the difference between its study and the COAG trial.

MOUNTAIN VIEW, Calif. – By the end of 2015, Iverson Genetics is hoping to report final data from a large-scale prospective trial to determine whether genetic testing helps patients avoid serious adverse events associated with the highly variable anticoagulant warfarin.

Iverson is conducting the Warfarin Adverse Event Reduction for Adults Receiving Genetic Testing at Therapy Initiation, or WARFARIN, study with the Centers for Medicare & Medicaid Services. In 2010, CMS announced that it would reimburse for pharmacogenetic testing conducted as part of the WARFARIN study under a "coverage with evidence development" scheme, even though the agency currently doesn't reimburse for such testing outside of a research setting.

At the Personalized Medicine World Conference here this week, An Pang Chieng, the principal investigator of the WARFARIN study, provided an update on the trial, in which researchers are enrolling patients at 60 sites across the US. To date, more than 1,000 patients are participating in the trial, but researchers plan to enroll a total of 3,800 patients over the next five years. Without reporting specific data, Chieng said at the meeting that investigators are finding that the adverse events rates seen among patients at interim analysis are on track with their expectations.

Warfarin is a widely used drug with a very narrow therapeutic window, which means that doctors often need to adjust the dose of the treatment to avoid serious adverse events in patients, such as excessive bleeding and blood clots. Studies suggest that polymorphisms in CYP2C9 and VKORC1 genes, along with clinical factors, are responsible for 60 percent of the variability seen in a person's warfarin dose.

The US Food and Drug Administration has updated warfarin's label twice, in 2007 and 2010, warning doctors that patients with certain variants of CYP2C9 and VKORC1 genes may require non-standard doses when they start therapy. However, physician practice guidelines don't recommend genotyping patients ahead of prescribing them warfarin, and absent data from prospective randomized controlled trials, the healthcare community is divided on whether genetic testing actually improves outcomes for patients on warfarin.

In the meantime, an estimated 100,000 patients experience warfarin-related adverse events each year. Previous health economic analyses have suggested that genetic testing that can improve the safety and effectiveness of the drug and could save the US healthcare system around $1.1 billion.

As such, industry observers are closely watching the WARFARIN study. If it shows that PGx testing can improve outcomes for warfarin-treated patients, it could shift standard practice toward broader adoption of the genetic intervention.

In WARFARIN, a randomized, double-blinded, parallel group study, investigators plan to genotype all study participants for CYP2C9 and VKORC1 gene variants on Iverson's GenoSTAT Test. Of those who don't harbor the variants of interest, 1,500 patients will be placed into a registry where they will be given a dose recommendation and minimally followed for 30 days. Investigators will randomize 2,300 patients with CYP2C9 and VKORC1 variants into two groups: one cohort will receive their warfarin dose based on a standard clinical algorithm and another will receive loading and maintenance doses based on an algorithm that factors in genetic testing results and standard clinical measures. The study is designed to determine patients' rates of warfarin-related adverse events at 30, 60, and 90 days from initial dosing.

Since the genetic testing is being paid for by CMS, patients enrolled in the study are 65 and older. "CMS is looking to see if there is enough evidence to warrant continued reimbursement" of Wafarin PGx testing, Chieng said. But regardless of the fact that CMS is interested in whether warfarin PGx testing is "reasonable and necessary" for the Medicare population, Chieng noted that the elderly population is also at greatest risk of experiencing complications from the anticoagulant.

He added that WARFARIN will aim to enroll patients of different ethnicities to gauge the impact of these variants on drug-related adverse reactions. To date, researchers have enrolled mostly Caucasians, approximately 6 percent African Americans, 4 percent Hispanics, and fewer than 100 Asians. "Asian populations, as you know, can be the ones that have the highest variations in terms of the genotypes," Chieng said.

Currently, the enrollment sites involved in the trial are spread across most states in the US. Chieng and his colleagues are hoping that eventually centers from all 50 US states will partake in WARFARIN. "If you look at the ethnicity and the age of those enrolled in our study, these are the groups for which the FDA wanted us to do pharmacogenetic testing," Chieng said.

There was much controversy recently over the publication of two prospective, warfarin PGx trials in the New England Journal of Medicine – the COAG trial and the EU-PACT study – which came to divergent conclusions about the impact of genetic testing to dose the anticoagulant.

COAG – where researchers randomized approximately 1,000 patients to receive either a wafarin dose as determined by an algorithm that factored in clinical variables and patients' genotypes or dosing only by a clinical algorithm – found that in the first four weeks of treatment, genotype-guided warfarin administration was no better than the clinical algorithm in terms of the mean time that the two groups remained in therapeutic range. The other study by the EU-PACT group, involving 455 patients, compared a cohort given warfarin with the help of a point-of-care genetic test and a PGx-based algorithm against a cohort given standard dosing. In this study, researchers found that in the first 12 weeks of warfarin therapy, patients in the PGx-guided group stayed longer within therapeutic range — the dose range required for desired treatment effect — compared to those in the control arm (67.4 percent versus 60.3 percent).

Some experts have said that the EU-PACT study more readily reflects clinical practice in the real world, and others have decided that PGx testing is not useful based on the findings from COAG. Still others have pointed out the important differences between the studies, and the fact that neither was designed to follow patients for outcomes, and have urged healthcare providers to wait for results from a study like Iverson's WARFARIN.

"Many people have asked us why we're continuing the WARFARIN study, now that the COAG and EU-PACT studies have come out," Chieng said. "But if you look at the primary endpoint, that really differentiates the WAFARIN study from these other two studies."

He also highlighted that the size of Iverson's trial dwarfs the other two studies. And although WARFARIN isn't employing a point-of-care test as EU-PACT researchers did, patients enrolled in the study will receive their genotyping results in 24 hours.

Similar to the strategy used in COAG, Cheing noted that in WAFARIN, investigators are comparing dosing wafarin using a clinical algorithm versus an algorithm that factors in patients' genotype and clinical information. However, some experts have pointed out that most healthcare providers in the community setting don't administer warfarin based on a clinical algorithm and this may have made it harder for COAG researchers to show a benefit from PGx-guided dosing.

"Unlike COAG we do not control the whole dosing process which should allow us to more easily show a difference in the dosing," an Iveson spokesperson clarified, adding that researchers will also follow patients for longer than the 28 days in COAG to "watch for events."

Many industry observers have also asserted that PGx testing for warfarin is no longer necessary given the availability of newer, less variable anticoagulants. However, the newer drugs, such as Boehringer Ingelheim's Pradaxa (dabigatran), are more expensive than generic warfarin, and can still cause bleeding in some patients.

"Despite the availability of newer oral anticoagulants, warfarin still remains the standard for the treatment of diseases resulting from thromboembolism," Chieng observed. "One of the criticisms of the newer oral anticoagulants is that there are no antidotes to them. So, if a patient does have a bleeding complication there is not much a physician can do except wait and see. But for warfarin, there is the antidote of Vitamin K."

According to Chieng, the WARFARIN study investigators hope to report their results by end of next year. Without revealing specific data, he noted that interim results show that the adverse event rate in WARFARIN is in line with what researchers had expected. "The people that are doing the analysis are giving us a thumbs up, saying that we're right on track, which means that our calculations and assumptions are actually correct," Chieng said. "And we will push forward with the study."

Through WARFARIN, Chieng and his colleagues also hope to identify novel genotypes associated with warfarin PGx. "We will be publishing a paper on what we've found so far on the discovery of [new] genotypes," he said.

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