AutoGenomics last week announced that the US Food and Drug Administration has approved its Infiniti Warfarin XP dose-response assay for identifying patients with CYP450 2C9 and VKORC1 genetic variants.
AutoGenomics, based in Carlsbad, Calif., submitted the assay to the FDA for 510(k) approval last December. The test runs on the company’s Infiniti platform, which the FDA cleared for multiplex testing earlier this year.
AutoGenomics is entering a crowded market. Four months ago, the FDA approved Nanosphere’s Verigene Warfarin Metabolism Nucleic Acid Test, which runs on the company’s Verigene platform [see PGx Reporter 09-26-2007].
There are also several companies, such as Clinical Data, LabCorp, Genelex, and Nanogen that market homebrew tests for this indication.
But Autogenomics’ test has several points that differentiate it from these rivals, the company said. For one, its warfarin panel was validated by the Harvard Medical School-Partners HealthCare Center for Genetics and Genomics. HPCGG also used AutoGenomics’ assay in the "CReating an Optimal Warfarin Nomogram," or CROWN, trial, a prospective study that used genetic tests to determine optimal warfarin dosing.
According to AutoGenomics, there can be more than a tenfold dosing variability among patients on warfarin. The Infiniti 2C9-VKORC1 panel “has the potential to optimize warfarin dosing and lower the risk of bleeding complications," Raju Kucherlapati, HPCGG scientific director, has said of AutoGenomics’ product.
In addition to being validated by independent researchers, the assay is able to test for variants that no other marketed test can assess. Most marketed warfarin assays test for CYP239*2 and *3 variants, and VKORC1 variant 3673 (-1639G>A).
The Infiniti assay tests for those variants plus CYP239 *4, *5, *6, and *11, as well as VKORC1 variants 5808, 6009, 6484(1173C>T), 6853, 7566, 8773, and 9041(3730G>A). Clinical studies have linked some of these variants to warfarin sensitivity in certain ethnic populations.
For instance, CYP2C9 *4 is exclusively identified in Japanese populations; CYP2C9 *5 and *6 are identified in African Americans; and CYP2C9 *11 occurs in 1 percent of Caucasian and African-Americans. CYP2C9 *11 carriers would require a 33-percent reduction in warfarin maintenance dose, the company states on it website.
Similarly, among the additional VKROC1 variants identified by Infiniti, 8773 is reported to be present in 21 percent of African Americans and 9041(3730G>A) is associated with a warfarin maintenance dose among Japanese patients, other studies have shown.
Additionally, in certain clinical trials, a warfarin dosing model using CYP2C9 *2,*3 plus VKORC1 6853, along with other clinical factors, such as age and weight, account for 56 percent of the dosing variability among Caucasian patients.
“Studies have shown that individuals with one or more CYP2C9-variant alleles have higher occurrences of above-target range INR values, longer periods of time to achieve stable dosing of warfarin, and are at significantly increased risk of serious bleeding events,” AutoGenomics states on its website.
In August, the FDA updated labeling recommendations for warfarin, stressing that people with variations of the genes CYP2C9 and VKORC1 may respond differently to the drug. The agency, however, stopped short of including stronger language in the label that would require physicians to genetically test patients, noting that additional outcomes studies needed to be done [see PGx Reporter 9-5-2007].
However, the re-labeled Coumadin package insert suggests that testing for CYP2C9 *2,*3, *5, *6 *11 plus VKORC1 -1639G>A may be beneficial in certain populations.
“The fact [is] the FDA made a weak recommendation in the package insert, so it has not necessitated that every PharmD or every warfarin clinic [must do] the testing.”
“Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9 and *11 alleles in Caucasians,” the updated warfarin label states. Additionally, the label notes that “certain [SNPs] in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin.”
A paper published in the New England Journal of Medicine in June 2005 that inspired the FDA to consider relabeling warfarin discussed a whole panel of variants that covered multiple ethnicities.
“Part of the problem is, most published studies in this area look at variants related to Caucasians,” Vairavan said. “Now, with the availability of our chip, other variants are being tested. We expect that as the relevance of these additional variants are determined, they will get integrated into the algorithms.”
Another advantage of the Infiniti assay is its automated platform, according to AutoGenomics.
“Ours is a ‘load and go’ type operation, which means it’s an automated platform,” Vairavan said.
The DNA can be extracted from blood or cheek swabs. After the sample prep is conducted through PCR, it is loaded onto the instrument along with the reagents. “After that, you can just walk away,” Vairavan said. “The instrument processes the test automatically.”
AutoGenomics said it will use a direct sales force and educational webinars to “drive up the demand for warfarin testing” by marketing the test to physicians nationally, particularly cardiologists, and other healthcare workers such as risk-management specialists and hospital administrators.
“The fact is that the FDA made a weak recommendation in the package insert, so it has not necessitated that every PharmD or every warfarin clinic [must do] the testing,” Vairavan said.
Approximately 2 million people in the US are initiated on warfarin therapy each year to prevent blood clots, heart attacks, and stroke. Complications from warfarin are the second-most common reason for emergency-room visits, behind adverse reactions from insulin, according to the FDA’s adverse events reporting database. Furthermore, adverse events associated with warfarin account for 15 percent of all severe AEs reported in the US.
AutoGenomics is currently conducting outcomes studies to make a stronger case for warfarin testing with payors. Currently, the company is using the American College of Medical Genetics recommendations, which suggest a $400 to $800 reimbursement rate for tests with Infiniti’s format.
AutoGenomics did not provide an estimate for how much its test would cost patients. Costs for currently marketed tests range between $300 and $500.
“I don’t know how many insurers will accept [the ACMG’s recommendations], but we have had coding experts who looked at the test and made those recommendations,” Vairavan said.