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Competition Heats Up in Warfarin Dx Market As New Tests Seek FDA OK

The market for warfarin dosage testing is ramping up as several companies developing diagnostics to gauge patients’ sensitivity to the anticoagulant warfarin are planning to submit their tests to the US Food and Drug Administration for clearance, while others are awaiting a response from the agency on pending applications.
Recently, the FDA required makers of the widely prescribed anticoagulant to include genetic testing information in the drug’s labeling. Last month the agency approved Nanosphere’s Warfarin Metabolism Nucleic Acid Test, making it the first test of its kind to receive FDA clearance [see PGx Reporter 09-26-2007].
Following these regulatory actions from the agency, a number of diagnostics that would compete with Nanosphere’s test are in line to win clearance.
AutoGenomics and Luminex Molecular Diagnostics, for instance, have had applications for their warfarin tests pending at the FDA since last year. A Third Wave spokesperson told Pharmacogenomics Reporter this week that the company still plans to submit a test based on its Invader technology to the FDA, but did not specify a timeline. ParagonDx, having acquired Gentris’ assets in August, has also said it will submit a warfarin sensitivity test for review by the agency.
“We have been in active communication with the FDA and are anticipating to hear back from the FDA very soon,” Ramanath Vairavan, AutoGenomics senior VP of sales and marketing, told Pharmacogenomics Reporter last week in an e-mail.
In Vairavan’s opinion, having the FDA clear his firm’s test would create “credibility in the minds of the customer in terms of quality and [it] certainly has the potential to increase utility.” Vairavan added that clinical labs are currently reporting results using AutoGenomics’ product.
In the third quarter of 2006, Tm Biosciences (now called Luminex Molecular Diagnostics after being acquired by Luminex) launched its Warfarin Tag-It PGx Mutation Detection Kit for investigational use only. Similarly, Third Wave earlier this year also began marketing ASRs to clinical laboratories so that they may become comfortable with its platform ahead of FDA clearance.
Newer players like Osmetech and ParagonDx have also announced plans to develop their own tests in this market, and both firms see an advantage in winning FDA clearance.
Osmetech announced in August that it will submit its warfarin assay along with its next generation eSensor XT-8 molecular diagnostic platform to the agency later this year. The UK-based company hopes to launch its FDA-cleared 2C6/VKORC1 assay in the first half of 2008.
“Rapid progress is being made towards the development of personalized medicine and this announcement by the FDA to approve a labeling change for warfarin is another step in that direction,” Osmetech CEO James White said in an Aug. 17 statement.
“Osmetech has been moving aggressively to place itself at the forefront of the molecular diagnostics industry through warfarin and its FDA-approved products. This development by the FDA confirms Osmetech is ideally placed to benefit in this rapidly growing sector.”
Similarly, ParagonDx, after acquiring Gentris’ assets, announced on Sept. 10 that it intends to file certain home-brew tests for FDA review. ParagonDx acquired from Gentris a new in vitro diagnostic designed to determine a safe starting dose for warfarin, and this is slated to be ParagonDx’s first product launch in the company’s new iteration [see PGx Reporter 09-12-2007].
Advantage Uncertain
Several companies currently offer homebrew warfarin testing, including ARUP Laboratories, Laboratory Corporation of America, Mayo Medical Laboratories, Kimball Genetics, PGXL Laboratories, Clinical Data, and Genelex.
Clinical Data launched PGxPredict: Warfarin last October, and the company has an ongoing collaboration with CVS Caremark’s pharmacy benefits arm PharmaCare to explore ways to commercialize the test.
Meantime, Seattle-based Genelex launched its warfarin test, based on LMD’ Tag-It platform, last October [see PGx Reporter 10-18-2006]. Similarly, Kimball Genetics this summer began marketing its Warfarin DoseAdvise service, based on Third Wave’s PCR and fluorescent signal-based Invader technology.
Kimball Genetics President and CEO Annette Taylor said that she has no problem using Third Wave’s technology, which is not FDA-cleared. However, while FDA clearance would not change Kimball Genetics’ service, it would increase customer confidence in the technology being used in the lab, Taylor noted.
“People assume that the test is supposed to be FDA approved, and because the warfarin testing market is so big, it’s worth it to take a test through the agency,” Taylor told Pharmacogenomics Reporter this week.
However, pharmacogenomics is still a murky, emerging regulatory area at the agency, and at least one laboratory test developer is not confident that FDA clearance will necessarily give companies a leg up in the market.
“While FDA approval may be the gold standard in the pharmaceutical industry, there is not yet much precedent for the impact of FDA approval within the pharmacogenomics industry,” a Clinical Data spokesperson told Pharmacogenomics Reporter last week over e-mail.
According to Clinical Data, FDA’s updated warfarin label is a “valuable endorsement” of the importance of pharmacogenetics in warfarin dosing, and in this current environment it is sufficient that testing conducted within the PGxPredict:WARFARIN service is being performed under CLIA regulations.
Standing Out in the Crowd
Since the warfarin-dosing market is beginning to flesh out, companies competing for market share will need to differentiate their offerings (see table below for further details on available tests).
For instance, Kimball Genetics’ Warfarin DoseAdvise service provides not only genetic testing, but also a turnaround of one business day and genetic consultation for doctors, patients, and their families. Its test can be performed on both blood and cheek samples, Kimball Genetics’ Taylor highlighted.
Clinical Data’s PGxHealth service provides “full support for warfarin genotyping, including sales, reimbursement support/claims processing, genotyping, and reporting.”
A Clinical Data spokesperson noted that Nanosphere provides equipment and reagents for testing; it does not conduct the testing itself. “Therefore, for those providers who do not wish to invest in the equipment and materials needed to use Nanosphere’s Verigene system, PGxHealth provides a fully supported program and works with insurers to maximize reimbursement coverage for patients,” Clinical Data said.
LabCorp, which has been offering warfarin testing on its own proprietary technology, as well as using other companies’ platforms since the start of this year, told Pharmacogenomics Reporter that it will review Nanosphere’s test to decide if it will offer it to customers. The company would not discuss the various technologies it utilizes in its laboratory, citing competitive reasons.
Meantime, AutoGenomics boasts that its INFINITI assay detects 15 2C9 and VKORC1 variants, more than any other company in the market. Most other warfarin sensitivity assays look for the 2C9 *2 and *3, and the 3673 (-1639G>A) VKORC polymorphisms.
Among the 15 variants the INFINITI assay detects, several polymorphisms will be specific to particular ethnicities – such as the *4 variant identified exclusively among Japanese people and the 8773 SNPs in VKORC1 found in 21 percent of African Americans.
Therefore, in marketing its test, AutoGenomics will likely specifically target certain ethnic groups, in addition to widely promoting it for the 200,000 to 500,000 patients who get initiated on warfarin each year.
Nanosphere claims on its website that its warfarin test, based on the Verigene system, can gauge allele frequency across CYP2C9*2 and *3, as well as across VKORC1 mutations at the 1173C>T positions.
“The VKORC1 polymorphism 1173C>T has been shown to be in strong linkage disequilibrium with another frequently assayed polymorphism, -1639G>A,” Nanosphere states. “Several large studies have genotyped subjects at both of these positions and confirmed the strong linkage disequilibrium between these two polymorphisms, suggesting that either may be used as a marker to identify a single phenotypic group.”
Turnaround time might be another way for players in this space to stand out.
In SEC filings, Nanosphere has claimed that its test, based on the Verigene System, is faster than currently marketed products.

“People assume that the test is supposed to be FDA approved, and because the warfarin testing market is so big, it’s worth it to take a test through the agency.”

“With a prepared sample, the Verigene System completes tests in 45 to 90 minutes and requires less than 20 minutes of technician time,” the company said. The system “allows laboratories to economically run tests at the time they are ordered, unlike other systems where laboratories must wait to process patient samples in batches to control reagent and labor costs.”

The Northbrook, Ill.-based company licensed the Verigene technology from NorthwesternUniversity’s International Institute for Nanotechnology in May 2000. The company is in a quiet period prior to a proposed initial public offering, and cannot comment on its FDA-approved test. However, in SEC filings Nanosphere has said the technology is at least 100 times more sensitive than systems based on enzyme-linked immunosorbent assays, and can detect nucleic acids with greater specificity “without the … risk of contamination inherent in the use of amplification techniques such as PCR.”
Most competing marketed warfarin tests are based on PCR, ELISA, and mass spectrometry.
Other turnaround times vary widely. AutoGenomics offers same-day results, while Kimball Genetics and Harvard Medical School’s testing services, which use Third Wave’s Invader assay, promise to return test results as early as one business day. Other companies have turnaround times ranging from three to seven days.
Experience in the market will also be a key advantage, a point that new player Nanosphere acknowledged in its SEC filing. The company, founded in 1998 by two NorthwesternUniversity chemistry professors, admitted that it “face[s] increasing competition from current and potential competitors, some of which have greater name recognition, more substantial intellectual property portfolios and longer operating histories.”
Hoping to build brand recognition and get a foot in the door, companies like Third Wave, AutoGenomics, and LMD have begun to familiarize labs and hospitals with their tests by allowing them to use their reagents and technologies under CLIA and for investigational use.
Although insurers have said that FDA approval often bolsters the chances that a test will be reimbursed, Aetna’s refusal to cover two FDA-approved tests – Roche’s AmpliChip and Third Waves’ Invader UGT1A1 test – illustrates the uncertainties diagnostic shops face in trying to garner reimbursement for their assays.
Thus, reimbursement is the most salient factor that will determine adoption rates for any marketed warfarin test. The list price for currently marketed tests ranges between $300 and $500.
AutoGenomics’ Vairavan said that customers using the INFINITI warfarin assay have reported that reimbursement for the test has been about $500. “With our 15-variant panel the potential for reimbursement can be $760,” he said. AutoGenomics charges $100 per variant.
Ahead of FDA approval, LMD has managed to integrate its product in reimbursement discussions. The pharmacy benefits manager Medco and the Mayo Clinic, who are researching the potential of warfarin testing to deliver cost-savings while improving patient outcomes, are using LMD’s platform for their tests [see PGx Reporter 12-06-2006].
While Clinical Data is also looking into the pharmacoeconomics of incorporating its test into warfarin therapy through its collaboration with the PBM PharmaCare, the company said “it is too early to predict the reimbursement for this testing, whether FDA-approved or not.
“There is increasingly a desire on the part of payors to see prospective pharmacoeconomic evaluations of new tools,” the company spokesperson said. “This presents challenges to the diagnostics industry but we believe that the value for pharmacogenetics will be clearly demonstrated.”
Despite FDA approval, large insurers like Aetna, WellPoint, and Cigna have not yet said they would cover Nanosphere’s warfarin test. However, there have been reports that United Health Group and the Centers for Medicare and Medicaid services plan to reimburse for the FDA-approved test.

Companies Developing Warfarin Sensitivity Tests
Company Test CYP2C9 Variants VKORC1 Variants Turn-Around List Price Platform Technology
Nanosphere Warfarin Metabolism Nucleic Acid Test
*2, *3
-1639G>A (3673); 1173C>T
45-90 minutes N/A Verigene System unknown proprietary; not PCR, ELISA, or mass spectrometry
Clinical Data PGxPredict: Warfarin
*2, *3
3-5 days $400 N/A PCR-RFLP assay
Kimball Genetics Warfarin DoseAdvise
*2, *3
1 day $495 Invader (Third Wave) PCR, fluorescent signal amplification
Genelex Warfarin Target Dose Safety Test
*2, *3, *4, *5, *6
4-5 days $550 Tag-It Universal Array platform (Tm Biosciences) microsphere-based assay that runs on Luminex's bead-based xMAP
Laboratory Corporation of America N/A
*2, *3
7 days or less N/A N/A N/A
Harvard Medical Warfarin Metabolism Panel
*1, *2, *3
1-2 days $417 Invader (Third Wave) PCR, fluorescent signal amplification
AutoGenomics INFINITI 2C9-VKORC1 Assay
*2, *3, *4, *5, *6, *11
3673, 861, 5808, 6009, 6484, 6853, 7566, 8773, 9041
Same day $100 per variant INFINITi Analyzer microarray
Tm Biosciences Tag-It PGx Mutation Detection Kit
*2, *3, *4, *5, *6
N/A N/A Tag-It Universal Array platform assay runs on Luminex's bead-based xMAP
*This is not a comprehensive list.

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