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Gentris to Enter IVD Market with Warfarin Dx As Shops Await FDA s Relabeling Decision

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Gentris plans to launch its own CYP450 2C9 test next year in a bid to take advantage of changes that the US Food and Drug Administration is expected to add to the label of the popular anticoagulant warfarin.

Enabling tests for warfarin dosing has become a much-anticipated role for pharmacogenomics, and Gentris hopes to join a handful of competitors, such as Tm Bioscience and Third Wave Technologies, all of which are waiting to learn whether the FDA will decide to require warfarin manufacturers to mention in their labels that a dosing test for the drug exists and should be taken.

It's now been a little longer than five months since an FDA subcommittee recommended the label change to the agency, and the FDA has remained tight-lipped on the matter.

Gentris hopes to start clinical trials for the 2C9 test late this year, but doesn't expect the product, which, if cleared, would be its first in vitro diagnostic, to launch until "at least 2007," Michael Murphy, the company's president and CEO, told Pharmacogenomics Reporter last week.

The company is also developing real-time PCR in vitro diagnostics, "initially for tests like [CYP450] 2C9, VKORC1 — the cast of players that I think is pretty obvious to most people," said Murphy. The company plans to include both 2C9 and VKORC1 on its warfarin-related real-time PCR test, he said. Patient genotypes for VKORC1 and 2C9 can on average explain a little more than 50 percent of warfarin response.


"I spoke to the FDA last month, and I know they're planning on it."

Gentris estimates that about 30 million prescriptions are written for warfarin in the United States annually. Of these, an average of 10 million have a 2C9 genotype that is closely associated with warfarin's adverse events. Another 4 million who are written long-term prescriptions for the drug will particularly benefit from a 2C9 test, said Murphy.

"Our estimate is that in the US annually right now, [there are] two to four million tests performed, and the current market is between $200 million and $400 million for 2C9 testing alone," assuming an average price of $100 per patient tested, said Murphy.

UGT1A1

In its other diagnostic plans, Gentris is considering developing an in vitro diagnostic for the gene UGT1A1, which could help prevent adverse events related to the chemotherapeutic irinotecan. Late last month, the company sub-licensed the *28 mutation of UGT1A1 from the Mayo Clinic for use in an in-house service in its CLIA laboratory, and a stand-alone product is "an option for us," said Murphy. The current license covers services and products, he added.

The original UGT1A1*28 license is held by the University of Chicago.

Even though the company has been offering UGT1A1 testing in its CLIA lab for about a month and has offered a research-use-only UGT1A1 test for nearly all of its existence, it won't be the company's first in vitro diagnostic test product. "Our first in vitro diagnostic test product will be 2C9," Murphy said.

Murphy sees the market for UGT1A1 testing services as underpopulated, and he cited that as one of the reasons that Gentris is beginning its clinical service offerings with that diagnostic. Another reason is the medical demand for the test. "We are launching our CLIA-based pharmacogenomics testing into the physician-referred market via the UGT1A1 license and also for [CYP450] 2D6 testing," said Murphy. The company will be "reaching out locally" in cardiovascular medicine to provide 2D6 testing, he said.

In the services market for UGT1A1 testing, Gentris competes against the Mayo Clinic itself, Quest Diagnostics, Laboratory Corporation of America, and Genzyme. Third Wave Technologies, which last year finished a test it had long had under development under encouragement from the FDA and licensed the *28 polymorphism, provides its test to Genzyme but does not perform testing services.

The UGT1A1 test's market includes "any and all patients" prescribed Camptosar (or its generic version irinotecan), said Murphy. About 40,000 to 50,000 patients a year are prescribed the drug for colorectal cancer annually, he said.

In November, Third Wave spokesperson Rod Hise estimated the number of new cases of colorectal cancer in the United States as 150,000 annually. "My understanding is that about half of them could potentially be prescribed Camptosar," he said.

Waiting for Relabeling

Like Camptosar before it, warfarin is awaiting changes to its label that are expected to trigger clinician demand for genomic tests. The FDA's Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science voted in November to relabel the drug, and the agency should next meet with Bristol-Myers Squibb, which held the drug's original patent, to discuss the next step, as well as the extent of any label changes, Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the US FDA's Center for Drug Evaluation and Research, said in a November interview.

Asked in November whether the FDA is in contact with diagnostic companies concerning a test intended to aid warfarin dosing, Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research, said, "That is the case. There were many companies who make diagnostics [that attended] … the advisory committee, and we did have conversations with them after the meeting, and I do know that this is going to be in a commercial-development mode with several companies over the next four to six months."

But it has now been a little longer than five months, and the FDA is tight-lipped on the matter of warfarin's relabeling. "The issue is still under review and we have no further updates at this time," a spokesperson for the agency told Pharmacogenomics Reporter last week.

"I spoke to the FDA last month, and I know they're planning on it," Brian Gage, an associate professor of medicine at the Washington University School of Medicine in St. Louis, said last week in an interview. "I would guess that they would make some recommendations about lower doses in patients with CYP450 2C9 *2, *3, certain VKORC1 SNPs, and later on they may revise that to have a more specific dosing algorithm, as opposed to just saying, 'decrease the dose.' But I'm just guessing."

Gage is the co-author of a New England Journal of Medicine study establishing that 20 percent to 25 percent of the variability in response to the drug warfarin can be explained by the VKORC1 genotype, making more than half of the variation in response explainable when 2C9 data are also available. He and colleagues are working on dosing algorithms for use with warfarin in a prospective study involving about 100 patients.

"The relabeling of drugs is a long and negotiated process," Ray Woosley, president of the Critical Path Institute, said last week. The largest factor holding up the process, in Woosley's view, is that "the FDA's budget stinks." Furthermore, the agency has no permanent leader, which negatively affects its morale.

The C-Path Institute works to facilitate meetings between scientists and the FDA on issues such as genomic-based warfarin dosing. "We're working with them on this warfarin project — they have no money to do this — they have to do it at night and on weekends," said Woosley.

The biggest limitation to genomic-based warfarin prescribing is the lack of prospective data, in Woosley's opinion. Until the FDA has new, prospective data to review, label changes will probably be limited to already published data, he speculated. "It's probably going to be [in the] 'scientific update' [section of the label], instead of 'recommendations for use' — that's my guess," he added.

Murphy considers the relabeling of warfarin long overdue. "You couldn't find, as far as the FDA is concerned, a more classic case in which relabeling makes sense in every regard" because the morbidity cost more than justifies the cost of the test, he said.

At its November meeting, the advisory committee did not address specific label changes, said Lesko. In order for changes to be made to a label, the company usually files a supplement to its drug application containing a labeling recommendation, he said. The advisory committee would also be required to brief the FDA's medical division covering hematology and ask for advice on the label's wording, he added.

— Chris Womack ([email protected])

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