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Tm Bioscience Licenses CYP450 SNP in Bid for 510(k) to Rival Roche; Also Plans Warfarin Dx


Tm Bioscience is gearing up to take on Roche Molecular Diagnostics' AmpliChip CYP450 assay, and it hopes to produce a diagnostic to help guide dosing with the anticoagulant warfarin, which may rival a test being developed by Third Wave Technologies.

"Our goal is to take all of those assays â€" and we'll have five cytochrome P450 assays, including the warfarin assay â€" and we intend to submit four of them this year for FDA approval," said Tm Bioscience CEO Greg Hines in an interview with Pharmacogenomics Reporter last week.

These will include assays for alleles of the genes CYP450 2D6, CYP450 2C9, and CYP450 2C19, while the warfarin-related diagnostic will interrogate both 2C19 and VKORC1. "Our first submission should go to the FDA within weeks," Hines said.

Last week, Tm said in a statement that it had licensed from Epidauros the rights to use the CYP450 2D6*41 allele in clinical diagnostic products. The allele, which is the second-most common 2D6 variant, can affect the way a patient metabolizes as many as 25 percent of the most commonly prescribed drugs.

Since Epidauros has to date only licensed the rights to the allele to Roche, and agreed not to license it to any other company as part of its deal with Tm Biosciences, Tm is the only company able to include all of the same alleles in its assay that Roche has in its AmpliChip CYP450 test. Although the market for these tests appears promising, its value is still unclear.

"Our goal is to take all of those assays â€" and we'll have five cytochrome P450 assays, including the warfarin assay â€" and we intend to submit four of them this year for FDA approval."

In an effort to match the AmpliChip, Tm has already incorporated *41 detection, as well as the other AmpliChip 2D6 SNP-reading capabilities into its Tag-It platform-based test for a 510(k) submission this year, said Hines. The company will not seek to get the test approved as an analyte specific reagent, he added. Roche had originally planned to sell the AmpliChip as an ASR but was forced to scuttle those plans and submit the test with the FDA for approval as an in vitro device after the agency faulted the company for making clinically specific claims.

"It would be interesting to see if someone else can get a 510(k) approved without *41," said Hines. "I don't know what the answer to that question is, but I wasn't ready to take that chance. And there's a market risk, as well, by not having it." Tm's CYP450 2D6 test will include "around 31" alleles, said Hines.

"Right now, the market is very small and I think we're just kind of in the throes of seeing the FDA weigh into cytochrome P450 with their proposal around warfarin." The proposal is expected to result in a relabeling of that drug to reflect the utility of testing patients' CYP450 2C9 and VKORC1 genes, said Hines. "We think there's lots of growth in this business for more than one company."

Hines continued, "the importance for us â€" that we recognized â€" is that by having a co-exclusive agreement on that marker, other companies that want to play in the cytochrome P450 business will be challenged, because a lab is not going to run one company's technology for one assay, and then someone else's technology for the other P450 assays."

The CYP450 2D6*41 allele is associated with reduced, or intermediate, metabolism, and is carried by as many as 20 percent of Caucasians, according to Sebastian Raimundo and Joachim Fischer, whose study of the allele appears in the October 2000 issue of Pharmacogenetics. [Raimundo S, Fischer J, Eichelbaum M, et al. Elucidation of the genetic basis of the common 'intermediate metabolizer' phenotype for drug oxidation by CYP2D6. Pharmacogenetics. 2000 Oct;10(7):577-81] Common alleles 2D6*2 and 2D6*3 are associated with extensive (or normal) metabolism and poor metabolism, respectively, while a gene duplication affecting an extensive-metabolizer allele can produce an ultra-rapid metabolizer.

As soon as Tm Bioscience saw that Roche had included the 2D6*41 allele in its IVD submission of the AmpliChip CYP450 assay, Tm "had to go back and make sure that we [had] all of the content in our 2D6 test to match Roche," said Hines. "So that's when we started looking at that license from Epidauros for that marker," he added.

Hines said he did not know how large the market for CYP450 2D6 diagnostics might become. But recent moves by the FDA to include gene-related drug response information in the labels of warfarin and irinotecan due to safety concerns suggest that the agency will get around to relabeling other drugs that are metabolized by 2D6, he said.

Eli Lilly's Strattera is a good bet, in Hines' estimation. The drug, which is indicated for attention deficit and hyperactivity disorder in children and adults, was originally labeled by the FDA in 2003 to note that 2D6 testing can identify poor- and extensive-metabolizer patients, and that "higher blood levels in [poor metabolizers] lead to a higher rate of some adverse effects of Strattera." Last month, the agency added a black-box warning to the drug's label warning of the possibility of cardiovascular adverse events.

According to Strattera's label, CYP450 2D6 poor metabolizers in clinical trials were either statistically significantly or twice as likely as extensive metabolizers to report the following adverse events: decreased appetite; insomnia; sedation; depression; tremor; early morning awakening; pruritus; and mydriasis.

Other important drugs metabolized by 2D6 include antidepressants Prozac and Paxil, manufactured by Eli Lilly and GlaxoSmithKline, respectively, and known generically as fluoxetine and paroxetine; and anti-psychotic drugs Risperdal and Haldol, made by Janssen Pharmaceutica and Ortho-McNeil, and known generically as risperidone and haloperidol.

The FDA makes decisions on relabeling by identifying drugs that have "disadvantages in terms of either their benefit or their risk." The agency compiles a list of drugs that might be suited to retrofitting based on the drugs' metabolic characteristics, benefit-risk ratios in the marketplace, MedWatch database information on adverse events of approved drugs, and the prevalence and the penetrance of the genotype of interest, Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the agency's Center for Drug Evaluation and Research, told Pharmacogenomics Reporter in November.

Companies themselves can also suggest candidates for relabeling consideration, said Lesko. "In this field, new studies occur every day," he added.

Tm's Hines declined to say which laboratories might sell the company's CYP450 2D6 test. However, the company is working with "a number of professional bodies to develop clinical practice guidelines" for the use of these tests with specific drugs, he said. Resulting guidelines "will be the basis for any continuing medical education programs that we sponsor, and our promotional activities as well."

At present, Tm sells its 2D6 test for research purposes only, and most of these trials and studies are focused on antidepressants, anti-psychotics, and Strattera, said Hines. Tests cost from $20 to $30 apiece. The Luminex platform on which they are performed costs about $45,000 to buy, he said.

â€" Chris Womack ([email protected])

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