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Cepheid Joins Tricky POC Space with Group B Strep Test as Third Wave Mulls Move with Japanese Allies


This article has been updated from a previous version to eliminate a reference to Cepheid's launch of a Brc/Abl diagnostic, which is not a point-of-care device.

Point-of-care devices with a pharmacogenomic function are finally appearing on the scene.

There are two main areas where there is lot of opportunity for point-of-care molecular diagnostics: infectious disease and adverse drug reactions, and two companies, Cepheid and Third Wave, are charging into the point-of-care space for these two indications, respectively.

Group B Strep and Enterovirus

Cepheid last week filed with the US Food and Drug Administration for clearance of a nucleic acid-based diagnostic to be used at the point of care for patients who may be infected with Group B Streptococcus. Other firms will surely follow Cepheid's lead, with likely candidates including Third Wave technologies, which is looking into developing a point-of-care version of a diagnostic to guide dosing with the ubiquitous anticoagulant warfarin.

"Given the fact that there is this tremendous push on shortening hospital stays, as well as a small issue of overall effectiveness in getting people up to therapeutic levels safely but quickly … you would see it used, certainly in the hospital setting."

In the field of infectious diseases, it is often important to have a result before a patient leaves the doctor's office, such as in chlamydia testing, where a test result might stop the spread of disease to new hosts, said Chris Price, a visiting professor in clinical chemistry at the University of Oxford and co-author of the book Point of Care Testing, published last year. Rapid results are also needed for pathogens that are particularly infectious, and in cases where time and treatment options are limited, such as in infections of methicillin resistant Staphylococcus aureus, he added.

Cepheid's GeneExpert Group-B Streptococcus diagnostic, which the company launched last week for testing in its own lab, appears to be the first point-of-care test to link nucleic acid testing to drug treatment. "We submitted it to [the US Food and Drug Administration] this week, and we'll be launching it in Europe in about a month," followed with a US roll-out, pending clearance of the 510(k) application in the US, Emily Winn-Deen, Cepheid vice president of strategic planning and business development, told Pharmacogenomics Reporter in an interview last week.

Cepheid is applying for clearance of the device for moderately complex labs — "it certainly won't be [for] all doctors' offices, but group-practice kinds of offices probably can do it," said Winn-Deen.

The PCR-based GeneExpert is intended to help physicians determine whether a pregnant mother is infected with a strep strain with the potential to cause neonatal sepsis or neonatal meningitis. "There's a reason that you want a quick answer — labor only goes on so long." Winn-Deen said that the test results determine which "very specific antibiotic" is prescribed.

The point-of-care test will probably only be used in off-hours when hospital labs are closed, Winn-Deen said.

Ordinarily, women are tested for the bacterium around the 37th week of pregnancy using typical culture-type assays, "but for women who aren't getting good prenatal care, or for women who deliver earlier [than the usual strep-B testing time], they really need to be tested when they show up at the hospital so that they can be treated," Winn-Deen said. Currently, "they are just given a course of antibiotics during labor," which can prevent mother-to-child transmission, she said.

The March of Dimes estimates that there were 508,000 pre-term births in the United States in 2004, according to preliminary data, a spokesperson said this week. There are approximately 143,000 patients annually who receive no prenatal care.

The next point-of-care device that Cepheid plans to release this year is for enterovirus, which must be quickly identified in order for clinicians to distinguish between viral and bacterial meningitis, said Winn-Deen.

Adverse Drug Reactions

Third Wave said last week that it had signed an agreement with Japanese companies Shimadzu and Toppan to develop point-of-care assays focused on the P450 family of metabolizing enzymes. "The final [gene] variations [to be interrogated by a point-of-care test] have not been nailed down, but there is interest in Japan in variations that may be associated with adverse reactions with warfarin" said Third Wave spokesperson Rod Hise in an interview this week.

Any point-of-care diagnostic produced by the deal would involve adding Third Wave's Invader chemistry to a prototype Shimadzu and Toppan developed in September, said Hise. The companies have not yet decided which genes a warfarin-related test would interrogate, should the companies pursue it, he added.

Conventional wisdom holds that most pharmacogenomics-related diagnostic tasks are probably not suited to point-of-care devices since a few days' wait for laboratory results is generally sufficient for all but emergency circumstances.

However, like with Group B Streptococcus or enterovirus, there is a clinical need for quick results for anticoagulation with warfarin. "Given the fact that there is this tremendous push on shortening hospital stays, as well as a small issue of overall effectiveness in getting people up to therapeutic levels safely but quickly — as opposed to running the risk of overshooting and getting [patients] into a range where they might more likely bleed — you would see it used, certainly in the hospital setting," said Richard Stein, a spokesperson for the American Heart Association and director of preventive cardiology at Beth Israel Hospital in New York.

The ability for clinicians to estimate higher-than-average doses for fast-metabolizing patients could save those individuals a full day in the hospital, Stein said. "That's a major expense issue for the hospital setting, so I think [hospital-based] physicians would be pressed into using these." However, Stein cautioned there is no guarantee that a point-of-care diagnostic for warfarin metabolism would work as well in practice as it would seem in theory, he said.

Patients who have been fitted with mechanical heart valves or who have deep-vein thrombosis would need to be put on an anticoagulant before they can go home, said Stein. Many of these individuals will likely require permanent anticoagulant maintenance therapy.

Variations within two genes, CYP450 2C9 and VKORC1, are generally responsible for the majority of patient responses to warfarin. The FDA's Clinical Pharmacology Subcommittee of the Advisory Committee on Pharmaceutical Science voted in November 2005 in favor of changing warfarin's label to reflect the fact that genetic information from these two genes can be useful in deciding a patient's individual dose. The FDA has not yet acted on the recommendation.

Hise said he did not know precisely when Third Wave, Shimadzu, and Toppan plan to finalize a list of genes that the test would check, but he expected an agreement on the subject before the end of the year.

If developed, a point-of-care test for warfarin metabolism would be an extension of similar research ongoing at Third Wave. The company said late last year that it planned to develop an IVD for guiding warfarin dosages, and company officers mentioned the test during a conference call with investors last week. Hise said the company would be developing the point-of-care diagnostic in addition to the IVD, which should launch this year pending FDA clearance.

"While this market is still emerging, we know that there are more than 300,000 new prescriptions written for these blood thinners each year," Third Wave CEO Kevin Conroy said during the conference call last week. The company is in discussion with potential partners about how to accelerate distribution of the test.

Tm Bioscience may adapt its respiratory virus panel to point-of-care applications "sometime in 2007," said Jeremy Bridge-Cook, the company's vice president of sales and marketing. GE Healthcare has developed CYP450 assays for other purposes, but is not working on a warfarin-related diagnostic.

Regardless of how useful a warfarin-supporting point-of-care diagnostic might be, market interest in it is spotty. "I keep getting mixed messages" about the need for point-of-care diagnostics from people involved in cardiovascular medicine, said Cepheid's Winn-Deen.

Third Wave's Hise, meantime, characterized the market for point-of-care pharmacogenomic devices as a subset of the larger emerging pharmacogenomics sector, and thus somewhat unpredictable.

"There needs to be a reasonable degree of acceptance in the laboratory-testing environment before one can really hammer the point of care," said Price, the visiting Oxford professor. "The whole area of point of care [takes] evidence to demonstrate utility and benefit, and then implementation takes far too long. I think that's going to be an issue for nucleic acids just as much" as other types of tests, he said.

Three main things can be done to help interest doctors in general testing for warfarin dosing, said David Veenstra, a research associate professor in the Department of Pharmacy at the University of Washington in Seattle, in an interview this week. The first of these is to provide testing that can be integrated into the normal flow of coagulation care, he said.

"For that first dose, point of care would be good because in typical practice nowadays, you're not ordering any kind of test before you initiate warfarin," he said.

The other two factors that might help convince doctors involve providing clear information about what actions they should take based on test results, and convincing them of the clinical value of testing, said Veenstra.

— Chris Womack ([email protected])

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