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Array Companies Upgrade H1N1 Flu Chips Despite Uncertain Market Opportunity

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Companies that offer array-based methods for the identification of different strains of influenza rushed last week to make the public aware of the availability of their tests while reaching out to regulatory bodies in the US, Mexico, and beyond to assist in the response to the spread of influenza A, subtype H1N1, also known as the swine flu.

In the space of a week, Mukilteo, Wash.-based CombiMatrix; Sunnyvale, Calif.-based Arrayit; Boulder, Colo.-based InDevr; Singapore-based Veredus Laboratories; and Hyderabad, India-based Ocimum Biosolutions all announced the ability of their respective flu chips to detect H1N1.

While companies selling array-based tests are keen to make their platforms available to laboratories for identifying the flu strain, the US Food and Drug Administration has only given emergency use authorization for the Centers for Disease Control and Prevention's rRT-PCR Swine Flu Panel diagnostic test. Furthermore, companies that sell flu chips are unlikely to see their technology adopted unless the current swine flu strain mutates, according to some sources.

"The CDC has now allowed five labs in the country to use a PCR test in an emergency authorization," Amit Kumar, CEO of CombiMatrix told BioArray News this week. "PCR is so ubiquitous that it is the most obvious approach because every lab can do it, but PCR has the weakness that if the sequence being measured mutates, the flu becomes invisible to PCR," he said. The strength of arrays is that users are more able to catch mutated sequences, Kumar claimed. "This is a better tool for something that is rapidly mutating."

CombiMatrix originally launched its Influenza Detection Array in 2005, the result of several projects funded through the US Department of Defense. Because the company uses electrochemical synthesis to make its arrays, it was able to update the Influenza Detection Array to include H1N1 overnight. Other strains on the chip include pathogenic bird flu (H5N1); the 1918 influenza pandemic (H1N1); the 1968 Hong Kong flu (H3N2); and the 1976 swine flu (H1N1). CombiMatrix claims its array can detect and distinguish each of these strains, as well as all other circulating subtypes and strains of influenza A.

To date, the array has been used mostly by military and government labs in various epidemiological studies. The Ontario Ministry of Health in Canada, for example, has published data on its experience with the chip. In response to the swine flu pandemic, though, CombiMatrix is now preparing to submit its chip to the FDA for an emergency use authorization. The company has also contacted the Secretariat of Health in Mexico.

"Immunoassays don't tell you what type of flu you have and PCR tests will tell you if its swine flu or not, but it won't tell you anything else," Kumar said. "We are seeing how this flu develops. There is always the chance that it mutates and becomes more communicable and pathogenic," he said. "This is not our main focus, but if the country needs it and there is commercial opportunity we'll ramp up to address it."

Unlike CombiMatrix's other tests, which are run through its molecular diagnostics subsidiary in Irvine, Calif., CombiMatrix's Influenza Detection Array is run in its Mukilteo headquarters. The difference, Kumar said, is that CombiMatrix has "not yet seen a market opportunity" to go through the rigorous process of validating the test for use in its Clinical Laboratory Improvement Acts-complaint lab.

Queuing for a EUA

While CombiMatrix prepares its EUA submission, other American companies with array-based flu tests are already waiting in line.

InDevr said last week that it recently licensed intellectual property from the University of Colorado at Boulder related to a FluChip developed by CU scientists and the Centers for Disease Control and Prevention. The project was supported by a $2 million National Institutes of Allergy and Infectious Diseases grant and led by Kathy Rowlen, now the CEO of InDevr.

The IP related to the test was originally licensed to San Diego-based Quidel for commercialization, but according to BioArray News sister publication Biotech Transfer Week, Quidel terminated the license late last year.

The FluChip's detection technology is based on a technique called non-enzymatic signal amplification, which uses photopolymerization of an organic monomer as opposed to a fluorophore tag, like many microarrays. Resulting signals can be detected with the naked eye or with an inexpensive laser scanner, according to InDevr.

The company said it will "immediately begin manufacturing FluChip kits for placement in a limited number of Colorado State public health labs." Specifically, the Colorado Department of Public Health and Environment will be the first site to receive FluChip assays for use as a complement to the rRT-PCR assay, the company said. Rowlen also told BTW that the firm was weighing an EUA request to the FDA. Rowlen did not respond to an e-mail seeking comment on the firm's ambitions for its FluChip.

Another firm planning to contact the FDA with a test is Arrayit. The firm said last week that it was developing a microarray-based diagnostic test to detect the H1N1 swine flu virus that it intends to begin producing over the next several weeks. Arrayit said that its H1N1 test kits will be validated, "then sold for emergency use by licensed clinics, laboratories, and other health care organizations worldwide."

"Arrayit has produced a variety of microarrays for the CDC and other governmental organizations doing similar work. Our relationship with the CDC goes back eight years, and we’re confident we will stand out in this endeavor," Paul Haje, director of marketing at Arrayit, told BioArray News this week.

Arrayit's test will rely on its variation identification platform, which the company claims enables it to hybridize 80,000 different samples to a chip simultaneously. "Imagine if you had to do millions of hybridizations at pandemic proportions. Even the best automated hybridization systems accommodate a limited number of microarrays in a given day," said Haje. "The VIP platform gives us an enormous competitive advantage, in price, speed, and accuracy over other molecular tests," he claimed.

Haje said that Arrayit is currently working with "several foreign ministries of health" and, once its test is validated, it will be able to ship it domestically.

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Meantime, Potomac Falls, Va.-based Tessarae said its Resequencing Pathogen Microarray-Flu was capable of detecting Swine Flu prior to the outbreak of the pandemic. The Affymetrix GeneChip-based array uses 956,000 array probes to interrogate 117,000 base pairs of pathogen gene sequences to detect and identify known and unknown upper respiratory pathogens, both viral and bacterial, according to the firm.

"We are very confident that our current RPM-Flu assay will definitively detect and identify the outbreak swine flu strains without any modification," said Matthew Lorence, vice president of marketing and sales at the firm. "There is also the additional benefit of detecting any co-infecting viral and bacterial pathogens that may be exacerbating morbidity and mortality in the Mexican cases, which seem to be more severe than the US cases," he told BioArray News last week.

Like CombiMatrix, Tessarae's main RPM-Flu customers have been military and foreign public health labs using its technology for surveillance. He said that the US public health system has not shown any interest in Tessarae's technology to date, but suggested that the swine flu epidemic could change things.

He acknowledged that RT-PCR and culture have been the "gold standard" methodologies for the CDC in the past, but said that Tessarae's technology offered some advantages. "RPM generates sequence data as the result, so pathogens present in the specimen are definitively identified based on the genomic sequences detected, versus accumulation of fluorescent signal from simple hybridization of probes to an intended pathogen target," Lorence said.

"Our assay definitively detected swine flu in five out of five specimens so far, and was able to do so without modification," he said. "This illustrates again the power of the technology to detect and identify unknown or emerging pathogens, something that PCR cannot do well or consistently, if at all."

At the same time, he noted that it took more than 10 years for PCR to become a standard diagnostic methodology in microbiology labs, and admitted that companies with array-based tests faced "resistance to new technologies." Still, Lorence said that it was in the labs' interests to adopt newer technology, like the RPM-Flu.

"Clinicians were not trained to expect multiple agents as the cause for infectious disease, so educating them on the benefits of being able to detect all pathogens present as opposed to the single pathogen that they suspect will enable better diagnosis and more appropriate treatment of patients," Lorence said.

Singapore and India

Outside of North America, companies with array-based flu identification assays have also touted the strengths of their platforms over the past week.

Singapore-based Veredus Laboratories said that its VereFlu chip, launched last year,
is able to detect H1N1, using a combination of PCR and array hybridization in a lab-on-chip system manufactured by partner ST Microelectronics.

VereFlu is portable and automated and the firm claims its platform can rapidly detect "all major influenza types at the point of need." CEO Rosemary Tan said in a statement that the company is now verifying the "efficacy of the tests on human samples" and plans to make its system available for swine flu identification over the next few weeks.

Tan told BioArray News last week that it is relatively simple for the company to upgrade VereFlu to include new strains, such as H1N1. "We align the sequences and design primers and probes to be able to detect, differentiate, and identify a particular strain or subtype," Tan said. "We use multiple gene targets with multiple probes to ensure that the detection is precise and specific," she said. "Optimization will be done to ensure that the multiplex PCR is working with high sensitivity and specificity and then we test the microarray panel for cross reactivity, sensitivity, and background noise level."

According to Tan, the firm is using synthetic sequences to test its assay for use. Once ready, Veredus will also collaborate with labs in Asia that can conduct the test on real samples. She declined to name the firm's collaborators.

In India, another company has also announced the availability of an array-based flu test. Ocimum Biosolutions said that it has upgraded its OciChip array platform to include probes for H1N1. The chip was originally developed three years ago during the avian flu outbreak.

Like Veredus, Ocimum is also validating its updated test. Ocimum said that it can also provide an RT-PCR based molecular diagnostic assay for use in India and Asia.

CEO Anu Acharya said in a statement that Ocimum is "ready to work with various public health labs in the India and the region that need help in setting up these assays, or running the samples in our labs."

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