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Though Open to Second-Gen Sequencers, Array-Based Dx Makers Will Stick to Chips

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Many molecular diagnostics companies that have developed tests that run on microarray platforms are open to the possibility of using alternative technologies, such as second-generation sequencing, but most said they will continue to deploy their assays on arrays in the coming years.
 
Second-generation sequencers, such as Illumina’s Genome Analyzer, Roche 454 Life Sciences’ GS FLX, and Applied Biosystems’ SOLiD platform, are widely considered to be useful discovery tools, but the concept of using them for molecular diagnostics applications is already being discussed.
 
During a roundtable at IBC Life Sciences’ Discovery2Diagnostics meeting in San Diego last month, several speakers discussed the increasing role of microarrays for diagnosing disease and for personalized genetics applications. But many speakers also acknowledged the role that second-generation sequencing platforms could play in the molecular diagnostics market.
 
“Sequencers are a standard molecular diagnostic tool in oncology testing; the majority are Sanger sequencers today but next-generation sequencers are starting to penetrate this market,” Harry Glorikian, managing partner at Scientia Advisors, a Boston-based life science consultancy, told BioArray News at D2D.
 
“Besides genotyping for pathogen resistance and genetic testing, next-generation sequencers are likely to greatly influence oncology predisposition and pharmacogenomic testing,” Glorikian said (see BAN 10/28/2008).
 
Illumina CEO Jay Flatley, who did not participate in D2D, has also discussed using the Genome Analyzer as a diagnostics platform. As BioArray News sister publication In Sequence reported in August, Flatley told investors and analysts in New York that in terms of second-gen sequencing, the clinical diagnostics market presents opportunities “mostly in areas like cancer,” where sequencing could play a “key diagnostic role in the future” (see In Sequence 8/19/2008).
 
Still, though talk of using second-gen sequencers for diagnostics applications is ongoing, most test makers who have created diagnostics on array platforms said they remain satisfied in their choice of technology. However, they hinted that they will remain “platform agnostic” and could develop tests on other technology platforms in the future.
 
One such “platform-agnostic” molecular diagnostic shop is Almac Diagnostics, which is developing several tests related to oncology on Affymetrix’s GeneChip platform, but is also open to the idea of using second-generation sequencers for the task.
 
Austin Tanney, Disease-Specific Array program manager at Almac, described currently available second-gen sequencers as more of an “excellent research platform” than a “viable technology” for delivering a clinical test, noting that these platforms are “a number of years” behind microarray technology from a diagnostic perspective.
 
“However, once this technology becomes a viable platform for this purpose we will most certainly be willing to use it,” he said.
 
Almac, based in Craigavon, UK, became a “Powered by Affymetrix” diagnostics partner in 2005, and has plans to submit expression-based tests for colorectal cancer recurrence and early-stage lung cancer over the next two years (see BAN 8/19/2008).
 
Tanney said that the company chose to work with the Affymetrix platform over other technology platforms because Almac’s aim is to “develop high-density custom microarrays as research tools, which are suited to the development of diagnostic tests, and to have the ability to use this platform for diagnostic purposes.”
 

“As a test maker, we are very much ‘platform agnostic’ and are capable of developing products using numerous different technical approaches.”

When Almac began developing its tests, “Affymetrix offered the highest capacity with the best reliability and reproducibility for such a platform,” he said. “Today, while other manufacturers have come closer to the Affymetrix platform, it is still the gold standard.”
 
Still, while Almac is satisfied with the Affymetrix platform, Tanney acknowledged that, as a test maker, the company is “capable of developing products using numerous different technical approaches.”
 
Tanney said that Affymetrix’s suitability as a diagnostics platform “depends on the application.” He said that Almac has used quantitative PCR to validate its assays, and suggested that Almac could use immunohistochemistry or fluorescence in situ hybridization, if it was a single-marker test.
 
“The platform on which this test is delivered is critically important, but will be decided on a case-by-case basis,” Tanney said.
 
According to Tanney, a second-generation sequencer is primarily “a research platform,” with many benefits, but many challenges. “The infrastructure and bioinformatics resources required to deal with the data are considerable, and much of it is still in its infancy,” he said.
 
“It is important to bear in mind, that while a burgeoning field, even microarray-based diagnostics are still in their infancy,” he added.
 
‘Displace Everything’
 
Almac is one of nearly a dozen companies in the Powered by Affymetrix program. Others developing tests for the GeneChip platform range from large, multinational diagnostics companies like Roche to smaller molecular diagnostics companies like the Netherlands’ Skyline Diagnostics or Denmark’s Medical Prognosis Institute.
 
Earlier this year, Sunnyvale, Calif.-based Pathwork Diagnostics received US Food and Drug Administration 510(k) clearance for its Tissue of Origin Test, the first diagnostic based on the Affy platform to be cleared by the regulatory body since Roche’s CYP450 AmpliChip test was cleared in 2004 (see BAN 8/5/2008, BAN 1/4/2005).
 
Dave Craford, vice president of commercial operations at Pathwork, said this week that the company believes second-generation sequencing tools are “useful for discovery in DNA applications today and will be useful in RNA applications soon.”
 
For “actual test delivery” though, the company believes it will be “a few years before [sequencing] is widely used as it needs to reduce the cost per experiment, cycle time, and instrument cost," he told BioArray News.
 
Shawn Becker, vice president of marketing and reimbursement at Pathwork, this week said that, despite the talk about emerging technology platforms in diagnostics, the company is committed to its platform. “Affymetrix microarrays are the gold standard for gene expression, based on the extensive literature documenting their use and successful application,” he said. The company has a “proven ability to manufacture large quantities of high-quality microarray chips.”
 
TessArae, a Potomac Falls, Va.-based company developing infectious disease-detection tools on the Affymetrix platform, is similarly confident in its choice of technology. Still, Matthew Lorence, vice president of marketing and sales at the firm, said that sequencing could displace arrays as a diagnostics platform at some point.
 
“I think it’s a possibility that it could happen, but I think a real test is that the FDA will not be real keen to let those technologies come on line as in vitro diagnostics devices,” Lorence told BioArray News. “Typically, that is what happens in the market,” he said. “PCR has been around for 20 years, but it is a fairly new entry into the diagnostics market, so I think that sequencing will probably displace everything in the research and diagnostics market, but it will take years for it to happen.”
 
Scientia’s Glorikian this week said that is unlikely that any one technology, be it qPCR, arrays, FISH, or second-gen sequencing, will win out in the end when it comes to molecular diagnostics.
 
“The market will always be diverse and no one will ever hang their hat on one technology platform because nobody likes to hang their hat on one thing,” he said. “People want a choice; they don’t want a single source.”
 
Still, Glorikian warned that if sequencing starts to cut into the array-based research market, it will eventually hurt the ability of array shops to support diagnostics programs. “These things feed each other,” he said. “If people are using the technology less for research projects, then you won’t get as many applications for your diagnostics business.”
 
While some may debate which technology will ultimately succeed in the molecular diagnostics market, Affymetrix believes that it stands to benefit as more of its partners begin to sell their tests in the US and Europe over the next few years.
 
Affy President Kevin King said during the firm’s third-quarter earnings call last month that the diagnostics business, which includes sales of “instrumentation, reagents, assays, and licenses” to partner companies, accounts for “less than 10 percent” of Affy’s total revenue.
 
Still, he said that the “vast majority of our diagnostic partners have cancer products” that will “provide growth” on the RNA side of the company’s business. “We’ve got a pipeline of other assays that are being developed by partners that includes prognostic tools for breast cancer, diagnostic assays for breast cancer, prostate cancer, liver cancer, as well as a whole host of others,” King said. “I think there are 14 products overall in the pipeline.”

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