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In Update on Next-Gen Sequencing Strategy, Qiagen Continues to Stress Workflow Advantages, Content

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As Qiagen approaches the commercialization of its GeneReader next-generation sequencing system next year, the company continues to stress the advantages of its "sample to insight" workflow, of which the sequencer is only one component, as well as its assay content for clinical applications.

"We're starting out with the upstream and the downstream," said CEO Peer Schatz during a Q&A session at the company's Analyst Day in New York this week, noting that Qiagen already sells sample prep kits, gene panels, the QiaCube sample prep instrument, and, through CLC Bio and Ingenuity, sequence analysis and interpretation software for next-gen sequencing.

"The new sequencing system is not really the quality differentiator per se," he said. "We have a significant quality differentiator on the upfront and on the downstream."

While many scientists are keen to find out about the read length and data quality of the GeneReader, "we think that is absolutely the wrong focus to have," Schatz told In Sequence during an interview.

The GeneReader will be "very competitive" on both accounts, but "something really innovative we can provide to the market is to integrate that with a very easy, push-button, automated sample-to-insight workflow," he said.

This, he added, will be very attractive to the clinical research and molecular diagnostics markets Qiagen intends to target with its NGS package. "Pathologists don't want to mess around with screwdrivers and [creating their] own workflow optimizations," Schatz said. "They want to ultimately have a solid business that they can rely on in the future, and we're giving them that tool."

As reported earlier, the upstream workflow consists of a QiaCube instrument for DNA extraction, target selection, and library preparation; a dedicated QiaCube NGS for library amplification preparation and bead enrichment; and the GeneReader.

This is followed by the primary analysis, or base calling, which is embedded in the GeneReader and generates a FASTQ file; the secondary analysis, consisting of read alignment and variant calling to generate a VCF file, using software from CLC Bio; and the tertiary analysis or biological and clinical interpretation, which utilizes software from Ingenuity. Qiagen acquired both companies earlier this year.

Qiagen will sell sequencing platform-independent versions of its sample prep instruments and software, but there will also be dedicated versions for the GeneReader that will be tightly integrated with that machine.

Pricing for the GeneReader or the entire package is not available yet, but Schatz told IS that the company plans to be "very competitive" with existing systems, which he said retail on the order of $100,000 to $120,000, including some front-end instrumentation.

As reported earlier this month, a pre-commercial version of the GeneReader is in the hands of a few early customers, and the company plans to commercialize the system next year.

Over the next few months, Qiagen intends to release more information about the system, and the Advances in Genome Biology and Technology conference next February would be an appropriate venue to talk about performance specs, Schatz said.

The first version of the instrument will likely take up to six flow cells, which can be added continuously through random access, even during an ongoing run. Customers will be able to upgrade the system to a version that can take up to 20 flow cells.

Through barcoding, each flow cell can sequence up to 12 samples, so at full capacity the system will be able to run up to 240 samples at a time.

Different applications requiring different read lengths can be run at the same time, for example, gene panels, RNA seq, or microRNA sequencing.

Qiagen said previously that each flow cell will generate up to 2 gigabases of data. Schatz said this week that this "is just the beginning" as the company continues to optimize its sequencing chemistry.

He told IS that the instrument "can do exomes" but is a "very efficient machine" for gene panels. For panels, the data accuracy will be Q30 "or better". A read length of 100 base pairs will be "more than enough," he said, and Qiagen will soon "be coming forward with some information on paired-end sequencing."

Qiagen's sequencing-by-synthesis chemistry, which it obtained through its acquisition of Intelligent Bio-Systems, uses reversible terminator nucleotides, so it avoids homopolymer errors encountered by chemistries that don't use terminators, Schatz said. It also uses a mixture of fluorescent and unlabeled "dark" nucleotides, which he said reduces cost and increases specificity.

During a Q&A, Schatz said that Qiagen exclusively licenses the technology from Columbia University, where it was developed by Jingyue Ju, and has freedom to operate under the license, irrespective of an ongoing lawsuit between Columbia and Illumina around the IP.

Asked about its FDA strategy for the GeneReader, Schatz said that while Qiagen wants to position it in the clinical market, "many of our customers tell us that they would prefer it not to be FDA-approved."

He said the company "will definitely pursue a CE marking" in Europe and is looking into "FDA approval options." He said there is interest from pharmaceutical partners, for example, in gene panels that can run alongside PCR assays. "It's quite clear in the market that there is a strong preference for a combination approach, real-time PCR and next gen [sequencing], and not only next-gen alone," he said.

"We're going to make a decision on if and when we take this to FDA based on what we see as the appropriate clinical and also economical approach," he said, noting that it is difficult to obtain reimbursement for NGS-based tests at the moment.

"We will not go forward with a 'fig leaf assay', that is simply an assay to approve a system, which a few months later, due to software changes and reagent changes, will be out of date," he said. "We do not think that makes sense. We will go forward with something that will have many years of lifetime in terms of clinical utility [and] economic utility for our customers in pathology and also in the clinic."

Besides clinical applications, Qiagen does see potential for the GeneReader in other areas, such as forensics. The firm is "deeply engaged" with "key opinion leaders" in that area, said Dirk Löffert, vice president and head of global product development for life sciences, who gave a presentation at the Analyst Day. He cautioned, however, that it will take time to develop content in that area.

Qiagen also provided additional information on its NGS sample prep systems. According to Löffert, the company plans to release a DNA extraction kit for FFPE samples, called GeneRead DNA FFPE NGS, early next year. Originally, the company had planned to make this kit, which will run on the QiaCube, available in mid-2013. The kits can run on the QiaCube, which can extract DNA from up to 12 samples at a time.

Further, the QiaCube will assist with target enrichment. Qiagen has already launched a number of gene panels for different cancer types, which are compatible with any type of sequencer. Tumor gene panels will also be the first application for the GeneReader, Löffert said.

Next year, the company is scheduled to release additional panels in the areas of inherited diseases, cardiomyopathy, cancer predisposition, hematological cancer, and other cancers. Panels for autoimmune disease and infectious disease are in the works, too, Schatz said.

Finally, the QiaCube can be used for library preparation, and Löffert said Qiagen has developed an automated library construction protocol, called Library Prep Q Kit, that is "much more efficient" in terms of number of steps and tubes, total time, and yield than competitors' protocols.

Qiagen said previously that it plans to make the QiaSymphony, which can process more samples at a time than the QiaCube, part of the GeneReader workflow, but Schatz said the firm has decided to focus on the QiaCube-based workflow first. "QiaSymphony provides an additional benefit on top of that," he said. "It will come, but we definitely put the priority on the QiaCube right now. We will reactivate the QiaSymphony program once this comes out."

The QiaCube NGS, which is not yet commercially available, prepares the library for bead-based clonal amplification. The amplification itself takes place outside the instrument, Löffert said, but the bead enrichment that follows is performed on the instrument.

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