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Illumina Sketches Strategy to Push NGS into Reproductive Health, Disease Testing, Oncology

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Illumina last week provided a glimpse into its strategy to establish next-generation sequencing in clinical markets, including plans to submit non-invasive prenatal tests on the HiSeq 2500, MiSeq, and NextSeq 500 to regulatory authorities, to launch a preimplantation genetic screening test called VeriSeq and an HLA typing product on the MiSeq, and to partner with pharmaceutical companies and oncology experts to develop targeted cancer genomics tests.

Also last week, the company announced a partnership with Amgen to develop and commercialize a multi-gene NGS-based test for the MiSeqDx as a companion diagnostic for the colorectal cancer drug Vectibix.

In addition, this week the firm revealed a multi-year supply agreement with the Laboratory Corporation of America that provides LabCorp with "expanded rights" to use Illumina's NGS and microarray platforms to develop lab-developed clinical tests in the US and Canada.

That collaboration follows a similar multi-year licensing agreement with Quest Diagnostics, announced earlier this month, under which Quest obtains "broad rights" to use Illumina's sequencing and genotyping technology to develop clinical lab-developed tests for several diseases in the US. Quest struck a similar agreement with Life Technologies regarding the Ion Torrent sequencing technology.

Pushing NGS into the clinic

During an event for investors last week, which was webcast, Illumina talked about its strategy for conquering new markets, many of them in the clinical arena. "One of the most important market expansion efforts we're working on is ways to practically push NGS into the clinic," CEO Jay Flatley said.

Overall, Illumina sees opportunities for its products in markets that total $20 billion this year, said Chief Commercial Officer Christian Henry. The biggest chunk of that is in oncology, about a $12 billion market today, including $8.5 million from theranostics, such as clinical diagnostics and companion diagnostics; about $2 billion from basic and translational cancer research; about $1 billion from inherited cancer testing; and about $500 million from molecular monitoring, such as the detection of residual disease.

Reproductive and genetic health is about a $2 billion opportunity, he said, with about $1.1 billion from non-invasive prenatal testing, $700 million from in vitro fertilization — both preimplantation screening and preimplantation diagnostics — and $200 million from neonatal and carrier screening.

HLA typing represents another $300 million market opportunity, according to the company.

Illumina has already started to penetrate some of these new markets, as evidenced by a shift in its customer base. Over the last five years, Illumina's revenue from commercial customers in markets like NIPT testing, cancer genomics, and agriculture grew 34 percent per year, while revenue from hospitals, though still small, grew 24 percent per year, Henry said. Revenue from academic and government customers, on the other hand — still Illumina's largest customer segment — only grew by 14 percent per year during that time.

In 2013, almost half of all HiSeq orders came from commercial customers, he said, including commercial molecular diagnostics customers, pharmaceutical companies, service providers, hospitals, and NIPT providers.

Pharma in particular appears to be on the verge of expanding its use of next-gen sequencing. Over the last few years, Illumina's pharma business has been growing steadily, Flatley said, driven mostly by the adoption of NGS as a standard tool in pharmaceutical research labs, while pharma tended to outsource large-scale sequencing projects to service providers.

However, "we're getting some sense that there might be a little bit of a shift in the air," he said, starting with Regeneron, which said last week that it has built its own genome center, where it plans to sequence the exomes of 100,000 patients.

Rick Klausner, Illumina's chief medical officer and general manager of its new oncology business unit, added that according to his recent discussions with drug developers, "at least three" big pharmas have made the decision to build their own internal genome centers, not so much for early discovery work but for translational research and clinical trials.

Illumina also grew its sales force in the Americas by a total of 20 percent last year "to focus on the emerging clinical opportunity," Henry said. This year, the company consolidated its clinical and non-clinical sales teams, which were separate for the last few years, "as we are seeing the lines between research and the clinic continue to get blurrier and blurrier," he said.

To help establish next-gen sequencing in the clinic, an important effort will be to increase the clinical utility of the genome, Flatley said, which will require the creation of very large-scale genotype-phenotype databases.

Part of the reason the company launched the HiSeq X Ten, a high-throughput sequencing platform dedicated to human whole-genome sequencing, is "to catalyze the creation of these large-scale databases, to increase the discovery rate, to feed clinical content back into the products that we'll deliver for routine use in the clinic," he said.

Moreover, Illumina will continue to work with the US Food and Drug Administration and other regulatory agencies to get next-gen sequencing platforms approved, Flatley said, a process that started last year with the MiSeqDx, which obtained premarket clearance from the FDA in November and CE marking earlier in 2013.

In addition, he said, Illumina plans to "work across clinical communities to help define NGS standards and guidelines" and to "partner around the world to help define content and protocols that customers [want] to use."

Reproductive health and genetic disease testing

One clinical area where Illumina's sequencing technology is already being used routinely is non-invasive prenatal testing. The company's newly-established Reproductive and Genetic Health business unit, which comprises array technology from BlueGnome and sequencing assays from Verinata Health, companies it acquired in 2012 and 2013, respectively, will continue to foster the use of sequencing in these areas, including in vitro fertilization, NIPT, newborn screening, carrier screening, and genetic disease testing.

In the second quarter of this year, Illumina plans to launch an NGS-based test for preimplantation genetic screening called VeriSeq. The test will initially run on the MiSeq platform, with plans to offer it on the NextSeq later on. It will be "an adjunct and addition to what we can do on array technology," said Tristan Orpin, general manager of the new unit, but will be less expensive and easier.

Ninety percent of all PGS testing today is performed with Illumina's BlueGnome microarray technology, he said, but it is currently only offered by about 3 percent of IVF centers due to a lack of results from clinical trials that demonstrate its benefits and safety — although these are starting to come out. But even in the absence of such studies, he said, the PGS market has been growing 60 percent annually.

NIPT is a $1.1 billion market opportunity if high-risk pregnancies alone are included, Orpin said, but it could increase by up to six-fold if testing is introduced for average-risk pregnancies as well.

Verinata currently offers a lab-developed NIPT, called Verifi, which it markets in the US through PerkinElmer. As reported last week, Illumina plans to submit an IVD version of the test on the HiSeq 2500 for FDA premarket approval by the end of this year. It will also submit the instrument and assay to obtain CE approval in Europe, Orpin said.

Illumina will continue to have a limited direct sales presence for NIPT, Orpin said, noting that "that is not the core focus of what Verinata is within the Illumina organization."

To drive the adoption of NIPT, Illumina plans to publish clinical trial data for average risk pregnancies, expand trials to other populations through partnership programs with other countries, and support trials that will allow it to go through regulatory processes, he said.

Illumina also plans to partner with advocacy groups, key opinion leaders, and professional groups such as the American Congress of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine to help expand existing guidelines for NIPT to average-risk pregnancies and other clinical conditions.

In addition, the company plans to engage with the China Food and Drug Administration to obtain approval for the MiSeqDx as a medical device and for a low-resolution NIPT scan that runs on the MiSeq.

Longer term, Orpin said, the NextSeq 500 platform, which Illumina just launched last week, is the "perfect instrument" for NIPT. The system, which uses a simplified sequencing chemistry and reagent cartridges, can analyze 16 to 20 NIPT samples per run, and "for most of the moderate-throughput labs, that's the absolute perfect number, so we will be certainly doing an FDA submission for the NextSeq instrument," he said. He did not provide a timeline.

Illumina also plans to establish a NIPT tech-transfer program to support non-US labs who cannot or do not want to send out NIPT samples to a service provider outside their own country. This will be a "full sample-to-answer solution" that integrates sample prep, sequencing on the HiSeq and later on the NextSeq, and BlueGnome's BlueFuse software for analysis, Orpin said. Eventually, the process will also involve the NeoPrep library prep platform that Illumina announced last week, which can process 16 samples in parallel.

"All this business we do in setting up these tech transfers in many other nations, in Europe and then extending out into Asia, will help us with our IVD portfolio when that gets launched," Orpin said.

Illumina will continue to collaborate on the NIPT front as well. It will have test send-out partnerships, especially with European partners, it will support and reinforce supply agreements with other providers, and it will continue to sell its test through partners such as PerkinElmer in the US. "You will see a build-out of many other formalized relationships around the area of non-invasive prenatal testing," Orpin said.

Another "very significant" market for Illumina is newborn screening, he said. Following the FDA's approval of its cystic fibrosis test on the MiSeqDx last year, Illumina and its partners plan to expand to "a broader panel of markers," he said, adding that NextSeq is an "ideal platform" for higher-throughput genetic disease screening.

Later on in the discussion, Flatley cautioned that the success of sequencing-based newborn screening hinges on ethical questions that need to be addressed on the one hand, and better clinical utility on the other hand. "We need, frankly, more clinical utility for newborn screening to begin to [get] payback in a big way," he said, adding that very few genetic alterations that sequencing can uncover at birth have treatments associated with them today.

The genetic disease testing market is another "very significant" opportunity for Illumina, according to Orpin. Illumina will continue to offer components for lab-developed carrier screening and inherited disease diagnosis tests, but over time, these will transition to more and more IVD products, he said.

HLA typing on MiSeq

Illumina also plans to bring a dedicated system for HLA typing to market, for use in transplant medicine. The system will use either the MiSeq or the MiSeqDx.

According to Matt Posard, general manager of Illumina's New and Emerging business unit, the HLA-typing market is about $250 million in total and "ready for a new technology that can address the shortcomings of the existing technology," mainly Sanger sequencing.

By the middle of this year, Illumina plans to launch a TruSight HLA system, he said, consisting of a sample prep kit for eight HLA genes, which will be sequenced completely and be fully phased; the MiSeq or MiSeqDx instrument; and integrated analysis software from an unnamed "market-leading" provider, so most customers won't need to change their existing software.

Customers will be able to decide between the standard MiSeq and the MiSeqDx, he said, but Illumina expects most customers to choose the MiSeqDx.

Unlocking the oncology market

By far the largest market opportunity for Illumina lies in oncology. According to the company's estimates, the accessible clinical oncology market totals about $12 billion today, including a clinical market of $11 billion and a basic and translational oncology research market of $1 billion.

According to Klausner, who is also the former director of the National Cancer Institute, the clinical oncology opportunity is split into germline testing for inherited cancer, theranostics, and molecular monitoring of disease, which might turn out to be "perhaps the most transformative use of NGS in oncology."

Oncology research is fueled not only by the new opportunities afforded by next-gen sequencing but also by approaches such as single-cell sequencing, which allows researchers to study heterogeneity within cancers, he said.

Oncology drug development is "changing dramatically" from empiric chemotherapy to molecularly targeted drugs, Klausner said. Dozens of such drugs, which require companion diagnostics, are currently either approved or close to approval, and "perhaps hundreds" are in development.

"The big change in oncology that we're now entering, and it's going to go fast, is combination targeted therapies," he said, similar to drug combinations used to treat HIV infections.

But combining drugs means "unprecedented needs for molecular diagnostics," and "only NGS is poised to handle the range and extent and complexity of challenges for not only the development of molecularly targeted drugs, but ultimately its use."

To assist pharmaceutical companies with the development of drugs, Illumina plans to develop NGS-based Onco Panels, Klausner said. These would be a universal platform that covers all targeted molecular alterations included in the development pipeline of all participating pharmaceutical companies.

Such a platform, the content of which would not be owned by any one company, would allow the industry to set standards for how to measure the molecular changes reproducibly, and would offer a streamlined and reliable regulatory pathway, he said. It would also facilitate combination trials of drugs across companies. "We're moving away from the era of companion diagnostics towards the era of companion therapeutics, because this is how physicians will choose what drugs and combinations of drugs to use," he said.

To develop the Onco Panels, which drug companies would access through a subscription model, Illumina is working closely with the FDA, Klausner said. The panels will be developed on an FDA-cleared sequencing platform and undergo regulatory review, eventually resulting in a commercial IVD. "There is enormous enthusiasm, both at the FDA and across the pharmaceutical industry, as we have been discussing this with virtually all pharmaceutical companies," Klausner said.

According to Flatley, the Onco Panels would be used in a typical clinical trial. As companies discover which molecular alterations actually matter for their particular drug, "the actual companion diagnostic to go with that drug may be either a scaled-down version of [the Onco Panel] or something where the extra genes are coded out, and that would become reimbursed and approved as a targeted companion diagnostic," he explained.

Besides Onco Panels for drug developers, Illumina also plans to develop a so-called actionable genome panel for use by practicing oncologists. This will be based on clinical utility, which will rely on "an agreed-upon community definition of clinical utility," Klausner said. It will also need to be included in major practice guidelines and approved by the FDA. The panel will be updated annually or more often as needed and will serve as an "evolving template for practice decisions, based upon clinical utility."

To develop the actionable genome panel, Illumina plans to engage with leaders in oncology, the FDA, the American Society of Clinical Oncology, the National Cancer Institute, the Broad Institute, and leading cancer centers. This year, it plans to develop a "rapid, easy and reliable" workflow, including sample preparation from challenging sources such as FFPE tissue, library preparation, sequencing, variant calling, and clinical reporting. It will then publish the resulting standards and submit them to the American Society for Clinical Oncology for inclusion in guidelines. Eventually, Illumina plans to take the actionable genome panel through regulatory approval and make it widely available.

Molecular monitoring of disease by next-gen sequencing is another area that Illumina plans to focus on. It is already being applied by companies like Sequenta and Adaptive Biotechnologies to provide information on minimal residual disease for leukemia "in a very limited way," Klausner said, and has potential for lymphomas as well.

According to Klausner, Illumina's "number one internal research project for oncology this year" is to explore the ability to measure circulating nucleic acids in cancer patients, with the ultimate goal to develop NGS-based real-time molecular monitoring tests for the point of care. He cautioned that this project is still at the research stage and "much more difficult than people generally think," but "its ability to transform oncology drives us to test this."

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