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Natera Preps Move into Cancer Dx Market as it Continues Building NIPT Capabilities

NEW YORK (GenomeWeb) – As it seeks to build out its non-invasive prenatal testing business, Natera is set to move into the cancer diagnostics space.

The San Carlos, Calif.-based firm, probably best known for its Panorama NIPT launched in early 2013 for detecting fetal aneuploidies, is in the midst of preparing that test for use in the lower-risk pregnancy population. Like other NIPTs, Panorama has largely been used for higher-risk populations.

Quietly, though, Natera has also been leveraging Panorama's underlying technology for the cancer space. Natera CEO Matthew Rabinowitz declined to provide an exact time frame for the company's oncology products, but told GenomeWeb Daily News recently that announcements in this area would be coming "very soon."

Panorama is based on next-generation sequencing technology and the key to the technology, and its utility for the cancer space, is its sensitivity. While other firms offering NIPTs have a cutoff of about 4 percent DNA fraction, Natera's technology can go down to .01 percent DNA fraction, Rabinowitz said, meaning that in a 5 milliliter sample of plasma, Natera can detect a single molecule that is characteristic of the mutation of interest.

"And that's really what you need for cell-free DNA for cancer because the fraction of DNA from tumors can be very low," Rabinowitz said.

Natera's technology uses cell-free DNA to look at both single-nucleotide variations and copy number variations, both of which may be indicative of cancer. While NGS forms the basis of the Panorama test, Natera uses multiplex PCR to create the material for sequencing, and according to Rabinowitz, its technology can multiplex about 20,000 PCR primers in a single reaction. Multiplex PCR can achieve high sensitivity, but because it is an exponential reaction, if too many primers are put in a single reaction well, cross reactions and hybridizations to multiple and inappropriate parts of the genome will result in getting "garbage out of these reactions," he said.

Changes to its PCR amplification, however, allow Natera to amplify a sequence with minimal chances of primers to cross react and form dimers, he said. By optimizing its method with primers that are designed to cover a set of targets, the primers have "very uniform thermodynamic characteristics," reducing the possibility of such reactions.

For use in cancer, Natera has made additional improvements so that the technology can look at thousands of targets on the genome in parallel — and with what Rabinowitz said is essentially single-molecule sensitivity.

Focus on CNV Detection

Natera has refined its bioinformatics to target polymorphic positions, such as SNPs, and by using information about the haplotypes that are present and the segments of chromosome that are absent or present, Natera can detect CNVs below .5 percent. "It all comes down to building a much more powerful test statistic and getting the cleanest data you possibly can," Rabinowitz told GWDN.

He added that rather than doing a "huge amount" of sequencing — which eventually will reach a point where the returns won't justify the costs and amount of work needed to repeatedly sequence a sample — Natera investigates the polymorphic loci to see what may be present or absent, a method that he said is a "a much more powerful approach to these problems," and a reason that the company can get down to such low DNA fractions.

The capabilities of Natera's technology are particularly important for cancer in the context of CNVs, Rabinowitz noted. Much of the scientific literature on cancer has focused on SNVs where pull-down methods have been used to target regions to detect point mutations that may be associated with the tumor.

While Natera's multiplex PCR approach can and has done "much better than what we've seen in the literature" — for example, going down to .01 percent DNA fraction — "it's not like we are so far completely ahead of what others can do in the context of SNVs," Rabinowitz said. But in its ability to detect CNVs, Natera's methods "are well above what we have seen in the literature."

This is particularly important for what are known as C class cancers, which are largely driven, especially in their early stages, by CNVs. C class cancers include ovarian, lung, and breast cancer, and the ability to detect both SNVs and CNVs together, Rabinowitz said, "substantially improves your detection rates for these cancers and can substantially impact your therapy decisions for" them.

According to Natera Vice President of Marketing and Business Development Solomon Moshkevich, in early stage work, Natera has been able to detect CNVs at below .5 percent of DNA and SNVs at .05 percent of DNA.

"We are developing our hypotheses now and testing them to … build something that actually helps physicians, [and better understand] what kind of clinical trials or experiments … we need to run in order to demonstrate clinical efficacy and utility," Moshkevich told GWDN.

Natera has a number of ongoing trials, in which the company is or will be collecting samples from a variety of cancers with the goal of seeing for each one the fraction of cell-free DNA present in the plasma at the different stages of disease.

Current cancers being investigated in such trials include breast, colon, lung, and ovarian cancer. Natera also intends to study its technology in prostate, bladder, melanoma, pancreatic, liver, and endometrial cancer, as well as in glioblastoma.

Natera will compare when a cancer is first detected or suspected with existing clinical methods and when the cancer can be detected using its cell-free DNA approach to see if its approach offers any advantages. "We seek to make an impact through early detection of cancer at stage 1, when it's curable, and ongoing therapeutic monitoring," Rabinowitz said.

Also, Natera is comparing tumor profiles from the biopsies performed at the time of detection using existing methods with tumor profiles of the biopsies when the cancer is detected using its cell-free DNA method. In connection with that effort, Natera is collaborating with more than five "top cancer centers around the country."

Rabinowitz declined the name the centers, except for the Feinstein Institute for Medical Research. That partnership is aimed at research on cell-free circulating tumor DNA in order to detect, diagnose, and monitor cancer.

Moshkevich said that the company's ability to detect CNVs will allow it to perform liquid biopsies in a manner that no one else can do. The technology, he added, could have particular use for tumor types that, so far, have been a challenge to biopsy, such as certain types of lung cancer or ovarian cancer, where the amount of samples that can be biopsied are limited. Using a liquid biopsy approach "offers a great way to do that," he said.

Tumor biopsies also can have heterogeneous mutations that may not be detected based on one sample of a tumor, whereas a liquid biopsy can offer a more complete picture since the tumor is theoretically releasing DNA from all the various DNA strands, he added.

Natera has targeted prospective studies of products for the early detection of certain cancers, as well as those focused on the therapeutic space. Rabinowitz declined to provide additional details, saying only they are "very large opportunities in cancer which will ultimately be bigger than NIPT even."

When its products are ready for commercialization, Natera will pursue a two-pronged sales strategy. It will have a direct sales force — but selling products directly for every cancer type would not be feasible, Rabinowitz said, so, additionally, the company will leverage relationships it already has with lab partners.

Rabinowitz said that Natera has an extensive network of partners that includes more than 60 labs internationally, to whom it will license its technology. The labs would then build their own cancer assays and make them available through their sales channels. Natera will be "very dependent on lab partners, so we are just trying to intelligently segment the market," he said, adding that in many cases, decisions about which cancers the company will address directly and which it will leave to partners have already been made.

Natera has already adopted such a model for its other tests. Until recently, all Natera-developed tests were run out of it San Carlos laboratory, but as of July all of the company's non-invasive paternity testing is being conducted by Fairfield, Ohio-based DNA Diagnostics Center, which has licensed Natera's intellectual property and developed its own laboratory-developed test using Natera's technology, Moshkevich said.

Natera's algorithms have been made available as a piece of software to DNA Diagnostics to analyze the data coming from the sequencer, "and the way that we're delivering that software is [as] a service … through the cloud," so that it is scalable and network-secure, he said.

"What we expect is that as the cost of sequencing comes down, as machines get smaller [and] cheaper, and as they penetrate not only the big research laboratories and then the big clinical laboratories, but also those hospital labs around the world in a really distributed fashion, we're going to ride that wave and make our content and our unique technology available to groups around the world that want to run that," he said.

Natera is also in discussions with the US Food and Drug Administration about the use of a version of the company's software to support its cloud-based distribution model in the US.

Decentralizing testing away from Natera's lab means a "totally new footprint for Natera," Moshkevich said. However, Natera will also continue to run tests out of its San Carlos facility. "The lab isn't going anywhere," he said. "One of the biggest challenges we face is scale. We are racing to keep up with demand, and it's not easy because you need organizational scale, you need space, you need hiring, and that's a real business challenge for us," he said.

According to Rabinowitz, Natera has had cancer in its sight from the beginning. The company was incorporated in 2007 as Gene Security Network with a mission to change how genetic diseases are managed. The firm started first with pregnancy tests — its first commercially available test was the Preimplantation Genetic Screening test, launched in 2009, and it currently has five tests on the market. Now that it has established itself in that space, Natera is moving to meet unfilled needs in other disease areas, company officials said.

Next for NIPT

To that end, Natera estimates that it is now one of the top-two NIPT companies in terms of test volume, alongside Ariosa Diagnostics. Because Natera is privately held, Rabinowitz declined to provide Panorama NIPT volume numbers, but a comparison with Ariosa and Sequenom's figures may provide a clue.

Ariosa said in a document filed with the US Securities and Exchange Commission that it tested more than 50,000 women with its Harmony NIPT during the first quarter of 2014, the most current quarter for which the company's figures are available. Meanwhile, Sequenom said it accessioned 39,800 MaterniT21 Plus tests during the same period. During the second quarter, Sequenom ran approximately 41,000 MaterniT21 Plus tests.

Moving forward, Rabinowitz told GWDN that there will be "substantial expansions" to the Panorama test, adding, "We want to cover as much as one can cover with high sensitivity and specificity as one can."

For example, in March, Natera expanded Panorama's capabilities to include five microdeletions, including 22q11.2 deletion syndrome.

Rabinowitz said that there are many more microdeletions on Natera's panel that have yet to be commercially launched as it waits for results to validate their efficacy. He added that the company plans to offer other indications on the test beyond microdeletions "that are just as relevant to the pregnancy and the health of the pregnancy," though he declined to provide details.

Panorama is still largely used for the higher-risk pregnancy population — either older women, or those with other indications of elevated risk of having a fetal aneuploidy — but during the summer, Natera published a study that demonstrated Panorama's high positive predictive value for lower-risk pregnancies, as well as higher-risk pregnancies.

"We are hypothesizing that that is because all of the false positives are caused on our test by mosaicisms, whereas the other tests will have false positives caused by all sorts of biological things that they just can't identify," Rabinowitz said. "We are separating out the maternal issues like vanishing twins, and maternal deletions, and duplications, and maternal mosaicisms, and also we are very robust with the amplification biases and quantitative variability, so we are not subject to any of those reasons for false positives," he said.

None of the major medical societies have yet thrown their support behind the use of NIPTs for lower-risk pregnancies, although the American College of Medical Genetics has not differentiated their use for lower- or higher-risk pregnancies. Nonetheless, Rabinowitz said that Natera is seeing increasing use by physicians for the lower-risk pregnancy population "because the doctors are reading the literature. They're not waiting on [the American Congress of Obstetricians and Gynecologists to issue its guidelines] anymore."

To further test the utility of NIPTs as a first-line screen for the general population, Natera is sponsoring a study to evaluate the use of Panorama in combination with its Horizon multi-disease genetic carrier screening test. About 3,000 women in Rhode Island will be offered Panorama as part of their prenatal care. The effect on care will be monitored and analyzed. Enrollment is ongoing for the study, dubbed DNAFirst: Primary Screening for Down Syndrome by Maternal Plasma DNA.

The women will also be offered the Horizon test as part of the study, which is being led by Glenn Palomaki, the assistant director of the division of medical screening and special testing at Women & Infants Hospital of Rhode Island, and an associate professor in the pathology and laboratory medicine department of the Alpert Medical School at Brown University.

Natera has also made available as one package to patients its Panorama, Horizon, and microdeletion tests, allowing a patient to get all three tests done with one needle stick.

"It makes no sense just to be testing for aneuploidies when some of these aneuploidies are much less prevalent than the inherited genetic conditions and the de novo microdeletions," Rabinowitz said.

Additionally, the New York State Department of Health recently conditionally approved Horizon and the Anora miscarriage test for marketing to residents in the state. Horizon screens for 39 diseases, including Fragile X, spinal muscular atrophy, and 127 cystic fibrosis mutations. Anora uses chromosomal microarray analysis featuring SNP technology for physicians and patients to understand why a miscarriage occurred.

"As we access the general population, a whole suite of our products are relevant to the Ob/Gyn market, and there are certain tests that are just as relevant, like karyotyping, irrespective of the risk profile and they're extremely well reimbursed," Rabinowitz said. "It's not just that you will see expanded uptick of NIPT/Panorama. It's also that we will be offering our whole suite of services to the lower-risk market and be servicing a lot more Ob/Gyn customers who will start offering testing to their patients."

During the summer, it appeared that the Panorama business was dealt a blow when Quest Diagnostics reached an agreement with Sequenom to offer MaterniT21 Plus. Quest and Natera had previously partnered to make Panorama available through Quest. Under the terms of its the deal with Sequenom, though, Quest will said it will stop offering Panorama.

According to Rabinowitz, however, it was Natera that opted to end its agreement with Quest after the reference lab asked for reduced pricing on the test.

"I would obviously much prefer that Quest was prepared to pay us for the value that we see in our test and was prepared to pay us for the quality," he said. "But it is absolutely the case that they asked us for reduced pricing, they asked us for substantially lower pricing for our microdeletions panel, and we said no.

"We would much rather go direct and see very good margins," Rabinowitz said, adding that Natera's deal with Quest ends in December. "The reality is that the gross margins that we see from the biggest labs are very low."

While the Quest termination could negatively affect Panorama's volume growth in the near term, he said that gross margins would improve. He declined to provide a percentage of revenues from direct sales versus from lab partners, but said that direct sales comprise "the vast majority."

In addition to expanding its NIPT capabilities and moving into the cancer space, Moshkevich said that Natera is looking at the transplant diagnostics market, where the ability of its technology to detect low DNA fractions could have value.

"Anytime you've got a mixture of DNA with a very low fraction of allele or something different from the host that you're trying to measure, we're going to have a platform that performs extremely well," he said, adding the technology would be well-suited for quantifying and qualifying what's happening with that DNA.