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Ambry Hones Focus on NGS-Based Tests for Rare Disease, Cancer; Discontinues Carrier Screening Test

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With 10,000 next-generation sequencing-based diagnostic tests performed since 2010, including more than 1,000 exome sequencing tests, Ambry Genetics plans to develop additional panels in the areas of rare disease and oncology, and expand some of its existing panels.

Additionally, the company has decided to discontinue its carrier screening test, AmbryScreen, which had originally been planned as a sequencing-based test, but was launched in 2010 as an array-based test. Instead, it is looking to license the rights to develop and distribute a test to another company, Ardy Arianpour, Ambry's vice president of business development, told Clinical Sequencing News.

Thus far, the company's exome sequencing product has yielded a molecular diagnosis in around 30 percent of the cases in which it has been used. Ambry offers a tiered approach to exome sequencing. Its First-Tier Exome analyzes full exons and flanking intronic regions of around 4,000 genes characterized in the Human Gene Mutation Database, while the Clinical Diagnostic Exome covers the entire human exome.

Aaron Elliott, the company's director of research and development, told CSN that clinicians will often choose the first-tier exome test if there is a strong family history "and they can trace the pedigree back" for a disease like X-linked intellectual disability that involves 81 genes that would all be found in the Human Gene Mutation Database.

Additionally, the first-tier exome is cheaper and has a faster turnaround than the full exome. The first-tier exome costs $5,800 and has a turnaround time of 10 to 15 weeks, while the clinical diagnostic exome costs $15,129 with a turnaround time of 24 to 28 weeks. The full exome also includes testing of the patient's family members. In both cases, the full exome is captured and sequenced, but for the first-tier exome, analysis is restricted to the 4,000 HGMD genes.

Often, customers "will order the first tier in hopes that we catch something on those 4,000 genes," said Elliot. "If that's negative, a lot of times it will reflex to the full test."

Ambry's first next-gen sequencing test was an 81-gene X-linked intellectual disability panel that it launched around three years ago. Since then, many of the customers for that test are now ordering the exome test, said Elliott.

Around 1,000 of the 10,000 diagnostic sequencing tests that the company has run to date have been exome tests and, of the remainder, the vast majority have been hereditary cancer panels.

For its exome test, the company has a diagnostic hit rate of around 30 percent. Elliott said that when the test was first launched, the diagnostic rate was a little higher because often customers would send known samples to test the technology's ability to identify the causative mutation. But as more people order the test, the hit rate has gone down a bit.

Ambry is also receiving reimbursement for its tests, typically on a case-by-case basis, but Arianpour said that the firm also has a couple of contracts with insurance companies.

Ambry requires that all families who receive exome sequencing undergo an informed consent process with a clinical genetic counselor, including an explanation of exome sequencing and its limitations.

Exiting the Carrier Screening Market

In 2010, Ambry was in the midst of developing a sequencing-based carrier screening test that would screen for variants involved in more than 90 genetic diseases. Since then, however, the company has decided to discontinue the test, called AmbryScreen, which it launched later that year as an array-based genotyping test.

Arianpour said that Ambry decided to discontinue AmbryScreen because the markets for that test and its next-gen sequencing panels were so different.

"Carrier screening was the odd ball out," said Arianpour. "The volume and demand for it would have required a change in investment in our company. … There are certain customers that order our panels and exome tests that would not order the carrier screening test, so it would have had to be a different sales force," he added.

Additionally, Arianpour said that several companies have contacted Ambry about licensing and distributing the test, so the company is now pursuing that option.

How the test will be licensed and whether the final product will be based on genotyping or next-gen sequencing is still to be determined, Arianpour said.

Future Tests and Technology

Moving forward, Elliott said the company has additional sequencing-based panels in its pipeline in the fields of rare disease and oncology. Despite now selling a full exome test, Elliott said that there is still a market for such targeted panels.

"When there are overlapping phenotypes and a large number of genes involved," for instance like in XLID, "we are seeing people switch over [to the exome test], but when you're talking about 20, 30 genes, people are still ordering the panel," he said.

"Once you start hitting 80, 90, 100 genes, there's really no reason to run a panel," he noted.

However, panels still have benefits, Elliott said. The targeted panels typically cover the entire gene, while exome sequencing can still miss some areas. And if there are only a handful of genes involved, then targeted panels are still more cost-efficient, quicker, and easier to interpret.

For future panels, Ambry is also evaluating different sequencing technology platforms. "We have been early access with some new technologies that have recently been announced, and we are evaluating almost every new sequencing technology that's out in the marketplace," Arianpour said, but declined to provide further details.

Currently, all of Ambry's tests run on Illumina platforms, including the GAIIx, HiSeq 2000, HiSeq 2500, and MiSeq.

The company uses certain platforms for different tests, Elliott explained, running its exomes on either the HiSeq 2000 or 2500, for instance.

Ambry's tests are currently marketed as lab-developed, adhering to CLIA and CAP guidelines. As such, Arianpour said that Ambry does not currently have plans to seek US Food and Drug Administration 510(k) clearance for its products.

While Illumina has submitted its MiSeq system for FDA clearance, Arianpour said that even if the system were to receive clearance, Ambry would not necessarily convert its MiSeq to the FDA-cleared version. "I'm not sure how that would enhance our products, unless the FDA required it," he said.

Competition in the NGS diagnostic panel space has been increasing in recent years with a growing number of academic institutions and diagnostic companies offering exome sequencing tests and targeted sequencing panels for various disease states.

Emory Genetics Laboratory, Baylor College of Medicine, and Washington University School of Medicine are just a few of the institutions offering such tests. Other companies have launched sequencing-based tests in their disease-area specialty, such as Foundation Medicine and Asuragen's cancer panels.

Arianpour said that Ambry continues to remain competitive by building on its reputation and years of experience. Additionally, he said, the competition is "very healthy" and "validates what we've been doing."

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