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Singular Bio Technology Offers Invitae Route to Low-Cost Testing

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NEW YORK – With its recent acquisition of San Francisco startup Singular Bio, Invitae is joining others that are aiming to bring down the cost of genetic testing, starting with cell-free DNA-based noninvasive prenatal screening.

The technology will also lend itself to other applications that involve cell-free nucleic acids, such as liquid biopsy cancer tests.

Invitae acquired Singular Bio last month for approximately $49.3 million in stock and $5.7 million in cash. The company was founded in 2012 by Hywel Jones, a former director of market development at Affymetrix, and Kalim Mir, a former researcher at the University of Oxford who also founded XGenomes. The firm had been working on a molecular counting technology that combines targeted probe amplification with fluorescence imaging.

Sean George, Invitae's CEO, said his company had been following Singular Bio's work from the beginning and was aware of its potential for lowering the cost of DNA testing. "As a key part of our strategy, we've always been on the lookout for technologies that can help us lower the cost of goods," he said. "We kind of knew what they were starting, we thought it was pretty interesting, and we stayed in touch with them."

About a year and a half ago, Invitae started talks about a potential partnership "in earnest," he said, and finally decided to acquire the firm to accelerate assay development, automation, and the commercialization process. 

The startup had about 10 employees, all of which have joined Invitae, which is located about half a mile away. It had been developing a universal platform for cell-free nucleic acid screening or monitoring applications with a primary focus on noninvasive prenatal screening.

"I'm very proud of the team and technology we built at Singular Bio," said Jim Collins, until recently chief technology officer at Singular Bio. "We believe that becoming part of Invitae gives us a platform to help significantly expand access to high-quality, affordable genetic testing for patients, beginning with women in early pregnancy."

Singular Bio's technology starts with a highly sensitive multiplex ligation-dependent probe amplification assay, which uses sets of two probes that get ligated and amplified when they hybridize to their target. The amplification products, which are fluorescently labeled, are then counted on a microarray using a high-powered imaging platform. In the case of fetal chromosomal aneuploidy, for example, there would be proportionally more labeled products from one chromosome than from others.

"The very simple upfront approach and the very simple, elegant readout allows you to do it at a substantially lower cost of goods than any kind of other multiplex amplification and shotgun sequencing approach," George said.

He added that Singular Bio had "some really unique intellectual property" that is key to the technology's ability to lower costs but that Invitae was less interested in expanding its patent estate than in getting the technology to work. Singular Bio is the assignee on six US patents issued between 2015 and 2017 that relate to methods for detecting genetic variants by counting the labels in probes and to spatially addressable low-density microarrays, as well as on several patent applications.

According to Collins, the technology is mainly based on a patent application filed by Mir in 2003 and originally assigned to the University of Oxford, which Singular Bio acquired in 2013. That application, US 2004/0248144 A1, covers spatially addressable low-density microarrays for single-molecule detection.

The approach chosen by Singular Bio, which does not involve next-generation sequencing like NIPTs from Illumina, Natera, LabCorp's Sequenom, or BGI, is similar in principle to other DNA-based prenatal screening assays that have taken a step back from sequencing.

PerkinElmer's Vanadis technology, for example, targets specific DNA fragments with probes and converts them into DNA circles, which it amplifies using rolling circle replication, resulting in DNA balls that are fluorescently labeled and imaged on a 96-well plate using a microplate scanner. At the time PerkinElmer acquired the technology in 2016, it touted its ability "to offer a simplified, cost-effective, high-throughput approach to NIPT to help facilitate wider access for pregnant women."

Roche Ariosa's Harmony test also employs targeted amplification of chromosomal regions, using DANSR (Digital Analysis of Selected Regions) assays that rely on three adjacent probes, which it reads out and quantifies using microarrays, switching from an earlier version that relied on sequencing.

Eurofins LifeCodexx, for its part, moved from a sequencing-based assay for its PrenaTest to a methylation-specific quantitative PCR assay that relies on methylation differences in specific gene regions between maternal and fetal DNA.

Collins declined to compare Singular Bio's technology to that of competitors. According to George, its molecular assay and the way it counts the amplification products is "quite different" from other approaches, even though they are similar in nature. "We've looked at a lot of different technologies, and there are a dozen other ways for doing this," he said. "We just felt this team was far enough along and the cost of goods profile was low enough to make it worth pushing this along."

Getting the cost down will be important to turn NIPT into a widely used screening test, he said, accessible to millions of women. "That's a lot of screening, and it's not all going to happen at $2,000 per test. It's gonna happen in the low hundreds," he said.

Invitae is already offering its current shotgun sequencing-based NIPT, which it launched earlier this year, for a patient-pay price of $99 if their insurance doesn't cover it. However, this does not mean that price covers the cost of the test, even though Invitae maintains that across all of its products — cancer tests, carrier screens, and prenatal screens — it has a gross margin of 50 percent.

The company currently uses Illumina's Verifi test technology, and the test is outsourced to Illumina, though Invitae plans to bring it in house this year.

George said he expects the Singular Bio technology to start entering its prenatal screening production line sometime between mid-2020 to mid-2021. Most likely, the new test will not require Invitae to pay license fees to Illumina, but even if it does need to, it would "dramatically reduce" the cost of testing, he said. The Singular Bio test will likely not replace the sequencing-based test completely, though, since "there are going to always be cases where you want to get the broad sequencing information," he added.

Beyond prenatal screening, Invitae is also looking at other uses for the Singular Bio technology. The next test will be a liquid biopsy cancer test, to be launched sometime between the end of 2020 and the end of 2021. "We're still kicking the tires" on the exact application, George said, but it will likely be for disease monitoring and recurrence testing, focusing on a handful of variants.

Early next year, Invitae plans to roll out its first somatic tumor test, and the next step after that would be a liquid biopsy-based recurrence test, he said.

Going forward, the technology might have yet other applications, such as for cell-free transcription profiling and epigenomics. In addition, with some development work, it could replace cytology assays that currently involve a lot of manual work, such as fluorescence in situ hybridization (FISH). "We have not really begun those efforts in earnest, but these are things that we anticipate we will be evaluating over the years to come," George said.