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BillionToOne Adapting Fetal Dx Tech for Liquid Biopsy, Cancer Therapy Response Monitoring

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NEW YORK – Prenatal testing firm BillionToOne said this week that it has taken the first steps to adapt its cell-free DNA sequencing technology for applications in cancer therapy selection and response monitoring.

The Menlo Park, California-based firm believes that its molecular counting technology can provide improved resolution and sensitivity for detecting actionable mutations in advanced cancer patients, as well as a tool to monitor individuals in real time to gauge their responsiveness or resistance to treatment.

The move comes on the heels of what BillionToOne CEO Oguzhan Atay described as a period of rapid growth for the company's carrier screening and fetal diagnostic product, Unity, which it launched about two years ago. The firm announced in June that it had raised $55 million to help pay for a lab expansion to support growing demand.

Unity employs a molecular counting technology developed by BillionToOne scientists. The method uses quantitative counting template, or QCT, synthetic DNA molecules that are spiked into a cell-free DNA sample prior to PCR amplification. These molecules are designed to amplify at the same rate as a specific gene of interest, with which they share certain sequences. Counting the number of QCT molecules in the resulting sequencing data can help determine the number of DNA molecules that are derived from a particular gene in the sample.

According to Atay, this ability to quantify is what marks the technology as particularly useful for other disease applications like cancer liquid biopsy.

"What we have realized and what I think some of the field is starting to realize as well, is the ability to quantify and ability to do molecular counting actually improves your signal significantly, and this is across the board [whether] for methylation assays, for SNVs, or for CNV," he said. "It's a significant boost."

In prenatal testing, the approach has allowed the company to create a noninvasive test that detects fetal disease risk for five inherited disorders — cystic fibrosis, spinal muscular atrophy, sickle cell disease, alpha thalassemia, and beta thalassemia — without the need for a paternal DNA sample.

Atay said that BillionToOne obviously viewed this as an improvement over the current standard but was somewhat unprepared for how rapidly the proposition seems to have been embraced by clinicians.

"There have been peer-reviewed publications that show that almost 60 percent of affected pregnancies are currently being missed due to the traditional carrier screening workflow where you need to test the mother and the father and then do amniocentesis," he said. "It's a multibillion-dollar industry and we are all testing the mothers. Medicaid and all the insurance providers are paying for that part, but it is not leading to actionable outcomes. Just kind of streamlining that process ... made us, I think, very attractive."

The pandemic may also have increased attention to the benefits of a maternal-only model for fetal screening, Atay added.

"We initially started with an extremely small sales force because we wanted to show that this is something that the providers and the doctors and patients would want to use. [But] we ended up growing extremely quickly to the point that we were dealing with lab capacity issues. We weren't scaling our sales team and were still growing 50 to 100 percent every quarter," he said.

After building out a larger lab, which Atay said went online a few months ago, the company now has about 100 employees, up from just 10 in 2019. The goal is to expand to a nationwide sales team, and although the firm does not currently have New York state approval, Atay said it expects to by the end of this year or early next.

Another recent shift for its prenatal testing business has been the inclusion of aneuploidy testing as an add-on to the five-disorder Unity maternal/fetal screen.

"We had been getting a lot of requests from our providers saying, 'Look … you are asking us to split our labs — to send one test for aneuploidy testing to one lab, and another to you.' So, we launched an alternative, which we call Unity Complete, which allows us to be a single source for [comprehensive] prenatal genetic testing," Atay said.

"A lot of the OB-GYNs using Unity have now switched to using us exclusively [for aneuploidy NIPT], as well. So, about 80 percent of our volume right now actually comes in as Unity Complete," he added.

With these expansions progressing in the background, BillionToOne's timeline for expanding into the liquid biopsy space is short.

Atay said the firm expects to launch in a CLIA setting sometime next year. "We are still doing clinical studies, and the initial data is very promising, but there's still a little iteration in product development that we want to do." After that, the company plans to work on submitting for US Food and Drug Administration approval, something it estimates would take another 12 to 18 months.

Although interest in early cancer detection and screening has grown significantly in recent years, BillionToOne has decided to target the more established market for comprehensive genomic profiling in advanced cancer patients, and to build on that with added utility for response monitoring.

"We didn't want to go into an area that required hundreds of millions of dollars in clinical trials [like] the early detection area … so, we decided [to] focus on an established part of the workflow, a little similar to how we did with prenatal," Atay said.

The firm also doesn't plan to compete with companies offering monitoring tests in the setting of early-stage tumors, where the goal is to detect minimal residual disease. In that setting, Atay said, the question is binary — is there a mutation in blood or is there not — and one that other technologies are well equipped to answer.

Where BillionToOne believes it can offer significant improvement over other methods is in monitoring changes in circulating tumor DNA that reflect advanced cancer patients' real-time response to drug treatment.

"It is very difficult to do this kind of therapy monitoring with qualitative methods because you are trying to compare [small changes in tumor load] ... and that's actually very difficult to do. Companies try to do it by converting molecules per ml but the error bars around those numbers are huge," Atay argued.

"This is where our technology, I think, really shines," he said, "with the ability to … have a coefficient of variation at the level of 2 percent, as opposed to the standards currently that are around 20 percent or 50 percent. It's an order of magnitude improvement that can make a difference in being able to have [accurate] treatment monitoring."

The firm has not yet published or presented data supporting these claims, but Atay said it intends to remedy that at a meeting of the Precision Medicine World Conference next January.

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