STILL EARLY DAYS FOR LIQUID BIOPSY

Multi-billion market opportunity draws variety of approaches from congested field of companies

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By Amanda Pedersen

Tuesday, April 26, 2016

Analysts and market researchers often try to put a monetary value on an emerging sector but estimating the market potential of a new technology category is far from an exact science. The liquid biopsy market is a prime example of that challenge.

“There are a variety of numbers that have been thrown out by a variety of different sources and I think that’s really all to say it’s an embryonic area and people don’t really know where this is going to go,” Gene Walther, CEO of Vortex Biosciences Inc., told Medical Device Daily. “Some of the big firms, J.P. Morgan and Piper Jaffray have indicated that it’s a $22 billion to $32 billion market opportunity, but many of those are looking at the clinical applications and not really including or incorporating what the research potential is.”

Walther said the research applications in this space alone represents a market anywhere between $1 billion to $8 billion. Vortex, of Menlo Park, Calif., is among the many players that have seen the opportunity and potential of the fairly congested liquid biopsy field.

Suffice is to say the market for liquid-based cancer tests will eventually grow to become a multi-billion opportunity and there will be plenty of pie slices to go around. But what really makes this an interesting space is the variety of approaches liquid biopsy companies are taking with the technology and the array of purposes for which these various tests will be used.

This week, in a two-part series, Medical Device Daily is exploring both the potential clinical and business opportunities this young but fast-growing market has to offer.

Looking at the liquid biopsy space from the broadest viewpoint, it can be segregated by the type of liquid being collected: urine or blood. So far San Diego-based Trovagene Inc. appears to be the lone wolf in the urine-based liquid biopsy category while the majority of companies are duking it out for leadership on the blood-based side.

Zooming in on the blood-based sector, the market can be divided into at least four different categories based on the specific components of the blood the test is designed to capture — circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), nucleosomes and exosomal RNA — and some of those categories can be further split into subcategories, such as whether or not the test is used for clinical or research purposes and, if it is used in the clinic, is it being used to find cancer (detection) or to follow it (monitoring).

“A lot that work still needs to be done. I think the biology of cancer and really how we can maximize the use of liquid biopsies, whether it be the application of circulating tumor cells or circulating tumor DNA and how they can work and compliment each other still needs to be proven,” Walther said.

Finding the needle in a haystack

Vortex is trying to differentiate itself by not using any kind of labels such as magnetic beads or stains, but rather isolating intact CTCs to allow the end user to perform a variety of different types of analysis, such as next generation sequencing, growing the cells to be able to study them further or looking at the proteomics and the way the gene expressions are happening within the isolated tumor cells.

“By having these intact CTCs you’re able to do much more of a thorough and broad analysis on those cells,” Walther said. “Within that space what we think differentiates our technology and our approach is a higher purity.”

Vortex has developed a fully automated benchtop system called the Vtx-1 for collecting intact CTCs using microfluidic technology. Inside the Vtx-1 chip, unlabeled CTCs in whole blood are trapped in microsale vortices while smaller red and white blood cells pass through. After selectively trapping into the microfluidic chamber, CTCs can be flushed and collected into a variety of containers for downstream analysis.

This technique is easier said than done though. Walther explained that each blood sample contains billions of very small red cells and millions of slightly larger white cells and a much smaller number, roughly one to 500, of CTCs. It’s a lot like looking for a needle in a haystack, he said, and being able to isolate the CTCs from those red and white blood cells is a tremendous challenge. In the end, the Vtx-1 is expected to capture the CTCs in a sample of blood and only a minimal amount of white blood cells.

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He said the technology is able to clear the red blood cells fairly well but there are some residual white cells that will be left in with the CTCs. “When you compare it to other technologies, at least based on published reports, we believe that the purity of our technology is actually a high differentiation from the other technologies that are available,” he said. “The market is going to want to see some direct comparisons in the not-too-distant future to be able to actually differentiate the technologies.”

Walther said the company has generated a fair amount of interest from research labs and clinical labs but Vortex also has received notable attention from pharmaceutical companies because the ability to isolate CTCs and grow them presents an opportunity to test the effectiveness of various compounds they may have in development. That’s a distinct advantage over tests that use ctDNA, he said, because ctDNA shows fragments of DNA from cells that have been killed, in theory, by the treatments the patients are on.

“What it doesn’t capture is the residual cancer that may have become resistant to that drug or that may not respond to that drug,” Walther said. “It may be more effective in being able to determine cocktails of drugs. If you think about the approach that the pharma industry has taken fighting Aids, it’s a cocktail approach, it’s not a single drug.”

The company recently did a soft launch of the system to introduce it to researchers and plans to do a formal product launch early next year.

nucleosomes are the haystack

Volitionrx Limited, of Namur, Belgium, is trying to set itself apart in this crowded market by focusing on a cost-effective platform designed to work in multiple cancers and by looking at nucleosomes in circulation. The company received CE mark approval in April for two blood-based assays for the detection of colorectal cancer. The biomarker assays, Nuqv001 and Nuqt003 are designed to analyze fragments of nucleosomes circulating within the blood for the presence of cancer signatures. Volitionrx plans to launch a panel test for the detection of colorectal cancer for clinical use in Europe toward the end of the year.

“We’re not looking for the needle. The nucleosomes are the haystack,” CEO Cameron Reynolds told Medical Device Daily at J.P. Morgan’s health care conference in January.

Reynolds said his company’s test is so low cost that Volitionrx only spent about $18 million over five years to develop the assay because it is using a “very old platform” that is easy to roll out worldwide. He said if the company delivers what it intends to, which is a low-cost, accurate diagnostic screening blood test, it will “change everything.”

“People say blood tests are the answer and they really are,” Reynolds said. “But I think anyone in our business has to accept nothing has worked. Everyone’s very skeptical because the last big break through was 35 years ago with PSA for prostate cancer.”

For example, Reynolds said, thousands of papers have been published but not one has been launched and widely adopted as a screening test. Other companies are also looking at nucleosomes, he said, but he said those competitors are actually looking at the DNA wrapped around the nucleosomes.

Don’t dismiss RNA

Exosome Diagnostics Inc. is taking a very different approach in the liquid biopsy field with its test designed to isolate and analyze exosomal RNA from a blood sample. The plasma-based diagnostic is intended to enable real-time detection of EML4-ALK mutations in patients with non-small cell lung cancer (NSCLC). The company said its platform provides a more direct and sensitive method of detecting fusions such as EML4-ALK, compared to cell free DNA alone. EML4-ALK is a gene fusion found in a subset of patients with NSCLC and predicts response to ALK inhibitor therapies.

John Boyce, CEO of the Cambridge, Mass.-based company, told Medical Device Daily in February that DNA alone is not enough to solve the puzzle. Just like there will never be one drug that can cure cancer by itself, oncology doctors need more than one liquid biopsy tool to treat and monitor their patients, Boyce said. If they only measure the cell-free DNA to see if a particular drug is working, all they know is what is dying in the blood.

“And that’s good, you can see what’s dying, you can see that you’re killing off the [tumor cells] but you’re not able to see what’s on the rise,” Boyce said. “So it’s natural selection. As soon as you kill one of them off there’s a new bully on the block in the tumor.”

That’s something that can’t be identified with cell-free DNA, he said. “The only way you can do that is looking at the RNA and the only way that you can get the RNA from the blood is from exosomes because RNA doesn’t float around in the blood freely.”

In the end, Boyce said, oncologists need to see both what is dying and what is living in the blood.

Published  April 26, 2016