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Resolution Bioscience Enters Liquid Biopsy Clinical Market, Planning Disseminated Growth

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NEW YORK (GenomeWeb) – After sharing the first data on its sequencing-based technology for the analysis of circulating tumor DNA earlier this year, liquid biopsy startup Resolution Bioscience is now planning to expand its testing with a model initially focused on targeted sequencing-based, tumor-specific tests.

According to Mark Li, the company's CEO, Resolution Bio also plans to move away from a centralized lab model to develop kits that can be used by any laboratory to perform its assays, which he said the company believes will be key in providing access to European and other labs that may not be able to work with US-based testing companies, as the firm aims to distinguish itself in a rapidly advancing market.

Though it recently received CLIA certification for its Washington State lab and completed CLIA validation for a ctDNA sequencing test for ALK translocations in NSCLC patients, Li said that Resolution's business plans are not focused on building a centralized clinical testing business.

"Our model is different than other companies who may be doing similar [sequencing-based NGS testing of circulating DNA]. We have our CLIA lab, but that's really to support R&D and clinical trials for pharma companies we are working with," he said.

Instead, Resolution is in discussions with partners to establish a group of early testers for an RUO kit version of its technology, and it is looking for other groups interested in participating.

"A lot of these companies we are competing with have more of a central lab model, but you can't legally ship samples from a lot of countries outside the US, especially in Europe, for privacy reasons, so it becomes an issue of how you are going to scale up," Li said.

"That's one reason we want to do kits, to enable researchers globally to get faster access to these technologies," he added. Based on internal goals, he said the company hopes to have a version of an RUO kit available for participating collaborators by the end of this year.

"It won't be the shiny box, it will be something they can actually play with … and there will be a process to understand how much effort it takes to do that technology transfer and how we can simplify the actual kit," Li said. "Some partners we are talking to have automation capabilities, so we may be looking at adding that as a second phase of rolling out kits as well," he added.

Resolution's technology, which involves targeted sequencing of circulating tumor DNA, has some commonalities with other methods, but the company believes it is distinct in several aspects. Li said the points of distinction are primarily in its target capture system and bias correction chemistry, which allow the company to detect all types of alterations, including point mutation, copy number variation, indels, and gene fusions.

"It is a targeted capture system, but we use very small probes, only 40 base pairs [long]," Li explained. "The average ctDNA fragment is 165 bases … and that makes fusions particularly tricky because if your probe is too long there is a high chance you'll span a fusion. So we needed really short probes, and we are down to 40 base pairs … compared to standard probes which can be 120 base pairs."

With a 120bp probe on a 165bp fragment, "it's almost guaranteed you'll span the fusion breakpoint and it won't pull it down," he added.

In addition to target capture design, Li said Resolution also spent a lot of effort developing proprietary chemistry for bias correction "to land probes on targets regardless of GC content."

Sequencing is then done on the Illumina MiSeq, which allows multiplexing of samples, lowering cost, simplifying informatics, and keeping turnaround time clinically relevant, Li said. In-house turnaround is about three to four days, but he said that for clinical testing, the company is stating about a week to include shipping and associated issues.

In contrast, Guardant Health, for example, performs its comprehensive ctDNA sequencing on the Illumina HiSeq with a reported turnaround of two weeks.

As it builds its RUO kit program, Resolution plans to work on validating panels for specific tumor types, and then to pursue US Food and Drug Administration approval of those assays for clinical use. The company is currently focused on a panel for non-small cell lung cancer, but Li added that it has also discussed partnerships around bladder, prostate, ovarian, and breast cancers, and head and neck tumors.

The company's work is not limited to predicting response to targeted therapies, Li said, and also has included developing panels using ctDNA to guide radiation dosing, for example.

Other panels could also result from RUO partners who want to develop their own custom sets of targets, an arrangement the company is already working with in the research setting.

"Because of our bias correction we don't have to reengineer and balance out all the temperatures and cycles to handle different probe sets," Li said. "We've done proof of concepts using internal cell line admixtures for pharma companies where we've gotten a list of genes, designed probes, and validated in house in a matter of a couple weeks."

In light of uncertainty around the FDA's path forward to regulating NGS tests, let alone NGS tests performed not on tissue, but on blood, Li said Resolution's regulatory strategy is somewhat up in the air. A lot, he said, is dependent on collaborators who are starting or have already started to process more samples and are beginning data analyses to build a clinical validity base for the lung cancer panel.

Rather than pursuing much broader panels of hundreds of cancer genes, Li said that Resolution sees comprehensive but focused panels for individual tumor types, like NSCLC, as more beneficial for clinicians.

"You look at Foundation Medicine, which has this massive tissue-based panel, and it seems now like everyone and their brother has basically the same thing, but from our standpoint … we think you've got to give doctors a tool that is actionable — and returning results on 200 genes that we don't know much about doesn't help them and doesn't help the patient."

"We want to focus on what will really direct decision-making," Li said. "I think in reality, at least for the foreseeable future, you are going to be dealing with a lung cancer doctor or a bladder cancer doctor not a 'cancer doctor,'" he explained. "It's going to take the field some time still to make that shift."

Resolution presented some data from a collaboration with researchers from the Dana Farber Cancer Institute earlier this year at the annual meeting of the American Association for Cancer Research showing that the lung cancer panel was able to detect hotspot base changes and indels with 100 percent sensitivity and specificity at mutant allele frequencies of about 1 percent and with 92.3 percent specificity at allele frequencies less than 0.1 percent.

The study also showed the test could detect known rare genetic alterations, including ALK, ROS1, and RET rearrangements in NSCLC patients. A more comprehensive publication is in peer review for publication in a scientific journal, Li said.

Despite some uncertainty among clinicians about liquid biopsy's path forward, Li said that it's clear to him that various players in the field have demonstrated at this point that detecting clinically relevant genomic information in blood is possible.

"Whether just a simple ddPCR or a broader panel, it's in the blood and people are finding it," Li said. "And though there are different ways to do it," he said, "we are clearly on the right path, and this is only going to benefit patients."

Resolution is currently seeking more collaboration partners worldwide for validation of its ctDNA platform as well as laboratories to be beta sites for upcoming RUO kits. It is also fundraising for a Series A round, Li said.

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