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VolitionRx Fine-Tunes Nucleosome Tech to Advance Cancer Dx Pipeline; Eyes COVID-19 Testing

NEW YORK – After several years of refining and optimizing its assay platform, epigenetic diagnostic firm VolitionRx is nearing its first implementation in cancer detection, while also eyeing a detour in infectious disease spurred by the emerging coronavirus pandemic.

The company is presenting three abstracts at the upcoming virtual annual meeting of the American Society of Clinical Oncology. One study of the performance of its core nucleosome isolation platform suggests it might be able to improve the sensitivity of liquid biopsy assays by enriching samples for tumor-derived DNA fragments and depleting them of what is normally a huge background of molecules from normal cells.

Two other studies provide early data for specific implementations of the company's technology in lung and hematologic malignancies.

Several epigenetics methods have emerged for blood-based cancer detection, but most rely on next-generation sequencing of circulating DNA molecules to discern methylation or fragmentation patterns that are specific to cancer.

Volition's approach, which it calls NuQ, eschews the details of the genomic code, relying instead on immunoassays to bind to and detect certain protein structures within circulating nucleosomes, the mixed molecular subunits that make up the larger chromatin architecture of a cell's chromosomes.

By creating NuQ assays specific to certain structures within these complexes, the company has been able to show that it can detect cancers, with early data in colorectal cancer, prostate cancer, and now in lung and blood malignancies as well.

Volition initially CE-marked a nucleosome assay pair designed to detect colorectal cancers in 2017.

The firm then began several trials in Asia followed, as well as another in the US led by investigators supported by the National Cancer Institute's Early Detection Research Network. But according to CEO Cameron Reynolds, the firm ended up turning much of its attention over the last few years away from clinical translation and toward perfecting its core technology — including switching to a magnetic bead-based platform and retuning its assays for use in plasma — in order to position itself for better success in bringing tests into the clinic.

"We've always believed that the epigenetic structures were going to be incredibly important [and] … I think that's really come to fruition," he said. "But we couldn't prove all of that … till we really had the tools [optimized]."

"We've now fully updated the antibodies and we've developed recombinant nucleosomes as controls, which are incredibly important to have a very good, stable, robust test," Reynolds said. Key to this was the firm's acquisition last December of epigenetic reagent supplier Octamer.

"They [were] one of the few groups that could really make good recombinant nucleosomes, so that's been really important because before that it was very hard to have a solid control," he said. "Anything biological … [is] going to have a lot of epigenetic structures on it … so we need [these tools to] be certain of what we are measuring."

Reynolds said that the company also tuned its approach to work with plama rather than serum, which improves its signal-to-noise ratio. The firm has now converted eight assays to a new chemoluminescent bead platform, he added.

Volition believes it is now poised to transition to what Reynolds described as a hybrid approach to clinical translation, which will include launching some of its own cancer tests, but also licensing its basic isolation technology and/or specific NuQ assay supplies to other labs.

According to Reynolds, the firm's work with Texas A&M, where researchers have adopted NuQ to detecting cancer in dogs, serves as a good model for the shape future outlicensing might take.

"With Texas, we don't run the samples, we don't collect the samples. We don't know anything about what the questions are clinically … [but] we send them kits," he said of the project.

The firm has also moved toward establishing a more disseminated model in Asia, with a partnership announced last year with Shanghai Fosun Long March Medical Science to introduce its NuQ blood-based cancer diagnostic platform in China. Under that agreement, the two companies are collaborating to clinically test NuQ assays in colorectal, lung, and ovarian cancer.

"We don't really know the market in China so we … [made an agreement] with them where we're adapting our assays to their platform, which, now that it's on magnetic beads, is actually quite simple for them," Reynolds said.

Reynolds said that it's likely that the veterinary cancer application will see the clinic before any of the human cancer forays.

In the meantime, the company continues to collect data, including the three upcoming ASCO presentations. In one, investigators from the firm working with a team of Belgian researchers at Liège University Hospital performed a pilot study to see if the NuQ technology could discriminate between lung cancer and healthy controls or chronic obstructive pulmonary disease (COPD).

In 142 subjects the Volition assays showed an AUC (area under the receiver operating curve) of 88 percent in discriminating lung cancer from healthy controls. For discerning cancer samples from COPD samples, the technology achieved an AUC of 85 percent.

A second abstract being shared at the virtual meeting reports data from a second study of whether nucleosomes containing the histone H3.1 isoform might be able to differentiate patients with hematologic tumors including non-Hodgkin lymphoma, and two types of leukemia from healthy subjects.

In a small cohort, the AUC for detecting patients with these blood cancers from healthy subjects was 91 percent with a sensitivity of 74 percent at 95 percent specificity.

Apart from cancer-specific assays, Volition has also made progress exploring more generalized utility for its technology, for example in concentrating specific subsets of nucleosomes or depleting others. In a third presentation for the ASCO meeting, the company is sharing data from a study applying its approach to enriching a sample for nucleosomes that carry shorter, rather than longer fragments of DNA.

Evidence has collected in recent years across the liquid biopsy field that these size differences reflect different cellular origins, with the shorter base-pair fragments skewing preferentially toward cancer and the longer molecules coming predominantly from normal cells. As a result, the ability to deplete the background of normal nucleosomes in a blood sample and enrich for those likely to have originated in a cancer cell could help boost diagnostic sensitivity not just for Volition, but also potentially for other assays including those based on DNA sequencing.

In its ASCO study, the company is reporting that its assays designed for this type of preferential capture could clearly separate short and long nucleosomes, both using recombinant nucleosomes from cancer cell lines, and in samples from clinical colorectal cancer patients versus healthy controls.

Following up on this data, Reynolds said the company is now in the process of sequencing samples to hopefully show, for example, that the size filtering results in increased detection of cancer mutations.

"We aim to start licensing this out this year or next year … once we've shown the next few steps: not just that we can do it but that it has clinical utility," he added.

Pivoting to COVID-19

Amid all of this, the company has also rapidly forged a side path to investigate how its technology could be applied to COVID-19.

The concept behind this work isn't entirely new, Reynolds said, as the firm has for years been exploring various non-cancer uses for assays targeting chromatin structures in other diseases, including in the reproductive space, for pre-eclampsia, and in non-cancer lung diseases.

One emerging discovery has been that the platform can detect what are known as NETs (neutrophil extracellular traps). "Our team did a bit of background research into what causes the damage in COVID … And [found that] it comes down, to a large extent, to the NETs … [which is] the body's last line of defense, where the white cells spew out large amounts of chromatin," Reynolds said.

"It is a very similar mechanism in pneumonia and flu, with the NETs sort of clogging up the lungs. And we had thought of that use before [but] we just hadn't pursued it because … it didn't seem quite as pressing as it does now," he added.

After discussions with collaborators, the company believes that there is a clinical need for not just COVID-19 diagnostics, but also prognostic tools. While many of those infected with SARS-CoV-2 recover well, or even show no symptoms, a percentage require serious intensive care intervention.

"The theory is … that we could potentially detect high-symptom COVID-19 from healthy [individuals] and then from low-symptom [presentations]," Reynolds said. "Clinicians are are very keen to get some longer lead time for someone who is getting on that really slippery slope to being in big trouble and on the ventilator."

A first step toward this has been creating new NET-directed NuQ assays, which Reynolds said the firm has now done. The current plan is to work with collaborators primarily in Europe to validate the approach.

Although the company hasn't published any peer-reviewed data, it said that in internal experiments it achieved a very high AUC for distinguishing samples from severe COVID-19 individuals compared to healthy controls. A proof-of-concept study involving 34 COVID-19 PCR-positive subjects and 50 control subjects revealed that nucleosomes were highly elevated in the PCR positive subjects, and the company said that it saw an AUC of 98.7 percent with a sensitivity of 100 percent at 94 percent specificity for an initial single NuQ assay.

"We were expecting a difference, but it was really quite stark," Reynolds said. "What we're doing now … is trying to be very cautious" he added. "There are a lot of critical questions we need to pick through … so we're collecting samples from a very wide range of people who had bad outcomes, and even serial samples, so [we can] see if we can detect  low from high symptoms to give as much lead time as possible."

Clinical collaborators are also expected to investigate whether the chromatin NET-based approach can add value to other biomarkers or vice versa, he added.

Because of the immediate need, Reynolds said that a resulting assay could potential enter clinical use within the year, ahead of the firm's cancer assays.