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Precision Epigenomics to Market Methylation-Based Cancer Screening Test to Functional Medicine Docs


NEW YORK – University of Arizona spinout Precision Epigenomics is gearing up for the April launch of its first commercial molecular test, an assay it calls EpiSeek, which employs a panel of epigenetic markers that it has validated for the early detection of multiple solid tumors.

The test, intended to pick up signs of unknown, undiagnosed tumors in otherwise healthy individuals, will join what is currently a single major competitor, Grail's Galleri assay, in a new and still experimental application for blood-based genomic tests: multi-cancer population screening.

Multi-cancer screening or early detection is not currently reimbursed by payors outside of a handful of pilot programs that Grail has inked with different groups to research the real-world impact of its assay. But Precision Epigenomics has a plan to begin its commercial operations by targeting integrated and functional medical practices that serve a large number of self-pay patients.

Precision Epigenomics Cofounder, CEO, and President Mark Nelson said the base technology for the test — methylation-specific PCR — isn't necessarily unique. The differentiating aspect is the markers in its panel, which he said were derived using proprietary software.

Although the company has published and presented some validation studies on its test demonstrating high sensitivity and specificity, the current data is dwarfed by what has been amassed by companies like Grail and Exact Sciences, which have validated their own epigenetic cancer detection test across tens of thousands of samples.

Studies thus far have explored EpiSeek's performance in distinguishing a handful of tumor types in blood. A 2020 study tested the company's platform in a cohort of 18 lung cancer patients of various stages and 47 matched health controls. The authors reported strong performance based on a measure known as the area under the receiver operating curve, or AUC, which read out at 0.956. The researchers also noted that the signal from the test's epigenetic markers correlated with decreases in tumor size or surgical resection.

Another study compared results from pancreatic cancer cases and benign pancreatic cysts. Although this study also showed strong performance, the cohort was limited to metastatic cancer patients, who were already diagnosed based on clinical symptoms or other tools and thus would not be the intended use population for a screening test like EpiSeek.

A poster presentation at the Association for Molecular Pathology 2023 annual meeting described another pilot using the test to distinguish malignant breast cancer in a small cohort of patients, almost all of whom were stage IV.

In terms of multi-cancer cohorts, the company's only published data has been its founders' initial discovery study which derived the test's DNA methylation markers from an analysis of TCGA Illumina HumanMethylation450 microarray data.

That foundational work used array data from over 8,500 tumors to identify cancer-specific DNA methylation markers — regions where methylation was either higher or lower than the equivalent area of a healthy genome.

Focusing on hypermethylated DNA, investigators chose the most predictive sets of six markers for each TCGA cancer type with high sensitivity and specificity as well as a universal 12-marker set that could detect tumors of all 33 TCGA cancer types.

With a planned April launch, Precision Epigenomics will target what Richard Bernert, the company's chief operating officer, called integrated and functional medicine clinicians.

Howard McLeod, director of the Center for Precision Medicine and Functional Genomics and a professor of pharmacy and medicine at Utah Tech University, said in an email that he believes marketing tests to alternative or functional medical providers, or even directly to consumers, isn't a problem in and of itself — as long as the products in question are backed up by good science.

"High-quality science can be useful in the hands of a consumer or an undertrained practitioner, but the opposite can cause confusion or worse," he wrote.

"Looking at the [company's] manuscripts and the website, there was dependence on public domain data for both retrospective discovery and retrospective validation of the algorithms," McLeod added. "The challenge with this is [that] … there are known (and presumably unknown) issues with diagnosis, stage, and sample handling in the TCGA dataset. This is not a big issue for much of the cancer genome initiative work, but makes their discovery set noisy."

McLeod also raised questions about the sample sizes of the company's studies, and the absence of "key metrics for risk prediction." 

"ROC curves are necessary as a first hurdle, but then pretty useless for showing value," he said. "There needs to be measures of negative predictive value and positive predictive value, to know how often patients will be harmed in each direction. There is also a need for some prospective data, to show that an algorithm derived from analysis/replication in a large, existing dataset can translate when it is now applied one patient at a time. Many assays stumble at this step, and we do not have clarity of how things will go here."

For its launch, Bernert said Precision Epigenomics has inked a B2B partnership with a lab called TruDiagnostic that currently sells biological age testing directly to consumers, as well as a handful of other tests to subscribed practitioners who want them on hand in their practices.

"They are very active in epigenomic testing already, with primarily cash paid clients who are looking to optimize their health … so, they're going to be basically doing our distribution and sales and quite a bit of the promotions as well. We'll be selling wholesale, and they'll be selling retail," Bernert said.

"About 25,000 clinicians are enrolled, and they have said about 10,000 are really active on their system, and each of those 10,000 obviously has quite a few patients," he added.

Some of these clinicians are likely already ordering the Grail Galleri test for some or all of their clients, but they, and others, may be interested in a much more targeted, and thus much less expensive test.

In comparison to Precision's methylation-specific PCR, Grail's Galleri relies on broad sequencing of methylated regions across the genome and costs at least $900 out of pocket. EpiSeek is listed at $699.

Functional medicine practices can include MDs and DOs that graduated from traditional medical schools and residencies, passed medical board exams, and are licensed to practice as medical doctors. But they can also be run exclusively by other types of practitioners, like naturopaths, who have not gone through those processes.

Bernert said that the informational material for EpiSeek specifies that the test should only be ordered by an "appropriately licensed medical practitioner," including MDs and DOs, along with dentists, optometrists, podiatrists, nurse practitioners, physician assistants, and chiropractors. However, it's unclear whether TruDiagnostic's ordering portal can wholly prevent practitioners without these licenses from buying test kits for their practice.

Nelson also stressed that Precision Epigenomics has worked hard to make sure it is very clearly informing those who order its test on both who should and should not be tested, and exactly how results should be followed up.

"In general, this is recommended for individuals greater than 50 years old, and we have people specifically that we recommend not take the test, including pregnant people and people already being treated for cancer," he said.

The company also plans to make it clear that this is not a replacement for conventional standard of care or screening, he added. "We really wanted to be judicious on this," Nelson said. "First, 'Do no harm' is something that rings very true. We want to make sure that this test is available for occult malignancies, but there's no way that we can say with any sense of confidence that this is superior to endoscopy and or low-dose CT."

Rules that govern whether non-MD or DO practitioners can order things like CT scans, mammograms, MRIs, or colonoscopies vary by state and region. But in the case where a functional medical practice couldn't directly order follow-up tests, it could certainly refer patients to another practice.

Qualms in the field regarding blood-based multi-cancer screening have centered in recent years around the risk of false positives, and the cost to the healthcare system that could result as patients seek out follow-up imaging and other diagnostic services for a cancer they don't necessarily have.

McLeod said that involving nontraditional practitioners could open up additional risk even for true positives, who might opt to delay standard-of-care follow-up and treatment in favor of unproven alternative therapies or interventions that are sometimes embraced among this community of providers.

Few genomic test firms have stated outright that they have specifically targeted the functional medicine or complementary medicine community. As of 2019, Biocept hoped to pursue a similar path with its liquid biopsy genotyping tests, but the company subsequently closed that arm of its business before filing for bankruptcy in October last year.

The US Food and Drug Administration has, in the past, taken action against certain direct-to-consumer companies marketing genomic testing, but it does not have a defined, risk-based cutoff point that guides these decisions. The agency declined to comment on whether it has ever done the same in the context of other gray areas of clinical practice, such as functional medicine.

Bernert said that Precision Epigenomics also has its eye on diagnostic applications. The firm's most recent publication in Scientific Reports last month reported results from a study using EpiSeek in pleural fluid from patients suspected of having lung cancer. Investigators recruited 104 patients including 48 with malignant diagnoses using standard cytology (MPE), 28 with indeterminate findings but known malignancy (IPE), and 28 with benign pleural effusion findings.

Analysis yielded an AUC of 0.912 for distinguishing either MPE or IPE from benign controls.

"Right now, the sensitivity isn't that great with routine cytology examination, but by stacking our test on top of that, we're able to really increase the sensitivity without affecting specificity," Bernert said.

According to the company's laboratory medical director Joshua Routh, the firm is also keeping its eye on a potential change in the FDA's rules on regulation of laboratory tests and is preparing for the type of prospective interventional study of EpiSeek that it would need to submit to the FDA if that does happen.

"We're launching now with pretty solid analytical validity, knowing that when we identify cancer, there's cancer, and when there's cancer DNA, we're able to detect it. But we are intending to do those additional studies as well," he said.

"Screening tests are a test for the masses, where there are real advantages to doing a cheaper, more accessible test," Routh added.