NEW YORK – Johns Hopkins University spinout Capsulomics is preparing to commercialize two PCR-based epigenetic tests for esophageal cancer and its precursor, Barrett's esophagus, over the next two years.

The first, a tissue-based prognostic, is slated for launch later this year. A second test, designed for screening and early detection in high-risk individuals will follow in 2023, after the company has secured regulatory clearance for its swallowable sponge sampling device.

Both platforms rely on the same epigenetic signature, developed initially by Hopkins professor Steve Meltzer, via retrospective bioinformatic analysis of epigenetic microarray and sequencing datasets.

Meltzer and his colleagues have developed a bead-based method to capture bisulfite-converted DNA, which is coupled with real-time quantitative methylation-specific PCR to detect a panel of target sequences.

Capsulomics CEO and Cofounder Daniel Lunz said in an interview that he met Meltzer while working on the development of multi-site clinical trials at the university after receiving his MBA. "I heard him give a talk at a faculty meeting, and he discussed this technology that his lab had developed that he felt like could save a lot of lives, but it felt like it was going to be stuck in the research realm."

"We explored some opportunities … and we felt like the best path forward was to go ahead and start a company," Lunz said.

The firm's initial prognostic assay is designed to better stratify patients after an initial BE diagnosis, so that those at a high risk of progression to esophageal cancer can consider more immediate treatment, while those at a low risk may avoid potentially unnecessary intervention.

"Let's say you're diagnosed with Barrett's esophagus today," Lunz said. "They're going to have you come back for the rest of your life every three years or so to do another upper endoscopy and take biopsies, and if it doesn't look like it's becoming dysplastic they just continue to do that indefinitely."

"What our first test is able to do is to … look five to 10 years out and predict if you're going to progress to cancer."

The company's second planned test, which Lunz called its flagship, is an early detection assay, which relies on the same panel of methylation biomarkers. For this, Capsulomics uses an eponymous capsule-on-a-string device to less invasively sample cells from the inner surface of the esophagus.

Patients swallow it, it sits in their stomach for three to five minutes during which time it dissolves, revealing a two-centimeter sponge, which is then "fished right back out."

"I've done it a couple times and it's not too bad, actually," Lunz said. "It's not one of those things that you look at and you're like, 'Sign me up!' But what's incredible about this is that it is so low cost, it is so easy to administer. We have ongoing studies in Uganda, Tanzania, and here in multiple sites in the United States, and we can accurately detect Barrett's esophagus — including the short-segment, very early cases — [as well as] esophageal adenocarcinoma and esophageal squamous cell carcinoma."

"Collectively, those kill 540,000 people per year worldwide," he added, so detection at an earlier, more curable state, has the potential for significant impact.

Esophageal adenocarcinoma, the more prevalent type in the US population, is associated with relatively dismal outcomes — just a 47 percent five-year survival rate for stage I tumors, according to Lunz.

"If already, at stage I, it's often too late for patients, we feel being able to catch [BE] before it actually becomes cancer is a huge opportunity," he said.

Capsulomics is currently working on getting 510(k) clearance for its capsule-sponge sampling device, and it expects to be able to launch its early detection assay by the end of next year.

"We have an aggressive timeline, but … the technology is performing really well in our clinical lab and validation is going really well, so we're excited to get this out," Lunz said. He added that the company uses Thermo Fisher Scientific's QuantStudio platform but did not disclose the number of targets in its final panel, which is still in its final stages of optimization.

Thus far, Capsulomics' only published data is a 2019 paper authored by Meltzer and colleagues, in Clinical Cancer Research , reporting on early validation of their capsule-sponge-based early detection approach.

Using the swallowed sampler, the team tested 80 individuals who had matched cytologic samples from a previous upper endoscopy, using an initial panel of five targets, which they later refined down to four.

Splitting the cohort into a training and a test set, the authors reported a sensitivity of 95 percent and specificity of 62 percent for the initial training, dropping to 79 percent and 93 percent, respectively, in the independent challenge samples.

Lunz said Capsulomics is working on a manuscript on its tissue prognostic application as well and recently submitted a publication specifically focused on detection of squamous cell cancers, an addition to the assay made after the initial 2019 study. The firm also plans to present data in posters at the Digestive Disease Week meeting in May.

The company's initial plan is to offer its two products as laboratory-developed tests, although Lunz said that in the longer term, the team plans to apply for FDA breakthrough device designation. Having a kit version of the tests approved by the agency will be necessary to serve ex-US markets where disseminable tests are particularly crucial in reaching lower-resource populations.

This goal is also why the company has stuck to PCR rather than expanding to a next-generation sequencing platform.

"We actually almost transitioned to sequencing," Lunz said. "The way these tests were developed, we used large microarray and sequencing datasets to narrow in on those genes that we felt could best discriminate … but as we started to increase the number of genes we ran into a challenge, which was that we were running out of DNA."

"Sequencing could solve that, but a big value that we feel we have compared to competitors [is that] we can also pick up the squamous cell cancers, which account for over 80 percent of global cases."

These tumors are not the dominant form in the US, but they are the "number one cancer killer of men in East Africa, in South Africa, up through Asia," Lunz said. "Many of these areas are low-income, so it was vitally important to us to really, really consider cost as we developed the company and as we developed this technology."

"We feel that in order for this to be a widely adopted screening mechanism it needs to be a comprehensive test that can pick up both types of cancers and precancers accurately enough to compete here in the United States but at a low enough cost to really make an impact globally," he added.

Lunz said that gaining payor reimbursement is likely to be a challenge. Capsulomics is working to develop clinical utility data that demonstrates its tests improve patient care, as a way of persuading insurers. In the meantime, upon launch, the plan is to offer tests at a "highly discounted price" to out-of-network patients.

In the specific niche of esophageal cancer and BE, the company will face immediate competition from a firm called Lucid Diagnostics, which markets its own methylation-based BE detection assay, EsoGuard, and received FDA breakthrough device designation in 2020.

That assay demonstrated over 90 percent specificity and 90 percent sensitivity in identifying BE in a 408-patient study published in Science Translational Medicine.

Lunz said Capsulomics believes it can distinguish itself both in its broader detection, which includes globally important squamous cell cancers as well as BE and resulting adenocarcinoma, and at its price point, which the company hopes to be able to maintain in the low hundreds of dollars.

Various multicancer early-detection assays are also making their way into clinical practice, but while those tests will likely play a role in detecting some esophageal cancers, Lunz argued that the need for tumor-specific assays with higher sensitivity will remain.

"We are huge fans of what [multicancer companies] are doing, but ... we know that [for] stage I cancers their sensitivity is low. It's better than a sensitivity of zero, but especially as you look at high-risk patient populations … screening for those patients should be higher sensitivity and higher specificity," he said.

"In the United States, one-third of the adult population has chronic acid reflux, and we predict 5 to 15 percent of those patients will have Barrett's esophagus. That's a well-defined high-risk patient population that should be receiving, according to the GI societies, some type of screening," Lunz added.

"So, I think we're absolutely going to see a molecular diagnostics realm that offers pan-cancer solutions that do sacrifice some of the sensitivity in order to form an easy blood test to be widely accessible for the general population. But it's not going to remove the need for more disease-focused diagnostics for those high-risk populations."

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