NEW YORK (GenomeWeb) – Neumann Diagnostics, a Hungarian startup developing molecular tests for sexually transmitted diseases and cancer, last week unveiled Confidence, a pair of assays designed to detect if a woman is infected with a high-risk human papillomavirus subtype and, if so, determine her risk of developing cervical pre-cancer or cancer.
The company, based in Budapest, recently completed a large clinical study that found that its assays, when compared with the gold standard of cytology (Pap smear), was able to detect severe cervical dysplasia or a worse condition with a sensitivity of about 92 percent and specificity of about 74 percent, and was able to find severe cases up to a year earlier than Pap smear.
In addition, because one component of the Confidence test portfolio assesses a woman's risk algorithmically based on her age and a proprietary epigenetic marker, Neumann believes that it can offer the first cervical cancer screening method in the world with fully automated evaluation — that is, without somewhat subjective human visual analysis.
Until two years ago, when Roche's Cobas HPV assay received US Food and Drug Administration approval for use as a primary cervical cancer screening test in women 25 years or older, cytology was the primary screening test "practically everywhere in the world, except for some regional tiny HPV screening programs," Miklós Nyíri, managing director at Neumann Diagnostics, told GenomeWeb.
"Pap smear has always been evaluated by [a cytopathologist], and that evaluation is obviously not automated," Nyíri added. "There have been attempts and there are now new technologies to automate the evaluation of Pap smear, but they are not widely accepted. We think that we have the first test that does not require any personal evaluation, and which has its own fully automated algorithm to evaluate the results."
The Confidence test consists of Confidence HPV, a multiplex RT-PCR test that detects viral DNA individually from four high-risk HPV genotypes (16, 18, 31, and 45) and several additional high-risk genotypes in a group; and Confidence Marker, a qRT-PCR test on bisulfite-converted DNA that measures methylation of the promoter sequence of the POU43 gene normalized to a quantitative measurement of the COL2A1 gene.
Neumann has licensed the HPV technology from a company called CellCall, where Nyíri is also managing director, and licensed the methylation marker from a laboratory at Taiwan's National Defense Medical Center. "Thus, even though Neumann is only about a year old, the technologies that we have turned into products all have been developed much longer than that," Nyíri said.
Like Roche's test and a number of other molecular HPV tests, the Confidence HPV assay provides a conventional "yes-no" result regarding a patient's HPV infection status. In the case of the Roche Cobas test, there is overwhelming clinical trial data demonstrating that this result is sufficient to use the assay as a primary cervical cancer screening tool.
Neumann believes the Confidence Marker portion of its test is what will set it apart from competing HPV assays. The methylation marker also gives a "yes-no" answer as to whether a patient should be reflexed to colposcopy.
"At the same time, we can also give a risk assessment value [for a] person's risk for having an underlying disease," Nyíri said. "This would be a percentage, and is not something that's been traditionally provided in the field of cervical cancer screening."
Nyíri noted that, for instance, the US National Cancer Institute is currently considering cervical cancer screening guidelines that focus on different risk levels, and Neumann believes it can be ahead of the curve in this regard.
"When we give a risk assessment, we don't want to make the life of the doctor more complicated; it's not a mathematical problem we are giving them," he said. "But on the other hand, we want to give them an understanding of what risk the person is carrying, and [we believe] decisions about repeat testing or colposcopy can be … made based on this risk level."
Nyíri cited as a hypothetical situation a patient who is HPV positive but cytology negative, which describes about a single-digit percentage of all women screened for cervical cancer. "Today, that's kind of a gray area," Nyíri said. "There are recommendations how to treat them, and some of these women can actually be very sick, but most of them are absolutely healthy. And we think with the risk assessment, which is based partly on their age and partly on the methylation level provided by the test, [we] can … stratify the women within this group."
In Neumann's recently completed multicenter clinical trial — which involved more than 7,000 cervical samples collected from more than 6,000 women — the Confidence test portfolio had a sensitivity of 91.94 percent for severe cervical dysplasia or worse in HPV-positive women 25 years or older. In that same group, specificity was 74.35 percent.
"If you want to complement an existing screening method, you don't want the costs to run out of control; you want to use a very specific test to improve the performance of an already-existing system," Nyíri said. "So the value in our triage test is that we can increase the sensitivity of the current system without decreasing significantly the number of referrals. We can be sensitive among these samples for which cytology is blind while being specific at the same time."
In the trial, Neumann also compared its test portfolio to the Roche Cobas assay and another unnamed HPV assay. In a sub-group of 3,310 women in which the Neumann and Roche assays were compared, there was 70.5 percent positive agreement between the tests, according to unpublished data that Nyíri provided to GenomeWeb.
Neumann is currently submitting all of these data to obtain CE marking for its test portfolio (the Confidence HPV assay already has CE marking but the Confidence marker does not), and is also preparing it for submission to a peer-reviewed journal. In addition, Neumann said it has signed an agreement with the Synlab GenoID Molecular Laboratory, part of the Synlab Group, to provide the assay. Synlab is Europe's largest laboratory services provider, with some 13,000 employees providing testing in 35 countries over four continents.
Neumann provides kits and recommends a workflow that "needs to be used," Nyíri said. This workflow includes the use of Thermo Fisher Scientific's Life Technologies real-time PCR platforms and specific liquid-handling robots. "Both of the tests are very robust, but have been made to be very robust," he added. "These are not open platform tests, so to speak."
Besides the Synlab agreement, Neumann is currently weighing its options to achieve further market penetration for its assay suite in Europe. The company is majority owned by the X-Ventures Beta Venture Capital Fund, co-financed by Hungarian private investors and the European Investment Bank as part of the Joint European Resources for Micro to Medium Enterprises (aka Jeremie) program.
Nyíri noted that Neumann has sufficient funding for the time being to expand the market for its assay and to pursue other projects. For instance, the marker that is the centerpiece of its triage test can also detect endometrial cancer, and "has shown very promising results for the detection of ovarian cancer," he said.
However, a foray outside the European market — to the US, for instance — would likely require additional funding, Nyíri said, something that the company is just beginning to evaluate.