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Pronota Validates Pre-Eclampsia Markers; Plans Clinical Study to Support 510(k) Submission

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Diagnostics firm Pronota said this week that results from a 300-patient validation study showed its protein biomarker test for pre-eclampsia identified 80 percent of women who developed pre-eclampsia leading to the birth of a pre-term baby.

The company now plans to embark on a prospective, 2,000-patient clinical study of the test that it hopes to use to support a US Food and Drug Administration 510(k) submission, as well as an application for a European Union CE mark, Pronota CEO Katleen Verleysen told ProteoMonitor. The firm aims to complete these submissions within the next two years, she added.

Founded in 2004 as a spinout from Ghent University and the Flanders Interuniversity Institute for Biotechnology, Pronota uses mass spec-based discovery and validation platforms – called MASStermind and MASSterclass, respectively – to develop protein biomarker-based diagnostics. In addition to pre-eclampsia, the company has ongoing efforts in sepsis, cardio-renal disease, and ovarian cancer.

Pre-eclampsia is Pronota's lead product and the closest to commercialization, Verleysen said. The company has translated the five protein biomarkers used in the test from their original mass spec platform to immunoassays to increase clinical applicability, and has begun looking for "strategic partners" to help move the test to market.

Because of the large potential market for such a test – more than 11 million women in Europe and the US, according to Verleysen – Pronota hopes to find a partner with significant clinical experience through which to offer it.

"We don't have the intention of putting a CLIA lab together and running the tests ourselves," she said. "Ideally you would run this test from prenatal screening facilities or a clinical hospital. So it's our intention to look for a partner that has a network of labs set up or to run [the test] in the hospitals themselves."

Verleysen suggested the test could prove a desirable complement to existing pre-eclampsia offerings from firms including Roche, Abbott, and PerkinElmer, each of which already has tests for the pre-eclampsia biomarker placenta growth factor, PlGF. She added that Pronota is currently in discussions with each of these firms about potential opportunities surrounding the test.

"Every big [in vitro diagnostic] company has an interest in pre-eclampsia because they all have licenses to PlGF," she said. "So if we have a test that can identify early on in pregnancy who will be at high risk of developing pre-eclampsia, that will be very useful to those companies."

This strategy of partnering with larger diagnostics outfits extends beyond Pronota's pre-eclampsia efforts, Verleysen said, noting that the company has deliberately pursued indications where "we knew later on in the process we would find [interested] partners."

"We didn't want to work on [exotic] diagnostic areas where we would have to take it to market ourselves because there's not anybody very active in that particular field," she said.

After pre-eclampsia, the company's cardio-renal program is the next closest to market, Verleysen said. It has two markers in the final stages of validation: the protein Quiescin Q6 (QSOX1), which it intends as a complement to the heart failure biomarker brain natriuretic peptide; and latent transforming growth factor binding protein 2 (LTBP2), which it is exploring as a prognostic marker for dyspnea patients. Pronota is now looking to partner with "opinion leaders" to more thoroughly validate these markers in various clinical settings before moving on to clinical studies, Verleysen said.

The company recently published a pair of studies on the two markers – one on QSOX1 in the European Heart Journal and another on LTBP2 in Clinical Science.

Pronota has also entered the validation stage for its ovarian cancer and sepsis efforts, Verleysen said. Its ovarian cancer program is focused on protein biomarkers for predicting whether pelvic masses are benign or malignant – similar to tests like Vermillion's OVA1, Fujirebio's ROMA test, and HealthLinx OvPlex.

One of the company's markers, however, has shown potential as an early detection marker when used in combination with CA125 and HE4 – the two markers in Fujirebio's ROMA test, Verleysen said. She added that while this finding has yet to be validated, if it holds up it could "open up avenues for a test that could potentially be used for [ovarian cancer] screening."

While Pronota could use CA125 freely in such a test, it would need a license from Fujirebio for HE4, Verleysen said. However, she noted, it is currently looking to see if it can replace HE4 with another protein that is not patent protected.

"We have other markers that we could [potentially] use [in place of HE4]," she said. "But if that seems the best possible [combination] requires HE4, then we would need a license from Fujirebio."

She added that the company is currently in discussions with Fujirebio about this possibility.

Pronota's sepsis efforts are aimed at validating a panel of protein markers that could be an alternative to the existing marker procalcitonin, which is currently the basis of sepsis tests offered by a number of firms including Roche and Thermo Fisher Scientific. The hope, Verleysen said, is that the company's markers will prove more specific to sepsis than PCT, which is a broad marker of inflammation.

Because PCT is a marker for inflammation, it "might work well in an emergency department setting but not in a hospital-wide setting," she said. "If you look at patients in an ICU, for instance, they are all very inflamed. So, a marker that is indicative of inflammation but can't distinguish sepsis from other types of trauma is a problem."

Pronota's MASStermind discovery system uses an Applied Biosystems 4800 MALDI TOF/TOF mass spec system. For discovery, the company's researchers spot 8,000 MALDI spots per sample, which they then analyze in an initial run to identify differential features. They then go back and perform MS/MS analysis to identify any differential features observed in that initial run.

For validation, Pronota uses selected-reaction monitoring mass spec on a Thermo Scientific Vantage triple quadrupole machine. Key to this process, Verleysen said, is an upfront, offline separation step that enables the company to reach sensitivities in the 10 to 100 picogram per mL range while maintaining the levels of throughput needed to screen dozens of proteins across hundreds of patient samples.

She declined to detail the company's separation system, calling it an "in-house trade secret," but she noted that it relies on techniques beyond conventional C18 chromatography. In a 2011 paper in Nature Protocols, researchers associated with the firm detailed a combined fractional diagonal chromatography workflow using strong cation exchange chromatography followed by reversed-phase peptide chromatography that they termed N-terminal combined fractional diagonal chromatography, or COFRADIC.

Verleysen suggested that the pre-eclampsia data released this week demonstrates that the company's mass spec workflow "can actually deliver novel content." She added that such validation would help attract additional proteomic service work from biotech and pharma firms, which she said comprises roughly 10 to 20 percent of the company's activity.

Pronota has no immediate plans to push its mass spec systems as a clinical platform, though, Verleysen said. This is in contrast to Sera Prognostics – one of its main competitors in the pre-eclampsia space – which has developed a nine-analyte pre-term birth diagnostic that it plans to launch as a mass spec-based laboratory-developed test sometime next year (PM 11/18/2011).

"I believe that mass spec will make it into the clinic and there are already some [such] applications, like from [Laboratory Corporation of America] and Quest… but I think it will still take a couple of years before mass spec will make it into the clinic for the read-out of proteins," Verleysen said, adding that translating the markers to immunoassays improved Pronota's options in terms of partnering with large IVD firms.

In January, Pronota closed on a $4.9 million Series C round to fund validation studies for its pre-eclampsia, sepsis, cardio-renal disease, and ovarian cancer programs. It now plans to extend that round, opening it to new investors, Verleysen said. She declined to say how much funding the company was targeting, but said that it planned to close the additional round towards the end of the year.

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