NEW YORK (GenomeWeb) – A Roche-funded study has validated a pair of protein biomarkers as effective for evaluating the near-term risk of preeclampsia in women presenting with symptoms of the disease.
Published this month in the New England Journal of Medicine, the study found that the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) was able to rule out a woman's chance of developing preeclampsia within a week following the test with a negative predictive value of 99.3 percent.
The same ratio was able to identify women who would go on to develop preeclampsia within four weeks with a positive predictive value of 36.7 percent.
The results could help further drive adoption of the markers as tools for evaluating patients suspected of having preeclampsia, Martin Hund, global medical leader Roche centralised and point of care solutions and an author on the study, told GenomeWeb. The markers are currently used clinically in a number of EU countries for purposes including confirming diagnoses of preeclampsia.
For instance, said Stefan Verlohren, senior author on the study and an obstetrician at Berlin's Charité, Campus Virchow Clinic, he and his colleagues use the sFlt-1/ PlGF ratio as part of their standard clinical practice, measuring the markers in every patient they suspect of preeclampsia.
The NEJM study, Verlohren said, is the first large-scale prospective study to look at the utility of the markers in predicting near-term preeclampsia risk in such patients.
"We achieved a very high negative predictive value [in the study], and that is a major step forward," he told GenomeWeb. "Because now, for example, if a woman presents with the symptoms of preeclampsia and she has an sFlt-1/ PlGF ratio of below 38 [the cut-off established by the study] we don't need to hospitalize her and take her out of her daily work or away from her family. We can say, 'Ok, you have signs of the disease, but you will not get it within the next week.'"
Characterized by high blood pressure and proteinuria, preeclampsia is a leading cause of preterm births and maternal-fetal deaths, with between 5 and 8 percent of pregnant women developing the condition.
Because preeclampsia symptoms overlap with a number of other conditions, however, it can be challenging to diagnose. As Hund noted, of patients presenting with symptoms characteristic of the disease, on average, only 20 percent will actually go on to develop preeclampsia.
The validated sFlt-1/ PlGF ratio "lets you triage the patient much better to decide who to send home for outpatient care and who to hospitalize," he said.
The Roche-funded study, named PROGNOSIS (Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study), consisted of a development cohort of 500 women that the researchers used to identify the ideal ratio cut-off and a second validation cohort of 550 women. The women were 18 year or older and between 24 weeks and 36 weeks and 6 days pregnant at the time of their first visit for symptoms of preeclampsia.
"These are the patients the physician sees in their daily routine," Verlohren said. "Patients who come to the hospital and say, 'I think I have preeclampsia or my doctor told me I have high blood pressure,' something like this. So it is a very practically relevant cohort."
He said that the likely next step in terms of validating the test would be a prospective randomized trial where it could be compared to current clinical practice. "Ultimately we want to really prove that these [markers] are able to really reduce fetal and maternal morbidity and mortality," he said.
Roche, Hund said, is currently working on such a trial with University of Oxford obstetrician Manu Vatish, who was also a co-author on the NEJM study.
Vatish "has a randomized control study design where one group receives the [sFlt-1/ PlGF] test and one other group does not, and he wants to demonstrate that the group receiving the test will be hospitalized less frequently," Hund said, adding that he expects results from that study to be available around the end of this year or the beginning of 2017.
In the US, Roche currently offers the markers for research use only, but the company is working to take them through the US Food and Drug Administration, Hund said.
A number of other companies also offer sFlt-1 and/or PlGF assays, including Abbott, PerkinElmer, and Thermo Fisher Scientific. The PROGNOSIS findings could also impact companies like MyCartis and Progenity that are developing proteomic-based tests for preeclampsia.
Progenity last year acquired proteomic diagnostics firm Carmenta Bioscience, a spinout of Stanford University focused on developing a test for preeclampsia. At the time of the acquisition, Carmenta was involved in a multi-center clinical trial for a six-protein preeclampsia panel, looking at a cohort of several hundred patients and controls with related conditions. As with the sFlt-1/ PlGF ratio, the main aim of the Carmenta panel was ruling out symptomatic women as not at risk of developing the disease.
One of Carmenta's primary competitors in developing a proteomic test for preeclampsia was Belgian diagnostics firm Pronota, which last year was incorporated into a new venture with MyCartis called BioCartis. The company's preeclampsia test is slated second in its development pipeline after a cardiac panel consisting of RNA and protein markers.
In previous interviews with GenomeWeb, both former Pronota CEO Katleen Verleysen and former Carmenta CEO Matthew Cooper (now chief science officer at Progenity) suggested that their companies' products could be attractive to large IVD firms like Roche as companions to established markers like sFlt-1 and PlGF.
Hund said that he and his colleagues at Roche have been "following all the new developments" around molecular markers for preeclampsia. However, he said, "up to now, the most convincing evidence points back to angiogenic biomarkers including sFlt-1 and PlGF."