NEW YORK ─ Presymptom Health believes a multimarker blood test it is currently evaluating in a clinical study could detect sepsis a few days before a patient develops symptoms, far earlier than current tests.
To detect signatures of a dysregulated host response to infection, the Wiltshire, UK-based startup is developing an RNA-expression test for PCR platforms used in hospital laboratories.
The firm, established in 2019, recently closed a seed round of financing to support development of the test, taking its total raised since early 2020 to almost £1 million ($1.4 million).
Presymptom Health's test leverages a set of RNA-expression biomarkers to predict "the likelihood of clinical sepsis within three days" after a test has been administered, the company's CEO Iain Miller said in an interview. "The main clinical decision we want to support is whether a patient needs to be admitted to the hospital or can safely be released."
If the company's plans materialize, the sepsis test could be in the market around the second quarter of 2023, Miller said, adding that its current focus is on developing an assay that would run on PCR platforms in hospital laboratories connected with emergency departments.
"Ultimately, we're trying to flag patients with the highest risk of deterioration from an infection, at a time when they may not experience symptoms," Miller said. "Though we need to prove it, our hope is that the test's negative predictive value will be high enough that it can be used to rule out a progression to sepsis."
He said that internal studies are promising and indicate that its combinations of biomarkers can have a negative predictive value in the high 90s.
In May, Presymptom Health kicked off a UK-based multisite study to validate the performance of the markers and its sepsis test in a follow-on clinical study. Study researchers are evaluating the performance of a panel of 47 RNA-expression markers, and plan to incorporate up to 10 of the best performing markers in the sepsis test.
Miller said that with clinical researchers, the company plans to recruit up to 600 patients that are entering emergency departments and being admitted to the hospital at four clinical sites. The investigators are drawing blood from the patients upon their admission to hospital and each day thereafter while the patient is still in the hospital, and then testing each blood sample to compare the panel's predictions with patient health outcomes.
Patients with and without COVID-19 are being enrolled, Miller said.
"A lot of people present with bacterial infections to emergency departments, but we are pointedly recruiting about a third of patients with suspected viral infections, including SARS-CoV-2," he said, adding that among their objectives the researchers are evaluating whether the test can predict the severity of a SARS-CoV-2 infection and the risk that a patient with SARS-CoV-2 will progress to sepsis.
Presymptom's target date to complete the validation study is early next summer.
The firm has outsourced prototype development and sample analyses for the study to BioXpedia, an Aarhus, Denmark-based contract research laboratory that had worked on the earlier biomarker discovery study for the sepsis test.
That study was managed by the UK Ministry of Defence's Defence Science and Technology Laboratory (DSTL), and had about £16 million in funding from the US Defense Threat Reduction Agency, UK Ministry of Defence, UK Home Office, and Deutsche Forschungsgemeinschaft (DFG).
The study ran for 10 years and recruited 4,400 individuals in eight hospitals ─ seven in the UK and one in Germany. To find individuals who were asymptomatic but had the potential to get an infection, the researchers recruited patients undergoing primarily abdominal surgeries, and collected blood samples from them prior to surgery, after surgery, and each day for the following week. Blood samples from patients who quickly developed symptoms of infection and progressed to sepsis provided the basis for discovery of its gene-expression signatures.
To develop the signatures, researchers at the University of Jena in Germany used machine learning to evaluate transcriptomic and proteomic results obtained from microarray and PCR testing of the blood samples.
When the study was completed in 2017, Presymptom licensed the technology for its test from DSTL. Miller noted that within the group of 47 genes selected by the researchers, one multi-gene signature among several is expected to become part of its early sepsis detection test.
Fast detection is needed for bloodstream infections such as sepsis given a high patient mortality rate that rises significantly with each passing hour. Current tests use a variety of technologies to detect pathogens associated with disease or to analyze a patient's immune response.
Several US Food and Drug Administration-cleared procalcitonin tests are on the US market, including from Roche, BioMérieux, and Thermo Fisher Scientific. Producers of highly multiplexed tests that detect sepsis bloodstream pathogens include Roche's GenMark Diagnostics and BioMérieux's BioFire. And this year, Tucson, Arizona-based Accelerate Diagnostics plans to target customers with a new IVD configuration of its PhenoTest BC kit that addresses the antimicrobial susceptibility testing needs of laboratories that have rapid identification for bloodstream infections already in place.
Among the IVD competitors with current tests in the market, only Lexington, Massachusetts-based T2 Biosystems has a test that operates without requiring a blood culture ─ a lengthy process that significantly slows the time to detect bloodstream infections such as sepsis. According to T2, its FDA-cleared T2Bacteria Panel and T2Candida panels detect sepsis-causing pathogens in whole blood in three to five hours.
Host response tests, which Presymptom Health is developing, also do not require a blood culture. Lumos Diagnostics' FebriDx test, which is currently on the market, is a single-use host-response assay for detecting and differentiating viral and bacterial infections in 10 minutes.
Inflammatix is developing HostDx Sepsis, a host-response RNA-expression test to detect and differentiate bacterial from viral infections in patients presenting with fever to hospital emergency departments, and Predigen Diagnostics is developing a multiplex platform that uses host gene expression signatures as a basis for the prognostic, diagnostic, and therapeutic monitoring systems.
Miller said that Presymptom's test would differentiate itself in the sepsis testing market because it seeks to detect sepsis infections earlier than current tests.
Its test, if it can be commercialized, will include a reagent kit and software patch supplied by Presymptom for current laboratory PCR machines, Miller said. The software patch is needed to apply a formula to expression levels derived from testing, and calculate a number representative of the level of patient risk, he said.
In addition to requirements to validate the test's performance, the firm will need to obtain regulatory clearances and raise capital to support ongoing test development. "It's unlikely we would take this test all the way to the market," Miller said, adding that the firm will probably look to collaborate with an IVD industry partner to obtain regulatory clearances and launch the test.
Given uncertainty around the implementation of new IVD regulations in Europe, Presymptom may look to launch it in the UK with a new UK Conformity Assessed (UKCA) mark, Miller said.
New European IVD Regulations are expected to come into effect on May 26, 2022, but most experts agree that notified bodies do not have the capacity to assess all the IVDs that are currently on the market.
Meanwhile, UKCA marking ─ used for products being placed on the market in England, Wales, and Scotland ─ became effective at the beginning of this year.
If Presymptom is successful in its plans to commercialize a lab test, it expects to also leverage protein biomarkers uncovered during the 10-year study to develop a point-of-care assay for early sepsis detection. The company may opt to develop a lateral flow strip using selected protein biomarkers, or look to partner with a point-of-care platform manufacturer, Miller said.