NEW YORK (GenomeWeb) – Israeli biotech firm MeMed has completed a clinical study demonstrating the usefulness of its proteomic ImmunoXpert test for distinguishing between bacterial and viral infections.
Detailed in a paper published this month in PLOS One, the multi-site study looked at blood samples from 1,002 prospectively recruited patients with suspected acute infection disease as well as patients without infections and found that ImmunoXpert's three-protein signature could distinguish between bacterial and viral infections with an area under the curve of .94.
According to MeMed Founder and CEO Eran Eden, the company has received regulatory clearance for the test in the EU, Switzerland, and Israel, where it is currently offering it in select early access sites. It plans to begin a broad roll-out in Europe towards the end of this year and aims to expand into theUSand Asia in the next two years, Eden told GenomeWeb.
The test is intended to guide physician antibiotic use with the goal of addressing the problems of overuse and the subsequent development of bacterial antibiotic resistance. Unlike bacterial infections, viral infections are not typically susceptible to antibiotics, but because it can be difficult to quickly tell the difference between the two, antibiotics are often prescribed to treat viral infections.
The current version of the ImmunoXpert test has a turnaround time of around two hours and is aimed primarily at the hospital market, Eden said. The company is also working on a point-of-care version of the test that will deliver results in around 15 to 20 minutes, making it suitable to settings like doctors' offices. He said MeMed plans to have that version of the test ready for regulatory submissions in around two years.
While established biomarkers like c-reactive protein (CRP), procalcitonin, and interleukin-6 (IL-6) are linked to bacterial infections, none alone is suitable for early, rapid determination of whether a patient has a bacterial or viral infection.
For instance, Eden said, "c-reactive protein is a great marker, but in the first 48 hours that it takes to build up, you have a blind spot." Additionally, he noted, the protein's level can go up in the case of adenoviruses, which are common in children, leading to unnecessary antibiotic use.
"Single biomarkers are not sufficient," he said. "You have to use several biomarkers and integrate them computationally."
The challenge of using multiple biomarkers, he noted, is finding markers representative of different biological processes so that they are complementary to one another, rather than overlapping.
"So far most of the focus in the clinical setting has been on bacterial biomarkers," he said. "But when you add them together, the value you get is limited, because they measure many of the same pathways."
In building the ImmunoXpert test, Eden and his colleagues focused not only on markers linked to bacterial infection but also on markers of viral infection, which, he noted, gave them the differentiating power they were looking for.
For instance, the most informative of their three-marker panel, the protein NF-related apoptosis-inducing ligand (TRAIL), appears to be down-regulated in bacterial infections and up-regulated in viral infections. "So you have this complementary dynamic of different proteins that together give you something that is sufficiently robust," Eden said.
Launched in 2009, MeMed grew out of a research project largely bootstrapped by Eden and his MeMed Cofounder and current Chief Technology Officer Kfir Oved. The duo financed their initial biomarker discovery work out of pocket until,Edensaid, they had enough clinical evidence to draw interest from outside parties.
The company has since raised several rounds of funding, though he declined to say how much has been invested to date. He also declined to say whether the company planned to raise additional money to support its commercialization efforts but did note that it had received interested from venture capital firms and other funding sources.
Eden and Oved's discovery work began with data and literature analyses through which they identified a set of 600 promising candidates. They then began evaluating these proteins in in vitro and in vivo studies using a variety of platforms including Luminex-based instruments, ELISAs, and flow cytometry.
The PLOS One study is the first large-scale study the company has published on the test. In it, they looked at 1,002 patients at different time points ranging from the first day of infection to 12 days out and across 56 different species of pathogen. They used half the patient cohort for training of their algorithm and the other half for validation, Eden said.
Jessica Colon-Franco, medical director of clinical chemistry at the Medical College of Wisconsin, noted that a key point of the study was the large number of markers the researchers looked at to arrive at their ultimate signature of three.
"There are a lot of reports out there where investigators look at groups of 10 or 15 proteins, so a strength of the study is definitely the large number of proteins they started with," she said. She suggested that this helped them discover markers beyond the usual suspects, noting that, for instance, established bacterial markers like CRP and procalcitonin did not make their final panel.
Colon-Franco, who has no relationship to the study or MeMed, also cited the good characterization of the patient cohort, noting that the study used both physician adjudication and microbiology tests to determine patient status.
She added, however, that additional studies in more heterogeneous populations would be needed.
"They included patients with a wide variety of infections, but they didn't include patients with other co-morbidities like transplant patients, immuno-compromised patients, or patients with hepatitis," she said. "When you bring this into a hospital setting, you are probably going to get a more heterogeneous population, so more studies are needed in wider and targeted populations."
According to Eden, the company has several additional clinical trials planned, including a 1,200-patient trial in the EU that it will roll out toward the end of this year using funding from the European Commission.
In terms of the test's potential place in the clinical workflow, Colon-Franco said she could envision it helping guide antibiotic use in a hospital setting, particularly in the case of patients suspected of having sepsis.
Current guidelines, she noted, call for physicians to immediately place such patients on broad spectrum antibiotics. "So, let's say they start everyone on antibiotics, then when they get this [ImmunoXpert] score, they could de-escalate [antibiotic use] as needed," she said.
Antibiotic stewardship "is a great niche for this test," she added. "There is a lot of need, because [excessive antibiotics use] is related to increased costs and increased resistance, so a lot of institutions are coming up with stewardship initiatives to lower the use of antibiotics."
And some such initiatives run into challenges due to a lack of good biomarkers, Colon-Franco said, giving the example of efforts to use procalcitonin as a marker for guiding antibiotic use.
Procalcitonin "is the only [US Food and Drug Administration]-approved biomarker for sepsis," she said. "But it is very controversial because the sensitivity and specificity are around 70 percent, which is really suboptimal."
Researchers, she noted, have developed algorithms using procalcitonin to de-escalate antibiotic use, the idea being that if the marker is below a certain threshold, the likelihood of a bacterial infection is low.
Many hospital pharmacy departments, Colon-Franco said, are working to convince doctors to use procalcitonin to de-escalate antibiotic use in this way. However, "they are facing a lot of resistance from physicians who don't think [the marker] is helpful."
Better markers of bacterial infection could help with this issue, she noted.