NEW YORK (GenomeWeb) – Sepset Biosciences, a company spun out by the Centre for Drug Research and Development (CDRD), a Canadian national drug development and commercialization center, is developing a rapid diagnostic blood test to aid in the early, targeted treatment of sepsis.
Sepset, one of several diagnostic companies that has recently taken aim at the sepsis testing market, said its differentiating factor is that its test detects a unique biomarker signature based on the body's immune response, rather than detecting the presence of a pathogen that could lead to sepsis.
The biomarker signature, identified by researchers at the University of British Columbia, consists of a core set of 31 genes identified from an original set of 99 associated with endotoxin tolerance in sepsis patients.
"Sepsis involves unusual immune responses to infection, but the exact nature of this immune dysfunction remains poorly defined," John Boyd, one of the UBC researchers developing the sepsis test, told GenomeWeb. Bacterial endotoxins, such as lipopolysaccharides, are potent inducers of inflammation, he said, and repeated exposure to endotoxins can produce cellular reprogramming — a state of immunological amnesia in which the immune cells forget how to respond to bacterial signals. That cellular reprogramming suppressed the immune system in patients and can lead to sepsis.
Because the researchers have identified a core set of genes associated with cellular reprogramming, they expect that their test — using technologies such as immunology-based assays, Cepheid's PCR-based platform, or NanoString's molecular barcoding technology already in place at hospitals — will be able to detect that a patient is at a high risk for sepsis soon after presentation for diagnosis.
"Clinicians desperately need a more accurate and rapid tool to diagnose sepsis," Boyd said. "This test will help physicians diagnose the infection sooner, which is critical to effective treatment and better patient outcomes."
"A platform capable of a 45- to 60-minute turnaround time would be ideal as infection progresses to severe sepsis during a six- to 12-hour period. A point-of-care or rapid diagnostic strategy is key in this fast-moving disease process," he added.
The University of British Columbia researchers, led by Robert Hancock, used a combination of published studies and clinical tests on patients to identify and characterize the unique endotoxin tolerance gene expression profile associated with sepsis and found that it presented early in the course of the condition and was linked not only to sepsis pathogenesis, but also to the risk of developing organ dysfunction.
In a published study that describes the details of the researchers work to discover and validate the gene signature, they reported that they were able to recruit sepsis patients within one hour of their presentation to the emergency department.
To obtain endotoxin tolerance and inflammatory gene signatures, the team searched in the US National Library of Medicine (PubMed) Database, and the public repositories of the National Centre for Biotechnology Information-Gene Expression Omnibus and the European Bioinformatics Institute. The group identified a set of 99 genes associated with endotoxin tolerance that they were later able to reduce to 31 genes.
Although the 99-gene, endotoxin tolerance signature was useful for characterizing immune dysfunction in sepsis, a smaller number of genes is more practical in diagnostic testing, said Boyd, who is also an associate professor at the University of British Columbia and works at St. Paul's Hospital, Vancouver, Canada, which was the setting for clinical studies that led to the validation of the genetic signature.
To reduce the number of genes required in the test, the researchers selected genes that showed greater than a 1.5-fold differential expression between sepsis patients and controls across the majority of 10 literature datasets in which they searched.
Importantly, the group demonstrated that the immune dysfunction could be detected at a clinically relevant diagnostic point in time, providing unique information regarding the patients' functional immune status.
"The clinically relevant time point was by and large at the time of emergency ward admission, well before a formal diagnosis," Hancock told GenomeWeb, "and the basis for narrowing down the signature was to take those genes that showed changes in the largest number of patients."
Hancock, director of the Centre for Microbial Diseases and Immunity Research at UBC, said that the initial clinical studies demonstrated that use of a gene-based signature for the detection of sepsis is a promising approach, and the team is advancing to larger multi-center and multi-country trials with up to 1,000 emergency ward patients.
The researchers are also looking to collaborate on the test's continued development with a partner diagnostic company that has a large number of placements in hospitals.
The team plans to eventually obtain US Food and Drug Administration clearance for use of the biomarker signature in a diagnostic test for early detection of sepsis. An addition option might be to explore opportunities with pharmaceutical companies with the objective of connecting the biomarker test with the development of a suitable drug for the treatment of sepsis, Boyd said. "The most potent use of the diagnostic test would be having it connected with a therapeutic for sepsis," he added.
Many of the current methods to diagnose sepsis take more than 24 hours after a patient enters the emergency ward, according to CDRD. By then, patients may be on their way towards tissue damage, organ failure, and death. For every three-hour delay in diagnosis, the rate of mortality and morbidity grows by almost 25 percent, CDRD said.
In addition to benefiting patients, accurate and early detection can result in significant savings in healthcare costs because of the reduction in the length of the hospital and intensive care stay.
Spending on sepsis accounts for more than $20 billion annually in healthcare costs in the US alone, according to CDRD. It contributes to more than 1.6 million hospital visits annually in the US and is the most common cause of death in the intensive care unit. The medical condition leads to the hospitalization of more than 18 million people around the world every year, according to CDRD, and around one in three of these patients will die due to complications related to severe sepsis.
In diagnostic tests for sepsis, rapid identification methods may have multiple, additional positive impacts on patient outcomes including reductions in mortality, morbidity, and antibiotic use. "Speed in providing test results and accuracy of the test are among the primary requirements [of a diagnostic test for sepsis], but all of the considered criteria fall within the umbrella of seeking actionable results," Donna Wolk, system director of clinical and molecular microbiology at Geisinger, an integrated health service organization, recently told GenomeWeb.
A number of companies including Roche, BioMérieux, T2Biosystems, OpGen, DNAe, and Accelerate Diagnostics are either developing or marketing advanced sepsis detection systems.
Physicians have available an array of technologies and products ranging from molecular tests to biomarkers. BioMérieux, for example, provides a number of options based on molecular technology, procalcitonin biomarkers, and MALDI-TOF mass spectrometry that enable physicians and laboratorians to not only identify pathogens leading to sepsis, but also to better understand how well a patient is responding to therapies and whether they should even be given antibiotics.
In July, the US Food and Drug Administration granted 510(k) clearances to procalcitonin assays from Roche and BioMérieux to test for the risk of severe sepsis or septic shock.
OpGen has been working to improve the visibility of its QuickFISH diagnostic for sepsis by publishing the results of a study in The American Journal of Clinical Pathology that elaborated on the benefits of using its molecular test at Winter Haven Hospital in Florida.
Among the company's longer-term goals is to develop a one-hour rapid ID test to help physicians make antibiotic treatment decisions.
The path to penetration in the sepsis testing space can be bumpy, as was experienced by T2 Biosystems, a maker of a non-culture-based diagnostic assay that uses magnetic resonance technology. Its shares tumbled more than 20 percent on July 8 after the company disclosed that it had secured fewer commitments for its T2Candida sepsis test than expected, that it has encountered problems with test results from T2Candida cartridges, and that it has had to delay plans to submit its upcoming T2Bacteria bacterial sepsis test to US regulators.
Nonetheless, a number of recent developments, including the progress of Sepset Biosciences, reflect heightened interest in the market for sepsis testing.
In July, Accelerate Diagnostics moved closer to selling an automated system and test kit in the US when the firm submitted a de novo request for evaluation of Automatic Class III Designation to the FDA for its Accelerate Pheno system and Accelerate PhenoTest BC kit for positive blood culture samples. Its system provides a measure of the minimum concentration level that will kill bacteria. Users of the test can challenge the bacteria with a specific antibiotic and then provide a minimum concentration level that determines whether the bacteria are susceptible or resistant to that antibiotic.
London-based DNAe said in August that it expects to start clinical trials next year for a diagnostic test based on semiconductor DNA analysis that it believes will provide rapid, accurate results at the point of need for bloodstream pathogens that could lead to sepsis.
And this week MBio Diagnostics and Cincinnati Children's Hospital Medical Center announced a collaboration to develop multiplex panels for septic shock on the MBio platform. MBio said it will be possible to place its portable multiplex reader into a wide variety of clinical situations, including the intensive care unit.