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Immunexpress, Collaborators Publish Clinical Validation of Host-Response Sepsis Assay

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NEW YORK (GenomeWeb) – Scientists from molecular diagnostics firm Immunexpress and collaborators in Australia and The Netherlands have published new research describing the development and clinical validation of SeptiCyte, the firm's flagship RT-qPCR host-response assay for sepsis diagnosis.

In a paper published yesterday in PLOS Medicine, the collaborators demonstrated that SeptiCyte, which measures the expression of four RNA biomarkers of host response to infection, was able to identify about 90 percent of patients with sepsis, depending on the patient composition of one of five cohorts comprising more than 300 total individuals.

Importantly, the assay was better at discriminating sepsis from infection-negative systemic inflammation than the various methods currently used to make such a diagnosis, independently or in combination, within 24 hours of a patient's hospital admission. In addition, the severity of disease did not affect SeptiCyte's performance.

"The other single biomarkers, particularly in host response, that are used to diagnose sepsis are very often correlated with severity, and there is no established method for being able to subtract that effect out of physicians' … diagnosis," Leo McHugh, corresponding author on the study and director of bioinformatics at Immunexpress, told GenomeWeb.

"We established fairly conclusively in the study that the test is not affected by severity," McHugh added. "It doesn't matter whether your patients have a very low level of severity, which is the result you'd expect at the beginning of a sepsis episode; or whether a patient is rampantly septic."

Privately held Immunexpress, which was founded in 2006 in Australia but has since established US headquarters in Seattle, has since its inception been developing various molecular approaches to diagnose sepsis with SeptiCyte being its first test. The company's aim is to market a test that can rule in or rule out whether patients have a septic infection within hours of their admittance to the critical care unit.

The potential value of such an assay is that it would be much faster than relatively accurate culture methods, which can take a few days; and more accurate than the array of parameters currently used by critical care doctors to quickly diagnose sepsis, including molecular tests for specific organisms or measuring levels of certain patient-response markers like procalcitonin or C-reactive protein.

"The use of host response rather than pathogen detection gives you an immediate answer, essentially, in 100 percent of cases," McHugh noted. "Very often with a pathogen-detection test, if you get a negative result, that doesn't mean the patient is negative, it just means that the test was not sensitive enough."

To develop SeptiCyte, Immunexpress scientists recruited subjects from a number of Australian hospitals between 2008 and 2011 — establishing a cohort of 74 patients with sepsis and 31 with infection-negative systemic inflammation — then measured the RNA expression levels of thousands of genes in patient blood samples using Affymetrix microarrays. They eventually identified four genes — CEACAM4, LAMP1, PLA2G7, and PLAC8 — that make up the SeptiCyte classifier.

Then, Immunexpress and its collaborators validated the test as part of the "Molecular Diagnosis and Risk Stratification of Sepsis" (MARS) consortium, a Dutch-led clinical study that examined some 8,000 patients and collected omics data and other clinical parameters that might be useful to develop new methods to diagnose and manage the condition.

"As soon as that consortium was announced, Immunexpress was very interested to get involved, and we were a natural partner for them on the transcriptomics side," McHugh said. "We've been working with our Netherlands collaborators for a couple of years now. It's the largest study specifically for this purpose, so it's natural that we'd use this for a validation cohort."

For the validation study, the researchers ported the SeptiCyte classifier from microarrays to several different qPCR technologies, depending on the cohort examined. These technologies included TaqMan Low-Density Array cards on the ABI 7900HT Fast Real-Time PCR system or TaqMan Gold RT-qPCR chemistry in strip tubes run on the ABI 7500 Fast Real-Time PCR system, all from Thermo Fisher Scientific; or Asuragen RT-qPCR chemistry on the ABI 7500 Fast system.

In the first cohort, comprised solely of 59 unambiguous cases and controls, SeptiCyte yielded an area under the curve of 0.95. In validation cohorts two through five — a more heterogeneous group comprising 249 total patients — the test gave an AUC of 0.89. Taken together, these results essentially mean that the test was able to successfully identify about 90 percent of patients with sepsis.

Despite the positive data, the assay did mistakenly identify some patients as being septic when they had systemic inflammation that was not caused by an infectious organism. And, there were limitations to the study, such as the fact that the composition of the patient cohorts were not truly reflective of an intended use population, and that biases may have been present due to the fact that there is currently no gold standard comparator for diagnosing sepsis.

Nevertheless, the company appears confident that it is on the right track to a clinically useful and relatively quick sepsis diagnostic assay, and the latest data bolsters several other studies that the company has conducted in its efforts to achieve regulatory approval for the test in the US and Europe.

Notably, earlier this year Immunexpress wrapped up a clinical trial of around 200 ICU patients, and told GenomeWeb at the time that it was planning to submit this data in May to the US Food and Drug Administration with the hope that it could achieve marketing clearance by the end of this year.

That timeline has been delayed, but McHugh said this week that the company has received feedback from FDA. "Things are encouraging. We're still collecting more data," he added. In a statement the company said that it would share data from its FDA studies next year.

Immunexpress President and CEO Roslyn Brandon further told GenomeWeb in an email this week that the company "has commitments to a clinical roll-out plan from HMOs in the US and other equivalent parties in the EU and UK," and intends to commercialize its assay first in those areas of the world, as opposed to Australia, where the company began.

One key to commercializing a clinically useful test may be the development or adoption of a point-of-care instrument platform that can run SeptiCyte relatively quickly. Right now, the test takes four to six hours to perform, which, while much faster than culture methods, might still not be fast enough when a patient's life hangs in the balance due to a rapidly progressing septic infection.

Brandon noted in April that the company was working with an undisclosed laboratory instrument manufacturer to develop a fully automated sample-to-answer platform that may be able to run the test in 60 to 90 minutes. That is still the case, she and McHugh noted this week.

"The platform will essentially determine the chemistry," McHugh said. "The TaqMan arrays are one option. When moving from microarray to the TaqMan format and then through to a proprietary format … we found very high correlations between them, so we don't anticipate problems porting the assay onto any particular platform."

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