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Astute Completes Multi-center Validation Study Supporting NephroCheck Test, 510(k) Submission

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Researchers have completed a prospective, multi-center clinical trial validating the performance of Astute Medical's NephroCheck protein biomarker test for acute kidney disease.

Detailed in a paper published last month in the American Journal of Respiratory and Critical Care Medicine, the study, which was funded by Astute, examined the test in a population of 420 critically ill patients and led to the finding that when added to existing clinical models it could identify patients who would go on to develop AKI with an area under the curve of .86.

This represents a significant improvement over standard clinical models alone, which were able to identify patients who would progress to AKI with an AUC of .70.

According to Astute CEO Christopher Hibberd, the company plans to use the study data to support a US Food and Drug Administration 510(k) submission for the test. Hibberd declined to comment on where in the submission process the company is currently, but he told ProteoMonitor that "based on the results of the trial we are very optimistic."

NephroCheck assesses AKI risk by measuring insulin-like growth-factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases (TIMP-2). Astute began selling the test in Europe in October 2012.

The AJRCCM work follows a previous validation study published last year in Critical Care, in which researchers examined its performance in a 744-patient multi-center effort. In that study, the test identified patients who would go on to develop AKI within the next 12 hours with an AUC of .80.

Both studies were led by John Kellum, professor of Critical Care Medicine at the University of Pittsburgh, who highlighted as one of the significant aspects of the recently published AJRCCM work the fact that it used development of AKI itself, as opposed to a surrogate biochemical marker like creatinine and urine output, as the study's endpoint.

This, he said, was the first biomarker trial in AKI to do so. Indeed, in an interview last year discussing the original Critical Care study, Jonathan Barasch, an associate professor of Medicine and Anatomy & Cell Biology at Columbia University whose research focus includes kidney biomarkers, told ProteoMonitor that benchmarking against surrogate markers was one of the main drawbacks of both that specific study and AKI biomarker work more generally.

"This is the fist time there's been a trial with not merely a biochemical endpoint, but that used an actual adjudication panel" to determine clinical endpoints," Kellum said, noting that this is similar to how biomarkers for other spaces, such as cardiac risk, were validated.

Kellum added that the test actually performed slightly better when compared against adjudicated clinical endpoints as opposed to a biochemical endpoint. "That, I think, is important because it tells you something about how robust this finding is," he told ProteoMonitor.

The researchers validated two pre-selected cut-offs, one where the markers were present at .3 (ng/ml)2/1000, and one where they were present at 2 (ng/ml)2/1000. Patients above the .3 threshold had seven times the risk for AKI as those below it, while those above the 2 threshold had 17 times the risk.

Kellum said that currently, the .3 cutoff was likely the more relevant one, noting that these patients could receive interventions such as increased monitoring of creatinine output, management of fluids, and possibly discontinuation of nephrotoxic drugs.

The higher 2 cutoff, he said, would likely prove more useful once better therapies targeted to AKI patients had been developed. Then, he said, "we could say, 'OK, if you're above 2, then you are in the group where I want to use an extensive therapy" to address AKI.' Right now, though, we don't really have that therapy, so the clinical utility of the 2 cutoff is in my mind really less than the .3."

According to Astute, AKI affects up to 2.5 million US hospital patients annually and results in significantly increased costs and longer patient stays. For instance, a 2008 study in Nephrology Dialysis Transplantation reported that critically ill cardiac surgery patients with no AKI had an ICU cost of $13,836 and 1.4 days of length of stay. Patients with severe AKI, on the other hand, had an ICU cost of up to $49,328 and up to 5.4 days of length of stay.

Kellum said that while, technically speaking, current treatment guidelines would recommend that all patients examined in the Astute studies receive interventions aimed at managing their risk for AKI, in reality, "when we look at what patients actually get, they aren't actually getting these recommended therapies."

"So what is needed is to provide clinicians with a guide to who to focus on, because for whatever reason – potentially because they just don't have the resources – they aren't providing these actions to these patients," he said.

He noted as well that even within this group of at-risk patients, it might be appropriate to continue to give potentially nephrotoxic drugs to patients stratified as low risk for AKI, while higher risk patients might require a change to their therapies.

Looking ahead, Kellum said he would also be interested in examining the performance of the NephroCheck test in non-critically ill patients.

"Up to this point, the studies have been limited to a focus on patients that are critically ill, whether in the ICU or on their way to the ICU, and who have known [AKI] risk factors," he said.

Hibberd and McPherson formed Astute in 2007. The company has largely maintained a low profile since then, raising more than $80 million in funding but offering little public comment on its plans.

In addition to the NephroCheck test, Astute has developed an immunoassay platform to perform it, the Astute140 Meter. Platform development is not the company's focus, but it chose to develop the device so as to better control the timing of NephroCheck's rollout.

Hibberd declined to disclose how many tests the company has performed since its European launch.

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