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Insilicos Using $1.2M SBIR Grant for 400-Subject Study Investigating Cardiovascular Biomarkers

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By Adam Bonislawski

Seattle-based biotech firm Insilicos plans within the next month to launch a 400-subject study evaluating its PreClue protein biomarker-based diagnostic for cardiovascular disease.

The company is looking to build on the results of a 38-patient study it published in the July issue of Clinica Chimica Acta identifying a proteomic signature tied to cardiovascular disease that forms the basis of the test. It hopes to develop PreClue as a clinical diagnostic for either screening or treatment-planning purposes, Insilicos president Erik Nilsson told ProteoMonitor.

The Clinica Chimica Acta study used MALDI-MS to identify a protein biomarker panel in high-density lipoprotein composed of apolopoprotein A-I, apolopoprotein C-III, apolopoprotein C-I, and lipoprotein(a) that was able to classify cardiovascular disease subjects and controls with area under the receiving operating characteristic curve of .82.

Unpublished results from the study also suggested the panel might be useful for guiding therapy, Nilsson said. In particular, he noted, data from the study indicated that the panel might be able to stratify patients according to their response to statins – a class of cholesterol-lowering drugs.

The new study, which will be funded by a $1.2 million grant from the National Institutes of Health's Small Business Innovation Research program and a $400,000 grant from the National Heart, Lung, and Blood Institute, will attempt to confirm these findings in a larger subject population. While officially the company is "platform agnostic," Nilsson said, it plans to start work on the study using MALDI-MS.

"We saw suggestions of [statin response] and a couple of other things in this [initial] study that make us excited to try it in bigger numbers," he said. "A study that size is powered enough to get you excited, but it's not powered enough to get you hard claims. We need the bigger numbers to know what's really going on there."

The study will take place at the University of Washington Medical Center, where researchers will be using blood samples taken from patients coming to the emergency room with symptoms of cardiovascular disease. In line with its goal of developing the test as a predictor of patient progression, the company plans to follow up on the 400 subjects enrolled in the study for an average of two years, Nilsson said.

"This is a university hospital, so the customer base is a little more stable, especially for cardiovascular disease," he said. "We have follow-up built in, and we're confident that we'll have minimal problems. We're going to have an average of two years of follow-up, which is just enough in this patient group for us to see something. We may try to follow [them] a little bit longer. We'll just have to see how it goes."

Depending on the data that emerge from the study, Insilicos will likely pursue commercialization of PreClue as either a treatment-planning test or a screening diagnostic, Nilsson said. Treatment planning would most likely be the easier application to bring to market given the high sensitivity and specificity required for screening diagnostics, although, he noted, giving a timeline for commercialization would be difficult in either case.

"It's a three-year study, and at the end of that time we'd really like to have something that we're ready to move forward with in terms of the [US Food and Drug Administration]," he said. "But, I think you have to look at what the FDA is doing with diagnostics and the 510(k) process right now and say that this is a really difficult time to try to predict how long it would take to get a cardiovascular test to market."

The FDA in August announced its intent to improve the 510(k) decision-making process, and released a set of preliminary recommendations for streamlining the approval process while guaranteeing safety. Meanwhile, the agency has also said that it plans to oversee all laboratory-developed tests — a change from its previous strategy of allowing the Centers for Medicare & Medicaid Services to regulate these tests under the Clinical Laboratory Improvement Amendments — but is still evaluating its policy in this area and has not provided a timeline for when it expects to begin implementing any changes.

Although Nilsson said he "wouldn't mind" exploring the possibility of developing PreClue as a CLIA-based test, he was wary of focusing solely on that route.

"I think in the current environment it would be foolish to depend on the CLIA homebrew route remaining open, because it's not clear that the FDA is going to leave it open," he said. "So our thought is that we have to assume that we're going to have to go the FDA [510(k)] route, and we're ready for that."

A Change in Direction

Insilicos launched in 2002 as a bioinformatics tools company, but in recent years decided to shift its efforts towards developing cardiovascular disease diagnostics in response to a difficult business environment, Nilsson said.

"We started out as a tools company, and some of the biomarker discovery work is still important to us, and we feel like we have a lot of capability in that area. But as far as the main thrust of the company, we've been a cardiovascular disease diagnostic company for several years now," he said, noting that the Clinica Chimica Acta study was the culmination of five years of work.
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"What it amounts to is that it wasn't a great environment for tools companies, so you have to think about what your capabilities are and really who is going to value that," he added. "So we looked at what we were doing and we did this cardiovascular project to prove what we could do."

If the study does eventually lead to a diagnostic capable of guiding treatment cardiovascular disease, it would fill a significant unmet need, Nilsson said.

"There are what we call advanced cardiovascular diagnostics that mostly take either HDL or LDL and look at subfractions of those particle populations, but so far none of those tests really have sufficient predictive power for future events to provoke a revolution in patient care," he said. "I think that a number of the advanced cardiology tests appear to be struggling right now because it's not clear how to use what they tell you to make clinical decisions. And that's what we would like to do."

The company is not alone in its quest to fill that niche, however. Celera, for example, has developed a diagnostic test based on a variant of the KIF6 gene, which has been associated with increased risk of primary and recurrent coronary heart disease events. The company is marketing the test for use in conjunction with clinical evaluation and patient assessment for identifying individuals at risk for CHD, and in patients for whom statin treatment is being considered.

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