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True Bearing Readies RNA-Based Coronary Artery Disease Diagnostic for FDA Review, Launch

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NEW YORK (360Dx) – Startup True Bearing Diagnostics has cemented plans to launch an RNA-based test for coronary artery disease and is working on collecting the validation evidence it intends to submit to the US Food and Drug Administration for the assay early next year.

The company, founded in 2015, is the fruit of support provided by St. Laurent Institute to encourage what True Bearing CEO Tisha Jepson said has been a variety of projects applying SeqLL's amplification-free sequencing platform to the identification of novel disease signatures.

Jepson, who is also executive vice president of the St. Laurent Institute, became director of corporate strategy, sales and marketing for SeqLL when it was founded in 2013 by Helicos scientist Daniel Jones and members of the St. Laurent Family as a way perpetuate Helicos' technology after the firm went bankrupt in 2012.

The St. Laurent family's investment firm Genome Diagnostic Technologies (GDT) funds the institute that carries the family name, under which Tim McCaffrey, a researcher at George Washington University and now chief scientific officer of True Bearing, began the RNA-seq discovery work that has led to the company's first product, currently called TruCAD.

"Around the time we started doing this, I had realized from other studies we were doing that there is this great research opportunity in looking at people who go into a coronary cath lab for elective diagnostic catheterizations," McCaffrey said.

According to McCaffrey, among the approximately one million cardiac catheterizations that are performed annually in the US to try to identify patients with obstructed blood vessels, 40 percent or more result in a negative finding — no evidence of the disease.

"That's great news for them," he said, "but it dawned on me that its also a great discovery opportunity, since we can take blood in the morning and by the afternoon we know if their arteries are blocked or not.

At about the same time, McCaffrey said, he became involved with the St. Laurent folk, and was introduced to what was at that time the Helicos Heliscope, which he believed could offer better sensitivity in detecting low-abundance RNA molecules in these subjects.

"Other people had done microarray studies of blood in similar veins, but there wasn't [good] agreement with the signatures coming out," he added. "Our hypothesis was maybe arrays just aren't sensitive enough at the lower limits of abundance, and that turned out to be true. We were able to get a very strong signal, but it was all in these transcripts at very low abundances."

McCaffrey said that that initial discovery work was conducted in about 100 patients — 48 of whom were found to be occluded via catheterization, and 48 who were clear.

The company's website says that the accuracy of the firm's RNA signature in that first research cohort was 80 percent.

True Bearing is now in the midst of a 600-subject, multi-site validation, which they are hoping will recapitulate or exceed that performance.

McCaffrey said that he and his colleague are in the process of publishing data from the discovery work now, so they couldn't share details about sensitivity and specificity. But, he said that its unlikely that any test in this space would show over 90 percent accuracy, simply because the gold standard being compared — cardiac angiograms — only measure blood flow in the larger vessels and can't detect more cryptic CAD cases.

According to Jepson, the firm expects to be done with the validation study and ready to submit its application to the FDA early next year.

Once that's done, the company would plan to launch the test as an LDT, so that it can begin to operate commercially on a smaller scale in anticipation of regulator clearance that should support a push to offer the test on a population scale. The company has said that TruCAD will cost about $1,000.

While the SeqLL system is responsible for the company's discovery of the RNA signature that makes up TruCAD, a commercial test will not require sequencing, and would also not benefit from the long turnaround time required. In light of that, Jepson said that the plan is to shift to a targeted platform, most likely BioRad's droplet digital PCR, which can meet the sensitivity thresholds needed for these low-abundance targets.

Bio-Rad has said it is seeking IVD clearance from the FDA — naming its BCR-ABL test in January as the first for which it would seek approval — but has not yet received a positive decision from the regulator.

When it comes to market, True Bearing's TruCAD will face competition from one established test, CardioDx's Corus CAD, which has been available to clinicians for several years and uses an algorithm that factors in a person's age, sex, and gene expression. The test has been shown to have a sensitivity of close to 90 percent but specificity of only about 52 percent in distinguishing patients who have CAD from those who don't.

Other companies have also taken aim at the diagnostic dilemma of CAD, including Prevencio, which has developed a four-protein panel that is combined with patient sex and history to identify those who have a coronary artery obstruction.

While both of those existing approaches incorporate clinical factors into the risk report they return to physicians, Jepson said that True Bearing believes it will be able to offer a test with competitive performance using only the prediction yielded by its molecular signature of seven markers.

Combination with clinical or other biomarker signals could potentially have added value, she said, but the company sees separating these factors our as more responsible, so that physicians don't potentially double-count clinical or other factors in the assessment of their patients.

The TruCAD assay as it stands currently is designed to distinguish patients to either side of a 20 percent occlusion cutoff point. In the future, though, Jepson said that the firm will potentially seek to expand application of the RNA signature to monitoring levels of CAD progression or regression.

True Bearing is also looking ahead to other areas of clinical assessment where it has already, or might be able to now glean predictive signatures via the SeqLL amplification-free system. One of these that is already in the works is a test to help distinguish patients with abdominal pain who have appendicitis from those who don't.

"This isn't one shot, we think this is a whole platform and a lot of very promising areas," McCaffrey said.

So far the company has been supported by investment from the  St. Laurent family. But, Jepson said that she will be working to try to involve new investors with expertise in the biotech and personalized medicine space as the firm seeks the funds it needs to support commercialization of its test.

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