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As Concussion Awareness Rises, BioDirection Moves to Bring Blood-Based Test to Market

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NEW YORK (360Dx) – Even as the deaths of former National Football League players have put the spotlight on concussions, diagnosing the injury remains a tricky business, sometimes relying on art as well as science.

Boston-based BioDirection hopes to change that with a blood-based test that it said can offer an objective diagnosis within 90 seconds. If all goes according to plan, the test could hit the market in Europe in about a year, followed by a launch in the US.

Called Tbit — short for traumatic brain injury test — the test leverages nanowire technology developed by Harvard University's Charles Lieber. Nanowires are functionalized with monoclonal antibodies to measure the levels of two proteins — glial fibrillary acidic protein, or GFAP, and S100 beta — which have been shown to increase in blood after traumatic brain injuries.

The test requires a pinprick of blood, which is dropped onto a chip containing the nanowires and placed inside the Tbit analyzer to record a resistance reading. An algorithm then correlates the reading to the amount of the two proteins in the blood and generates a score that is used for diagnosis, providing essentially a "yes" or "no" answer to whether someone has suffered a concussion.

According to BioDirection President and CEO Eric Goorno, the nanowire technology allows the Tbit platform to measure the levels of the two proteins directly from whole blood, eliminating the need for steps typically required with an ELISA format, as well as the need for fluorescent labels. It also enables the platform to be smaller — approximately about 5 inches by 7 inches by 9 inches — and to cost a fraction of an ELISA instrument, which can get into the hundreds of thousands of dollars, he added.

"It can be even under the capital budget minimums of some of the hospital purchasing" amounts, or between $2,500 and $3,000, Goorno said. 

Because BioDirection is not a protein biomarker company, the firm was agnostic as far as proteins to use for Tbit. It chose GFAP and S100 beta because they were the "most ready for prime time," Goorno said.

Both have been extensively studied and clinically validated for diagnostic use in TBI, for example, and a search of PubMed found nearly 1,700 studies investigating GFAP's role in brain injuries. S100 beta, similarly, has been studied for decades and is already used in Scandinavia by physicians to screen suspected concussion patients who may need a CT scan.

Both proteins also jump the blood-brain barrier in TBI incidents, enabling their measurement in peripheral blood from a finger pinprick.

The market for a test like Tbit could be enormous. According to BioDirection, a traumatic brain injury, including concussions, occurs every 15 seconds in the US, resulting in more than 10 million concussions each year, and over $76 billion in direct and indirect costs.

Goorno said that just in the US, approximately 5 million CT scans are performed annually for suspected TBI to decide whether surgery is needed to repair hemorrhaging. Yet only 6 percent to 8 percent of the scans turn out to be TBI-positive, and surgery is required in only 1 percent of cases.

"One of the values of our test will be to reduce … up to 30 to 50 percent or more of these unnecessary CT scans," he said.

BioDirection plans to initially target hospital emergency rooms for its technology, but longer term, it envisions Tbit being used in settings such as ambulances, nursing homes, and sporting events, Goorno said.

The company has finished its first round of preclinical testing, which confirmed the Tbit technology on human samples. Next up is finalization of the system's design specs, followed by a formal pilot study with more statistical sampling of human samples, which would allow BioDirection to optimize the threshold levels of GFAP and S100 beta, and its algorithm.

Once that is completed, the company will embark on a pivotal trial for the US Food and Drug Administration, with whom BioDirection recently had its first meeting, helping to validate the company's clinical pathway, Goorno said.

Tbit will initially be launched, however, in Europe, where regulatory barriers are less rigorous. Goorno anticipates Tbit being available by the end of 2017.

Proof of concussion in blood

Concussions have made headlines in recent years after scores of autopsies of former NFL and the National Hockey League players revealed they suffered from a degenerative brain condition called chronic traumatic encephalopathy, or CTE, which has been linked to concussions.

Additionally, seniors are at a risk for concussions from falls, as are members of the military engaged in combat. According to the US Department of Defense, more than 350,000 active military personnel received first-time diagnoses of concussions between 2000 and the first half of 2016.

But much about the injury remains a mystery. In an effort to shed light on the condition, the NCAA and the DoD have embarked on a $30 million study called the CARE-Consortium to elucidate the "neurobiopsychosocial" nature of concussions. In September, the NFL also pledged $100 million to fund research into concussions, after it was roundly criticized for playing down the long-term effects of concussions and accused of trying to influence the findings of a concussion study conducted by the National Institutes of Health. The NFL had previously given $30 million to NIH for the study.

In the past, concussions were often undiagnosed or misdiagnosed because their symptoms are general enough that they can suggest numerous other conditions. In addition to CT scans, cognitive testing, and balance, movement, and eye tests can be used to diagnose a concussion.

As awareness of concussions and TBIs, in general, have climbed, so has the call for more diagnostic tools. To date, though, no definitive blood-based test for concussions exist, though one firm, San Diego-based Banyan Biomarkers, has been developing one since 2002.

University of Pennsylvania Perelman School of Medicine professor of neurology Ramon Diaz-Arrastia said that a blood-based concussion test could extend beyond diagnoses to help guide care for concussion patients, especially the 10 to 15 percent of patients who may require months to recover from their injuries.

For now, however, BioDirection is developing Tbit only for diagnostic use. The test is not to measure the severity of the concussion, or to determine the recovery status of someone who's had a concussion. Similarly, it will not be marketed as a prognostic device to predict who may be prone to a concussion.

For a point-of-care test, a blood-based technology would need to be exceptionally sensitive to have any value, Diaz-Arrastia cautioned, pointing to rare instances of patients who seemingly suffered mild head injuries, only to experience grave consequences later.

In 2009, for example, the actress Natasha Richardson fell while taking a skiing lesson. Initially, she appeared to be fine and refused medical care. Two days later she died. An autopsy revealed she had suffered from a TBI resulting in a buildup of blood in the brain.

Tbit's sensitivity is currently at the nanogram-per-milliliter level, but based on other work that Lieber has conducted, Goorno said that it may be possible to further push that to femtogram-per-milliliter sensitivity.

"We can measure viruses, DNA. This thing really, truly gets down to the molecular level," he said.

Regardless, Tbit will have its competitors. Banyan recently completed enrolling 2,011 patients for its pivotal study for its test and anticipates filing with the FDA early next year to market it, said Tony Grover, the company's vice president of business development. The test will be for diagnosing mild TBI, and Banyan aims to market the technology primarily to hospitals, as well as centralized labs and stat labs.

"All three of them are very important to Banyan Biomarkers," Grover said.

Its technology comprises GFAP and ubiquitin carboxyl-terminal hydrolase isozyme L1. Banyan has inked a licensing agreement with Abbott to use the test on its i-STAT handheld analyzer, and a joint development deal with Royal Philips for Banyan's technology for use on Philips' Minicare handheld instrument.

Banyan also has a research-use-only deal with Quanterix for the test targeting researchers investigating the GFAP and UCH-L1 biomarkers.

Lexington, Massachusetts-based Quanterix, meanwhile, has agreements also with ADx NeuroSciences to develop a blood-based concussion test, and made an investment in ImmunArray in September, providing it access to that firm's portfolio of biomarkers for TBI. Quanterix CEO and Chairman Kevin Hrusovsky told 360Dx that its Simoa platform can detect a number of proteins associated with TBIs and minor TBIs, including GFAP, tau, amyloid-beta peptides, UCH-L1, and neurofilament light.

The company is developing its technology as laboratory-developed tests, he said.

As research into concussion-related proteins evolves, Goorno said that BioDirection may add more biomarkers onto Tbit, which can measure up to 20 proteins on a panel. That may be necessary for the test to have clinical use, according to Diaz-Arrastia.

Because GFAP and S100 beta are proteins produced by astrocytes, they measure the same pathology — astrocytic activation.

"And my gut feeling is … what would be ultimately clinically useful would be a test that combines several biomarkers — probably more than two but no more than eight or 10 — that truly access the heterogeneity of the pathology," such as vascular and endothelial cell injury, Diaz-Arrastia said.

Goorno said that along with TBI, other brain-related conditions such as Alzheimer's disease and strokes could be addressed by BioDirection's technology, though that would be longer term in the development pipeline.

Founded in 2010 by Brian McGlynn, now BioDirection's chief technology officer, the company has raised a total of $10 million through individual investors. A $2 million interim funding round is currently under way, and early next year, the company anticipates embarking on a $15 million Series C financing round to finish Tbit's design specs and its preclinical testing. The money will also be used to complete the FDA submission and approval process and start commercialization of the test, Goorno said.