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True Bearing Preps for Multi-Site Validation Trial in Pivot to Infectious Disease Detection

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NEW YORK – Having put its initial work in heart disease testing on hold during the COVID-19 pandemic, genomics firm True Bearing has emerged with a new near-term target for its technology in detecting infections in patients presenting with inconclusive or equivocal symptoms.

After publishing initial proof-of-concept data, the company is currently preparing to conduct a multi-site validation study for its lead product in aiding the detection of abdominal infections in individuals with abdominal pain. Tisha Jepson, the firm's CEO, said that the company intends to seek US Food and Drug Administration clearance using the results.

The company, founded in 2015, is advancing research led by George Washington University investigator Tim McCaffrey applying SeqLL's amplification-free sequencing technology to the identification of novel disease signatures.

Prior to the COVID-19 pandemic, True Bearing had made some breakthroughs in its efforts to advance the platform in cardiovascular disease including exploring partnering with Illumina Ventures. But as it emerged from lockdown, the decision was made to refocus on an application that would be easier and quicker to bring to market.

"We were well along the way with the heart disease blood test, and then COVID hit, and we are such a small team that we felt that … a shift to our infection diagnostic would be best," Jepson said in an interview. The company already had studies running in parallel for this indication, so the transition was smooth.

The company has larger plans for the technology, but its first commercial foray will be in the detection of abdominal infections. "Doctors really don't have a tool in the toolbox for this prior to seeking scans and investigational surgery, especially if we're talking about chronic abdominal pain," Jepson said.

Estimates of the current accuracy of clinical diagnosis of abdominal infections vary. A 2017 paper published by the World Society of Emergency Surgery describes a consensus meeting on diagnosis and treatment of intra-abdominal infections, which endorsed a step-up approach, starting with clinical evaluation and progressing to imaging.

The WSES group wrote that sensitivity and specificity of MRI for the diagnosis of acute appendicitis has been reported at up to 94 and 96 percent, respectively. Laproscopy, meanwhile, results in definitive diagnosis rates between 86 and 100 percent in unselected patients.

Jepson said that True Bearing's aim is not to supplant these measures, but rather to ensure that when they are performed, it is for patients that need them.

"If it's an infection, you're going to go in one direction. If it's not, it could be psychosomatic or injury-based or as a result of an allergy. There are so many other areas in which you could look, and [this could] make it much more efficient and effective for the doctor," she said.

In the company's studies thus far, its test — which comprises a panel of mRNA transcripts related to immune activation — was able to discriminate infections from non-infections with accuracy above 95 percent.

In a recent publication in Scientific Reports, the True Bearing team reported results of a study evaluating the test — made up of the three biomarkers alkaline phosphatase (ALPL), interleukin-8 receptor-β (IL8RB), and defensin-1 (DEFA1) — in a cohort of 89 emergency department patients who received an abdominal CT scan as part of their evaluation.

They compared the mRNA biomarker levels to clinical outcomes — based on CT scan results and medical records — assessing the test's ability to predict diagnoses of infection, surgery, and hospital admission.

Among the 34 patients who were admitted and treated for a presumed infectious disorder, 33 tested positive using True Bearing's panel.

With its now-paused coronary artery disease assay, True Bearing ran into some issues with signal-to-noise using amplification-based methods, which would have made it difficult to test at scale using a platform like digital PCR, which had been its plan.

"You're making more copies of that which is abundant and fewer copies of that which is rare. So, with a low-abundance target, by the time sequencing occurs, you have a problem because the target either looks like noise or it's completely gone," Jepson said.

The infection test has been a much easier prospect because "there is a whopping signal for infection" compared to CAD, she explained.

According to Jepson, True Bearing has also spent significant effort overcoming issues with sample preparation. "One of the things that we had trouble with from the beginning was preserving the cells and extracting the neutrophils such that they weren't destroyed, [but] that's something that we have been able to achieve."

In the Scientific Reports publication, McCaffrey and colleagues reported using RNA preservation and isolation tools from Tempus.

Jepson stressed that the firm's test is designed to diagnose infection agnostically, not to detect the specific pathogen responsible

Experimentally, the company has found that its platform can achieve some discrimination, for example, differentiating between biofilm versus viral or bacterial infections — and their upcoming initial bid for FDA Clearance will include both the detection of infection and differentiation, when possible, to guide physicians next steps. Other future applications could include infection testing in patients with joint replacements, something True Bearing is already exploring in new studies, Jepson added.

"Shoulders, hips, knees, at this point if they become feverish or inflamed, the new part is pulled out, everything's scraped down and a new part is installed. And this undermines the patient's likelihood of success and really slows the whole medical process down," she said.

"Our test could allow the physician to determine if an infection is likely to respond to antibiotics and administer antibiotics instead of immediately removing the part. It's not where we're going right at this moment, but that is within the scope of what we could do."

Another promising aspect of the technology, Jepson said, is that it can also measure the magnitude of infection, allowing doctors to monitor and titrate their use of antibiotics.

"When a patient undergoes a course of antibiotics, at the end of that course, they're sent home, but often some period of time later, they come back with a raging infection and now they're resistant to antibiotics. Test could indicate if infection is resolved or has been reduced, but not resolved. In that case, continue the course of antibiotics until the infection is indeed eradicated and then send that patient home," Jepson said. "Option three would be the infection has not been impacted at all. Instead of having that patient go away and come back … the physician can move to some other approach that would hopefully be more appropriate and effective."

The firm has also considered the possibility of advancing the technology for respiratory infection testing, generating early data in COVID-19 patients.

According to Jepson, True Bearing doesn't have a timeline for completing its multi-site validation study or submitting the abdominal infections test to the FDA but said the goal is to recruit at least 500 and up to 1,000 patients. In addition to George Washington University, the University of Virginia hospital system and Children's National Hospital have agreed to participate.

She declined to discuss fundraising but implied that the firm will need additional support to complete the trial for its FDA submission.

Eventually, if the infection test is successfully commercialized, True Bearing plans to return to its coronary artery disease test and hopefully bring that to market as well.

"We're a tiny team. We have about 10 technicians working with us, [so] our capacity is small," Jepson said. "We're running forward full throttle with the science, but we're having to be incredibly frugal with everything."

"Infection alone is a hundreds of billions of dollars industry," she added. "If we could just take a half a percent of that, that would be a really good place to be."

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