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Cytovale Aiming to Enter Sepsis Testing Market With Rapid, Direct-From-Blood, Point-of-Care Platform


NEW YORK ─ Diagnostic test developer Cytovale this month took a step closer to its goal of commercializing a host-response test that has the potential to provide an assessment for the risk of sepsis in 10 minutes.

The firm and its clinical investigators have just kicked off a 600 patient, multisite clinical trial to evaluate the performance and clinical utility of a high-speed imaging platform, called IntelliSep, and set the stage for a submission to obtain regulatory clearance from the US Food and Drug Administration.

San Francisco-based Cytovale's overall objective is to develop technology it has licensed from the University of California, Los Angeles to diagnose immune-mediated medical conditions, but it now has a laser focus on executing the new study, the firm's cofounder and CEO, Ajay Shah, said in an interview.

"We've been pretty quiet to date, but this is the beginning of people starting to hear more about Cytovale," Shah said. If the IntelliSep platform can be commercialized, he said, it has a number of important clinical features including its potential to slot easily into emergency department diagnostic workflows.

"As we were looking to translate the technology into clinical applications, we recognized the critical clinical need for a solution for early sepsis detection," Shah said. "We believe that there is a nice fit between the unique attributes of this technology and that critical need."

Because patients with sepsis can quickly become critically ill, physicians are under intense pressure to diagnose it rapidly and decide whether to prescribe antibiotics, as well as figure out which antibiotics to prescribe.

Cytovale's platform uses biophysics as a basis for its tests; its core technology analyzes the mechanical properties of single cells to understand cell state and behavior.

"The IntelliSep test is attractive because it uses routinely collected blood samples, has quick turnaround time, and does not require extensive clinical or laboratory analytics," Cornelius Clancy, chief of infectious diseases at the US Department of Veterans Affairs Pittsburgh Healthcare System, said in an interview.

He added that while Cytovale "has marked its sepsis index as a tool to monitor as further studies are performed," the peer-reviewed data generated so far for the test represent "early steps in the long and tortuous process of validating a test and getting it approved and to market."

Clancy is not affiliated with Cytovale but participated in a pivotal clinical trial for a direct-from-blood infectious disease test developed by Lexington, Massachusetts-based T2 Biosystems.

Hollis O’Neal, critical care physician at Louisiana State University Health Sciences Center and principal investigator for Cytovale's pivotal study, said in an interview that the firm's test can help physicians make quick decisions by testing the innate immune system, which reacts with such strength to the onset of sepsis that it can injure other parts of the body at a distance from the site of infection and cause fatal organ failure.

The investigators are enrolling patients at Louisiana State University, the University of Washington, the University of Missouri, and Wake Forest University. The clinicians expect to complete enrollment by the end of this summer, which could enable an application to the FDA for clearance of the test early in 2022, or sooner, O'Neal said.

Working from a whole-blood draw, the IntelliSep platform automatically removes red blood cells and uses microfluidic channels to align white blood cells in single file. The cells collide with a column of fluid, which alters their properties.

"Patients who have more active innate immunity have larger numbers of cells that are more squishy and bouncy, and that can be detected by the test," O'Neal said.

The platform deploys machine learning and high-speed imaging to measure the biophysical properties of the white blood cells as they are stretched through a microfluidic channel. It captures 500,000 image frames per second, while gathering information about the immune system's neutrophils and monocytes, and uses the measurements to create an index that guides clinicians.

Machine learning enables the platform to measure the cells' properties and provide a result, via an IntelliSep Index, indicative of the risk for sepsis. On an index scale of 0.1 to 10, 0.1 represents a less active immune system and the lowest risk for sepsis, and 10 represents a more active immune system and a high risk of sepsis.

In clinical studies to date, the test had a negative predictive value of 98 percent, and positive predictive value of between 50 and 60 percent. The negative and positive predictive values combined mean the test can be used to prioritize resources and identify patients at greatest risk, O'Neal said, adding, "It takes a huge burden off the healthcare system and allows clinicians to focus their efforts on all those patients with the highest risk while saving resources in addressing those patients at the lowest risk."

Clinicians could run the instrument and test patients, if needed, alongside complete blood count tests that they often order for those they suspect are at risk of sepsis. The test requires only 100 microliters of blood, meaning almost everybody who enters an emergency department for diagnosis and treatment has enough blood to take a test, O'Neal said, adding that because the test uses biophysics instead of chemistry for detection, it does not require special labeling, incubation, or extensive pretreatment that increases expense and the need for highly skilled laboratorians.

No blood culture

O'Neal further noted that the IntelliSep test does not require the completion of blood culturing, a time-consuming process that current molecular and phenotypic in vitro diagnostic tests require prior to their use. The time spent conducting a blood culture, running a diagnostic test to identify a disease-causing pathogen, and performing an antimicrobial susceptibility test to select the most appropriate treatment can be problematic for clinicians.

A test like Cytovale's would take a huge burden off healthcare systems as they look to treat patients suspected of sepsis, O'Neal said. For this condition, there are two sides to healthcare expenditures. First, longer lengths of stay in hospitals and intensive care units are associated with ballooning costs and are hallmarks of unsatisfactory sepsis diagnosis and treatment. Under these circumstances, mortality rates increase and adverse long-term health outcomes drive up expenses. Second, costs related to overtreatment, or the treatment of patients for sepsis when they do not have it, "are just as important and more difficult to calculate," O'Neal noted.

O'Neal has known about Cytovale's test since 2014 when he participated in the first pilot study to validate its potential to detect sepsis in samples collected from patients presenting to the emergency department with symptoms of infection. He and his colleagues have continued to evaluate the test including in studies that have recruited ethnically diverse patient populations and people with and without sepsis. The investigators described the IntelliSep Index and its validation in a study published in PLOS One in April.

"The results of that early-stage study were promising for distinguishing patients with sepsis from those who did not have sepsis," Clancy said, adding that distinguishing sepsis from other similar conditions, such as fever or low blood pressure, can befuddle physicians and result in "widespread empiric use of antibiotics, corticosteroids, and other drugs in emergency departments and acute care settings."

When physicians prescribe treatments that are not needed, there are risks of side effects, complications, and the promotion of antibiotic resistance. As a result, "time to initiation of appropriate therapy — be it antibiotics for infections or drugs like corticosteroids for noninfectious systemic inflammatory conditions — is a crucial determinant of successful treatment of sepsis," Clancy noted.

For these reasons, many organizations are attempting to develop rapid novel diagnostic tests, and technologies at various stages of development are using diverse strategies.

They include tests that directly detect bacterial or fungal cell components in patients' samples; measure and detect host inflammatory cell or chemical signatures of sepsis in blood; and employ machine learning and health record data mining to identify high-risk subjects for sepsis.

Among companies developing novel technologies, Burlingame, California-based Inflammatix and Durham, North Carolina-based Predigen are separately developing host-response tests for sepsis that use gene expression at the point of care.

Tucson, Arizona-based Accelerate Diagnostics expects to launch two new products this year and is developing a third with the aim of achieving better penetration in the market for bloodstream pathogen identification and for antimicrobial susceptibility testing.

T2 Biosystems has an early-mover advantage in the market for direct-from-blood sepsis testing and is seeing revenue growth from its FDA-cleared T2Bacteria Panel and T2Candida panels.

Cytovale hopes to be one of the next companies to reach the market with a direct-from-blood sepsis test.

Established to commercialize technology developed at UCLA by Dino Di Carlo, one of Cytovale's cofounders, and Henry Tse, its chief technology officer, the firm has been developing its testing platform since 2013.

It is considering different sales and marketing options for the platform, including using distributors and hiring an internal team. Long term it has its eye on international expansion and obtaining regulatory approvals outside the US. For test reimbursement, it intends to piggyback on established payor codes, Shah said.

The price for the IntelliSep platform and sepsis test is expected to be in line with that of a hematology analyzer and far less than for a sophisticated molecular diagnostic instrument and test, according to Cytovale, but it is not disclosing anticipated pricing at this time. However, complete blood count hematology analyzers can be purchased for less $4,000.

In 2019, the firm received $15 million in financing to advance the development of its technology for the early detection of sepsis including a $7.4 million extension of a Series B equity financing and $7.6 million from the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority, or BARDA.

Longer term, Cytovale has its eye on other diagnostic uses that can benefit from its host-immune testing platform and technology. Shah said that additional future tests are likely to be "related to sepsis, indications outside the emergency department, and generally where immunology intersects with acute care."

The firm is investigating the potential for a test for the ongoing monitoring of patients who have been treated for sepsis. Last year, it nabbed an additional $3.8 million from BARDA to evaluate its platform's ability to detect respiratory infections.

Clancy said that overall, it is unclear which products and approaches will emerge as most successful for the diagnosis of sepsis over the next decade. "Hopefully, new tools and approaches will succeed in lowering the high mortality rates we currently encounter with sepsis," he said.