NEW YORK (360Dx) – Sepsis, which kills more than 250,000 people in America alone each year, is receiving growing attention from in vitro diagnostic industry players. In 2017, the US Food and Drug Administration cleared several new diagnostic tests, startups advanced technologies towards commercialization, and large industry players struck deals to strengthen their infectious disease testing menus.
Sepsis is a complicated and dynamic syndrome, Nour Shublaq, European product manager at DNAe, said in an interview. The sepsis-related pathogen spectrum is a challenge and varies depending on the source of infection and epidemiological factors, and this is compounded by an antimicrobial resistance landscape which is growing and evolving, she added.
"The MDx and IVD companies have responded with a variety of tests, each with its own unique features," Shublaq said. "It is foreseeable that multiple types of tests working together would aid clinicians. However, these combinations would have to be carefully selected [for] timely gain of information to impact patient care."
In the month of February, the FDA announced three clearances for tests in the sepsis diagnostics market.
It cleared a highly anticipated bloodstream infection test from Accelerate Diagnostics.
The firm said that its blood culture kit is indicated for susceptibility testing of specific pathogenic bacteria associated with bacteremia, the leading cause of sepsis. It also provides information about antibiotic sensitivity, and with the clearance, Accelerate began marketing the test and platform in the US.
Accelerate's PhenoTest BC Kit can identify bacteria or yeast from a positive blood culture in about 1.5 hours, compared to the 24 to 48 hours it takes with traditional identification and antibiotic susceptibility tests, the FDA said.
BioMérieux received clearance for the expanded use of its Vidas BRAHMS PCT Assay, an automated test that measures levels of procalcitonin, to aid clinical decisions about the optimal use of antibiotics in patients with lower respiratory tract infections or sepsis.
At around the same time, Immunexpress received 510(k) clearance from the FDA for use of its Septicyte Lab, an RNA-based blood test that helps clinicians determine whether an infection has caused a patient's systemic inflammation.
Immunexpress noted that being able to rapidly differentiate infection-positive systemic inflammation, or sepsis, from infection-negative systemic inflammation, or systemic inflammatory response syndrome (SIRS), can save lives and reduce healthcare costs.
In April, Diazyme Laboratories received 510(k) clearance to market a test for diagnosing sepsis that, similar to BioMérieux's clearance, uses procalcitonin as a biomarker.
The firm's homogenous immunoturbidimetric PCT assay can be used on most clinical chemistry analyzers to measure PCT levels in serum and plasma samples, providing results in minutes, Diazyme said.
Procalcitonin-based technology acquired by Thermo Fisher Scientific with its purchase of Hennigsdorf, Germany-based BRAHMS for $470 million in 2009, and which Thermo Fisher has licensed to BioMérieux and other companies, also received an FDA clearance in July this year.
The clearance covers the expanded use of the firm's procalcitonin-sensitive Kryptor assay for antibiotic resistance. It provides clinicians in emergency departments, intensive care, and other hospital units with a tool for antibiotic stewardship, BRAHMS said, adding the assay will help clinicians decide whether to start patients with suspected or confirmed lower respiratory tract infections on antibiotic therapy. It also will allow them to determine when patients with LRTI and sepsis can be safely taken off therapy.
In June, the FDA cleared another procalcitonin assay, this one made by Beckman Coulter Diagnostics in collaboration with Diazyme Laboratories. The assay is the first homogeneous PCT assay for use on Beckman Coulter AU model chemistry analyzers and can be used to manage bacterial infections and sepsis. The fully automated assay, which features a latex-enhanced immunoturbidimetric methodology based on antibodies for enhanced sensitivity and specificity, can be used with Beckman Coulter AU analyzers, models 480, 680, and 5800.
The company is collaborating with Diazyme Labs, a cGMP and ISO 13485-certified medical device manufacturer, to make the assay available.
An alternative to the use of procalcitonin as a marker of sepsis received CE marking in July. It enabled T2 Biosystems to begin marketing its T2Bacteria Panel as part of a sepsis diagnostics solution in Europe during the third quarter.
In the US, the panel is available as a research-use-only assay, but T2 said upon receiving CE marking that it was in the "final stages of completing" an FDA pivotal trial, after which it planned to apply for 510(k) clearance that would enable it to sell and distribute the panel in the US.
Molecular tests have an advantage because of their speed to result compared to traditional biochemical approaches to identification or susceptibility, T2 Bio's Chief Scientific Officer Tom Lowery said.
MDx tests "can greatly speed identification of organisms off a positive blood culture," he said. "However, it is important to note that all tests currently on the market, with the exception of T2 Biosystems' tests, are run on a positive blood culture, which may miss as much as 50 percent of infections that T2MR, [T2's technology], identifies."
Lowery noted that in today’s landscape of sepsis testing, several types of tests are required to be used in conjunction on the patient. Rapid, culture-independent tests such as those from T2 Biosystems can help get a patient onto the appropriate therapy quickly, he said.
"Blood culture allows for a comprehensive, albeit less sensitive, assessment of infection followed by species identification and susceptibility," he said.
He noted that most decisions for treatment are driven by species identification, which is supplied by molecular testing. Additional biochemistry would identify susceptibility to antibiotics, which is advisable if you have positive blood culture results, he added.
He also noted that MALDI-TOF platforms for species identification after a positive blood culture "are becoming fairly widespread."
Financings and alliances
Investors have taken note and money has flowed into the market.
For example, earlier this month, Qvella, a developer of rapid, multiplex molecular diagnostics, said it had raised $20 million in a Series B financing. The funding round was co-led by the firm's existing investor syndicate, including RA Capital, Whitecap Venture Partners, Hatteras Ventures, and Sands Capital, which previously supplied Qvella $20 million in Series A funding. New investor BioMérieux also participated in the round.
Qvella is developing multiplexed PCR-based assays to detect infectious disease agents directly from patient samples using its proprietary electrical sample prep technique called Field Activated Sample Treatment, or FAST. The Toronto-based company’s first product in development is a rapid bloodstream infection test that can detect pathogens causing sepsis from whole blood samples in under one hour.
Earlier in the year, blood collection device firm Magnolia Medical said that it had raised $7.25 million, bringing the total funding it has secured to date to $30 million.
Several institutional investors participated in the financing, including Canepa Advanced Healthcare Fund. The funding followed $13.8 million in funding the firm received in July 2016. It said it would use the money to accelerate commercialization of its SteriPath blood collection system, which the firm said is the only clinically proven device to virtually eliminate "false positive" blood culture test results from patients suspected of having sepsis.
Meanwhile, other firms have jumped into sepsis testing through alliances, such as the deal signed between Ortho Clinical Diagnostics and BRAHMS to develop a procalcitonin assay for use on Ortho's Vitros systems. Ortho said that it is developing the assay for use on Vitros immunodiagnostics and integrated systems for small-, mid-, and high-volume clinical labs.
Another player in the market, Hennigsdorf, Germany-based Sphingotec, is evaluating the use of adrenomedullin as a biomarker for shock in sepsis patients, and earlier this month, it signed an agreement with Mayo Clinic to collaborate on the evaluation and use of biomarkers that could improve the diagnosis of certain disease states, including kidney disease, breast cancer, sepsis, and cardiovascular disease.
T2 Biosystems also announced a partnership. Its tie-up with Cidara Therapeutics announced in September would enable the commercial placement of the diagnostics firm's T2Dx instruments to support clinical trials for Cidara’s antifungal CD101s.
Roche Diagnostics also recently inked an agreement to collaborate in developing a biomarker-based companion diagnostic test for a septic shock treatment that biotech startup Inotrem is evaluating in clinical trials.
Roche Diagnostics' tie up with Inotrem is the first collaboration undertaken with a biotech startup by the company's centralized and point-of-care business, an indication of Roche's confidence in the therapeutic compound, Jean-Jacques Palombo, a senior vice president and lifecycle leader in Roche Diagnostics, said in an interview. Roche is developing the companion diagnostic under an exclusive agreement.
Emerging companies also told 360Dx this past year about the advances they are making with clinical studies and product development.
DNAe, for example, has moved closer to commercialization with its direct-from-blood semiconductor-based diagnostic platform by achieving a low limit of detection in identifying bloodstream pathogens that contribute to sepsis and by identifying markers that detect antimicrobial resistance.
In a poster presentation at the Association of Molecular Pathology annual meeting in Salt Lake City in November, the firm presented the results of internal tests that reflected the end-to-end functionality of its testing platform, and showed that it could detect infection-causing pathogens in spiked samples at limits of detection as low as 1 CFU/ml.
Meanwhile, Medical University of Vienna researchers have shown in a study that a Roche PCR test has superior sensitivity rates and can more rapidly identify pathogens in the blood of neonatal patients than traditional blood culture testing.
As a result, the researchers deemed the Roche SeptiFast Mgrade PCR test using a modified DNA extraction protocol acceptable for rapid detection of neonatal sepsis alongside conventional blood culture. The researchers published their findings in the journal PLOS One.
Karius, a three-year-old startup with a commercial test to diagnose infectious diseases by sequencing cell-free pathogen DNA in blood, is beginning to narrow its focus on the most promising immediate applications for its assay.
At the Infectious Diseases Society of America's annual IDWeek conference in October, Karius Cofounder and CEO Mickey Kertesz said that the company believes that its test, called the Karius Digital Culture, is already proving its worth in two key areas: identifying the cause of sepsis and diagnosing infections in immunocompromised patients, especially bone marrow and stem cell transplant recipients.
Diagnostics firm Prenosis continues to progress in its sepsis test development program as well, with research published in September in Nature's Scientific Reports demonstrating the utility of protein biomarkers in combination with patient medical records to detect the condition. Launched as a spinout from the University of Illinois in 2014, Prenosis has targeted sepsis as the primary focus of its test development program.
Stanford University spinout Inflammatix is seeking to measure gene expression patterns of a patient's immune response to diagnose infectious disease. The firm anticipates its first product will be a sepsis diagnostic — an 18-gene panel that will be able to tell from a blood sample whether a hospitalized patient has a bacterial, viral, or no infection so that physicians will be able to administer more appropriate treatments earlier.
Several diagnostic companies have noted that developing solutions for sepsis testing and reducing the overuse of antibiotics go hand in hand.
Cardiff, Wales-based Momentum Bioscience said that its enzyme template generation and amplification (ETGA) test relies on blood culture growth that takes 12 to 15 hours and then combines phenotypic and molecular analyses to validate within 3 hours that the blood test is negative. Normally, that takes around five days to accomplish, Momentum said.
BioMérieux told 360Dx that more than a year after a US Centers for Medicare and Medicaid Services proposal recommended that hospitals put in place robust antimicrobial stewardship programs, many hospitals in the US were still out of compliance. The company is responding by deploying diagnostics consultants within hospitals to support their decision-making around implementing diagnostic tests that would augment antimicrobial stewardship programs.
With a blood culture system approved earlier this year, new indications for its procalcitonin diagnostic assay, and an arsenal of molecular testing tools, BioMérieux is aiming to become a leader in the increasingly competitive field of antibiotic stewardship.
Researchers at Uppsala University Hospital said that they have found a way to make the human neutrophil lipocalin (HNL) biomarker detectable in blood plasma, opening the potential to develop a test that could be used at the point of care to rapidly detect bacterial infection, leading to better use of antibiotics. More than a year after Philips and Uppsala University Hospital spinout Diagnostics Development began a collaboration to integrate an immunoassay based on that biomarker with the Philips Minicare I-20 point-of-care platform, the European Union awarded the partners a Horizon prize in recognition of their work to develop a test.
A positive blood culture initiates immediate antibacterial intervention, but false-positive cultures can lead to expensive and toxic overtreatment. A new technology, however, could improve diagnostic accuracy by reducing tenfold the rate of blood cultures that incorrectly indicate the presence of a pathogen, making sepsis misdiagnosis a remnant of the past, according to Magnolia Medical Technologies, which developed the technology.
Closer to the patient
While gains are being made in developing tests for centralized laboratories, the sepsis market is gaining interest from parties that are developing near-patient testing solutions.
Researchers from the University of Illinois are developing a test that they said can help clinicians diagnose and monitor sepsis in its early stages. If successful, they added, it could potentially be turned into an at-home test. The UI researchers are developing the test in collaboration with the Carle Foundation Hospital. It uses a microfluidic chip that targets the immune system by measuring levels of CD64 expression, a biomarker of the onset of sepsis that surges in response to the arrival of the infection.
Emeryville, California-based diagnostics firm Nanomix is developing a point-of-care test leveraging an electrochemical biosensor platform and enzyme- and immune-based assays to simultaneously probe for three biomarkers. Nanomix said that its test, which is expected to be used at the point of care in critical and emergency situations, could determine whether a patient has sepsis within 10 minutes.
Specific Technologies is collaborating with infectious disease diagnostic nonprofit FIND to advance the firm's rapid blood infection testing system for use in low-resource settings, a move that Specific called a big step forward in the development of its technology. Its solution combines pathogen detection with species identification in standard culture tubes, taking what can be a highly manual, two-day process and translating it into a single, labor-free instrument that the company says delivers comparable results within 12 hours.
Lausanne, Switzerland-based Abionic has begun clinical evaluations of a CE-marked nanofluidic in vitro diagnostic assay that identifies sepsis using a fingerstick of blood within five minutes. The test, being targeted for use in intensive care units and emergency centers, combines a nanotech-based point-of-care ELISA with a pancreatic stone protein biomarker to identify sepsis and quantify the health risk for patients suspected of developing the potentially lethal infection.
If all goes as planned, the assay, which received CE marking in January, could be on the market by the end of 2018, the firm said.