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Inflammatix Preps Immune-Response Sepsis Dx for FDA Clinical Trial, Lays Out Future Test Plans

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NEW YORK – Responding to an ongoing need for biomarkers that can quickly and accurately predict and diagnose sepsis, Stanford University spinout Inflammatix is moving closer to commercialization with an immune response testing platform that uses machine learning to analyze mRNA expression.

Inflammatix Cofounder and CEO Tim Sweeney announced last week that the firm expects to start a clinical trial in January to support a submission to the US Food and Drug Administration for regulatory clearance.

During a presentation at the American Association for Clinical Chemistry Annual Scientific Meeting & Clinical Lab Expo in Anaheim, California, he noted that the company is also planning to validate and verify the performance of its sepsis test during a separate, overnight interventional study next year.

The Inflammatix platform uses isothermal assays for rapid quantitation of mRNA expression from patient samples. The company's first product, a blood test called HostDx Sepsis, may enable physicians to one day quickly determine whether a patient suspected of having sepsis has no infection, or whether the infection is bacterial or viral. In clinical studies, the test has also enabled physicians to determine sepsis risk or the severity of a patient's condition, the firm said. 

Such a test, if it can be commercialized, could help physicians prescribe the correct therapies and enable quick intervention that may reduce the incidence of mortality, according to Inflammatix.

"A lot of people are recognizing that detecting bacteria in blood is not going to cover all of the heterogeneity that we see with sepsis," said Khushbu Patel, an associate director of clinical chemistry at Children's Medical Center in Dallas, Texas. "The approach that Inflammatics is taking, where you are incorporating multiple biomarkers into an algorithm to predict the potential for sepsis or the presence of the condition is really a step forward," said Patel, who is not affiliated with Inflammatix.

Among the company's strengths, she said, is the manner in which it is using advanced informatics to interrogate large-scale transcriptomics studies and to pick out immune-response biomarkers that are the best indicators of the host response to disease.

The availability of a rapid test that can enable clinicians to receive results from an emergency-room laboratory in up to 45 minutes is important in light of concerns over the rate of mortality in sepsis stemming from a delay in administration of treatments, or use of incorrect treatments. "The common thing you hear about sepsis is that a delay in administration of antibiotics for a bacterial infection increases the chance of mortality by 10 percent every hour," Patel said.

Getting patients on the correct treatment enabled by identifying whether an infection is bacterial or viral has implications not only for patients' health, but also reducing the length of stay in the hospital associated with the diagnosis and treatment of sepsis, Sweeney said in an interview.

The firm is developing its HostDx Sepsis test to provide a result within 30 minutes from the time a blood sample is loaded into the machine.

Inflammatix recently completed a pre-submission of clinical results for its sepsis test to the FDA. Sweeney said he expects the firm will apply for CE marking, which would enable sales of the test in European countries and other nations that accept that designation. Regulatory clearances could take a few years, depending on the speed with which Inflammatix and its study investigators can recruit patients and submit trial results to regulatory authorities, and on the agencies' responses to the submission.    

Competing against 39 other applicants, Inflammatix won a disruptive technology award at the AACC meeting last week. Patel was among a group of four people who evaluated applications for the award, but she noted that her perspective on Inflammatix and its technologies were her own and she was not speaking for AACC.

Test pipeline

Sweeney described in the interview the various tests the firm has in development, their market potential, and the company's plans for product development and commercial launch.

The company's HostDx Sepsis test generates mRNA expression profiles that clinicians can use in making more accurate decisions for several conditions, and during different clinical circumstances while treating a single condition, Sweeney said.

In a series of clinical studies completed so far involving thousands of patients and sponsored by his firm or initiated by clinical investigators, the sepsis test has shown high sensitivity and specificity levels tied to three scores that the instrument triggers when an infection is detected. The scores reflect whether a patient has a bacterial or viral infection, how sick the patients are, and whether the infection is viral or bacterial. Each score is broken into four interpretation bands — very unlikely, unlikely, possible, and very likely. Sensitivity levels tied to a "very unlikely" score are between 97 percent and 98 percent, and specificity levels tied to a "very likely" score are between 93 percent and 99 percent in studies completed so far, Sweeney said.

While it prepares its Host Sepsis Dx test for a pivotal trial to obtain regulatory clearances, Inflammatix is also developing a broader pipeline of tests that could prove to be just as important to patients, Sweeney said.

Farthest along in the development cycle after HostDx Sepsis is the firm's test to detect and differentiate bacterial from viral infections in patients presenting with fever, a capability that would enable physicians to decide during an office visit whether to prescribe an antiviral treatment or antibiotics, or just recommend rest. The diagnostic test, HostDx Fever, uses expression of seven mRNAs to produce its gene expression profile and is expected to produce results within minutes.

While the firm anticipates targeting hospitals, and particularly their emergency department laboratories, with its sepsis test, it expects to target outpatient settings, pharmacy clinics, and similar point-of-care settings with its fever test. In these settings, patients are increasingly looking to obtain a decision about whether they should take an antibiotic or antiviral drug in a single visit.

The company will look to obtain regulatory clearance and a CLIA waiver for the fever test, Sweeney said. It is as far along in development as the sepsis test but it is likely to take longer to commercialize partly because of the need to obtain a CLIA waiver and because the test uses a finger-stick sample rather than the more traditional venipuncture used by HostDx Sepsis.

Longer term, Inflammatix anticipates launching a test called HostDx FeverFlu, which currently consists of a 15-mRNA expression profile to determine from nasal swab samples whether a patient has influenza and whether an infection is bacterial or viral. Sweeney and his colleagues are also developing HostDx Endotypes, which consists of a 33-mRNA expression signature and would monitor a patient's response to therapy treatments for sepsis.

In research associated with HostDx Endotyes, Inflammatix has developed and validated a test that identified three sepsis subtypes — inflammopathic, adaptive, and coagulopathic. The findings from the study may enable a precision medicine approach involving matching immunomodulatory therapies with the septic patients most likely to benefit, Sweeney said.

Also early in the product development cycle is a test to monitor a patient's autoimmune response to tumor necrosis factor alpha therapy, and a separate test targeting low-resource, high-burden settings to detect in one panel whether a patient has a bacterial or viral infection, or malaria or tuberculosis.

Addressable markets

Sweeney said that, according to his firm's research, around 80 million patients are tested in the US each year who are candidates for use of the HostDx Fever test, and around 21 million patients are tested in the US per year who are candidates for use of Host Dx Sepsis.

For its HostDx Sepsis, Inflammatix plans to implement a razor and razor-blade model, in which it would place instruments at a low cost and expect to make margin on sales of cartridges. Sweeney said at the AACC meeting that he believes the firm may be able to achieve a cost of goods sold of $15 per cartridge.

If it receives FDA clearance, the company plans to apply to the US Centers for Medicare and Medicaid Services for a proprietary laboratory analysis (PLA) code, which would enable reimbursement for HostDx Sepsis patients not admitted to hospitals. For patients admitted, hospitals pay for the tests from a lump sum received from CMS that is associated with a diagnostic-related group (DRG) code for sepsis, Sweeney noted.

Inflammatix, through clinical studies and economic modeling, expects to show that tests such as HostDx sepsis could enable reducing the number of days a patient spends in the intensive care unit, enable earlier discharge of patients from the hospital, and reduce readmission rates, Sweeney said.

The Inflammatix sepsis test may address challenges with existing single-biomarker host response tests and technologies that look to identify pathogens causing sepsis, according to some clinicians.

"There has been a push to implement procalcitonin as a biomarker of sepsis at a lot of hospitals," Patel said. However, procalcitonin and other single biomarkers are unable to address the complicated nature of the infectious disease condition, and Children's Medical Center is not currently offering procalcitonin testing for sepsis, Patel added.

Nathan Ledeboer, a scientific advisor to Inflammatix, noted that in addition to procalcitonin, clinicians are using other single markers, such as lactate, in diagnosing sepsis, but "ultimately that approach is like trying to pound a square peg into a round hole."

Ledeboer, who oversees medical and technical activities at the Medical College of Wisconsin clinical microbiology and molecular diagnostics laboratories, said, "Single biomarkers don't take into account the complexity of patients, their backgrounds, their exposures, and how each one reacts to infection. Complexities associated with diagnosing sepsis are taken into account by a test like HostDx Sepsis that uses multiple markers derived from broad population data and applies machine learning to help interpret results, he said.

Inflammatix can expect competition from a number of established diagnostic companies marketing products for sepsis diagnosis. For example, several FDA-cleared procalcitonin tests are on the US market, including those produced by Roche, BioMérieux, and Thermo Fisher Scientific. Producers of highly multiplexed tests that detect sepsis bloodstream pathogens, such as GenMark Diagnostics, are also competing in this space.

And T2 Biosystems said recently that the US Centers for Medicare & Medicaid Services has approved a New Technology Add-on Payment for the company's direct-from-blood T2Bacteria sepsis panel. Sweeney said that such an approval is encouraging for new companies entering the market for sepsis diagnostics, because it can provide a way for them to "bridge the gap" between market access and receiving reimbursement approvals.

Earlier this year, Accelerate Diagnostics said that it will seek a New Technology Add-On Payment approval to help drive sales of its genotypic and phenotypic sepsis test.

 

 

 

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