A Paradigm Shift in Sepsis Diagnostics

Immunexpress is advancing next-generation clinical sepsis diagnosis tests for use in emergency room and intensive care unit settings. The company’s lead test SeptiCyte® RAPID is clinically validated and has received 510(k) FDA clearance indicated for the diagnosis of sepsis in adults. It is the first gene expression host response test to receive the 510(k) FDA clearance. The test integrates into current clinical practice and enables clinicians to accurately identify septic patients and triage them based on severity, all the while doing so cost-effectively, easily (a push button automated solution) within one hour – as we all know in the ER and ICU every minute counts. The test is poised to transform patient care, lower associated medical costs and decrease the burden on the healthcare system. The company has developed a sales strategy, informed by market learning and adoption studies, and is in discussions with several medical centers, some of which are advancing to adoption commitments.  

In this interview, Rolland Carlson, PhD, CEO of Immunexpress, discusses sepsis and the company’s FDA cleared SeptiCyte® RAPID test, as well as a take on the company’s differentiated value and outlook.

Anna MacDonald (AM): Can you set the stage for us – what is sepsis and how big is the problem?

Rolland Carlson (RC): Infections – a familiar topic to many of us. Infections can be caused by a diverse set of pathogens, including bacteria, fungi, parasites and viruses, most top of mind being SARS-CoV-2 that causes COVID-19. But what happens when our immune system overreacts to the response to an infection? Sepsis. The overactive immune response triggers a toxic cascade that suddenly decreases the function of one or more organs and often progresses to complete organ failure and death.

Like strokes or heart attacks, sepsis is a medical emergency that requires rapid diagnosis and treatment. Clinicians need a fast, push-button and high-performing test to differentiate the life-threatening condition of sepsis from other slowly progressing and less severe medical conditions. Marketed diagnostics are inadequate.

Sepsis is a big problem across the axes of medicine and economics. Sepsis – the highest in-patient deaths, highest in-patient costs, and the most under reimbursed for diagnosis and treatment. In the US, prior to 2018, sepsis was the leading cause of death in US hospitals (>270,000/year; 1:5 deaths, ~27% in-hospital and ~43% in intensive care units), as well as the medical condition with the highest in-hospital costs (>$42B in 2018) and the most under reimbursed. The COVID-19 pandemic has exacerbated these numbers and added two new figures – (1) sepsis accounts for ~33% of deaths for COVID-19 patients and (2) more and more survivors of COVID induced sepsis have long-term negative issues well beyond the initial presentation.

Our team at Immunexpress is pioneering first-in-class sepsis solutions and our most advanced solution,  SeptiCyte® RAPID, is clinically validated and has received 510(k) FDA-clearance indicated as an aid in the diagnoses of sepsis in adults. We are advancing necessary studies specific to COIVD induced sepsis, as well as studies to expand the intended use population. We have conducted studies in over 400 COVID-19 patients and found SeptiCyte® RAPID detects sepsis when patients are hospitalized and identifies patients who often will progress to more severe disease within two or three days. We compared our test results and risk scoring to an IL-6 diagnostic that received emergency use authorization and found that our solution has superior performance for predicting severity and progression.

AM: What makes sepsis difficult to diagnose?

RC: Current clinical practice does not adequately or efficiently enable clinicians to identify patients with sepsis or further triage those likely to worsen faster. There is a large unmet need for a clinical test for sepsis diagnosis that has sufficient performance – accuracy, speed, ease-of-use and price point – to integrate with existing sepsis clinical practice and diagnostic workflows. What makes sepsis difficult to diagnose? Early in the disease course, life-threatening sepsis presents very similarly to a far less severe condition known as systemic inflammatory response syndrome (SIRS) which is infection-negative. 

Clinicians need to evaluate acutely ill patients exhibiting signs of systemic immune response, either sepsis or infection-negative systemic inflammation, and only put septic patients on antibiotics and estimate what other sepsis-specific care to provide and when. Septic patients need life-saving care fast. Sepsis can suddenly worsen and rapidly progress to what clinicians refer to as septic shock characterized by insufficient oxygen in the blood, dysregulated levels of necessary proteins in the blood, reduced organ function and, in some cases, the damage is irreversible. Clinicians need to deprioritize infection-negative systemic inflammation patients in the ER and ICU to treat more urgent medical conditions. There are not enough beds and not enough clinicians.

How is current clinical practice for diagnosing sepsis inadequate? Poor accuracy and slow. The patient presents with abnormal vitals that include 2 signs of SIRS (i.e. fever, elevated heart rate and respiratory rate). The clinician typically orders two tests – white blood cell counts and lactate levels. High white blood cell counts suggest the presence of an infection and high lactate levels suggests oxygen levels in the blood are low. In some cases, clinicians submit samples for a battery of additional tests, including those that measure levels of procalcitonin protein, C-reactive protein, among others. Every minute counts and by now one hour has passed potentially up to three. Together, these tests indicate an infection may be present but do not with sufficient accuracy distinguish the two possibilities – sepsis or infection-negative systemic inflammation. It is a toss-up. Clinicians typically will default to treating them with antibiotics which frequently results in an extended length of stay. In most cases, a blood draw is taken and cultured over a period of 12 to 20 hours. During the culture period, if the patient has sepsis the organism causing the infection will grow to levels above the detection limit of diagnostics and readout as positive, indicating the patient is septic. The results, while accurate, are not actionable in ~85% of cases because septic patients often progress within this time. At this point, those with a negative blood culture test, those with infection-negative systemic inflammation patients will be taken off antibiotics, however during that period they occupied a much-needed ER/ICU bed and clinician bandwidth, as well as potentially contributed to the broader threat of antibiotic resistance.

AM: How does Immunexpress’ SeptiCyte® RAPID test integrate with existing clinical practice to address the significant unmet need in sepsis diagnosis?

RC: We designed our test for clinicians, hospital technicians and hospital systems from day one. It is critical for companies to design clinical tests with the end users in mind. The clinician and hospital technician users have low bandwidth – meaning time and the ability to process complex information. The test steps ideally are a few in number, require little hands-on time, are simple and include no unique steps. Think – a standard blood draw, clinicians take these all the time for many downstream tests. Think – a single and very common manual step of inputting a small sample into a cartridge that slots into a push-button instrument with automated data analysis that the technician has familiarity operating. The hospital technician does not need additional training and the test workflow seamlessly fits in parallel to other workflows. Now both combined – the test ideally cross-shares fixed investments the hospital has already made to support clinicians using the results to make clinical care decisions quickly. These include instrument purchases and maintenance, dedicated lab space and trained personnel, and similar workflows with precedent for meeting regulatory and reimbursement criteria.

At Immunexpress we considered all of these key parameters in the design phase, and therefore anticipate fewer adoption hurdles and both higher and durable sales. Our early and ongoing conversations with hospital systems informed us about preferred design, necessary performance and acceptable cost. We engaged with hospital systems during design, R&D, prototyping, clinical trials and performance assessments.

How does our solution work? The test measures the abundance of select RNAs in white blood cells. By select we mean those that are high or low only in septic patients. Our SeptiCyte® RAPID test complements current medical practice to more accurately distinguish sepsis from non-infectious systemic inflammatory response syndrome. Our test provides an actionable risk score between 0 and 15 with a low score indicating a low risk/probability of sepsis and vice versa for a high score. The clinician takes a standard blood draw. The hospital technician transfers a small volume of blood into our proprietary cartridge and slots the cartridge into an Biocartis Idylla^TM System. By several estimates the Biocartis Idylla^TM Systems install base in US hospitals is over 100 and >75% of these systems are dedicated for targeted genomics (DNA) and transcriptomics (RNAs) in clinical patient samples. Many of the use cases pertain to precision medicine for cancer patients. This approach saves lives. A bit more context is helpful here – there are chemotherapy regimens and biopharmaceutical drugs that work better in cancer patients whose cancers have particular genetic abnormalities. Finding out those specific abnormalities enable clinicians to quickly and accurately adjust the clinical care. Hospitals with these Biocartis Idylla^TM Systems enable clinicians to use the on-site generated results to make treatment decisions for cancer patients. Our test piggy backs on this existing fixed infrastructure and policy development.

We have conviction that our solution could potentially lower hospital 30-day sepsis mortality rates and further improve hospitals’ Inpatient Quality Patient Report (IQPR) required by the Centers for Medicaid and Medicare Services (CMS). Said simply, the test could improve patient outcomes, lower in-patient hospital costs and lower the burden on the medical care system. More septic patients will be effectively treated, and non-septic patients will not be overtreated with unnecessary antibiotics. Additionally, the length of hospital stays for both groups is likely to decrease.

AM: What is on the horizon – what industry needs will Immunexpress work to address next?

RC: One – we are planning longitudinal studies/prospective studies in the approved population, adults, to show the cost benefit of the test. We believe that is not only going to demonstrate improved patient outcomes, but also the economic benefit to hospital costs and justification/rationale for payer reimbursement.

Two – we are developing SeptiCyte® RAPID to address unmet needs in additional populations, including neonatal, pediatric, immunocompromised adults and cancer patients. We are encouraged by our data and have published an abstract with a manuscript being submitted; these show that while immunocompromised patients have suppressed immune systems our test has significant and robust utility.

Three – The next iteration of SeptiCyte® technology is the development of our second-generation tests, which has the core rapid capability of telling clinicians whether a bacterium or virus caused the initial infection in septic patients. This knowledge enables them to tailor treatments more specifically for that, particularly if it is viral infection then they should not be administering antibiotics on that patient. Over subscribing has led to a lot of antibiotic resistance, and we are getting towards the last line of defense here with a limited repertoire of effective antibiotics. There have been some projections that if IV antibiotic resistance is not significantly reduced there is going to be more people dying of hospital acquired infections and antibiotic resistance than from cancer by 2050.

Four – There is a need for better sepsis treatments. We have no intention of becoming a therapeutic company, but we do see the potential for licensing or partnering sepsis drug targets that we have discovered in our R&D process for the sepsis diagnosis tests.

Five – We are considering adapting our test for improving clinical trials focused on treatments for sepsis. There is a need for better patient inclusion criteria. Today, an estimated 50% of patients enrolled in clinical trials are not septic. Our test solutions can potentially help pharmaceutical companies better design clinical trials. It is key to select/screen patients who are more likely to exhibit a safe and efficacious response. We welcome the opportunity to work with companies advancing sepsis treatments and methods of managing the clinical care of for septic patients.

Rolland Carlson was speaking to Anna MacDonald, Science Writer for Technology Networks.