NEW YORK – Molecular diagnostic assay developer SpeeDx plans to expand into host-response biomarker testing with a single biomarker called interferon alpha inducible protein 27, or IFI27. The Sydney, Australia-based firm expects to develop the biomarker into a PCR assay called Insignia intended for triaging COVID-19 patients in 2021, and is also developing its own SARS-CoV-2 tests.
Changes in gene expression in response to infection can differ depending on whether a person is infected by a virus or bacteria, in some cases in anticipation of symptoms.
Colin Denver, CEO of SpeeDx, said in an interview that IFI27 specifically is "an early marker about what is coming from your own body's response to the viral infection."
SpeeDx licensed the IFI27 biomarker from New South Wales, Australia-based Nepean Hospital where it has been studied and patented by a team of genomics researchers also affiliated with the University of Sydney.
Denver said that the biomarker "can quite confidently predict" whether patients will need a high level of care, such as ventilation or a stay in the ICU, or whether they could instead be discharged and self-isolate.
SpeeDx is developing Insignia for a high-throughput lab setting and also expects to develop a test for near-patient settings. Initially, Insignia will likely be used after a diagnosis is made with another commercial respiratory infection test, but SpeeDx is also developing two SARS-CoV-2 tests of its own — a test for the virus alone and a multiplex test for SARS-CoV-2, influenza, and respiratory syncytial virus.
Benjamin Tang, head of Nepean Hospital's genomic research group in the department of intensive care medicine, is part of the team that has developed the IFI27 biomarker.
Tang said in an interview that his team initially used empiric methods to select IFI27 from published gene expression datasets as well as its own datasets of host gene expression responses to respiratory viruses.
The same appears to be holding true for SARS-CoV-2, and Tang said it is not surprising that interferon genes are upregulated in this new respiratory viral infection. His team also has unpublished data on COVID-19 showing IFI27 "outperforms other similar genes, and that the superior performance is quite consistent across patients. The team is now undertaking mechanistic studies to understand why this is the case, as well as a large prospective clinical outcomes study of complications in COVID-19 patients.
Other work is accumulating that tends to suggest the team may be on the right track. For example, researchers in Qatar using single-cell transcriptomic analysis identified IFI27 among the genes upregulated in respiratory samples and peripheral blood mononuclear cells (PBMCs) from a small number of COVID-19 patients.
Tang said his team is now expanding its work from blood-based testing to nasopharyngeal and throat swab samples, and has detected IFI27 in airway samples.
The team's IFI27 approach is currently patented in the US, the European Union, Australia, Japan, and China, Tang said.
SpeeDx's Denver said that all signs are pointing to the COVID-19 pandemic continuing for some time. "As all of the second and third wave scenarios roll out, even though there is better resourcing of the healthcare facilities ... it is not over by a long way."
The Insignia test can thus potentially be a tool for managing patients in this pandemic, but also any future viral respiratory pandemic as well.
The firm launched its own multiplex respiratory panel, called PlexPCR RespiVirus. The test, which was granted Australian regulatory clearance in May of last year, detects and distinguishes flu A, flu B, RSV A and B, rhinovirus, parainfluenzas 1 through 4, adenovirus, and human metapneumovirus.
SpeeDx's core business is PCR-based sexually transmitted infection testing, with a particular focus on detecting resistance genes. Denver said this business rebounded quickly after a small slowdown in the height of the pandemic, and has been surprisingly stable since STI rates have not gone down.
SpeeDx also announced a partnership with LabCorp earlier this year to develop diagnostics tests focused on women's health and infectious diseases. It has also partnered with Cepheid to put an STI test on the FleXible cartridge, and with Roche to expand global access to infectious disease and antibiotic resistance tests. In March, SpeeDx announced it had raised $15 million in Series B funding.
The host-response space
For host-response biomarker testing, the standard approach in the field is to have a multi-gene panel, Nepean's Tang said. But, using a single biomarker offers several potential advantages.
A single-marker assay could make for a simpler and faster test that is easier to deploy at the point of care, for example, and could potentially be easier for clinicians to interpret. Although a multi-marker test could theoretically be mathematically manipulated into a single score, the weighting of the individual components is likely to vary between patient cohorts, so validation of a panel would be more challenging than a single-marker test.
In the Nepean Hospital group's early studies, they compared the performance of IFI27 alone to a multi-gene biomarker, Tang said. "What we found is that the multi-gene biomarker works a little bit better, but it is only marginally better."
That said, there is a very specific context in which this single gene is useful, Tang said, noting for example that it is not likely to be informative in cases that have advanced to very severe illness or respiratory failure.
Among the groups pursuing a multi-marker approach, researchers at Duke University have launched a startup in order to commercialize a set of biomarkers that can indicate exposure to pathogens and tell if an infection is caused by a bacteria or a virus.
Now called Predigen, the spinout expects to have a first product in front of US Food and Drug Administration sometime in 2022. The Duke team has also been adapting its panel test in collaborations with BioMerieux and Qvella.
Chris Woods, co-founder of Predigen and executive director of Duke's Hubert-Yeargan center for global health, confirmed in an email that the firm's panel includes IFI27, but indicated that a multi-marker approach is most likely to be clinically useful.
Woods co-authored a study in Lancet Infectious Diseases last month that showed IFI27 was among a set of genes that could serve as a biomarker panel for viral infections prior to symptom onset.
The prospective study monitored levels of 36 genes in blood samples and in particular confirmed that IFI27 performed well "to distinguish between individuals with viral illness and those who are healthy," with upregulation observed in cases of viral infection.
However, the authors also noted that increasing diversity in patient cohorts is likely to change expression profiles, such that "more intricate biomarker panels will probably be required to maintain high fidelity" in real-world clinical settings.
The Duke team also recently evaluated transcriptomic responses to SARS-CoV-2 in peripheral blood, revealing 76 genes that were differentially expressed in COVID-19 as compared to influenza, seasonal coronavirus, and bacterial infections. "Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states," the authors noted in a medRxiv preprint.
Overall, Woods said he suspects that IFI27 would perform well in certain limited use cases of viral infection compared to healthy subjects. "It is a very capable viral marker, but alone will not sufficiently distinguish bacterial from viral" infections, he said.
Regarding IFI27 and COVID-19, Woods said a reduction in expression with disease resolution may occur, but that would be of little clinical value. On the other hand, "I have seen absolutely no evidence that this will be a predictive severity marker at this point in time in our work on pre-COVID viruses, or COVID," he said.
Inflammatix is another firm taking the multi-marker approach. The firm incorporates IFI27 in its infection biomarker panel for sepsis, and it presented a poster at IDWeek in 2018 describing validation of a seven-gene host biomarker test — including IFI27 — called HostDx Fever that discriminates between bacterial and viral infections.
Inflammatix recently expanded into COVID-19 host-response testing using $1.1 million in funding from the US Department of Defense's Defense Advanced Research Projects Agency (DARPA) and the firm expects to use an assay it calls CoVerity to help clinicians stratify patients based on the likely severity of their infections. The firm also presented work at the European Society of Clinical Microbiology and Infection Diseases validating its test, which it has described as using a set of six mRNA biomarkers.
Unfortunately, with respect to COVID-19, there is likely to be room in the market for a number of approaches for some time.
SpeeDx's Denver also suspects the demand for diagnostics for viruses in general will accelerate as the pandemic increases savviness among clinicians and patients.
Customers or patients who previously may have been told by their doctor 'It's just a virus, go home,' now have a desire and expectation that a clinician can tell them what specific virus it is, and that it is not SARS-CoV-2. "I think that is going to be something that sticks around for a few years at least," Denver said.