3D rendering of graphene surface.

NEW YORK – UK technology company Paragraf is moving ahead with plans to develop and launch in vitro diagnostics to the clinical market, with a test for guiding prescription of antibiotics at the top of its list. The Somersham-based firm announced this week that it had received a £550,000 ($659,000) Innovate UK Biomedical Catalyst grant to undertake a feasibility study of the point-of-care test that could be used to guide treatment selection.

Malcolm Stewart, business development director of Paragraf's biosensor business, said in an interview that should the feasibility study be a success when it winds up in 2024, the company could conceivably have a test platform on the European clinical market by 2026, including in the UK. Stewart also said that Paragraf is planning a full menu of tests for infectious diseases that will employ its graphene biosensor technology.

"If you look at IVD products globally, the biggest area for IVDs is in infectious diseases," said Stewart, who joined Paragraf in January. "We decided that was a good target to go for," he said.

Paragraf is a spinout of the University of Cambridge where Cofounder and CEO Simon Thomas was a research associate focused on developing equipment and hardware to produce two-dimensional materials, especially layer graphene and other materials. The company is based in an old double glazing factory about a half hour north of Cambridge. Since its launch in 2017, Paragraf has specialized in manufacturing two-dimensional graphene sheets for different industries. The company's hall effect sensors, for instance, have been adopted in the automotive and industrial automation industries for position, rotation, torque, proximity, and current sensing.

Diagnostics is another and somewhat newer opportunity for Paragraf. The firm maintains that by using its 2D graphene sensors, it can enhance the sensitivity and speed of biomarker detection and functionalize multiple markers on a chip. Sample preparation is minimal and requires small volumes, too, according to the firm. Paragraf believes that eventually its sensors could be used in IVDs for infectious diseases and oncology, as well as cardiovascular and metabolic diseases.

Its first push will be into guiding antibiotic therapy selection, where Stewart said there are not enough new therapies around, and diagnostics are therefore needed to "do the heavy lifting" to get the right therapy to the right patient. Stewart noted that other companies have tried to address the problem but said that other approaches are hindered by turnaround time or the need for sample preparation, while decisions need to be done quickly and at the point of care in the ICU.

For its first test, Paragraf decided to employ its technology to measure two markers of inflammation, C-reactive protein (CRP) and procalcitonin (PCT). CRP levels rise in patients with both bacterial and viral infections, whereas a spike on PCT is linked to bacterial infections alone. By making both markers available on its platform, clinicians could be able to determine both the presence of an infection in a patient, as well as whether it was bacterial or viral, Stewart said.

"By putting them together in one test, you get a critical, unique selling point," he said.

The newly awarded Biomedical Catalyst grant will support a feasibility study of the company's test, which consists of a portable device that can measure the amount of CRP and PCT in a patient's blood sample with a turnaround time of "single digit minutes," according to Stewart.

The device consists of a graphene field effect transistor (GFET) placed atop a semiconductor wafer. The FET is functionalized with chemistry that detects the target proteins and binds them, causing a change in conductivity. Blood containing the target proteins is deposited into a well in the cartridge, and voltage is passed across the GFET. By measuring changes in conductivity, the device can determine whether a marker is present in a sample, as well as its abundance.

For CRP, Paragraf's sensor offers nanogram-level detection, Stewart said, while for PCT, it can detect to the picogram level. "It's a linear measurement of concentration and it happens almost instantly," said Stewart. "As soon as we get binding, we can detect whether it is there and how much is there," he said. "That is the power of graphene," Stewart added. "We can get to a very low level of detection."

Stewart acknowledged that Paragraf had not yet discussed its technique in a publication, but it intends to do so. Graphene diagnostics, however, are in development and by multiple players at the moment. Several companies, including Grip Molecular Technologies and IdentifySensors Biologics, have sought to use the cheaply manufactured material to deliver tests of SARS-CoV-2 testing, for instance. Others like Spain's Catalan Institute of Nanoscience and Nanotechnology (ICN2) in Barcelona are developing graphene tests for application in oncology.

To undertake a feasibility study of its test, Paragraf has partnered with investigators at the University of Liverpool, the University of Manchester, and the University of Newcastle. Newcastle upon Tyne Hospitals NHS Foundation Trust and Manchester University NHS Foundation Trust are also part of the consortium.

The partners will compare the performance of Paragraf's test against the standard of care, enzyme-linked immunosorbent assays. Though Paragraf is a relative newcomer to the diagnostics field, Stewart said that it was able to win over the "top drawer clinicians" in Britain because of its approach. "Our value proposition is superb and was immediately recognized by clinicians," he said. "We got the clinicians and facilities because we had the right idea."

The planned study will trial Paragraf's test in the ICU setting on 50 patients by measuring their blood five times and mapping the change in concentration of the CRP and PCT markers. These results will be compared against standard-of-care ELISA results. Paragraf is currently preparing the device for the study, Stewart said, which will take place next year. Should it be successful, a larger study to support submissions to obtain both CE-IVD and UKCA marks will follow.

"It could take two more years to do a full regulatory study," noted Stewart. The current estimate for having a product ready for submission is sometime in 2026, he said. Submissions to regulators in other geographies, such as the US, China, and Japan, would eventually follow.

Paul Dark, chair of critical care medicine at the University of Manchester, said in an email that the research teams involved in the feasibility study of Paragraf's platform have "leading expertise in appraising diagnostic health technologies for their potential to disrupt emergency patient care."

Dark said that the teams' interest in delivering new multiplexed biomarker point-of-care diagnostics to clinicians overlaps with Paragraf's vision. "In this proof-of-concept translational clinical project, we are focusing on the grand challenge of making urgent clinical decisions for appropriate antibiotic treatments in the setting of suspected life-threatening severe infections," commented Dark.

He added that the research teams involved in the study look forward to partnering with Paragraf to develop what is believed to be the first in a pipeline of portable graphene-based IVDs, tests that "will at least match the performance of the most advanced hospital laboratory, but at the point of care."

As noted, Paragraf sees the current test as the first of what will eventually be a suite of assays that could be used not only in healthcare settings but also in environmental monitoring or food safety testing. But first in line will be infectious diseases, with sexually transmitted diseases, urinary tract infections, and tropical diseases some of the indications that interest Paragraf.

"We have a pipeline of products in infectious disease that will tell you what is wrong, what virus you have, and how to treat it appropriately," Stewart said. "There are quite a lot of infections we will be able to characterize and guide therapy for."

To accomplish that will require more investments. Paragraf in March closed a Series B round worth $60 million. Stewart said that the money will fund capital equipment so that Paragraf can make its graphene products at scale. The company is also investing in a manufacturing facility in Huntingdon, about 20 minutes west of its Somersham headquarters. Paragraf currently employs about 90 people, Stewart said, but the new funding will also help with some new hires.

By the end of 2022, Paragraf should have about 120 employees, he said.

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