NEW YORK – Dutch microbiology diagnostics developer Inbiome is one step closer to marketing its Molecular Culture ID test for clinical use in the US after receiving breakthrough device designation from the US Food and Drug Administration late last week.
The firm also recently appointed PCR pioneer Carl Wittwer to its board of directors as part of a larger effort to bring its approach to the US clinical market.
The Molecular Culture ID test is PCR instrument agnostic and uses high-resolution melt curve analysis to identify more than 200 bacterial organisms with a turnaround time of between two and four hours.
With an ultimate stated goal of achieving same-day diagnosis for all infectious diseases by 2030, "we're now demonstrating our technology for specific applications," said Inbiome CEO Dries Budding.
Budding cofounded Amsterdam-based Inbiome with his brother Jord Budding in 2019 after winding down his former company IS-Diagnostics, and last year, the firm was awarded a European Innovation Council grant worth €5.7 million ($6.1 million).
Jord Budding, who serves as Inbiome's chief operating officer, noted that breakthrough device designation now provides a fast track at the FDA for regulatory clearance, with prioritized review and extra support from a dedicated team.
The designation is also rare for microbiology, Jord Budding said. There have been 933 total breakthrough device designations from 2015 through 2023, but only 32 were microbiology-related technologies, according to an FDA website.
Among these are T2 Biosystems' AMR Resistance Panel, Selux's Next Generation Phenotyping AST system, BioMérieux's Specific Reveal AST platform, Pattern Biosciences' ID/AST Pneumonia Action Panel, Q-linea's ASTar, a pathogen ID system from Molzym, and the Pathogenomix Patho-Seq assay.
And, while the FDA site also notes that only 95 of the 933 breakthrough devices have obtained marketing authorizations so far, this number includes at least a dozen representatives of the diagnostics space.
'Molecular Culture'
The Inbiome Molecular Culture ID test relies on variations in the length of the internal transcribed spacer region of bacterial ribosomal DNA.
Its IS-pro method attaches fluorescently labeled phylum-specific primers targeting 16S rDNA and unlabeled primers targeting 23S rDNA, according to the test's instructions for use, and can then read out the length polymorphism together with the color to identify the bacteria by comparison with the Inbiome database.
The database currently contains 255 bacterial signatures, Dries Budding said, but "if it's a bacteria that we can't identify, we still see the signal," thus confirming that bacteria is present or ruling out an infection.
The test also uses an artificial intelligence-based approach to separate noise from signal and to process the data, as matching DNA fragment lengths, colors, and amounts of DNA in the raw data to libraries becomes complex quickly, Budding said.
Paul Savelkoul, head of medical microbiology, infectious diseases, and infection prevention at Maastricht University medical center and a co-inventor of the IS-pro technology, has used Molecular Culture ID to test orthopedic, respiratory, fecal, and oral samples.
"The method is easy to use, fits in our standard molecular diagnostic routine, and we didn't need new equipment in our lab," Savelkoul said in an email. Furthermore, he noted, "It is a replacement for non-cultivable bacterial species in a broad sense, meaning that we have an open system detecting basically all bacterial DNA present in a given clinical sample in contrast to current PCR approaches."
However, Savelkoul also cautioned that "the method detects all bacterial DNA, which means that any contamination will be detected." Thus, it requires "strict procedures and a clean environment," he said, adding that "the results should be interpreted with this in mind."
Ruling out the presence of bacteria in a sample may also make Molecular Culture ID useful to query so-called "unexpected negative" cultures, or UNCs, in hip and knee arthroplasty revision cases.
Sujeesh Sebastian, a microbiologist at the Orthopaedic Hospital Vienna-Speising in Austria, presented data from a study using Molecular Culture ID on 81 UNCs at the annual meeting of the European Bone and Joint Infection Society in Barcelona on Friday.
According to slides of the presentation, the study looked at synovial fluid alone and paired with tissue samples. The Molecular Culture ID test was able to find pathogens in 33 percent of the UNC cases and in all cases with more than one positive tissue sample.
The study also suggested that more than half of the cases with positive molecular detections could have been more accurately treated if the Molecular Culture ID test was available at the time of specimen collection.
More than 40 organisms overall were detected by the test, and approximately 3 percent of the infections were polymicrobial. Importantly, 85 percent of the patients with a positive Molecular Culture ID result were on antibiotics.
"Although the sample number may seem small, this is a selected patient group, for which it is particularly difficult to know how to treat," Dries Buddings said of the evaluation.
The study "underscores that our assay is not only much faster than culture but also much more accurate and able to diagnose cases that culture can't," Budding also said.
The firm is also finding comparable results with samples of lung cavity infections, and in cases of peritonitis, pericarditis, and meningitis, with publications on these studies underway.
The market and the adviser
In terms of PCR-based competition, a platform using combined PCR/electrospray ionization mass spectrometry (PCR/ESI-MS) called Plex-ID, rebranded as Iridica, was able to perform agnostic microbiology ID, but it was reportedly discontinued by manufacturer Abbott in 2017.
Since then, the BioMérieux BioFire Joint Infection Panel obtained de novo clearance in 2022 and is currently the only FDA-cleared PCR panel specifically for bone and joint infections.
Meanwhile, the fate of the Invasive Joint Infection panel from OpGen's Curetis subsidiary is unclear following that firm's sale of its Unyvero instrument installed base to Singapore's Camtech for $218,000 and the recent suspension of its shares from trading on the Nasdaq.
Budding noted that bacterial panel-based PCR tests are hypothesis driven and a negative panel test can't rule out infection.
"Because we detect any bacteria, if the test is negative, you don't have to treat with an antibiotic because there are no bacteria," Budding said. "That really fundamentally sets it apart," he added, particularly in the case where ruling out a prosthetic joint infection could prevent unnecessary surgery.
A sequencing-based liquid biopsy test from Karius has also been used to detect periprosthetic joint infections, while other competing systems for pathogen ID include whole genome sequencing-based ID/AST from Day Zero Diagnostics, and a 16S rRNA sequencing approach from Pathogenomix. However, there has also been debate regarding the clinical utility and cost of PCR-based testing versus targeted sequencing approaches.
To navigate this space, Dries Budding said that Inbiome sought out PCR pioneer Wittwer as an adviser due to his scientific and business track record and his notable legacy in the molecular diagnostics industry.
A professor emeritus of pathology at the University of Utah, Wittwer previously worked to develop the LightCycler PCR instrument that was subsequently acquired by Roche and further commercialized. Roche debuted its LightCycler 480 in 2005 and was seeing double-digit sales growth a few years later. The smaller LightCycler 96 was launched in 2012, and Roche launched a next-gen model called the LightCycler Pro last year while also expanding into the digital PCR space with the Digital LightCycler system.
At BioFire, Wittwer also pioneered the FilmArray system and syndromic respiratory panel that was acquired by BioMérieux in 2014 for approximately $486 million. As of the end of last year, there were more than 25,400 FilmArray units installed globally. BioMérieux has also recently launched the BioFire SpotFire system, which uses core technology patented in 2021 by Wittwer and his University of Utah colleague Jared Farrar.
To Wittwer, the Inbiome technology, "combines highly parallel molecular sizing with melting analysis, a combination I have not seen before," he said in an email.
In addition to his recent Inbiome appointment, Wittwer said he also currently serves as an adviser to Co-Diagnostics, Scope Fluidics, Magic Lifescience, and Star Array.
And, although he is retired and relocated from Salt Lake City to Maine, Wittwer said he keeps a private molecular biology and instrument prototyping laboratory where he continues to explore extreme real-time PCR as well as high resolution and high-speed melting analysis.
"Much of this work is a continuation of what I did at the University of Utah," he said, but he also noted that he evaluates instruments and reagents from groups bent on simplifying and speeding up molecular diagnosis.
Going forward, and with the support from the FDA's breakthrough devices program and Wittwer's advising, Inbiome hopes to tackle the many cases where traditional diagnostics are just not enough, Dries Budding said.
The Inbiome team has also recently coauthored a pilot study using its IS-pro approach to investigate the impact of microbial composition on fertility as well as a protocol to investigate the use of Molecular Culture ID in cases of neonatal sepsis.
And, the firm has begun running pilot implementations at undisclosed US hospitals, he said, to better understand what a US rollout will look like and expects to seek additional funding soon to accelerate commercialization.