Road to PMA approval of Biocartis’ Idylla™ CDx MSI Testi
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When the US Food and Drug Administration (FDA) grants Premarket Approval (PMA), it is signalling that a diagnostic test has passed the highest regulatory bar in medicine. That milestone has now been reached on 15 August 2025 by the Idylla™ CDx MSI Test from Biocartis – a fully automated companion diagnostic on the Idylla™ Platform that determines microsatellite instability (MSI) status and guides immunotherapy decisions for patients with metastatic colorectal cancer.
At the core of this test is a panel of seven DNA biomarkers discovered in the lab of Prof. Diether Lambrechts at the VIB-KU Leuven Center for Cancer Biology. What began as an “odd” tumour genome in an academic sequencing project has become an FDA-approved companion diagnostic that can be run on Idylla™ Platforms in hospitals worldwide.
A genome that looked “wrong” – and turned out to be right
More than a decade ago, Lambrechts’ team used whole-genome sequencing on endometrial and colorectal tumours with support from VIB’s Tech Watch programme. One sample seemed like a technical failure: it carried an unusually high number of mutations.
“At first we thought the sample was simply bad data,” recalls Prof. Diether Lambrechts. “But when we looked closer, we saw that the mutations were clustered in short homopolymers – exactly what you’d expect from a classic MSI-high tumour with defective DNA repair.”
This finding led to a systematic comparison of the whole genome sequences of MSI-high and microsatellite-stable (MSS) tumours. While MSI testing at the time focused on very long repeats and complex size-based methods, the VIB team showed that the same signal was consistently present in much shorter homopolymers of 6-11 bases. Crucially, these shorter repeats could potentially be measured with standard PCR- and probe-based techniques, making MSI detection compatible with compact diagnostic qPCR-based platforms like Idylla™.
Why MSI status matters for patients
In about 10–15% of colorectal cancers, the DNA mismatch repair system is defective (dMMR). These tumours build up many mutations, especially in repetitive DNA, creating a high mutational burden and lots of neoantigens that make them, in principle, clearly visible to the immune system.
To escape, the tumour switches on inhibitory pathways like PD-1/PD-L1. Checkpoint inhibitors such as nivolumab and ipilimumab block these brakes and can re-activate anti-tumour immunity. The difference between MSI-high and MSS disease is striking: in metastatic colorectal cancer, response rates to PD-1–directed immunotherapy are around 1% in MSS tumours versus roughly 40-50% in MSI-high tumours.
“MSI testing doesn’t tell you who will respond for sure,” says Diether, “but it tells you very clearly who should be considered for immunotherapy and who almost certainly should not.”
MSI testing has therefore become a true gatekeeper for immunotherapy. With PMA approval, the Idylla™ CDx MSI Test now serves as the FDA-approved companion diagnostic for nivolumab-based regimens in MSI-high or dMMR metastatic colorectal cancer, ensuring that these treatments are directed to the right patient group.
From academic insight to protected IP
Once Lambrechts’ team saw that short homopolymers gave a robust MSI signal, the next question was how to protect it. Biomarker patents are tricky, especially when you start from a long list of >50 candidate loci.
Together with VIB’s patent attorneys, they decided to move fast and file a patent family on both the specific markers and the underlying concept of using defined homopolymer loci to detect MSI. At the time, MSI was mainly a prognostic tool and used for Lynch syndrome screening; its role as a predictive biomarker for immunotherapy was only emerging.
“From a business perspective, this was a calculated bet,” notes Erwin Sablon, who at the time was heading the Biocartis R&D organisation and today serves as Head of Business Development at VIB. “We were protecting something whose full clinical impact we couldn’t yet fully see – but we felt strongly that the biology was too compelling to ignore.”
That early, forward-looking IP strategy later proved crucial when Biocartis went searching for MSI markers to build into the Idylla™ Platform.
A perfect fit for the Idylla™ Platform
Biocartis was expanding its colorectal cancer menu on Idylla™ with KRAS, NRAS and BRAF assays, and clinicians were also asking for MSI testing in line with guidelines. Classical MSI assays based on long repeats, however, were not compatible with the closed, cartridge-based Idylla system.
The VIB-CCB MSI markers, located in shorter homopolymer regions, were ideal for qPCR- and probe-based detection inside an Idylla™ cartridge. Through the Flemish ecosystem – including an introduction via philanthropist Luc Verhelst and his endometrial cancer fund – Lambrechts was put in contact with Biocartis founder Rudi Pauwels.
“When we saw the VIB marker set, it clicked immediately,” remembers Dr. Geert Maertens, CSO at Biocartis at the time. “Short homopolymers meant we could finally bring MSI onto Idylla™ in a way that fit both the chemistry and the cartridge.”
Formal talks began around 2012; in 2013 Biocartis licensed the VIB MSI IP and, over the following years, refined a long candidate list into a focused seven-marker panel, first as a research-use-only (RUO) assay and later in regulatory formats that could be used for actual patient management.
Engineering a robust cartridge-based MSI test
Turning the biomarkers into a reliable IVD on Idylla™ came with several technical hurdles. The same polymerase slippage that creates DNA insertions and deletions in tumours also occurred in vitro: consequently, with standard Taq polymerase, early experiments generated MSI-like artefacts in wild-type DNA, leading to high false-positive rates.
Biocartis solved this issue by introducing a proofreading polymerase to correct slippage during amplification, and then re-engineering probe chemistry and reaction conditions so the enzyme would not degrade the probes. All of this had to fit within the tight constraints of the Idylla™ cartridge, which integrates sample prep, amplification, controls and detection in just five wells while running seven MSI markers plus internal controls.
“We were pushing the boundaries of what you can do inside a closed cartridge,” says Geert. “Getting the biochemistry, the controls and the algorithm to work together took years of iteration – and strong belief that the endpoint would be worth it.”
On top of the wet lab work, Biocartis built dedicated classification software algorithms to interpret probe-based melting curves and deliver a robust MSI-high versus MSS call, and secured additional patents on the enzyme system, probe design and analytics to protect the full technology package.
This was only possible through a long-term collaboration between VIB, Biocartis and the Flemish innovation agency VLAIO, which co-funded multi-year joint projects.
That support from VLAIO allowed Biocartis to sustain the long and complex development programme and Lambrechts’ lab to deepen the biology of MSI. It’s a good example of how Flemish public support can help to de-risk ambitious innovation.
From RUO test to FDA PMA companion diagnostic
The regulatory journey progressed stepwise. Biocartis first launched the Idylla™ MSI Assay (for RUO) so labs could adopt the technology and generate data. In 2023, it obtained US FDA 510(k) clearance based on substantial equivalence to an existing MSI Test used to screen for Lynch syndrome in colorectal cancer.
For the Idylla™ CDx MSI Test, FDA PMA approval required a far more extensive package, including extended analytical validation and clinical data from pivotal Bristol Myers Squibb immunotherapy trials, in which patients initially selected with local MSI tests were centrally retested using Idylla™. Only a small number of molecular tests ever achieve PMA, and even fewer as companion diagnostics, making this first PMA a strong validation of the Idylla™ Platform. In parallel, the MSI test has been approved as a CDx in Japan and is currently undergoing certification under the EU (IVDR).
“Reaching PMA means the test is not just technically sound – it’s woven into the evidence base of how patients are treated,” says Erwin. “That’s a very high bar for any diagnostic assay.”
Bringing precision oncology closer to patients – and what comes next
One of the most concrete outcomes of this story is access. The Idylla™ Platform is compact and fully integrated, so it can be used in hospitals without a specialised molecular lab: an instrument, cartridges, a bench, a power socket and staff with basic training are enough. Sample in, result out.
With over 2,500 instruments installed in more than 75 countries, the Idylla™ CDx MSI Test can reach far beyond major cancer centres. For patients with metastatic colorectal cancer, this means MSI status – and thus eligibility for immunotherapy – can be determined more quickly and locally, so more patients are tested, more MSI-high tumours are found, and more eligible patients can receive life-extending immunotherapy.
An important next step is moving MSI testing earlier in the disease course, where immunotherapy for MSI-high tumours can achieve very high response rates and potentially change standard treatment pathways. From a biomarker perspective, the field is evolving from single markers to integrated signatures that combine genomic, transcriptomic and other data – often interpreted with AI – to better predict response and monitor minimal residual disease.
“For us, MSI is proof that a discovery in a Flemish lab can grow into a globally approved companion diagnostic,” concludes Diether. “It demonstrates that when the right science meets the right partners, patients everywhere can benefit.”
In this landscape, the Idylla™ CDx MSI Test stands as a powerful proof of concept: a sophisticated biomarker panel discovered in a VIB lab, engineered into a cartridge-based assay, protected by strong IP, and taken through the most demanding regulatory pathways to global clinical adoption. It reflects a shared vision of VIB, Biocartis, and their partners: discoveries born in Flanders can become essential tools for precision oncology worldwide.
[i] Idylla™ CDx MSI Test (A0220/6) is approved in the US under P250005. Idylla™ MSI Test is CE-marked in Europe in compliance with the EU IVD Directive 98/79/EC and registered in many other countries worldwide.
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