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Sysmex Inostics, Merck Aim for 2015 CE Mark for ctDNA Kit for Metastatic Colorectal Cancer

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NEW YORK (GenomeWeb) — In a deal signed ceremoniously at the American Society of Clinical Oncology meeting earlier this week in Chicago, Merck and Sysmex Inostics will collaborate to develop and commercialize a kit to assay RAS mutations in circulating tumor DNA. The kit will be based on Sysmex's emulsion-based digital PCR technology, called BEAMing. Terms of the agreement were not disclosed.

In an interview with PCR Insider, Sysmex Inostics CEO Fernando Andreu said that the kit will likely launch some time in 2015. The company intends to seek CE IVD marking to sell the kit in Europe. It may be used to guide therapeutic strategy for metastatic colorectal cancer treatment with Erbitux (cetuximab), according to a statement.

Currently, Hamburg, Germany-based Sysmex Inostics — formed when Japan's Sysmex acquired Inostics last year for an undisclosed amount — offers both a KRAS and a NRAS test in the US on its OncoBEAM platform. These are available as CLIA lab tests in which physicians send samples to the company's facilities in Baltimore, Md. Here, the company uses the BEAMing technology, which stands for beads, emulsions, amplification, and magnetics. The workflow includes pre-amplification, emulsion PCR, hybridization, and flow cytometry.

The new kit will be based on this technology, but "transferring a test from an LDT to a kit is not a trivial thing," Andreu noted.

"We are targeting two genes, KRAS and NRAS. It's a multiplex assay, so we are looking to a large number of mutations in these two genes. We are measuring circulating tumor DNA [by] doing an emulsion PCR ... hybridization with magnetic beads, and then ... readout with flow cytometry."

Andreu commented on how Inostics might integrate flow cytometry technology from Partec, a company acquired by Sysmex at the same time as Inostics last year.

"The Partec acquisition had its own logic, it was not only related to the Inostics acquisition, but definitely there are synergies," Andreu said.

"We have validated our BEAMing technology for multiple flow platforms. Our plan is to develop an IVD integrated platform, and we will build on the experience and expertise coming from Partec in realizing this vision," he said.

The companies first intend to obtain a CE IVD mark on this kit, as the regulatory process is less stringent in Europe than in the US.

In a US market, the kit could be used to guide therapeutic strategy, but to be certified as a companion diagnostic by the US Food and Drug Administration it would require clinical trials. Still, Andreu did not rule out this option.

"Today the scope of the agreement with Merck is non-US. This means from a regulatory point of view we are going to focus on ... CE mark and other regulatory pathways," Andreu said. "But of course this doesn't mean that if we see the opportunity, even from a commercial point of view, that we would not also pursue the FDA [approval], but this is not the primary scope of the agreement."

In June of 2012, two studies published in Nature validated Inostics' technique to detect KRAS mutations in ctDNA. At that time, Inostics had recently received GCP/GMP certification for its Hamburg-based laboratory facilities, and was anticipating CLIA certification of its Baltimore labs within a month, as reported in PCR Insider.

In July of 2012, a companion diagnostic to Erbitux — Qiagen's TheraScreen — received FDA approval. That test also measures KRAS mutations, but from formalin-fixed, paraffin-embedded tissue biopsies. The approval process was perilous, as reported by Pharmacogenomics Reporter, potentially offering lessons for other companies interested in companion diagnostic development.

A statement released at the signing of the Merck/Sysmex Inostics agreement does not specifically claim the new RAS kit will be a companion diagnostic to Merck's Erbitux.

Rather, "this collaboration reflects our commitment to leveraging our expertise in personalized medicine and predictive biomarkers in order to enhance Erbitux's value proposition for patients, physicians, and payers," Belén Garijo, president and CEO of Merck Serono, said in the statement.

However, a blood-based biomarker might be an improvement over FFPE-based tests of RAS mutations, such as TheraScreen, Andreu noted.

"[Qiagen's] TheraScreen is a tissue test, ours is a ctDNA test. There are obvious situations when there is an advantage for ctDNA, for example when there is no tissue available ... or when a biopsy can be dangerous," he said.

Andreu also noted that ctDNA overcomes problems with tumor heterogeneity. "When you're sampling tissue … you're choosing one specific region," he said.

Another advantage is that a blood-based ctDNA test could provide real-time status of a tumor, Andreu said. "Very often FFPE [results] are referring to samples taken months before a clinical decision is being made. There are mutational changes in these periods, and this is something that you are missing with the FFPE test, and that you can see with ctDNA."

Andreu added that he knows "no other test which has the accumulated experience in terms of clinical samples; we have tested in the range of 10,000 clinical samples in clinical trials in the last [few] years. I don't know of any other company that has this degree of solidity in the technology."

There are currently two companion diagnostics for Erbitux approved by the FDA. TheraScreen uses PCR, while Dako's EGFR PharmDx Kit uses immunohistochemistry. There are only five PCR-based companion tests now approved, and they use biopsy tissue; none are specifically blood-based biomarker assays.

Andreu declined to comment on which research labs will undertake clinical validation of the new assay.

Frank Diehl and colleagues at Johns Hopkins University have previously developed ctDNA assaysusing BEAMing technologies. Diehl is also a co-founder of Inostics, and remained as CSO after the acquisition by Sysmex. He is now vice president of lab operations and research and development, according to the company's website.

Meanwhile, Roche licensed its emulsion patent portfolio to Sysmex Inostics in February, and Diehl recently received a patent on emulsion-based PCR.

In terms of future developments, Andreu said that the company is currently developing more ctDNA-based tests for different biomarkers.

"We see a lot of value for ctDNA and plasma-based testing in general," he said. "We see a lot of value in patient monitoring … really giving the oncologist not just a snapshot of the situation with one patient, but a continuous look at what is going on and the dynamics. This is opening a huge field for oncologists to change the way they are treating patients."

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