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Seegene Submits First MDx to FDA with More Highly Multiplexed Test to Follow in 2015


CHICAGO (GenomeWeb) — Seegene this week plans to submit its first molecular diagnostic test for US Food and Drug Administration clearance, an assay for herpes simplex virus I and II that uses the company's TOCE primer technology for multiplexed real-time PCR.

Although the two-target HSV I and II assay does not showcase the full capabilities of the TOCE technology, which can enable the detection of multiple nucleic acid targets in a single tube on any existing real-time PCR system, it could serve as a gateway for the company to expedite future FDA submissions, Seegene Founder and CEO Jong-Yoon Chun told PCR Insider in an interview at the American Association for Clinical Chemistry annual meeting, held here this week.

In addition, Chun said, Seegene has developed a 26-target respiratory pathogen panel using both TOCE and MuDT — a new data analysis method from the company that essentially doubles the number of analytes that can be detected with standard real-time PCR instruments — and hopes to submit that test for FDA clearance sometime next year.

Seegene, which is based in Seoul, South Korea, with additional offices in Gaithersburg, Md., and Eschborn, Germany, has since its inception specialized in developing new technologies to expand the capabilities of real-time PCR.

These technologies have included so-called dual-priming oligonucleotides (DPOs), designed to generate consistently high specificity by blocking extension of non-specially primed templates and eliminating primer competition; and tagging oligonucleotide capture and extension (TOCE), an artificial template-based detection technology that delivers real-time signal generation and enables multiple melting temperature analyses per optical channel of a real-time PCR system, thus allowing the system to simultaneously detect and quantify up to seven targets per channel from a single sample in a single reaction.

Additionally, in May Seegene introduced a data-analysis technology called Mdisc that is designed to enable multi-threshold cycle (Ct) values in a single channel for multi-target detection. That technology has since been renamed MuDT.

Over the years the company has employed a dual business model of licensing these technologies out to various entities for use in applied markets and molecular diagnostic development while developing its own multiplexed MDx tests with regulatory clearance in Korea, Europe, and the Middle East, but not the US. These tests include the aforementioned respiratory panel; a 31-target sexually transmitted infection panel; an assay to detect, genotype, and quantify 19 high-risk and nine low-risk HPV types; a combined tuberculosis and drug-resistance assay; and EGFR and KRAS mutation assays.

However, the firm's entry into the North American market has been a long time in the making, and the submission of its first test for FDA clearance is a major milestone.

"This is our first submission [to FDA], and has taken over one and a half years. Anything for the first time, takes time," Chun said.

Owing to the FDA's unfamiliarity with Seegene's bevy of multiplexing technologies, the HSV I & II test submission will be for use on the Cepheid SmartCycler, a well-established system with prior FDA clearance.

However, for future highly multiplexed tests, starting with the respiratory panel next year, "the instrument should be optimized to work with the MuDT [technology]," Chun said, and as such the company is currently seeking a partner in the real-time PCR instrument space. The timing of the respiratory panel submission, then, is "dependent on whether we can make an agreement in the next year," Chun said.

Whereas all of Seegene's technologies to date have been in the area of PCR chemistry — novel primer and probe schemes such as TOCE — the MuDT method is on the data analysis side of things. Essentially, without any hardware upgrade, MuDT can "double up" the number of fluorescence channels on an existing real-time PCR system, enabling the detection of a pair of target genes — although three is theoretically possible — in a single channel without melt curve analysis, the company claims. For example, a Bio-Rad or Qiagen real-time PCR system may have six fluorescence channels, but that could be essentially doubled to 12 using the MuDT technology.

"Since real-time PCR was introduced, common sense has been one channel, one analyte, one Ct," Chun said. "With one fluorescence dye, and one channel, how can you distinguish two [targets] with the same color? [With MuDT], even in the same color [channel] we can precisely distinguish two targets. Just using simple software without [additional] hardware, you can double up function."

Chun also noted that MuDT can be used with well-established PCR chemistries such as TaqMan or Molecular Beacons, but multiplexing would still be limited to the number of channels on the real-time PCR instrument.

However, by combining the MuDT and TOCE technologies, Seegene believes it can enable single-assay multiplexing of 15 targets, practically speaking, and 20 targets theoretically speaking, with a much lower cost and turnaround time than could be achieved using existing real-time PCR systems and chemistries. Because of these practical limitations, the company's highly multiplexed panels, such as the 26-target respiratory panel, would be clustered into two or three reaction tubes — still a marked improvement in efficiency over other multiplexing solutions.

Furthermore, Seegene's multiplexed panels would be quantitative, which Chun said would provide the company an advantage over other multi-analyte panels. For instance, Luminex, BioFire Diagnostics (part of BioMérieux), and GenMark all have molecular respiratory panels that can tell you if a pathogen is present but can't quantify it. Seegene's panel would be able to do this, which is important, Chun said, because a physician may want to diagnose a co-infection and better understand which is the dominant pathogen.

Chun added that Seegene plans to publish details of the MuDT technology soon in a peer-reviewed scientific journal, and it has applied for patent protection on the method.