Molecular diagnostics developer PrimeraDx is making headway in its efforts to reach out to pharmaceutical companies to spur adoption of its highly multiplexed, quantitative PCR-based DNA testing platform for companion diagnostic development, according to a company official.
In doing so, the company has trained its focus primarily on the oncology space — both in its internal development and external partnership efforts — while putting infectious disease test development on the back burner for the time being.
In addition, PrimeraDx has delayed submitting its platform and first test — an assay for Clostridium difficile — for approval by the US Food and Drug Administration in order to develop a more complete submission reflecting the highly quantitative and multiplexed nature of its technology, with an eye toward the type of multiple-analyte testing desired for oncology and companion diagnostic applications.
Based in Mansfield, Mass., privately-held PrimeraDx has developed an assay technology called scalable target amplification routine, or STAR, which integrates standard endpoint PCR with capillary electrophoresis to simultaneously quantitatively measure multiple target nucleic acids; and a benchtop instrument called ICEPlex for running STAR-based assays.
The STAR technology and ICEPlex platform work by continuously sampling PCR reactions containing fluorescently labeled primers during sequential cycles of amplification. The amplified products can then be detected by size using capillary electrophoresis, and the amplification kinetics can be reconstructed using real-time PCR algorithms to quantify the amount of material in the initial sample.
PrimeraDx claims that the STAR technology and its proprietary primer design method enable a much higher level of multiplexing than is possible with real-time PCR techniques that use fluorescent probes, such as TaqMan-based methods. The upshot is that the system can simultaneous quantify multiple gene targets — a few dozen for practical purposes but a few hundred, theoretically — from a single reaction.
David Jackson, the company's recently hired vice president of business development, told PCR Insider last week that the company has conducted experiments demonstrating the ability of its platform to test more than 50 analytes simultaneously in a single-tube assay using a single fluorescence channel, but that the theoretical limit is much higher.
"The capillary electrophoresis part is the artificial limiter," Jackson said. "It's artificial because we arbitrarily have chosen to restrict the length of the CE gel to a 14-centimeter tube. The reason for that is it allows the entire run time to map to a conventional real-time PCR system.
"We could, and have, extended the length of the CE substantially … and [ICEPlex] has two lasers, and we can combine labels using the two excitations and put at least three labels per light source, so we have a theoretical limit of around 300 [analytes]," he added.
Jackson said that PrimeraDx currently is conducting experiments to push the system "into that triple-digit range," but practically speaking, most potential customers are interested in a number closer to 50, which is much higher than is possible with other real-time PCR methods, which can simultaneously multiplex around half a dozen analytes.
"We could probably overbuild for the need now, and at some point the need will catch up with our instrumentation," he said. "But at end of day we can run a full EGFR panel in a single tube. Or, we could run 50 SNPs, which is more than any combination of SNPs that are currently used to analyze any given tumor type, all from the same slide. We can run any expression panel anybody wants to as long as the tissue is handled decently."
Last July, CEO Matthew McManus outlined the company's new strategy for building interest in its technology platform. This strategy consisted of both offering the STAR approach and ICEPlex platform to laboratories to develop their own molecular tests; as well as collaborating with academic medical centers and pharmaceutical companies to develop various multi-analyte oncology assays for use in companion diagnostic development (PCR Insider, 7/14/2011).
In January PrimeraDx took another step toward that goal when it hired Jackson, who had previously served as a member of the companion diagnostics team for DxS and subsequent parent company Qiagen. Jackson has been charged with accelerating the new strategy by working with pharma to consider PrimeraDx's platform early on in the drug- and companion diagnostic-development cycle.
"We are securing our relationships with pharma earlier in both the drug and diagnostic development process because … simply put, drug companies are risk-averse," Jackson told PCR Insider last week. "Adding a companion Dx program much later in the process, especially using a technology that is so different from many others, causes all sorts of challenges at the top."
In addition, when considering its own multi-analyte oncology assay development, PrimeraDx is making an effort to keep its eye trained on the final goal of an approved drug-CDx combination.
"It's about the conversion speed … from a [laboratory-developed] version to an IVD," he said. "We don't build crummy assays in a box that we call [research-use only] that are not appropriately validated so that they could go forward as an IVD. Instead we build an RUO version … as if it's going to become an IVD. Even though that's more expensive to do, it has the huge benefit … of being a very value-added service product for the end user."
Jackson said that "all the usual suspects [in pharma] are intrigued and in some cases working with us already," although he declined to identify any of these partners due to confidentiality agreements.
However, Jackson said that the relationship with a previously disclosed pharma partner, Eli Lilly, "is not just ongoing, but maturing. We don't have a contract with Lilly to build and register an FDA-approvable IVD under this agreement, but the agreement is comprehensive, and that is the end goal. It just doesn't contract us to that goal."
PrimeraDx has not disclosed the nature of the development program for which Lilly is evaluating its platform, although Jackson said that he anticipates being able to publicly disclose details about the partnership in the coming months.
PrimeraDx is also attempting to work with clinical reference labs in order to help them become comfortable with the ICEPlex platform and STAR technology in anticipation of pharma customers needing to work with the labs to conduct their clinical trial work.
"The tradeoff between PrimeraDx and labs that we're talking about is always the same: They want some kind of preferred pricing, and they also want some exclusivity … at least to perform clinical trial work before the IVD is actually released. We're happy to do that, because if they have experience with the test, they will be able to broadly distribute that within their network … and have a full argument for reimbursement."
Further helping its cause, PrimeraDx also this week won a new US patent, No. 8,182,995, entitled "Real-time gene expression profiling" and covering important aspects of its technology. According to the patent's abstract, it covers methods that allow "improved determination of the abundance of one or more target nucleic acids, especially target RNA species, in one or more original samples," according to its abstract (see IP Watch, this issue).
Delayed Submission
In July, McManus also noted that PrimeraDx was developing its own molecular diagnostic tests internally, and said that the company planned to submit the ICEPlex platform and first STAR-based assay for C. difficile to the FDA in the first quarter of this year for clearance as an in vitro diagnostic device.
However, last week Jackson told PCR Insider that "although we did have the plan to submit last quarter," the company has postponed those plans.
"We needed to provide more data for the use of the platform with claims about its multiplexing capacity," Jackson said. "We brought in the C. diff assay, which is a single target, but because we use a set of calibrators that are co-amplified in the same reaction tube, the FDA was opening the door to this multiplexing claim."
At first the company was unconcerned because the C. diff assay is not a multiplexed test, per se. "However … we don't want to go back and renegotiate with the FDA on issues related to the platform when we come in with the next IVD that will obviously be a multiplexed application," Jackson said. "We're just doing C. diff for the clearance of the device — it isn't really going to make us any money. So that's the primary reason we postponed."
In addition, he said, the FDA considered that the way the ICEPlex C. difficile assay is performed makes it a quantitative test. "We had put in a qualitative draft claim, because we were actually using quantitation and a cutoff to derive a qualitative answer. So in order to fully prosecute that claim, we thought we'd better do this right and get both the quantitative and complexity captured in the first go around."
"That has required a little bit of re-engineering to build it to the standard, and subsequently there are plenty of studies that need to be repeated," he added. "We pushed pause, decided to incorporate [FDA's] suggestions, and are now doing work to complete that." Jackson did not provide a new timeline for clearance of the platform.
Rejiggering its C. difficile test is likely the primary work the company will do in the infectious disease area in the short term, however, considering the more lucrative oncology and companion diagnostic opportunities that may exist for its technology platform.
"Infectious disease is a great application area for the platform, but largely we aren't going to register a few dozen infectious disease IVDs, because it would cost too much to register them relative to the yield," he said. "We will publish on those kinds of things, and maybe develop assays for them, but we won't likely sell the assays. That pretty much means labs will develop [infectious disease] assays on the platform, which they already are. It features assay-design software that makes it easy to do that."
Lastly, looking further into the future, PrimeraDx is working on a technology that may allow it to assay a peripheral blood supply source in the body for distal information on tumor development.
"I'm not alone in my desire to move to a liquid biopsy," he said. "I think everybody keeps talking about things like [circulating tumor cells]. Another pharma has come to appreciate this aspect of our tech and is providing us with matched samples so we can demonstrate concordance between [formalin-fixed, paraffin-embedded] samples and a plasma resource from the same patient. If it turns out that works, we will shout it from the rooftops."