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HTG Sets Sights on the FFPE Treasure Chest

By John Russell

January 27, 2010 | Locked up in the vast quantity of FFPE tissue collected over the years is a treasure trove of genomic information about patients. Now, High Throughput Genomics (HTG), a small company based in Tucson, believes it has the key to unlock that bulging treasure chest and to catapult itself into prominence as a company offering pharmacogenomics (Pgx) and diagnostic services and products.

Formalin Fixed Paraffin Embedded (FFPE) tissue is notoriously tricky to deal with when attempting to extract RNA. The required preprocessingcDNA synthesis and RNA amplification, for examplegenerally degrades the sample and the signal. HTG sidesteps these problems altogether with a process it calls, quantitative nuclease protection assay or qNPA (technology backgrounder link). Just slice off a piece of the sample, put it in a well, and run the assay.

A proprietary lysis buffer is the main secret sauce, but HTG has managed other impressive technical feats such as developing the ability to anchor multiple probes in a well to perform multiplexed assays. The basic idea is once researchers have used other technologies – e.g. whole genome sequencing studies - to identify what they think are promising markers, HTG technology can validate those finding by ‘mining’ relevant FFPE tissue.

“Right now this is an area of explosion and growth. For the last decade pharma and most researchers have been doing these whole genome profiling studies and now the classic ‘pig in the python’, the bolus, is in validation and how do we get these to the clinic. That’s where we reside,” says CEO Tim Johnson.

Strong support for the HTG technology emerged in July 2008 in a paper in Blood"Gene Expression Predicts Overall Survival in Paraffin Embedded Tissues of Diffuse Large B Cell Lymphoma Treated with R-CHOP" - by cancer researcher Lisa Rimsza of the University of Arizona Center. Using qNPA to conduct a retrospective study of a class of lymphoma patients, Rimsza and her colleagues, which included HTG founder and CSO Bruce E. Seligmann, discovered two genes that were highly predictive of poor outcome. 

Here’s an excerpt from the paper’s abstract: “…We used a quantitative nuclease protection assay (qNPA) to analyze formalin-fixed, paraffin embedded tissue (FFPET) blocks for 36 previously identified genes…Our results solve a clinical research problem by demonstrating that: prognostic genes can be meaningfully quantified using the qNPA technology on FFPET blocks…”

That would be music to any marketer’s ears. In all of 2008, HTG added six new customers. In 2009, it added 52. The burst in growth seems to be the direct result of the growing validation and awareness of its technology and its energetic CEO.

“We have 25 employees and of those, about half are people that joined the company since I took over about 20 months ago. We have almost a fully new management team so we have a very fresh company,” says Johnson, who is a veteran of both the medical device and diagnostics industries, including stints at Ventana Medical Systems, now owned by Roche, and Hill-Rom.

“The company is going through a transition from what was a broad-based life sciences tool company to more of a focused personalized medicine company. Specifically we believe we have unique capabilities with multiplexing and the ability to work with fixed tissues that are going to provide us the ability to build assays for pharma as a pharmacogenomics (Pgx) provider and also to work with translational medicine and academicians on unique gene signatures, which we can then take into the clinical market.

Not only is the ability to work with FFPE samples a major competitive advantage, but also the multiplexing proficiency enables HTG to design assays that are more efficient and cost-effective says Johnson. HTG has also moved into the microRNA arena and signed an agreement last year with Roche-NimbleGen to provide HTG assays on Roche-NimbleGen’s glass planar arrays as a service.

“We’ve got all three specieshuman, rat, and mouse—the entire (miRbase) database so we are able to offer on this platform the entire transcriptome. Once they’ve run this product and have identified specific mRNAs of interest, we can bring them to our other platform to do more detailed analysis and interrogation,” Johnson says. “It is yet to be determined the relevance of microRNAs but everybody’s working with it and we believe we have an opportunity to have a great leadership position, especially in the microRNA analysis of fixed tissues.”

To drive demand HTG has expanded its sales and marketing team to eight. Johnson reports HTG has signed its first contract with a large pharma to build a companion diagnostics assay and that HTG has licensed a lymphoma signature “hopefully preparing it for the end of 2010 submission as a clinical test.” As a small company, Johnson recognizes not all the big players will feel comfortable working with HTGat least yet. He says HTG has an effective screening process to quickly determine if a potential collaborator is a good fit.

“We’re working with what we call our key collaborator program to identify folks who already believe they have something unique or something that answers an unmet question or an unanswerable question today and once we find those individuals we will basically tell them that for either a reduced cost or some agreement we’ll work with you to validate your signature,” Johnson says.

“In other words if you have 300 samples, tissue samples in archive, we’ll work with you at a drastically reduced price, we’ll actually pay for the patent applications and prosecutions, and all we ask for in return is a license to the technology. You can license it out to PCR. You can do whatever you want with it,” he says.

“We don’t have a lot of idle cash sitting around to be paying people large sums of money up front fees so we tend to do more risk-sharing. We’ll help you with the risk of validation by providing you with these kinds of services, we’ll risk-reward you with royalties if this hits the diagnostic market, but in the meantime we need low cost access to the signatures.”

He is excited about proving the company’s business model with the lymphoma signature. “We have a two-gene signature [that says] in essence if you have both of these genes in your profile your likelihood of survival drops from in the high 80s to below 40 percent. These are diffuse large B cell lymphomas. The standard of care today is to do a triage of the patient and put them into an IPI risk profile.”

It turns out, says Johnson, that many patients with the two-gene marker would still get a low IPI scores. “They would have been told they have an 80 percent likelihood of five-year survival when based on this signature they actually have a very low likely hood of 15-month survival. I’d want to know that if I am a lymphoma patient so I can talk with doctor about taking me right to second line therapy or ask what are my alternatives because by the time we figure out I am failing first line therapy, it may be too late.”

Johnson says this is not a huge marketroughly 40,000 cases a year—and that most big diagnostic players “wouldn’t bother to build a business case around it.” For HTG it’s an excellent niche market in which to demonstrate its capabilities and to have a positive effect on patient care. A partnership with Clinical Research Laboratories enables HTG to offer CLIA services.

Other companies also say they work effectively with FFPE tissue samples, but Johnson is skeptical. “We believe we are the only extraction-free RNA tool for clinical use available today. There is one other extraction-free technology that is out there from Panomics which was purchased by Affymetrix. But when Affy purchased Panomics, it only had the license to the for research use, not for clinical use.”

It also doesn’t hurt that HTG’s technology is not so mysterious to frighten away collaborators: “Labs are very familiar with our protocols, in other words they are not that familiar with our assay because we’re still not a lot of brand equity in the market as a small company but when you explain our assay to them they say, “Oh yeah, just like an ELISA or that’s just immunohistochemistry on the front end.”

Johnson is convinced HTG is in the driver’s seat with regard to performing gene expression analysis on FFPE samples: “If only I had a dollar for every time a researcher looked at me and said if you can truly do that you’re going to change the way we do things around here.” So we have to prove it, which we are now in the process of doing, and we have proved it in enough places that people are now signing up.” 

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