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Metabolon Pushes Metabolomics Boundaries

By John Russell

November 24, 2009 | Quality data generation is a solved problem, says John Ryals, CEO of metabolomics pioneer Metabolon. Data interpretation is the challenge now and no one handles it better than Metabolon, he contends. Founded in 2000, deep in biochemistry and informatics expertise, and strengthened by having run 500 commercial projects, Metabolon has outlasted many competitors. Its services business is profitable and growing nicely, Ryals says, while efforts to launch a diagnostics business during the next 12-18 months are also on track.

“There had been a number of companies in this space but some of them changed their business models or they had technology problems. I think we’re pretty far ahead of anyone in this space at this point in time. We have a very comprehensive U.S. patent portfolio so I think it’s going to be very difficult for people to compete with us going forward,” he says.

Like most of the omics disciplines, metabolomics has struggled to industrialize itself and sometimes even to define itself. This offering from
Wikipedia (heresy I know) is actually not too bad:
“Metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind" - specifically, the study of their small-molecule metabolite profiles. The metabolome represents the collection of all metabolites in a biological organism, which are the end products of its gene expression. Thus, while mRNA gene expression data and proteomic analyses do not tell the whole story of what might be happening in a cell, metabolic profiling can give an instantaneous snapshot of the physiology of that cell.” (Here is another description from the Metabolomics Society:

There are a variety of metabolome projects (e.g. The Human Metabolome Project (HMP)
) and estimates vary on what the number of metabolites in humans is. The current HMP estimate is roughly 2900. While metabolomics has generated a fair amount of excitement, it has also been largely overshadowed by genomics and proteomics. Identifying and quantifying metabolites typically involves heavy duty biochemistry allied with sophisticated mass spectrometry and other analytical techniques.

Early on, clients were often unfamiliar with the technology and ill-equipped to understand the results. A fair amount of work was also needed to clearly link metabolomic markers with underlying disease processes and biochemical pathways. Those challenges are steadily being overcome, Ryals says.

“We’ve developed a huge amount of software that allows us to kind of functionalize mass spectrometers into instruments that will now collect this type of data [quickly]. The challenge is to interpret it. It’s not plug-and-play at this point. We still have to counsel people on what they are looking at and how to interpret things. Nobody had really seen multivariate biochemical data before and we are learning a huge amount in terms of understanding how these pathways are interacting with each other, what are the common features of something like oxidative stress or the common features of liver toxicity.”

The technology has broad applicability. In biopharma it can be used for compound selection, drug safety assessment, and mode action studies. Ryals says it’s also very useful in bioprocessing, “We can look at fermenter runs, bioreactor runs, and [if] something has happened in these bioreactors and we can figure it out very quickly.”

mVision is the top service offering from Metabolon. “We work with the client on how to define a project, how would you approach it statistically that sort of thing,” explains Ryals. “One way we do this is to actually provide a very comprehensive analysis biochemically of what has gone on. What are the markers that they’re seeing; how do those markers relate to biochemical changes; what’s known in the literature. In the end the product is virtually a scientific paper that comes back to them explaining all that has happened.”

He points to work done with Gemin X to illustrative the power of the approach. “We used the metabolomics approach to nail down the mode of action of a cancer drug as being a NAD synthitase inhibitor; there had been many papers published on this drug in the past saying it was an NF kappa b antagonist and it clearly isn’t.  It only took us a few weeks in a small study to give them those ideas.”

Gemin X and Metabolon recently published in Molecular and Cellular Biology* describing the work. Here’s a brief extract: “The compound GMX1778 is a very promising cancer therapeutic drug currently in phase I clinical trials. However, despite years of intensive research, its mode of action remained unclear…by using an untargeted metabolomic approach based on Metabolon’s proprietary platform, the mode of action of GMX1778 was clearly identified to be in the inhibition of nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway…Gemin X scientists convincingly validated this finding and further narrowed down the target to be nicotinamide phosphoribosyltransferase (NAMPT), a key regulatory enzyme in NAD biosynthesis. Because of its unique mode of action, GMX1778 can be used as a novel therapeutic approach in the treatment of human cancers.”

Typical projects produce results to review within 2-4 weeks, says Ryals, and wrap-up in 8-12 weeks. The company has two other service offerings, mSelect, a scaled down version mVision, and mView, a newly-launched academic offering.

Building a diagnostics business is the second and potentially more lucrative part of Metabolon’s business model. Work is underway to launch diagnostics in prostate cancer and insulin resistance with teams devoted to each.

“We got into these areas mainly because we had done projects in the areas, had outstanding results, and had a paper** published in Nature on prostate cancer back in February and I think that caught a lot of people’s attention. It’s really a fundamental paper in the field of metabolomics and cancer and so it brings new view to how aggressiveness can be manifest at the level of biochemistry. There is a huge amount now of interest in the biochemistry of cancer,” Ryals says.

Metabolon has identified several biomarkers and owns the necessary IP or has patent applications covering both prostate cancer and insulin resistance. Ryals says the company plans to establish a CLIA lab in the prostate area and will develop its own sales force. The nature of the insulin resistance opportunity – large affected population and widely spread - is such that Metabolon will probably pursue a partnering strategy says Ryals.

Regulatory issues remain. “It’s unclear, at least from our perspective, exactly what the regulatory environment will look like,” he says. “There’s been a lot of discussion that FDA wants to regulate these multivariate indexing assays and it’s a very complex area to regulate.  FDA is having a lot of discussions with genomics companies now, and if they step in to regulate, some of our tests actually won’t fall under that because they don’t use that many variables. Some of the tests might.”

Piling up scientific proof of metabolomics’ value is also part of Ryals strategy.  “We’ll always be doing studies with key opinion leaders to further demonstrate the performance of our tests in disease. If you look at Genomic Health, I think they published 14 or 15 papers around the breast cancer test. That’s what we intend to do. We develop areas of strength with opinion leaders in these areas and we’ll be publishing a lot of papers on these tests,” he says.

Metabolon doesn’t burn a lot of cash says Ryals and it has been effective in raising capital. Last month the company closed its Series C round, raising $12.3 million. However launching the diagnostics business is likely to require more capital, he says. Meanwhile, the services business is growing steadily.

* Molecular and Cellular Biology, “The Small Molecule GMX1778 is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in NAPRT1-Deficient Tumors” appears online ahead of print.

** Nature 457, 910-914 (12 February 2009), Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression

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