New York Times March 26, 2013 New Prostate Cancer Tests Could Reduce False Alarms By Andrew

Pollack http://www.nytimes.com/2013/03/27/business/new-prostate-cancertests-may-supplement-psa-testing.html?pagewanted=all&_r=0 Sophisticated new prostate cancer tests are coming to market that might supplement the unreliable P.S.A. test, potentially saving tens of thousands of men each year from unnecessary biopsies, operations and radiation treatments.

Some of the tests are aimed at reducing the false alarms, and accompanying anxiety, caused by elevated P.S.A. readings. Others, intended for use after a definitive diagnosis, probe the genetic workings of the cancer to distinguish dangerous tumors that need treatment from slow-growing ones that might be left alone. The tests could provide a way out of the bitter debate over whether healthy men should be screened for prostate cancer.

The problem with the P.S.A. blood test is that many of the cancers it detects are unlikely to cause harm. But there is no reliable way to identify them. So a large majority of men with positive tests undergo surgery or radiation treatment, and many suffer for years, needlessly, from complications like incontinence and erectile dysfunction.
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In late 2011, the United States Preventive Services Task Force, a government

advisory body, provoked a furor by recommending against screening, saying that far more men were harmed by unnecessary biopsies and treatments than were saved from dying of cancer. But if new tests can better determine risk, screening could become more useful.

Its not that screening doesnt work; its that we havent done a great job of targeting treatments for the tumors that need it, said Dr. Matthew R. Cooperberg, an assistant professor of urology at the University of California, San Francisco who has been a consultant to some of the testing companies. Reducing unnecessary treatments could also reduce the $12 billion in estimated annual spending related to prostate cancer. Test developers hope that such savings will make their tests cost-effective, even at prices that will exceed $3,000 in some cases.

More than a dozen companies have introduced tests recently or are planning to do so in the near future. Rather than looking at a single protein like P.S.A., which stands for prostate-specific antigen, many of these tests use advanced techniques to measure multiple genes or other so-called molecular markers. Its the cancer for the next 18 to 24 months that will be transformed by molecular markers, said Dr. Doug Dolginow, chief executive of GenomeDx Biosciences, a start-up planning to introduce a test later this year. Experts caution that it is too early to tell how well most of the tests will perform and whether they will make a difference. Although the tests are intended to help men make treatment decisions, the onslaught of so many could cause more confusion.

Its a little tricky to find out which one applies to you and whether it will be paid for by insurance, said Jan Manarite, who runs the telephone help line for the Prostate Cancer Research Institute, a patient education organization.
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Prostate cancer specialists say that screening has declined since the task force recommended against it, but millions of men in the United States still get regular blood tests to measure P.S.A. As many as a million undergo biopsies each year, with about 240,000 prostate cancer cases diagnosed and 28,000 deaths from the disease. The biggest battle among test developers could be between Genomic Health and Myriad Genetics, which are moving into the prostate cancer field after successes in breast cancer testing.

Myriad is known for its test for genetic mutations that raise a womans risk of getting breast cancer. Genomic Healths Oncotype DX test helps determine if a woman should receive chemotherapy. Both companies have developed prostate tests analogous to Oncotype DX. They analyze gene activity levels in the tumor sample obtained by biopsy to gauge how aggressive the cancer is, helping doctors and patients decide whether to treat it. The companies say their tests provide better information than the Gleason score, the main tool now used to assess tumor aggressiveness, which is based on how cells look under a microscope. One study of Myriads test looked at stored biopsy samples from 349 British men who were found to have prostate cancer from 1990 to 1996 and did not receive immediate treatment.

About 19 percent of the men with the lowest risk scores on Myriads test died from prostate cancer within 10 years, compared with 75 percent of the men with the highest risk scores, according to results published last year in the British Journal of Cancer.

Still, some prostate cancer specialists say the test, which is called Prolaris and went on sale last year, has not been adequately validated, and sales have been very low. Noridian, the Medicare contractor for Utah, where Myriad is based, said it would not pay for the $3,400 test.
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Genomic Health says it plans to start selling its test, the Genomic Prostate Score, after releasing supporting data at the American Urological Associations annual meeting in May.

Insurers might be reluctant to pay for the new tests without evidence that men will trust the results enough to forgo treatment if so indicated. The tests still leave some uncertainty, and many men do not want to live with cancer, no matter how slight some test says the risk is. We already know from conventional information that there are a group of men who are very unlikely to have progression, but they still get treated, said Dr. Lee N. Newcomer, senior vice president for oncology at UnitedHealthcare.

Angel Vasquez, for example, resisted when his urologist told him that he could forgo treatment based on his low Gleason score and P.S.A. levels. I said, No, my philosophy is if there is something in my body that is not supposed to be there, I want it to come out, said Mr. Vasquez, 67, of Matthews, N.C.

The doctor ordered Myriads Prolaris test. Rather than justifying a decision to watch and wait, the test showed the tumor to be more aggressive than thought, a finding later confirmed after Mr. Vasquez had surgery. Had I left it alone, it would have really progressed, he said. Some experts say that even if the new tests are not perfect, they are better than what is available now.

Even if we can only convince 15 to 20 percent of men that we have enough confidence that they dont need to be treated, that will be a big step forward, said Dr. Eric A. Klein of the Cleveland Clinic, who has worked with Genomic Health. Another company, Bostwick Laboratories, already sells a tumor
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aggressiveness test called ProstaVysion, and Metamark Genetics is developing its own. GenomeDx is focusing on a test that would be used after surgery to help determine whether additional treatment with radiation or drugs would be useful. Danaher already sells such a test.

Hologic, MDxHealth and Mitomics sell tests that they say can reduce the number of unnecessary second biopsies, which are often done when a first biopsy is negative but P.S.A. levels remain high.

One published study showed that Opkos test could have reduced unnecessary biopsies by about 50 percent, though it would have missed 12 percent of highgrade cancers. Yet another test could come from the discovery by researchers at the University of Michigan that a particular fusion of two genes is found in half of prostate cancers, and only in prostate cancer.

Opko Health, Beckman Coulter and Metabolon are developing tests that would be used in conjunction with P.S.A. screening. Because P.S.A. levels can be elevated for reasons other than cancer, as many as three-quarters of biopsies do not find cancer and the biopsies can cause pain and infections.

Youd still miss 50 percent of the disease, but at least you know if you have it you have prostate cancer, said Dr. Arul M. Chinnaiyan, a professor of urology and pathology. He said a urine test was being developed that combines the gene fusion with PCA3, another marker.

The new tests are singles and doubles at best, said Dr. William J. Catalona, director of the prostate program at Northwestern University, who helped bring the P.S.A. test to market in the 1990s.
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Some experts say unnecessary procedures can be reduced simply by using the P.S.A. test less frequently, and also by improving imaging.

But, Dr. Catalona said, this is only the start.

This field is moving kind of like cellphones,

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Predicting Diabetes thediabetesresource.com Allie Beatty November 17, 2011 http://www.thediabetesresource.com/your-diabetes-health/predicting-diabetes/ Metabolon has a revolutionary tests that uses biomarkers to identify a patients susceptibility to insulin resistance leading to diabetes. The test, called Quantose, can predict when a person will develop diabetes. It can be used as a tool to promote lifestyle changes in at-risk patients. Quantose is able to assess the risk of developing Type 2 diabetes above and beyond traditional risk factors and glycemic tests. The test exists now, but Metabolon is working on partnering with testing companies to have them added to standard blood panel tests. A test like Quantose can help evade the risk of developing Type 2 diabetes simply and cost effectively. A report said that 1 in 10 adults will have Type 2 diabetes by 2030. If a statistic like that can be reduced by adding a simple test to your doctors office visit the opportunity cost is extremely reasonable. The price you pay with diabetes, mentally, physically, and emotionally is obscene. Not to mention the national healthcare crisis cant afford this predicted reality. Diabetes is growing like a weed. Given the right tools to get the job done we can effectively prune some roots and perhaps nip it in the bud. Visit the Your Diabetes Health section of our website for more resources about health.

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Drug Discovery & Development A Better Route for Diagnostics? June 11, 2012 By Jeffrey M. Perkel http://www.dddmag.com/articles/2012/06/better-route-diagnostics From the moment of its inception, the Human Genome Project was expected to yield substantial benefits in diagnostics. But the genome is only part of the story. Equally important are the mRNA transcripts that carry out the genomes orders, the proteins they encode, and ultimately, the metabolites upon which they act. Today, thanks to rapid advances in DNA sequencing, mass spectrometry, and microarrays, among other technologies, researchers can query these biomolecules on a grand omics scale. From there, its a short statistical jump to sifting through those datasets to find signatures that predict disease, prognosis, or drug efficacy. The scientific literature is full of such studies. Yet relatively few omics biomarkers have actually made the transition to clinical practice. One possible reason for this limited progress is that there has not been a widely agreed-upon process for translation of omics discoveries into clinical omics-based tests intended to improve patient outcomes and care, suggests an Institute of Medicine report, released in March, that lays out best practices for the development of translational omics diagnostics.1 In its 260 pages, the report effectively brings together much of the conventional wisdom regarding omics diagnostics development into a single guidance document, says Jeffrey Bojar, vice president for legal and regulatory affairs at BioDesix, a Boulder, Colo.-based company that develops proteomics-based diagnostics. Yet the reports impetus was a scientific scandal at Duke University in which an omics-based gene expression diagnostic that could purportedly predict patient response to chemotherapeutics was moved into the clinic without proper validation. The test, as it turns out, didnt work. Three clinical trials involving 127 individuals have now been terminated, and some 27 papers have been retracted2 problems that might have been avoided had these best practices been in place, the report suggests. Typically, says Harry Glorikian, managing partner at Scientia Advisors, a life science consulting firm based www.SpecOpsComm.com

in Cambridge, Mass., the movement of laboratory biomarkers into the clinic is a relatively circumspect process. To take a very complicated system and drive it directly into a clinical setting, there could be potholes and land mines along that path, he says. In part, thats because, as the report lays out, development of omics diagnostics presents complications that are not typically seen with traditional single analyte assays. First, omics technologies produce many more datapoints per subject than the number of subjects themselves. A transcriptome analysis, for instance, might report the abundance of tens of thousands of mRNAs for everyone in a 50-person study. But the more observations one makes per subject, the greater the likelihood of false discovery or overfittingfinding seemingly discriminatory molecular signatures that do not in fact exist. Complicating that problem, the omics signatures do not always bear any obvious relation to the condition being studied, such that the scientific rationale underlying why a particular biomarker panel should work is not always clear. Another issue is that, because of the number of datapoints involved, omics diagnostics development typically involves computational steps, or algorithms, that weigh a number of variables and produce an answer. For instance, Oncotype DX from Genomic Health in Redwood City, Calif., quantifies the likelihood of breast cancer recurrence based on the expression of 21 genes, five of them controls. But the complexity of omics data, the proprietary nature of commercial algorithms, and a lack of a clear mechanism for sharing data and software, all conspire to make it difficult for researchers to vet each others data and the mechanisms by which those scores are determined. Finally, regulatory and infrastructure issues can complicate accountability, peer review, and oversight, especially in academic labs, which typically are less familiar with the nuances of translational medicine than industry, and yet operate with greater freedom. The report recommends, but does not mandate; it is effectively a guidance document. It offers steps and standards researchers in academia and industry should follow to migrate an omics diagnostic into the clinic, including using distinct patient populations in discovery and validation steps; locking down analytical algorithms; data and code sharing to allow peers to independently evaluate the work; and consultation with regulatory agencies. According to Mitchell Nelles, chief operating officer at XDx Inc. (Brisbane, Cailf.)whose gene expression-based AlloMap assay for predicting the likelihood of heart transplant rejection is one of the few so-called in vitro diagnostic multivariate index assays (IVDMIAs) approved by the U.S. Food and Drug Administration (FDA) to datethese recommendations arent new; they represent common practice among diagnostics development firms. This is standard product development using a phase-gate approach with rigorous checks and balances, Nelles says. This is what you do. In fact, AlloMap was highlighted (along with five other IVDMIAs, one univariate biomarker, and a final IVDMIA that failed in validation) as a case study in the IOM report, an example of how to do things properly. The report specifically highlighted the lack of subject overlap between discovery and validation; the interaction of the company with the FDA during development; and the fact that the company locked down its analytical algorithm. www.SpecOpsComm.com

According to James Yee, the companys chief medical officer, locking down the algorithm is a critical step in omics diagnostics development and involves precise documentation of how the IVDMIA works, including the genes involved, how they are measured, expected values, mathematical manipulations, and so on. Thats what we validate, he says. So even if, later on, someone has the bright idea to change that plan, were not allowed to do that; that requires a whole amendment process. The locking down step is also important in proteomic biomarker development, and the algorithm underlying BioDesixs VeriStrat has been locked down since 2005, says Paul Beresford, the companys vice president for business development and strategic marketing. Validated in some 25 clinical trials to date involving more than 3,000 subjects, VeriStrat is a mass spectrometry diagnostic used to help physicians guide therapy for non-small-cell lung carcinoma patients. The test identifies patients who are likely to have good or poor outcomes after treatment with EGFR tyrosine kinase inhibitors based on the integrated intensities of eight spectral peaks, and was developed using a training set of 139 patients from three cohorts and two independent validation cohorts of 67 and 96 samples each. The algorithm was locked down early in that process, Bojas says. The development process was almost exactly what they [the IOM] recommended. In fact, BioDesix, is now ramping up development of new diagnostics, and the company recently revisited its internal development process procedures. We used the IOMs guidance as a gut-check of our product development process, which we implemented a couple of years ago, says Beresford. Its almost identical to what the IOM came forward with. Of all the omics, metabolomics likely presents the simplest path to diagnostics development, says Michael Milburn, chief science officer at metabolomics diagnostics firm Metabolon (Durham, N.C.), because the data it produces is so much less complex than in other omics disciplines. That means the false discovery rate is lower, as well. Were typically measuring on the order of about 600 to 1,000 biochemicals [per sample], Milburn says, two or three orders of magnitude fewer than in transcriptomics or genomics. Another advantage, Milburn says, is that the diagnostics the company develops typically include one and no more than three or four metabolites, which are assayed using analytical tools most clinical labs already have on hand. Thats in contrast to Irvine, Calif.-based Agendias MammaPrint assay for breast cancer recurrence, which uses a 70-gene signature measured on a microarray platform. Metabolites are a very commonly measured diagnostic readout, he says. Though Metabolon has not yet released any diagnostic assay for clinical use, it hopes to launch its first for assessing insulin resistance in diabeticsthis year, says Milburn, who notes the companys development process was pretty in-line with the IOMs recommendations. Company scientists scanned 500-odd metabolites in some 400 sera samples, collected at some 19 centers in 13 countries across Europe, to identify three metabolites that independently contribute to the assessment of insulin resistance. Now the company is validating that signature in an additional 4,000 or 5,000 patients in a clinical setting, and preparing to offer it in the companys in-house CLIA-certified lab. Indeed, most companies surveyed for this article said their processes largely align with IOM recommendations. Its academics who could have the biggest problems, they suggest, because

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universities have different infrastructures, different mechanisms for oversight and accountability, and different metrics of success, than industry. It really is a different set of core competencies, says Yee. Any industry scientist worth their salt, Glorikian agrees, will adhere to a rigorous process. We do step A and then we validate with step 1A, and theres a process you follow. But if youre in academia, you might not follow every one of those steps, in part because academics dont have to, and in part because the required oversight or infrastructure is lacking. The IOM report suggests that, If an institution does not have the infrastructure or capability to follow the recommended Test Development and Evaluation Process defined in this report, then the committee believes that institution should consider not engaging in the translation of omics-based discoveries into validated tests intended for clinical use. That said, diagnostics development still continues in academia. Emanuel Petricoin and Lance Liotta, codirectors of the Center for Applied Proteomics and Molecular Medicine at George Mason University, used reverse-phase protein microarrays, a proteomics tool, to identify a dysregulated signaling pathway called ALK in women with inflammatory breast cancer, a particularly malignant form of the disease. That discovery is now being applied in a clinical trial for an ALK inhibitor, which uses fluorescence in situ hybridization assay to quantify ALK gene amplification when selecting patients for the trial. Thats not, per se, an omics diagnostic, says Petricoin, but, ALK is either activated or it isnt, and this is because ALK is either amplified, or its not. At the Laboratory for Molecular Medicine at the Partners Healthcare Center for Personalized Genetic Medicine, a CLIA-certified lab associated with the Dana-Farber Cancer Institute, researchers developed and clinically implemented next-generation DNA sequencing-based diagnostics for cardiomyopathy, hearing loss, and Noonan spectrum disorders. The first such test, for pan-cardiomyopathy, took the lab more than a year to validate and implement, says assistant lab director Thomas Mullen, and involved acquiring necessary technology, setting up the analytical pipeline, assessing sensitivity and specificity, and so onsteps that basic research labs might balk at but that are de rigeur in CLIA labs. Indeed, it isnt discovery, but the hard work that comes after that makes the difference between a basic research finding and a clinical diagnostic. Take, for instance, a biomarker for predicting patient response to anti-depressants. In a project initiated by the National Institutes of Health (NIH)-funded Pharmacometabolomics Research Network, Rima Kaddurah-Daouk at Duke University Medical Center, Richard Weinshilboum at the Mayo Clinic, and Oliver Fiehn at the University of California, Davis, are collaborating on a multi-omics approach to this question that the team calls pharmacometabolomics-informed pharmacogenomics. Fiehns lab collected metabolite profiles from 40 individuals from the Mayo-PGRN SSRI study, who either do or do not respond to certain selective serotonin uptake inhibitor anti-depressants. Bioinformatic analysis of those profiles at Duke and North Carolina State University identified differences in glycine metabolism between the two groups. Targeted genotyping of genes associated with glycine synthesis and metabolism in an additional 529 subjects identified a polymorphism in glycine dehydrogenase that was associated with treatment outcome phenotypes. Finally, the team validated that SNP in 1,779 patients from a separate patient cohort, suggesting this one genetic marker really does correlate with

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treatment outcome. Yet the team still has a long way to go to prove clinical utility, says Kaddurah-Daouk. Moving this observation into the clinic would require, at a minimum, expanding their search to determine whether other metabolites and polymorphisms or genes might provide a better signal; replicating the observations using orthogonal detection methods; and performing blinded studies on independent patient cohorts. We have many more studies to do, she says. These are really the first early steps. The same could be said for omics-based diagnostics overall. About the Author Jeffrey Perkel has been a scientific writer and editor since 2000. He holds a PhD in cell and molecular biology from the University of Pennsylvania and did postdoctoral work at the University of Pennsylvania and at Harvard Medical School. References 1. Institute of Medicine. 2012. Evolution of Translational Omics: Lessons Learned and the Path Forward. Washington, DC: The National Academies Press. http://www.iom.edu/Reports/2012/Evolution-ofTranslational-Omics.aspx. 2. Kaiser J. Panel calls for closer oversight of biomarker tests. Science Insider, March 23, 2012. http://news.sciencemag.org/scienceinsider/2012/03/panel-calls-for-closer-oversight.html.

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High risk, high payoff Drug Discovery News September 2012 By Lori Lesko http://www.drugdiscoverynews.com/index.php?newsarticle=6523

RESEARCH TRIANGLE PARK, N.C.With obesity and cancer on the rise worldwide, the recent marriage of mega-tech giants Metabolon Inc. and Sacramento Calif.-based Lipomics Technologies holds not only the promise of new, more effective treatments for these major health risks, but provides opportunities to develop more diagnostics, personalized medicine and commercial services across the globe. Metabolons friendly acquisition of Lipomics in August combines Metabolons metabolomics technology platform for commercial services and diagnostics with Lipomics TrueMass Profiling lipids technology platform. Financial details of the transaction were not disclosed. Michael Milburn, chief scientific officer of Metabolon, says, Metabolon has pioneered metabolomics technology and is the largest provider of solutions globally to the pharmaceutical, healthcare, consumer products, nutrition and agricultural industries, as well as to hundreds of academic institutions. Lipomics is the leader in technology to analyze lipids, including metabolites of fatty acids, acylcarnitines, sterols, amino acids, bile acids and eicosanoids. Together, we have an unprecedented suite of technologies and capabilities to benefit our expanding customer base. Lipomics, in partnership with pharmaceutical, biotechnology and nutrition companies, also has the capacity to improve clinical trial stratification, reduce late-stage drug attrition, develop early tests for monitoring drug response and enable individualized health management.

For the past 10 years, Lipomics has taken pride in providing the best technology and science for understanding the role of lipids in human disease, principally in metabolic diseases associated with obesity and the lipid remodeling aspects of cancer, Lipomics Founder Steven M. Watkins stated in a press release. The prospect of combining our approach with Metabolons global platform is extremely exciting. Integrating the technologies will provide a

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deep and coherent understanding of biological systems and allow us to produce unparalleled services and products for years to come. As the world population battles obesity, more cases of diabetes come into play, causing more complications and a bigger strain on the healthcare budget. Metabolons lead diagnostic product, Quantose IR, is a metabolomics-based insulin resistance diagnostic test for type 2 diabetes. The test measures levels of three novel non-glycemic biomarkers and insulin, with the goal of detecting prediabetes earlier and with greater sensitivity than traditional glycemic markers such as glucose and hemoglobin A1C. Thus, the combined efforts of Metabolon and Lipomics offers the industrys leading metabolomics platform providing a global, comprehensive analysis of biological samples for the discovery of markers and pathways associated with drug action and disease, says Todd Lynch, Metabolons chief financial officer. Lipomics brings to the table a suite of analytical panels that provide focused, quantitative coverage of key pathways involved in metabolic, cardiovascular and inflammatory conditions, and both Metabolon and Lipomics provide expert biochemical interpretation across major therapeutic areas, Lynch says. Metabolon has completed more than 1,500 studies across a broad range of disease areas, Lynch tells ddn. Metabolons diagnostic discovery efforts are focused on cancer and obesityrelated diseases, while Lipomics expertise in metabolic, cardiovascular and inflammatory conditions is very complementary to Metabolons efforts in both bringing solutions to our customers as well as discovering novel diagnostic tests. Lynch expects positive developments from the transaction in the near future and possible changes in his companys current business model. Lipomics laboratory facilities will remain at its headquarters in Sacramento, while Metabolons headquarters and laboratories will stay in Research Triangle Park. The biggest change in personnel is that Watkins has joined Metabolons executive team as chief technology officer. In the short term, we do not anticipate any changes to the Lipomics site or personnel as a result of the acquisition, Lynch says. Longer-term, we expect significant growth at Lipomics as Lipomics expertise is integrated with Metabolons Metabolytics service offerings and diagnostic discovery efforts. Currently, our primary focus is to integrate the Lipomics technology with Metabolons global biochemical profiling platform in a way that provides more value to our customers. We believe the combined capabilities of these two technologies provides the most powerful solution to answer globalas well as more focused questionsrelated to smallmolecule research. The acquisition of Lipomics will have positive impact on our Metabolytics service business growth and enhance our efforts to discover and develop novel diagnostic tests that we believe will provide significant benefit to overall healthcare, Lynch adds. Metabolon CEO John Ryals predicts, In 2013, we will be marketing additional diagnostic products aimed at diseases related to obesity and cancer. The combined company will have www.SpecOpsComm.com

more than 140 employees and 450 clients, 2,000 completed commercial projects and 200 scientific papers either published or under review, Ryals adds. Last year alone, Metabolon completed more than 500 client studies and processed over 50,000 samples for customers, he notes.

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Genetic Engineering News August 1, 2012 Diagnostics Deal Weds Metabolon, Lipomics

http://www.genengnews.com/gen-news-highlights/diagnostics-deal-weds-metabolon-lipomics/81247126/

Metabolon said today it has completed its acquisition of Lipomics Technologies for an undisclosed amount. Lipomics founder Steven M. Watkins, Ph.D., will join Metabolons executive team as chief technology officer as part of the deal, which weds Lipomics TrueMass Profiling lipids technology platform with Metabolons metabolomics technology platform for commercial services and diagnostics. Metabolons lead diagnostic product, Quantose IR, is a metabolomics-based insulin resistance diagnostic test for type 2 diabetes. The test measures levels of three novel non-glycemic biomarkers and insulin, with the goal of detecting prediabetes earlier and with greater sensitivity than traditional glycemic markers such as glucose and Hemoglobin A1C. We expect that in 2013 we will be marketing additional diagnostic products aimed at diseases related to obesity and cancer, Metabolon CEO John Ryals, Ph.D., said in a statement. Metabolon will retain its headquarters and laboratories Research Triangle Park, as well as the laboratory facilities of Lipomics at what was its headquarters in Sacramento, CA. The combined company will have more than 140 employees and 450 clients, 2,000 completed commercial projects, and 200 scientific papers either published or under review. Last year alone, Metabolon completed more than 500 client studies and processed over 50,000 samples for customers. Financial terms of the transaction were not disclosed.

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Expanding Beyond Service Offering, Metabolon Adds Diagnostics to Business GenomeWeb.com Tony Fong May 25, 2011

http://www.genomeweb.com/dxpgx/expanding-beyond-service-offering-metabolon-adds-diagnosticsbusiness?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+genomeweb%2Fgenomeweb-dailynews+%28GenomeWeb+Daily+News%29

NEW YORK (GenomeWeb News) Having built up a profitable service business, metabolomics firm Metabolon has turned its attention to the diagnostics market, and in a few weeks, it anticipates the launch of its first test. Founded in 2000 and headquartered in Research Triangle Park, NC, Metabolon is one of a handful of firms in the metabolomics space, focusing on providing research services. Today, the company has a customer base of about 300, including all the major pharmaceutical and biotechnology firms, as well as nutrition and consumer product firms, and universities, according to its CEO. But in the process of partnering with its clients on studies, the company discovered that its technology "is a very powerful approach to identifying biomarkers, especially biomarkers of disease," President and CEO John Ryals told GenomeWeb Daily News last week. So, a few years ago, Metabolon decided to leverage its knowledge and experience gained from conducting those studies and start R&D work in "a couple of diseases." The first fruit of its efforts is a test for insulin resistance, called Quantose, to be launched in Metabolon's new CLIA laboratory at the end of June, Ryals said. Also in the pipeline are two tests for prostate cancer, and further in the future are tests for determining the aggressiveness of cancers and for assessing tolerance to chemotherapies, directed at bladder and kidney cancers. The initial chemotherapy diagnostic being developed targets the drug cisplatin. In developing metabolomics-based diagnostics, Metabolon is entering unmapped terrain. Metabolomics remains a nascent technology and Metabolon faces limited competition, with BG Medicine possibly it biggest challenger, while a young firm called Stemina is combining stem cell and metabolomics technology to develop biomarkers for disease detection and drug screening.

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Also, Phenomenome has metabolomic research directed at Alzheimer's disease and colon cancer, and Molecular Biometrics is doing metabolomic-based work in reproductive health, Parkinson's disease, and pulmonary health. Several drug manufacturers, such as Novartis, Roche, Abbott, Bayer, Bristol-Meyers Squibb, and Pfizer have metabolomics programs, as well. According to Ryals, one advantage of Metabolon's approach is that it allows "a very accurate assessment of the phenotype of what's happening." While genetic tests may be useful at evaluating a person's risk and predisposition for cancer, for example, "where we're very good is taking a cancer that's already there and figuring out a lot about it." Metabolomics has become a crucial technology for cancer-related research, he added. "The oncogenes and tumor suppressor genes and tumor enhancer genes [have] shown to affect metabolism," Ryals said. Even as the company prepares to put more resources into its diagnostics business, Metabolon has no intentions of moving away from its service business, which is doing "really very well," Ryals said, adding that in 2010, Metabolon posted about $14 million in revenues. However, he sees the possibility for rapid growth in its diagnostics business. It is not expected to generate significant revenue for 2011, and in 2012 it may post "a couple of million dollars," Ryals said. But in three to four years, it may be able to match Metabolon's service business in terms of revenues. "The diagnostics, once we launch it, we believe will be profitable pretty quickly," he said. Mulling Marketing Options Metabolon is "in a number of significant negotiations" with potential sales and marketing partners for its Quantose test, while it intends to sell its prostate cancer tests directly. The difference in its commercialization strategy is based on what Metabolon believes will be the infrastructure needed for its tests. In the case of Quantose, the company is looking to partner because it doesn't have a big enough sales and marketing operation, and it would be too costly to build one. According to Ryals, upwards of 1,000 marketing and sales representatives across the country would be needed in order to fully cover the 300,000 primary care physicians in the US, all of whom would be potential providers of the insulin-resistance test. He said that in the US about 30 percent of the total population is at risk for type 2 diabetes, and potentially, between 20 million and 30 million Quantose tests, which will be priced between $100 and $125, could be performed each year. The test is comprised of three analytes and will be initially launched as a mass spec-based test because it was developed on the platform, but in order to hit the potential target market of 30 million tests annually, "we're probably going to have to get off the mass spec," Ryals said. Meanwhile, Metabolon is targeting an end of the year launch of CLIA tests for its prostate cancer diagnostics, which is being co-developed with researchers at the University of Michigan.

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By selling those tests directly, Metabolon will move toward its vision as a "fully integrated company in the cancer space" and not merely a licensing firm for its technology, Ryals said. One of its prostate cancer assays is for detecting tumors in urine sediment. The target patient population is men who have had digital rectal exams that are negative for the disease, but whose PSA levels are between 4 and 10 nanograms/mL, a gray zone in which it is unclear whether a man has prostate cancer. "With our tests, looking at these urine specimens, we can improve that accuracy of that call greatly," Ryals said. "We still haven't locked down exactly how much we improve it, but it is a great deal of improvement on that group of patients." Currently, men with PSA levels in the gray area are monitored by their doctors and undergo testing every few months to see whether the levels rise or fall or whether a palpable mass can be detected by DRE. Metabolon's test would eliminate this "state of purgatory" by providing physicians an additional tool that allows them to make a better-informed decision about whether a patient needs a prostate biopsy, Ryals said. The second prostate test from the company targets those patients who have had a biopsy and received a Gleason score used to assess the prognosis of a patient's prostate cancer between 5 and 8, a "noman's land" in terms of how aggressive a physician should be in treating the disease. The test would be used to help guide clinicians in treatment decisions. Metabolon's tests are being developed not for the initial diagnosis of cancer, but rather to help physicians and patients make treatment decisions to manage the disease. "Many times a biopsy analysis is not very conclusive as to the course of treatment that the patient should have," Ryals said. "We have the ability to look at metabolism to make that much clearer." No decision has been made yet about pursuing clearance from the US Food and Drug Administration for its tests. On the Quantose test, Ryals said that that decision may depend on its marketing partner, but for broad distribution, the test would have to be available in a kit format, which would require FDA approval. Whether FDA is equipped to evaluate such a test is another matter. While the agency is relatively wellversed in gene-based tests, that may not be the case with diagnostics that are based on other more exotic 'omics technology. For example, FDA cleared the first proteomics in vitro diagnostic multivariate index assay, from Vermillion, less than two years ago. But metabolomics is a more niche technology than proteomics, and the FDA may have even less experience evaluating tests such as those being developed by Metabolon. Ryals said, however, that the company's tests are not metabolomics tests, per se. Though the technology was used to find the biomarkers, "in the end the test is essentially an analyte-driven test, and it's no different than testing cholesterol," which is a small-molecule metabolite, he said.

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Trends in Diabetes Care and Prevention NurseZone.com Debra Wood Nov 16, 2011 http://www.nursezone.com/printArticle.aspx?articleID=38390 While a cure for diabetes remains out of sight, nurses, scientists and others are making progress with prevention education and management options. There are many neat new things coming, said Virginia Valentine, CNS, BC-ADM, CDE, FAADE, CEO and co-owner of Diabetes Network, a health care practice in Albuquerque, N.M. Diabetes is a huge problem and is projected to have a four-fold increase in prevalence between now and 2050, from 26 million to 100 million people. Diabetes, unless we get a handle on it, could bankrupt any healthcare system. The fastest growing group of diabetic patients is 45 to 55 years of age, added Geralyn Spollett, MSN, ANP-CS, CDE, president-elect of health care and education at the American Diabetes Association, associate director of the Yale Diabetes Center and an associate clinical professor of nursing at Yale University in New Haven, Conn. Diabetes is a chronic disease where nurses can make a difference, Spollett said. No matter their specialty, practicing nurses work with diabetic patients. About one-third of patients admitted to Unity Hospital in Rochester, N.Y., have diabetes, and readmissions occur more often in patients with diabetes than those who do not, said Jean Bauch, director of Unity Health Systems Diabetes Center. These patients are everywhere, and they impact the health system, Bauch said. They are patients you want to keep healthy and keep out of the hospital and prevent complications. Its a life-changing disease for the patient and an expensive disease for the health system. Prevention Studies show weight loss and exercise can help prevent diabetes. Unity Health is training nurse care managers in its primary care offices to conduct a 26-week prevention program for patients. The Diabetes Prevention and Control Alliance, a collaboration among the Centers for Disease Control and Prevention, the YMCA and UnitedHealth Group, aims to help people at risk for diabetes prevent the disease through healthy eating, increased activity, and other lifestyle changes. The goal is for participants to lose 5 percent to 7 percent of their body weight, said Jeannine Rivet, executive vice president of UnitedHealth Group. Its a great program, Spollett said. Nurses should be able to look at their patients at high risk for diabetes and recommend they get in touch with these programs. It will be affordable and will have longterm follow up. The American Diabetes Association also has launched educational campaigns to inform people about their risks and to assist primary care providers with patient education.

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Another interesting advancement is the Type 1 Diabetes TrialNet, an international network of researchers funded by the American Diabetes Association, the National Institutes of Health and the Juvenile Diabetes Research Foundation. The investigators are conducting clinical trials with relatives of patients with diabetes, assessing risk factors and genetic screenings. If we can predict who will develop Type 1 diabetes, there are different medications being trialed to reduce the risk and the antigen-antibody formation, which we see in patients with Type 1 diabetes, Spollett said. Metabolon of Research Park, N.C., is developing a system of tests that use chemical biomarkers to identify a patients susceptibility to insulin resistance to help doctors predict the risk of a patient progressing to Type 2 diabetes. Managing the disease The disease is best managed when it is self-managed, Valentine said. And that requires comprehensive patient education about maintaining a healthy weight, diet and exercise. Jane Giambrone, RN, CDE, a nurse educator at the Diabetes Center at Unity Health, reported that diabetes is 97 percent self-managed. She encourages nurses to learn as much as they can about the disease and its treatment. What nurses can do is be good listeners, said Jiambrone, adding that by finding out what motivates the patient, the nurse can tailor the message accordingly. Angel Anthamatten, DNP, APN, ADM, FNP-BC, assistant professor in the family nurse practitioner program at Vanderbilt University School of Nursing in Nashville, Tenn., said lifestyle modification is the most effective but one of the hardest things in the fight against diabetes. Nurses need to help patients figure out how to modify their lifestyle, said Anthamatten. Technology advances New technologies are helping with diabetes management. Unity Health has found the electronic medical record in primary care practices helpful in monitoring diabetic patients. The registry shows how each practice is doing toward meeting the standards of care set by the American Diabetes Association and then addresses gaps in care. Care managers will contact patients to help trouble shoot why gaps exist, Bauch said. Bauch indicated other technologies are assisting patients in managing diabetes. Unity downloads information from patients blood glucose meters when they come for an appointment. iPad and iPhone apps can help patients track their glucose levels, food intake and activity. Unity has created an online community to engage patients in their care and chat with each other or experts, as has the American Diabetes Association. Bauch also reported improved management with the increased use of insulin pumps and continuous glucose sensing. With continuous glucose monitoring, a sensor inserted under the skin checks glucose levels in tissue fluid and sends a signal to a monitor, which will alert the patient to trends and high and low blood sugars. Pharmaceuticals Valentine reports an increase in the use of incretin mimetics, such as the glucagon-like peptide-1 agonists exenatide (Byetta) and liraglutide (Victoza). She expects a once-a-week version of Byetta will be available in February. They are the future of diabetes care, Valentine said. They not only lower blood glucose and help you lose weight, they also protect the cardiovascular system and preserve beta cells. Anthamatten reported nearly 200 diabetes drugs are in the pipeline, some in the same classes and some new classes, with most for Type 2 diabetes. Pharmaceutical companies are working on developing drugs in a new class called odium glucose cotransporter-2 (SGLT2) inhibitors, which would work in the kidney to increase excretion of glucose in the urine, Valentine reported.

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Spollett reported that the multicenter Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study will investigate the best treatments for specific patients with Type 2 diabetes. With the explosion in the number of oral meds that we have, its important that we understand which ones will work with which patients, Spollett said. Managing complications Once someone is diagnosed with diabetes, the clock starts ticking toward complications, Bauch said. Researchers also are investigating ways to manage complications. Ian de Boer, M.D., an assistant professor of medicine at the University of Washington in Seattle, reported at the American Society of Nephrology Kidney Week in November 2011 that maintaining good glucose control early in the course of Type 1 diabetes could lessen long-term risk of kidney disease, as measured by glomerular filtration rate (GFR). A low GFR also can contribute to heart and blood vessel complications of diabetes, he said in a written statement, adding that once GFR is impaired, progression to end-stage kidney disease and major blood vessel disease precipitating heart attacks or stroke occurs at unacceptably high rates, even with optimal medical management. Derma Sciences, Princeton, N.J., has developed DSC127 gel, a topical angiotensin analog shown to trigger the body into utilizing its mesenchymal stem cells, found in bone marrow, to heal chronic wounds. A recent study found that diabetic foot ulcers were five times more likely to heal at 24 weeks when using the gel as compared with a placebo, with no drug-related adverse effects. Anthamatten encourages nurses to monitor patients screenings for complications, including vision and foot exams, lipid monitoring and other therapies, several times per year. Diabetes templates or flow sheets can be helpful for tracking this information. Nurses can facilitate quality health visits by helping with proactive and routine assessment of diabetes records to verify that patients are up to date on recommended screenings and other diabetes essentials, she said. Nurses can help by proactively assessing what has been done and needs to be done.

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Metabolomic profiling could benefit personalized med efforts R&D Directions Insider Michael Christel September 12, 2011 http://blog.rddirections.com/index.php/2011/09/12/metabolomic-profiling-could-benefit-personalized-medefforts/ The most extensive and comprehensive genome wide associating study ever conducted was recently published in Nature. The study found clear links between human genetic markers and diseases such as cancer, diabetes, cardiovascular and kidney disorders, gout, venous thromboembolism, and Crohns disease. The topic of personalized medicine via chemical biomarkers, or metabolomics, is an emerging one at the moment, and these new results could offer valuable insight for development of individualized therapies for people who may be at risk for serious disease. In the study, researchers at the Helmholtz Zentrum Munchen Institute, Kings College, and Metabolon Inc., a biochemical profiling and diagnostic company, used metabolomic profiling on patient blood samples to identify 37 markers for genome associated diseases, with 23 of those markers describing new genetic associations with metabolic traits. These individual biomarkers, researchers say, could be identified with a simple blood test during a routine doctors visit, and could determine a patients susceptibility to certain diseases, giving their physician a blueprint for a personalized disease treatment program. We caught up with Mike Milburn, Ph.D., Metabolon chief scientific officer, to talk more about the study and its implications for drug development. Metabolons biomarker discovery platform has been used to identify markers for a number of diseases. These markers are being incorporated into clinical diagnostic tests in such areas as prostate cancer, bladder cancer, kidney cancer, nephrotoxicity of chemotherapy drugs, and diabetes/insulin resistance. The company is based in Research Triangle Park, N.C. R&D Directions: What key insights do the new marker discoveries provide for personalized medicine efforts in diseases such as cancer, diabetes, and cardiovascular disease, among others? Dr. Milburn: Once you understand the implications of this study, you realize that it could have very profound significance for personalized medicine. We established in this paper that each individual has his or her own metabotype that is driven by their genetics. In other words, many biochemical levels are significantly influenced by genetics, which is counter to the way a lot of people think about biochemistry.

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Most people think that biochemicals go up and down with diet, environment, time of day. This study clearly demonstrates that ones genetics is strongly penetrant to your blood biochemical levels. The concept, however, is really not new. Archibald Garrod, who first developed the concept of inborn errors of metabolism, had also postulated that the metabolic individuality, which he termed chemical individuality, gives us predisposition or protection for disease. Only now can we measure that chemical individuality with our metabolomics technology and see if it is true. We are now starting to see pharmaceutical companies interested in profiling subjects from clinical studies to see if they can be segregated into different populations that have strong drug efficacy or unwanted side effects. Our technology could very well become a routine method of discovering companion diagnostics for individualized medicine. R&D Directions: How was this particular genome wide association study able to overcome many of the traditional limitations associated with these kinds of studies? Dr. Milburn: Probably the best answer to this question from a technology standpoint is the quality control measures we have in place with Metabolons technology to ensure that samples run with the least amount of variance for all the biochemicals we measure. Thirty-five percent of the samples we run each day are quality control samples (process blanks, process control, and technical replicates) that allow us to maintain a very tight measurement for all the biochemicals, even when we measure thousands of samples in one experiment. We also have over a dozen QC scientists that check each experimental data set to ensure the quality of the final data set. We published the variation per biochemical in the supplemental text of this Nature paper. Maintaining this low variability obviously helped with getting such strong associations. We also think that measuring biochemicals is closer to the primary effect of the gene and thus the associations are stronger. R&D Directions: Can you explain the science behind metabolomics and why you think it will change the face of medicine? Dr. Milburn: Metabolomics is profiling biochemicals, and for many reasons its a much more practical technology for solving many biological problems and for identifying highly relevant biomarkers. Genomics and proteomics are much more complicated in many respects than biochemicals and are farther removed from reflecting the current biological state. The difficulty with metabolomics is that the underlying technology is not easily developed. We are many years ahead of anyone else with our technology. Many academics with mass specs or [nuclear magnetic resonance spectroscopy] are trying to do this, but they really dont compare to the breadth of our biochemical coverage, speed, quality control, or ability to understand the biochemical data. We also own many pioneering issued patents in the field of metabolomics for biomarker discovery that people are just now becoming aware of. R&D Directions: What is the potential economic impact of stalling and preventing disease progression? Dr. Milburn: Take our fasting blood test for insulin resistance that we recently published. Many of these metabolites are relatively new blood metabolites with very little literature associated with them. However, they can accurately assess how insulin resistant you are long before you have any glucose impairment.

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In fact, we found that glucose itself is very far down on the list of metabolites when you really isolate insulin resistance. However, IR is the earliest predictor of potentially developing diabetes, and we believe the costs of managing diabetes is much more expensive than the costs of making someone aware that they are insulin resistant and have an opportunity to intervene earlier. R&D Directions: Are pharmaceutical and biotechnology companies showing increased interest in incorporating metabolomics into their drug-development programs? Dr. Milburn: We run a business to provide the technology on a fee-for service basis. We have doubled the number of studies we do in this business every year since 2005. We completed 320 client studies in 2010, processing over 30,000 samples. That is about what we have done so far in the first half of 2011. Today, we can completely fund our company off this business and we are over 100 employees. The clinical applications of this technology, as this paper suggests, is staggering and could take the technology to a whole new level of routine applications.

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Raleigh News & Observer August 2, 2012 Metabolon Completes Acquisition of California-based Lipomics By Mary Cornatzer http://blogs.newsobserver.com/business/metabolon-completes-acquisition-of-california-basedlipomics Durham-based Metabolon has competed it acquisition of the California-based Lipomics Technology. Lipomics' expertise is in analyzing lipids the fatty molecules in the body and the role they play in metabolic and cardiovascular diseases. Metabolon tests medicines and other products for pharmaceutical companies, universities and other customers. It also has developed a diagnostic test to detect insulin resistance, which can lead to type 2 diabetes. The acquisition will ead to further opportunities for personalized medicine and commercial services, Metabolon CEO John Ryals said in a statement. "We expect that in 2013 we will be marketing additional diagnostic products aimed at diseases related to obesity and cancer, and are committed to maintaining our position as the world's leader in metabolomics," Ryals said. Financial terms of the deal were not disclosed. Lipomics lab facilities, which employ 13 people, will remain at its headquarters in Sacramento, Calif. Lipomics founder Steven M. Watkins will join Metabolon's executive team as chief technology officer based in Sacramento. The combined companies will employ 140 people.

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Biotech Company adds jobs for new business The News & Observer David Ranii 5.13.11

http://www.newsobserver.com/2011/05/13/1194123/biotech-company-adds-jobs-for.html

Life sciences technology company Metabolon has more than doubled its workforce in the past 24 months and expects to double it again during the next two years as it diversifies its business. John Ryals, CEO of the privately held Durham company, sees its coming diagnostics business as having even greater potential than its existing analytics services business. Metabolon's analytics work for drug and consumer product companies and universities generated $14 million in revenue last year, double the 2009 total. "This year we're probably looking at $20 million," said Ryals, who previously co-founded and led publicly traded Paradigm Genetics. Founded in 2000, Metabolon has about 100 workers, up from 45 in May 2009. About 85 of Metabolon's workers today are based in Durham; 37 have doctorates "They have flown under the radar," said Carol Marino, vice president and head of U.S. investing at Syngenta Ventures, the venture capital arm of agribusiness giant Syngenta, which is an investor in Metabolon. "They haven't done enough PR on their own. They're a terrific company." Metabolon, which has raised $32 million in funding to date, was founded in 2000 but existed mostly on paper until Ryals was recruited as president and CEO in April 2002. Ryals joined the business a few months after he was fired for undisclosed reasons as CEO at Paradigm; he had refused to resign. Although Paradigm was struggling at the time he left, under Ryals the company raised more than $100 million in financing - including an initial public offering of common stock - and had 280 workers at its peak. Metabolon's patented analytics technology finds biomarkers, or biochemicals, that point to a disease's existence or severity. It performs these analyses for a host of drug companies, including Merck, Pfizer and GlaxoSmithKline, that want, for example, to understand how a medication works or pinpoint problems in manufacturing biotechnology drugs. It also works for consumer product companies such as Colgate-Palmolive. www.SpecOpsComm.com

"We've done many studies on (Colgate) Total toothpaste, because they're trying to prove that Total actually affects gingivitis and periodontitis," Ryals said. "We've published now three papers in the Journal of Dental Research on this where we can show ... a very dramatic effect." A new insulin test The company's technology also can be used for diagnostic products. Its first, Quantose, which is expected to be ready to launch shortly, is aimed at detecting insulin resistance. That can lead to Type 2 diabetes, cardiovascular disease and hypertension. "It's a very huge market," Ryals said. "About 30 percent of all the people in the developed world are at risk for insulin resistance." Currently, the prevailing test for insulin resistance is an oral glucose tolerance test, which involves imbibing a glucose drink and sitting in a doctor's office for two hours or more while your blood is drawn at regular intervals. Neither patients nor doctors like it, Ryals said, and many general practitioners don't use it. Quantose, by contrast, involves taking a single blood sample and no glucose drink is necessary. Quantose is a test that would be administered by primary care physicians, which is why Metabolon is seeking a marketing partner. "There are 250,000 GPs in the U.S. It takes a very large sales force to reach them," Ryals said. "We're talking to a lot of major lab testing companies and diagnostic companies." Next on the agenda are two diagnostics for prostate cancer that the company hopes to introduce next year, including a detection test that could help avoid unnecessary biopsies. About 70 percent of all biopsies for prostate cancer turn out to be negative, Ryals said. Since the cancer diagnostics would be marketed to a much smaller group of doctors - urologists and urooncologists - Metabolon plans to market those on its own. Raising capital It's an ambitious agenda that requires major funding. Ryals envisions raising about $10 million in additional capital this year and a significantly larger amount next year to hire a sales force and start its cancer diagnostics business.

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Given the company's record, Ryals and the company's investors, which include Aurora Funds of Durham, don't anticipate difficulty raising $10 million this year. Next year's much larger target, however, is a question mark because of the difficult funding environment. An initial public offering of common stock would fit the bill, but who knows what shape the IPO market will be in a year from now? The good news, said Jeff Clark of Aurora Funds, is that Metabolon can afford to be patient because its analytics business is already approaching break-even. He is optimistic that the company could use its own cash to get its diagnostic cancer products off the ground if necessary. david.ranii@newsobserver.com or 919-829-4877

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The Sacramento Bee August 1, 2012 N.C. Firm Acquires West Sacramentos Lipomics Technologies By Mark Glover

A North Carolina-based diagnostic services and products company says it has completed its acquisition of Lipomics Technologies Inc. in West Sacramento. Lipomics studies how disease, nutrition and other factors influence a person's metabolism and biology. Metabolon Inc., headquartered in Durham, N.C., said Lipomics' laboratory facilities on Industrial Boulevard will remain in place, and Lipomics founder Steven Watkins will join Metabolon's executive team as chief technology officer. Financial terms of the transaction were not disclosed. John Ryals, Metabolon's CEO, said the combined companies have more than 140 employees and 450 clients.

http://www.sacbee.com/2012/08/01/4682635/nc-firm-acquires-west-sacramentos.html

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Analysis: Cover Story - Markers Marking diabetes Science Business Exchange (SciBX) Joanne Kotz

http://www.nature.com/scibx/journal/v4/n16/full/scibx.2011.444.html

Kotz, J. SciBX 4(16); doi:10.1038/scibx.2011.444 Published online April 21 2011

A Massachusetts team has identified amino acid1 and triacylglyceride2 signatures that can predict increased risk of developing type 2 diabetes. The researchers now plan to look at whether the signatures can distinguish which prediabetic patients will benefit from lifestyle changes or therapeutic intervention. The key unknown is whether a cutoff value for the signatures can be identified that will prospectively predict an individual's risk or response to treatment. We know that the current tools for diagnosing diabetesglucose and HbA1care not particularly good at predicting diabetes, said Steven Watkins, CSO of Tethys Bioscience Inc. This is because changes in the blood levels of these markers tend to occur late in the disease process. Tethys markets PreDx DRS, an assay that predicts an individual's risk of developing diabetes. The test is conducted in a CLIA-certified laboratory and incorporates seven circulating biomarkers including glucose and hemoglobin A1c (HbA1c). In a search for other early markers of type 2 diabetes, a team led by researchers from Massachusetts General Hospital and the Broad Institute of MIT and Harvard conducted two studies. One looked at levels of metabolites, and the other looked at levels of lipids in the blood of 378 participants in the Framingham Offspring Study. For a person off the street, what would be a cutoff level that constitutes a danger sign? www.SpecOpsComm.com

Christopher Newgard Duke University School of Medicine At the time of an examination conducted from 19911995, none of the participants had diabetes but all were judged to be at high risk for the disease. Out of this cohort, only half went on to develop diabetes over the next 12 years. The Massachusetts team set out to identify the markers that could help better predict who would go on to develop the disease. In serum samples from the 19911995 examinations, the team used mass spectrometry to identify metabolites or lipids that were present in different concentrations in the blood of people who went on to develop diabetes compared with in the blood of those who did not. In the first study, three amino acidsisoleucine, tyrosine and phenylalaninewere present at higher levels in the serum of people who later developed diabetes. In the study analyzing lipid levels, triacylglycerides (TAGs) with shorter chain length and fewer double bonds were present at higher levels in the blood of people who later developed diabetes than TAGs with longer chain length or more double bonds. After controlling for age, sex, BMI and fasting glucose, the top quartile of patients with the highest amino acid signature had a sixfold greater risk of developing diabetes than those having a signature in the bottom quartile. Similarly, top-quartile TAG signature patients had a 4.3-fold higher risk of becoming diabetic than bottom-quartile TAG signature patients. Results from the metabolite study were published in Nature Medicine, and results from the lipid study were published in The Journal of Clinical Investigation. A relationship between branched-chain amino acids or triacylglyceride composition and diabetic processes has been known for a while, but this is the first large-scale clinical validation of the observation, said Watkins. Top of page Risk prediction

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The predictive power of these signatures for diabetes risk is real but relatively modest, said Watkins. Thus, he thinks the markers likely will need to be combined with other measures to provide clinically useful predictive power. These papers report intriguing markers, said Michael Milburn, CSO of Metabolon Inc. Determining how practical they are is really the next step. Metabolon is developing a test for insulin resistance that measures three metabolites and can be used to predict the risk of developing diabetes and other diseases. Milburn said the company hopes to launch the test around year end. Because the current studies normalized for glucose levels, they did not directly test how these signatures compared to the predictive power of glucose levels, noted Milburn. Thus, he said it will be important to conduct additional studies to see how these signatures perform compared with current clinical standards such as glucose measurements. In addition, Milburn thinks there will be challenges in moving from looking at a whole population to demonstrating clinical utility for a particular individual. This is a key question to be addressed, agreed Christopher Newgard, professor of pharmacology and cancer biology and director of the Sarah W. Stedman Nutrition and Metabolism Center at the Duke University School of Medicine. For a person off the street, what would be a cutoff level that constitutes a danger sign? he asked. Robert Gerszten and Thomas Wang, who co-led both studies, said the Massachusetts team now plans to run additional studies in larger, heterogeneous populations to examine how their findings can be generalized to individuals with a variety of backgrounds, for instance, different ethnicities and age groups. Gerszten is director of the clinical and translational research program at the MGH heart center, associate professor of medicine at Harvard Medical School and a senior associate at the Broad Institute. Wang is associate director of the heart failure and transplantation program at MGH and associate professor of medicine at Harvard Medical School.

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Another angle being pursued by the team is to determine whether the amino acid and TAG signatures are independent of one another and whether they could be combined to predict diabetes risk more accurately. The early look is that the signatures are not highly correlated, so they may well add information to each other, but this still needs to be proven formally, said Gerszten. These papers report intriguing markers. Determining how practical they are is really the next step. Michael Milburn Metabolon Inc. Top of page Therapy guide Markers that more accurately predict the risk of an individual developing diabetes would clearly be useful clinical tools, but the real home run would be markers that can guide the individual treatment of prediabetic patients. Prediabetes encompasses multiple different metabolic dysfunctions, including insulin resistance, cell dysfunction and dyslipidemia. These different conditions are poorly differentiated with current tests, said Milburn, and an important future direction is identifying markers for each of these distinct conditions that can help predict response to different types of treatments. There are some hints that the amino acid signature may be up to that task. Newgard cited a 2010 study that looked mechanistically at the insulin-sensitizing action of thiazolidinediones.3 In obese, insulin-resistant rats, the extent of tissue-specific transcriptional changes in the branched-chain amino acid pathway correlated with efficacy of four thiazolidinediones, including Avandia rosiglitazone from GlaxoSmithKline plc and Actos pioglitazone from Takeda Pharmaceutical Co. Ltd. Where we now need to go is to overlay pharmacotherapies that are available today on top of our understanding of the predictive nature of these amino acid signatures, said Newgard. Watkins agreed that a next step will be determining whether interventions that change the marker concentrations lead to positive outcomes in individual patients.

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Indeed, Gerszten said the Massachusetts team is planning to look at whether the amino acid or TAG signature can predict response to intervention. The team plans to look at drug and lifestyle intervention studies for prediabetics to see if either signature correlates with response. Gerszten told SciBX that the team would be interested in partnering with pharma to identify patient subsets that are most at risk for disease and/or most likely to derive benefit from therapeutic interventions. Patent applications have been filed covering both diagnostic and therapeutic applications for the results reported in both papers and are available for licensing, said Gerszten. Top of page References 1. Wang, T.J. et al. Nat. Med.; published online March 20, 2011; doi:10.1038/nm.2307 | Article | Contact: Robert E. Gerszten, Massachusetts General Hospital and Harvard Medical School, Charlestown, Mass. e-mail: rgerszten@partners.org Contact: Thomas J. Wang, same affiliation as above e-mail: tjwang@partners.org 2. Rhee, E.P. et al. J. Clin. Invest.; published online March 14, 2011; doi:10.1172/JCI44442 | Article | Contact: Robert E. Gerszten, Massachusetts General Hospital and Harvard Medical School, Charlestown, Mass. e-mail: rgerszten@partners.org Contact: Thomas J. Wang, same affiliation as above e-mail: tjwang@partners.org Contact: Clary Clish, Broad Institute of MIT and Harvard, Cambridge, Mass. e-mail: clary@broadinstitute.org 3. Hsiao, G. et al. Am. J. Physiol. Endocrinol. Metab. 300, E164E174 (2011) | Article | PubMed | ISI |

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Triangle Business Journal August 1, 2012 Metabolon Buys California Company By Lauren K. Ohnesorge http://www.bizjournals.com/triangle/news/2012/08/01/metabolon-buys-california-company.html Research Triangle Park-based genetic research company Metabolon Inc. has acquired a Sacramento, Calif.-based company called Lipomics Technologies, Inc. Financial details were not disclosed. Lipomics will keep its laboratory facilities at its California headquarters while Metabolons headquarters and laboratories will remain in RTP. Lipomics will combine its lipid profiling technology with Metabolon technology. By combining our two companies, we have more than 140 employees and 450 clients, have completed 2,000 commercial projects and have 200 scientific papers either published or under review, Metabolon CEO John Ryals said in a news release. Lipomics founder, Steven Watkins, will join Metabolon as chief technology officer.

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