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In late 2007, Isis Pharmacueticals (ISIS) and Alnylam Pharmaceuticals (ALNY) created a joint venture, operated as an independent company, called Regulus Therapeutics. The mission of Regulus is "to discover, develop, and commercialize micro RNA therapeutics".

As a pioneer in RNA antisense technology, ISIS has a large pool of intellectual property dealing with RNA manipulation (over 1,600 patents worth). As a pioneer and exclusive lisencee to the "Tuschl III" patent, which describes the most important microRNAs in animals and lays the foundation for the discovery and development of a new class of therapeutics, it is match made in heaven. Indeed, Regulus in showing to be a powerhouse in the field, signing a partnership with Glaxo (GSK) worth up to $600 million.

However, there is a much smaller company that may be giving Regulus some pause: Rosetta Genomics (ROSG) is the other leading developer of microRNA-based molecular diagnostics. Rosetta has discovered hundreds of biologically validated novel human microRNAs that have a wide variety of potential medical uses.

Rosetta Genomics has filed more than 35 patent applications in the U.S. and more than 36 patent applications worldwide to protect each aspect of its commercial diagnostic products. Many of these applications protect the specific microRNAs used in the company’s products. In addition, the company is pursuing more than 50 patent applications to protect methods of detecting microRNAs and methods of diagnosing and treating diseases with microRNAs.

“Rosetta Genomics owns or has access to intellectual property related to microRNAs that is among the broadest of any commercial entity, and these two notices of allowance further solidify our position,” said Kenneth A. Berlin, president and chief executive officer. “Our patent applications and issued patents cover approximately 51% of publicly registered microRNAs, plus 168 non-public, newly discovered microRNAs. microRNAs are at the forefront of an exciting revolution in personalized medicine and we believe that Rosetta is leading the way in diagnostic uses as we harness this knowledge to advance our deep pipeline of products.”

The company’s first three microRNA-based tests, miRview™ squamous, miRview™ mets, and miRview™ meso, are commercially available through its Philadelphia-based CLIA-certified lab. Rosetta Genomics is the 2008 winner of Wall Street Journal’s Technology Innovation Awards in the medical/biotech category. With all this in mind it may not be a big surprise that Rosetta has earned very bullish recommendations by analysts.

But what the average investor may not grasp is that Rosetta is a leader in a brand new field of diagnostic, preventative, and practical medicine that relies on understanding and utilizing the biology of microRNAs. This field is just now being incorporated into pharmaceutical drug development, and the next generation of drugs will definitely be centered around the use of microRNAs as diagnostics of therapies.

MicroRNAs were only discovered less than 10 years ago and only recently have scientist begin to understand how they relate to diseases. Previous to the discovery of miRNAs, biologists focused on genes affecting disease: A mutation in gene or amplification of a gene and the functional product of the gene would cause disease. This has been the emphasis of scientific studies since the completion of the Human Genome Project which gave us the entire sequence of our DNA. But scientists remained perplexed about all the “junk”, or non-coding DNA and what its role was. Now scientists understand that some of this “junk” DNA is actually full of functional DNA that may in fact be more important than the genes themselves.

Normally the activity of a gene is controlled by another gene or a combination of a couple genes; but once activated that single gene only makes one gene product. Indeed, that one gene product may be the cause of a disease, but in most cases a disease is influenced by ten or twenty genes working together. Currently, pharmaceutical companies design drugs that target only a single gene product, and thus the drug only has a limited effect.

However, it has been discovered that a single type of microRNA can influence dozens of genes! MicroRNAs accomplish this by binding to the gene message (RNA) of multiple genes and causing them to be degraded. Thus, a single miRNA essentially “reprograms” the entire cell by influencing entire networks of genes. MicroRNAs are so potent, that a single miRNA can turn a less harmful benign cell into a aggressive and metastatic cancer cell, or vice-versa. Thus, understanding and utilizing miRNAs to treat disease in essence offers the power of dozens of drugs targeting specific gene targets.

As well, because of the power of these miRNAs, detecting their presence of absence can be used to diagnose disease in the absence of any clinical method of detection. For example, miRNA can be found in people’s blood, and the presence of a certain type of miRNA using a blood test can signal the presence of disease not clinically detectable. As well, the miRNA can tell the clinician how far the disease has progressed and this information can be used to decide the course of therapy. This method is so sensitive that only a single cell is needed to detect miRNAs. As well, archived tissue even 10 years old can be analyzed, not requiring an immediate analysis. This provides flexibility and high value practicality for simple incorporation into established medical practices.

MicroRNA profiling is clearly the backbone of personalized medicine, where drugs are matched to an individual’s genetic profile. Using the miRNA as a biomarker, patients will be pre-selected for a treatment with particular drug related to the function of the miRNA. This requires the development of a companion diagnostic to select for the suitable patients, which in three cases Rosetta has already developed. These are a series of microRNA-based diagnostic products offered by Rosetta Genomics called miRview™.

miRview™ mets accurately identifies the primary tumor site in metastatic cancer and Cancer of Unknown Primary (CUP). It is estimated that more than 70,000 patients in the US are diagnosed with CUP, and many of those are diagnosed through metastatic disease for which there is no known primary tumor. Knowing the source of the metastases is critical for determining the course of treatment, and batteries of tests are often run which yield no answers. This test relies on an expression pattern of 48 miRNAs to determin the tissue of origin of 25 different classes of cancer from 17 different tissues. In a recent peer reviewed article, Rosetta demonstrated it was able to determine the tumor of origin 90% of the time from a set of 200 tumor samples, 100 of which were from metastases, using this test. This is a breakthrough in CUP diagnosis, and is sure to become the standard for CUP.

miRview™ squamous accurately identifies the squamous subtype of NSCLC, which carries an increased risk of severe or fatal internal bleeding and poor response to treatment for certain therapies. In a recent peer reviewed journal, Rosetta demonstrated the value of this test using fine needle aspirates (FNA) of non-small cell (NSCLC) lung tumors to classify the cancer into squamous or non-squamous with 95% accuracy.

This is significant, as approximately 1/3 of these patients have non-squamous disease, which carries the increased risk of severe bleeding with the standard of care Avastin regimin. As well, other approved therapies such as Tarceva should be used in this population and Alimta is indicated only for this population. It is estimated that 30%-40% of cases are treated even though they are unclassified or were misclassified. Clearly, patients will benefit as a result of better therapy by incorporating Rosetta's test prior to treatment.

miRview™ meso diagnoses mesothelioma, a cancer connected to asbestos exposure. This test is to provide objective diagnostic data to diagnose and administer the appropriate treatment to the patient. Because this and the other tests work using archived formalin fixed, parrafin embedded (FFPE) tumor samples. There may be a lot of litigation value for this test: Even if a lung cancer patient has already succumbed to mesothelioma cancer, his/her family might still be entitled to compensation from already established settlement funds if the cause of death was found to be mesothelioma and occupationally related. It is estimated that between 1940 and 1979, approximately 27.5 million people were occupationally exposed to asbestos in the United States. Correspondingly, between 1973 and 1984, there has been a threefold increase in the diagnosis of pleural mesothelioma in Caucasian males. Apart from any litigal value, there is clear medical need for accurate diagnosis for this disease as it continues to manifest in aging populations.

In addition, to these test, Rosetta is developing tests which demonstrate how the association of a particular miRNA with a disease directly tells us what genes influence a disease. For example, miR-527 has recently been shown by Rosetta to be a predictor of progesterone receptor status in breast cancer. As well Rosetta has shown that miR-491 is involved in colorectal cancer and liver necrosis, and miR-135b is highly expressed in colon cancer specimens relative to normal colon tissues. Drugs can be developed around the gene targets of these miRNAs to treat disease.

With pharmaceutical companies focusing on molecular targeted therapies (MTTs) and antibody therapies which have one specific target, the need to identify cancer patients which have the target and classify patients predicted to respond to the targeted therapy, there is an absolute need for a companion diagnostic to identify and treat those specific patients. Indeed, this is the clear future of Rosetta.

In partnership with Rosetta, companies will create new medicines to meet the targets of miRNAs identified by Rosetta. As well, Rosetta will provide the companion diagnostic to select patients for treatment. The drugs and companion diagnostics will be combined to treat the patients with the genetic markers which predispose a patient to a disease and also to respond to a particular drug

This powerful combination of diagnostic/patient selection/targeted therapy will result in high success for the treatment. Rosetta is on track with these types of developments: In their most recent conference call, Rosetta stated that it is considering developing their own sales force for launch in 2011. In addition, they have stated that they are considering developing tests "one other non-oncology disease". Finally, they stated that they will "announce one new collaboration by the end of the year".

Even though the science is complicated, you don’t need to be a medical professional to see the potential in Rosetta’s product for helping the treatment of diseases. As an investor you can see direct application of Rosetta’s products in medical diagnosis and treatment, and how pharmaceutical companies will incorporate Rosetta into the development of their drugs.

In the future, we expect to hear news about lucrative partnerships between Rosetta and large pharmaceutical companies. Rosetta has stated that it is seeking partnerships with companies who are developing therapies based on miRNAs, and is seeking to develop companion diagnostics for differential diagnosis. Rosettas current and future products may be used in early detection and monitoring for specific diseases. These goals allow Rosetta to tap into the rapidly expanding $700 million companion diagnostic market.

Currently ROSG is at a tremendous bargain price for biotech investors. Its initial IPO price in 2007 was $7, with analysts setting a one year price target of $11 to $15. Since then, ROSG has spent much of its IPO funds but has performed well, generating the 50+ patents, 3 diagnostic tests, and capturing 50% of the current intellectual property (IP) surrounding commercial use of microRNA’s (the other major player in this field is ISIS and Alnylam Pharmaceuticals, who have captured most of the remaining IP space). With a tiny market cap of less than $20 million compared to the combined $1.5 billion market cap for ISIS and ALNY, it seems probable that they may acquire ROSG for their intellectual property. Even at a substantial premium, this would be a bargain.

ROSG recently raised $5 million in February at a share price of about $2.25. With about $8 million in cash, no debt, and a strong IP franchise, ROSG is currently trading at its calculated book value of $2.25. Recent price targets for ROSG include $3 from Cantor Fitzgerald and $5 from Rodman and Renshaw.

However, these price targets are based on the solo development of Rosetta’s business plan and don’t reflect the strong possibility of a lucrative partnership for drug development or companion diagnostic using their microRNA platform in the marketing of the next generation of drugs.

Perhaps ROSG is so undervalued because the average investor has a hard time understanding the complicated science behind its products. However, the investor who does understand this science is quite bullish on ROSG. Given its small market capitalization and the incredible practical value in its pipeline, Rosetta is potentially an acquisition target at a substantial premium. The sound science and changing strategies in pharmaceutical drug development give Rosetta a yet unrecognized value way beyond its current share price, and this is clearly what has made the analysts bullish about ROSG.

Disclosure: Author hold a long position in ROSG

Source: Rosetta Genomics: Giving Isis and Alnylam a Run for Their miRNAs?