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Two are better than one
October 2010
by David Hutton  |  Email the author
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  Nature
  FDA

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The age-old saying is that two heads are better than one, and it is proving to be true in drug research and development.

In an evolving landscape, advancements in technology, an improved understanding of disease pathophysiology and the emergence of personalized medicine are putting new demands on drug development. The old paradigm of one blockbuster drug for everyone is quickly becoming a distant memory.
 
Developing targeted therapies and companion diagnostics is all about discovering and validating clinical biomarkers. PCR, microarrays and expression profiling are being used to improve the sensitivity and selectivity of companion diagnostics.
 
"The use of molecular diagnostics for detecting variations such as mutations or amplifications of specific genes, in order to target therapies to patients who are most likely to benefit, is becoming increasingly common in anticancer drug development," Jocelyn August, a senior analyst at San Diego, Calif.-based Sagient Research Systems, says in a recent issue in the journal Nature.
 
Indeed, companion diagnostics will play an increasing role in cancer care. Pharmaceutical companies developing targeted therapies for cancer must consider the potential benefits of developing a companion diagnostic. As they join the rush to identify critical biomarkers, however, they also need to consider technology options, potential diagnostics partners and regulatory hurdles. In this, the third installment of our Trends in Cancer Research series, we examine one company's efforts to build its diagnostics capability and another company's continued efforts in the area.
 
Eli Lilly & Co. 
Tiffany Olson, vice president of diagnostics at Eli Lilly & Co., says the company has announced plans to build a diagnostics capability.
 
"A big part of the company's innovation strategy is providing improved outcomes for individual patients, which can be achieved through tailored therapies," she says.
 
Olson notes that companion diagnostics can have a great impact on current cancer treatment trends, and building Lilly's diagnostics capability will allow patients, payers and prescribers to know, through diagnostics tools such as blood tests, biopsies or imaging, which characteristics or biomarkers exist in which patients—and in turn, which Lilly medicines are likely to work in which patients, and which are not.
 
"This offers many advantages from earlier understanding of efficacy and target populations to potentially lower development costs and improve outcomes for individual patients," she says. "We see opportunities for companion diagnostics across approximately 40 percent of our portfolio of pipeline molecules, including many in cancer."
 
In companion diagnostics, there are two primary categories: in vitro and in vivo diagnostic testing.
 
 "Tests done in vitro—literally, 'in glass'—are performed on specimens taken from the human body to diagnose disease or conditions," Olson explains. "Tests would include blood glucose testing and genetic screening. In-vivo tests use diagnostics to assess health 'within the living body,' such as a CAT scan or MRI. Other specific technologies that may be used include PCR, microarrays and expression profiling, to name a few."
 
Olson also points out that there are several technologies that enable the development of biomarkers into companion diagnostics. PCR, microarrays and expression profiling are being used to improve the sensitivity and selectivity of companion diagnostics.
 
Next-generation sequencing and proteomics are two other growing areas of interest.
 
"Biomarkers that are validated have the ability to lead to safer and more effective products, especially when developed into a companion diagnostic," she says.
 
For companies like Lilly that are developing companion diagnostics, there are plenty of challenges on the path to success.
 
"There is a lot of movement within and among companies as they buy, build and partner to access diagnostic capabilities," Olson says. "The market is evolving rapidly, so we'll be ramping up quickly while ensuring total quality."
 
To be on the leading edge of companion diagnostics could prove to be a boon to a drug company's drug pipeline and revenue stream.
 
"Building this capability, we believe, will in turn build our bottom line by showing through clinical and diagnostic data that Lilly medicines are improving outcomes for individual patients," Olson says.
 
Still, there are plenty of road bumps along the way, as diagnostics have a different FDA review and approval process from pharmaceuticals, with different offices in the agency having regulatory oversight. Currently, only draft guidance is available, Olson notes.
 
"Due to the momentum that diagnostics are gaining, the FDA has announced plans to make a guidance document available at the end of the year to clarify regulatory expectations," she says. Even after the regulatory hurdles are covered, science must continue to evolve, including the development and validation of biomarkers, which are one piece of the companion diagnostics puzzle.
 
"Diagnostic biomarkers are a measure to help determine the characteristics of a particular patient's disease in order to determine the best treatment option for that specific patient," she says. "The development and validation of biomarkers are the fundamentals for developing a companion diagnostic."
 
Olson also points out that there are a select lucky few biomarkers that will "grow up" to be a diagnostic, and a subset of these that will be companion diagnostics. Lilly's goal is to embed the diagnostic tool into the drug development process, Olson says.
 
"By co-developing and then launching both a pharmaceutical and a diagnostic, our goal is to provide customers with a better benefit-risk profile and lower total healthcare costs," she says.
Genentech Inc. 
Based in South San Francisco, Calif., Genentech's scientists and doctors continue to research the basic biology of cancer and look for biomarkers that show how certain pathways are important for the growth of particular cancers. 
 
"Finding new biomarkers that can be measured with companion diagnostics could help us determine what pathways are important to target with new investigational agents," says Amy Berry, a Genentech spokeswoman.
 
According to Berry, biomarkers are an important part of cancer research and personalized medicine, "but they are only important if they help us improve the care patients receive. We believe in the potential for biomarkers and companion diagnostics to personalize medicine and help us develop new potential medicines for people with cancer.At Genentech, all new agents in our pipeline include a corresponding biomarker program that may help us determine which people are the best candidates for clinical trials."
 
Moreover, the technology used in a given companion diagnostic depends on what the test is designed to measure, Berry adds.
 
"For example, to measure the amount of protein on a cancer cell surface, immunohistochemistry (IHC) can be used to detect the protein itself or fluorescent in situ hybridization (FISH) can measure the number of copies of a gene present," she says. "When detecting specific mutations in the cancer cell DNA, often polymerase chain reaction (PCR)-based techniques are used."
 
Berry also says the field of companion diagnostics is full of new developments and has a bright future on the horizon. 
 
"One of the best-known examples of how a biomarker and companion diagnostic can work to personalize cancer treatment was pioneered at Genentech, and involves measuring the amount of the HER2 protein or the number of corresponding genes," Berry says. "Women with HER2-postive breast cancer have a more aggressive form of the disease, but also have the best chance of responding to medicines that target HER2, like Herceptin. About a quarter of all breast cancers are HER2-positive."
 
Roche/Genentech and Plexxikon are co-developing RG7204 (PLX4032), a first-in-class investigational molecule called a BRAF inhibitor, designed to block the activity of the mutated form of the BRAF protein. 
 
"Tumors in approximately half of patients with metastatic melanoma have been shown to be positive for the BRAF mutation," Berry explains. "The companies are also developing a companion diagnostic to test for the BRAF mutation in order to determine which patients are most appropriate for RG7204."
 
Another advantage of companion diagnostics is the fact that they can lead to safer and more effective products. For example, Berry notes that a companion diagnostic could help identify who and who is not an appropriate candidate for a particular medicine. 
 
"They could possibly also be used to identify who might be at higher risk for a particular side effect," Berry says. "However, the only way to determine if a medicine paired with a companion diagnostic is superior to a medicine without a companion diagnostic is to evaluate them in well-designed, head-to-head clinical trials. For example, we are testing RG7204 compared to dacarbazine chemotherapy in a randomized Phase III study for patients with BRAF-mutation positive metastatic melanoma."
 
Though most all cancers have common characteristics, Berry notes that there is no "one-size-fits-all" solution to biomarker discovery because each drug and disease are different and unique. "In order to determine which patients should and should not receive a certain medicine, biomarkers and companion diagnostics must be rigorously tested and validated in clinical studies," she concludes.
 
 
Code: E101027

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