Two are better than one

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, animproved understanding of disease pathophysiology and the emergence ofpersonalized medicine are putting new demands on drug development. The oldparadigm of one blockbuster drug for everyone is quickly becoming a distantmemory.

Developing targeted therapies and companion diagnostics isall about discovering and validating clinical biomarkers. PCR, microarrays andexpression profiling are being used to improve the sensitivity and selectivityof companion diagnostics.

"The use of molecular diagnostics for detecting variationssuch as mutations or amplifications of specific genes, in order to targettherapies to patients who are most likely to benefit, is becoming increasinglycommon in anticancer drug development," Jocelyn August, a senior analyst at SanDiego, Calif.-based Sagient Research Systems, says in a recent issue in thejournal Nature.

Indeed, companion diagnostics will play an increasing rolein cancer care. Pharmaceutical companies developing targeted therapies forcancer must consider the potential benefits of developing a companiondiagnostic. As they join the rush to identify critical biomarkers, however,they also need to consider technology options, potential diagnostics partnersand regulatory hurdles.

In this, the third installment of our Trends in CancerResearch series, we examine one company's efforts to build its diagnosticscapability 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 diagnosticscapability.

"A big part of the company's innovation strategy isproviding improved outcomes for individual patients, which can be achieved throughtailored therapies," she says.

Olson notes that companion diagnostics can have a greatimpact on current cancer treatment trends, and building Lilly's diagnosticscapability will allow patients, payers and prescribers to know, throughdiagnostics tools such as blood tests, biopsies or imaging, whichcharacteristics or biomarkers exist in which patients—and in turn, which Lillymedicines are likely to work in which patients, and which are not.

"This offers many advantages from earlier understanding ofefficacy and target populations to potentially lower development costs andimprove outcomes for individual patients," she says. "We see opportunities forcompanion diagnostics across approximately 40 percent of our portfolio ofpipeline molecules, including many in cancer."

In companion diagnostics, there are two primary categories: invitro and in vivo diagnostic testing.

"Tests done in vitro—literally,'in glass'—are performed on specimens taken from the human body to diagnosedisease or conditions," Olson explains. "Tests would include blood glucosetesting and genetic screening. In-vivo tests use diagnostics to assess health 'within the living body,' suchas 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 technologiesthat enable the development of biomarkers into companion diagnostics. PCR,microarrays and expression profiling are being used to improve the sensitivityand selectivity of companion diagnostics.

Next-generation sequencing andproteomics are two other growing areas of interest.

"Biomarkers that are validated have the ability to lead tosafer and more effective products, especially when developed into a companiondiagnostic," she says.

For companies like Lilly that are developing companiondiagnostics, there are plenty of challenges on the path to success.

"There is a lot of movement within and among companies asthey buy, build and partner to access diagnostic capabilities," Olson says."The market is evolving rapidly, so we'll be ramping up quickly while ensuringtotal quality."

To be on the leading edge of companion diagnostics couldprove to be a boon to a drug company's drug pipeline and revenue stream.

"Building this capability, we believe, will in turn buildour bottom line by showing through clinical and diagnostic data that Lillymedicines are improving outcomes for individual patients," Olson says.

Still, there are plenty of road bumps along the way, as diagnosticshave a different FDA review and approval process from pharmaceuticals, withdifferent offices in the agency having regulatory oversight. Currently, onlydraft guidance is available, Olson notes.

"Due to the momentum that diagnostics are gaining, the FDAhas announced plans to make a guidance document available at the end of theyear to clarify regulatory expectations," she says.

Even after the regulatory hurdles are covered, science mustcontinue 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 thecharacteristics of a particular patient's disease in order to determine thebest treatment option for that specific patient," she says. "The developmentand validation of biomarkers are the fundamentals for developing a companiondiagnostic."

Olson also points out that there are a select lucky fewbiomarkers that will "grow up" to be a diagnostic, and a subset of these that willbe companion diagnostics.

Lilly's goal is to embed the diagnostic tool into the drugdevelopment process, Olson says.

"By co-developing and then launching both a pharmaceuticaland a diagnostic, our goal is to provide customers with a better benefit-riskprofile and lower total healthcare costs," she says.

Genentech Inc.

Based in South San Francisco, Calif., Genentech's scientistsand doctors continue to research the basic biology of cancer and look forbiomarkers that show how certain pathways are important for the growth ofparticular cancers.

"Finding new biomarkers that can be measured with companiondiagnostics could help us determine what pathways are important to target withnew investigational agents," says Amy Berry, a Genentech spokeswoman.

According to Berry, biomarkers are an important part ofcancer research and personalized medicine, "but they are only important if theyhelp us improve the care patients receive. We believe in the potential for biomarkers and companiondiagnostics to personalize medicine and help us develop new potential medicinesfor people with cancer.At Genentech, all new agents in our pipeline include acorresponding biomarker program that may help us determine which people are thebest candidates for clinical trials."

Moreover, the technology used in a given companiondiagnostic depends on what the test is designed to measure, Berry adds.

"For example, to measure the amount of protein on a cancercell surface, immunohistochemistry (IHC) can be used to detect the proteinitself or fluorescent in situhybridization (FISH) can measure the number of copies of a gene present," shesays. "When detecting specific mutations in the cancer cell DNA, oftenpolymerase chain reaction (PCR)-based techniques are used."

Berry also says the field of companion diagnostics is fullof new developments and has a bright future on the horizon.

"One of thebest-known examples of how a biomarker and companion diagnostic can work topersonalize cancer treatment was pioneered at Genentech, and involves measuringthe amount of the HER2 protein or the number of corresponding genes," Berrysays. "Women with HER2-postive breast cancer have a more aggressive form of thedisease, 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/Genentechand Plexxikon are co-developing RG7204 (PLX4032), a first-in-classinvestigational molecule called a BRAF inhibitor, designed to block theactivity of the mutated form of the BRAF protein.

"Tumors in approximately half of patients with metastaticmelanoma have been shown to be positive for the BRAF mutation," Berry explains."The companies are also developing a companion diagnostic to test for the BRAFmutation in order to determine which patients are most appropriate for RG7204."

Another advantage of companion diagnostics is the fact thatthey can lead to safer and more effective products. For example, Berry notesthat a companion diagnostic could help identify who and who is not anappropriate candidate for a particular medicine.

"They could possibly also be used to identify who might beat higher risk for a particular side effect," Berry says. "However, the onlyway to determine if a medicine paired with a companion diagnostic is superiorto a medicine without a companion diagnostic is to evaluate them inwell-designed, head-to-head clinical trials. For example, we are testing RG7204compared to dacarbazine chemotherapy in a randomized Phase III study for patientswith BRAF-mutation positive metastatic melanoma."

Though most all cancers have common characteristics, Berrynotes that there is no "one-size-fits-all" solution to biomarker discoverybecause each drug and disease are different and unique. "In order to determine which patients should and should not receive acertain medicine, biomarkers and companion diagnostics must be rigorouslytested and validated in clinical studies," she concludes.