Biomarkers on the Back End
by Gina Shaw
January 2008
Biomarkers may be more common in early clinical development, but their utility extends into post-marketing research as well.
A quick look at the U.S. Food and Drug Administration’s (FDA) Critical Path Opportunities Initiated During 2006 indicates biomarkers rank high on the FDA’s priority list. Biomarkers play a key role in no fewer than 15 of the 40 or so Critical Path activities and collaborations undertaken in 2006. From oncology and liver safety biomarkers to the development of a paper on just what constitutes a valid biomarker in the first place, the concept of biomarkers appears throughout the FDA report. In light of the increasing importance of biomarkers in the early stages of drug development, almost all pharmaceutical companies today include in the development plan some sort of concomitant exploration of specific biomarkers that might be associated with the drug’s efficacy and toxicity when beginning the development of a new compound.
To date, most of the work in biomarkers has focused primarily on the discovery and development stages in the life cycle of a new drug. But biomarkers don’t lose their utility once a drug is placed on the market.
Increasingly, drug developers recognize the long-term benefits of biomarkers in the post-marketing phase: to help identify potential new target markets for a drug, to help better stratify the existing market and to assist in pharmacovigilance. These aspects of biomarker development are in their infancy compared to preclinical and clinical stages, but they may soon become reality.
Target Practice
Schering-Plough has “a couple of very active” programs looking at biomarkers in Phase IV development according to Jim McLeod, who heads the Early Clinical Research and Experimental Medicine group at the Schering-Plough Research Institute, in Kenilworth, N.J., USA. A high priority for Schering-Plough is a recently announced collaboration with Oncomethylone—a molecular diagnostics company that develops gene methylation tests—to utilize its patent-protected assay for methylation of the MGMT gene, a biomarker that has been shown to be methylated in a number of cancer types.
That’s potentially useful for Schering in identifying potential new clinical targets for its drug Temodar (temozolomide), the only drug now widely used for treatment of glioblastoma multiforme, the most deadly type of brain cancer. Patients with methylated MGMT genes respond particularly well to Temodar. Since the biomarker is present in about 75 percent to 80 percent of gliomas, these cancers are rich targets for the drug, but MGMT methylation also is present in a number of other tumors at a much lower frequency.
“It ranges from 5 to 10 percent in non-gliomas,” McLeod says. Utilizing Oncomethylone’s assay, Schering will conduct ongoing trials both in gliomas—fine tuning Temodar’s targeted patient population—and in other cancers where the responders may be fewer and far between.
Patient Selection
AstraZeneca is engaged in a slightly different post-marketing biomarker quest with its lung cancer drug Iressa (gefitinib), an EGFR inhibitor. It received FDA approval in 2003, but in 2005, after a large trial failed to show a survival benefit, the FDA issued a statement indicating that the drug should only be used in patients who already have shown a benefit from Iressa. In other words, the FDA essentially told oncologists not to start newly diagnosed lung cancer patients on this drug outside a qualified clinical trial. AstraZeneca now distributes Iressa to patients already on the drug through an early access program.
But that doesn’t halt the search for new biomarkers that might identify subsets of patients who respond well to Iressa—or weed out or suggest alternatives for those patients who don’t. In June 2007, Vanderbilt University researchers reported that a mass spectrometry test of serum prior to treatment can predict the response of non-small cell lung cancer patients to both Tarceva (erlotinib) and Iressa (J Natl Cancer Inst. 2007;11:838-46). Their predictive algorithm, based on eight distinct features, distinguishes patients with good prognoses from patients with poor prognoses. Those in the “good prognosis” group, the study found, had median survival rates ranging from twice as long to nearly three times as long when compared to those in the poor prognosis group.
Oncology is particularly fertile ground for biomarker development, and Phase IV is no exception—but it’s not the only field, McLeod says. “We have a number of post-marketing activities trying to identify expanded and more targeted patient populations for a drug, more and more in the immunology area,” he says.
McLeod points to Remicade (infliximab) as one example. Originally approved in 1998 by the FDA to treat adult Crohn’s disease, the drug is used to treat pediatric Crohn’s, rheumatoid arthritis, ankylosing spondylitis, psoariatic arthritis and ulcerative colitis.
“Over many years, we’ve been expanding this drug into new populations that are defined,” McLeod says. “We’re looking at a variety of biomarkers—DNA, circulating proteins, chemokines and cytokine factors—trying to understand the biology of the diseases this drug treats. It’s a virgin area for information; literally every few years there are a whole new set of factors you have to look at, so we continue to look for new indications.”
Roche also has invested significantly in Phase IV biomarker research, says Tom Metcalfe, head of the Roche Biomarker Program, in Basel, Switzerland. One significant area of interest is the correlation of FC Gamma RIIIA receptor status with patient response to treatment with Rituxan (rituximab) in non-Hodgkins lymphoma.
“We’ve tried to understand whether or not there is any basis for using this biomarker to select patients for therapy,” says Metcalfe. He notes that much of the research pointing to this connection has been in patients who were on Rituxan monotherapy, something that rarely is the case in clinical practice, where patients usually receive Rituxan on top of a background of chemotherapy. “These polymorphisms in the FC Gamma receptor seem to play a much smaller role in this situation, so this may be less useful, but we’re trying to keep on top of this potential biomarker and investigate whether we can use it in clinical trials ourselves.” Roche also is investigating novel markers that may point to efficacy for Rituxan in other diseases, such as chronic lymphoid leukemia.
Phase IV biomarker development is a growth area for Roche and for the pharmaceutical industry as a whole, says Metcalfe. “We’re definitely going to see more of this, for a number of reasons. One is because we’ll be doing more work on biomarkers during the development of the compounds, so we will have better insights by the time the drugs reach market. We will have developed plans to study various biomarkers post-launch in many more cases, as well as in a wider variety of markers,” he says. “Another reason is that third parties, such as academics and even other commercial entities more on the diagnostic side, will be looking into post-marketing biomarkers in greater depth, particularly if they believe there is value to be generated.”
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