Industry dollars are flowing into biomarker discovery as companies realize its potential, particularly in oncology.
Shaw is a freelance writer based in Montclair, N.J.
As recently as five years ago, you could probably have found a number of pharmaceutical companies and life sciences organizations that weren’t investing much, if at all, in biomarker discovery. Today, you would have to look far and wide to find such an organization. A December 2004 study by Life Science Insights found that industry
investment in biomarkers had increased 200% over the past several years—a trend that is expected to grow exponentially as technology improves, pressure on industry to accelerate drug discovery grows, and the FDA pushes biomarker discovery efforts through its Critical Path Initiative.
The lure of biomarkers is obvious. As the success-to-failure ratio has declined over the last decade while the cost to bring a new drug to market has skyrocketed, the heat is on to find objective, valid, and measurable ways to determine whether a drug works or doesn’t work—and what patients it works in—as early as possible in the discovery process. Some think biomarkers could be the holy grail.
Companies with the most invested in biomarkers—at least in terms of patents held—include Novartis, Hoffman-La Roche, Pfizer, SurroMed, Bayer, and Bristol Myers Squibb, says S. Ravi Shankar, an industry analyst with Frost and Sullivan. Most of these companies have fully integrated biomarker strategies from discovery through phase IV development. The lion’s share of their investment is aimed at oncology, which represents 30% of the biomarker discovery market, trailed by cardiology at 25% and neurology at 20%.
“Cancer is a great place to use genetic and genomic biomarker strategies, because ultimately cancer is a disease of the genome, and it is in a very real way mechanistically linked to events that happen there,” says Ken Carter, President and CEO of Avalon Pharmaceuticals, Germantown, Md. Genetic damage can be found in every cancer cell, and so, theoretically, can potential biomarkers for drug targets. The approach has already proven fruitful: drugs like Herceptin and Erbitux would have been dismal failures without the HercepTest and the EGFR pharmDx test to sift through thousands of patients and find the potential responders.
If biomarkers are truly to be integrated into the drug discovery process, cancer will likely lead the way. So what are some of the most promising cancer-related biomarkers under investigation today? Frost and Sullivan’s Shankar points to several promising oncology markers that are currently in the late discovery stages:
• Berlin, Germany-based Epigenomics has developed a colon cancer screening test based on its DNA methylation technology. DNA methylation is a naturally occurring modification of cytosine, one of the four bases of the DNA molecule.
• Scientists at the University of Michigan have found a gene called EZH2 utilizing DNA microarrays. This gene is said to play a major role in the development of prostate and breast cancer. EZH2 is a transcriptional repressor, which belongs to the polycomb group of proteins.
• The University of Georgia Cancer Center is researching glycosyltransferases. The institute has been studying glycobiology for over two decades and has recently started to focus more on glycome research. The main objective of this research is to understand the role of carbohydrate interactions in a cancerous cell. This is leading to the development of serum-based cancer diagnostics. In addition, specific glycosyltransferases are being studied to identify potential therapeutic candidates.
James Merryweather, executive vice president of Pharmaceutical Development at Ciphergen, Fremont, Calif., is excited about markers that may be able to differentiate women with benign ovarian masses from those whose masses are malignant. “We hope to be able to deliver a biomarker-based test sometime this year.”
At Avalon, Carter’s team is taking a systems biology approach to new biomarker discovery, combining multiple indications to develop a more complex and nuanced
readout—what many consider to be the wave of the future for biomarkers. “In the development of our lead drug, AVN944, even as early as phase I we are tracking multiple points of interest using a set of about two dozen genes that we believe will be important in assessing the efficacy of the drug,” he says. “But we are also, in some patients, actually tracking the activity of certain cell types across the entire genome to see how the drug is affecting the genome in the diseased cells before, during, and after treatment.”
Avalon is also in phase I trials for a drug that Carter says has potential in a number of different malignancies. In the two-arm trial, one involving acute leukemias and the other multiple myelomas and lymphomas, investigators are performing full genome scans at identified time points before and after treatment. “The ultimate success would be to pull a pattern out of an untreated patient that you could retrospectively use to say that this is a patient who is responsive to a drug, and use that pattern to look for other such patients,” he says. “We’re also focusing in more tightly, using a set of about two dozen gene-based biomarkers that have been chosen because we think they’ll be specifically informative for things like monitoring the targeted pathway and off-target effects, and monitoring activity indications at different concentrations.”
Fremont, Calif.-based Scios, a biopharmaceutical company acquired by Johnson & Johnson in 2003, has integrated biomarker discovery throughout its investigations of protein kinases as drug targets for cancer and other diseases. “For example, with the p38 MAP kinase inhibitor, which is currently in clinical investigation for multiple myeloma, we have integrated into that trial sample collection for pharmacogenomic samples and exploratory analysis for pharmacodynamic markers, as well as looking for patient response markers,” says Ann Kapoun, group leader of biomarker research and development. “With analysis both from our in-house models as well as data from the clinical trials, we can more tightly correlate the preclinical models to the clinical setting.”
Validating these and other biomarkers and fully integrating them into the drug discovery process won’t happen overnight. Frost and Sullivan’s Shankar ticks off some of the obstacles to wholesale biomarker success: “The complexity of the human proteome is creating hurdles in terms of resolution and purification of protein mixtures. It is virtually impossible to find an analytical technique suitable for all proteins. Samples such as tissue, blood, and urine used for identifying and analyzing biomarkers are limited in quantity. There is a lack of success in identifying and developing biomarkers that can be used as a stand-alone test,” he says.
Given these hurdles, collaboration is essential to make the most of limited resources and develop consistent approaches. It’s a lesson that pharmaceutical scientists increasingly seem to be taking to heart, with new biomarker discovery collaborations being announced at a rapid clip.
• Ciphergen and Sanofi-Aventis recently announced an oncology drug biomarker discovery partnership in which Ciphergen will analyze samples at one of its biomarker discovery center laboratories using its suite of proteomic solutions. Ciphergen also has research collaborations with several key players such as Johns Hopkins Medical School and Novartis.
• Epigenomics is currently collaborating with Roche Diagnostics to develop a range of cancer molecular diagnostics and pharmacodiagnostic products. Epigenomics also recently partnered with AstraZeneca for development of DNA methylation biomarkers for AstraZeneca’s oncology drugs, initially focussing on Iressa.
• Aclara Biosciences Inc. has pharmaceutical research collaborations for its eTag Assay System with Pfizer Inc., Genentech, GlaxoSmithKline, Vertex Pharmaceuticals, and Procter & Gamble Pharmaceuticals.
• Caprion Pharmaceuticals and ICOS Corp. recently announced a protein biomarker discovery collaboration which will use Caprion’s CellCarta proteomics discovery platform to identify pharmacodynamic markers in plasma relating to ICOS’ pre-clinical oncology programs.
• SurroMed has biomarker discovery agreements with companies including Merck, Wyeth, and Eli Lilly.
“For the future, we will probably spend at least as much time investigating biomarkers in preclinical settings as in clinical ones,” says Ciphergen’s Merryweather. “That’s an advantage of outsourcing and collaboration: we can apply a high-throughput, fast-turnaround approach to an organization that is looking for an answer very quickly. In our discovery technology centers, we have experts in SELDI [surface enhanced laser desorption ionization], multiple instruments, and robotics that can turn around very large studies in a short period of time.”
Preclinical discovery is where collaborations are most important, agrees Kapoun. “Everybody wants access to human tissues and samples. We’re currently looking into studies that can be set up with biorepositories and translational studies with academic collaborators, so we can advance the science with access to tissues and ex vivo blood samples to test some of the pharmacodynamic markers we have been developing in preclinical models. The earlier you start doing that, the more prepared you are when you get to the clinical phase.”
Just as important, says Kapoun, is internal collaboration: close contact between discovery R&D teams and clinical teams. “What you need to do, and what we’re doing here, is testing and evaluating preclinical biomarkers in a clinical setting, and vice versa—doing exploratory research for biomarkers in early phase clinical trials. The discovery process goes both ways, and really the only way to do this is to have tight communication among groups.”
She suggests a model in which representatives from each of the project teams are part of a biomarker discovery team. “There needs to be an infrastructure that goes beyond hierarchy within departments in order to be efficient and develop and use new markers most appropriately.”
Filed Under: Drug Discovery