Recent reports of an increased risk of heart attack with the Cox-2 inhibiting drugs Vioxx and Celebrex have resulted in a huge setback for arthritis therapeutics. These drugs had become staples for the treatment of osteoarthritis (OA) and rheumatoid arthritis, both debilitating inflammatory diseases.
It seems that the only hope of keeping these drugs available would be to find some way to identify patients who are susceptible to the cardiovascular effects, possibly by nature of a genetic difference. The FDA has recently begun to solicit data, on a voluntary basis, from pharmaceutical companies, and some time this year will issue a final set of standards for pharmacogenetic data.
At the same time, technology such as GE Healthcare's (Little Chalfont, U.K.) Codelink has overcome some key hurdles in terms of data accuracy and reproducibility. Now, experts across the industry are waiting and wondering whether Vioxx and Celebrex will be the first blockbuster drugs to be rescued by pharmacogenetics.
Meanwhile, the science of personalized medicine is progressing on many fronts at smaller pharmaceutical and biotech organizations. Interleukin Genetics' (Waltham, MA) specialty is inflammation, a phenomenon involved in both arthritis and heart disease. Interleukin-1 and TNF-alpha are important regulators of inflammatory response.
Studies show that elevated levels of C-reactive protein (CRP) are strongly predictive of future cardiovascular events. According to Phillip Reilly, M.D., CEO of Interleukin Genetics, CRP levels correlate with interleukin haplotype. Those with high levels of interleukin have a more robust inflammatory response.
"Maybe that was good evolutionarily thousands of years ago. Now, as we live longer, for example, the response to the deposition of cholesterol plaque in arteries is too robust and predisposes for heart disease."
Currently, Interleukin's primary focus is understanding the genetic factors that contribute to the risk for heart disease and osteoporosis, and the company is trying to develop risk assessment tests in those areas using an approach based on SNPs.
Interleukin also has a program to study genetic influences on the efficacy of anti-IL-1 and anti-TNF-alpha therapy in adults with rheumatoid arthritis. There is great variation in patient responses to these disease-modifying anti-rheumatic drugs (DMARDs), as well as a high incidence of adverse side effects.
Based on observations that the roles of IL-1 and TNF-alpha in inflammation vary between individuals, Interleukin has developed computer models to extrapolate long-term effects of small fluctuations of these cytokines.
In 2002 and 2003, Interleukin launched a clinical study tracking the responses of patients with common IL-1 and TNF-alpha alleles to commercial rheumatoid arthritis drugs Enbrel and Remicade (anti-TNF-alpha) or Kineret (anti-IL-1). Ideally, this would result in an inexpensive test that physicians could use to select patients who would benefit most and have the least risk.
There are two main approaches to pharmacogenetics: SNPs and gene expression profiling. One tool for gene expression profiling is the RNA microarray. Gene expression profiling is particularly useful for diseases like arthritis, where it's difficult, if not impossible, to sample the joint itself.
Inflammation creates biomarkers, which circulate in the blood, and can be analyzed for RNA transcripts, yielding a profile detailing the stage, severity, and prognosis of the disease. RNA microarrays have been criticized, however, for being unreliable.
Scott Magnuson, Ph.D., president and founder of GenUs Biosystems (St. Charles, IL), developed the Codelink microarray while he was working for Motorola. He believes that the technology has finally come of age in 2004.
"I get excited because I think the technology is there right now, and it's so applicable." This is a serendipitous development given the FDA's increasing interest in and scrutiny of pharmacogenetic data.
Large pharmaceutical companies have traditionally not been motivated to pursue pharmacogenetics because it would segment the market and weaken sales for their blockbuster drugs. Now, with blockbuster drugs in jeopardy due to serious adverse side effects, they are looking at pharmacogenetics with interest.
Microarray gene expression screening, however, is expensive in terms of equipment, manpower, and training. Dr. Magnuson hopes that the pharmaceutical giants will turn to outsourcing companies like GenUs for their gene expression profiling needs.
GenUs offers services beginning with RNA isolation from tissue samples through data analysis, with extensive customer support. "Every pharmaceutical company is going to be doing this," says Dr. Magnuson. "The data is so intriguing and so predictive. It can only go in one direction."
Identifying Biomarkers for OA
Toronto-based ChondroGene formed a collaboration with Pfizer (New York City) to identify new therapeutic targets and biomarkers for osteoarthritis. Osteoarthritis differs from rheumatoid arthritis in that the inflammation is not caused by an autoimmune disorder, but by so-called "wear and tear" on the joints.
Unlike rheumatoid arthritis, there are no drug treatments that can halt or reverse the progression of the disease. Chondrogene is contributing a database of osteoarthritis tissue-specific clinical and gene expression information to identify potential novel therapeutic targets for the disease.
Chondrogene has studied more than 3,000 patients with 50 different diseases, with particular focus on cancer, cardiovascular disease, central nervous system diseases, and arthritic disease.
These are diseases with known blood-based biomarkers with decent therapies available, but with diagnostics not available, not sensitive enough, too expensive, or too invasive. Chondrogene uses the Affymetrix GeneChip platform for its expression screens.
However, early diagnosis of a disease like osteoarthritis has little usefulness if there's no treatment for the disease itself. Chondrogene's quest is to slow down or halt the progression of OA. K. Wayne Marshall, M.D., Ph.D., president and CEO of Chondrogene, describes tissue repair and OA reversal as "the holy grail."
In addition to early diagnostics and development of new therapeutics, the collaboration will study individualized patient response to treatment.
"There's a general recognition in pharmaceutical and biotech companies to try to develop tools and identify which patients are likely to respond to a particular treatment," explains Dr. Marshall, "and which patients are likely to have an adverse event associated with a particular treatment."
Risk is a real concern with any drug treatment, but Dr. Marshall warns that the risks of not treating osteoarthritis have not been given sufficient consideration. "When patients with osteoarthritis don't have access to Cox-2 inhibitors, they have to move to more aggressive treatment like surgery.
They become more sedentary, less physically active. Loss of cardiovascular fitness and gain of weight associated with increasing severity of osteoarthritis symptoms may be associated with increased cardiovascular risk. That's the side that hasn't really been considered as this whole controversy has unfurled."
Another company addressing the issue of risk with arthritic disease is Millennium Pharmaceuticals (Cambridge, MA). By combining the study of molecular mechanisms underlying disease with genetic differences between patients, the firm seeks to develop better, smarter therapeutics. Millennium's program uses multiple technologies, including transcriptional profiling, SNP detection, bioinformatics, and proteomics.
The proteomics approach involves a two-stage discovery and verification process. First, mass spectrometry is used to characterize protein profiles from synovial fluid. Then identified biomarkers are quantified in serum.
One of Millennium's most important research areas is rheumatoid arthritis and the risks associated with the DMARD class of drugs. Using a registry approach, rather than clinical trials alone, the firm can identify predictors of disease severity and response to therapy. The ability to identify patients who are most resistant to therapy allows the customizing of patient study groups.
Ronenn Roubenoff, M.D., senior director of molecular medicine at Millennium, says, "We try hard to identify people who will benefit and minimize the risk." Typically, clinical study control group A would be given placebo, but placebo is not ethical for people suffering from arthritis. Instead, biomarkers are used to find people who are not responding to conventional therapies.
Millennium maintains cohort groups of 1,0002,000 at major medical centers all over the country, in therapeutic areas as diverse as inflammatory bowel disease and atherosclerosis, to be followed prospectively for five years. Patients are seen every six to twelve months and their clinical situation, health, and measurements of genetic and proteomic markers recorded.
Millennium is also conducting clinical trials for RA inhibitors of chemokine receptors, signal cells that come into the area of inflammation.
"These are storm flags that are raised in an area of infection. If we can prevent those signals from being read by the white cell, and keep the white cell moving past the traffic accident, fewer white cells are going to the site of the injury. "In autoimmune disease, the immune system fails to differentiate friend from foe. Friendly fire does the damage," says Dr. Roubenoff.
It's not clear whether Merck and Pfizer will pursue pharmacogenetic solutions to the cardiovascular complications associated with their Cox-2 inhibitors. However, there is a great deal of anticipation and speculation as to when this technology is going to make its mass market debut.
Possible approaches to rescuing these drugs include searching for SNPs in genes that affect inflammation pathway or the metabolism of the drug and gene expression profiling of patients on Cox-2 inhibition therapy.
However, it is apparent that new drugs coming down the pipeline will be subjected to increasing pharmacogenetic testing due to greater interest among drug makers, doctors, patients, and the FDA.