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.