Rheumatoid arthritis (RA) patients with a particular allele of tumor necrosis factor alpha (TNF-α) respond better to etanercept therapy than their counterparts without the single-nucleotide polymorphism (SNP),1 according to a study appearing in the April issue of the journal Rheumatology. The finding brings rheumatologists one step closer to realizing a practical role for pharmacogenetics in the treatment of RA.
Researchers led by Dr. C.P. Kang, Department of Biological Sciences, Korea Advanced Institute of Science and Technology in Daejeon, found that a C/T SNP at the -857 position of the TNF-α promoter was associated with the efficacy of etanercept therapy, and that patients carrying at least one copy of the T-allele responded better than homozygotes for the C-allele. "When the results have been confirmed, this SNP could become a useful genetic marker for predicting responses," they conclude.
The emerging field of pharmacogenetics, which is only beginning to see clinical application, was also bolstered this week when the US Food and Drug Administration (FDA) issued a guidance document and published a new Web page that provide tools for companies to more easily submit pharmacogenetic data earlier in the development cycle of a drug. This will hopefully result in the quicker discovery of meaningful relationships between particular genotypes and drugs' efficacy and safety. The hope is that personalized medicine will ultimately allow physicians to make better prescribing decisions based on a patient's genetic profile.
Effect revealed by non-responder analysis
In the context of a 12-week clinical trial evaluating the efficacy of etanercept in 70 Korean patients, researchers analyzed genomic DNA from each subject. They genotyped 13 SNPs within the TNF-α and lymphotoxin alpha genes to determine whether alleles at any of these positions were linked to responses to etanercept therapy.
The study found that the -857T allele had a significant effect when patients were analyzed as responders or nonresponders to etanercept. The frequency of the T-allele was 5% in the ACR20 nonresponders but 39% in the ACR70 responders. Moreover, the ratio of ACR70 responder number to ACR20 nonresponder number among T-allele carriers was >10-fold higher than in the C-allele homozygotes.
The -857C/T SNP falls in a binding site for the OCT1 transcription factor, which only interacts with the sequence with the T-allele, inhibiting TNF-α promoter activity. Another study of the TNF-α promoter revealed a link between the -308G/A SNP and responsiveness to infliximab.2
The promise of personalized medicine
"The whole area of responsiveness to TNF inhibitors would be a great example of personalized medicine and will improve their utility," Jack Klippel, MD, president and CEO of the Arthritis Foundation, tells CIAOMed.
In the near future, "we will better understand genes that may be associated with response so we can say 'yes, you will respond' and 'no, you won't,' and 'this is your risk of developing side effects,'" he says. Such information "will make these drugs more cost-effective because they will be used in responsive populations, and that will drive health care costs down," he adds. By some estimates, as much as 25% of patients do not respond to treatment with TNF-inhibitors.
"I think in many ways personalized medicine is an ideal model of health care, particularly when it comes to RA," Dr. Klippel tells CIAOMed. "Increasing the likelihood of deriving benefit from therapy and decreasing side effects are laudable goals."
However, "it raises issues about access because in order for it to be taken advantage of, you need access to specialty care and the tools that are going to be used to craft personalized medicine."
Peter K. Gregersen, MD, director of Robert S. Boas Center for Genomic and Human Genetics at North Shore/Long Island Jewish Research Institute in Manhasset, New York, says that "there is clearly a genetic component to response to drugs in autoimmune disease. There is already some evidence, although it's not sufficiently predictive that it can be used in clinical setting yet. We are still in the early stages, and don't fully understand how to use the data."
Ultimately, genetic data will be combined with other information such as autoantibody profiles to determine how an individual will respond to treatment, he predicts. "The critical thing is to make sure we are in a position to gather data going forward to analyze and tease apart so we can determine what factors can be useful in managing therapy," Dr. Gregersen says, adding that he believes all clinical trials should require participants to deposit DNA in a bank.
If such a database existed, for instance, "you could go into a DNA database of all people who had received COX-2 inhibitors and perhaps be able to find genetic markers for adverse cardiac events," he says. Then, in the future, "we would just not give these drugs to people [with those genotypes]."
The FDA has taken a significant step to stimulate the collection, centralization, and analysis of data that are necessary to reap these clinical benefits. In a press release announcing the initiation of a new Web site and guidelines for submission of pharmacogenetic data,3 Janet Woodcock, MD, the FDA deputy director for operations, expressed high hopes for the promise of personalized medicine. "This new technology will allow medicines to be uniquely crafted to maximize their therapeutic benefits and minimize their potential risks for each patient."
She continues, "We hope ultimately to bring pharmacogenomics, a way in which to foster the personalizing of medicine, to every health care professional's prescription pad for the benefit of their patients and US consumers." The FDA's new pharmacogenomics Web site is available at: http://www.fda.gov/cder/genomics/default.htm
References:
- Kang CP, Lee KW, Yoo DH, et al. The influence of a polymorphism at position -857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology. 2005;44:547-552.
- Martinez A, Salido M, Bonilla G, et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum. 2004;50:1077-1082.
- FDA Works to Speed the Advent of New, More Effective Personalized Medicines [press release]. Washington, DC: March 22, 2005.