On the Doorstep
February 2007
As personalized medicine advances, the drug development community is making adjustments.
By Adam Istas
Through the extensive cooperation of researchers and regulators, targeting therapeutics for patients with specific genotypes is slowly becoming a reality. As the pharmaceutical industry moves away from the blockbuster-dependent business model, the many benefits of personalized medicine are becoming clear. From facilitating smaller, more efficient trials, to simplifying post-marketing safety surveillance, the benefits of genetic testing can turn even a seemingly failed trial into a successful one.
Pharmacogenomic’s critical role in a clinical trial program is demonstrated by the continued development of rosiglitazone (RSG) for Alzheimer’s disease. The drug is approved for type 2 diabetes and marketed as Avandia. Researchers at GlaxoSmithKline conducted a trial in 2004 and 2005 testing the efficacy and tolerability of RSG in patients with mild to moderate Alzheimer’s disease (Pharmacogenomics J. 2006;6:246-254). As an additional element of the trial, genotyping results were obtained for over 60 percent of the subjects, an act that would eventually lead to the continuation of the program.
Although the study failed to meet the primary endpoint of improving cognitive function across the whole population of study subjects, there were apparent improvements in the population of patients who were negative for the APOE e4 gene—associated with the risk of Alzheimer’s and early onset of the disorder—and given RSG at the highest tested dosage. The cognitive impairment of patients who were positive for the gene may have advanced to a stage at which a benefit from rosiglitazone could not be demonstrated, says Ann Saunders, Ph.D., director of pharmacogenetics, neuroscience, at GlaxoSmithKline R&D, in Research Triangle Park, N.C., USA. The decision to test RSG for Alzheimer’s disease in a specific genetic population was based upon promising data gathered in preclinical discovery, and was made with the hope that the drug would alter glucose metabolism in the brain. The working hypothesis was that the APOE e4 gene would affect how well a patient responded to the medication, Saunders says.
Analysis of the results from the 24-week, double-blind, parallel-group study proved that the hypothesis regarding RSG’s benefits in treating Alzheimer’s has some validity. “Once we were able to separate the data, we saw who could respond and who could not respond [to the treatment],” Saunders says. The GSK researchers took the data to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for assistance with developing a protocol for a Phase III trial—specifically, testing RSG’s effect on Alzheimer’s patients with and without the APOE e4 gene. The result was a cutting-edge trial design that enabled researchers to stratify patients around a specific genetic biomarker, Saunders says.
Currently, GSK is enrolling more than 2700 patients in two trials to determine the efficacy and safety of RSG as adjunctive therapy for Alzheimer’s disease in APOE e4-stratified patients. The REFLECT-2 trial is testing extended release RSG in patients currently taking donepezil (Aricept), while the REFLECT-3 trial is testing extended release RSG in patients taking any drugs in the class of acetylcholinesterase inhibitors.
A drug tailored to a specific genetic population would be a valuable tool for physicians treating the millions of patients worldwide with Alzheimer’s disease. But in order for the benefit of these personalized therapies to be fully realized, physicians require education on how to incorporate genetic testing into their treatment regimens.
Enhancing a physician’s ability to determine which patients will benefit from a drug is the primary advantage of personalized therapies, says Felix Frueh, Ph.D., associate director for genomics in the office of clinical pharmacology at the Center for Drug Evaluation and Research of the FDA in Silver Spring, Md., USA. But the biggest challenge to translating pharmacogenomics into clinical practice is changing physician behavior, he says. Pharmacogenomics will only realize its full potential when physicians consider it to be one more tool for making better treatment decisions. “The important thing is that genetic technologies shouldn’t be used in a vacuum, but in a context,” he says.
To promote pharmacogenomic education, the FDA, in conjunction with the American Medical Association and the American College of Clinical Pharmacology, currently is developing online courses for physicians, Frueh says. The FDA also published the Guidance for Industry: Pharmacogenomic Data Submissions in 2005, in order to provide the industry with the agency’s position on the subject and encourage the use of pharmacogenomics in drug development.
Frueh expects to see a major shift in drug development over the next decade, one in which pharmacogenomics will be a regular feature of clinical trial design, even in the very early phases. “It would be a lot easier to have the use of genomic technology from the get-go,” he says. “We’ve learned a lot more about the pathophysiology of some diseases, and this knowledge should be used in drug development.” There currently are good genetic biomarkers for both safety and efficacy that could be beneficial in designing trials, Frueh says. If a biomarker is known, it should be used, he says. “We certainly know a lot more about these biomarkers than we did [before], which makes it much easier to evaluate [a drug’s] clinical utility.”
In addition to providing regulatory agencies with better data from which to make approval determinations, pharmacogenomics also can be used to enrich recruitment. When trial sponsors have advance knowledge of which patient groups are more likely to respond to a treatment, the variability in trials is lessened, Frueh says. This likely will help to design better clinical trials and increase their chance for success, which will in turn lead to a more efficient, streamlined process, he says.
Although a more efficient clinical trial process certainly is appealing to many in industry, the promise of personalized medicine starts and ends with better patient care, Saunders says. In the end, “this technology allows us to direct the right drugs to the right patient groups.”
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