Industry and Personalized Medicine

Vol. 20 • Issue 6 • Page 43

Guide to the Genetics Revolution

Recent advances in genomics research have resulted in the discovery of a growing number of genetic mutations linked to various diseases. These discoveries have significantly impacted the manner in which a patient is being diagnosed and treated.

Genetic variations in an individual affect the metabolism of various drugs; hence, dosing of medication becomes a key factor in effective therapeutic intervention. These considerations have resulted in the advent of personalized medicine, which enhances the quality of patient care by providing individualized treatment based on genetic variations in an individual.

Companion Diagnostic Tests

Adverse effects of drugs are routinely monitored by the FDA and warnings are updated in their package inserts often indicating genetic testing as an important step prior to therapeutic treatment. A greater appreciation of the importance of genetic variation has resulted in the FDA recommending a companion diagnostic test with almost every new chemotherapeutic agent that they have recently approved.

Personalized medicine approaches have significantly impacted the way pharmaceutical companies conduct and perform drug development and design clinical trials to release a drug. Their clear goals are to ensure drug safety, facilitate rapid patient enrollment and contain costs. Biomarkers play a key role in facilitating this process. Biomarkers are essentially genetic variations or gene expression profiles or proteins that can predict response to specific drugs.

The diagnostics industry has responded rapidly by developing biomarker assays to determine drug toxicity, safety and efficacy. Development of such companion diagnostic tests provide physicians with the potential to optimize treatment effectiveness, minimize adverse events and reduce hospitalization costs. This provides key benefits to patients, payers, providers and manufacturers.

Black Box Warnings

The FDA as part of its enforcement policies in ensuring drug safety recently re-labeled the package insert of the oral anticoagulant Coumadin®. The black box warning on the label indicates that “lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes.”

Similarly, the label of the widely used anti-platelet agent, clopidogrel (Plavix®), contains a black box warning indicating that the effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 system, principally CYP2C19. It further states that poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome or percutaneous coronary intervention than patients with normal CYP2C19 function. Tests are available to identify a patient’s CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. One such test is AutoGenomics’ INFINITI® 2C19 test, which recently received FDA clearance.

Biomarker Assays

The personalized medicine approach for many diseases can become complex due to the involvement of multiple genes and their polymorphisms. This requires single tests that can determine multiple polymorphisms or mutations simultaneously. Biomarker assays, which identify mutations in the KRAS gene (codons 12,13 and 61) and the BRAF gene (codon 600), are useful in determining whether metastatic colorectal cancer patients should be administered anti-EGFR agents such as Erbitux® or Vectibix®. Similarly, the testing of greater than 50 mutations of the Epidermal Growth Factor Receptor (EGFR) is helpful in determining whether drugs such as Astra Zeneca’s Iressa® or Roche’s Tarceva® should be administered to patients with non-small cell lung cancer (NSCLC).

Real-time PCR, Microarrays

Implementation of personalized medicine approaches requires efficient diagnostic platforms that provide results in a timely manner. While the gold standard for genetic testing is sequencing, this is not a practical way for such testing. Accordingly, diagnostic companies have developed a variety of testing platforms such as real-time PCR or microarrays. The limitation of real-time PCR is that the number of mutations that can be tested simultaneously is minimal and dependent on the number of channels available in the platform. Widely used platforms are the Applied Biosystems Inc. TaqMan® assays and the Roche Diagnostics LightCycler®.

Microarrays, on the other hand, provide the versatility to determine multiple mutations simultaneously. To meet this emerging need, companies like AutoGenomics have developed an automated multiplexing microarray platform with a wide array of personalized medicine assays.

Dosing Algorithms

For the laboratory, the major challenge today in keeping up with these advances is to determine which dosing algorithm should be used for the specific drug. Such dosing algorithms are available on websites such as or through companies such as Genelex or PGXL Laboratories where algorithms have been customized based on specific methodologies. However, universal algorithms for such drugs require the completion of randomized clinical trials. Such studies are currently ongoing for several drugs.

Meanwhile, as technology evolves, the industry is actively striving toward the goal of point-of-care testing to realize the full benefit of personalized medicine so that patients can be tested and dosed safely, effectively and immediately.

Ramanath Vairavan is senior vice president of AutoGenomics.