The Right Drug at the Right Dose

Pharmacogenomic testing allows drug companies and doctors to modify patients’ exposure to drugs based on their genomic drug-response profile. By incorporating genomic biomarkers into the drug development and selection process, pharmacogenomics is revolutionizing the clinical trial process and improving treatment efficacy.

One of the major hurdles facing biopharmas in the process of delivering drugs to market is the problem of adverse drug reactions. The incorporation of genomic biomarkers into the drug development and clinical trial continuum allows investigators to better select the optimal group of patients to be enrolled into trials, and reduce the number of adverse events. Chemotherapeutics tend to display an even greater toxicity than other drugs, so the application of pharmacogenomics can be particularly helpful in the clinical trial selection and market application of anti-cancer therapies.

By better predicting how patients will respond to drugs, pharmacogenomics leads to more successful clinical trials and decreases the time to market for compounds. Whether genomic biomarkers are incorporated into early phase development to selectively enroll patients, or assessed for severe adverse events in post market monitoring, the intrinsic value ultimately lies in matching a patient’s genetic information to the appropriate treatment.

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Impact of Pharmacogenomics on Drug Development

  • Deliver more predictable responses to drug therapy, particularly in chemotherapeutics
  • Minimize the occurrence and severity of adverse drug reactions (ADRs)
  • Accelerate the drug discovery and development process
  • Conduct more cost-effective clinical trials


Examples of Pharmacogenomics-Driven Medicine

HER2 Testing
Human epidermal growth factor receptor 2, or HER2, is a protein that controls cancer cell growth. HER2 is over-expressed in 15-20% of breast cancers, and has been found to be a valuable biomarker for determining the optimal treatment for breast cancer patients. HER-2 testing can be performed using one of three technologies – immunohistochemistry (IHC), fluorescent in-situ hybridization (FISH), or in-situ hybridization (ISH). IHC measures levels of the HER2 protein, while FISH and ISH measures copy number of the HER2 gene. Cancer Genetics offers IHC, FISH, and ISH testing for HER2.
Patients who test positive for HER2 are considered to be good candidates for HER2 targeted therapies, like trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), and adotrastuzumab emtansine (T-DM1; Kadcyla), whereas these therapies are not recommended for patients who test negative for the HER2 biomarker.
HER2 testing may be performed during initial diagnosis, if disease recurs after treatment, or when disease has spread to other parts of the body (metastasized). HER2 testing may also be performed in order to identify candidates for specific treatment in gastric cancers.
BRAF and vemurafenib
Vemurafenib is the first and only FDA-approved personalized medicine shown to improve survival in people with BRAF V600E mutation-positive metastatic melanoma. It is designed to target and inhibit some mutated forms of the BRAF protein found in about half of all cases of melanoma, the deadliest and most aggressive form of skin cancer. The BRAF protein is a key component of the RAS-RAF pathway involved in normal cell growth and survival. Mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival. The FDA approval of Zelboraf is based on results from two clinical studies (BRIM3 and BRIM2) in people with BRAF V600E mutation-positive, inoperable or metastatic melanoma as determined by the cobas BRAF Mutation Test.
KRAS and cetuximab
Cetuximab is an EGFR inhibitor that has been shown to be ineffective in treating metastatic colon cancer patients with specific mutations in the KRAS gene. KRAS encodes a small G protein in the EGFR signaling pathway. Studies have demonstrated that characterizing mutations in the KRAS gene can assist physicians in determining the appropriate treatment for patients. In 2009, the FDA added label information to both cetuximab and panitumumab regarding the association between certain KRAS mutations and efficacy in treating metastatic colon cancer. As such, genetic testing to confirm the absence of KRAS mutations is now clinically routine before the start of treatment with EGFR inhibitors.
CYP2C19 and clopidogrel
CYP2C19 is a drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs including antidepressants, barbiturates, proton pump inhibitors, antimalarial, and antitumor drugs. Clopidogrel, or Plavix, is an antiplatelet prodrug for prevention of strokes and heart attacks and is metabolized by CYP2C19 into an active form. Several landmark studies have proven the importance of 2C19 genotyping in treatment using clopidogrel. These studies have demonstrated that CYP2C19 poor metabolizers, up to 14% of patients, are at high risk of treatment failure due to a lack of conversion of the prodrug into its active form. The findings led to an FDA black box warning on clopidogrel in 2010 to communicate the importance of genotyping patients before prescribing clopidogrel.
CYP2D6 and tamoxifen
CYP2D6 is another drug-metabolizing enzyme that is responsible for the biotransformation of the prodrug tamoxifen into its active form. Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because the prodrug is converted to the active form too slowly. Clinical studies have shown that CYP2D6 variations in breast cancer patients can lead to worse clinical outcomes for tamoxifen treatment. In 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about genotyping for CYP2D6 in the package insert.
CYP2C9 and warfarin
Warfarin, a commonly prescribed anticoagulant, has a very narrow therapeutic index and wide inter-individual variation in dose requirements. A number of studies suggest that genetic variation in two genes is partially responsible for the observed differences in dose requirements between patients. CYP2C9 is the primary metabolizer of warfarin. Polymorphisms in CYP2C9 significantly slow the metabolism of warfarin, which leads to longer circulation times of the drug and thus lowering the dose needed to achieve therapeutic efficacy. VKORC1 encodes the protein subunit targeted by warfarin to exert its anticoagulant effect. Individuals with a particular mutation in VKORC1 produce less of the protein and require less drug to achieve the necessary anticoagulant effect. The FDA has now suggested that healthcare providers can use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients.