The incorporation of genomic biomarkers into the drug development and clinical trial continuum allows
biopharma to select the optimal group of patients to be enrolled into trials and reduce the number of adverse events. This will lead to more successful clinical trials and decrease 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.
Impact of Pharmacogenomics on Drug Development
- Deliver more predictable responses to drug therapy
- Minimize the occurrence and severity of adverse drug reactions (ADRs)
- Accelerate the drug discovery and development process
- Conduct more cost-effective clinical trials
Government regulators continue to encourage companies to evaluate and incorporate genomic biomarkers in clinical trials, releasing an updated draft guidance for Clinical Pharmacogenomics in February 2011. Gentris, in compliance with the FDA, EMEA, ICH, Laboratory Standards Committee, and other regulatory bodies, has implemented company-wide policies and procedures that meet and exceed regulatory guidelines.
Gentris has 10 years of experience in designing, implementing, and interpreting pharmacogenomics to improve clinical trials. Examples include genotyping patients for oncogene mutations that affect the efficacy and/or safety of specific drugs and measuring gene expression markers of drug metabolizing enzymes to identify variations associated with drug response.
Examples of Pharmacogenomics-driven Medicine
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.
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.
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.