Pharmacogenomics: Bringing Hope

Pharmacogenomic research provides an understanding of the correlation between genetic factors. It serves to explain how these factors affect responses to treatment, and identifies new targets for prospective treatments. Minor differences in an individual’s genetic makeup, such as variations resulting from single nucleotide polymorphism (SNP), may potentially enhance or diminish the efficacy of a given medication or vary its side effects. An individual’s unique response to a medication may be due to variations in the drug target itself or in genetic variations pertaining to absorption, distribution, metabolism and excretion. Figure 1 illustrates how the treatment outcome can be determined by genetic variations in the drug target/target pathway, or drug-metabolizing pathway. Pharmacogenomic studies encompass both of these potential treatment determinants.

Determining Appropriate Drug Dosages Variations among individual hereditary genetic profiles may alter the rate of drug metabolism, resulting in differential therapeutic effects and toxicity levels for patients receiving the same dosage of medicine. According to Implementation of Genetics to Personalize Medicine, Gender Medicine Vol 4, No 3, 2007, these variations are common within the population and affect the majority of patients taking medication. For example, 20 to 40 percent of patients do not respond to medications commonly prescribed for hypertension, depression, coagulation, and diabetes. Potentially, genotyping can be used to assist in preventing the adverse effects of a medication and to enable the timely administration of effective treatment.

Through scientific research, the connection between a variation in a given gene and the subsequent change in drug metabolism and drug action, enables medical practitioners to prescribe suitable medications more accurately while tailoring dosages to each individual. This process is a favorable alternative to the current method of trial and error.

Improvements in Drug Discovery and Approval

Pharmacogenomics plays an important role throughout the development of biotherapeutics, from target identification through clinic trials, followed by patient care. In addition to speeding up drug discovery, it can aid in increasing therapeutic efficacy while decreasing the risks of toxicity.

Pharmaceutical companies can use pharmacogenomics to identify new drug targets and to create drugs based on the proteins, enzymes, and RNA molecules associated with specific genes and diseases. Since drug efficacy is influenced by genetic variation, drug discovery now includes pharmacogenomic screens to identify common genetic polymorphisms as part of the drug development process. This provides pharmaceutical companies with the potential to develop therapeutics that target populations which have specific genetic profiles.

As the development of a potential drug moves into the clinical trial stages, earlier work from pre-clinical stages can be used to help identify trial participants. Simple molecular diagnostic genotyping assays have been used to qualify participants for trials. The cost and risk of clinical trials can be reduced by only selecting the participants with genotypes that are likely to respond positively to the drug.

The process of obtaining regulatory approval should also be simplified as tailored drugs are targeted towards a specific genetic population, providing a higher rate of success. Finally, it is possible that failed drug candidates may be revived as they can be matched to a more niche specific population.

Pharmacogenomics analysis may reduce adverse drug events/reactions (ADR). In the US, it is estimated that ADR affects more than 2.2 million patients and kills about 100,000 people each year, making it one of the leading causes of hospitalization deaths today. Additionally, ADR is a principal reason why drugs may be withdrawn from the market, causing financial losses in the pharmaceutical industry. It is possible however, through pharmacogenomics, to identify the genes responsible for ADRs and subsequently limit prescriptions to individuals with the genotypes that will tolerate the drug.

Advanced Screening for Disease

Population-based genetic screening can identify markers and provide an opportunity for improved health outcomes through preventive medicine. Population stratification refers to differences in allele frequencies due to systematic differences in ancestry. Screening can facilitate population stratification and identify individuals who are at increased risk to various diseases. These individuals are likely to benefit from preventive medications, while the increased awareness of their susceptibility to a disease could provide the motivation to comply with recommended changes in lifestyle. For example, exercise and weight control for individuals with a higher risk of diabetes; and smoking cessation for those who are susceptible to lung cancer.

Decrease in Health Care Costs

In many clinical programs, patients with a diverse genetic composition are recruited to address inter-patient variability. However, even with the large sample sizes in current trials, the characterization of rare ADR (less than 1 in 1,000) presents a major challenge. The current solution is to perform extensive safety testing on large and heterogeneous populations prior to market approval. This significantly increases the time and cost of clinical evaluation, which creates a barrier to drug development.

An alternative solution may be found in the use of pharmacogenomics not only as a tool to develop medicines but also to enhance current drug-surveillance strategies. This surveillance approach would allow high volume, high quality, safe and accurate genetic/medical data to be gathered from several hundred thousand patients, instead of only those evaluated in post-marketing clinical trials or by voluntary reporting mechanisms. The implementation of this strategy requires the collection and storage of blood samples from each patient. This allows DNA to be extracted from a sample which corresponds to a patient who experiences ADR, to be compared with the DNA from patients who do not demonstrate any ADR.

Testing for Genetic Variation

Despite these benefits, the application of pharmacogenomics is still in its infancy. There are several applications where pharmacogenomics currently plays a role. Two of these applications are exemplified via the cytochrome P450 (CYP). This family of liver enzymes is responsible for breaking down more than 30 different classes of drugs. DNA variations in the genetic code for these enzymes can influence a person’s ability to metabolize certain drugs. The less active forms of CYP enzymes are unable to break down and aid in the efficient purging of drugs from the body. This may result in a drug overdose in patients.

Genetic tests for the detection of variations in cytochrome P450 genes are now commercially available. One such test (AmpliChip CYP450 test, Roche Diagnostics) offers the ability to genotype 29 polymorphisms, mutations, deletions, and duplications for cytochrome P450 2D6 (CYP2D6); and two polymorphisms for CYP2C19. CYP2D6 and CYP2C19 are responsible for the metabolism of approximately 25 percent of drugs, such as tricyclic antidepressants, proton pump inhibitors and benzodiazepines.

Information from the 31 assays are integrated to produce a simple interpretation, classifying a patient’s predicted metabolism as poor, intermediate, extensive, or ultra rapid. Package inserts for selected medicines may contain dosage information specific to the predicted metabolizing phenotype.

CYP enzymes also play a role in coagulation therapy. The administration of anticoagulants is a challenging therapy that has been made easier and safer by implementing a pharmacogenomic approach. Deriving the accurate dosage is critical for anti-coagulants to be effective. An insufficient dosage may deem the anti-coagulant ineffective for thrombophilia treatment, while an overdose may result in adverse effects such as bleeding. '

In the process of adjusting the dosage of Warfarin, approximately 29,000 patients are expected to suffer from bleeding complications that may require emergency room visits. Pharmacogenomic tests are now available for both the Warfarin-metabolizing gene CYP2C9 and the target vitamin K receptor VKORC1. In conjunction with other known variables such as age, gender, weight, ethnicity, diabetes and smoking status, pharmacogenomic assays help in the selection of a suitable initial dose and in reducing the length of time required to achieve optimum therapeutic results.

The detection of thiopurine methyltransferase (TPMT) in the patients to assist in the treatment of childhood leukemia is another example of a pharmacogenomic application. TPMT plays an important role in the chemotherapy treatment for common childhood leukemia. It breaks down a class of therapeutic compounds called thiopurines. A small percentage of Caucasians have genetic variants that prevent them from producing an active form of this protein.

As a result, the thiopurines become elevated to toxic levels in such patients because the inactive form of TMPT is unable to break down the drug. By using a genetic test to screen patients for such a deficiency, the TMPT activity in the patients can be monitored. This then allows the appropriate thiopurine dosage levels to be administered based on the TMPT activity.

Confidentiality Issues

To be successful at implementing a pharmacogenomics methodology, the healthcare industry needs to address patient concerns. Foremost among these is the issue of confidentiality and the potential misuse of personal genotype data. If appropriate protection measures are not implemented, public concern may become an obstacle to data collection. Implementation of a pharmacogenomics-based drug discovery approach to medicine will require large-scale genotyping of populations.

This data set presents serious implications for the pharmaceutical industry, regulatory bodies, health professionals and patients. As with any medical intervention, breaching confidentiality with respect to pharmacogenomic test results could lead to discrimination by third parties, such as insurance providers and employers.

Changing the Business Model

Pharmacogenomics offers significant advantages to drug development and commercialization. However, the segregation of patient populations could potentially limit the revenue per therapeutic approval. It costs several hundred million dollars to bring a single drug to market. Incurring such costs by introducing multiple variations of a drug to serve only small segment of the population is not financially viable. The current one-size-fits-all financial model to drug development will need to give way to a model where a pharmacogenomics approach will be fiscally motivated.

Future Needs

Pharmacogenomics is expected to provide one of the solutions to overcome the drug development barriers of toxicity and drug response. The pharmaceutical industry seems to be using pharmacogenomics increasingly for both drug selection and proper dosage determination. Molecular diagnostics and other polymerase chain reaction (PCR)-based techniques coupled with the ability to provide global views on genome sequence and gene activity, have emerged as key analytical tools in the field of pharmacogenomics. Vast amounts of data need to be collected and analyzed to meet pharmacogenomics’ goals, ranging from identifying markers that predict individuals’ responses to therapy, to discovering new drug targets. The mentioned techniques are likely to be instrumental to these efforts as they provide various sources of gene expression and genotypic data.

While the goal of personalized medicine may still take decades to materialize, the techniques that make up pharmacogenomics continue to drive this progress. In the near future, it may be possible to determine the susceptibility of individuals to disease, and the specific pharmacologic and lifestyle-based precautions that can be taken to intervene effectively. These processes can be performed in real time and at different stages in the life of individuals.

Using pharmacogenomics to rationally select appropriate medications with the correct dosage may help to prevent or treat disease more efficiently, with fewer adverse outcomes. The future of the pharmacogenomic approach to drug discovery relies on researchers to use gene manipulation technologies to better understand and/or modulate gene function as it pertains to drug treatment.

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Pharmacogenomics for Personalized Medicine

The completion of the Human Genome Project was a major milestone ushering in the era of genomics. Human gene sequence information provides avenues for the development of personalized medicine. Pharmacogenomics is fundamental to personalized medicine strategies and holds the key to drugs that may one day be customized for one’s specific genetic makeup. The FDA defines pharmacogenomics as “The study of variations of deoxyribonucleic acid (DNA) and riboNucleic acid (RNA) characteristics as related to drug response” or simply put, how an individual’s genetic inheritance influences the body’s response to drugs.

Environmental, dietary, age, lifestyle and state of health factors can all influence an individual’s response to medicines. Pharmacogenomics is expected to improve positive patient outcomes by increasing the understanding of the genetic basis for both the disease and the response to treatment. Therefore, the potential benefits resulting from the study of pharmacogenomics range from a reduction in ADR and the cost of treatment, to improving the overall pharmaceutical development workflow.

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Gene-Editing Tools for Research

Several gene-editing tools with the potential to facilitate pharmacogenomics research have been introduced. Advancements in gene editing and RNA interference (RNAi) technologies provide the critical tools required for the study of gene functions, the exploration of disease development mechanisms, and the identification of drug targets.

As Dr Edward Weinstein, director of Sigma-Aldrich Transgenics postulates, “When personalized medicine is thought of as a means of subdividing patients suffering from a common disease into populations of ‘responders’ and ‘non-responders’ to a certain treatment, rather than the tailoring of drugs to individuals, we can say that we are on the brink of significant breakthroughs in this field. The RNAi Consortium (TRC) library is a pharmacogenomics tool that can be integrated into both basic R&D and pre-clinical studies. It provides a significant enhancement in the understanding of the mechanisms of both candidate drugs and established therapeutics.”

The application of RNAi technologies in pharmacogenomics substantially speeds up the process of pharmacogenomics development. The short hairpin RNA (shRNA) libraries are developed by the RNAi Consortium (TRC), which is a public-private effort based at the Broad Institute. The mission of the Broad Institute is to create a shRNA library as well to validate tools and methods that will enable the scientific community to use RNAi to determine the function of human and mouse genes. In addition to traditional RNAi technologies, zinc finger nuclease (ZFN) technology has recently been commercialized. ZFNs are a class of engineered DNA-binding proteins that facilitate the targeted editing of the genome by creating double-strand breaks in DNA at user-specified locations.

ZFNs consist of an N-terminal zinc finger DNA-binding domain, a variable peptide linker and a C-terminal endonuclease domain. By introducing a break at a desired location, ZFNs can be used to insert or delete a gene from the human genome, or be used to modify gene expression patterns. Current expectations are that the field of gene manipulation and gene editing will advance the field of pharmacogenomics.

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