Current PharmacoGenomics Assignment

8/7/2019 Current PharmacoGenomics Assignment

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Name: Mirza Ahmed Hammad Subject: Genomics Roll No: 1255

Department Of Bio-Informatics(M) Session: 2007-2011

PHARMACOGENOMICS

PharmacoGenomics is the study of how genes affect the way individuals responds to drugs. In thisreport, the term PharmacoGenomics refers to products that use any variety of biomarkers for diagnosis, drugprescription, or patient treatment. These biomarkers can include differences in the DNA, RNA, alleles, andsingle nucleotide polymorphisms (SNPs) among patients. This definition also includes all technologies thatinvolve Gene Therapy, Gene Expression, Proteomics, and Bio-Informatics.

PharmacoGenomics uses markers in individuals genetic code to pinpoint the underlying causes of disease. The science is enabling researchers to better identify drug targets and mechanisms of action of investigational new drug candidates. Genomics-related technology facilitates the elimination of unfavorableproducts at earlier stages of development than is currently possible. It also could guide companies indesigning clinical trials that would more definitively prove drug efficacy, in turn decreasing the time, costs,and risks of drug development. In the clinical setting, PharmacoGenomics will help physicians better definelong-term health risks patients face, more precisely diagnose the stage of patients disease, and moreaccurately predict their responsiveness to specific drugs or the likelihood for adverse event.

The Pharmaceutical Industry Today:In the past 40 years, the Pharmaceutical business has grown into a $250 billion industry in the United

States. At the top are about a dozen multinational Pharmaceutical giants that control the majority of theresources and products that drive the industry. Supporting these larger firms, as well as making discoveriesand commercializing drugs alone or in collaboration with their peers, are the life sciences companies.

Blockbuster Business Model:The Pharmaceutical industry is dominated by the

Blockbuster business model, in which companies build

their operations around a few products that produce thebulk of their revenues and dictate their strategicdirection. Currently, a blockbuster drug is defined as onewith peak annual global sales exceeding $1 billion. Beyondthe strict market definition, a Blockbuster drug typically islabeled for use by the general population or largersubsets thereof. Frequently it is prescribed for a chroniccondition, providing for long term sales. TheseBlockbuster drugs have a great impact on Pharmaceuticalindustry by becoming a barrier to new drugs.

Now, the industry needs to develop new discovery,development, manufacturing and marketing process

techniques to take new drugs in the market.

THE BLOCKBUSTER MODEL UNDER PRESSURE:The blockbuster model assumes that a single compound could effectively treat most or all patients who

have a particular condition. The drug approval process and scientific expectation given the availabletechnologies have assumed the same. Yet blockbuster drugs may be efficacious in only 40 to 60 percent of the general population. As long as there is no adverse affect in the remaining patients, physicians are able to





prescribe them on a trial-and-error basis. Patients, who benefit, continue taking them while those who donot, try something else.

Societal Pressures:Drugs can be shown to be safe and effective in closely controlled clinical trials, as long as the trials are

large enough to account for non-responders. With market, launch come problematic factors not present inthe clinical studies. Patterns and adverse events not obvious in the relatively small pivotal trials are moreapparent once a drug has been prescribed to hundreds of thousands of patients. For example, patients donot always comply with their treatment regimen. On the other hand, categories of patients not included inclinical trials, such as children, the elderly, and pregnant women, now have access to the product. Severalrecent incidents have given the public reason to doubt the safety and effectiveness of blockbuster drugs.

The most recent blockbuster product pulled off the market for safety issues was Merck s Vioxx(rofecoxib), for the treatment of arthritic pain. It was found to increase the risks of stroke and cardiovascularevents in some patients. Vioxx was a $2.5 billion product for Merck. As of January 2005, the company hadlost a significant amount of its market capitalization with the product withdrawal and was facing numerousproduct-related lawsuits. Pfizer s Celebrex, also for the treatment of arthritic pain, has also been pulled fromclinical studies in cancer patients due to increased risks of heart problems in those subjects.

Such incidents have repercussions throughout the industry. Drug companies realize significant monetaryand credibility losses even if they stay in business. The safety of other drugs within the same categories isscrutinized, and label changes often extend across a class of compounds. The approval process becomes evenmore cautionary, and payers, physicians, and patients lose confidence in the products.

Alliances of PharmacoGenomics:1. Genomics studies the makeup of the individual s DNA, which is set at conception and

remains the same.2. Proteomics focuses on the constellation of proteins within the cell, which can be altered by

health, environmental, and physical changes.

3.

Pharmacokinetics is the study of the body s absorption, distribution, metabolism, andexcretion of drugs.4. Bioinformatics: Working with researchers and sponsors, bioinformatics companies process

massive amounts of data and look for patterns across patient groups or disease progression. Very fewbioinformatics-only companies remain, of which Genetics Squared and Lion Biosciences are examples, asare divisions of IBM and General Electric.

The Promise of PharmacoGenomics:Genomics studies the genome of living organisms; PharmacoGenomics applies the results of those

studies toward treating disease. The promise of PharmacoGenomics is that it will transform medicine fromprescribing treatment based on a patient s symptoms to therapies based on the patient s genetics. Byidentifying genetic markers associated with specific conditions, researchers expect to find targets for drugs or

therapies to cure diseases, rather than just alleviate symptoms. Ultimately, PharmacoGenomicscontributions to R&D productivity will be evaluated on four measures: number of resulting products, revenuepotential, time saved, and costs-to-return ratios. By bridging the chasm between gene discovery and drugdevelopment, PharmacoGenomics holds great potential in all four metrics.

More Predictable Trial Outcomes:By stratifying clinical trial participants to include those most likely to benefit from the drug candidate

and exclude those who likely will not PharmacoGenomics-based clinical trials should attain more specific





results with smaller numbers of patients. Smaller numbers mean fewer costs. However, the more importantaspect for trial participants and internal review boards (IRBs) is that stratification, given the correctbiomarker, may reduce or eliminate adverse events. Furthermore, PharmacoGenomics data gathered in anyof the trial stages can be used to improve the compound or alter the trial design going forward. That is,where in traditional drug development a drug would be considered a failure if data were inconclusive,PharmacoGenomics enables educated data mining to better define the appropriate patient population, andmove forward as costs and anticipated returns warrant.

Archiving DNA information from ongoing clinical studies with patients consent could be used toeffectively analyze pharmacokinetic outliers from uncorrelated patient responses, and possibly acceleratefuture research. The data also could guide the development of next-generation compounds, which may haveimproved efficacy.

PHARMACOGENOMICS IN PATIENT CAREIn lay terms, PharmacoGenomics advances healthcare from the trial-and-error and one-size-fits-all

approaches of traditional products to an age of truly personalized medicine. The anticipated advantages topatient care are numerous.

Increased Safety and Efficacy:The shift from broad treatment strategies to more individually, genetically selected approaches wouldhelp ensure that therapies would be both safer and more effective. Today, nearly 3 million prescriptions outof the approximately 3.5 billion written annually are wrong that is, patients are treated with an incorrect orineffective drug. While most of those errors are minor, numerous studies have identified a rising incidence of adverse drug reactions (ADRs) in patients. According to the FDA, more than 100,000 U.S. patients die eachyear from ADRs. At the core of the issue is that traditional drugs cannot differentiate among different typesof patients.

In one measure, there are high responders, those who demonstrate high-drug efficacy; poorresponders, those who demonstrate incomplete drug-efficacy; and non-responders, those who demonstrateno drug response. This latter group may have a heightened risk of ADRs. The way different individuals bodies

metabolize drugs also can come into play. As poor metabolizers cannot clear drug from their bodies, theyface higher risks of toxicity and other ADRs.

Another factor contributing to poor drug response can be poor patient compliance. Patients who arebenefiting from a treatment are more likely to stay with it. PharmacoGenomics products, which areprescribed to the patients who are genetically predisposed to respond, deliver health benefits. Dosages canbe better controlled and side-effects, while not always avoidable, can be better anticipated withPharmacoGenomics products.

More Precise Diagnosis and Prognosis:Complex diseases, such as Cancer, comprise numerous subtypes. Because the symptoms and risk factors

look the same, it has not been possible with traditional medicine to differentiate among the types, much less

customize treatment regimens to each. PharmacoGenomics, through sequencing and screening technologies,is able to define precise disease types.

As importantly, physician can use PharmacoGenomics technologies to determine a patient s progressionin disease by using diagnostic tests on a routine basis to monitor a patient s disease state. This informationcan be extremely helpful to the patient in making treatment decisions and future arrangements. It can alsoimprove long-term treatment of the condition as products and doses can be prescribed based on actualdisease progression.





Earlier Detection and Possible Prevention:Among early genetic tests have been those that show heightened risk for certain diseases or conditions.

PharmacoGenomics companies are looking for Markers for many others, including those for cardiovasculardisease, Alcoholism, Obesity and Lung cancer. Individuals at higher than normal risk for these developedconditions might be convinced to make lifestyles choices, such as not Smoking or not drinking alcohol, toavoid the condition. If not, their physicians would know to screen them more frequently and to select moreaggressive treatment options if the condition manifested. For diseases such as Alzheimer s and rheumatoidarthritis, where the available therapies primarily work to slow progression, early diagnosis could prove mostbeneficial.

Biomarkers and their significance in drug development: A biomarker has been defined as a characteristic that can be measured and evaluated as an indicator

of normal biologic processes, pathologic processes or pharmacologic responses to therapeutic intervention (NIH Biomarker Definitions Working Group, 1998). Other definitions have since evolved and the discussion onwhat biomarkers should be and where to apply them continues. Biomarkers are currently being used invarious areas, including disease identification, target discovery and validation, volunteer/patient inclusionand stratification during clinical studies, drug efficacy and safety and prediction of drug response.

The rising costs of drug development are putting considerable demands on efficiency in the selection of suitable drug candidates. An effective strategy in improving the selection process in R&D is the properselection and application of biomarkers for efficacy and safety during the different stages of the drugdevelopment pipeline. There are two basic approaches to the identification and selection of biomarkers.

y The classical method involves hypothesis and is based on a priori knowledge of a process or mechanism.However, non-biased approaches are becoming increasingly applied.

y Genomics-based methods (transcriptomics, proteomics and metabolomics) combined with multivariate(pattern recognition) statistics form the basis for the discovery of novel biomarkers and biomarkerpatterns.y Beyond Genomics applies Systems Biology to discover novel biomarkers and develop biological

pathway knowledge for detecting disease and measuring drug response. Systems biology uses anintegrated approach to study and understand the function of biological systems, and howperturbations of such systems, for example the administration of a drug, affect their function

Biomarker validity: It is not the intention of this document to make any statements or claims on the validity of an individual

biomarkers or sets of biomarkers. Validity is a complex characteristic and subject to much discussion. Validitydescribes the extent to which a biomarker reflects a designated event in a biological system. Validity requiresnot only analytical but also biological and sometimes epidemiological knowledge as well as knowledge of the(many) interference factors.

For a detail, I have also included a list of Biomarkers and their uses providing current developments inDrug Improvement Program with some Other References in CD.

Current PharmacoGenomics Assignment

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