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

P HARMACO G ENOMICS

PharmacoGenomics is the study of how genes affect the way individuals responds to drugs. In this
report, the term PharmacoGenomics refers to products that use any variety of biomarkers for diagnosis, drug
prescription, or patient treatment. These biomarkers can include differences in the DNA, RNA, alleles, and
single nucleotide polymorphisms (SNPs) among patients. This definition also includes all technologies that
involve 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 unfavorable
products at earlier stages of development than is currently possible. It also could guide companies in
designing 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 define
long-term health risks patients face, more precisely diagnose the stage of patients’ disease, and more
accurately 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 the
resources and products that drive the industry. Supporting these larger firms, as well as making discoveries
and 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 the
bulk of their revenues and dictate their strategic direction.
Currently, a blockbuster drug is defined as one with peak
annual global sales exceeding $1 billion. Beyond the strict
market definition, a Blockbuster drug typically is labeled
for use by the general population or larger subsets
thereof. Frequently it is prescribed for a chronic condition,
providing for long term sales. These Blockbuster drugs
have a great impact on Pharmaceutical industry 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 available
technologies 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

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

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

prescribe them on a trial-and-error basis. Patients, who benefit, continue taking them while those who do
not, 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 in
the clinical studies. Patterns and adverse events not obvious in the relatively small pivotal trials are more
apparent once a drug has been prescribed to hundreds of thousands of patients. For example, patients do
not always comply with their treatment regimen. On the other hand, categories of patients not included in
clinical trials, such as children, the elderly, and pregnant women, now have access to the product. Several
recent 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 cardiovascular
events in some patients. Vioxx was a $2.5 billion product for Merck. As of January 2005, the company had
lost a significant amount of its market capitalization with the product withdrawal and was facing numerous
product-related lawsuits. Pfizer’s Celebrex, also for the treatment of arthritic pain, has also been pulled from
clinical 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 monetary
and credibility losses even if they stay in business. The safety of other drugs within the same categories is
scrutinized, and label changes often extend across a class of compounds. The approval process becomes even
more 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, and
excretion 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 few
bioinformatics-only companies remain, of which Genetics Squared and Lion Biosciences are examples, as
are 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 from
prescribing treatment based on a patient’s symptoms to therapies based on the patient’s genetics. By
identifying genetic markers associated with specific conditions, researchers expect to find targets for drugs or
therapies to cure diseases, rather than just alleviate symptoms. Ultimately, PharmacoGenomics’
contributions to R&D productivity will be evaluated on four measures: number of resulting products, revenue
potential, time saved, and costs-to-return ratios. By bridging the chasm between gene discovery and drug
development, 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

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

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

results with smaller numbers of patients. Smaller numbers mean fewer costs. However, the more important
aspect for trial participants and internal review boards (IRBs) is that stratification, given the correct
biomarker, may reduce or eliminate adverse events. Furthermore, PharmacoGenomics data gathered in any
of 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, and
move forward as costs and anticipated returns warrant.
Archiving DNA information from ongoing clinical studies—with patients’ consent— could be used to
effectively analyze pharmacokinetic outliers from uncorrelated patient responses, and possibly accelerate
future research. The data also could guide the development of next-generation compounds, which may have
improved efficacy.

PHARMACOGENOMICS IN PATIENT CARE

In 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 to
patient care are numerous.

Increased Safety and Efficacy:

The shift from broad treatment strategies to more individually, genetically selected approaches would
help ensure that therapies would be both safer and more effective. Today, nearly 3 million prescriptions out
of the approximately 3.5 billion written annually are wrong—that is, patients are treated with an incorrect or
ineffective 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 each
year from ADRs. At the core of the issue is that traditional drugs cannot differentiate among different types of
patients.

In one measure, there are high responders, those who demonstrate high-drug efficacy; poor responders,
those who demonstrate incomplete drug-efficacy; and non-responders, those who demonstrate no 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, they
face higher risks of toxicity and other ADRs.

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

in disease by using diagnostic tests on a routine basis to monitor a patient’s disease state. This information
can be extremely helpful to the patient in making treatment decisions and future arrangements. It can also
improve long-term treatment of the condition as products and doses can be prescribed based on actual
disease progression.

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

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

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 cardiovascular
disease, Alcoholism, Obesity and Lung cancer. Individuals at higher than normal risk for these developed
conditions might be convinced to make lifestyles choices, such as not Smoking or not drinking alcohol, to
avoid the condition. If not, their physicians would know to screen them more frequently and to select more
aggressive treatment options if the condition manifested. For diseases such as Alzheimer’s and rheumatoid
arthritis, where the available therapies primarily work to slow progression, early diagnosis could prove most
beneficial.

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 on
what biomarkers should be and where to apply them continues. Biomarkers are currently being used in
various areas, including disease identification, target discovery and validation, volunteer/patient inclusion
and 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 proper
selection and application of biomarkers for efficacy and safety during the different stages of the drug
development pipeline. There are two basic approaches to the identification and selection of biomarkers.

 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.
 Genomics-based methods (transcriptomics, proteomics and metabolomics) combined with multivariate
(pattern recognition) statistics form the basis for the discovery of novel biomarkers and biomarker
patterns.
 Beyond Genomics applies Systems Biology to discover novel biomarkers and develop biological
pathway knowledge for detecting disease and measuring drug response. Systems biology uses an
integrated approach to study and understand the function of biological systems, and how
perturbations 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. Validity
describes the extent to which a biomarker reflects a designated event in a biological system. Validity requires
not 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 in
Drug Improvement Program with some Other References in CD.

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