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Genes and Drug Development
GlaxoSmithKline (GSK) uses
and
to advance the way we discover new medicines. These approaches
give us the capability to identify genes and understand their
role in the disease process and in treatment. The results
of this research improve our understanding of the interaction
among genes, diseases and patients' responses to medicines.
We then can apply knowledge to the development and delivery
of new medicines — getting the right medicine to the
right patient.
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Pharmaceutical companies spend up to $800 million
and 15 years to bring a new drug to the market. According
to the Pharmaceutical Research and Manufacturers of America,
for every 5,000 potential medicines discovered, only about
five are tested in patients, and only one of those five is
eventually approved for patient use. Using new genetics and
genomics technologies, it may be possible to develop more
effective medications for less cost and in less time. Only
a few years ago, the entire range of pharmaceutical products
was based on approximately 500 targets, whereas today, thanks
to genetics, the number of targets available for investigation
ranges into the thousands. As a result, patients may have
access to better medications to help treat their disease.
Drug Development Process
The drug development process involves three stages:
Drug Discovery
In the first step — target identifiction—
scientists are looking for a ‘target’ or a particular gene
sequence that they believe might influence the course of a
specific disease. Scientists are using new genetic technologies
to increase our understanding of disease at its most basic,
molecular level. They study DNA from individuals with a particular
disease and their family members to look for genes that may
make someone more susceptible to that illness. They also use
DNA sequence information from resources such as the Human
Genome Project to compare the sequences (order of DNA base
pairs) in identified genes with those of genes whose function
is already known. This helps them make educated guesses about
which genes might be related to specific biochemical pathways
in the body and how they might affect the occurrence or treatment
of disease.
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After researchers identify and validate a gene
sequence or target associated with a particular condition,
they study the role of the protein encoded by the gene. Typically,
proteins have proven to be good drug targets, so with the
rapid progress recently made in the identification of genes,
an explosion in the number of potential drug targets has occurred.
Using this information about the protein and
having an identified target can help scientists develop compounds
that might interact with the target to alter how it affects
a biochemical pathway and ultimately, the disease. This is
the first step leading to the development and discovery of
new medicines.
Drug Development
Once a target has been identified, chemists
develop compounds that may interact with that particular target.
To screen these compounds, a suitable assay or laboratory
test is developed to indicate when a compound has interacted
with a target. Scientists may screen more than a million compounds
to find a promising lead. Using an automated robotics system,
scientists can test thousands of compounds daily.
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Scientists use other techniques to screen these
compounds for their likelihood of causing some serious side
effects before they are tested in humans. For example, we
know of many common variations in genes that affect the breakdown
(metabolism) of medicines, and these
vary among ethnic groups. People who carry one of these gene
variants may need a higher or lower dose of a certain drug
for it to be effective or to avoid serious side effects. The
impact of these genes on a compound's potential safety and
effectiveness will help determine whether the pertinent compound
should be further developed or abandoned.
Other tasks completed during the drug development
process include the creation of dosage forms (for example,
tablet, capsule, caplet, aerosal, topical, etc.) and the design
of additional assays that will support its development. Physical
and chemical properties of the compound such as stability
and shelf-life are determined. It is at this stage - before
expensive clinical trials begin - that many potential drugs
are screened out for various reasons. Finally, scientists
develop a protocol for a first time study using a small number
of healthy human volunteers.
Drug Delivery
The studies, or clinical trials, involving human testing
are divided into three phases. Phase I trials test the safety
and effects of a new drug in healthy volunteers to determine
how the body interacts with the drug and what the drug does
in the body — how it is absorbed, metabolized and excreted.
During Phase I, scientists may examine the genetic basis
of patients' responses to medicines to understand why some
medicines work better for some people than others and why
some people are more likely than others to experience serious
side effects. This type of research, called ,
provides results that may ultimately lead to safer and more
effective use of medicines.
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By evaluating patients' DNA samples and clinical trial data
regarding drug safety and efficacy early in the drug
development process, researchers may be able to correlate
patient response to a medicine with variation in one or more
SNPs. Investigators then can recruit patients with specific
pharmacogenetic profiles for later clinical trials, making
those trials smaller, faster and less expensive. Doing so
reduces the need to recruit a large number of patients and
helps to reduce the overall cost of drug development.
Phase II trials are typically conducted in approximately
100 to 300 patients with a primary emphasis on evaluating
safety and gaining insight into the side effect profile. Some
evidence of the effectiveness of the medicine is gathered
during Phase II, but clear indication of its efficacy is unlikely
until large-scale Phase III trials are complete. In addition,
pharmacogenetic information obtained during this phase helps
to clarify the design and dosing regimen for use in Phase
III trials.
A Phase III trial typically involves thousands of patients
in centers worldwide and may require years of effort. These
studies fully establish efficacy while continuing to evaluate
safety.
Pharmacogenetic testing during Phase III, together with other
information collected in the clinical trials, allows GSK to
study patients' responses to a medicine based on their .
This information allows scientists to identify polymorphisms
that may determine the effectiveness of the medicine for individual
patients.
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The entire data package from all the studies performed to
support the drug's safety and efficacy is submitted to regulatory
agencies around the world. This represents a formal application
for government licenses to market the product. Regulatory
authorities evaluate the data and decide whether to grant
a product license for a particular use or indication of the
medicine.
Pharmacogenetic testing during drug development has important
implications for the development and delivery of medicines.
Currently, the "one-size-fits-all" prescribing practice
means that patients sometimes may take medicines that they
cannot tolerate because of side effects or go through trial
periods with several drugs before finding one that works.
The results of pharmacogenetic testing may lead to the development
of a Medicine Response Test (MRT) for some drugs — a
"mini genetic profile" that will assess just those
genes or SNPs found to be associated with a specific response.
In the future, health care providers may use MRTs to predict
which patients are likely to have a serious side effect or
to benefit from a given medicine. Specific pharmacogenetic
profiles, in the form of MRTs, will differentiate those who
have a greater chance of responding in a certain way to a
particular medicine.
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