Tailor made medicine

TAILOR MADE MEDICINE

BY,
DR. SHREERAJ SHAH
ASSOCIATE PROFESSOR,
DEPT. OF PHARMACEUTICAL
TECHNOLOGY,
L.J. INSTITUTE OF PHARMACY,
AHMEDABAD.

CONTENTS
 Introduction
 Definition
 Brief History
 Difference between common drug and personalize medicine
 Driving the Movement to Personalized Medicine
 Goals for personalized medicine
 Benefits of Personalized Medicine
 Limitation of personalized medicine
 Potential applications
 Selected Personalized Medicine Drugs, Treatments, and Diagnostics
 Biomarker and theranostics with reference to medicine of 2050
 Future of “Theranostics”
 “Medicine 2050”- with respect to Personalized medicines
 Societal Benefits and Costs
 Conclusion
 References
2

INTRODUCTION
 Scientific achievements have had an immeasurable influence on
the uses of innovative biopharmaceuticals and methods in
medicine. These breakthrough discoveries have contributed to an
irreversible change in the perception and use of diagnostics in
contemporary treatment of many illnesses.
 Today, in addition to the well-established types of physical and
chemical examination and our growing understanding of
biochemical processes occurring in the body, we now have at our
fingertips state-of-the-art diagnostics and therapies based on the
molecular pathomechanisms of illnesses.
 Although the discovery of specific pathogens revolutionized
medicine in the 19th and 20th centuries, making it possible to
create pharmaceuticals essential to treat certain illnesses,
generally improve health, or extend patients’ lives.
 So this will require the implementation of a fully innovative,
individualized approach to illness and its treatment in patients. 3

TAILOR MADE MEDICINE OR PERSONALIZED
MEDICINE

 Personalized medicine refers to the tailoring of medical
treatments to the individual characteristics of each
patient.

 It does not literally mean the creation of drugs or
medical devices that are unique to a patient but rather the
ability to classify individuals into subpopulations that
differ in their susceptibility to a particular disease or
their response to a specific treatment.

 Preventive or therapeutic interventions can then be
concentrated on those who will benefit, sparing expense
4
and side effects for those who will not.

“It’s far more important to know what person the
disease has than what disease the person has.”

Hippocrates (ca. 400 BCE)

5

BRIEF HISTORY
 1898:- Sir Archibald Garrod coins the term “chemical individuality” to describe inherited
predispositions to metabolizing sulphonal drugs.
 1900:- Gregor Mendel’s work, conducted in 1865 and largely ignored, is rediscovered,
launching the genetic era.
 1902:- Lucien Cuenot advances the hypothesis that genetically determined differences in
biochemical processes could be the cause of adverse reactions after the ingestion of drugs.
 1941:- The relationship between genes and the production of proteins is discovered.
 1956:- The “chemical individuality” hypothesis is proven when a genetic deficiency of
glucose-6-phosphate dehydrogenase is found to be linked to antimalarial primaquine
toxicity.
 1959:- The term “pharmacogenetics” is coined by the German geneticist Friedrich Vogel.
 1967:- The genetic code is cracked, revealing how DNA sequences code for protein.
 1975:- Gene sequencing techniques are invented.
 1977:- Metabolism of drugs by enzymes of the CYP450 system is identified as a key
genetically determined cause for variation in drug response.
 1983:- A polymerase chain reaction technique is invented for in vitro amplification of
DNA sequences.
6
 1990:- The Human Genome Project is launched.

 April 2003:- The sequencing of the human genome is declared complete
after 13 years and a $3 billion investment.
 May 2004:-The Office of the National Coordinator for Health Information
Technology is established.
 November 2004:- The Personalized Medicine Coalition (PMC) is launched
with 18 members from industry, government, and academia.
 December 2004:- The Oncotype DX® gene profile for optimizing breast
cancer therapy is introduced.
 March 2005:- The FDA issues a Guidance for Industry on
Pharmacogenomic Data Submissions.
 April 2005:- The FDA issues a white paper on co-developed diagnostic
therapeutic products.
 October 2005:- A haplotype map of the human genome is published,
providing a powerful tool for linking genetic variation to disease
susceptibility and response to treatment.
 February 2006:- The National Institutes of Health (NIH) launches the
Genes, Environment and Health Initiative. 7
 August 2006:- Senator Barack Obama introduces the “Genomics and
Personalized Medicine Act.”

 February 2007:- MammaPrint® becomes first predictive genetic test for breast cancer to
receive formal approval by the FDA. A major genome-wide association study identifies
gene variants linked to type 2 diabetes.
 March 2007:- The Department of Health and Human Services (HHS) announces the
Personalized Health Care Initiative.
 June 2007:- The Wellcome Trust Case Control Consortium analyzes 17,000 Britons to
find genetic variants linked to bipolar disorder, high blood pressure, coronary artery
disease, Crohn’s disease, type 1 and type 2 diabetes, and rheumatoid arthritis.
 August 2007:- The FDA re-labels the blood thinning drug warfarin to recommend
adjusting the dose based on genetic variation.
 April 2008:- James Watson’s genome is sequenced in two months for $1,000,000.
 May 2008:- The Genetic Information Non-Discrimination Act (GINA) is signed into law.
The first high-resolution sequence map of human genetic variation is produced.
 July 2008:- The FDA recommends genetic testing before taking the HIV drug abacavir
to reduce allergic reactions.
 August 2008:- Pharmacy benefits manager Medco collaborates with FDA to study the
impact of genetic testing on the prescription of drugs and their effectiveness.
 September 2008:- The President’s Council of Advisors on Science and Technology
(PCAST) issues the report, Priorities for Personalized Medicine.
 October 2008:- Ten prominent individuals release their genomic data as part of the
Personal Genome Project.
 March 2009:- Massachusetts General Hospital announces plans to genotype every cancer
8
patient to implement personalized medical care.
 April 2009:- Senate brings personalized medicine into national budget discussions.

Difference between common drug and personalized
medicine
Current Practice Personalized Medicine

One size fits all

The right treatment
Trial and error for the right person
at the right time 9

Personalized medicine recognizes that individual patients may react in very 10
different ways to the same treatment given for the same problem. The goal
is to tailor therapies based on a patient's DNA profile.

WHAT IS DRIVING THE MOVEMENT TO
PERSONALIZED MEDICINE?

Consumer Demand for:-
Safer and More Effective Drugs

Faster Time to a Cure

Cost-Effective Healthcare
11

GOALS FOR PERSONALIZED
MEDICINE
 Identify genetic differences between people that affect drug
response

 Develop genetic tests that predict an individual’s response to
a drug

 Tailor medical treatment to the individual
# Increase effectiveness
# Minimize adverse side effects

12

BENEFITS OF PERSONALIZED MEDICINE

 Shiftemphasis in medicine from reaction to
prevention

 Select optimal therapies

 Increase safety, reduce adverse drug reactions

 Increase patient compliance

 Reduce the time, cost, and failure rate of clinical trials
13
 Reduce the overall cost of healthcare

LIMITATION OF PERSONALIZED
MEDICINE
 Healthcare workforce (incl. physicians): currently no
adequate training to make use of Personalized Medicine, not
implemented in medical school curricula

 Public may be inhibited by full participation in personalized
medicine research or clinical care, unless full genetic privacy
is put in place

 Healthcare IT needed for linking patient information to
genomic research (Electronic Medical Records)
14

POTENTIAL APPLICATIONS
 Fields of Translational Research termed "-omics"
(genomics, proteomics, and metabolomics) study the
contribution of genes, proteins, and to human
physiology and variations of these pathways that can
lead
to disease susceptibility. It is hoped that these fields
will
enable new approaches to diagnosis, drug development,
and individualized therapy.

I. Pharmacogenetics

II. Pharmacometabonomics
15

III. Cancer management

I. PHARMACOGENETICS:-
 Pharmacogenetics (also termed pharmacogenomics) is the
field of study that examines the impact of genetic variation on
the response to medications.

 This approach is aimed at tailoring drug therapy at a dosage
that is most appropriate for an individual patient, with the
potential benefits of increasing the efficacy and safety of
medications.

.
16

EXAMPLES OF PHARMACOGENETICS:-

 Genotyping variants in genes encoding Cytochrome
P450 enzymes (CYP2D6, CYP2C19, and CYP2C9),
which metabolize neuroleptic medications, to improve
drug response and reduce side-effects.

17

II. PHARMACOMETABONOMICS:-
 Researchers at Imperial College London have demonstrated that
pre-dose metabolic profiles from urine of rats and humans can be
used to predict how they will metabolize drugs such
acetaminophen (paracetamol).

 The authors observed that individuals having high pre-dose
urinary levels of p-cresol sulfate, a gut bacteria co metabolite,
had low post-dose urinary ratios of acetaminophen sulfate to
acetaminophen glucuronide.

18

III. CANCER MANAGEMENT:-
 Oncology is a field of medicine with a long history of
classifying tumor stages based on anatomic and pathologic
findings. This approach includes histological examination of
tumor specimens from individual patients (such as HER2
(Human Epidermal Growth Factor Receptor 2 /Neu in breast
cancer). Thus, "personalized medicine" was in practice long
before the term was coined.
 New molecular testing methods have enabled an extension of
this approach to include testing for global gene, protein, and
protein pathway and/or somatic mutations in cancer
cells from patients in order to better define the prognosis in
these patients and to suggest treatment options that are most
likely to succeed. 19

EXAMPLES OF PERSONALIZED CANCER
MANAGEMENT:-
(A) Testing for disease-causing mutations in the BRCA1
(human caretaker gene that produces a protein called breast
cancer type 1 susceptibility protein, responsible for repairing
DNA) and BRCA2 genes, which are implicated in familial
breast and ovarian cancer syndromes.
 Discovery of a disease-causing mutation in a family can
inform "at-risk" individuals as to whether they are at higher
risk for cancer and may prompt individualized prophylactic
therapy including mastectomy and removal of the ovaries.
 This testing involves complicated personal decisions and
is
20
undertaken in the context of detailed genetic counseling.

(B) Minimal residual disease (MRD) tests are used to quantify
residual cancer, enabling detection of tumor markers before
physical signs and symptoms return. This assists physicians
in making clinical decisions sooner than previously possible.

(C) Herceptin (Trastuzumab; trade name Herceptin), a
monoclonal antibody that interferes with
the HER2/neu receptor ) is used in the treatment of women
with breast cancer in which HER2 protein is overexpressed.

21

INEFFECTIVE THERAPIES CAN CAUSE HARM

 Estimated 100,000 deaths per year

 6th leading cause of death in the US

 Medication-related health problems account for an
estimated
3% to 7% of hospital admissions

 During their hospital stay, 15% of patients experienced
adverse drug reactions
22
 Increased patient non-compliance

ONE SIZE DOES NOT FIT ALL

 ANTI-DEPRESSANTS 38%

 ASTHMA DRUGS 40%

 DIABETES DRUGS 43%

 ARTHRITIS DRUGS 50%

 ALZHEIMER’S DRUGS 70%

 CANCER DRUGS 75%
23
Here, study was carried out on 100 patient for
each disease condition.

 A report from the Personalized Medicine
Coalition: The Case for Personalized Medicine puts
the advent of personalized medicine in context:
"Since the mapping of the human genome in 2003,
the pace of discovery, product development, and
clinical adoption of what we know as personalized
medicine has accelerated."
 For the pharmaceutical industry the advances in
personalized medicines are something of a
revolution. With arguably the most significant
investment in bringing products to market than any
other industry – it’s estimated that it takes 15 years
and $1 billion in development, testing and licensing
to bring a drug to market – personalized medicine
brings with it significant opportunities to bring
much greater efficiencies to the highly costly area of 24

clinical trials.

SELECTED PERSONALIZED MEDICINE DRUGS,
TREATMENTS, AND DIAGNOSTICS
THERAPY BIOMARKER/TEST INDICATION

Breast cancer: “…for the treatment of patients with
Herceptin® metastatic breast cancer whose tumors over express the
(trastuzumab) HER-2/neu receptor HER2 protein and who have received one or more
Tykerb® (lapatinib) chemotherapy regimens for their
metastatic disease.”

Aviara Breast Cancer Breast cancer: Calculates a combined risk analysis for
Tamoxifen IndexSM (HOXB13, recurrence after tamoxifen treatment for ER-positive, node-
IL17BR) negative breast cancer.

Breastcancer: Prognosticimmunohistochemistry (IHC) test
used for postmenopausal, node
Chemotherapy Mammostrat® negative, estrogen receptor expressing breast cancer
patients who will receive hormonal therapy and are
considering adjuvant chemotherapy.

Breast cancer: Assesses risk of distant metastasis in a 70
Chemotherapy MammaPrint®
gene expression profile.

Cardiovascular disease: “an increased bleeding risk for
25
Coumadin®
CYP2C9 patients carrying either the CYP2C9*2 or CYP2C9*3
(warfarin)
alleles.”

Cardiovascular disease: Predicts risk of statin-induced neuro-myopathy, based on a
Statins PhyzioType SINM
patient’s combinatorial genotype for 50 genes.

Cardiovascular disease: “Doses should be individualized according to the
Atorvastatin LDLR recommended goal of therapy. Homozygous Familial Hypercholestremia (10-
80mg/day)and heterozygous (10-20mg/ day).”

Colon cancer: “Variations in the UGT1A1 gene can influence a patient’s ability to
Camptosar® (irinotecan) UGTIA1 break down irinotecan, which can lead to increased blood levels of the drug and a
higher risk of side effects.”

Erbitux® (cetuximab)
KRAS Colon cancer: Certain KRAS mutations lead to unresponsiveness to the drug.
Gefitinib

Colon cancer: “Patients enrolled in the clinical studies were required to have…
Erbitux® (cetuximab)
evidence of positive EGFR expression using the DakoCytomation EGFR pharmDx™
Gefitinib EGFR expression
test kit.” EGFR positive individuals are more likely to respond to the drug than those
Vectibix®
with reduced EGFR expression.

Erbitux® (cetuximab) and
Vectibix® (panitumab) Colon cancer: Provides information of the expression of key molecular targets—
Target GI™
Fluorouracil KRAS, TS, and TOPO1—to guide therapy.
Camptosar®(irinotecan)

Epilepsy and bipolar disorder: Serious dermatologic reactions are associated with
the HLAB*1502 allele in patients treated with carbamazepine. “Prior to initiating
Tagretol (carbamazepine) HLA-B*1502
Tegretol therapy, testing for HLA-B*1502 should be performed in patients with
ancestry in populations in which HLAB*1502 may be present.”

Heart transplantation: Monitors patient’s immune response to heart transplant to
Immunosuppressive drugs AlloMap® gene profile
guide immunosuppressive therapy.
26
HIV: “Patients who carry the HLA-B*5701 allele are at high risk for experiencing a
Ziagen® (abacavir) HLA-B*5701 hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir,
screening for the HLA-B*5701 allele is recommended.”

Multiple diseases: FDA classification 21 CFR 862.3360: “This device
is used as an aid in determining treatment choice and individualizing
Drugs metabolized by Amplichip®
treatment dose for therapeutics that are metabolized
CYP P450 CYP2D6/CYP2C19
primarily by the specific enzyme about which the system provides
genotypic information.”

Rifampin Multiple diseases: N-acetyltransferase slow and fast acetylators and
Isoniazid NAT toxicity- “slow acetylation may lead to higher blood levels of the drug,
Pyrazinamide and thus, an increase in toxic reactions.”

Non-Hodgkin’s lymphoma: Detects CD-20 variant (polymorphism in
PGx PredictTM:
Rituximab the IgG Fc receptor gene FcgRIIIa) to predict response to cancer drug
Rituximab
rituximab.

Pain: “Patients who are known or suspected to be P450 2C9 poor
metabolizers based on a previous
Celebrex® (celecoxib) CYP2C9 history should be administered celecoxib with caution as they may
have abnormally high plasma levels due to reduced metabolic
clearance.”

Risperdal® Psychiatric disorders: Predicts risk of psychotropic-induced
(resperidone) PhyzioType PIMS metabolic syndrome, based on a patient’s combinatorial genotype for
Zyprexa® (olanzapine) 50 genes.

Stomach cancer: “Gleevec® is also indicated for the treatment of
Gleevec® (imatinib
c-KIT 27
patients with Kit (CD117) positive unresectable and/or metastatic
mesylate)
malignant gastrointestinal stromal tumors (GIST).”

BIOMARKER AND THERANOSTICS WITH
REFERENCE TO MEDICINE OF 2050
 In medicine, a biomarker is a term often used to refer to a protein measured
in blood whose concentration reflects the severity or presence of some
disease state.
 More generally a biomarker is anything that can be used as an indicator of a
particular disease state or some other physiological state of an organism.
 A biomarker can be a substance that is introduced into an organism as a
means to examine organ function or other aspects of health. For
example, rubidium chloride is used as a radioactive isotope to evaluate
perfusion of heart muscle. It can also be a substance whose detection
indicates a particular disease state, for example, the presence of
an antibody may indicate an infection.
 More specifically, a biomarker indicates a change in expression or state of
a protein that correlates with the risk or progression of a disease, or with the
susceptibility of the disease to a given treatment.
 Biomarkers are characteristic biological properties that can be detected and
measured in parts of the body like the blood or tissue 28

 In oncology the most commonly used biomarkers are enzymes and hormones linked with
tumors. They can be detected using biochemical tests, although their presence is not always
indicative of the presence of a specific tumor. For example, an increase in the levels of the
prostate-specific antigen (PSA) indicates a high likelihood of a prostate tumor being
present, but it can also be a result of a mild hyperplasia. Similarly, raised levels of the
carcino embryonic antigen (CEA) are characteristic in between 60–90% of colon cancer
cases and 50–80% of pancreatic cancers.
 Now it is possible to monitor the course of many illnesses by studying differences in the
structures of nucleic acids.
 DNA biomarkers include chromosome abnormality, single nucleotide polymorphisms
(SNPs), a change in the number of copied DNA fragments, or differences in the degree
of methylation of promoter regions. Research shows that using a biomarker that defines
the degree of DNA methylation may be a factor in differentiating between prostate cancer
from mild hyperplasia.
 RNA biomarkers include differences in the transcription levels, or RNA molecules that
29
take part in regulation.

BRINGING BIOMARKERS TO MARKET
 Bringing biomarkers into general use must be preceded by
thorough analyses of their safety in patients, reliability, efficacy,
and the financial implications of their use in diagnostics
 In the US, the steps involved in introducing a new biomarker
include:
 identification of relevant information in the patient’s biological material (using
DNA microarrays, gene chips, restriction fragment length polymorphisms (RFLP)
and others, depending on type),
 establishing possible applications, and final step
 clinical and analytical validation

 The final stage must be carried out, if the biomarker is to be
approved by the FDA for clinical use, although it can be
bypassed if it is to be used purely for research. The final
decision regarding bringing a biomarker to market lies with
the Center for Medicaid & Medicare Services (CMS),
responsible for carrying out an analysis of costs versus 30
benefits including social aspects.

FUTURE OF “THERANOSTICS”
 Researchers have even suggested introducing a new term “Theranostics,”
(a portmanteau of therapeutics and diagnostics) which is a proposed process
of diagnostic therapy for individual patients - to test them for possible
reaction to taking a new medication and to tailor a treatment for them based
on the test results.
 Effort to promote this new coin-age show how far advanced the introduction
of personalized medicine is in various branches of medicine. Some scientists
are no longer debating whether such medicines are will be used at all, but
when its use will become widespread in clinical practice.
 Personalized medicine (with Theranostics) is closely linked with several
clinical applications, and is most advanced in oncology and infectious
diseases. In the latter case, defining the genotype of the virus (HIV, hepatitis
B and C) and establishing the viremic concentration play a crucial role in
selecting an appropriate therapy, predicting its efficacy, discovering any
drug resistance and any necessary modifications of the treatment.
31

“MEDICINE 2050”- WITH RESPECT TO
PERSONALIZED MEDICINES
 The personalization of medicine is an irreversible process whose
benefits can already be observed, and whose potential benefits cannot
be overstated. This is excellently illustrated by a communication from
the European Commission on 10 December 2008, which includes a
declaration of support for scientific research in pharmaceutical
development
 “With the emergence of new technologies like pharmacogenomics
and patient-specific modelling and disease simulators, personalised
medicine is now on the horizon. In the long term, doctors may be able
to use genetic information to determine the right medicines, at the
right dose and time. This field is already affecting companies’ business
strategies, the design of clinical trials and the way medicines are
prescribed. Although it is too early to say whether ‘omics’
technologies will indeed revolutionize the sector, the Commission
32
closely monitors the area and will reflect on how it can support its
development.”

SOCIETAL BENEFITS AND COSTS
 Alongside the high hopes and optimism brought by the prospect of “made to
measure” medicine, there are also some ethical concerns. The most frequently cited
examples revolve around personal data protection, potential discrimination by
insurance firms or employers against people who have a tendency towards certain
illnesses, or personal stigma. These may become deciding factors in whether this
novel treatment strategy ultimately gains societal acceptance, therefore they should be
put forward for thorough discussion, eventually leading to concrete legislative
measures
 Doubts may also arise because of the potential costs of introducing personalized
medicine. In this instance it is essential to take a close look at the problems of
efficacy and safety of current therapies, and the intentions and options in investing in
innovative technologies
 In this specific instance it is very important to stress that a significant part of the
diagnostic costs should be recompensed through targeted and effective therapeutics.
Contemporary biopharmaceuticals (hormones, interferons and interleukins) are
very expensive, and yet ineffective, and therefore unnecessary (or badly dosed) use of
expensive drugs is wasteful
 The application of proteomics and transcriptomics to personalized medicine will 33
make it possible to optimize the possibilities of medicine in both economic and social
aspects.

CONCLUSION
 We cannot predict what medicine will be like in 2020 or
2050, although we can be certain that it will be quite
different from what it is today. The scientific, economic,
and social circumstances all indicate that “tailor-made”
medicine is likely the way of the future.

34

REFERENCES
(1) President’s Council of Advisors on Science and Technology (PCAST) “Priorities for
Personalized Medicine” September 2008

(2) Brian B. Spear, Margo Heath-Chiozzi, Jeffrey Huff, “Clinical Trends in Molecular
Medicine, Volume 7, Issue 5, 1 May 2001, Pages 201-204.

(3) National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology

for Colon and Rectal Cancer. Volume-2, 2009

(4) Abrahams A, Ginsburg GS, Silver M. The Personalized Medicine Coalition: Goals
and

strategies. Am J Pharmacogenomics , 2005;5(6): 345-355.

(5) Personalized Medicine Coalition May 2009
35
(6) The future of red biotechnology, Tailor made medicine, by Aleksandra Małyska

and Tomasz Twardowski page no:-12-15

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