A SEMINAR ON TAILOR MADE MEDICINE

Keyur Vasava...

(1) Tailor Made Medicine (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 and side effects for those who will not. Personalized medicine offers a structural model for efficient healthcare. It is preventive, coordinated, and evidence-based. It relies on a network of electronic health records that link clinical and molecular information to help patients and physicians make optimal treatment decisions. It is proactive and participatory, engaging patients in lifestyle choices and active health maintenance to compensate for genetic susceptibilities. We have prevailed over many of the diseases that have plagued humanity throughout the ages, what remains are diseases of greater complexity: diabetes, cancer, heart disease, and Alzheimers disease. They are not caused by a single gene or a single event but by a combination of genetic and environmental factors, and they tend to be chronic, placing a heavy burden on the healthcare system. Personalized medicine provides the tools needed to better manage chronic diseases and treat them more effectively. Its far more important to know what person the disease has than what disease the person has. Hippocrates (ca. 400 BCE) u

(2) History: 1898:- Sir Archibald Garrod coins the term chemical individuality to describe inherited predispositions to metabolizing sulphonal drugs. 1900:- Gregor Mendels 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.t 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.
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 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 amplifi- cation of DNA sequences. 1990:- The Human Genome Project is launched. September 1998:- Herceptin, a drug that works on a 25 percent subpopulation of breast cancer patients, is approved by the U.S. Food and Drug Administration (FDA). On the same day, the HER2 test identifying the target population is also approved. 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 codeveloped 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. 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, Crohns disease, type 1 and type 2 diabetes, and rheumatoid arthritis. July 2007:- The FDA issues a Draft Guidance for In Vitro Diagnostic Multivariate
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Index Assays. August 2007:- The FDA re-labels the blood thinning drug warfarin to recommend adjusting the dose based on genetic variation. April 2008:- James Watsons 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 Presidents 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 patient to implement personalized medical care. April 2009:- Senate brings personalized medicine into national budget discussions.

(3) Difference between common drug and personalize medicine:Common drug: - One size fits all Personalized medicine: - The right treatment for the right person at the right time

(4) What is driving the Movement to Personalized Medicine?

Consumer Demand for Safer and More Effective Drugs End of one size fit all drug. New drug will be safe and effective for specific population Consumer Demand for Faster Time to a Cure Using genomic information to find disease targets. Speedier clinical trial based on high responder population Consumer Demand for Cost-Effective Healthcare Reduced costs, due to avoidance of futile treatments and improved clinical outcomes

(5) Goals for personalized medicine: Identify genetic differences between people that affect drug response Develop genetic tests that predict an individuals response to a drug Tailor medical treatment to the individual Increase effectiveness Minimize adverse side effects

(6) Benefits of Personalized Medicine: Shift emphasis 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 Reduce the overall cost of healthcare

(7) Limitation of personalize medicines: 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) Regionally fragmented reimbursement policies hinder adaptation of diagnostic tests.

(8) 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.
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 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. Gene-centered research may also speed the development of novel therapeutics.

Examples of pharmacogenetics include: Genotyping for SNPs in genes involved in the action and metabolism of warfarin (coumadin). This medication is used clinically as an anticoagulant but requires periodic monitoring and is associated with adverse outcomes. Recently, genetic variants in the gene encoding Cytochrome P450 enzyme CYP2C9, which metabolizes warfarin, and the Vitamin K epoxide reductase gene (VKORC1), a target of coumarins, have led to commercially-available testing that enables more accurate dosing based on algorithms that take into account the age, gender, weight, and genotype of an individual. Genotyping variants in genes encoding Cytochrome P450 enzymes (CYP2D6, CYP2C19, and CYP2C9), which metabolize neuroleptic medications, to improve drug response and reduce side-effects.

Pharmacometabonomics: Researchers at Imperial College London have recently demonstrated that predose metabolic profiles from urine of rats and humans can be used to predict how they will metabolise drugs such asacetaminophen (paracetamol). The authors observed that individuals having high predose urinary levels of p-cresol sulfate, a gut bacteria co metabolite, had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide.

Cancer management: Oncology is a field of medicine with a long history of classifying tumor stages and subtypes based on anatomic and pathologic findings. This approach includes histological examination of tumor specimens from individual patients (such as HER2/NEU in breast cancer) to look for markers associated with prognosis and likely treatment responses. Thus, "personalized medicine" was in practice long
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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 activation expression profiles 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. Examples of personalized cancer management include: Testing for disease-causing mutations in the BRCA1 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 undertaken in the context of detailed genetic counseling. 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. Targeted therapy is the use of medications designed to target aberrant molecular pathways in a subset of patients with a given cancer type. For example, Herceptin is used in the treatment of women with breast cancer in which HER2 protein is overexpressed. Tyrosine kinase inhibitors such as Gleevec have been developed to treat chronic myeloid leukemia (CML), in which the BCR-ABLfusion gene (the product of a reciprocal translocation between chromosome 9 and chromosome 22) is present in >95% of cases and produces hyperactivated abl-driven protein signaling. These medications specifically inhibit the Ableson tyrosine kinase (ABL) protein and are thus a prime example of "rational drug design" based on knowledge of disease pathophysiology.

Ineffective Therapies Can Cause Harm in world population 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
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During their hospital stay, 15% of patients experienced adverse drug reactions Increased patient non-compliance

Patients can respond differently to the same medicine

For example, Disease Anti-depressants Asthma drugs Diabetes drugs Arthritis drugs Alzheimers drugs Cancer drugs Difference 38% 40% 43% 50% 70% 75%

Here, study was carried out on 100 patient for each disease condition.

(9) Selected Personalized Medicine Drugs, Treatments, and Diagnostics:-

THERAPY Herceptin (trastuzumab) Tykerb (lapatinib)

BIOMARKER/TEST

HER-2/neu receptor

Tamoxifen Chemotherapy

Aviara Breast Cancer IndexSM (HOXB13, IL17BR) Mammostrat

INDICATION Breast cancer: for the treatment of patients with metastatic breast cancer whose tumors over express the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease. Breast cancer: Calculates a combined risk analysis for recurrence after tamoxifen treatment for ER-positive, node-negative breast cancer. Breastcancer:
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Chemotherapy Coumadin (warfarin)

MammaPrint CYP2C9

Coumadin (warfarin)

VKORC1

Coumadin (warfarin)

PGx PredictTM: Warfarin

Coumadin (warfarin)

Protein C deficiencies

Statins

PhyzioType SINM

Atorvastatin

LDLR

Camptosar (irinotecan) Erbitux (cetuximab)

UGTIA1

KRAS

Prognosticimmunohistochemistry (IHC) test used for postmenopausal, node 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 gene expression profile. Cardiovascular disease: an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Cardiovascular disease: Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. Cardiovascular disease: Determines CYP2C9 and VKORC1 genotypes to predict likelihood of adverse events with warfarin therapy. Cardiovascular disease: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, has been associated with tissue necrosis following warfarin administration. Cardiovascular disease: Predicts risk of statin-induced neuro-myopathy, based on a patients combinatorial genotype for 50 genes. Cardiovascular disease: Doses should be individualized according to the 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 patients ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. Colon cancer: Certain KRAS mutations lead
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Gefitinib

to unresponsiveness to the drug. Colon cancer: Patients enrolled in the clinical studies were required to haveevidence of positive EGFR expression using the DakoCytomation EGFR pharmDx test kit. EGFR positive individuals are more likely to respond to the drug than those with reduced EGFR expression. Colon cancer: Provides information of the expression of key molecular targetsKRAS, TS, and TOPO1to guide therapy. Epilepsy and bipolar disorder: Serious dermatologic reactions are associated with the HLAB*1502 allele in patients treated with carbamazepine. Prior to initiating 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 patients immune response to heart transplant to guide immunosuppressive therapy. HIV: Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended. HIV: Selzentry, in combination with other antiretroviral agents, is indicated for treatment experienced adult patients infected with only CCR5-tropic HIV-1 detectable... Inflammatory bowel disease: Identifies subset of patients who will benefit from budesonide. Leukemia: Gleevec (imatinib mesylate) is indicated for the treatment of newly
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Erbitux (cetuximab) Gefitinib Vectibix

EGFR expression

Erbitux (cetuximab) and Vectibix (panitumab) Fluorouracil Camptosar(irinotecan)

Target GI

Tagretol (carbamazepine)

HLA-B*1502

Immunosuppressive drugs

AlloMap gene profile

Ziagen (abacavir)

HLA-B*5701

Selzentry (maraviroc)

CCR5 receptor (1)

Budesonide Gleevec (imatinib mesylate)

IBD Serology 7 BCR-ABL

Dasatinib

Philadelphia Chromosome

Busulfan

Philadelphia Chromosome

Purinethol (mercaptopurine) Thiaguanine Azathioprine Tarceva (erlotinib)

TPMT

EGFR expression

Capecitabine

DPD

Pharmaceutical and surgical treatment options and surveillance Chemotherapy

MLH1, MSH2, MSH6

CupPrintTM Aviara CancerTY PE ID

Chemotherapy

Elitek (rasburicase)

G6PD deficiency

diagnosed adult and pediatric patients with Philadelphia chromosome positive [indicated by presence of BCRABL] chronic myeloid leukemia (CML) in chronic phase. Leukemia: Dasatinib is indicated for the treatment of adults with Philadelphia chromosomepositive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy Leukemia: Busulfan is clearly less effective in patients with chronic myelogenous leukemia who lack the Philadelphia (Ph1) chromosome. Leukemia: Guides adjustment of dose in treatment of acute lymphoblastic leukemia: Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe Purinethol toxicity from conventional doses Lung cancer: The test determines patients most likely to respond. Multiple cancers: Rarely, unexpected severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. Multiple cancers: Guides surveillance and preventive treatment based on susceptibility risk for colon and other cancers. Multiple cancers: Determines cancer classification for tumors of unknown primary origin. Multiple cancers: Classifies 39 tumor types from tumors of unknown primary origin, using a gene expression profile. Multiple cancers: Rasburicase administered to patients with glucose- phosphate dehydrogenase (G6PD) deficiency can cause severe hemolysis. It is recommended that
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Drugs metabolized by CYP P450

Amplichip CYP2D6/CYP2C19

Rifampin Isoniazid Pyrazinamide

NAT

Rituximab

PGx PredictTM: Rituximab

Celebrex (celecoxib)

CYP2C9

Risperdal (resperidone) Zyprexa (olanzapine)

PhyzioType PIMS

Gleevec (imatinib mesylate)

c-KIT

patients at higher risk for G6PD deficiency be screened prior to starting ELITEK therapy. Multiple diseases: FDA classification 21 CFR 862.3360: This device is used as an aid in determining treatment choice and individualizing treatment dose for therapeutics that are metabolized primarily by the specific enzyme about which the system provides genotypic information. Multiple diseases: N-acetyltransferase slow and fast acetylators and toxicity- slow acetylation may lead to higher blood levels of the drug, and thus, an increase in toxic reactions. Non-Hodgkins lymphoma: Detects CD-20 variant (polymorphism in the IgG Fc receptor gene FcgRIIIa) to predict response to cancer drug rituximab. Pain: Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance. Psychiatric disorders: Predicts risk of psychotropic-induced metabolic syndrome, based on a patients combinatorial genotype for 50 genes. Stomach cancer: Gleevec is also indicated for the treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).

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 References:(1) Presidents Council of Advisors on Science and Technology (PCAST) Personalized Medicine September 2008 Priorities for

(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

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