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The case for Genomic Medicine, (Personalized, Individualized Medicine). Medical Revolutions
- 1. The Case for Personalized Medicine Mathura Shanmugasundaram PhD Oct 2016
- 2. Scientific Advances 2 2 1950s 1990s 2016 and beyond! Structure of DNA Watson & Crick Human Genome Project Next Big Milestone? Image Sources: Nature Magazine, 15th Feb 2001 http://dataphys.org/list/watson-and-cricks-3d-model-of-dna/ www.wallpaperup.com/236587/pills_DNA.html Mathura Shanmugasundaram PhD© 2016
- 3. Technological Advances 3 Personalized Medicine Green Paper, June 2015 – Roadmap for Brining Personalized Medicine to British Columbians www.lifesciencesbc.ca (Accessed Oct 2016)3 Mathura Shanmugasundaram PhD© 2016
- 4. Health Care Cost is Increasing 4 The Commonwealth Fund – thecommonwealthfund.org –U.S Health Care from a Global Perspective (Accessed Oct 2016) US spending/person = $9,086/year! 4 Mathura Shanmugasundaram PhD© 2016
- 5. Adverse Drug Reactions (ADRs) 5 1. Johnson JA, Bootman JL. Drug-related morbidity and mortality. A cost-of-illness model. Arch Intern Med 1995;155(18):1949–1956. 2. 2..Lazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200–1205. 3. Classen DC er al.,. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. JAMA 1997;277(4):301–306. 4.Nelson KM, Talbert RL, Pharmacotherapy 1996;16:701-7; Mathura Shanmugasundaram PhD© 2016 ADRs cost $136 billion/year1 4th Leading cause of Death (100,000s/year) 2 Leading cause of Hospitalization2 2.2 million ADRs reported/year2 ADRs increase exponentially with 4 or more medications2 (82% Americans take at least one and 29% take more than 5!) Mean length of stay, cost, mortality for hospitalized patients with ADRs DOUBLE than that of control (Patients without ADRs)3 5 Adverse Drug Reactions: Undesirable/unexpected response to a drug under normal conditions of use ADRs ARE OFTEN PREVENTABLE!4
- 6. A Real NEED to Rethink Health Care 6 The TIME for Personalized Medicine has Arrived… Image Source: Time Magazine, Jan 15th 2001 6
- 7. One Size Does NOT Fit All. 7 Brian B.Spear, Margo Health-Chiozzi, Jeffrey Huff “Trends in Molecular Medicine, Volume 7, Issue 5, May 2001, Pages 201-204 Adapted from www.personalizedmedicinecoalition.org Patients respond differently to the same medicine Due to Individual Genetic Differences 7 Mathura Shanmugasundaram PhD© 2016
- 8. Why? 8 Adapted from: Wrighton Sa et al. Crit Review Toxicology 1992;22:1-22 1 Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211–21. 2. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–24. 3. Kashuba and Bertino. Mechanisms of drug interaction. In Drug Interaction in Infections Diseases. Humana Press, 2001. Genetic Factors account for up to 95% of Drug Response Variability3 Genetic Differences Responsible For ADRs These few genes are responsible for metabolizing >80% of all drugs1,2 8 Mathura Shanmugasundaram PhD© 2016
- 9. The Solution: Individualizing Treatment Xie H., Frueh., F.W; Personalized Medicine (2005) Ultrarapid Metabolizers: Metabolize drug rapidly; suffer lack or efficacy Normal/Extensive Metabolizers: Metabolize drug normally; effective general drug dose Intermediate Metabolizers: Metabolize drug partially; may benefit by altering dose Poor Metabolizers: Metabolize drug poorly; increase in risk of toxicity if drug is not cleared Phenotype (Variability of Metabolizing Enzyme) >2 copies of CYP450 gene 2 functional alleles Of CYP450 gene 1 functional & 1 defective allele (heterozygous) / 2 partially defective Lack a specific functional CYP450 enzyme due to defective/deleted genes (2 null alleles) Increases efficiency of drug and time of treatment Reduces Rate of ADRs and cost associated with it Likely to improve treatment adherence 9
- 11. 1. Dosing Optimization & Reducing ADRs 11 1. Pirmohamed M, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329:15–9. 2. 2. Treating Individuals: From Randomised Trials to Personalised Medicine edited by Peter M. Rothwell 3. McWilliam A, Lutter R, Nardinelli C. Health Care Savings From Personalizing Medicine Using Genetic Testing: The Case of Warfarin. Working Paper 06–23. AEI-Brookings Joint Center for Regulatory Studies; November 2006 4. Amplichip Information (ROCHE) :http://www.roche.com/products/product-details.htm?productId=f3ac4e73-ca80-4de4-bd7c-e613fd590fdb Use of warfarin genetic tests could prevent 17,000 strokes and 85,000 serious hemorrhages/year and $1.1 billion savings in healthcare/year3 11 Warfarin Leading causes of ADR (10% of all ADR events) Widely prescribed for patients at increased risk of developing serious blood clots1 (21 million /year)1 Narrow therapeutic index and wide range of inter-individual dosage variability (Up to 20-fold)1 Genetic variations in CYP2C9 and VKORC1 play a role2 World’s 1st PGx Microarray for Clinical Application (2004) To identify CYP 450 variations (29 polymorphisms) in CYP2D6 and CYP2C194 Amplichip CYP450 Test (Roche)
- 12. 2. Targeting Specific Disease Markers 12 1. American Cancer Society. Targeted therapy for breast cancer. http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-treating-targeted-therapy, 2015. 2. Edith A. Perez et al., Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831. JCO (2014) Image adapted from https://www.eupati.eu/personalised-medicine/new-research-areas-personalised-medicines/ (Accessed Oct 2016)12 Herceptin®(Trastuzumab) – Against HER2+ Breast cancer Over 10 years: Overall survival rate and Overall disease-free survival were 37% and 40% better in women who got Herceptin plus chemotherapy compared to women who got only chemotherapy.2 Inhibits cellular signaling and thus proliferation HER2 receptors expressed on the cell surface – sending signaling inducing proliferation Herceptin antibody: selectively targets the extracellular domain of the HER2 protein 25-30% Breast Cancer Patients : 10-100 X increase in the overexpression of HER2 proteins1 HER2+ Breast Cancer CellHER2 normal breast cancer cell Mathura Shanmugasundaram PhD© 2016
- 13. 3. Enhancing Drug Safety 13 Mallal S, Nolan D, Will C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-32 Abacavir (For HIV) - Hypersensitivity In 5-8% Patients Symptoms: Fever, Rash, GI problems Discontinuation reverses symptoms Re-challenge can result in serious low bp/death Hypersensitivity strongly associated with patients with a specific Human Leukocyte Antigen: HLA -B*5701 allele - 117 times more likely to be hypersensitive to Abacavir Clinicians now safely prescribe Abacavir for the right patient and the incidence of these reactions has diminished worldwide. Genetics has allowed for an enhanced drug safety approach and can also act as a preventive measure for patients who can potentially develop hypersensitivity (genetically linked) 13 Mathura Shanmugasundaram PhD© 2016
- 14. A greater understanding of the molecular basis of disease has transformed what was once known collectively as “disease of the blood” into multiple subtypes of leukemias and lymphomas with a 5-year survival rate of 70% collectively. Targeted Therapies – Lower rates of failure in R&D, Trials 4. Advancing Therapies 14 Slamon et al., Science 1987;235:177-82; 2. Saini KS et al., Breast. 2011 Oct;20 Suppl 3:S20-7. Adapted from Genentech Herceptin® Product Information and “aboutcancer.com/herceptin_0211.htm” (Accessed Oct 2016) Adapted from https://www.eupati.eu/personalised-medicine/new-research-areas-personalised-medicines/ (Accessed Oct 2016) 14
- 15. 5. Changing Paradigms: Reactive -> Preventive 15 Source: Personalized Medicine Coalition, “The Case for Personalized Medicine, Nov 2006. The right patient, the right drug, the right dose and the right time. 15 Trial & Error Method Preventive Care Mathura Shanmugasundaram PhD© 2016
- 16. The Challenges Ahead… 16 Adapted from Jeanette JM, Howard LM, Geoffrey SG., Science Translational Medicine, 2013 Complexity of Polygenic Drug Responses Potentially smaller and more specialized drug markets Resistance to genetic testing Legal issues 16 Mathura Shanmugasundaram PhD© 2016
- 17. The Case for Personalized Medicine 17 Dosing Optimization and Reducing ADRS Targeting Specific Disease Markers Enhancing Drug Safety Advancing Therapies & Reducing Cost Changing Paradigms Reactive Preventive 17 Mathura Shanmugasundaram PhD© 2016
- 18. The Case for Personalized Medicine 18 “The good physician treats the disease; the great physician treats the patient” - Sir Osler William Osler, 1892 18
- 19. But the beginning of a new Era… The End
Editor's Notes
- Good afternoon everyone. Thank you for making time and coming down to my presentation. Do feel free to stop me if you have some questions or you want to discuss some something. I am going to present about my case for personalized medicine and I hope that at the end of time, you appreciate this field as much I do.
- Biotechnology really has two pillars that fuels it. One of it is indeed scientific advances which has allowed us to come all the way we are now. It was only in the year 1953, that we knew the structure of the DNA, that was just 70 years ago. And by the millenium, we had already taken bold and impressive moves to sequence the human genome. Truly science has advanced remarkably and it really makes you wonder what the next big milestone is as we enter the area of personalized genomic. We did one limitation that was restricting us earlier though – that was technology and how expensive it was to sequence!
- Biotechnology is really hand in hand with biology and technology. Genome sequencing as I mentioned was a billion dollars when they started the Human Genome Project. 13 years later when it ended, it was abour 50 million dollars. And as you can see, the costs of genomic sequencing have dropped dramatically and exponentially – in fact, way beyond our predicitions made by moorse’s law. This is phenomenal and the striking drop in 2007 Is absolutely amazing. We hit the 1000 dollars genome a few years ago and really, it is a matter of time before it is just a couple of dollars even. So, given all these scientific and technological advances, it is really puzzling to realize that the health care costs in the US remains really high!
- The united states leads the world in all aspects – including a very high heath care cost! In 2012, The US has spent 17.1 % of all its GDP on healthcare alone. That’s an incredible 9000-10000/person/year. I mean think about it – spending 10 000 dollars every person every year in the United States. That’s A LOT of money! And we really need to understand what we are doing.
- In fact, just adverse drug reactions account for almost 136 Billion dollars a year! Adverse drug reactions are undesirable or unexpected responses to a drug under normal circumstances. They are the 4th leading cause of death in the United states with 100,000s dead each year due to this. It is not only the leading cause of hospitalization as well but also 2.2 million adevers drug reactions are reported every year! Also, ADRs, increase exponentially with 4 or more medications and did you know, that 82% of americans take at least one and more than a quarter take more than 5?! There is a true need of concern right there! In addition, the mean length of stay, cost and mortality for hospitalized patients with ADRS are literally double than that of patients without ADRs. And the reason why I am emphasising this is that really – Adeverse drug reactions that is a huge burden on our healthcare – is often preventable! And we really think to rethink our healthcare and find a solution to our problems.
- Personalized medicine might just hold the key to solve some of our major problems. And really with the advancements of science and technology, we are at the perfect time in history to embark On individualized treatments!. For that though, we have to understand why drugs are failing.
- In fact, with some of the highly prescribed drugs in the United states – we have very very low efficacy. This diagram illustrates this sad fact really well. For cancer drugs, out of 10 patients you give it to – it is only effective to 3! That is a 75% case of inefficiency which is not sometime we should stand by and watch. In fact, this is the case for many more drugs as well. Alzehimer’s drugs – It is ineffective in 70% of the population. 7 out of 10 patients do not get the full benefit. The list really does go long. The in effectiveness for arthritiis drugs is 50%, for diabetes 43%, for asthma, 40% and anti-depressants -38%. We have to accept and understand that patients simply respond differently to the same medicine and this is due to individual Genetic differences. One Size simply does not fit all!. Period.
- Although of course, they are many reasons to indivdual variability including age, gender, BMI and even lifestyle One of the important genetic variations to drug responses can be linked to principally to this small group of enzymes know as the cytochrome P450 enzymes. These few enzymes you see here alone are responsible for metabolizing more than 90% of the drugs in the market! That’s a lot! And more importantly than that, genetic variations amongst us accounts for really up to 95% drug response variability. This only means there is only one effective way to treat patientss: Indodivually! And indeed, it’s all these genetic differences that are responsible for the high amounts of ADRs.
- As really we have to move away from our traditionally one-dose-fits all approach and stop giving the same drug at the same dose to all individuals regardless of their genetic variability. We have to understand to treat patients understanding the patients themselves. In deed, we can broadly categorize the population into 4 main groups based on their genotypes and thus phenotypes. One of that is the ultrarapid metabolizers who have 2 or more copies of the enzyme gene that allows them to metabolize the drug rapidly and even suffer from the lack of efficiay as a result.
- In 2005, the FDA approved the first pharmacogenetic test based on microarray technology for genotyping 27 alleles in CYP2D6 and three alleles in CYP2C19 genes associated with different metabolizing phenotypes. Today, pharmacogenetic testing has become an integral part of the treatment of breast cancer with trastuzumab. Overexpression of the HER2 oncogene is correlated with a poor prognosis, increased tumor formation and metastasis, as well as resistance to chemotherapeutic agents. HER2 testing predetermines patients who overexpress HER2 and who will respond to trastuzumab. The two common ways to determine HER2 status are: Immunohistochemistry (IHC) testing detects the number of HER2 protein receptors in the cancer cells. Fluorescence in situ hybridization (FISH) testing detects the number of HER2 genes in the cancer cells. Ki-67 The Ki-67 test is a common way to measure proliferation rate. When cells are growing and dividing (proliferating), they make proteins called proliferation antigens. By counting the number of cells with these antigens, a pathologist can determine a tumor's proliferation rate. The antibody to Ki-67 attaches itself to the proliferation antigen. The more cells the Ki-67 antibody attaches to in a tissue sample, the more likely the tumor cells are to grow and divide rapidly. The result of this test is reported as the percentage of Ki-67-positive cells. It shows whether a low, moderate or high proportion of cancer cells are in the process of dividing.
- Abacavir-induced hypersensitivity reaction has been associated with the presence of the major histocompatibility complex class I allele HLA-B*5701. A screening test for the HLA-B*5701 allele can assist clinicians to identify patients who are at risk of developing a hypersensitivity reaction to abacavir. Symptoms of an abacavir hypersensitivity reaction include skin rash, fever, malaise, gastrointestinal symptoms, and respiratory symptoms. Severe forms of the skin rash may result in Stevens-Johnson Syndrome, toxic epidermal necrolysis, or systemic lupus erythematosus [3]. If a patient experiences a hypersensitivity reaction, abacavir is discontinued and symptoms generally resolve within 72 hours [4]. Restarting abacavir is contraindicated as it can result in a potentially life-threatening reaction and even death [5],[6],[7],[8]. The HLA-B*5701 screening test minimizes potential toxicities to abacavir by identifying patients who may be at risk of developing a hypersensitivity reaction. Findings HLA-B*5701 was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients (odds ratio 117 [95% CI 29–481], pc<0·0001), and the HLA-DR7 and HLA-DQ3 combination was found in 13 (72%) of hypersensitive and five (3%) of tolerant patients (73 [20–268], pc<0·0001). HLA-B*5701, HLA-DR7, and HLA-DQ3 were present in combination in 13 (72%) hypersensitive patients and none of the tolerant patients (822 [43–15 675], pc<0·0001). Other MHC markers also present on the 57·1 ancestral haplotype to which the three markers above belong confirmed the presence of haplotype-specific linkage disequilibrium, and mapped potential susceptibility loci to a region bounded by C4A6 and HLA-C. Within the entire abacavir-exposed cohort (n=200), presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 had a positive predictive value for hypersensitivity of 100%, and a negative predictive value of 97%. Interpretation Genetic susceptibility to abacavir hypersensitivity is carried on the 57·1 ancestral haplotype. In our population, withholding abacavir in those with HLA-B*5701, HLA-DR7, and HLA-DQ3 should reduce the prevalence of hypersensitivity from 9% to 2·5% without inappropriately denying abacavir to any patient.
- So with this, I suppose this is the end of my presentation but really, a beginning of a new era.