the case for genomic medicine, (personalized, individualized medicine). medical revolutions

The Case for Personalized Medicine

Mathura Shanmugasundaram PhDOct 2016

Scientific Advances

22

1950s 1990s 2016 and beyond!

Structure of DNAWatson & Crick

Human Genome Project

Next Big Milestone?

Image Sources: Nature Magazine, 15th Feb 2001http://dataphys.org/list/watson-and-cricks-3d-model-of-dna/

www.wallpaperup.com/236587/pills_DNA.htmlMathura Shanmugasundaram PhD© 2016

Technological Advances

3 Personalized Medicine Green Paper, June 2015 – Roadmap for Brining Personalized Medicine to British Columbianswww.lifesciencesbc.ca (Accessed Oct 2016)3

Mathura Shanmugasundaram PhD© 2016

Health Care Cost is Increasing

4The Commonwealth Fund – thecommonwealthfund.org –U.S Health Care from a Global Perspective (Accessed Oct 2016)

US spending/person = $9,086/year!

4Mathura Shanmugasundaram PhD© 2016

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

A Real NEED to Rethink Health Care

6

The TIME for Personalized Medicine has

Arrived…

Image Source: Time Magazine, Jan 15th 2001

6

One Size Does NOT Fit All.

7Brian 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

Why?

8Adapted 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


The Solution: Individualizing Treatment

Xie H., Frueh., F.W; Personalized Medicine (2005)

UltrarapidMetabolizers:

Metabolize drug rapidly; suffer lack or efficacy

Normal/ExtensiveMetabolizers:

Metabolize drug normally; effective general drug dose

IntermediateMetabolizers:

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 MetabolizingEnzyme)

>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

1010

Personalized MedicineIn Action

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)

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


3. Enhancing Drug Safety

13Mallal 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)


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 – Lowerrates of failure in R&D, Trials

4. Advancing Therapies

14Slamon 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

5. Changing Paradigms: Reactive -> Preventive

15Source: 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


The Challenges Ahead…

16Adapted 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



17

Dosing Optimization and Reducing ADRS

Targeting Specific Disease Markers

Enhancing Drug Safety

Advancing Therapies & Reducing Cost

Changing Paradigms Reactive Preventive



18

“The good physician treats the disease; the great physician treats the patient”

- Sir Osler William Osler, 1892

18

But the beginning of a new Era…

The End

the case for genomic medicine, (personalized, individualized medicine). medical revolutions

Health & Medicine