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
8Mathura Shanmugasundaram PhD© 2016
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
Mathura Shanmugasundaram PhD© 2016
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)
13 Mathura Shanmugasundaram PhD© 2016
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
Mathura Shanmugasundaram PhD© 2016
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
16Mathura Shanmugasundaram PhD© 2016
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
The Case for Personalized Medicine
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
Top Related