Demystifying Pharmacogenetics: its evolution and challenges. June 15, 2016

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1 Demystifying Pharmacogenetics: its evolution and challenges June 15, 2016

2 Welcome! Dr. Brendan Byrne Chief Innovation Officer, TELUS Health Karen Kesteris Director, Product Management, TELUS Health 2

3 Today Pharmacogenomics and Pharmacogenetics are most often used interchangeably; traditionally Pharmacogenetics refers to the inherited differences in drug metabolism and response whereas Pharmacogenomics refers to the general study of many different genes that determine drug behavior. 3

4 Many drugs do not work for the conditions they have been prescribed for Percentage of patients for whom drugs are ineffective FDA Report Paving the Way for Personalized Medicine October (Data taken from chart on page 12 - source of data: Spear, B.B., Heath-Chiozzi, M., & Huff, J. (2001). Clinical application of pharmacogenetics. TRENDS in Molecular Medicine, 7(5), ) 4

5 Drugs are dangerous 700, , , , , , ,000 Heart Disease Cancer Stroke Rx Car Crashes 2.2M severe adverse drug events per year FOURTH leading cause of death in the U.S. 100,000 deaths per year by properly prescribed drugs 80,000 deaths per year by improperly prescribed drugs 0 Gurwitz JH. Et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 2003;189(9):

6 Drugs are expensive Hospitals 29% $30B spent on prescription drugs Drugs 16% 16% of total health care spend Physicians 14% In Canada we spend more on drugs than on doctors 6

7 Drug Metabolism 101 The Therapeutic Window The difference between an ineffective, safe or dangerous drug lies in the plasma concentration of the drug 7

8 Drug Metabolism 101 Metabolic Enzymes Drugs are activated and/or deactivated by enzymes in the liver in a process called metabolism Any factor that increases of decreases the function of these metabolic enzymes will affect the concentration of a drug within the therapeutic window and therefore alter its efficacy and safety Phase I Metabolism Cytochrome P450 (CYP) enzymes: Activate a pro-drug to active drug Convert an active drug to an active or toxic metabolite Convert an unexcretable drug to an excretable form Inactivate a drug Humans have 57 genes divided into 18 families and 43 sub-families of CYP Phase II Metabolism In order to be cleared from the body some drugs require additional steps Methylation Sulphation Acetylation Glucurionadation Glutathione conjugation Glycine conjugation Performed by a multitude of different enzymes 8

9 Drug Metabolism 101 Genetics of Drug Metabolizing Enzymes Drug metabolizing enzymes are proteins made by liver cells The instructions for making proteins are encoded in genes Humans have over 20,000 genes stored on 23 chromosomes, with a complete set located in the nucleus of every cell Hundreds of genes are related to drug metabolism Chromosomes and genes are made of DNA, the famous double helix structure consisting of two strands with alternating base pairs There are over 6B base pairs 99.9% of these are identical in all humans 0.1% difference = 6M variations Pharmacogenetics is the study of how inter-individual differences in genes result in differences in drug metabolism, specifically predicting the efficacy and/or 9 toxicity of a drug.

10 Drug Metabolism 101 The challenge for physicians is every individual is profoundly different in how they handle medications Age, gender, weight, kidney function, liver function all matter Genetics matter: >90% of the population have at least 1 genetic variant in the enzymes responsible for drug metabolism Only 7% have all normal variants of the 5 major CYPs For a given drug, genetic variations result in patients being classified as Poor metabolizers Normal metabolizers or Ultra metabolizers Complicating this, multiple drugs will have antagonistic or synergistic effects on the same metabolic pathway Without understanding the individual and cumulative effects of multiple drugs on an individual s unique genetics, a physician cannot accurately predict how a medication will behave 10

11 Adverse Drug Events (ADE) Top three causes Drug-Drug interactions (DDI) Most EMR and PMS systems check for drug interactions 44% Drug-Drug 14% Multi-Drug 58% Drug-Gene interactions (DG) 19% of ADE s caused by Drug-Gene Interactions Multi-Drug- Gene interactions (DDG) 23% of ADE s caused by Drug-Drug-Gene Interactions Up to 42% of ADE s will still be missed without a pharmacogenetic service 11

12 Pharmacogenetics: Right Drug, Right Dose Without Genetics Advertised Dose One Size Fits All With Genetics Personalized Dose Responds to normal dose Responds to lower dose Responds to higher dose Responds to alternative medication The promise of Pharmacogenetics is a personalized dose to optimize efficacy and safety 12

13 Pharmacogenetics can reduce hospitalizations and ER visits 18.00% 16.00% 14.00% 12.00% 10.00% 8.00% 39% reduction 71% reduction control arm 6.00% 4.00% intervention arm 2.00% 0.00% Hospitalizations (p=.0273) ER visits (p=.0002) Patients > 65 years on 3 or more medications Source: AMCP 2015 Meeting Abstract U36 Major economic impact caused by ER visits, hospitalizations and disability from work 13

14 Whole Genome Sequencing vs Pharmacogenetics Whole Genome Sequencing: Sequencing of all chromosomes, including all 20,000+ genes Not yet accurate or cost effective enough for routine diagnostic tests Many findings of variations are of unknown significance Many known variations associated with increased or decreased probability of disease Interpretation is a major issue; consultation with a genetic counsellor is necessary Pharmacogenetics: Gene panels that look only for specific known variations in genes associated with drug metabolism and response Does not test for any variations of unknown significance Tests are accurate and cost effective enough to be performed routinely 14

15 Approximate evolution of test costs Whole Genome Sequencing 2007 $1M 2009 $100K 2016 <$ $100? Pharmacogenetic testing 2000 $ $ $ $100? *Additional tests ( $6/gene) 15

16 Significant numbers of Canadians would benefit from Pharmacogenetics Patient Profiles All Ages 65+ <65 5+ Medications 3,018,143 1,728,497 1,289, Medications 4,375,468 2,387,522 1,987, Medications 6,245,548 3,167,947 3,077,601 Decreases in ER visits, hospitalizations and disability from work will have a major impact on health care and disability 16 costs.

17 Interplay of 3 Forces affecting Pharmacogenetics 1. Standard of care 2. The economics of preventable adverse drug events 3. Digital health platforms 17

18 Standard of care emerging (examples) Drug and gene involved Function Average frequency (in Caucasians) Effect (with recommended dose) Recommendation Normal 45% N/A Conventional dosage Celexa citalopram (CYP2C19) Reduced 30% Side effects Reduce the dose Increased 25% Therapeutically ineffective Increase the dose / alternative drug Normal 78% N/A Conventional dose Codeine (CYP2D6) Reduced 20% Therapeutically ineffective Alternative drug Increased 2% Side effects Alternative drug Plavix clopidogrel (CYP2C19) Normal 45% N/A Conventional dose Reduced 30% Therapeutically ineffective Alternative drug Increased 25% N/A Conventional dose 18

19 Payer economics Costs associated with side effects and complications Costs of pharmacogenetic screening tests 19

20 Role of digital health platforms in Pharmacogenetics The value of the tests will only be realized if a platform exists to bring results to the health care providers at the point of care Pharmacists and Physicians - in a simple and actionable recommendation format 20

21 Pharmacogenetic ecosystem Consumers Pharmacogenetics Apps Analytics Point of Care Platform Payers Lab Repository A platform to connect health care stakeholders 21

22 Ethical and Legislative Concerns There is concern that genetic results could be used by employers and insurers in a manner that would discriminate against an individual Legislation is currently in the Senate Bill S-201 that would prevent such potential discrimination. As it stands now, Canada is the only G7 country without such legislation The type of testing used in Pharmacogenetics is very specific to drug metabolism and does not predict or assess any risk that could be the subject of potential discrimination There is minimal ethical concern about the potential use of Pharmacogenetic information to discriminate against individuals 22

23 What is happening in the world of group insurance? Continued confusion over definition Ongoing privacy concerns Pricing model Administrative model

24 How will Pharmacogenetics benefit the insurance industry? Right drug, right person, the first time Prior authorization Improved health outcomes Reduced drug spend

25 Conclusion 1.The use of pharmacogenetics is becoming a standard of care for the prescription of some drugs. 2.The widespread use of pharmacogenetics will likely reduce health care and disability costs but this needs to be proven to be cost effective 3.Widespread use of pharmacogenetics in primary care will depend on an effective pan-canadian digital health platform that brings simple, actionable recommendations to health care providers at the point of care. 25

26 Thank you