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Pharmacogenomics as a proof of principal for genomic medicine: emphasis on real endpoints December 5, 2011 Dr Howard L. McLeod Eshelman Distinguished Professor and Director Institute for Pharmacogenomics and Individualized Therapy (IPIT)

SLIDE 1

Pharmacogenomics as a proof of principal for genomic medicine: emphasis on ‘real’ endpoints

December 5, 2011

Dr Howard L. McLeod Eshelman Distinguished Professor and Director Institute for Pharmacogenomics and Individualized Therapy (IPIT) University of North Carolina – Chapel Hill, NC

SLIDE 2

Pharmacogenetics: what is your intent?

Human genetic discovery

po BID

Clinical practice Drug Safety Explain variation in phenotype

Clinical trial inclusion/exclusion

EM PM

SLIDE 3

Marker Discovery Marker Validation Routine Clinical Use

po BID

Why is IPIT succeeding?

Integration into Practice

SLIDE 4

Germline Pharmacogenomic examples-2011

Thiopurine S-methyltransferase—mercaptopurine and

azathioprine*

IL28B-interferon
UGT1A1-irinotecan**
CYP2C9/VKORC1-warfarin*
HLA-B*5701-abacavir *
HLA-B*1502-carbamazepine *
CYP2C19-clopidogrel
Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists,

antidepressants, ADHD drugs, pimizide, and codeine derivatives, tamoxifen*

SLIDE 5

CP1229323-16

% Years after randomization

2-year RFS EM 98% IM 92% PM 68% Log Rank P=0.009

EM IM PM

Goetz et al. Breast Cancer Res Treat. 2007

20 40 60 80 100 2 4 6 8 10 12

Relapse-free Survival

EM-extensive metabolizer IM-intermediate PM-poor

SLIDE 6

Endoxifen concentration (ng/ml)

5 10 15 20 25 30 35 40 45 50

CYP2D6-guided tamoxifen dosing normalizes endoxifen levels N=119

Start of study 4 months on study

P=0.84

EM IM

Study of 500 patients across NC is completed, with

versampling of African American and Hispanic patient

SLIDE 7

Germline Pharmacogenomic examples-2011

Thiopurine S-methyltransferase—mercaptopurine and

azathioprine*

IL28B-interferon
UGT1A1-irinotecan**
CYP2C9/VKORC1-warfarin*
HLA-B*5701-abacavir *
HLA-B*1502-carbamazepine *
CYP2C19-clopidogrel
Cytochrome P-450 (CYP) 2D6—5-HT3 receptor antagonists,

antidepressants, ADHD drugs, pimizide, and codeine derivatives, tamoxifen*

SLIDE 8

Marker Discovery Marker Validation

SLIDE 9

Translational science: The steps to success

Step I

Discovery

Step II

Validation

Step III

Integration into practice

Step IV

Integration into policy Boring!

SLIDE 10

Marker Discovery Marker Validation

SLIDE 11

changing old habits

Marker Discovery Marker Validation Health Economics $$$ $$ Medical informatics

IF THEN

Routine Clinical Use

po BID

Health system integration ? ! Research assay to Clinical assay

SLIDE 12

We now have new audiences

Past

– Ourself – Editors/reviewers – Study section

Now

– Clinic administrators – Payers – Patients

SLIDE 13

We now have new (additional) endpoints

Past

– survival – Stent thrombosis – Severe adverse drug reaction

Now

– Selection from amongst ‘equal’ therapies – Return on investment for medical home – Quality measures – Patient satisfaction

SLIDE 14

Preemptive action is a clinical major weapon

Renal dysfunction Age Drug interactions vaccination We already know factors associated with ADR Comorbidity Polypharmacy Certain medical conditions Certain types of medication

SLIDE 15

Increase risk = intervention Breast cancer screening

SLIDE 16

1,000 2,000 3,000 4,000 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age at diagnosis Number of cases

Male cases Female cases

Increase risk = intervention Colon cancer screening

SLIDE 17

Increase risk = intervention Down Syndrome screening

SLIDE 18

Drugs are toxic

Adverse drug events are 5th leading cause of death in USA Adverse drug events are heavily litigated Many adverse drug events are predictable

SLIDE 19

10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100

Age (decade) % with drug prescription

Increase risk = intervention Drug therapy

SLIDE 20

Why wait for a problem?

We know who is ‘at risk’ for needing prescription medicines We know examples where a particular genetic configuration = risk of toxicity or altered benefit We know our current model of ‘wishful waiting’ isn’t adequate

SLIDE 21

Genes Drugs Issue CYP2C9/VKORC1 warfarin bleeding HLA-B5701 abacavir hypersensitivity HLA-B1502 carbamazepine SJS/TENS HLA-B*5801 allopurinol SJS/TENS CYP2C19 clopidogrel stent thrombosis CYP2D6

xycodone,