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TRANSCRIPT
Pharmacogenomics: Assessment of
Therapeutic Risk vs Benefit
Lawrence J. Lesko
Clinical Professor
Center for Pharmacometrics and
Systems Pharmacology
University of Florida at Lake Nona
November 15, 2016
Acknowledgment
I wish to thank Dr. Stephan Schmidt, Assistant
Professor and Associate Director in the UF
Center for Pharmacometrics and Systems
Pharmacology for making this presentation on
my behalf.
Three Goals For This Presentation
1. Define pharmacogenetics (PGx) –
bring granularity to the concept
2. Scenarios where PGx has benefited
health outcomes
1. Major barriers to actually applying PGx
more widely in clinical medicine
Nomenclature: Words Matter
Pharmacogenomics (disease variability) is
much broader than pharmacogenetics.
Pharmacogenomics has revolutionized
treatment of cancer. Period.
Pharmacogenetics (dose variability) has not
had the impact of pharmacogenomics.
Definition of Pharmacogenetics (PGx)
The term is meant to cover
all types of investigations
that provide information
about a person’s genetic
makeup that address
questions about the choice
of drug and drug doses
that are likely to work best
for that particular person
Inspiration Thought: The Secret of
Success for DNA
We have all the genetic information we need
at birth to select drugs and identify doses.
In the ideal world we carry that information
with us and use it when needed
When Would We Need to Use PGx?
Define qualitative/quantitative differences
between subgroups in terms of PK and PD
Improve a priori drug and dose selection
(predict) rather than a posteriori (react) for
individual health (precision medicine)
Provide better and more cost-effective clinical
outcomes for population (population health)
PGx in 2016
Prevention of disease is better than cure – we
can all agree
But when disease occurs – cancer, diabetes,
heart disease – drug selection and dose choice
guided by companion diagnostics is preferred
over empiric approaches
Companion diagnostics are designed
to be paired with specific drugs if there
is a specific genetic trait that is present
in some, but not all patients.
Foundation of PGx is Companion
Diagnostics
Genetic tests – intended to separate variability in
clinical response among subgroups causes by
genes from that caused by lifestyle, environment
or other non-genetic factors
PD GENES
PK GENES
LAB TEST
Composite Phenotype
--Other therapies
--Disease factors
--Demographics
--Approved labels
--Literature
Approved Drug Labels With PGx
Information: Improve “Old” Drugs
Lesko and Woodcock, Nat Rev Drug Discov (2004), 3(9), 763-769
More Important Use of PGx Is Dosing
NTI Drugs Such as Warfarin
If you gave warfarin
to a huge sumo
wrestler and a tiny
sumo wrestler, the
large sumo wrestler
could bleed
uncontrollably at a
dose much smaller
than what you gave
the tiny sumo
wrestler
PGx Test Information in 140 Labels
Actionable44%
Informative28%
Required24%
Recommended4%
Sources: PharmGKB and FDA Table of Pharmacogenomic Biomarkers in Drug Labels (2016)
Examples of Interpretation of Genetic Tests
HLA-B*5701
CYP2C9
VKORC1
CYP2C19
PK & PD
GENES
PD GENE
PK GENE
AVOID OR USE WITH
CAUTION WITH
FREQEUENT
MONITORING
USE WITH CAUTION WITH
DOSE ADJUSTMENT AND
WITH FREQEUENT
MONITORING
USE AS DIRECTED IN
PRODUCT LABEL
The True Story of Jeff Cluse
The Rest of the Story
A 51 yr old and I can’t enjoy my 4 grandchildren
“My chronic back injury limits my mobility and back pain is a way of life for the
past 5 years. Physical therapy and multiple drugs did little to ease the pain.”
“I visited the UF Pain Management Clinic and I was prescribed oxycodone but
my back pain got worse. My clinical pharmacist told me about a CYP2D6 test
and I agreed to have it done.”
“The test changed my life. I was a CYP2D6 poor metabolizer and I could not
convert oxycodone to oxymorphone. I was given meperidine (Demerol@) which
work better in reducing my back pain.”
“Now I can do more with my grandkids” (Clinical Utility)
GeneSightR: For Neuropsychiatric Drugs
• An integrated and weighted multivariate
genetic test of 8 PK genes and 4 PD genes
• Indications• Uncontrolled symptoms when considering a drug
or dosage change
• Lower than expected efficacy or higher than
expected unwanted side effects
• Polypharmacy where drug-drug interactions
conferring less benefit or greater risk
Note: I am on the SAB for Asssurex
Barriers: Prevailing Attitude Among
Payers
“…there is good evidence that persons having
gene variants of CYP2C9 and VKORC1 have
heightened response to warfarin, the evidence
for improvied health outcomes attributed to PGx
testing to determine warfarin responsiveness
fails to meet standards of evidence to establish
a basis for coverage.”
Center for Medicare and Medicaid, May 4, 2009
How Payers and Clinicians Perceive Cost,
Effectiveness and Value of PGx Testing
ALess effective,
Moreexpensive[Reject]
DMore effective,More expensive
[Problem]
BLess effective, Less expensive
[Unusual]
CMore effective, Less expensive
[Adopt]
PGx testing
less effectivePGx testing
more effective
PGx testing less expensive
PGx testing more expensive
Reasons That Reimbursement and Adoption
of PGx Tests Been So Limited
Considerations Key Points
Costs Easy to define ($400 FOR 2C9/VKORC1 test)
Effectiveness
Evidence in all cases AFTER approval of drug
Evidence often DISEASE- or DRUG-specific
Small sample sizes
Meaningful RCT approaches non-existent
Value and
Judgment
Is the evidence reliable?
What % of variability remains unexplained?
Is evidence generalizable?
Are clinical outcomes improved?
Are there alternatives that are just as good?
Warfarin Genetic Testing: More Effective,
Less Expensive?
① The % of patients within 20% of steady state
dose: 52% (PGx) vs 37% (empiric)
① The odds of patients being properly dosed
using a PGx algorithm vs empiric: 2.18
② The PGx algorithm performed much better
than empiric in patients requiring higher (>49
mg/week) and lower (<21 mg/week)
Finkelman et al. JACC (2011), 57:612-618. Woodcock and Lesko, NEJM
(2009), 360:811-813
Physician Education and Lab Reports
Clinical medicine does not yet have the tools to
put PGx test results to good use
For instance, would your physician know whether
CYP2C9 *1/*3 is good or bad when treating a
patient with warfarin?
Or worse yet, if lab results came back as
CYP2C9*3 (1075A>C) and VKORC1 AA (-
1639G>A)?
We Need More Decision Support Tools to
Reap the Benefits of PGx
Pre-emptive PGx Testing Can Be Cost-
Effective To Improve Benefit/Risk
Testing HIV patients for HLA-B*5701 before
giving abacavir saved $30,000 per hyper-
sensitivity reaction avoided in Caucasians
Mandatory testing for HLA-B*1502 in
Singapore before giving CBZ saved $37,000
per Chinese to avoid SJS
Schackman et al, AIDS (2008), 22:2025-2033. Dong et al, Neurology (2012), 79:1259-
1267
Lessons From Abacavir and CBZ: PGx and
Drug Safety Works Very Well
The cost of genotyping will get cheaper
and cheaper with increasing use meaning:
Benefit/Risk ~ Infinity
http://www.qd-qts.com
