Personalized Medicine
The Promise,
The Hype,
The Reality
Glenn A. Miller, Ph.D.
Vice President
General Manager
Genzyme Analytical Services
Genzyme Corporation
Analytical Services
Need for Change:
Strong case for personalized medicine
US drug spending $250+B per
year and growing fast
50% of drugs not efficacious as
prescribed
US diagnostics spending
decreased since 1984
Adverse drug reactions 6th
leading cause of death
Building the Case
for Personalized
Medicine
FDA interested in biomarkers
and diagnostic algorithms
Feb. 2005 PriceWaterhouseCoopers report titled Personalized Medicine: the Emerging Pharmacogenomics Revolution
Nov. 2005 Thomas Weisel Partners report titled Beneficiaries of Personalized Medicine and Market Update
Pharmacogenetics and the concept of individualized medicine published in The Pharmacogenomics Journal (Vol 6, Pg 16-21).
Molecular
Diagnostics and Personalized Medicine 2003, Drug & Market Development August 2003
2
Society can’t afford low efficacy
Frequency of
Absent or
Incomplete
Efficacy (%)1
Total Market
Size
Cost to the Health
Care System of
Ineffective
Therapy
Angiotensinconverting enzyme
(ACE) inhibitors
10-30
$3.9B2 (2003)
$390M-$1.2B
Beta blockers
15-25
$ 2.3B2 (2003)
$345M-575M
Anti-depressants
20-50
$11.7B3 (2003)
$2.3B-$5.8B
Statins
30-70
$12.6B4 (2004)
$3.8B-$8.8B
Beta agonists
40-70
$1.4B5 (2004)
$560M-$1B
Drug Class
1 Ross
JS & Ginsburg GS, Am J Clin Pathol 2003;119:26-36
August 1, 2005
3 Global Industry Analysts, October 10, 2004
4 Carnegie Research
5 Specialty Pharmaceutical Pulse, SG Cowen, October 2005
2 Datamonitor,
3
Patients don’t have time for trial and error
Disease
End stage renal disease
Heart failure (male-female)
Breast Cancer (node positive)
Lung cancer (small cell-non small cell)
1 Levy,
Perspectives U.S., 2004 Fourth Edition, DaVinci Healthcare Partners
2005 USRDS Annual Data Report
4
5 Year
Survival
78%
38%
76-72%
41-55%
98%
79%
36-41%
6-13%
et. al., Long-term trends in the incidence and survival from heart failure, NEJM, 2002; 347(18):1397-402
2 Cancer
3
1 Year
Survival
Spending more and testing less
• Medicare & Medicaid
represented 21% of the 2007
Federal Budget
• Continued growth expected
(from 2005-2015)
• Medicare = 9%
• Medicaid = 8%
• Laboratory spending fell
(Medicare Part B)
• 40% reduction in real terms from
1984 to 2004
5
Saving Lives
Positive Impact on Hematologic Cancers
60
Years Ago
50
Years Ago
40
Years Ago
5 year
survival
Leukemia or Lymphoma
Chronic Leukemia
Acute Leukemia
Preleukemia
Today
~ 0%
“Disease of the Blood”
Indolent Lymphoma
Aggressive Lymphoma
!38 Leukemia types identified:
!51 Lymphomas identified:
Acute myeloid leukemia (!12 types)
Mature B-cell lymphomas (!14 types)
Acute lymphoblastic leukemia (2 types)
Mature T-cell lymphomas (15 types)
Acute promyelocytic leukemia (2 types)
Plasma cell neoplasm (3 types)
Acute monocytic leukemia (2 types)
Immature (precursor) lymphomas (2 types)
Acute erythroid leukemia (2 types)
Hodgkin’s lymphoma (5 types)
Immunodeficiency associated lymphomas (!5 types)
Acute megakaryoblastic leukemia
Other hematolymphoid neoplasms (!7 types)
Acute myelomonocytic leukemia (2 types)
Chronic myeloid leukemia
Chronic myeloproliferative disorders (5 types)
Myelodysplastic syndromes (6 types)
Mixed myeloproliferative/myelodysplastic syndromes (3 types)
70%
Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2002, National Cancer
Institute.
6 Bethesda, MD, http://seer.cancer.gov/csr/1975_2002/, based on Nov 2004 SEER data submission, posted to
the SEER web site 2005.
Prescription Medication Compliance
Up to 50 % of patients do not
take medications as prescribed
Take medications
as prescribed,
54%
Stop taking
medicine before it
runs out, 22%
Don't fill
prescription, 12%
Fill prescription but
don’t take
medicine, 12%
7
Source: www.americanheart.org
Prescription Medication Compliance
! 10 % hospitalizations due to noncompliance
! 3.5 million patients
! Average hospital stay in 4.2 days due to noncompliance
! $15.2 billion cost
! 23 % of all nursing home admissions are due to
noncompliance
! 380,000 patients
! $31.3 billion cost
! Noncompliance causes 125,000 deaths annual in the
United States
8
Prescription Medication Compliance
! Factors Believed To Affect Compliance
!
!
!
!
!
Patient knowledge
Prior compliance behavior
Ability to integrate into daily life / complexity of drug regimen
Health beliefs and perceptions of benefits of treatment
Social support, including practitioner relationship
! Factors Believed NOT To Affect Compliance
! Age, race, gender, income or education
! Patient intelligence
! Actual seriousness of disease or efficacy of the treatment
9
Personalized Medicine: The Future
" FDA
# Insist on diagnostic links that decrease side effects and
improve efficacy with new therapies
" Payors
# Demand diagnostics to manage drug costs and improve
patient care
# CMS approval for targeted drugs depends on efficacy
" Pharmaceutical Companies
# Reduce drug failures in late clinical trials (and on the
market)
# Increase efficacy - show real value of drug
" Patients
# Improved care – more effective treatments with fewer side
effects
10
Personalized Medicine: The Future
" Diagnostics – Turn the Hype into Reality
# 3% of the costs – 70% of the medical decisions
# Make new drugs work
# More than 50% of cancer drugs in development today are
targeted and will need diagnostics to determine use
# Save money
# Reduce ineffective use of drugs and treatments
# Save lives
# Give physicians information to better use options available
# Deliver on the promise
# The right drug to the right patient at the right time
11
The Key to Personalized Medicine:
Diagnostics
Current - Diagnostic Testing
Identify disease state with high level
of resolution
Emerging Today - Prognostic Testing
Clarify probable outcomes
Monitor disease
Emerging Tomorrow - Predictive
Testing
Predict response to therapeutics
Screen for adverse outcomes
Define risks for development of
common diseases
12
Genetic Testing Market
Number of Available Tests*
* Excludes genetic tests for hereditary cancers and infectious diseases
13
Source: GeneTests.org
The Department of Human Genome Impact:
Pharmaceutical Division
! Like drinking from a fire hose
! Lots of volume
! Huge amounts of novel data
! Everyone gets wet
! New discoveries affect every facet of disease management
! Not everyone’s thirst is quenched
! Genomics is not the answer to every question
! Trying to drink too fast can hurt
! A disorganized approach to the use of genomics can waste
money and time
! A little thought on how to capture and use the water
later can be helpful
! Incorporating genomic information early in development
can lead to benefits in later clinical trials
14
Standing on the Shoulders of Giants
"We wish to suggest a structure for the salt of
deoxyribose nucleic acid (D.N.A.). This structure has novel
features which are of considerable biological interest...
...It has not escaped our notice that the specific pairing we
have postulated immediately suggests a possible copying
mechanism for the genetic material.“
-James Watson and Francis Crick
15
Nature 171:737, 1953
Anatomy of the Human
Vesalius
1543
Harvey
1628
!" #$%&'()%*+ #,-$-#. / 0 1 . . / 2 + #. 3 3 4
16
Morgagni
1761
Anatomy of the Human Genome
1950’s
1960’s
1980’s to Today
The Future?
17
Human Genome Project
We’ve come a long way with a long way to go
akdjfhqlweuehlkjwekbalsdkfiuk
ajsdasdclinicasdflkjheuallyadfh
jhojwerusejhafyyqrewfuljbadbk
fbkdinforadfjbkjdkjbmationjhas
djkjhskdjhkljhlekrjhwkejrbkbjbf
Clinically useful information
“Celera’s genome sequence will be a
truth serum for the field”
J. Craig Venter, NY Times 2/13/01
“They have to say something about a
worthless database”
William A. Haseltine, NY Times 2/13/01
18
Why This Matters
! Benefits patients
! Improved diagnostics (Dx)
! Targeted therapeutics (Rx)
! Individualized care will become a reality
! Best treatment for the individual patient
! Actual “evidence” for Evidence Based Medicine
! The public expects this to happen
! A need to manage expectations
! Understand and anticipate scientific advances and educate the
public about the impact
19
Genetics is news
1990
1994
2001
“targeting”
20
The Prediction
“Prediction is very difficult,
especially about the future”
Niels Bohr
! Someday your genome will be on a credit
card-sized device…or iPod®
! “Dr. Will Gilbert at UNH is already carrying around
the latest version of several genomes on his iPod”
Scarlet Pruitt, IDG News Service
Monday, January 20, 2003
Is this the correct prediction?
Why would this be desirable?
What might the future really look like?
21
Challenges to Implementation
! Technology
! Information
! Cost
! Need
! Desire
22
Technology
! Entire human genome occupies about 1Gb of
storage when compressed.
! 1Gb USB drives available for less than $20
! Future storage advances will easily solve any
portable storage issue
! With broadband access may not even need to
carry information with you
This is an absolutely achievable goal
! Whole genome sequencing on a populationwide scale is a significant technical leap away
This goal will take significant effort
23
Information
! What kind of information is needed?
! The task of sorting through the Human Genome
Project
! Over 3 billion bases
! 25,000+ genes
! Over 40% of which have no known function
! Millions of variants
! Most discoveries will be diagnostic before they are
therapeutic
! Problem of knowledge with no recourse
! Lack of understanding of which sequences and
sequence changes are important
24
Cost
! Assume the sequencing cost is $1000
! Does not include shipping, labor, results analysis, reporting
and markup
! 4 million births annually
! $4 billion/year in sequencing costs
! Assume only those with a certain level of education
! High school & college grads = $2.2 billion/yr
! Postgraduate = $1 billion/yr
! Roughly 88% have health insurance of some kind
! ~$2.8 billion to health insurance plans/year
! This does not include the bolus of sequencing for the
existing population
! Estimated market size for all of genetic testing in 2004
is $600 million (Frost & Sullivan)
National Vital Statistics Reports
Final data for 2000
Centers for Disease Control
National Center for Health Statistics
25
Need
(the So What?!? test)
! To what use will this information be put?
! For centuries medicine has been geared
towards problem solving
! Information is requested at the time of illness
not gathered in advance
! Trial and error medicine predominates
! FDA approves based on safety first, efficacy second
26
Desire
! Do we really want to know this information?
! This is not the philosophical “All and ever present good”
! Many individuals prefer not to know
! ~50% of women seeking amniocentesis decide
otherwise after non-directive genetic counseling
! ~57-84% of at risk individuals for Huntington’s Disease
indicated interest in test before it was available. Less
than 20% (2-16%) actually took the test after it was
launched
! Fear of being unable to undo the knowledge
! Loss of insurance, job
! Survivor guilt
Maat-Kievit et al. J Neurol Neurosurg Psychiatry 2000;69:579-583
27
Educational Challenges
! Educating healthcare workers
! Genetics as a part of medical education is
increasing but remains a low emphasis subject for
the current student
! The current healthcare workforce has had minimal to
no genetics education
! For the practicing physician >45 years old most of the era of
genetic discovery has come since they graduated medical
school.
! May take a generational change to fully incorporate these
medical practice advances
28
I want that new test! vs.
Why should I use/pay for that?
The Yin/Yang of Providers, Payors & Employers
! Inability to fully evaluate tests
! Large number of areas to cover
! Current clinical responsibilities leave little time for study
! Utilization management and cost containment are primary
drivers
! Employers focus on health care costs
! Certain that tests costs will rise with no real benefit to them
! Employees want the tests covered
! Providers and payors are bombarded by requests for
new tests
! Effect of plan members with access to Internet, NY Times, USA
Today, local papers, TV, radio, Bill Nye the Science Guy
29
Payors and the information glut
It is all a matter of individual perspective
Questions and comments from managed care
! “What about privacy concerns when everyone’s genome is on a credit
card sized device?”
! “They can clone sheep, what about humans? What do I need to plan
for in my budget?”
! “Genetics is nothing, Bariatric surgery is the most over hyped clinical
event in 25 years! It has dramatically hit my budget.”
! “You are wrong if you think you are going to price a test based on the
amount of money you are saving me divided by the patients tested.”
! “Why should I care, I just deny everything anyway!”
! “Why don’t we just wait until the proteomics tests come to market?”
! “Genetic testing is just for rare diseases that don’t occur in the
members of this plan.”
30
The providers are just as perplexed
! “Is DNA really found in every cell?”
! “The last genetics I took was in medical school 30 years ago!”
! “Just tell me which box to check off and what the rights codes
are.”
! “They found the gene for disease X. My (patient, mother,
husband, child…) has disease X. Where can I get the (test,
therapy, cure…)”
! “I keep hearing about these microarray things. What is the big
deal?”
! “Can you explain to my patient (and me) what the genetic
information means?”
! “My professional organization has established this as standard of
care. Now what do I do?”
31
The Doe Family
Janet
John
Jane
Jackie
Jake
32
Joseph
Jane
Diagnostic Impact
! Born in 1942
! Jane’s mother had no genetic testing offered to her
during her pregnancy
! 1980 gives birth to daughter Jackie
! Offered amniocentesis, karyotype analysis &
biochemical genetic analysis
! Standard of care determined by age due to invasiveness of
procedure
! 2010 Jackie gives birth to Jake
! First trimester screening routine
! Genetic analysis done via blood sample test of Fetal
DNA in maternal circulation, pre & post test genetic
counseling
! Minimal invasiveness means no age cutoff; Information available
for all pregnancies
33
Jane
Pharmacogenetics
! 2000
! 2007
! Jane is diagnosed with depression
! One of ~20 million individuals
diagnosed each year
! Placed on standard dose tricyclic
anti-depressant
! Shows signs of confusion
! Difficulty concentrating
! Physician interprets as further signs
of depression, incr. dose
! Agitation
! Nausea and vomiting
! Jane switched to alternative TCA
34
! Jane is diagnosed with depression
! CYP450 genotype determined
! Deficient in CYP2D6
! Placed on SSRI successfully
The genotype also explains why Jane
does not respond to codeine based
analgesics
Joseph
Pharmacogenetics
-: ;"
789 "
,56"
! 2002
! Joseph is diagnosed with
hypertension and placed on his
first "-blocker
! Experiences wheezing and
shortness of breath
! Hypertension is not adequately
resolved
! Joseph is switched to another "blocker
! While his hypertension is eased
Joseph experiences dizziness at
the effective dose
! Joseph speaks to a friend, sees
his physician as a new patient
! Receives his third different "blocker
! Hypertension controlled without
significant side effects
35
! 2009
! Joseph is diagnosed with
hypertension
! Physician orders a CYP450
genotype
! Test identifies Joseph as a poor
metabolizer for a class of drugs
requiring CYP2D6
! Physician uses this information to
select a "-blocker not metabolized
in this manner
! Joseph’s hypertension is controlled
without significant side effects. All
in one visit and with one drug
Jane & Janet
Prognosis & Treatment Impact
! Jane, 2000
! Undergoes colonoscopy
! Found to have a Dukes A
adenocarcinoma
! Successful surgical resection,
unremarkable hospital stay,
no further Rx
! Returns at regular intervals for
follow-up colonoscopy
! Found to have widespread
metastasis at 5yrs. post
resection
Both sisters receive genetic
counseling concerning colon
cancer risk and options
36
! Janet, 2009
! Molecular test to detect colon
cancer
! Undergoes colonoscopy
! Found to have a Dukes A
adenocarcinoma (15%
metastasize)
! Learns from the Internet
about a molecular test for
cancer spread
! Successful surgical resection
& hospital stay
! Molecular profiling determines
her tumor has high metastatic
potential
! Treated with 5-FU
! Disease free at 5yrs.
Human Genome Project Impact
Genetic Counseling
! Responsible approach
based on evidence-based
practice guidelines
! Enhances informed
decision-making &
consent
! 45%-55% of patients
accept amnios after
genetic counseling
! Improves health care
coordination and
supports health plan
goals
! Right test for the right
patient at the right time
37
Janet
Jane
John
Joseph
Jackie
Jake
! Better prenatal testing & cancer diagnostics
! The right drug to the right patient at the right
dose
! Novel targeted treatments
! Reduced adverse events
Boston Metropolitan Area
Janet
Transition from age
restricted testing to testing
for all
Testing optimizes
Rx selection for
anti-depression/anti-anxiety
38
John
Jane
Jackie
Jake
Joseph
Prenatal Testing
Transition From Age-Restricted Testing to Testing For All
39
Pharmacogenetics
Testing Optimizes Rx Selection for Anti-Depression/Anti-Anxiety
40
Boston Metropolitan Area
Janet
John
Jane
Jackie
Drug class selection for
best results
Jake
41
Joseph
Pharmacogenetics
Drug Class Selection for Best Results
42
Boston Metropolitan Area
Janet
John
Jane
Jackie
Targeted therapies and
diagnostics for cancer
Jake
43
Joseph
Targeted Therapy and Molecular Profiling
Targeted Therapies and Diagnostics For Cancer
44
Boston Metropolitan Area
Janet
John
Jane
Jackie
The real impact of the
Human Genome Project
Jake
45
Joseph
Boston Metropolitan Area
The Real Impact Of The Human Genome Project
46
Summary
! The use of genetics in drug development is increasing
as a result of a:
!
!
!
!
Greater understanding of disease mechanisms
Response to competition
Recognition that approval times can be shortened
Recognition that regulatory agencies are now expecting this
kind of data in support of an application
! The healthcare community is moving to adopt targeted
therapy
! Better efficacy
! Safer treatments
! Better outcomes
! The future of Personalized Medicine is secure
! Now begun, there are too many benefits to the public to
prevent its adoption
47
Two closing thoughts
“The danger with the information revolution is that we will
overestimate the short term implications, and underestimate
the long term impact. “
Bill Gates
Much the same can be said of the
genomic revolution
“Even if you are on the right track,
you will get run over if you just sit there.”
Mark Twain
48