personalized medicine - whitehead...

Analytical Services

Personalized Medicine

Glenn A. Miller, Ph.D.Vice President

General Manager

Genzyme Analytical Services

Genzyme Corporation

The Promise,The Hype,The Reality

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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

Need for Change:Strong case for personalized medicine

50% of drugs not efficacious asprescribed

FDA interested in biomarkersand diagnostic algorithms

US diagnostics spendingdecreased since 1984

Adverse drug reactions 6thleading cause of death

US drug spending $250+B peryear and growing fast

Building the Casefor Personalized

Medicine

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Society can’t afford low efficacy

40-70

30-70

20-50

15-25

10-30

Frequency ofAbsent or

IncompleteEfficacy (%)1

$1.4B5 (2004)

$12.6B4 (2004)

$11.7B3 (2003)

$ 2.3B2 (2003)

$3.9B2 (2003)

Total MarketSize

$560M-$1BBeta agonists

$3.8B-$8.8BStatins

$2.3B-$5.8BAnti-depressants

$345M-575MBeta blockers

$390M-$1.2BAngiotensin-converting enzyme(ACE) inhibitors

Cost to the HealthCare System of

IneffectiveTherapy

Drug Class

1 Ross JS & Ginsburg GS, Am J Clin Pathol 2003;119:26-362 Datamonitor, August 1, 20053 Global Industry Analysts, October 10, 20044 Carnegie Research5 Specialty Pharmaceutical Pulse, SG Cowen, October 2005

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Patients don’t have time for trial and error

79%98%Breast Cancer (node positive)

36-41%

76-72%

78%

1 YearSurvival

6-13%

41-55%

38%

5 YearSurvival

Lung cancer (small cell-non small cell)

Heart failure (male-female)

End stage renal disease

Disease

1 Levy, et. al., Long-term trends in the incidence and survival from heart failure, NEJM, 2002; 347(18):1397-402

2 Cancer Perspectives U.S., 2004 Fourth Edition, DaVinci Healthcare Partners

3 2005 USRDS Annual Data Report

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Spending more and testing less

• Medicare & Medicaidrepresented 21% of the 2007Federal Budget

• Continued growth expected(from 2005-2015)

• Medicare = 9%• Medicaid = 8%

• Laboratory spending fell(Medicare Part B)

• 40% reduction in real terms from1984 to 2004

6

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 CancerInstitute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2002/, based on Nov 2004 SEER data submission, posted tothe SEER web site 2005.

Saving LivesPositive Impact on Hematologic Cancers

50

Years Ago

Leukemia or Lymphoma40

Years Ago

Chronic Leukemia

Acute Leukemia

Preleukemia

Indolent Lymphoma

Aggressive Lymphoma

60

Years Ago

“Disease of the Blood”

Today

!38 Leukemia types identified:

Acute myeloid leukemia (!12 types)

Acute lymphoblastic leukemia (2 types)

Acute promyelocytic leukemia (2 types)

Acute monocytic leukemia (2 types)

Acute erythroid leukemia (2 types)

Acute megakaryoblastic leukemia

Acute myelomonocytic leukemia (2 types)

Chronic myeloid leukemia

Chronic myeloproliferative disorders (5 types)

Myelodysplastic syndromes (6 types)

Mixed myeloproliferative/myelodysplastic syndromes (3 types)

!51 Lymphomas identified:

Mature B-cell lymphomas (!14 types)

Mature T-cell lymphomas (15 types)

Plasma cell neoplasm (3 types)

Immature (precursor) lymphomas (2 types)

Hodgkin’s lymphoma (5 types)Immunodeficiency associated lymphomas (!5 types)

Other hematolymphoid neoplasms (!7 types)

5 yearsurvival

~ 0%

70%

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Prescription Medication Compliance

Stop taking

medicine before it

runs out, 22%

Don't f ill

prescription, 12%

Fill prescription but

don’t take

medicine, 12%

Take medications

as prescribed,

54%

Up to 50 % of patients do nottake medications as prescribed

Source: www.americanheart.org

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! 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 tononcompliance! 380,000 patients

! $31.3 billion cost

! Noncompliance causes 125,000 deaths annual in theUnited States

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! 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

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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 improvepatient 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

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"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 aretargeted 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

Personalized Medicine: The Future

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Current - Diagnostic TestingIdentify disease state with high level

of resolution

Emerging Today - Prognostic TestingClarify probable outcomesMonitor disease

Emerging Tomorrow - PredictiveTesting

Predict response to therapeuticsScreen for adverse outcomesDefine risks for development of

common diseases

The Key to Personalized Medicine:Diagnostics

13* Excludes genetic tests for hereditary cancers and infectious diseases Source: GeneTests.org

Genetic Testing MarketGenetic Testing MarketNumber of Available Tests*Number of Available Tests*

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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 waterlater can be helpful! Incorporating genomic information early in development

can lead to benefits in later clinical trials

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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 Nature 171:737, 1953

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!"#$%&'()%*+ #,-$-#. / 0 1. . / 2 + #. 3 3 4

Vesalius1543

Harvey1628

Morgagni1761

Anatomy of the Human

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1950’s

1960’s

1980’s to Today

The Future?

GenomeAnatomy of the Human

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Human Genome ProjectWe’ve come a long way with a long way to go

Clinically useful information

akdjfhqlweuehlkjwekbalsdkfiukajsdasdclinicasdflkjheuallyadfhjhojwerusejhafyyqrewfuljbadbkfbkdinforadfjbkjdkjbmationjhasdjkjhskdjhkljhlekrjhwkejrbkbjbf



“Celera’s genome sequence will be atruth serum for the field”

J. Craig Venter, NY Times 2/13/01

“They have to say something about aworthless database”

William A. Haseltine, NY Times 2/13/01

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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 thepublic about the impact

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Genetics is news

19941990

2001

“targeting”

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The Prediction

!Someday your genome will be on a creditcard-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

“Prediction is very difficult,especially about the future”Niels Bohr

Is this the correct prediction?Why would this be desirable?What might the future really look like?

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Challenges to Implementation

!Technology

! Information

!Cost

!Need

!Desire

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Technology

!Entire human genome occupies about 1Gb ofstorage when compressed.! 1Gb USB drives available for less than $20

! Future storage advances will easily solve anyportable storage issue

!With broadband access may not even need tocarry information with you

This is an absolutely achievable goal

!Whole genome sequencing on a population-wide scale is a significant technical leap away

This goal will take significant effort

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Information

!What kind of information is needed?

! The task of sorting through the Human GenomeProject! 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 aretherapeutic! Problem of knowledge with no recourse

! Lack of understanding of which sequences andsequence changes are important

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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 theexisting population

! Estimated market size for all of genetic testing in 2004is $600 million (Frost & Sullivan)

National Vital Statistics ReportsFinal data for 2000Centers for Disease ControlNational Center for Health Statistics

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Need (the So What?!? test)

!To what use will this information be put?

!For centuries medicine has been gearedtowards problem solving

! Information is requested at the time of illnessnot gathered in advance

! Trial and error medicine predominates

! FDA approves based on safety first, efficacy second

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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 decideotherwise after non-directive genetic counseling

! ~57-84% of at risk individuals for Huntington’s Diseaseindicated interest in test before it was available. Lessthan 20% (2-16%) actually took the test after it waslaunched! Fear of being unable to undo the knowledge

! Loss of insurance, job

! Survivor guiltMaat-Kievit et al. J Neurol Neurosurg Psychiatry 2000;69:579-583

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Educational Challenges

!Educating healthcare workers

! Genetics as a part of medical education isincreasing but remains a low emphasis subject forthe current student

! The current healthcare workforce has had minimal tono genetics education! For the practicing physician >45 years old most of the era of

genetic discovery has come since they graduated medicalschool.

! May take a generational change to fully incorporate thesemedical practice advances

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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 primarydrivers

! 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 fornew tests! Effect of plan members with access to Internet, NY Times, USA

Today, local papers, TV, radio, Bill Nye the Science Guy

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Payors and the information glutIt 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 planfor in my budget?”

! “Genetics is nothing, Bariatric surgery is the most over hyped clinicalevent in 25 years! It has dramatically hit my budget.”

! “You are wrong if you think you are going to price a test based on theamount 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 themembers of this plan.”

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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 codesare.”

! “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 bigdeal?”

! “Can you explain to my patient (and me) what the geneticinformation means?”

! “My professional organization has established this as standard ofcare. Now what do I do?”

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The Doe FamilyThe Doe Family

Janet JosephJane John

Jake

Jackie

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JaneDiagnostic Impact

! Born in 1942

! Jane’s mother had no genetic testing offered to herduring 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 FetalDNA in maternal circulation, pre & post test geneticcounseling! Minimal invasiveness means no age cutoff; Information available

for all pregnancies

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JanePharmacogenetics

! 2000

! Jane is diagnosed with depression

! One of ~20 million individualsdiagnosed each year

! Placed on standard dose tricyclicanti-depressant

! Shows signs of confusion

! Difficulty concentrating

! Physician interprets as further signsof depression, incr. dose

! Agitation

! Nausea and vomiting

! Jane switched to alternative TCA

! 2007

! Jane is diagnosed with depression

! CYP450 genotype determined

! Deficient in CYP2D6

! Placed on SSRI successfully

The genotype also explains why Janedoes not respond to codeine basedanalgesics

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JosephPharmacogenetics

! 2002! Joseph is diagnosed with

hypertension and placed on hisfirst "-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 atthe effective dose

! Joseph speaks to a friend, seeshis physician as a new patient! Receives his third different "-

blocker! Hypertension controlled without

significant side effects

! 2009! Joseph is diagnosed with

hypertension! Physician orders a CYP450

genotype! Test identifies Joseph as a poor

metabolizer for a class of drugsrequiring CYP2D6

! Physician uses this information toselect a "-blocker not metabolizedin this manner

! Joseph’s hypertension is controlledwithout significant side effects. Allin one visit and with one drug

,56"

789"

-:;"

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Jane & JanetPrognosis & Treatment Impact

! Jane, 2000! Undergoes colonoscopy

! Found to have a Dukes Aadenocarcinoma

! Successful surgical resection,unremarkable hospital stay,no further Rx

! Returns at regular intervals forfollow-up colonoscopy

! Found to have widespreadmetastasis at 5yrs. postresection

! Janet, 2009! Molecular test to detect colon

cancer

! Undergoes colonoscopy! Found to have a Dukes A

adenocarcinoma (15%metastasize)

! Learns from the Internetabout a molecular test forcancer spread

! Successful surgical resection& hospital stay

! Molecular profiling determinesher tumor has high metastaticpotential

! Treated with 5-FU

! Disease free at 5yrs.

Both sisters receive geneticcounseling concerning colon

cancer risk and options

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Human Genome Project ImpactHuman Genome Project Impact

Janet Jane

Jake

John

Jackie

Joseph

Genetic Counseling

! Responsible approachbased on evidence-basedpractice guidelines

! Enhances informeddecision-making &consent! 45%-55% of patients

accept amnios aftergenetic counseling

! Improves health carecoordination andsupports health plangoals! Right test for the right

patient at the right time ! Better prenatal testing & cancer diagnostics

! The right drug to the right patient at the rightdose

! Novel targeted treatments

! Reduced adverse events

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Jake

Jackie

Transition from agerestricted testing to testing

for all

Testing optimizesRx selection for

anti-depression/anti-anxiety

Boston Metropolitan AreaBoston Metropolitan Area

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Prenatal Testing

Transition From Age-Restricted Testing to Testing For All

40

Pharmacogenetics

Testing Optimizes Rx Selection for Anti-Depression/Anti-Anxiety

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Jake

Jackie

Drug class selection forbest results


42

Pharmacogenetics

Drug Class Selection for Best Results

43



Jake

Jackie

Targeted therapies anddiagnostics for cancer

44

Targeted Therapy and Molecular ProfilingTargeted Therapy and Molecular Profiling

Targeted Therapies and Diagnostics For Cancer

45


Jake

Jackie

The real impact of theHuman Genome Project


46

The Real Impact Of The Human Genome Project


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Summary

! The use of genetics in drug development is increasingas 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 thiskind of data in support of an application

! The healthcare community is moving to adopt targetedtherapy! 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

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Two closing thoughts

“The danger with the information revolution is that we willoverestimate the short term implications, and underestimate

the long term impact. “Bill Gates

Much the same can be said of thegenomic revolution

“Even if you are on the right track,you will get run over if you just sit there.”

Mark Twain

personalized medicine - whitehead...

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