Personalized Medicine and Patient - Milken Institute · customized to an individual’s genetic makeup. Do you think that personalized medicine will have a positive or negative

Personalized Medicine and Patient

Empowerment

Positive, 73%

Negative, 13%

Don't Know, 14%

Personalized Medicine Will Have Positive Impact

Personalized medicine refers to testing and treatment customized to an individual’s genetic makeup. Do you think that personalized medicine will have a positive or negative

impact on future health care?

SOURCE: THE PARADE/RESEARCH!AMERICAHEALTH POLLCHARLTON RESEARCH COMPANY, 2004

Don't Know, 4%

No, 34%

Yes, 62%

Americans Support Genetic Testing for Improved Medications

Would you want to be genetically tested to determine which medications might be most effective and safest for you?


Americans Willing to Share Medical Information

Assuming that there is no way anyone will have access to your identity, would you be willing to

release your health information so that…

69

67

56

27

29

37

4

4

7

Doctors and hospitalscan try to improve

their services

Researchers can learnabout the quality ofhealth care, diseaseand prevention, and

related issues

Public health officialscan scan for

bioterrorist attacks

Yes No Don't KnowSOURCE: THE PARADE/RESEARCH!AMERICA HEALTH POLLCONDUCTED BY CHARLTON RESEARCH COMPANY, 2004

Public Trust in Sources of Research Information

As you are probably aware, there are many sources of information about medical and health research issues. For

each of these sources, I’d like you to tell me how trustworthy you think the information they provide is?

96%

95%

95%

93%

92%

89%

83%

56%

55%

53%

Nurses

Pharmacists

Your physician

Medical schools and teaching hospitals

Your dentist

Voluntary health agencies (such as theAmercian Heart Association)

Government agencies (such as NIH and CDC)

Internet

Media sources

Pharmaceutical companies

SOURCE: NATIONAL SURVEY, 2005CHARLTON RESEARCH COMPANY FOR RESEARCH!AMERICA

Clinical Research is ValuableHow do you perceive the value of clinical research? (In

clinical research, volunteers choose to participate to test the effectiveness of certain treatments, drugs or devices in improving the care of patients and understanding and

preventing disease.)

Don't Know, 3%

Not Much, No Value, 2%

Some Value, 27%

Great Value, 68%


Don't Know, 4%

Would Not, 18%

Not Likely, 24%

Likely, 54%

Many Would Participate in a Clinical Research Study

How likely would you be to participate in a clinical research study?


Don't Know, 9%

Less Likely, 9%

Somewhat more Likely,

36%

Much More Likely, 46%

Americans Associate Research and Training With Good Hospitals

If you knew that a hospital was doing research and training medical students and other health professionals, would that

make you more or less likely to think that it was a good hospital?

SOURCE: NATIONAL SURVEY, 2004CHARLTON RESEARCH COMPANY FORRESEARCH!AMERICA

Factors Affection Participation in Clinical Research

How much of a concern would the following factors be in your decision to participate as a volunteer in a clinical research study?

70%

58%

55%

46%

15%

Reputation ofinstitution

Improve health ofself/others

Privacy,confidentiality

Physician'srecommendation

Incentives toparticipate

SOURCE: THE PARADE/RESEARCH!AMERICA HEALTH POLLCHARLTON RESEARCH COMPANY, 2004

Targeting MM CellIGF-1 inhibitorsCD40 AbTelomestatin

Targeting BM Milieup38MAPK inhibitors

Targeting MM Cell &BM MilieuBortezomibThalidomide/Revlimid

Novel Therapies Targeting Multiple Myeloma

MultipleMyelomaCell

StromalCell

Bone Marrow

CellularCross-Talk

After Kenneth AndersonAfter Kenneth Anderson

Novel Therapies Novel Therapies Targeting Multiple Targeting Multiple MyelomaMyeloma

Multiple MyelomaCell Growth

Bone Marrow Stromal Cells

IL-6

Bone Marrow Vessels

ICAM-1VCAM-1

VEGFbFGF

TNFVEGF

Hideshima et al. Cancer Res 61: 3071, 2001Hideshima et al. Oncogene 20: 4519, 2001

Mitsiades et al. Blood 99: 4079, 2002Hideshima et al. J Biol Chem 277: 16639, 2002

Quality Improvement Model Adapted to Individualized Oncology

Waste

Empiric Therapy

Targeted Therapy

Waste due toExcessive Rx

Waste due toInsufficient Rx

OptimalIntervention

ExcessiveIntervention

InsufficientIntervention

Qua

lity

Preempt the Cancer Process

SusceptibilityPre-Cancerous

Changes

Malignant Transformation

Metastatic Progression

Life Span NaturalDeathBirth

Death due to CancerDeath due to Cancer

20052005

Prevent Detect Modulate Eliminate

20152015

Milken InstitutePersonalized Medicine and

Patient Empowerment

April 20, 2005

HIV Viral Load and Genotyping TestingAn Early Example of Personalized Medicine

u Death from AIDS in the U.S. climbed to over 50,000 per year until the introduction, in 1994, of protease inhibitors and combination therapy, monitored with viral load testing and followed by genotyping for drug resistance

u The combination became the standard of care and resulted in an immediate reduction in fatalities and improved quality of life for those affected

Source: U.S. Department of HHS HIV/AIDS Surveillance Report 12/01

0

10,000

20,000

30,000

40,000

50,000

60,000

1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

Dea

ths

Dur

ing

Inte

rval

1

Patient Selection: Potentially Active Therapy Could be Missed

Easy to miss a potentially active new therapy as target prevalence decreases

SIMULATED MODEL

7000 182 months1.5 months (7.5%)All Patients

900 36 months6 months (30%)FISH (+)

Patients Only6 months

Required Sample Size and Study Duration

Actual Benefit(All Patients)

Enrolled Patients

Benefit in FISH (+) Patients

Example: First-line metastatic breast cancerHerceptin data: Median survival ~ 20 months

Source: Genentech2

u Improving current response rates:1

• Alzheimer’s Disease – 30%

• Cancer – 25%

• Osteoporosis – 48%

• HCV – 47%

• Rheumatoid arthritis – 50%

u Avoiding adverse drug reactions:2

• Of 2.8 billion annual prescriptions, 2 million resulted in adverse drug reactions (ADR’s) and >100,000 deaths

• ADR’s could be the 4th – 6th leading cause of death in the U.S., with annual cost of ~$1.3 billion

1 Spear, Heath-Chiozzi and Huff, Trends in Mol Med 7, 201 (2001).

2 Lazarou et al., JAMA, 279, 15 (1998).

Targeted MedicineRecent Technical Advances Make It Possible

3

Drug Development Costs Escalate

0

0.5

1

1.5

2

2.5

1995-2000 2000-2002

Preclinical

Phase I

Discovery

Phase II

Launch

Phase III/File

$1.1B

Discovery

PreclinicalPhase I

Phase II

Phase III/File

Launch

$1.7B

Investment required for one successfuldrug launch (discovery through launch)

CriticalPath

CriticalPath

Costs are becoming prohibitiveu FDA estimates the cost to develop one successful drug will increase to $1.7B –

up from $800MM – $1B just 4 years ago

Investment Escalation per Successful Compound

Source: Windhover’s In Vivo. The Business & Medicine Report. Bain drug economics model, 2003

($ in

Bill

ions

)

4

$803m

$20m$24m

$43m

$316m $403m

$400m

Phase I Phase II Phase III Clinical Failures

Successful NDA

Time Value ofmoney

Total costSuccessful NDA

Cost of Drug DevelopmentCumulative Cost per Step Including Failures to Get 1 NDA

Source: DiMasi et al, JHE 2003

Failures are the main cost component

~4xCost for Ph I-III

Failures

5

Why are NCEs terminated?

Source: Tufts Center for the Study of Drug Development, Hambrecht & Quist and Citigroup estimates

5 – 10%Other

30 – 35%Economics

20 – 25%Safety

35 – 40%Efficacy

6

u Aimed at modernizing preclinical/clinical medical product development

u Many evaluative tools (e.g. animal toxicology) have not changed much in over 50 years

u Need to invest in tools used to translate good ideas into actual products

u This approach will segment market but simplify and speed development process, while making it more informative

FDA’s Critical Path Initiative

Source: FDA7

u Targeted therapy to maximize benefit and minimize potential for harm

u New evaluative tools to assess toxicity and efficiency

u Linked diagnostics/pharmaceuticals (theranostics) to allow better drug selection

u Pharmacogenomic methods to individualize dose

FDA—New Science Provides a Way Forward

Source: FDA8

u Clarify process for adopting new biomarkers and surrogate markers for regulatory use

u Collaborate on development of important biomarkers (e.g., safety markers, imaging techniques)

u Assist in moving specific markers to surrogate status

FDA—Biomarkers and Surrogate Markers

Source: FDA9

u Voluntary submission can help FDA attain greater understanding • Prevents further delays if pharmacogenomics may be

utilized

u Pharmacogenomics is becoming an integral part of the FDA process

u FDA is flexible regarding integration

u FDA focus on utilizing a biomarker to establish scientific foundation• Physiologic, pharmacologic, toxicologic, and clinical

significance

FDA Recent Guidance

10

Pharmacogenomics' Key Applications, According to FDA

Area is ripe for investigation, but not currently done.Study of marketed drugs developed without PG information

Some clinical applications of this are emerging.Assess completeness of response to treatment

We don't really understand this phenomenon well. All AIDS patients are now genotyped for likelihood of developing drug resistance before going on therapy and before they become resistant.

Monitoring for development of drug resistance

Response to treatment. Widely done, particularly in life-threatening diseases such as AIDS and cancer, using traditional and some new markers. Genotyping is emerging as important here.

Therapeutic monitoring

This field is completely unexplored at present. Co-development may be very important to improve risk/benefit profiles of drugs.

Identify individual risk for side effects

This is a huge area of interest, with near-term applications. Currently can be done using metabolic markers, which generally provide insight but are not necessarily definitive as other proteins in the body also influence correct dosage. Will expand in future.

Individualize dose

This is an emerging application in cancer.Identify potential responders/ non-responders

Addresses important need to differentiate diseases better, but this doesn't necessarily dictate one treatment over another.

Diagnose disorders more precisely

Status/Impact on Drug UseApplication of PG

Source: Talk by Janet Woodcock & other FDA officials at FDA/Drug Industry Association meeting on July 29, 2004

11

u Shorter and smaller human clinical trials

• Faster clinical development and FDA turnaround

u More rapid uptake with managed care

u Lower marketing costs

u Easier reimbursement

u 12 years of effective patient life vs. 7 – 10 years

Why Personalized Medicine Should Be Embraced

12

Cancer Treatment DecisionsDisease Progression and Drug Response

DiagnosedPatients

Test for drugresponse

andprogression

Slow progressors/Non-responders

Slow progressors/Responders

Fast progressors/Responders

Fast progressors/Non-responders

Treat immediately

Consider delayingor changing

treatment

New therapies

Source: Celera13

uBlockbuster model being re-assessed

uEvery pharmaceutical and biotechnology company thinking about it• Difficult to do retrospective analysis

uBest if integrated early in drug development

uA fall-back strategy: can it save compounds?

Personalized Medicine Observations

14

u Is there a true benefit to checking all patients with an expensive test(s) to predict rare events

• May get a relative risk

• Primary care doctors not trained to handle these tests

u Is a marker or mutation a smoking gun for primary care?

• Will probably require multiple markers

u Could Tysabri have been avoided?

• Unlikely but patient stratification/monitoring may rescue it

Personalized Medicine Observations (continued)

15

u If Merck utilized markers to stratify patients according to potential cardiovascular complications, sales would have been much less

u Primary care—not the initial target of personalized medicine

u Many people respond differently to VIOXX (platelets, blood pressure, oxidative stress)

u Maybe look at simple blood or urine tests to find a signal or imaging to exclude patients?

u Most extensive pre-market clinical work until then marketed NSAIDS

• No signal of cardiac events in pre-market activities

Personalized Medicine and VIOXX

16

u Specialty fields

• Life threatening diseases

– Significant adverse affects

– Critical to avoid major toxicity and enhance response rates

– Beginning to understand the genetic patterns

u Primary care

• Not life threatening

• Lower disease severity/impact

• Multifactorial and complex mechanisms

• Genetic pathways not well understood

Near-term Benefits of Personalized Medicine

17

u Regulatory guidance for data in drug applications

• FDA approval of diagnostic tests/platforms

u Developing robust diagnostic tests and platforms and data analysis packages that can be used easily by physicians to tailor drug therapy and dosage

u Overcoming pharma/biotech companies’ fear that targeted medicine could limit blockbuster potential of future therapies

Challenges of Pharmacogenomics

Source: Baird Equity Research and Citigroup18

u Cost-benefit analysis by hospitals and clinics

• Reimbursement issues by payors such as gov’t and insurance companies

u Ethical issues of patient stratification

• Privacy issues of genetic data

• Potential repercussions of future insurability—discrimination

Challenges of Pharmacogenomics(continued)

Source: Baird Equity Research and Citigroup19

u Pre-Vioxx, discussion that statins and other categories were headed to OTC

• Zocor available “under the counter” in the UK

• Most Americans who need a statin don’t take one

• Many who do, discontinue

• FDA officials have been quoted that the benefit to risk ratio is strongly in favor of switching a statin to OTC

Consumer Empowerment

20

uGetting, filling, and re-filling a prescription is a major barrier

uWe may see anti-obesity, BPH, respiratory, and even hypertension drugs get switched from Rx to OTC

uOne big pharma is planning a low dose OTC and high dose Rx from scratch

• Advertise the OTC to the public to drive Rx sales, as DTC may get banned

Consumer Empowerment (continued)

21

©2004 Burrill & Company. Confidential & Proprietary.

37

G. Steven Burrill, CEO

Burrill & Company

Milken InstituteGlobal Conference

April 20, 2005

Comments on

Personalized Medicine


38

US, European, Canadian & Australian Biotech

$13.8 B

81

7,440

470

$0.6 B

$1.7 B

Canada

$5.0 B

58

6,393

226

$0.1 B

$1.0 B

Australia

$25.6 B$400.5 BMarket Capitalization

96356Number of Public Cos.

32,470146,100Number of Employees

1,8781,473Number of Companies

$4.2 B$16.8 BAnnual R&D

$7.5 B$59.5 BSales / Revenue

EuropeUSA

Source: Burrill & Company, Ernst & Young


39

A New Revolution is Taking Place . . . Systems Biology

§ Taking whole-genome biology to the next level

§ Integrated understanding of cellular components and how they function to create biological systems

§ Computational methods and capabilities to better understand (and predict) complex biological systems . . . and their behavior

§ Understanding of how microbial and human cells respond to environmental changes

§ . . . integrating “wet” biology the “digital” biology


40

Today’s medicine challenge: One size doesn’t fit all


41

Pharmacogenomics shapes the healthcarebusiness in 2000+


42

Paradigm Shift

Traditional Medical Evaluation and Record

• Chief Complaint• History of Illness• Past Medical History• Family History• Social History • Physical Exam• Diagnostic Tests• Assessment and Plan

Prospective Evaluation and Record

• Health Profile Summary• Current (immediate) Health

Status• Health Risk Analysis

– Genetic– Environmental– Lifestyle

• 1 year health plan• 5 year health plan

• Risk Assessments• Early Detection• Means for prevention/ early intervention• Individual health plan• Effective delivery system• Effective reimbursement

Requires:

© 2004, Ralph Snyderman


43

Stratifying into risk categoriesDiabetes type 1: What’s becoming possible?


44

What’s Personalized Medicine Really All About?

§ Genetic testing becomes routine

§ Diseases will be understood at a molecular level§ Proteins, pathways, mechanisms

§ Patient populations at risk for ADR will be identified

§ Targeted clinical trials patient selection

§ Healthcare moves to predictive, preventative care with pre-symptomatic Dx and Rx routine


45

What Will Drive Personalized Medicine?

§ Convergence in technology…scientific advances and new technology

§ Patient care and rising consumerism

§ Payors (of all types) have economic incentives§ Government health policy and global spending (e.g.: CMS)


46

Market Trends and Drivers: Revolutionary Technologiesand Evolutionary Practices


47

MDx is at the Center of the New Dx World


48

G. Steven Burrill, CEO

Burrill & Company

Milken InstituteGlobal Conference

April 20, 2005

Comments on

Personalized Medicine

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Personalized Medicine and Patient - Milken Institute · customized to an individual’s genetic makeup. Do you think that personalized medicine will have a positive or negative