Foundation.cap.org v. #

Promulgating Uptake of Personalized Medicine

Robert Epstein, MD, MSApril 17, 2011

Outline of Discussion

• Who sees the benefit?

• Notes from the field.

• What does the near-term future hold?

Legal disclaimer

Source: Peter Pitts. www.pacificresearch.org, April 13, 2005.

““Change is inevitable, except Change is inevitable, except from vending machines.” from vending machines.”

––Woody AllenWoody Allen

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Therapy ResponseMonitoring

Focus of talk: Pharmacogenomics

Source: Personalized Medicine Coalition: Personalized Medicine 101. Available at http://www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php

Predisposition, DxPredisposition, Dx PharmacogenomicsPharmacogenomics

Using an individual’s genetic information to identify diseases or predict their future risk of developing other medical conditions

A science that examines the inherited variations in genes that dictate drug response (whether a drug will be effective or safe)

RiskAssessment Prevention Targeted

Monitoring

Early Detection Testing

Diagnosis

What we fear will be patient reactions

My DNA? Are you trying to clone me?My DNA? Are you

trying to clone me?

Isn’t that going a little

too far?

Isn’t that going a little

too far?

You need

my spit? You need

my spit?

That’s crazy talk

That’s crazy talk

Ew…that’s grossEw…that’s gross

Really? Mail you the wet Q-tip?

Really? Mail you the wet Q-tip?

What do you mean

What do you mean

you want to get into

you want to get into

my genes?!?

my genes?!?What do you mean

What do you mean

you want to get into

you want to get into

my genes?!?

my genes?!?

Pharmaco-what?

Pharmaco-what?

Patient perspective

“Knowing your molecular identity is irresistible”*

Anita Cosgrove, 23andme, personal communication

Patients want to know - -

• Experience with women on tamoxifen who want 2d6 test

o 83% say “YES”

700 Payers Vote – This Topic Tied for #2 Topic of Interest!

3.03

3.10

3.51

3.40

3.40

3.35

3.33

3.13

0 1 2 3 4

New benefit design strategies

Pharmacogenomics

Consumerism

Drug pipeline

Emerging trends in science

Specialty cost reductionstrategies

Member communications

Generic opportunities

36.1 million patients with ≥1 Rx fill in 2006

8.7 million (24%) with Rx for a drug with human PGx info in label

Why do payers care? 1 in 4 Medco patients take a drug with pharmacogenomic considerations

Source: Frueh et al. Pharmacotherapy. 2008;28(8):992-998.

How fast this has changed medical care - Oncology

20th Century Cancer care

• Cut it

• Burn it

• Kill it

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Sal

es (

$M)

Antihormonal Therapies Cytotoxic Therapies Molecular Targeted Therapies

21st century is about targeted therapy for oncology

Source: Datamonitor forecasts and MIDAS Sales Data, IMS Health, April 2007.

In 2006, the molecular targeted therapies overtook the cytotoxic therapies for the first time, with sales of $10.7 billion and $8.9 billion, respectivelyIn 2006, the molecular targeted therapies overtook the cytotoxic therapies for the first time, with sales of $10.7 billion and $8.9 billion, respectively

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Newer cancer drugs that target pathways

DrugDrug PathwayPathway ConditionCondition TestTest

Gleevec, Sprycel, Tasigna

BCR-ABL kinase

Chronic Myelogenous Leukemia

BCR-ABL copies

HerceptinHER-2

receptorBreast cancer HER-2 status

Rituxan CD-20 protein Lymphoma FCGR3A gene

Avastin VEGF Colon cancer VEGFA?

TamoxifenEstrogen receptor

Breast cancer CYP 2D6

Tarceva, Iressa

EGFR kinase Lung, pancreatic cancer EGFR

SutentTyrosine

kinasesGI cancer KIT mutations

Erbitux, Vectibix

EGFR Colon, head/neck cancerKRAS

mutations

Anticancer Drugs Approved by the Food and Drug Administration (FDA) with Labeling Regarding

Pharmacogenomic Biomarkers.

Wang L et al. N Engl J Med 2011;364:1144-1153.

Challenges of Promulgating Pharmacogenomics (Pgx)

Case of Warfarin

Background

• Warfarin exhibits large inter-individual dosing requirements

• Warfarin is a leading cause of morbidity and mortality

• Two genes account for ~33% of variance in dosing

o Cytochrome P450 2C9 (CYP2C9) – pharmacokinetics

o VKORC1 – pharmacodynamics

• Meta-analysis of 3 clinical trials of warfarin genotyping showed a 32% decrease in major bleeding (RR 0.68, CI 0.22-2.06)*

*Eckman MH, Rosand J, Geenberg SM, Gage BF: Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Int Med 2009;150(2):73-83.

Pharmacogenomics. 2009, 10 (12) :1955-1965

Variability in warfarin dosing

Expected warfarin dosing by genotype - FDA

Source: FDA approved product label, viewed Feb 1, 2011

Does Incorporation Of Pharmacogenomics with Warfarin Therapy Lead to Better Outcomes?

US Clinical Trials of Genetic Testing for Warfarin (Clinical Utility)

Trial GIFT COAG WARFARIN MM-WES

Design Prospective RCT; 2x2 factorial Prospective RCT Prospective RCT Quasi-experiment CER

Population

MedicareAt least 1 mo warfarin for hip/knee arthroplastyNo prior genotype info

Outpatient in AC clinicAt least 3 mos warfarin Target INR 2-3

≥65 years oldNew to warfarin for long-term AC, INR >2.0

Adults 40-75 years old New to warfarin Tx

ArmsPGx vs. clinical dosingTarget INR <2.0 versus 2.5 Active Comparator

PGx vs clinical dosingPGx vs clinical dosing(www.warfarindosing.org)

Matched historical controls; Parallel concurrent external controls.

SettingWUSTL, UUtah, Intermountain Medical Center, HSS (NY)

12 academic medical ctrs 50 clinical sites

Any community-based prescriber; (49 states)~25% cardiologists

Sample size 1600 1238 >7000896 tested subjects2688 historical and concurrent controls

Follow-up 4-6 weeks 4 weeks 4 weeks 6 months

1° outcomes

Non-fatal VTE 4-6 wks

NF major bleeding 4-6 wks

Vascular death

% time in therapeutic INR

range in first 4 wks

All-cause hospitalization

and hospitalization for

atherothrombotic or

bleeding events

Major hemorrhage and

thromboembolic events

All-cause hosp. and

hosp. for

atherothrombotic or

bleeding events

Status Ongoing Ongoing Ongoing Completed/published

Comparative Effectiveness Research (CER)

• Study characteristicsoReal world comparatorsoTypical practice settingsoReal world patientsoRelevant outcomes (including resource use

and costs often)

• Does not necessarily have to be a RCT – could be observational, quasi-experiment

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But – here we are in 2000s………..• Leeches inject hirudin that

inhibits platelet aggregation and the coagulation cascade

• This relieves venous congestion

• Clinical studies in the 2000s showed 70-80% success rate in salvaging tissue (skin grafts, reattachment surgery)

• Leeches gained 510K FDA clearance in 2004 – Recarimpex SAS was the company involved.

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And a National Payer (Aetna) covers

leeches

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• Clinical Policy Bulletin:Bio-Surgery: Medicinal Leech Therapy and Medical Maggots

• Number: 0556

Aetna considers medicinal leech (Hirudo medicinalis) therapy medically necessary for any of the following conditions:o Poor venous drainage (venous congestion/venous

outflow obstruction); oro Salvage of vascularly compromised flaps (muscle,

skin, and fat tissue surgically removed from one part of body to another); or

o Salvage of vascularly compromised replants (limbs or other body parts re-attached after traumatic amputation).

Actual Origin of CER may be…

• Also may be the origin of the expression – • Blowing smoke up one’s a**

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Participants from 49 US states

Actionable information

Translation into

clinical practice – can

we?

Physician Adoption of Pgx Testing

Medco/AMA Partnership: Nationwide Survey of >10,000 Physicians (2008)

98%

23%

10% 12%

26%

57%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Believe GeneticsAffects Drug

Response

Prior Education On PGx

Feel InformedAbout PGx

Testing

Ordered PGxTest for Patientin Last 6 Mos

Anticipate Ordering Testin Next 6 Mos

Test Not OrderedDue to Inadequate

Info

Stanek et al. ASHG meeting, October 2009

Warfarin Pgx testing is rarely done

National Benchmark for Pgx Testing Rates in Patients New to Warfarin Therapy

2007 2008

PGx testing within 12 months before and after new warfarin Rx claimNMedian age, yrs≥65 years

Female

2,26752

16%54%

2,26453

17%52%

PGx testing within 2 months before to 3 months after new warfarin Rx claim

1724 1730

Warfarin PGx testing rate 1.70% 1.84%

Background PGx testing rate (in patients not on warfarin) 0.12% 0.13%

Apparent warfarin genetic testing rate 1.58% 1.71%

Median number of days from index warfarin claim date and genetic testing (IQ range)

Before index warfarin claim

On or after index warfarin claim

14 (5-60)

30 (5-107)

12 (4-53)

31 (5-107)

Stanek et al. Clin Pharmacol Ther 2010;87(Supplement 1):S44.

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New Pgx Testing Program ProcessCreating a Teachable Moment

Identify patients who are eligible

for a test(prescriptions;

eligibility)

Contact patients to inform about test and how it

can help him/her with the therapy

the doctor prescribed

Contact physician to

provide information

about the test; ordering

information

Facilitate the delivery and

management of the test, ensures

that test is performed and

results are delivered

A teachable moment has been created to inform a physician and a patient about the use of a genetic test to help guide therapy

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Physician consent for testing

Testing potentially appropriate in 32,192 patients

Testing agreed to in 15,827 patients

49.2%

WARFARINPhysicians

Stanek E et al. ASHG 2010

New discoveries - all about partnership and collaboration

What’s around the corner?

• With new knowledge – specific individual Pgx tests will become important to promulgate

oALK for NSCLCoBRAF for metastatic melanomaoDNA repair markers for triple

negative breast cancers

What’s around the corner?

• Movement from individual tests

• To panels of Pgx tests

• To whole genome sequencing−Esp. relevant in oncology

What’s around the corner?

• Circulating tumor cells

oEnumeration

oCharacterization

What’s around the corner?

• Infrastructure related to the dataoStoring, managing billions of

dataoInterrogating the data to find

specific gene variants?oIntelligence to create action-

able information from the test?

What’s around the corner?

• Gene therapy – and who to give this to?

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Corey Haas, 9 year old boy from Hadley, NY

• Was in gene therapy trial at CHOP, Philadelphia

• Single subretinal injection of RPE65 gene for congenital amaurosis

• Was able to “see stars” in the night sky for first time

• “I’m going into Little League” to play baseball

• First approval projected to be 3 years from now — for hereditary blindness

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Source: Maguire AM, High KA et al: Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009 Nov 7;374(9701):1597-605. Epub 2009 Oct 23.

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Concluding Thoughts

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Many thanks

• Advocacy position – trusted 3rd party endorsementsoCAP support of warfarin Pgx

testing – really mattered

• Education and outreach and support of innovation

• Humanitarian efforts

All of us can make a difference

• "If you think you're too small to have an impact, try going to bed with a mosquito in the room."

- Dame Anita Roddick, 1942-2007, British businesswoman, humanitarian, founder of The Body Shop