Promulgating Uptake of Personalized Medicine

2. Promulgating Uptake of Personalized Medicine Robert Epstein, MD, MS April 17, 2011

3. Outline of Discussion • Who sees the benefit? • Notes from the field. • What does the near-term future hold?

4. Legal disclaimer “Change is inevitable, except from vending machines.” –Woody Allen Source: Peter Pitts. www.pacificresearch.org, April 13, 2005. 4

5. Focus of talk: Pharmacogenomics Diagnosis RiskAssessment TargetedMonitoring Prevention ResponseMonitoring Therapy Early Detection Testing Predisposition, Dx Pharmacogenomics • Using an individual’s genetic information to identify diseases or predict their future risk of developing other medical conditions • A sciencethat examines the inherited variations in genes that dictate drug response (whether a drug will be effective or safe) Source: Personalized Medicine Coalition: Personalized Medicine 101. Available at http://www.personalizedmedicinecoalition.org/sciencepolicy/personalmed-101_overview.php

6. What we fear will be patient reactions Isn’t that going a little too far? Pharmaco-what? What do you mean you want to get into my genes?!? Ew…that’s gross My DNA? Are you trying to clone me? You need my spit? That’s crazy talk Really? Mail you the wet Q-tip?

7. Patient perspective “Knowing your molecular identity is irresistible”* Anita Cosgrove, 23andme, personal communication

8. Patients want to know - - • Experience with women on tamoxifen who want 2d6 test • 83% say “YES”

9. 700 Payers Vote – This Topic Tied for #2 Topic of Interest!

10. Why do payers care? 1 in 4 Medco patients take a drug with pharmacogenomic considerations • 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 Source: Frueh et al. Pharmacotherapy. 2008;28(8):992-998.

11. How fast this has changed medical care - Oncology 20th Century Cancer care • Cut it • Burn it • Kill it

12. 21st century is about targeted therapy for oncology In 2006, the molecular targeted therapies overtook the cytotoxic therapies for the first time, with sales of $10.7 billion and $8.9 billion, respectively Antihormonal Therapies Cytotoxic Therapies Molecular Targeted Therapies Source: Datamonitor forecasts and MIDAS Sales Data, IMS Health, April 2007. 12

13. Newer cancer drugs that target pathways

14. 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.

15. Challenges of Promulgating Pharmacogenomics (Pgx) Case of Warfarin

16. 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 • Cytochrome P450 2C9 (CYP2C9) – pharmacokinetics • 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.

17. Variability in warfarin dosing Pharmacogenomics. 2009, 10 (12) :1955-1965

19. Expected warfarin dosing by genotype - FDA Source: FDA approved product label, viewed Feb 1, 2011

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

22. Comparative Effectiveness Research (CER) Study characteristics Real world comparators Typical practice settings Real world patients Relevant outcomes (including resource use and costs often) Does not necessarily have to be a RCT – could be observational, quasi-experiment

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24. 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. 24

25. And a National Payer (Aetna) covers leeches • Clinical Policy Bulletin:Bio-Surgery: Medicinal Leech Therapy and Medical Maggots • Number: 0556Aetna considers medicinal leech (Hirudo medicinalis) therapy medically necessary for any of the following conditions: • Poor venous drainage (venous congestion/venous outflow obstruction); or • Salvage of vascularly compromised flaps (muscle, skin, and fat tissue surgically removed from one part of body to another); or • Salvage of vascularly compromised replants (limbs or other body parts re-attached after traumatic amputation). 25

26. Actual Origin of CER may be… Also may be the origin of the expression – Blowing smoke up one’s a** 26

28. Participants from 49 US states 28

30. Actionable information

32. Translation into clinical practice – can we?

33. Physician Adoption of Pgx Testing Medco/AMA Partnership: Nationwide Survey of >10,000 Physicians (2008) Believe Genetics Affects Drug Response Prior Education On PGx Feel Informed About PGx Testing Ordered PGx Test for Patient in Last 6 Mos Anticipate Ordering Test in Next 6 Mos Test Not Ordered Due to Inadequate Info Stanek et al. ASHG meeting, October 2009

34. Warfarin Pgx testing is rarely done Stanek et al. Clin Pharmacol Ther 2010;87(Supplement 1):S44.

35. New Pgx Testing Program ProcessCreating a Teachable Moment Identify patients who are eligible for a test (prescriptions; eligibility) 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 Contact patients to inform about test and how it can help him/her with the therapy the doctor prescribed A teachable moment has been created to inform a physician and a patient about the use of a genetic test to help guide therapy 35

36. Physician consent for testing WARFARIN Physicians Testing potentially appropriate in 32,192 patients Testing agreed to in 15,827 patients 49.2% Stanek E et al. ASHG 2010 36

37. New discoveries - all about partnership and collaboration

38. What’s around the corner? • With new knowledge – specific individual Pgx tests will become important to promulgate • ALK for NSCLC • BRAF for metastatic melanoma • DNA repair markers for triple negative breast cancers

39. What’s around the corner? • Movement from individual tests • To panels of Pgx tests • To whole genome sequencing • Esp. relevant in oncology

40. What’s around the corner? • Circulating tumor cells • Enumeration • Characterization

41. What’s around the corner? • Infrastructure related to the data • Storing, managing billions of data • Interrogating the data to find specific gene variants? • Intelligence to create action-able information from the test?

42. What’s around the corner? • Gene therapy – and who to give this to?

43. 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 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. 43 43

44. Concluding Thoughts 44 44

45. Many thanks • Advocacy position – trusted 3rd party endorsements • CAP support of warfarin Pgx testing – really mattered • Education and outreach and support of innovation • Humanitarian efforts

46. 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