Pharmacogenomics: Assessment of Therapeutic Risk vs Benefit

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1 Pharmacogenomics: Assessment of Therapeutic Risk vs Benefit Lawrence J. Lesko Clinical Professor Center for Pharmacometrics and Systems Pharmacology University of Florida at Lake Nona November 15, 2016

2 Acknowledgment I wish to thank Dr. Stephan Schmidt, Assistant Professor and Associate Director in the UF Center for Pharmacometrics and Systems Pharmacology for making this presentation on my behalf.

3 Three Goals For This Presentation 1. Define pharmacogenetics (PGx) bring granularity to the concept 2. Scenarios where PGx has benefited health outcomes 1. Major barriers to actually applying PGx more widely in clinical medicine

4 Nomenclature: Words Matter Pharmacogenomics (disease variability) is much broader than pharmacogenetics. Pharmacogenomics has revolutionized treatment of cancer. Period. Pharmacogenetics (dose variability) has not had the impact of pharmacogenomics.

5 Definition of Pharmacogenetics (PGx) The term is meant to cover all types of investigations that provide information about a person s genetic makeup that address questions about the choice of drug and drug doses that are likely to work best for that particular person

6 Inspiration Thought: The Secret of Success for DNA We have all the genetic information we need at birth to select drugs and identify doses. In the ideal world we carry that information with us and use it when needed

7 When Would We Need to Use PGx? Define qualitative/quantitative differences between subgroups in terms of PK and PD Improve a priori drug and dose selection (predict) rather than a posteriori (react) for individual health (precision medicine) Provide better and more cost-effective clinical outcomes for population (population health)

8 PGx in 2016 Prevention of disease is better than cure we can all agree But when disease occurs cancer, diabetes, heart disease drug selection and dose choice guided by companion diagnostics is preferred over empiric approaches Companion diagnostics are designed to be paired with specific drugs if there is a specific genetic trait that is present in some, but not all patients.

9 Foundation of PGx is Companion Diagnostics Genetic tests intended to separate variability in clinical response among subgroups causes by genes from that caused by lifestyle, environment or other non-genetic factors Composite Phenotype PD GENES PK GENES LAB TEST --Other therapies --Disease factors --Demographics --Approved labels --Literature

10 Approved Drug Labels With PGx Information: Improve Old Drugs Lesko and Woodcock, Nat Rev Drug Discov (2004), 3(9),

11 More Important Use of PGx Is Dosing NTI Drugs Such as Warfarin If you gave warfarin to a huge sumo wrestler and a tiny sumo wrestler, the large sumo wrestler could bleed uncontrollably at a dose much smaller than what you gave the tiny sumo wrestler

12 PGx Test Information in 140 Labels Recommended 4% Required 24% Actionable 44% Informative 28% Sources: PharmGKB and FDA Table of Pharmacogenomic Biomarkers in Drug Labels (2016)

13 Examples of Interpretation of Genetic Tests HLA-B*5701 PD GENE AVOID OR USE WITH CAUTION WITH FREQEUENT MONITORING CYP2C9 VKORC1 PK & PD GENES USE WITH CAUTION WITH DOSE ADJUSTMENT AND WITH FREQEUENT MONITORING CYP2C19 PK GENE USE AS DIRECTED IN PRODUCT LABEL

14 The True Story of Jeff Cluse

15 The Rest of the Story A 51 yr old and I can t enjoy my 4 grandchildren My chronic back injury limits my mobility and back pain is a way of life for the past 5 years. Physical therapy and multiple drugs did little to ease the pain. I visited the UF Pain Management Clinic and I was prescribed oxycodone but my back pain got worse. My clinical pharmacist told me about a CYP2D6 test and I agreed to have it done. The test changed my life. I was a CYP2D6 poor metabolizer and I could not convert oxycodone to oxymorphone. I was given meperidine ) which work better in reducing my back pain. Now I can do more with my grandkids (Clinical Utility)

16 GeneSight R : For Neuropsychiatric Drugs An integrated and weighted multivariate genetic test of 8 PK genes and 4 PD genes Indications Uncontrolled symptoms when considering a drug or dosage change Lower than expected efficacy or higher than expected unwanted side effects Polypharmacy where drug-drug interactions conferring less benefit or greater risk Note: I am on the SAB for Asssurex

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18 Barriers: Prevailing Attitude Among Payers there is good evidence that persons having gene variants of CYP2C9 and VKORC1 have heightened response to warfarin, the evidence for improvied health outcomes attributed to PGx testing to determine warfarin responsiveness fails to meet standards of evidence to establish a basis for coverage. Center for Medicare and Medicaid, May 4, 2009

19 How Payers and Clinicians Perceive Cost, Effectiveness and Value of PGx Testing PGx testing more expensive PGx testing less effective A Less effective, More expensive [Reject] B Less effective, Less expensive [Unusual] D More effective, More expensive [Problem] C More effective, Less expensive [Adopt] PGx testing more effective PGx testing less expensive

20 Reasons That Reimbursement and Adoption of PGx Tests Been So Limited Considerations Costs Effectiveness Value and Judgment Key Points Easy to define ($400 FOR 2C9/VKORC1 test) Evidence in all cases AFTER approval of drug Evidence often DISEASE- or DRUG-specific Small sample sizes Meaningful RCT approaches non-existent Is the evidence reliable? What % of variability remains unexplained? Is evidence generalizable? Are clinical outcomes improved? Are there alternatives that are just as good?

21 Warfarin Genetic Testing: More Effective, Less Expensive? 1 The % of patients within 20% of steady state dose: 52% (PGx) vs 37% (empiric) 1 The odds of patients being properly dosed using a PGx algorithm vs empiric: The PGx algorithm performed much better than empiric in patients requiring higher (>49 mg/week) and lower (<21 mg/week) Finkelman et al. JACC (2011), 57: Woodcock and Lesko, NEJM (2009), 360:

22 Physician Education and Lab Reports Clinical medicine does not yet have the tools to put PGx test results to good use For instance, would your physician know whether CYP2C9 *1/*3 is good or bad when treating a patient with warfarin? Or worse yet, if lab results came back as CYP2C9*3 (1075A>C) and VKORC1 AA (- 1639G>A)?

23 We Need More Decision Support Tools to Reap the Benefits of PGx

24 Pre-emptive PGx Testing Can Be Cost- Effective To Improve Benefit/Risk Testing HIV patients for HLA-B*5701 before giving abacavir saved $30,000 per hypersensitivity reaction avoided in Caucasians Mandatory testing for HLA-B*1502 in Singapore before giving CBZ saved $37,000 per Chinese to avoid SJS Schackman et al, AIDS (2008), 22: Dong et al, Neurology (2012), 79:

25 Lessons From Abacavir and CBZ: PGx and Drug Safety Works Very Well The cost of genotyping will get cheaper and cheaper with increasing use meaning: Benefit/Risk ~ Infinity

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27 Thank you for your time and attention