1. Pharmacogenetics: Improvement of Existing Drug Treatments Clinical Pharmacology Subcommittee Advisory Committee for Pharmaceutical Sciences April 22-23, 2003 Rockville, Maryland Lawrence J. Lesko, Ph.D. Director, Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research Food and Drug Administration

2. Milestones April 2003 –50th anniversary of the discovery of DNA’s helical structure –announcement of the completion of the 10 year Human Genome Project –50th anniversary revision of the Webster’s New World College Dictionary

3. Reflections Dictionary: Newly updated to reflect the changes in our language and in our social, cultural, political, and scientific worlds. New uses and meanings have been added to many existing definitions and an all-new reference Genome: What’s written in the form of the double helix is an amazing text, and we are only beginning to understand how it is encoded.

4. Label and Off-Label Use of 6MP Drug Use in Thousands IMS Health NDTI, cited in Pamer CA report, October 2002

5. Off-Label Uses of 6MP Inflammatory bowel disease Autoimmune diseases –rheumatoid arthritis –ulcerative colitis –psoriatic arthritis –multiple sclerosis

6. Metabolism of 6MP by TPMT: Genotypes Three major SNPs (single gene) define mutant alleles (v) Common: TPMT *3A (85%), TPMT *3C (<5%), TPMT *2 (<5%), Rare: TPMT *3B (1:120,000) Remaining allele: TPMT*3D, but also contains TPMT*3A SNP

7. Three Factors To Be Considered When Deciding on the Use of Pharmacogenetic Testing Analytic validity –accuracy of identifying a DNA sequence variant Clinical validity –accuracy of predicting a clinical outcome Clinical utility –likelihood that it will lead to improved health outcome

8. Screening for TPMT Genotypes Test –reliable and accurate, virtually no false + or - for homozygous deficient patients

9. Evidence of Validity and Utility Interrupting therapy for recovery from toxicity lessened intensity of treatment Reduction of 6MP dose allowed for full dosages of other chemotherapy TPMT polymorphism is important even for heterozygous patients Relling et al, J Natl Cancer Inst 1999;91:1983-1985

10. Evidence of Validity and Utility Relling et al, J Natl Cancer Inst 1999; 91:2001-8.

11. Screening for TPMT Genotypes Test –reliable and accurate, virtually no false + or - for homozygous deficient patients Utility and validity –virtually all homozygous deficient patients will become toxic at usual 6MP doses –intervention (dose reduction) to prevent toxicity in those that test positive (*3A, *3C, *2)

12. Proposal on How the 6-MP Label Could Be Improved? Clinical Pharmacology There is wide interpatient variability in the inactivation of 6-MP by TPMT to an inactive metabolite because of a common genetic defect in TPMT. 10% of the population have intermediate TPMT activity and 0.3% of the population are virtually TPMT-deficient. Dosage and Administration Tests for TPMT genotype and phenotype are commercially available. Consideration should be given to testing patients for their TPMT status. Patients with poor or intermediate TPMT activity may tolerate only 1/10th to 1/2 of the average 6-MP dose.

13. CPSC (October 23, 2002) “…for TPMT and 6-MP, there is considerable enthusiasm, and considerable use for having genetic tests available (in the label) although there are some scientific and clinical issues remaining…” “…the proposed labeling seems to be a very logical positioning of the information as well as the type of information…”

14. TPMT Screening and Intervention All patients prior to receiving 6-MP –lower starting dose Patients with overt signs of toxicity (e.g., CBC, neutrophils) within a few days or weeks after starting 6-MP –patients receiving combination chemotherapy with overlapping toxicities (e.g., neutropenia) –reduction in induction and maintenance dose

15. CPSC (October 23, 2002) “…mandatory testing for TPMT in the absence of clear pharmacoeconomic analysis, is too early…” “…(tests for TPMT) increases awareness that there is a problem and that something can be done about it. That, I don’t think is too much to ask. I think there is enough data to support that sort of thing.”

16. CPSC (October 23, 2002) “In terms of trying to generalize this type of consideration (pharmacogenetics) it seems very likely that it would need to be done on a case-by-case basis…taking into account risk-benefit considerations that depend on the drug and the types of efficacy and toxicity.”

17. Pharmacogenetic Data Beyond the Issue of TPMT Genotyping “New therapies will be developed with genetic or phenotypic tests that can identify an appropriate treatment population and detect patients who need different doses or are prone to certain toxic effects” - Dr. McClellan, FDA Commissioner, in Washington Drug Letter, April 13, 2003

18. 5 12 44 52 57 70 0 10 20 30 40 50 60 70 Total Number Found in Database 9-20011-20022-20025-20026-20028-2002 Timeline of Database Search (month-year) Database Search for Genotyping and Phenotyping in INDs and NDAs Wendy Chou, Ph.D. and Others OCPB, FDA (ASCPT Poster, Thursday, April 3, 2003)

19. Breakdown of Applications of Genotyping and Phenotyping in FDA Survey CYP2C19 14.3% CYP2C9 4.3% CYP3A4/5 14.3% CYP1A2 7.1% PhaseII 11.4% Pgp 4.3% Receptors 7% Others 22.9% CYP 2D6 72.9% Genotyping and phenotyping performed in some submissions Phase II enzymes measured: NAT-2, UGT, GSTM1, etc Receptors: Dopamine, 5-HT, beta-adrenergic, alpha-1 adrenergic, potassium channels, etc Others: HMC, CETP, ACE, alpha-reductase, AAG, CYP2B6, glyceraldehyde 3 -phosphate dehydrogenase, ApoE etc.

20. A Recent Example of Pharmacogenetic Information in a Product Label: Atomoxetine (Straterra R )* Human PK A fraction of the population are PM’s resulting in … Drug-Drug Interactions Inhibitors of CYP2D6 in EM’s increase exposure…similar to PM’s Adverse Reactions The following ADR’s were either twice as frequent or statistically significantly more frequent in PM’s compare to EM’s... Laboratory Tests Laboratory tests are available to identify CYP 2D6 PM’s * Approved by FDA’s Neuropharmacology Division in January 2003

21. But, How Can Existing Therapies Be Improved Using Pharmacogenetics? Existing Therapies All medicines that have been approved by the FDA for prevention or treatment of any disease in humans, under patent or not.

22. Variability in Drug Toxicity: Is Some of This Attributable to Pharmacogenetics? 28% of hospitalized patients have drug-related ADRs… Miller et al, Am. J. Hosp. Pharm 30, 584, 1973 17% of hospitalized children have drug-related ADRs… Mitchell et al, Am. J. Epid. 110, 196, 1979 Overall incidence of drug-related ADRs is 7%… Lazarou et al, JAMA, 279, 1200, 1998 Cost of drug-related morbidity and mortality is $177 billion… Ernst et al, J. Am. Pharm. Assoc., 41, 192, 2001

23. Circumstantial Evidence: Pharmacogenetics as a Factor in ADR’s 27 drugs frequently cited in ADR studies –59% (16/27) metabolized by at least one enzyme with variant allele causing poor metabolism (PM) 69% (11/16) metabolized by specific enzyme CYP 2D6 –mainly drugs acting on CNS and cardiovascular systems such as antidepressants and beta blockers In contrast, only 7-22% of randomly selected drugs are known to be metabolized by enzymes with this genetic variability Phillips et al, JAMA, 286 (18), 2001, 2270-2279

24. Translating Pharmacogenetic Science into Bedside Medicine What’s working? Pharmacogenetics in the PDR Search of the electronic 2003 version of the PDR containing 2000 entries identified 51 labels containing pharmacogenomic information. In most cases, the information could not be easily translated to clinical practice.

25. Translating Pharmacogenetic Science into Bedside Medicine What’s missing? –well-designed and well-conducted investigations of analytic validity, clinical validity and clinical utility –systematic assessment of evidence-based research findings from peer-reviewed journals –opinions and evaluations by professional associations and consensus groups –good premarket searches for pharmacogenetic factors influencing risk/benefit –thorough evaluation of FDA post-marketing reports of adverse events

26. Translating Pharmacogenetic Science into Bedside Medicine What’s next? –general question for discussion by the committee What level of detail of genomic data should be included in the label? –example: CYP 2D6 gene on chromosome 22 phenotype (PM’s), allele (*4/*4), enzyme activity (deficient), PK information (AUC), allele frequency (22%) and/or mutation (G1934A) Where is label should genomic data related to drug metabolism be included?