Pharmacogenetics: Improvement of Existing Drug Treatments Clinical Pharmacology Subcommittee Advisory Committee for Pharmaceutical Sciences April 22-23, 2003 Rockville, Maryland

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Pharmacogenetics Improvement of Existing Drug
TreatmentsClinical Pharmacology
SubcommitteeAdvisory Committee for
Pharmaceutical SciencesApril 22-23,
2003Rockville, Maryland

• Lawrence J. Lesko, Ph.D.
• Director, Office of Clinical Pharmacology and
  Biopharmaceutics
• Center for Drug Evaluation and Research
• Food and Drug Administration

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Milestones

• April 2003
• 50th anniversary of the discovery of DNAs
  helical structure
• announcement of the completion of the 10 year
  Human Genome Project
• 50th anniversary revision of the Websters New
  World College Dictionary

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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 Whats written in the form
of the double helix is an amazing text, and we
are only beginning to understand how it is
encoded.
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Label and Off-Label Use of 6MP
IMS Health NDTI, cited in Pamer CA report,
October 2002
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Off-Label Uses of 6MP

• Inflammatory bowel disease
• Autoimmune diseases
• rheumatoid arthritis
• ulcerative colitis
• psoriatic arthritis
• multiple sclerosis

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Metabolism of 6MP by TPMT Genotypes

• Three major SNPs (single gene) define mutant
  alleles (v)
• Common TPMT 3A (85), TPMT 3C (lt5), TPMT 2
  (lt5),
• Rare TPMT 3B (1120,000)
• Remaining allele TPMT3D, but also contains
  TPMT3A SNP

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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

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Screening for TPMT Genotypes

• Test
• reliable and accurate, virtually no false or -
  for homozygous deficient patients

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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
1999911983-1985
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Evidence of Validity and Utility
Relling et al, J Natl Cancer Inst 1999
912001-8.
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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)

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Proposal on How the 6-MP Label Could Be Improved?
Clinical PharmacologyThere 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 AdministrationTests 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.
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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
remainingthe proposed labeling seems to be
a very logical positioning of the information as
well as the type of information
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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

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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 dont think is too much
to ask. I think there is enough data to support
that sort of thing.
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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 basistaking into account
risk-benefit considerations that depend on the
drug and the types of efficacy and toxicity.
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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
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Database Search for Genotyping and Phenotyping in
INDs and NDAs
70
70
57
60
52
50
44
40
Total Number
Found in Database
30
20
12
5
10
0
9-2001
1-2002
2-2002
5-2002
6-2002
8-2002
Timeline of Database Search (month-year)
Wendy Chou, Ph.D. and Others OCPB, FDA (ASCPT
Poster, Thursday, April 3, 2003)
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Breakdown of Applications of Genotyping and
Phenotyping in FDA Survey

• 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.

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A Recent Example of Pharmacogenetic Information
in a Product Label Atomoxetine (StraterraR)
Human PK A fraction of the population are PMs
resulting in Drug-Drug Interactions Inhibitors
of CYP2D6 in EMs increase exposuresimilar to
PMs Adverse Reactions The following ADRs were
either twice as frequent or statistically
significantly more frequent in PMs compare to
EMs... Laboratory Tests Laboratory tests are
available to identify CYP 2D6 PMs
Approved by FDAs Neuropharmacology Division in
January 2003
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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.
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Variability in Drug Toxicity Is Some of This
Attributable to Pharmacogenetics?

• 28 of hospitalized patients have drug-related
  ADRsMiller et al, Am. J. Hosp. Pharm 30, 584,
  1973
• 17 of hospitalized children have drug-related
  ADRsMitchell et al, Am. J. Epid. 110, 196, 1979
• Overall incidence of drug-related ADRs is
  7Lazarou et al, JAMA, 279, 1200, 1998
• Cost of drug-related morbidity and mortality is
  177 billionErnst et al, J. Am. Pharm. Assoc.,
  41, 192, 2001

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Circumstantial Evidence Pharmacogenetics as a
Factor in ADRs

• 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
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Translating Pharmacogenetic Science into Bedside
Medicine

• Whats working?

Pharmacogenetics in the PDRSearch 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.
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Translating Pharmacogenetic Science into Bedside
Medicine

• Whats 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

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Translating Pharmacogenetic Science into Bedside
Medicine

• Whats 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 (PMs), 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?