Prospettive della farmacogenetica e della farmacogenomica

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Prospettive della farmacogenetica e della
farmacogenomica

• Stefano Vella
• Dipartimento del Farmaco
• Istituto Superiore di Sanità

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Pharmacogenetics Pharmacogenomics

• An opportunity to improve drug development
• Choice of drug targets
• An opportunity to improve clinical care
• Individualized medicines through stratification
• More rational decisions on therapeutic options

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Pharmacogenetics Pharmacogenomics

• An opportunity to improve drug development
• Choice of drug targets
• An opportunity to improve clinical care
• Individualized medicines through stratification
• More rational decisions on therapeutic options

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Druggable Genome Predictions
Druggability Prediction Method No. Molecular Targets
Targets of approved NCEs 170
Sequence homology to NCE drug targets 945
Targets of chemical leads with activities (binding affinities) below 10uM 707
Targets of Ro5 chemical leads with activities (binding affinities lt 10uM) 587
Sequence homology to targets with chemical leads 2921
Feature-based druggability sequence probability prediction 2325
Structured-based prediction 427
Sequence homology to proteins predicted druggable by structure-based method 3541
Predicted Drugglable Genome (small molecules) 3505
Human Genome 24000
GPCRs
Kinases
Proteases
Transporters
Ion Channels
Gene family distributions of predicted druggable
genome
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Future Drug Target Space
Human Genome
24000
Predicted druggable genome
genetic association
mouse K/O
Lead/chemical tools
Drugs
6465 2400
145 160 170 578 3505
320
1769
Zambrowicz Sands, Nature Drug Disc. Rev.
(2003), 2,38-51C
Genetic association linkage data estimated by
text-mining from entity co-occurrence within
Medline abstracts. Data produced by Anna Gaulton
and Andrew Hopkins, using a modified version of
Lucene, by Lee Harland, to text-mine Medline,
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Accessible Genome protein therapeutics
Druggability Prediction Method No. of Molecular targets
Targets of approved antibodies 15
Targets of approved biologicals 59
Secreted protein (high confidence) 1384
Secreted proteins (low confidence) 6560
Transmembrane predictions (high confidence) 973
Transmembrane predictions (low confidence) 1407
Unique, combined transmembrane and secreted predictions (high confidence) 2287
Feature-based biological target sequence probability prediction 1637
Total unique genes predicted to be accessible via protein therapeutics 3258
1516 genes likely to encode proteins drugable by
both small molecules and protein therapeutics
Total number druggable by protein therapeutics
3258 genes
Total number druggable by small molecule
therapeutics 3505 genes
Human Genome
24000
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Stages of HIV-1 Life Cycle Targeted by Anti-HIV
Drugs
The International AIDS SocietyUSA
In Gulick RM, Topics HIV Med, 200210(4).
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Chemokine Co-receptors in HIV Entry

• HIV gains entry into cells that express CD4 and 1
  of 2 secondary receptors, either
• C-C chemokine receptor 5 (CCR5)
• Expressed on monocytes and T cells
• C-X-C chemokine receptor 4 (CXCR4)
• Expressed on T cells, B cells, monocytes, and
  neutrophils

1Deng H, et al. Nature. 1996381(6584)661-666.
2Feng Y, et al. Science. 1996272872-877.
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HIV Attachment and Fusion Targets for Inhibition
Adapted from Moore JP, et al. Proc Natl Acad Sci
U S A. 200310010598-10602.
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CCR5 D32
? CCR5 ?32
CCR5 wild type ?
Normal
Heterozygotes
Homozygotes
wt/wt
wt/?32
?32/?32
2 normal copies
1 copy of ?32
2 copies of ?32
Standard disease progression
Delayed disease progression
Resistant to HIV infection
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CCR5-tropic HIV (R5 virus)

• Nearly all new sexually transmitted HIV-1
  infections are with R5 virus
• Infect dendritic cells, macrophages, and T cells
• Predominate throughout infection
• X4 virus may appear over time, but 50 of
  patients with HIV-1 subtype B who die from AIDS
  have only R5 virus1,3
• A tropism shift from R5 to X4 virus is associated
  with the presence of basic amino acids at codons
  11 and/or 25 of the V3 loop of gp1204

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Maraviroc (UK-427,857) Activity ResultsMean
Reduction in Viral Load over Time
Last day of dosing
0.5
0.0
Maraviroc dose
n
-0.5
Placebo 015
4
Change from baseline (log10 HIV-1 copies/mL)
Placebo 007
12
25 mg QD
8
-1.0
50 mg BID
8
100 mg QD
8
100 mg BID
7
150 mg BID Fast
8
-1.5
150 mg BID Fed
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300 mg QD
8
300 mg BID
8
-2.0
5
10
15
20
25
30
35
40
Baseline
Time (day)
Study 1007/1015
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Pharmacogenetics Pharmacogenomics

• An opportunity to improve drug development
• Choice of drug targets
• Optimization of clinical trials
• An opportunity to improve clinical care
• Individualized medicines through stratification
• More rational decisions on therapeutic options

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Are Drugs Effective?
Disease Efficacy Annual Rx
Cost
Alzheimers 30
1,500 Analgesics 80
1,350 Cardiac arrhythmia 60
650 Depression 60 700 Diabetes 55 1,300
Hepatitis C 45 5,000 Incontinence
40 1,000 Migraine 50 600
Oncology 25 3,500
Prescribed drugs are generally effective in about
50 of patients.
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Are Drugs Safe?

• Adverse drug reactions (ADRs) represent the 4th
  leading cause of hospitalization (2 million/yr)
  and are responsible for 100,000 deaths/yr in the
  U.S.

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Pharmacogenetics of Phase I Drug Metabolism
Weinshilboum R. N Engl J Med 2003348529-537
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Pharmacogenetics of Nortriptyline
Weinshilboum R. N Engl J Med 2003348529-537
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Pharmacogenetics of Acetylation
Weinshilboum R. N Engl J Med 2003348529-537
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Genetic Polymorphisms in Drug Target Genes That
Can Influence Drug Response
Evans W and McLeod H. N Engl J Med
2003348538-549
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Tamoxifen and Breast Cancer

• 1971 some breast tumors express the estrogen
  receptor (ER), which drives tumor growth
• Tamoxifen (ER receptor antagonist) was first
  administered regardless of tumor ER status
• Ligand binding assay for ER status introduced
  complex assay requiring fresh tissue
• Immunohistochemical assays variable results

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ErbB2 expression is associated with metastatic
breast cancer!
1995
Reactivity on tumour samples
About 25-30 of women who have metastatic breast
cancer overexpress HerB2(EGF) receptor
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Relapse-free Survival (Panel A) and Overall
Survival (Panel B) among Women with Breast
Cancer, According to HER2 Amplification Status on
FISH
Pritchard K et al. N Engl J Med 20063542103-2111
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Herceptin (TrastuzuMAb) (anti-HER MAbs)
1999Approved
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HER-2/neu Genetic Test
Current genetic testing uses fluorescence markers
(FISH technology) look for increased copies of
HER-2/neu gene with fluorescent DNA probes
labor-intensive and expensive
Gene amplified
Normal
HER-2/neu positive patients Most responsive to
therapy
HER2 testing is covered by and required for most
drug benefit plans
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Real-time quantitative PCR for detection of
HER-2/neu gene amplification
10-fold amplified Her-2/neu
non-amplified Her-2/neu
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Polygenic Determinants of Drug Response
Evans W and McLeod H. N Engl J Med
2003348538-549
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Potential of pharmacogenetics the right dose of
the right drug, the first time
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• Possible Designs for
• Pharmacogenomic
• Clinical Trials

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Retrospective Design
Randomized, Double Blind, Placebo-controlled Trial
Treatment period
Placebo
Drug A
entry

• Patient numbers in a arm maybe unbalanced?
• Sampling maybe limited in some patients?
• Results are not confirmative?

? Confirmative trial would be necessary
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Prospective Design 1
Drug A
randomized

• To test clinical utility
• PGx test is really necessary?
• Cost-benefit relationship
• Results are confirmative

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Prospective Design 2
Randomized, Double Blind, Placebo-control Trial
Enrichment approach
No entry

• Increase analytical power of trial
• Results are confirmative

• But, data in gene(-) patients can not be obtained
• May lose a chance of treatment for (-) patients

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Prospective Design 3
Randomized, Double Blind, Placebo-control Trial
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Benefit of Pharmacogenomics

• Improving benefit/risk ratio
• More safe, more effective drugs
• Adjusting Dose
• Determine the best dose
• Increasing successful rate of clinical trials
• Focusing on data in responder

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• Except for monozygotic twins, each person's
  genome is unique.
• All physicians will soon need to understand the
  concept of genetic variability, its interactions
  with the environment, and its implications for
  patient care.
• With the sequencing of the human genome, the
  practice of medicine has now entered an era in
  which the individual patient's genome will help
  determine the optimal approach to care, whether
  it is preventive, diagnostic, or therapeutic.

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A possible future.

1. Doctor Examines Patient and Makes Initial
   Diagnosis

1. Laboratory Buccal Swab or Blood Sample

1. Genetic Analysis

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Drug Prescribing Based on the Patients Genetic
Markers
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18
16
14
12
10
8
6
4
2
0
-5.0
10.0
25.0
40.0
55.0
Responders
Non-Responders
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