Transcript Ana Alfirevic - Health in Wales

Pharmacogenetics
The Impact of Genomics on Public Health
Cardiff, 6th November 2014
Ana Alfirevic
The Wolfson Centre for Personalised Medicine
Department of Molecular and Clinical Pharmacology
University of Liverpool
Pharmacogenetics/pharmacogenomics
the study of how genetic differences
among individuals cause various
responses to a drug in terms of both,
efficacy and safety
Pharmacogenetic testing
• Drug efficacy
“The vast majority of drugs - more than 90 per cent –
only work in 30 or 50 per cent of the people” (GSK)
• Drug safety
Adverse drug reactions are common-6.5% hospital
admissions in the UK (Pirmohamed 2004), ADRs vary in severity
• Drug Dosing
Drugs with narrow therapeutic index
Personalised Medicine
Stratified Medicine
Precision Medicine
BBC News
Direct to Consumer Genotyping Services
PERSONAL GENOME
DNA collection kit
Health Inequalities
• Is this going to be
reserved only for the
reach within society?
• Will it only be used in high
income countries?
• Is it going to exacerbate
health inequalities?
FDA- Pharmacogenomic
Biomarkers in Drug Labelling
• Drug labelling may contain information on genomic biomarkers
and can describe:
– Drug exposure and clinical response variability
– Risk for adverse events
– Genotype-specific dosing
– Mechanisms of drug action
– Polymorphic drug target and disposition genes
• FDA-approved drugs with pharmacogenomic information in
their labelling N=144
Drug safety
Dear Dr Alfirevic,
• 29 year old
• Epilepsy
• Treatment with antiepileptic drug
carbamazepine (CBZ)
• Good seizure control , however...
• 6 weeks after starting therapy
SKIN RASH, jaundice
• I read your article –biomarker HLAA*31:01 associated with CBZ-induced
skin rash
• My PERSONAL GENOME contains
several risk alleles
HLA allele
SNP
My genotype
HLA-B*1502
Rs3909184
GG
HLA-B*1502
rs2844682
GG
HLA-B*1502
rs9271366
AA
HLA-B*1502
rs3130690
GG
HLA-B*1502
rs1058026
AA
HLA-B*5801
rs3117583
AG
HLA-B*5801
rs1058026
AA
HLA-B*5701
rs2395029
TT
HLA-B*5701
rs3093726
TT
HLA-A*3101
rs1633021
CT
HLA-A*3101
rs1061235
AA
HLA-A*3101
rs2571375
AA
HLA-A*3101
rs1116221
CT
HLA-A*3101
rs2844796
AG
HLA-A*3101
rs1736971
GT
HLA-A*3101
rs1611133
CT
HLA-A*3101
rs2074475
TT
HLA-A*3101
rs7760172
TT
HLA-A*3101
rs2517673
GG
HLA-A*3101
rs12665039
TT
HLA-A*3101
rs1362088
TT
Dear Dr Alfirevic,
HLA allele
SNP
My genotype
HLA-B*1502
Rs3909184
GG
rs2844682
GG
rs9271366
AA
rs3130690
GG
rs1058026
AA
rs3117583
AG
rs1058026
AA
rs2395029
RASH
TT
rs3093726
TT
rs1633021
CT
rs1061235
AA
rs2571375
AA
rs1116221
CT
rs2844796
AG
rs1736971
GT
rs1611133
CT
HLA-A*3101
rs2074475
TT
HLA-A*3101
rs7760172
TT
HLA-A*3101
rs2517673
GG
HLA-A*3101
rs12665039
TT
HLA-A*3101
rs1362088
TT
HLA-B*1502
• 29 year old
HLA-B*1502
• Epilepsy
HLA-B*1502
• Treatment with antiepileptic drug
HLA-B*1502
HLA-B*5801
carbamazepine (CBZ)
HLA-B*5801
• Good seizure control , however...
What is my genetic risk forHLA-B*5701
SKIN
• 6 weeks after starting therapy
HLA-B*5701
with antiepileptic drugs
?
HLA-A*3101
SKIN RASH, jaundice
HLA-A*3101
• I read your article –biomarker HLAHLA-A*3101
A*31:01 associated with CBZ-induced
HLA-A*3101
skin rash
HLA-A*3101
HLA-A*3101
• My PERSONAL GENOME contains
HLA-A*3101
several risk alleles
Immune mediated ADRs
• Rare, but could be life threatening (30% fatality)
• 1 in 1,000 to 1 in 10,000 patients on antiepileptic
drug CBZ develop severe skin reactions
Drug-induced exanthema
Toxic Epidermal Necrolysis
Immune-mediated ADRsdrug hypersensitivity
Caused by diverse classes of drugs
•
•
•
•
•
Antiepileptics
Antiretrovirals (anti HIV)
Antimicrobials
Anti gout
Non-steroidal anti-inflammatory
Diagnosis
• Clinical
Absence of safe, validated diagnostic test to confirm the diagnosis
Phenotype Standardisation Project (Pirmohamed et al., 2011)
• In vivo tests
Skin patch test (specificity, sensitivity unknown)
Re-challenge
• In vitro research tools
Lymphocyte toxicity assay (LTA)
Lymphocyte transformation test (LTT)
Human leukocyte antigen (HLA)
associations with hypersensitivity reactions
Drug
Drug class
HLA association Odds
ratio
Reference
Abacavir
Anti HIV
B*57:01
117
Mallal, 2002
Nevirapine
Anti HIV
DRB1*01:01
Cw8, B14
C*04:01
5.5
8.3
17.5
Martin,2005
Littera, 2006
Carr, 2012
Allopurinol
Anti gout
B*58:01
Haplotype in LD
with B*58:01
580
Hung, 2005
Genin, 2011
B*15:02
A*31:01
2,504
9
9.5
Chung,2004
McCormack, 2011
Ozeki, 2011
Carbamazepine Antiepileptic
HLA alleles
HLA complex helps the
immune system distinguish the
body's own proteins from
proteins made by foreign
invaders such as viruses and
bacteria
Class I
• Chromosome 6
• The most polymorphic region
in human genome
Class III
• Immune function
Class II
TNF
LTA
HSP-70
Clinical utility of genetic testing
Abacavir Hypersensitivity
Genotype
• antiretroviral drug
• 9% hypersensitivity
• immunogenetic
etiology
Association with
HLA-B*57:01
Phenotype
Clinical utility of genetic testing
Abacavir Hypersensitivity
Genotype
• antiretroviral drug
Phenotype
Association with
HLA-B*57:01
• 9% hypersensitivity
• immunogenetic
etiology
Pre-treatment genetic testing →
Reduced hypersensitivity
(Mallal, NEJM, 2008)
ITCH - International Consortium on Drug
Hypersensitivity
• Liverpool- global coordinating centre for ITCH
study for the International
Serious Adverse Event
Consortium (iSAEC)
• Aim- to recruit patients
with hypersensitivity
reactions to a variety of
drugs
1,500 patients
with most
severe skin
ADRs
Antiepileptic drug-induced
hypersensitivity reactions
Drug
Phenotype Phenotype
SJS/TEN
DRESS
Carbamazepine HLAB*15:02
Carbamazepine HLAA*31:01
HLAA*31:01
Phenotype
MPE
Population
HLAA*31:01
Asian
HLAA*31:01
Caucasian
Lamotrigine
HLAB*15:02
Asian
Phenytoin
HLAB*15:02
CYP2C
cluster
Asian
Carbamazepine-induced SJS/TEN and HLAB*1502 in Asian populations
HLA-B*1502 testing → 0 incidence of SJS/TEN
Meta-analysis of HLA-A*31:01 and
CBZ-hypersensitivity
ALL PHENOTYPES, DIFFERENT ETHNICITIES
Yip et al, 2012
Panel of HLA markers
• 22 HLA markers are associated with drug-induced toxicity
• Developing assays to determine all these markers in individuals
before prescribing a number of drugs
• Low cost tests
• Short time-to-results
• Low volume of whole blood
Portable genotyping device
Battery powered
Real-time results without need for PC connectivity
Isothermal amplification
Dear Dr Alfirevic,
HLA allele
SNP
My genotype
HLA-B*1502
Rs3909184
GG
rs2844682
GG
rs9271366
AA
rs3130690
GG
rs1058026
AA
rs3117583
AG
rs1058026
AA
rs2395029
RASH
TT
rs3093726
TT
rs1633021
CT
rs1061235
AA
rs2571375
AA
rs1116221
CT
rs2844796
AG
rs1736971
GT
rs1611133
CT
HLA-A*3101
rs2074475
TT
HLA-A*3101
rs7760172
TT
HLA-A*3101
rs2517673
GG
HLA-A*3101
rs12665039
TT
HLA-A*3101
rs1362088
TT
HLA-B*1502
• 29 year old
HLA-B*1502
• Epilepsy
HLA-B*1502
• Treatment with antiepileptic drug
HLA-B*1502
HLA-B*5801
carbamazepine (CBZ)
HLA-B*5801
• Good seizure control , however...
What is my genetic risk forHLA-B*5701
SKIN
• 6 weeks after starting therapy
HLA-B*5701
with antiepileptic drugs
?
HLA-A*3101
SKIN RASH, jaundice
HLA-A*3101
• I read your article –biomarker HLAHLA-A*3101
A*31:01 associated with CBZ-induced
HLA-A*3101
skin rash
NO RISK ALLELES HLA-A*3101
FOR
HLA-A*3101
• My PERSONAL GENOME
contains
CARBAMAZEPINE
HLA-A*3101
several risk alleles
NATURE GENETICS, 26th October 2014
2-5% children <5y febrile seizures
Febrile seizures following measles, mumps and rubella
vaccination 3x risk 
• interferon-stimulated gene IFI44L, P=5.9 x 10-12
-11
Interferon-stimulated gene (IFI44L)
Efficacy/Drug dosing
Warfarin
• Number of users UK:
600,000
• Dose (mg) range per day:
0.5-20
• Fold variability in dose:
40
• Major bleeding rate per
100-person years:
2.6
• Ranking in ADR list:
3
Approved for human use in 1954
Warfarin
O
Clotting factors
II, VII, IX, X
O
Carboxylase
CH3
epoxidase
OH
O
OH
O
CH3
CH3
O
R
OH
R
O
VKORC1
S
R
CYP1A2 CYP2C9
CYP3A4
Vitamin K
Warfarin
Metabolites
GWAS Warfarin Mean Weekly Dose
(UK Prospective Cohort; n=714)
VKORC1
CYP2C9
Determinants of Anticoagulation
Control
McLeod and Jonas, 2009
European Pharmacogenetics of
Anticoagulation Therapy (EU-PACT) Trial
Randomise
Intervention Arm
(Genotype guided)
Control Arm
(Non-genotype guided)
Loading dose calculation
Loading dose calculation
Dose adjustment
Dose adjustment
3 month follow up
Outcome comparison
Pharmacogenetic-Based Dosing: Warfarin
Randomised Controlled Trial
FP7 sponsored EU trials
 454 patients
 226 in genotype arm
 228 in standard care
arm
 Point of Care test for
genotyping

European Union
Pharmacogenetics of
AntiCoagulant Therapy
Genotyped arm
%TTR
Standard dosing
(control) arm
%TTR
Adjusted
Difference
P value
ITT ANALYSIS (n= 211 vs 216)
67.4%
60.3%
7%
P<0.001
PER-PROTOCOL (n=166 vs 184)
68.9%
62.3%
6.6%
P=0.001
PRIMARY OUTCOME MEASURE: Percent time within therapeutic INR range 2.03.0 (TTR) during 12 weeks following the initiation of warfarin therapy
Differences Between GenotypedGuided Group and Control Group
International Normalized Ratio
Time in Therapeutic Range
US COAG investigators
No difference between
genotyped and control
arm
Kimmel SE et al. N Engl J Med 2013;369:2283-2293.
Nov 23, 2013
Differences between EU-PACT and
COAG warfarin studies
• Patient heterogeneity greater in COAG
• Genotyping not available in ~50% of patients prior to first
dose in COAG
• Did not utilise CYP2C9 polymorphisms on day 1
Dosing Algorithms
EU-PACT
Day 1-3: Loading dose
algorithm
Day 4/5: Dose revision
algorithm
Up to 3 months: AC
clinics (computerised
dosing)
•
•
•
•
COAG
Day 1-3: Maintenance
dose algorithm
Day 4/5: Dose revision
algorithm
Up to 1 month: Protocol
driven
S-warfarin elimination half-life: 18-35 hours
Time to steady state: 90-175 hours
Dose revision algorithm on day 4 dependent on INR
What proportion of patients will have had a change in INR by day 4?
Conclusions
• New technologies to investigate genetic factors in drug
response
• Strong genetic associations related to drug safety and efficacy
• Slow clinical implementation of genetic tests
• Patient and general public requests for interpretation of
genetic tests
• Further functional work and next-gen sequencing to define
causal variants associated with drug efficacy and toxicity