Transcript Focus on regulatory points

CYP 2C19
Polymorphism
How can we
®
save Plavix ?
Duvernois Julie
Dor Julie
Fontaine Quentin
Le Beherec Ronan
Colin Jean-Baptiste
03/02/2011
0
In another world Plavix® would be…
Clopidogrel problems only related
to CYP 2C19 metabolism
Clopidogrel with no patent
expiration until the
year 2020 …!
1
SUMMARY
Plavix ® presentation
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Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
3
Physiology
Active metabolite
30%
Individual variability
4
Mechanism
Plavix works by irreversibly inhibiting a receptor called P2Y12, an adenosine diphosphate ADP
chemoreceptor
5
Clinical trials
Phase III clinical trials:
CAPRIE
CURE
COMMIT
(N=19,185)
(N=12,562)
(N=45,852)
- Trial endpoint: combined MI, ischemic stroke, or vascular death
- Treatment regimen:
PLAVIX vs aspirin
Or
PLAVIX+aspirin vs placebo+aspirine
- Results:
Reducing the risk of ischemic stroke, myocardial infarction (MI),
or vascular death
6
www.plavix.com
Clinical trials
CURE: Primary Endpoint—MI/Stroke/CV Death
7
Indication
- patients who have recently had a myocardial infarction
- patients who have had a recent ischaemic stroke
- patients with peripheral arterial disease
- patients who have a condition known as ‘acute coronary syndrome’
including patients who have had a stent inserted
8
http://www.ema.europa.eu
Pathology
Acute coronary syndrome
Set of symptoms linked to erosion or rupture of the atheromatousplaque
Consequences :
non-ST segment elevation MI
- Myocardial infarction
ST segment elevation MI
- Unstable angina
9
Acute Coronary Syndrome
Prevalence
2° leading cause of mortality: 120.000 MI/an, more than 47.000 deaths
10% of total year mortality
10
Market authorization
1997
Centralized procedure
1998
11
Market study
Market share
Price: 56.90€
Reimbursement: 65%
In terms of value
Row
Product
1
PLAVIX
2
TAHOR
3
SERETIDE
4
INEXIUM
5
ENBREL
In terms of quantity: 18°
Plavix is the top-selling antiplatelet agent in the market: $9,1bn in 2009
Blockbuster: the 2nd top selling drug in the world
12
www.afssaps.fr - Thomson pharma
Plavix presentation
Conclusion
Because health matters
- Efficacy demonstrated with Better Safety profile
- Solution for a big public health problem which touch many patients
an effective drug which deserves to be fought for
ASMR II
13
SUMMARY
 Plavix ® presentation
Studies
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Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
14
Cytochrome P-450 polymorphisms & response
to Clopidogrel
 CARRIERS
 NON-CARRIERS of at least one CYP 2C19 reduced-function allele
→ Extended categorical classification:
 ultrarapid
 extensive
 intermediate
 poor metabolizer
CARRIERS of at least one CYP2C19 reduced-function allele
= 34% of the study population
PHARMACOKINETIC
→ 32.4% reduction in plasma
exposure to the active metabolite
Ultrarapid → highest exposure
Poor metabolizer → lowest exposure
PHARMACODYNAMIC
→ 25% reduction in platelet
inhibition
Ultrarapid → greatest platelet inhibition
Poor metabolizer → least platelet inhibition
16
CARRIERS of at least one CYP2C19 reduced-function allele
= 27,1% of the study population (395 subjects)
CARDIOVASCULAR
OUTCOMES
CARRIERS
→ Significantly
NON-CARRIERS
higher risk for
cardiovascular
outcomes
15 months
→ 3-times more
risk of stent thrombosis
17
Cytochrome P450 2C19 polymorphism in young
patients treated with clopidogrel after myocardial
infarction
CARRIERS
*1/*2 & *2/*2 (73 patients)
 NON-CARRIERS
*1/*1
(186 patients)
Lancet 2009: 373; 309–17
CARDIOVASCULAR
OUTCOMES
NON-CARRIERS
CARRIERS
19
Lancet 2009: 373; 309–17
CLOVIS-2
Hypothesis
Determine whether
of clopidogrel can
Study design
Heterozygous
*1/*2
Homozygous
*2/*2
Homozygous
*1/*1
300 mg
300 mg
900 mg
900 mg
20
Average residual platelet
aggregation :
the lowest
the highest
patients *1/*1
patients *2/*2
High clopidogrel LD
21
Conclusions…
Heterozygous
*1/*2
Homozygous
*2/*2
For ±
30% of the population
→ 25% reduction in platelet inhibition
→
Significantly higher risk for
cardiovascular events
Heterozygous
*1/*2
For ±
25% of the population
→ 3-times the dosage = 1 time the dosage in *1/*1
NORMAL metabolizer
22
SUMMARY
 Plavix ® presentation
 Studies
Pharmacogenomics
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


FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
23
Pharmacogenomics
CYP 2C19
genotype
CYP2C19*1 allele
FULLY functional
CYP2C19*2 and *3 alleles
NO functional
24
Distribution
Homozygous
NORMAL
metabolizer
*1/*1
Heterozygous
INTERMEDIATE
metabolizer
*1/*2
Homozygous
POOR
metabolizer
*2/*2
± 70%
± 25%
± 5%
25
Ethnical distribution
CYP2C19*2 and *3 alleles
Majority of reduced
Function alleles in White (85%) & Asian
(99%) poor metabolizers
Poor metabolizer patients possess 2 loss-of-funtion alleles
Poor CYP 2C19
metabolizer
Genotypes are
approximately
White : 2%
Black : 4%
Asian : 14%
26
SUMMARY
 Plavix ® presentation
 Studies
 Pharmacogenomics
FDA & EMA actions
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Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
27
FDA Black Box Warning
In March 2010: Plavix received a boxed warning to its US label
WARNING: Diminished effectiveness in poor metabolizers
The Boxed Warning in the drug label will include information to:
- Warn about reduced effectiveness in patients who are poor metabolizers of Plavix.
Poor metabolizers do not effectively convert Plavix to its active form in the body
- Inform healthcare professionals that tests are available to identify genetic differences
in CYP2C19 function
- Advise healthcare professionals to consider use of other anti-platelet medications or
alternative dosing strategies for Plavix in patients identified as poor metabolizers
An appropriate dose regimen for « poor metabolizers » has not been established
28
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm
European Medicines Agency
European Public Assessment Reports
No safety alert about CYP2C19
29
http://www.ema.europa.eu/
European Medicines Agency
Summary of product characteristics:
30
http://www.ema.europa.eu/
SUMMARY
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Plavix® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance






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
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
31
Competitor
 No CYP2C19 polymorphism
Prasugrel
 Significant increase
in serious bleeding
Centralised Procedure
French market
February 2009
January 2010
Price 56,04 € (30 tablets) ASMR V
32
NICE guidance
Prasugrel is prefered to Clopidogrel for treating ACS
Guidance based on Triton-Timi 38 study
Fewer hospitalisations = savings
33
http://guidance.nice.org.uk/TA182
SUMMARY
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Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco







Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
34
Focus on Medco (USA)
Medco is a PBM (Pharmacy benefit manager)
« improving quality and reducing costs in order to extend access »
2C19 test for each clopidogrel prescription (after patient consentment) 35
SUMMARY
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Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation






Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
36
Why is it important to save Plavix® ?
Plavix® really doesn’t work in only
5% of the population
POOR
metabolizer
For 95% of the population 
very good and known DRUG !
EXCLUSION of this small proportion
 Better trust in the drug & in Sanofi
 Better compliance
 Only 5% loss of the market !
37
Our clinical
Investigation
38
Our Clinical Investigation
2 cardiologists
Biopathology center
Lille
Evaluation of
prescribing
cardiologists
deal with nonresponders
Plavix®
Dijon
4 cardiologists
4 cardiologists
Marseille
39
Questionnaire
to
CARDIOLOGIST
(city & hospital)
40
What we observed…
Cardiologists know there is a problem with Plavix®
But the origin of the problem isn’t really known
Information at medical meeting, studies but not by Sanofi, Afssaps or EMA
They know that genotyping test exist in hospital
Phenotyping test : VASP, VerifyNow®
In case of emergency  Efient®, no genotyping test !
If the test is recommended, so they will
They are saying that currently there are no answers to this
problem
41
Currently
Response
to Plavix®
No response to Plavix ® ?
Efficacy
tests
CYP 2C19
TEST
42
Biopathology center
Most important biopathology center in
Europe
Interview of Pr BROLY
2C19 test is already available (2009)
DNA sequencing : 2C19 + ABCB1
43
In practice in Lille
Test
prescripted
Informed consent
Information by
prescriptor
5 days
x2
Results reported
by the biologist
DNA sequencing
44
Prescription conditions
Genetic testing needed
Submitted to bioethical law
Patient written
consent required
45
Biopathology Center
CYP2C19 polymorphisms study
Prescriptors’
opinions
doesn’t convince
agree with genomic test
studies differ from practice
Pr Broly follows FDA recommendation: FDA recommends, but does not require
Today: no consensus on interpretation because doctors think that there are others
factors involved in clopidogrel response
Interpretation-decision is prescriptor-dependant
BHN 730 = 197 € (no refund)
46
Conclusion of our study
Analysis….to find solutions!
No technical or availability barrier
Interpretation by cardiologist ?
Inform every prescriptor about genomic test
- test must be inserted in practice
- modify Plavix® prescription habits
Who will pay ?
the test seems to be too expensive for patient
47
SUMMARY
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

Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan





What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
48
Safety concerns ?
Clopidogrel response
variability
Disminished activity
Increased risk of CV event ?
Important potential risk
Risk Management Plan
Scientific advice
49
PV plan
Routine PharmacoVigilance
ADR collection systems
Reports – ADR PSUR
Plavix® variability ?
Distinguish normal incidence & response variability
related events
Additional PV activities
50
PV plan
Additional PV activities
Mesure variability rates
incidence
Active surveillance
Patients follow-up
Comparative observational studies
Epidemiologic methods
Test assessment
PASS
Clinical Trial
51
SUMMARY

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




Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?




Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
52
What about drugs with combined
genotyping test ?
53
Extract of ABACAVIR SmPC
54
4.4 switch to 4.1
Clinical study required
55
Abacavir study PREDICT 1
RESULTS
56
N Engl J Med 2008; 358:568-579,
Price : 102 €
Charged to the
patient
57
Extract of MARAVIROC SmPC
TROFILE test only available in California
(price : 800 $)
58
SUMMARY

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





Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance,
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
 Communication
 Focus on regulatory points
 Pharmacoeconomy
59
How can
we
do with
?
We must show a
significant difference
between doing the
test or not.
 CLINICAL STUDY60
Our study simulation
The Prospective Randomized Evaluation of
CYP2C19 Genotype Screening in a Clinical Trial
hypothesis
 prospective pharmacogenetic screening for CYP 2C19
 exclusion of those patients carrying the loss of function allele
from Clopidogrel treatment
as compared with
61
STUDY 1 DESIGN
Recruitment : ≥ N sufficient
Control
group
patients
received
VS
prospective-screening
Group
CYP 2C19 TEST
NORMAL
metabolizer
patients
Allele 1*1
CYP 2C19
TEST
POOR
metabolizer
INTERMEDIATE
metabolizer
patients
Allele 1*2 and 2*2
30%
exclusion
62
STUDY 2 DESIGN
Recruitment : ≥ N sufficient
What about intermediate metabolizer ?
INTERMEDIATE
metabolizer
patients
Allele 1*2
Only 5% excluded
63
Consequence on the SmPC
If the results confirm the hypothesis
Possible switch from 4.4 to 4.1 by the EMA
4.1 Therapeutic indications
[…]
« Before initiating treatment with clopidogrel, screening for carriage of the CYP 2C19 *2
and *3 alleles should be performed in any patient, irrespective of racial origin . Screening
is also recommended prior to re-initiation of clopidogrel in patients of unknown CYP 2C19
*2 and *3 status who have previously tolerated clopidogrel. »
[…]
64
THEN
Obligation for the cardiologists to prescribe a test prior
the first administration of Clopidogrel
Any test possible (no information about that in SmPC!)
Written consent of the patient required
Importance of the test disponibility !
65
In practice…
RESULTS
NORMAL
metabolizer
INTERMEDIATE
metabolizer
POOR
metabolizer
± 70%
± 25%
± 5%
66
Evaluation of the need for RMA
New indication condition
Genetic testing
Suficient for this purpose ?
Solution found but implementation needed
Additionnal risk minimisation actions needed
COMMUNICATION
67
SUMMARY

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







Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
 Focus on regulatory points
 Pharmacoeconomy
68
Communication
What?
Genetic variation
Test
Still a significant
benefit
Support AE
notification
69
Cardiologists
Information letter
to the cardiologists
sales
representatives
Information to
the cardiologists
70
Healthcare professionals
Direct
Indirect
71
Public
Healthcare professionals
Patients association
72
Risk min assessment
Test prescribed ?
Reliable ?
Test performed ?
False - ?
False + ?
Patients agreement ?
Still variability related CV events ?
WHY ?
73
SUMMARY
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








Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
What already exists ?
Risk Management Plan
Study simulation
Communication
Focus on regulatory points
 Pharmacoeconomy
74
Focus on regulatory points
Regarding diagnostics tests
Tests are evaluated by FDA
CDRH (Center for Devices and Radiological
Health) is part of FDA
Tests must be approved
75
Focus on regulatory points
interactions
Center for Drugs
Evaluation and
Research
(CDER)
Center for
Biologics and
Evaluation and
Research (CBER)
Center for
Devices and
Radiological
Health (CDRH)
Center for
veteran
medicine
(CVM)
Center for
Food Safety
and Applied
Nutrition
(CFSAN)
AmpliChip CYP 450 array (Roche)

2D6 : 31 mutations and deletions/duplications

2C19 : 2 mutations
24/12/04 : AmpliChip CYP450 test is the first FDA approved
pharmacogenetic test
76
Focus on regulatory points
Regarding diagnostics tests
Tests are evaluated by FDA
CDRH (Center for Devices and Radiological
Health) is part of FDA
Tests must be approved
24/12/04 : AmpliChip CYP450 test is the
first FDA approved pharmacogenetic
test
Tests are not evaluated by
EMA
AMM for tests doesn't exist
CE label is enough
Directive on in vitro Diagnostic
Medical Devices (IVDD 98/79/EC)
« Member States shall
presume compliance with the
essential requirements »
77
Focus on regulatory points
Regarding diagnostics tests in SPC
To use a diagnostic test can be labelled in SPC
Directive on in vitro Diagnostic Medical Devices (IVDD 98/79/EC)
Pharmacogenomic not mentionned
Test supposed/said reliable by RMS
Test performances not evaluated
Non-proprietary tests (if not co-developed with the drug,
Celsentri-Trofile)
« with a reliable and robust method » as demonstrated by...
78
SUMMARY












Plavix ® presentation
Studies
Pharmacogenomics
FDA & EMA actions
Threat : Prasugrel, NICE guidance
Medco
Clinical investigation
Risk Management Plan
What already exists ?
Study simulation
Communication
Focus on regulatory points
Pharmacoeconomy
79
Pharmacoeconomy
Who will pay the CYP2C19 genomic test ?
Medco $120
Biopathology center 197€
Patient
Insurance
Health
In US Medco refund the80test
Cost-Effectiveness
Prasugrel vs Clopidogrel
TRITON-TIMI 38 Study:
VS
Evaluation of the cost-effectiveness of Prasugrel vs Clopidogrel from the perspective
of the US healthcare system by using data from TRITON-TIMI 38
Medication costs:
$4.62/d
$5.45/d
81
Journal of American Heart Association
Cost-Effectiveness
Prasugrel vs Clopidogrel
Rate of hospitalization for MI,
stroke, death
higher for Clopidogrel
(12,1 VS 9,9 P<0,001)
Rate of hospitalization for
major bleeding
higher for Prasugrel
(2,4 VS 1,8 P=0,03)
82
Journal of American Heart Association
Cost-Effectiveness
Prasugrel vs Clopidogrel
Gastrointestinal
hemorrhage
83
Journal of American Heart Association
Cost-Effectiveness
Prasugrel vs Clopidogrel
Hospitalization cost
Clopidogrel > Prasugrel
84
Journal of American Heart Association
Cost-Effectiveness
Prasugrel vs Clopidogrel
Conclusion
Drug costs
Rehospitalizations costs
Life-years lost
$4.62/d
$24 734
0.530
$5.45/d
$24 205
0.428
Treatment with Prasugrel vs Clopidogrel appears to be an economically
dominant strategy, resulting in both lower costs and greater life expectancy
BUT no stratified patients with 2C19 genetic testing
85
Journal of American Heart Association
Cost-Effectiveness
Prasugrel vs Clopidogrel
STUDY 1 DESIGN
STUDY 2 DESIGN
We can calculate the hospitalization costs between the prospectivescreening group and the control group to prove the test could reduce the
hospitalization cost
86
Medco Analysis
Genetic test is
NOT cost-effective
> $ 380
$ 380.0
Genetic test is
cost-effective
< $ 380
$ 4,62
87
www.medcoresearch.com
Medco Analysis
Genetic test is
NOT cost-effective
> $ 200
$ 200.0
Genetic test is
cost-effective
< $ 200
As the cost of clopidogrel decreases, the cost of genetic
testing also has to decrease to keep the cost-effectiveness
88
Medco Analysis
Cost-effectiveness calculated with following criterias :
Cost of the hospitalizations
 Cost of genetic test
 Cost of the switch : clopidogrel → prasugrel (for 30% of patients max)

Cost-effectiveness
≠ prasugrel-clopidogrel Cost of the genetic test
↓ cost of clopidogrel → ↑ ≠
↓ cost of the genetic test
89
Who will pay ?
TODAY : patients have to pay the test but
 savings because fewer hospitalisation
with clopidogrel
 company image, still have strong sales
Patient  part of his genetic ID,
French mentality ?
90
Back in reality
91
CONCLUSION
GENETIC Factors
• Polymorphisms of P2Y12
• Polymorphisms of CYP 3A4
• Polymorphisms of CYP 2C19
CLOPIDOGREL RESPONSE VARIABILITY
CLINICAL Factors
CELLULAR Factors
• Poor absorption
• Drug-drug interactions (IPP)
• Diabetes mellitus/insulin resistance
• Elevated body mass index
• Accelerated platelet turnover
• Increased ADP exposure
• Up-regulation of the P2Y12 pathway
92
SWOT
Strengths
Good tolerance if it is active
Prescriptors habits with Plavix
More indications than Prasugrel
Already tested in USA by Medco
Only 5% of market lost with test
Opportunities
Risk of major bleeding with Prasugrel
Tests are available
Already leader
Weaknesses
Cost of new study to change SPC
Test is expensive and no reimboursment
Cardiologists need to be informed
Threats
Concurrence of Prasugrel and others
NICE recommendation in favour
of prasugrel
Many others variability problems
Study results ???
93
Thank you for
your attention !
94
Back-up
slides
95
The Thienopyridine Family
Ticlopidine
(1st
generation)
P2Y12 ADP receptor antagonism: antithrombotic
treatment of choice for coronary stenting
Side effects: neutropenia, thrombocytopenia, rash,
diarrhea, not use if patient has severe liver disease
Delayed time frame to achieve full antiplatelet effects
Solution to these problems:
Better Safety profile - Fewer side effects
(CLASSICS trial. Bertrand NE et al. Circulation. 2000;102:624-629.)
Clopidogrel
(2nd generation)
Rapid onset of action with a loading dose
(Cadroy Y et al. Circulation. 2000;101:2823-2828.)
Better clinical outcomes
(Bhatt DL et al. J Am Coll Cardiol. 2002;39:9-14.)
96
Where perform
the Abacavir HLA test ?
 Laboratory with special approval from the Ministry of Health for
research of genetic markers (11 in France)
 Laboratory known as "HLA" (33 in France)
- HLA laboratories of EFS
- HLA laboratories specializing in marrow or organs,
- HLA laboratories of hospitals
97
Test VASP
•Échantillon sanguin, dure 24h
•Mesure de l’état de phosphorylation du VASP = vasodilator
stimulated phosphoprotein (protéine exprimé sur les
plaquettes)
•Plus le CLOPIDOGREL se fixe moins le VASP est
phosphorylé
< 50% ok
> 50% résistance au clopidogrel
98
Test VerifyNow®
•Échantillon sanguin
•Detection optique  mesure de l’agrégation plaquettaire
(niveau de blocage du R P2Y12)
99
Prasugrel Indication
• syndrome coronarien aigu (angor instable ou IM avec ou
sans sus-décalage du segment ST)
• chez les patients traités par angioplastie primaire ou
retardée
• CI chez > 75ans et < 60kg
100
GECCO by Medco
Genotype Guided Comparison of Clopidogrel and Prasugrel Outcomes Study
Objective
Compare the effectiveness of clopidogrel in CYP2C19 extensive metabolizers with prasugrel
in adults recently hospitalized for acute coronary syndrome with primary, delayed, or
planned percutaneous coronary intervention.
Study design
Group with 5 or 10 mg of prasugrel
VS
Group with 75 mg of clopidogrel, extensive metabolizers
CYP 2C19 TEST