Role of genomics in pharmacovigilance prof. MUDr. Ond ej Slana , - - PowerPoint PPT Presentation

• prof. MUDr. Ondřej Slanař, Ph.D.

Daepartment of Pharmacology, 1st Faculty of Medicine, Charles University in Prague General Teaching Hospital, Prague

Role of genomics in pharmacovigilance

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The Wall Street Journal, Friday, April 16, 1999

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Genetics in cancer therapy

• Healthy (host) cells:

> 12,000,000 SNPs > 100,000 VNTRs > 1500 CNV

• Cancer cells:

> 12,000,000 SNPs > 100,000 VNTRs > 1500 CNV + tumor-specific aquired Mutations

Genetic biomarkers

• Disease Risk

– To identify SNPs that put individual to higher risk of disease development

• Early detection

– diagnosis

• Predictive

– Treatment/dose selection

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How much do we know about genetic biomarkers? Real life example - Rare disease X

• 2,300 theoretical non-synonymous point

mutations that lead to unique single amino acid substitutions

• 800 identified so far

– Recent annual rate 40/year

• 600 tested for predictive value for treatment Y

– 250 has a predictive value for treatment Y

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PGx pre-/post-approval guidance

EMA FDA Pre-approval Post- approval Pre-approval Post- approval When to sample DNA +

• /+

+

• When to

conduct PGx +

• /+

+

• genotyping

methodology +

• /+

+

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EU PGx in pharmacovigilance guideline in preparation/draft version

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Maliepaard et al 2013

The European Medicine Agency’s decision-making tree

PGx in the PhV

• systematic consideration of pharmacogenetics in

the risk management plan (RMP)

– Extent of PG effects and implications on BM use in target population – whether use in patients with unknown or different genotype could be a safety concern or requires additional data to be generated – If important genomic polymorphism identified but not fully studied, this should be reflected in safety specification and PhV plan

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post-authorisation collection of genomic data

• Pharmacogenomic surveillance system:

genomic biological samples should be collected prior to prescription

• Every patient receiving a medication and

experiencing serious ADRs or lack of effectiveness should be encouraged that genomic samples be collected especially in the initial post-authorisation phase

• Collaborative actions, such as a consortium

(biobanking)-based approach involving MAHs, academia and regulatory authorities

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Risk Evaluation

• genomic BM testing for idiosyncratic reactions

– precisely define the clinical variables – frequencies of genetic variants in relevant population – PPV and the NPV calculated

• genomic BM related to PK or PD

– drug concentrations, in addition to lack of efficacy or particular toxicity

• phenotype cannot always be predicted from a

genotyping

• the presence or absence of therapeutic

alternatives should be considered

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Level of evidence

• Ideally, data from well conducted RCT(s)
• Retrospective data analysis

– Biological sample or BM status availability from all or majority of the subjects from RCT – Prospectively planned – Replication of results – Biological plausibility – Difference between BM+ vs BM- is large – Isolated retrospective observations are expected to provide confirmatory evidence whenever clinically and ethically appropriate

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Risk minimisation measures

• Label information – based on SPC guideline
• Additional RM

– restricted access to the medicinal products based on specific test – a patient registry – additional educational materials to the prescribers or patients regarding important PGx information

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Effectiveness of RM measures

• Knowledge on the recommendations on BM use
• Are the recommendations followed
• Availability /use of the test

A genetic test

Shall demonstrate

• analytic validity
• clinical validity
• clinical utility
• ethical, legal and social implications

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Centers for Disease Control and Prevention

Utility of PGx test

Drug registration PhV HTA patients Treatment +/- +++ +++ +++ +++ Maximum efficacy/safety + +++ ++ +++ Relative efficacy

• +

++ +++

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Abacavir

• registred 1999, prospective confirmation study

Mallal et al. 2008, clear clinical validity/utility

• HLAB*5701 (all races) 6-8% in Caucasians , 1%

in Asian populations and less than 1% in African populations

• Hypersensitivity, serious
• 48% to 61% of patients with the allele vs 0% to

4% of patients without the allele

• PPV 55%, NPV 100%

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SPC section 4.1 – Indications Abacavir (Ziagen)

Before initiating treatment with abacavir, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin. Abacavir should not be used in patients known to carry the HLA-B*5701 allele, unless no other therapeutic option is available in these patients, based on the treatment history and resistance testing.

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Azathioprine

TPMT activity [u/ml RBC]

5 10 15 12 10

TPMT TPMT TPMT

Thiopurin S-methyltransferase (TPMT)

Woodson, J Pharmacol Exp Ther 1982; 222:174

TPMT frequency 0.3 % PM 11 % IM 89 % EM

N NH N N S N N O2N CH3

% population 5

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AZA

6-MP

thio-IMP

Thioquanine metabolites

6-methyl MP

hypoxantin-guanin-fosforibosyltranferase inosin-5‘-monofosphate dehydrogenase guanosin-monophosphate- syntetase TPMT

methyl-thio- IMP

azathioprine

6-merkaptopurine

TPMT

thio-inosinmonophosphate

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AZA

6-MP

thio-IMP

Thioquanine metabolites

6-methyl MP

hypoxantin-guanin-fosforibosyltranferase inosin-5‘-monofosphate dehydrogenase guanosin-monophosphate- syntetase TPMT

methyl-thio- IMP

azathioprine

6-merkaptopurine

TPMT

thio-inosinmonophosphate

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TPMT

• Strong evidence that PM are at extremely high risk for

development of myelosupression (80-100%)

• the size of the effect of TPMT variant alleles on the risk of

myelosuppression ?

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Deficiency TPMT – high risk for myelotoxicity…. …..genetic test does not identify all patients at risk

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SPC Imuran PGx information section 4.4.

Sharon et al, Pharmacogenetics, 15, 2005, 365-369

Gen No of labs

(phenotype+genotype)

Conducted tests

(phenotype+genotype)

CYP2C9

warfarin

6 3 CYP2C19

phenytoin

4 2 NAT2 4 150 Pseudocholinest.

Suxamethonium/mivacurium

16 2000 TPMT

AZA/6-MP

6 2500

(2003, Australia + New Zeeland)

Does PGx translate in the clinics ?

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Does PGx translate into the clinics?

1982 2015 1995 Fargher EA, J Clin Pharm Ther. 2007 Apr;32(2):187-95. TPMT phenotype by 67% (n = 189) respondents (dermatologists 94%, gastroenterologists 60%, rheumatologists 47%) 91% of testing was carried out prior to prescribing AZA Genotype testing is not typically available to NHS clinicians but 5% (n = 15) clinicians (2% dermatologists, 2% gastroenterologists, 1% rheumatologists) reported using it. 328 prescribing physicians of AZA, 65% screen for TPMT

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Taylor-Gjevre et al. 2013 11 rheumatologists of AZA, 55% screen for TPMT, province of Saskatchewan

Warfarin

• approval in 1954
• VKORC1 gene 2004
• Multiple candidate gene studies:

– VKORC1 and CYP2C9 genotypes influence the inter- patient variability in warfarin dose requirements, together explaining 10–45% of the overal variance

• confirmed by several GWAS

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Warfarin

• COUMAGEN-II Anderson et al. 2012

– PG dosing led to significantly fewer out-of-range INRs at 1 and 3 months

• The Clarification of Optimal Anticoagulation

through Genetics (COAG) Kimmel et al. 2013

– No diference in percentage of time within therapeutic INR range (45% in both arms), in African American lower (TTR 35% versus 43.5%)

• European Pharmacogenetics of Anticoagulant
• Therapy (EU-PACT) Pirmohamed et al. 2013

– PG dosing led to significantly higher percentage of time within therapeutic INR range (67% vs. 60%, p 0.001)

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Xu et al. 2014

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Xu et al. 2014

Warfarin

• GIFT study results to come

– powered to detect a difference in thrombotic and major bleeding events with genotype-guided dosing

• ENGAGE AF-TIMI 48 trial 14,348 patients 4833 taking

warfarin (Mega et al. 2015) – sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days

• f treatment

– and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1.31, 95% CI 1.05-1.64, p=0·0179; highly sensitive responders 2.66, 1.69-4.19, p<0·0001). – greater early safety benefit from edoxaban compared with warfarin

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Warfarin

• Controversy if PGx improves treatment if treatment managed

correctly and patients monitored ……is this the situation in reality?

• screening for all patients - still controversy
• PGx may help to identify reason for suboptimal treatment
• utcomes

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Warfarin SPC PGx info

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SPC PGx info

Ehmann et al. 2014

Ehmann et al. 2014

Conclusions I Individualization via PGx

• Fully personalised medicine (autologous cellular therapy)
• Multiple-stratified personalised medicine (TPMT, breast ca)
• Bimodal-stratified personalisation (HER2+/HER2-)

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Conclusions II

• Challenges in obtaining the information post-

approval

• Hesitance of prescribers to use the tests,

especiall for products long on the market

• Over-optimistic expectations by lab workers
• Valid PGx biomarkers appeared in recent

years, data for others on the way

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Thank you for your attention

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