Genome Sequencing in Predicting Drug

Response

All drugs are not created equal, neither are the patients

who use them” (JAPHA 2011)

© GenesFX

Pharmacogenomics – The First Application of Personalised Medicine

• Pharmacogenomics = study of genetic variations that

influence drug response

– correlate genetic change such as single-nucleotide polymorphisms

(SNPs) with a drug’s efficacy or toxicity

– Up till now do single genes and

• Specific mutations.

© GenesFX

Who can drink coffee before bed?

• Caffeine is converted to xanthenes (theobromine,

aminophylline)

• Converted by an enzyme called Cytochrome P450 1A2

(CYP1A2)

• 50% of people are fast metabolisers of CYP1A2

• Some drugs won’t work for those people

© GenesFX

Individual differences in response to medications

• Inter-individual differences in response was first described by

Pythagoras in 510 BC. He noted that some individuals

developed anaemia in response to fava bean ingestion.

(G6PD)

• Cytochrome P450s developed to protect the body from

poisons and now involved in drug metabolism

• About 40% of drug metabolism is mainly carried out by the

enzymes CYP2C9, CYP2C19 and CYP2D6

© GenesFX

1. Non-genetic

Factors

Intrinsic

• Age

• Gender

• Pregnancy

• Disease

Extrinsic

• Diet

• Smoking

• Medications

• Medical

Interventions

• Haemodialysis

• Organ

transplant

Variability in Drug Response

2. Genetic

Factors

• Drug metabolising

enzymes

• Drug transporters

• Drug receptors

• Channel proteins

• HLA- immune

factors

http://www.healthplexus.net/files/images/2008/CGS/prescribingfig1.jpg

“Matching”

in RCT

3. Cancer cell

genetic changes

Genotype then prescribe

The practice of psychopharmacology is gradually becoming more evidence

based, and clinicians can accurately predict how individual patients will

respond to specific medications Mrazek (2006), “Psychiatric pharmacogenomics”

Case study

A 16 year old girl presented with

depression and anxiety

She was prescribed sertraline (Zoloft) and

diazepam (Valium)

Became suicidal , agitated, tachycardia

(serotonin syndrome), made several suicide

attempts and was hospitalised.

Gradually taken of the drug and made

complete recovery

The RIGHT DRUG - Depression

CYP2C19 enzyme is the main enzyme responsible for metabolising both

sertraline and diazepam

Results: CYP2C19 *2/*2 Poor Metaboliser

Personalised treatment of Depression

What Happened?

CYP2C19Sertraline Desmethylsertraline

(negligible action)

NordiazepamCYP2C19

Diazepam

Narrow therapeutic index

Active Drug

CYP450 Enzyme

• Inactive Metabolite

No effect

Toxicity

Effect of non function of CYP450

CYP 2D6, CYP2C9,CYP3A4,CYP2B6

© GenesFX

SLOW REDUCED NORMAL FAST

Metabolic Speed

Dru

g C

on

cen

trati

on

Optimal

Drug Effect

No efficacy

TOXICITY

The effect of metabolism on the level of the drug

© GenesFX

CYP450 Allele Nomenclature

Family

(>40%)

Isoform

CYP 2 D 6

Cytochrome P450

SuperfamilySubfamily

(>55%)

*4

ALLELE

© GenesFX

DNAdose – the right medication at the right dose

based on your DNA

Presented at HGM2012 (March

GenesFX in-house data on genotype diversity in

Australian population (n=1619)

Study many genes -

• Web tool genesfx.com and dnadose.com

© GenesFX

Adverse Drug Reactions- Australia

• GP’s report 10% of patients experience ADR’s, of which

45% rated as moderate to severe. 7.6% resulted in

hospitalisation. (30% over 80years)

(MJA 2006;184(7):321).

• Therapeutic Goods Administration

– 140,000 patients admitted to hospital with an ADR

each year

– The cost is $14,000 extra per admission (Deloitte

report)

Second National Report on Patient Safety from the Australian Council for Safety and Quality in Health Care (2002)

© GenesFX

ADVERSE DRUG REACTIONS-US

• Over 2 million ADRs/year in the US.

• Over 100,000 deaths annually (6th leading cause of death in the U.S.*)

• Drug-related injuries occur in ~ 6.7% of

hospitalized patients

• Annual Hospital cost US$1.6 to 4 billion*Lazarou et al: Incidence of adverse drug reactions in hospitalized patients: a meta

analysis of 39 prospective studies. JAMA 1998; 279:1200-1205.

Gurwitz JH. Am J Med. 2000 Aug 1;109(2):87-94

© GenesFX

Macro economic benefits-Deloitte report 2008

• Potential economic $2.1 billion - $5.5 billion

over 5 yr

– 0.5%-1% all admissions

• Avoided wastage: $360 million - $720 million

over 5 years

• Improved quality: reduced strokes and breast

cancer / equivalent to more than $1 billion -

$6billion

• Total Savings 12 Billion over 5 years in

Australia

© GenesFX

Standard dose/drug hope for the best

Preliminary work with Garvan Institute using whole gene sequencing

• Started with genes of DNA dose

• Send the outputs and read the genotypes

• Incorporate into pharmacogenomic reports

SnpTool(Genotype Calculator)

CYP2C19 *1/*2

Report writing/decision support software

XXConstruct

LibraryXX Sequence

Analyse Data

Genotype Drug Report

Genotype

Genotype

• *4/*4Drug

Pharmacogenomic Whole Genome Sequence Pipeline

C,G,A,T

Report

© GenesFX

Current testing of 4 genes beneficial- much improved

benefit from WGS?

• DNAdose is a multi-gene test that covers ~ 50% of commonly prescribed

medications- (4 Genes)

• Test 4 genes and separate common mutations

• Eg CYP2D6 15 mutations

• CYP2C19 -3

• Multi-gene test

• CYP2D6• CYP2C19• CYP2C9• VKORC1

• 1300 Support line for doctors

• Online support tool at www.genesfx.com

Narrow therapeutic index

Sertraline

CYP450 Enzyme

• Inactive Metabolite

No effect

Toxicity

Which CYP450?- All known mutations?

CYP 2D6, CYP2C9,CYP3A4,CYP2B6

as well CYP2C19 all mutations

The literature and WGS

• 2013 Potential and difficulties

• JAMA March 2014- Tested Genes in DNAdose and regarded as significant findings recommended by PharmGKB CPIC. 11/12 had a >=1 with associated recommendation. Each individual had 1-3 changes. 3-10 additional changes per individual with PharmGKB evidence level 1B or higher.

• 2014(March) Huser et al 6 CPIC guidelines. 69 patients-Statin recommendation in 16%

Francis Collins and Pharmacogenomics

• Head of USA National Genome Research Institute Group(2003).

• “pharmacogenomics was expected to be one of the first benefits of the genome sequencing knowledge”

• In December 2013 , as the Director of NIH, and the 10 year anniversary of the sequencing he said that Pharmacogenomics was a major area of opportunity which is yet to be fully exploited.

Why not widely used in hospitals?

• Not realised because individual tests have to be ordered. If the whole genome results were in the EMR which allow a much faster use of the information to “get the right drug in the right dose for each patient”

• However our experience says this information is useless unless you have a whole a proper report matching the genetic findings with the drugs.

Implementing a pharmacogenomic testing and a pharmacogenomic decision support software system in a public hospital

Pharmacogenomics Decision Support System:

Market Validation Program (MVP)

A Major Teaching Hospital in Melbourne

• Accurate, fast and relatively cheap sequencing

• Methods of storing this and making it readily available

• For pharmacogenomics you need a system to be

knowledgeable about how the PGx genotypes interact with

specific drugs and drug combinations (extra steps in the

pipeline)

• You need a decision support system to help make this

information usable.

To make the most of WGS and Pharmacogenomics we

need

The right drug in the right dose OR?

Favourite Drug A or B?

And/Or what shall I eat for lunch ?

© GenesFX

CPIC Guidelines for CYP2D6 and CYP2C19 Genotypes and

Dosing of TCAs - 2013

Adapted from: Hicks JK et al. Clinical Pharmacogenomics Implementation Consortium Guidelines for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clinical Pharmacology & Therapeutics. 2013 May;93(5):402-408.

Some items in case presented recently published in

growing body of evidence

Swen et al (2011)