Pharmacogenomics and Disease Pharmacogenomics and Disease Genetics in the Pharmaceutical Genetics in the Pharmaceutical

Industry:Industry:An UpdateAn Update

BIO Japan 2005

Dr. Mark Watson

Director, Translational Medicine and Genetics, GlaxoSmithKline

Philadelphia, PA

““A new age for the treatment of A new age for the treatment of diseases with safer and more diseases with safer and more targeted medicines is beginningtargeted medicines is beginning””..

Allen Roses, Nature Reviews Genetics, Sept. 2004

Patients are expecting change . .

Business Week, September 5, 2005

As are investors . .

“Clearly the model of significant investment in the pursuit of blockbuster drugs is failing to deliver the products and growth that these major international companies need to support their cost base”

“The industry needs to critically appraise how it acquires and develops new drug candidates if it is to return to the days of year-on-year double-digit growth.”

Dr. James Featherstone, Global Head Dr. James Featherstone, Global Head of Consulting, Wood Mackenzieof Consulting, Wood Mackenzie

OutlineOutline

Environment

Preclinical Discovery

PGX in Development- Safety and Efficacy

New Technologies

The Regulatory Environment

EnvironmentEnvironment

Preclinical: More, but mainly Better Quality targets

Improved drug development process

Cheaper, faster

Higher likelihood of success

Picking ‘Winners’ earlier, and at each step

Evolving PGX examples and success stories

Identification of

PGX Subgroups

Identification of

PGX Subgroups

ADMEPGX

ADMEPGX Rare

ADRStudies

RareADR

StudiesDiseaseCohortsDiseaseCohorts

MolecularSubtypesMolecularSubtypes

Compound OptimizationPre-Clinical

Testing

ChemicalScreening

Phase 1Safety

andMetabolism

Phase 2POC

Efficacy,Safety

RegulatoryReview

DrugOn

Market

Phase 3Proof ofEfficacy,Safety

Drug Target,Identification,For SpecificPatient Need

New DrugMechanism

Understanding

New DrugNew DrugMechanismMechanism

UnderstandingUnderstanding

GenomicProfiling of CompoundTox, Carc

GenomicGenomicProfiling of Profiling of CompoundCompoundTox, CarcTox, Carc

Enrichmentof

Responders

EnrichmentEnrichmentofof

RespondersResponders

PGX EpidemStudies

PGX PGX EpidemEpidemStudiesStudies

New and More Relevant TargetsNew and More Relevant TargetsGSK HiTDP - High Throughput Disease-specific Intellectual Property

Need for improvement in target selection to focus on patients’ medical needs

– Avoid complete reliance on animal /tissue culture models of disease

Screening ‘chemically tractable /screenable’ gene targets: GPCRs, Ion channels, NHR and cofactors,Kinases, Proteases

17+ diseases, 1800 genes, 7000 SNPs

A. Roses et al. Disease-specific target selection: a critical first step down the right road, DDT 1 February 2005

GSK “HiTDP” Screening

Roses et al. Disease-specific target selection: a critical first step down the right road, DDT, 1 February 2005

PatientPatient-- FirstFirst Screening for TargetsScreening for Targets

HiTDP requires pioneering statistical approaches

Replication is a key feature and planned from beginning

Permutation testing allows better indication of number of false positives expected

After analyses, expert interpretation using clinical expertise is required

Allows follow up studies that include analysis of specific genes of interest

PGX in Drug DevelopmentPGX in Drug Development

PGX and Biomarker research can be broadly divided into two areas based on the drug response being studied, Safety PGX and Efficacy PGX.

Both impact drug development and use

Each has different strategic planning and study designs

PGX has a large pipeline to addressPGX has a large pipeline to address

2008 2004 2005 2006 2007 2003

new productsapprovable

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Imitrex/napr

Requip CR

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Boniva

Rotarix

alvimopan

nelarabine

Priorix Tetra

Boostrix (US)

Wellbutrin XLSAD

Lamictalneuropathic pain

solifenacin

Ariflo

Epivir/Ziagen

Avandaryl

Requip RLS

Paxil CR PMDDintermittent

new formulationsnew indications

http://www.gsk.com/financial/presentations/merrill_lynch_feb2004/merrill_lynch_feb2004.pdf

Challenges: PGX in Drug Challenges: PGX in Drug DevelopmentDevelopment

Powering Issues: Current drug efficacy trials are almost always statistically powered for clinical endpoints, not for PGX subgroup analyses

Need for Understanding of the exploratory nature of studies by our partners:

Patients, Clinical development teams, Ethics Committees, and Regulators

– Historical drug development paradigm is using the clinical trial only as hypothesis-testing

– Now Trials are Hypothesis-Generating

Often PGX studies may be facing exploration andconfirmation in tight development timelines for a given new drug

Challenges: PGX in Drug Challenges: PGX in Drug DevelopmentDevelopment

Just as with Target Discovery, clinical expertise is important to interpret results

Again, Novel statistical approaches are needed

– Requires Clinical Trial Statisticians to learn new analyses and gain some understanding of genetic markers as covariates

Often limited / no data in the literature on candidate gene effects-

– Drugs are called New Chemical Entities because they are ‘new’ -their drug responses have never been studied

Adverse Drug ResponsesAdverse Drug ResponsesCosts to Health CareCosts to Health Care

Almost three billion outpatient prescriptions each year (2/ 3 of office visits) and 2 million serious ADRs

4th leading cause of death, ahead of pulmonary disease, diabetes, AIDS, pneumonia

– Estimate over 100,000 deaths

Costs USA $136 billion/ yr.

Examples: SJS, IC, LQT, HSR, MI (Cox2), PML

ADR’s are a huge Public Health problem

Center for Education and Research on Therapeutic, http://www.arizonacert.org/medical-pros/education/module01.htm

Safety PGXSafety PGX

Mission to identify associations between markers and subjects likely to have an ADR

Safety issues may impact drugs as early as Phase I or as late as after launch

– Depends on frequency of ADR, dose /durationdependency

Early issues in development very often represent signals instead of overt safety events

Genetic association studies for Safety PGX can require as few as 20 or fewer cases (slide 21), provided a large number of controls is available

“I cannot answer except to assure that it will be spectacular” -

Orville Wright, when asked to forecast the future of aviation

Whole Genome InformationWhole Genome InformationThe Spectacular is Just Beginning The Spectacular is Just Beginning

Allows for ‘assumption free’ PGX studies

Can be genotype information or gene expression

‘No stone unturned’

Creates huge datasets that require novel statistics

Best used if complemented with clear way to progress to hypothesis testing

18µm

Hybridized Probe Array Image

500,000 specific 25mer oligonucleotide probes

* ** *

*

1.28cm

Probe ArrayProbe Array

Anatomy of aAnatomy of a GeneChipGeneChip®®

Probe ArrayProbe Array

GSK demonstrated that a GSK demonstrated that a genome scan would be genome scan would be able to find loci associated able to find loci associated with ADR ofwith ADR ofhyperbilirubinemiahyperbilirubinemia in Pts in Pts takingtaking TranilastTranilast

Density of SNPs at 35 kb, Density of SNPs at 35 kb, then 5 kbthen 5 kb

Typical density with new Typical density with new whole genome chipswhole genome chips

Completely confirmed Completely confirmed finding of UGT1A1 finding of UGT1A1 association byassociation by DanoffDanoff et al. et al. (2004)

RareRare ADRsADRs

(2004) Roses et al., Nat Rev Genetics, Sept 2004

Only a Few cases may define Only a Few cases may define AssociationsAssociations-- TranilastTranilast exampleexample

If large number of matched controls used, smaller number of cases needed to detect

Depends also on linkage to genetic variation likely responsible for clinical variation

Cases Controls SNP4082379 SNP3729885 SNP3730948 SNP3737550

10 3,000 0.10392 0.01542 0.04623 0.00644

20 3,000 0.00143 4.37 × 10–6 0.00014 9 .96 × 10–8

30 3,000 3.93 × 10–6 2.91 × 10–7 4.14 × 10–5 5.59 × 10–9

50 3,000 8.69 × 10–8 7.39 × 10–8 2.47 × 10–5 1.32 × 10–10

From Roses, et al, 2005, results reflect p valuesFrom Roses, et al, 2005, results reflect p values

Whole Genome ConsiderationsWhole Genome Considerations

How best to follow up associations with more studies

– Rigorous plan for confirmation/ hypothesis-testing necessary due to significant false discovery

Replication

– How similar are findings in population subgroups?

Are there holes in the current genome chips?

– Clearly yes

MolecularMolecularPharmacopidemiologyPharmacopidemiology

Large Patient Care Databases that contain cohorts of patients on marketed drugs

Studies on existing drugs will certainly inform new drugs

– Note that new NCEs often build on existing drugs

Finding Subgroups of patient responses are key

Rare events /subgroups (<1:10,000) can be detected and collected, using appropriate consent

Precisely-defined population distribution of drug response compared to clinical trial population

Example: General Practice Research Example: General Practice Research DatabaseDatabase

World’s largest computerised database of anonymised patient data from general practice.

Greater than 44 million patient years of data.

Over 3 million patients, equivalent

to 5% of the UK population

Data are provided by contributing general practices from all around the UK

GPRD has been collecting patient records in the United Kingdom continuously since 1987

Molecular Biomarkers in Clinical Trials

Goal is enrichment for most likely responders

Builds on identification of Likely responders and likely Non-Responders

Higher likelihood of Success to show Proof of Efficacy

Doesn’t exclude generalizability to ‘All Comers’

Efficacy PGXEfficacy PGXThree outcomes of POC studies

– ‘Registerable’ efficacy

– Failure to show sufficient efficacy

– Marginal i.e. ‘Sub-registerable’ efficacy

PGX especially important for the last result

Without PGX, development would normally stop at Phase IIA in last two cases

Much has been invested by Pharma by this point, including toxicology and chemical /formulation development

Trial Designs ‘Classical Trial’‘‘All ComerAll Comer’’ Clinical TrialClinical Trial

Randomized by Randomized by Clinical VariablesClinical Variables

(Mixture of Test + and (Mixture of Test + and Test Test -- Subjects)Subjects)

N Treatment Arms, +/-Pb

Clinical Testing

Drug Passes or FailsDrug Passes or FailsBased on Based on

Classic EndpointsClassic Endpoints

Retrospective Analysis‘All Comer’ Clinical Trial

Randomized by Clinical Variables

(Mixture of Test + and Test - Subjects)

N Treatment Arms, +/-Pb

Clinical Testing

‘‘ Positive GenotypePositive Genotype’’Cohort ResultsCohort Results

(Identified Post Hoc)(Identified Post Hoc)

‘‘Negative GenotypeNegative Genotype’’Cohort ResultsCohort Results

(Genotypes Identified (Genotypes Identified Post Hoc)Post Hoc)

Likely Responders Only (Decode Ex)

‘‘Genotype FirstGenotype First’’ Clinical TrialClinical Trial(Exclude Test Negatives)(Exclude Test Negatives)

and and Randomize by Randomize by

Clinical VariablesClinical Variables

-+N Treatment Arms, +/-Pb

Clinical Testing

‘‘Positive GenotypePositive Genotype’’Cohort ResultsCohort Results

‘‘Negative GenotypeNegative Genotype’’CohortCohort

Not RandomizedNot Randomized

Prospective PGX Efficacy TrialProspective PGX Efficacy TrialDecode FLAP example with DG031Decode FLAP example with DG031

H. Hakonarson, et al, JAMA 2005

Culmination of many years of CAD / MI disease genetics studies by Decode

Supported by biochemical evidence of role of inflammation in coronary artery atherosclerosis

Many candidates involved in atherosclerosis/ inflammation

DeCode Genetic information points to 5-Lipo-oxygenase pathway that generates inflammatory cytokines

Decode FLAP Inhibitor Trial ( DG031)Decode FLAP Inhibitor Trial ( DG031)

H. Hakonarson, et al, JAMA 2005

Decode Prospective TrialDecode Prospective Trial

Builds on ‘High-risk” patient genotypes discovered by disease gene mapping

Phase II, ~200 patients randomized by risk-genotype

Placebo plus 3 doses of DG031

Primary endpoint represents a composite of 10 biomarkers related to inflammation

Result: Positive decrease in some endpoints e.g. leukotriene B4 reduction by 26%

Eventually, confirmation in trials with clinical endpoints will be required

But confidence will be high prior to study spend

‘Genotype First’Clinical Trial

Randomize by Genotypeand Clinical Variables

Randomize Both (Albuterol Ex)

‘‘Positive GenotypePositive Genotype’’CohortCohort

‘‘Negative GenotypeNegative Genotype’’CohortCohort

Clinical TestingClinical Testing

-N Treatment Arms,

+/-Pb

+

Example of Example of ‘‘Randomize BothRandomize Both’’

Randomization by residue 16 of Beta 2 Adrenergic R

Gly/Gly genotype showed significantly greater improvement in PEFR during albuterol treatment period (24 L/min difference)

Other measures (FEV1, FVC, rescue use) also better for Gly/Gly

Authors suggest potential adverse consequences of use of albuterol in Arg/Arg patients (1/6 of Patients)

Israel et al., The Lancet, 2003

PGX in Clinical TrialsPGX in Clinical TrialsRetrospective trials are the most common in the Pharmaceutical Industry

– Usually Exploratory studies to identify Associations

– Often necessary as a first step

– Helpful to define during exploratory trials:

– magnitude of effect

– allele frequencies, others.

Follow up Randomization and Enrichment trials require good confidence that marker is predictive

The Regulatory EnvironmentThe Regulatory Environment

The FDA has made Molecular The FDA has made Molecular Biomarkers a Key Component of Biomarkers a Key Component of the the ‘‘Critical PathCritical Path’’

http://www.fda.gov/oc/initiatives/criticalpathhttp://www.fda.gov/oc/initiatives/criticalpath

What Is the What Is the ‘‘Critical PathCritical Path’’??

“The development process – the critical path to patients – is becoming a serious bottleneck to delivery of new products”

“We are using the evaluation tools and infrastructure of the last century to develop this century’s advances”

Dr. Janet Woodcok, “FDA’s Critical Path Initiative”

June 2, 2004

FDA Critical Path Initiative: FDA Critical Path Initiative: GoalsGoals

Get more innovative products to patients.

Achieve robust product development pathways that are efficient and predictable.

Develop new toolkits that bring scientific advances into the product development process.

Perform research on tools that remove specific identified obstacles in product development.

Dr. Janet Woodcock 2004

Optimism Based onOptimism Based onNew Biomedical DiscoveriesNew Biomedical Discoveries

Sequencing of the human genome, Genomic and proteomic technologies, Systems biology, Advances in medical imaging, Nanotechnology advances, Tissue engineering, Drug discovery: combinatorial chemistry and automated microscalescreening

Note that 4 out of 7 of these FDA “areas of optimism” are based on molecular /biomarkers

Some Good NewsSome Good NewsRegulatory agencies globally have embraced PGX

Japan- MHLW initiative for information gathering

Europe- EMEA Working Group /Party on Pharmacogenetics

– Terminology Concept Paper

– Briefing Meetings Paper

Groups such as the Industry Pharmacogenetics Working Group is seeking to educate, and enable PGX by working with stakeholders

Pharmacogenetics Working Pharmacogenetics Working Group (PWG)Group (PWG)

The PharmacogeneticsWorking Group

P W GP W G

A Pharmaceutical Industry Working Group composed of 23 Pharmaceutical Companies

Mission is to educate and advocate for incorporation of PGX in medicine development and use, to make better medicines

Published several papers on Terminology, Informed Consent, Return of Genetic Data to subjects

We meet once a month by teleconference, and 2-3 times per year face to face

Pharmacogenetics Working Pharmacogenetics Working Group (PWG)Group (PWG)

Welcome Japanese colleagues, only requirements are:

– Marketing of a therapeutic agent

– Interested in Pharmacogenomics We meet once a month by teleconference, and 2-3 times per year face to face

Co-sponsor of Regulatory events

Japanese Pharma companies are welcome, Eisai Pharmaceuticals has been one of the Members

– Sanae Yasuda/Kitazawa lead member

The PharmacogeneticsWorking Group

P W GP W G

FDA Plan for PGX is Progressing FDA Plan for PGX is Progressing

Staffing of the ‘Genomics’ group at FDA- Dr Felix Frueh, Director of IPRG, Dr. Federico Goodsaid, Organizing molecular biomarker initiatives

FDA Guidance documents and symposium

– Voluntary Genomic Data Submission Guidance now final

– “FDA III” April 11-13, Marriott Bethesda North

– IPRG group formed to specifically address PGX submission

Good communication between global agencies and with industry

– Example, FDA was willing to present at a recent PWG monthly meeting on Guidance progress (F. Frueh)

VGDSVGDSVoluntary Genomic Data Submissions

Intended to create open discussion between industry and FDA, in preparation for ‘regulatory’ data

First official VGDS- March 2005

At least 15 VGDS submissions underway or planned

First joint EMEA- FDA has occurred- May 2005

– More are scheduled for 2005

Some PGX data will already involve ‘valid biomarkers’ or be used as pivotal data in development

– Cytochrome 2D6, UGT1A1, others

These data will be reviewed as part of the regular submissions

ChallengesChallengesWork needed to define regulatory requirements, handling of exploratory and decision-making

– What constitutes “Known Valid” and “Probable Valid”biomarkers versus exploratory biomarkers?

– How will FDA learnings be transmitted to pharma, at the same time respecting confidentiality?

Will the bar be set higher for Molecular Biomarkers?

– Note that Clinical trials to demonstrate safety and efficacy have historically use specific enrollment criteria -eventually this did not affect the label

Future Future

Harmonization should continue to be a topic for regulatory agencies and ethical bodies to work toward

Helpful to Pharma to continue to deliver new medicines if harmonization in how genetic data is viewed and used during review of regulatory process

Broad consent for exploratory studies from samples from clinical trials will continue

– Consider PGX data like other clinical data- and Pharma Cos must continue to rigorously protect confidentiality

Both-way Education and Discussion with all partners needed:

Patients, Providers, Regulatory Agencies and Ethics Committees

Future Future

New Opportunities- Post marketing surveillance with possibilities for sample collection will enable studies

New Opportunities- Large population-based studies in the post-marketing represent an exciting opportunity

Whole Genome Scans more feasible, available

– More experience with these large datasets

Pharmacogenetic Epidemiology- leveraging existing drug databases

DiscussionDiscussion

Thank you for your attention Thank you for your attention and interestand interest

Please　contact mark.l.watson@gsk.com