Pharmacogenomics and Disease Genetics in the ... · Genetics in the Pharmaceutical Industry: An...
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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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683699
644784
681323
799943
597901
Valtrex XR
480848
501516
427353
159797
590735
270773
274150
362115
Cervarix
piboserod
Beyond Advair
766994
842470
873140
497115
695634
406725
468816
715992
IL18
204937
Simplirix
talnetant
181771
odiparcil
Streptorix
Avodart + α
406381
640385
353162
597599
685698
Lamictal XR
Lamictalbipolar acute
SeretideCOPD mort.
572016
meningitis
275833
Avandamet XR
Coreg CR
Imitrex/napr
Requip CR
Avandiapsoriasis
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 [email protected]