Biomarker Based PGx Strategies
Rick Hockett, MD
Chief Medical Officer
Affymetrix
2Affymetrix Confidential
One size fits allOne size fits all
GoalGoal: Improve individual patient outcomes and health outcome predictability through tailoring drug, dose, timing of treatment, and relevant information
assess spectrum of patient response to therapy; stratify patient populations; optimize benefit/risk.
“Providing meaningful improved health outcomes for patients by delivering the right drug at the right dose at the right time.”
Tailoring (e.g. oncology productscomprising drug and companion diagnostic)
Targeted Targeted TherapyTherapy
Tailoring is Broader Than Pharmacogenomics
Measure something in a patient to learn how to prescribe medicine
Why Are Biomarkers So Important?
3Affymetrix Confidential
Increased Benefit:Risk Scenarios““Providing meaningful improved health outcomes for patients Providing meaningful improved health outcomes for patients by improving diagnosis, prognosis, or therapy choice.”by improving diagnosis, prognosis, or therapy choice.”
Can apply one or more scenarios to each Lilly compound. Can apply one or more scenarios to each Lilly compound. Scenarios can often be interdependent.Scenarios can often be interdependent.
Accommodate info for patient diversity, questions specific to payors or providers, or provide tools to meet needs of customers
Tailoring “Tailoring “Information/Information/ ToolsTools””
Identifying “Identifying “PatientPatient”” DiagnosisDiagnosis PrognosisPrognosis TherapyTherapy
Diagnosing patients with particular traits
Identifying responders for targeted therapies (essentially highly tailored therapies)
Identifying who have an alternate prognosis (perhaps needing additional therapy)
Optimize dosing regimen for patient subpopulation(s) to achieve optimal benefit/risk Tailoring “Tailoring “DoseDose””
Identify time to intervene during disease progression, time to complete therapy, or time to alter treatment regimen
Tailoring “Tailoring “TimeTime””
4Affymetrix Confidential
Why do we think genetics will play?
5Affymetrix Confidential
Pinpoint the ‘right’ biomarker
DNA ----ACGTGGGCAGTAGACTCAT---- ----TGCACCCGTCATCTGAGTA----
Protein----Thr Trp Ala Val Asp Ser ----
RNA ----ACGUGGGCAGUAGACUCAU----
Large Scale ‘Fishing’
Whole Genome Scan
Medium Scale ‘Confirmation’Many Different
Groups
Small Scale ‘Validated’Clinical Trial
Support
Large Scale Fishing
DNA – 100K to 2x106 SNPsChip BasedElectrophoresis
RNA – 30K+Chip Based -oligosSlide Based - cDNAs
Protein – 1K upwardMass Spec
Med. Scale Confirm.
DNA –2K to 30KChip BasedElectrophoresisPCR Based
RNA – 30 to 1KChip Based -oligosSlide Based – cDNAsRT-PCR Based
Protein – 50 to 500Mass SpecLuminex Type
Small Scale Valid.
DNA – 1 to 25PCR BasedElectrophoresis
RNA – 1 to 25RT-PCR Based
Protein – 1 to 30ImmunoAssay
Clinically Utilized PGx Tests
Shrinking Clinical PGx Funnel
Hercept Test
Philly Chromosome
VariationY
Resp
on
se
N
Y
N
VariationY
Resp
on
se
N
YNvs.
≥ 3
Predictive
Situation SpecificOnc vs. Neuroscience
c-kitTPMT HLA
Disease vs.Response
Interesting Genetic Associations
ProspectiveClinical Proof
Genetic PolymorphWith Rel. Risk
GeneticVariant
Freq
Genetic PolymorphWith Good
Sens. & Spec
Apo E, CETP
5 - LO
Variants in Growth Genes
DMET
Needs Examples
OncotypeDxUGT1A1
EGFrCYP2C9/VKORC1
Tissue of Origin
7Affymetrix Confidential
Hurdles to applying -omics to medicine Strategic
Gearing the infrastructure Obtaining the talent
Technologic Information overload Lack of biologic understanding Platform challenges
Regulatory Understand how to apply technology
Implementation Clinician education, understanding, and acceptance
X
??
DMET PlusDrugMetabolismEnzymes &Transporters
An Example of Applying New Technologies to the Clinical Marketplace
9Affymetrix Confidential
The Genesis of DMET:
March of 2004: Collaboration initiated between Lilly, ParAllele, and Affymetrix
The goal for Eli Lilly was to develop a clinical solution for better understanding the genetic components behind metabolism and transport:
Better ability to understand PK outliers in early phase trials
Build a database for selective recruitment of healthy volunteers with a defined genotype
Work with the FDA in an attempt to decrease the number of biopharm (DDI) trials needed for future NDAs
June 2006 was the inception of a working assay for clinical trials Dec 2007 first NDA was submitted the FDA
10Affymetrix Confidential
Pinpoint the ‘right’ biomarker
Large Scale ‘Fishing’
Whole Genome Scan
Medium Scale ‘Confirmation’Many Different
Groups
Small Scale ‘Validated’Clinical Trial
Support
Large Scale Fishing
DNA – 100K to 2x106 SNPsChip BasedElectrophoresis
RNA – 30K+Chip Based -oligosSlide Based - cDNAs
Protein – 1K upwardMass Spec
Med. Scale Confirm.
DNA –2K to 30KMIP BasedTrue Materials
RNA – 30 to 1KPanomics Expression
Protein – 50 to 500Mass SpecLuminex Type
Small Scale Valid.
DNA – 1 to 25MIP BasedTrue Materials
RNA – 1 to 25Panomics Expression
Protein – 1 to 30ImmunoAssay
Using existing Affymetrix technology
11Affymetrix Confidential
Setting the stage for adoption of genetic analysis tools for use in personalized medicine
Risks associated with taking
popular heart disease medication
Plavix (Clopidogrel)
Paper published in New England Journal of Medicine
Conclusion: Patients taking Clopidogrel and
who were carriers of a certain gene variation had higher rates of heart attack, death and other cardiac-related events
Two additional independent studies recently published in NEJM and Lancet show similar PGx associations.
12Affymetrix Confidential
No Relationship between Genetics and PK/PD for Prasugrel, Significant Effect for Clopidogrel
Pharmacokinetics
Integrated Genetic Analyses in Healthy Subjects
Pharmacodynamics
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PGx associated clinical outcomes of 1459 acute coronary syndrome patients treated with clopidogrel were significant
1477 Patients were randomly assigned Plavix treatment with 98.8% being genotyped
CYP2C19 variant allele (1) frequency in treated population was 27.1%.
Primary efficacy outcome: composite of death from cardiovascular causes, MI and stroke.
395 variant carrier patients had a 1.5 fold higher risk of death vs non-carriers.
1389 Rx patients had stents implanted with a secondary endpoint of stent thrombosis.
375 2C19 variant patients had a 3 fold increase in risk of thrombosis.
Two additional independent studies recently published in NEJM and Lancet show similar PGx associations.
14Affymetrix Confidential
Identification ofpotential biomarkeror drug targetDNA markerRNA expression levelProtein
DNA orRNA Samples
Plasma orSerum Samples
Use of markerin prospectiveclinical trials
Patient Stratification
Literature
Cell Lines
Retrospectiveconfirmationon clinicalsamples
Tissues
A.B.
C. D.
Pharmacogenomics in drug development
Development of a biomarker
Patient Samples are the Key
Biomarker: A physiological response or laboratory test that occurs in association with a pathological process and that has putative diagnostic and/or prognostic utility
15Affymetrix Confidential
What we Must Do to Enable -omics Impact
Align focus on what can be done and where genetics is likely to work
Analyze, Integrate and Learn from data Enable the field of Molecular Epidemiology
Enhance our biologic understanding of genetic influence of complex traits and produce more examples
Develop and validate technologies for clinical use IT Infrastructure Standards & Controls
Educate the medical infrastructure Engage patients and third party payers
16Affymetrix Confidential
How Do We Enable -omics Uptake?
We cannot maintain silos
We must enable certain, common functions Sample banking
Clinical trials
We must look to the regulators for direction Standards
Controls
Critical Path Initiative
FDA
Industry
Academics
Labs
DiagnosticCompanies
17Affymetrix Confidential
The Biotech/GenomicsRevolution:
Increase the Benefit:Risk Ratio
Develop clinical aids for:DiagnosisPrognosis
DosingTherapy Decisions