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Medicine in the 21st Century: Biomarkers and Personalized Therapeutics

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Title: Medicine in the 21st Century: Biomarkers and Personalized Therapeutics


1
Medicine in the 21st CenturyBiomarkers and
Personalized Therapeutics
Terrence L. Sills, PhD Vice-president,
OCBN TBI April 22, 2008
2
Outline...
  • Established treatment paradigm
  • Inherent problem
  • Need for paradigm shift
  • biomarkers
  • Biomarker discovery to diagnostic
  • Integration of biomarkers into drug development
  • Examples of some early successes
  • Challenges
  • Summary

3
The Traditional Treatment Paradigm
Trial and Error
Symptoms Diagnosis TreatmentDosing
NonspecificBroadNonselectiveOne-size-fits-all
Phenotype
4
  • PROBLEM!!!!

5
Problem...
The Practice of Medicinein 1892
2008
If it were not for the great variability among
individuals, medicine might as well be a science
and not an art
6
Old Paradigm - Problem
7
Yikes!!!!!!
And gt2 million ADRs reported annually in US,
including 100K deaths
8
Need for a new approach
  • To meet the clear medical need for safer, more
    effective treatments

9
So...the way forward...
10
Medicine in the 21st Century
  • Beginning of a sea change in how medicines
    developed and delivered to better treat our
    patients
  • Catalyzed by Humane Genome Project and genomics
    revolution
  • Era of molecular medicine personalized medicine
  • Use of biomarkers in drug development and
    delivery of treatment - Pharmacogenomics

11
Regulatory take on the matter
FELIIX FRUEH,, PHD Associate Director for
Genomics, Office of Clinical Pharmacology and
Biopharmaceutics, CDER, FDA
12
FDA Guidances for Industry
  • Pharmacogenomics Data Submissions, March, 2005
  • Drug-Diagnostic Co-Development Concept Paper,
    April, 2005
  • Pharmacogenetic Tests and Genetic Tests for
    Heritable Markers, February, 2006
  • Goals of FDA
  • Critical Path facilitate development of more
    predictive evaluative tools
  • Critical Path improve path for development of
    pharmacogenomic assays for use in clinical
    medicine
  • Public Health Mission facilitate availability
    of medical products that improve health and
    therapy outcomes

13
Biomarker - Definition
  • A characteristic that is objectively measured and
    evaluated as an indicator of
  • Normal biologic processes
  • Pathogenic processes
  • Pharmacologic responses to a therapeutic
    intervention
  • Biomarkers Definition Working Group, 2001

14
Biomarkers can be
  • Anatomical
  • Histological
  • Imaging
  • Genes
  • mRNA
  • Proteins
  • Metabolites
  • etc...
  • Essentially, some aspect of biology that has
    predictive power

15
Biomarkers can be used for
  • Diagnosis
  • Presence of disease or id at-risk patients
  • Staging of disease (severity)
  • Prognosis of disease (metastases)
  • Stratification of patients
  • Responders/non-responders
  • Monitoring/predicting Toxicity
  • Monitoring therapeutic effect or pharmacodynamic
    effect

16
Old dog new tricks
  • Use of biomarkers in delivering appropriate
    treatment not a new concept
  • HbA1c as a predictor/marker of diabetes
  • Oxidized LDL is marker for sub-clinical
    development of atherosclerosis
  • Viral load in HIV
  • Baseline viral load and changes in viral load
    with time predict HIV disease progression and
    death
  • These also serve as surrogate endpoints
  • Establish treatment effects on these markers
    market the drug

17
Biomarkers How To...
18
Central Dogma
19
Biomarker discovery Basic workflow
20
Looking To Establish Predictive Power Segregate
Patients
Non-response or toxicity
Response or no toxicity
21
Biomarker Discovery To Diagnostic Pathway
ASR analyte specific reagent (active ingredient
of an in-house (home brew) test, eg., antibody)
22
Drug development pathway
23
Drug-diagnostic co-development Roche model
24
Collaborative enterpriseand how!!!
  • Clinicians
  • Biorepository scientists
  • E.g., Pathologists
  • Genomic, proteomic, other omic scientists
  • Bioinformaticists
  • Clinical research scientists
  • Pharma, biotech
  • Diagnostic companies
  • Regulatory authorities
  • Rules still being written
  • Instrument manufacturers

25
Examples Of Diagnostic/Drug Combinations In Use
In The Clinic
26
Example 1 Herceptin
  • 25-30 of breast cancer pts over-express HER2neu
    protein
  • Herceptin is monoclonal antibody against HER2neu
    receptor
  • Herceptest measures HER2neu overexpression
  • Positive test predicts response to Herceptin
  • Negative test redirects therapy elsewhere

FDA approved
27
Example 2 UGT1A1 Testing - Irinotecan toxicity
Mutation in UGT1A1 gene leads to reduced UGT1A1
activity in 10 of population and increased
incidence of neutropenia
28
Regulatory consequence
  • Revised labeling
  • FDA approval of PGx test (Invader UGT1A1) to
    identify patients at risk of Camptosar toxicity
    (August 2005)

29
Example 3 CYP450 polymorphisms(not drug nor
indication specific)
  • Individual differences in the metabolism of drugs
    lead to variability in response and toxicity
    significant challenge in dosing
  • Four types of metabolizers (phenotypes)
  • Extensive metabolizers who can be administered
    drugs following "standard" dosing practices
  • Intermediate metabolizers metabolize drugs at a
    slower-than-normal rate
  • Poor metabolizers with a "deficiency" in drug
    metabolism, which could lead to life-threatening
    drug accumulation and severe adverse reactions
    (TOXICITY problem)
  • Ultrarapid metabolizers who break down drugs at
    faster rates than extensive metabolizers
    (EFFICACY problem)
  • Roche Amplichip
  • Analysis of variations in CYP2D6 and CYP2C19, two
    genes in the cytochrome P450 system (liver
    enzymes that metabolize drugs)
  • antidepressants, antipsychotics, and ADHD drugs

30
Example Of Biomarker In Use In Drug Development
31
PD example
  • PD
  • Confirm and predict biological activity
  • Dose finding
  • Dose regimen
  • Early in drug development

32
PD example
33
PD example
34
Challenges
  • How best to integrate biomarkers into drug
    development programs?
  • How to align timelines for biomarker discovery,
    development, and validation with DD timelines?
  • Are Rx and Dx both done in-house or Dx via
    collaboration/partnership?
  • Is there a business model for diagnostic company
    working with Pharma company?
  • Will diagnostic company risk investing when
    therapeutic product may not make it to market?
  • How to manage IP associated with biomarkers?
  • How to manage extra cost of biomarker program?
  • How to fund diagnostic companion studies?
  • Is it even possible for small biotechs?

35
Challenges
  • How to deal with perception of segmented market?
  • Nichebusters vs. blockbusters
  • Is there profit in segmentation?

36
Concluding remarks
  • Biomarkers drug optimized therapy
  • Way forward for developing and delivering
    personalized therapeutics
  • Payoff will be tremendous
  • Reduction in time and cost of drug development
  • Rescue of failed medications
  • Rx may only be effective in subpopulation
  • Real Economic Impact
  • Real Added Value
  • Reduce healthcare burden due to safer, more
    effective therapies
  • Still in infancy opportunities abound
  • Success ultimately depends on doing sound science

37
Opportunities...
38
The Beginning?...
39
(No Transcript)
40
Receiver Operating Characteristic (ROC) Curve
Ovarian cancer
True Positive Rate
False Positive Rate
Signal detection theory
41
And...
42
Need for a new approach
  • To meet the clear medical need for safer, more
    effective treatments
  • To revitalize a stagnant product pipeline in
    Pharma
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