Medicine in the 21st Century: Biomarkers and Personalized Therapeutics

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Medicine in the 21st CenturyBiomarkers and
Personalized Therapeutics
Terrence L. Sills PhD Vice-president
OCBN TBI April 22 2008
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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

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

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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
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Old Paradigm - Problem
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Yikes!!!!!!
And gt2 million ADRs reported annually in US
including 100K deaths
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Need for a new approach

• To meet the clear medical need for safer more
  effective treatments

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So...the way forward...
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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

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Regulatory take on the matter
FELIIX FRUEH PHD Associate Director for
Genomics Office of Clinical Pharmacology and
Biopharmaceutics CDER FDA
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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

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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

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Biomarkers can be

• Anatomical
• Histological
• Imaging
• Genes
• mRNA
• Proteins
• Metabolites
• etc...
• Essentially some aspect of biology that has
  predictive power

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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

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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

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Biomarkers How To...
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Central Dogma
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Biomarker discovery Basic workflow
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Looking To Establish Predictive Power Segregate
Patients
Non-response or toxicity
Response or no toxicity
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Biomarker Discovery To Diagnostic Pathway
ASR analyte specific reagent (active ingredient
of an in-house (home brew) test eg. antibody)
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Drug development pathway
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Drug-diagnostic co-development Roche model
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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

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Examples Of Diagnostic/Drug Combinations In Use
In The Clinic
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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
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Example 2 UGT1A1 Testing - Irinotecan toxicity
Mutation in UGT1A1 gene leads to reduced UGT1A1
activity in 10 of population and increased
incidence of neutropenia
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Regulatory consequence

• Revised labeling
• FDA approval of PGx test (Invader UGT1A1) to
  identify patients at risk of Camptosar toxicity
  (August 2005)

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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

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Example Of Biomarker In Use In Drug Development
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PD example

• PD
• Confirm and predict biological activity
• Dose finding
• Dose regimen
• Early in drug development

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PD example
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PD example
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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

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Challenges

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

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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

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Opportunities...
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The Beginning...
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Receiver Operating Characteristic (ROC) Curve
Ovarian cancer
True Positive Rate
False Positive Rate
Signal detection theory
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And...
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Need for a new approach

• To meet the clear medical need for safer more
  effective treatments
• To revitalize a stagnant product pipeline in
  Pharma