Your SlideShare is downloading. ×
BIO International Convention
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

BIO International Convention

1,117

Published on

Boston Biotech Clinical Research (BBCR) Presentations at the BIO International Convention.

Boston Biotech Clinical Research (BBCR) Presentations at the BIO International Convention.

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
1,117
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
24
Comments
0
Likes
0
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide
  • A qualified biomarker must link a biomarker with biology and clinical end points.Wagner, Webster, 2007, Nature
  •  
  • SMs are therapies that are matched to patient subpopulations with the aid of clinical biomarkers that predict with some reliability patient differential response – be it in efficacy or safety. Our notion of clinical biomarkers is not limited to genotyping – also includes imaging, clinical observation, or even patient self-report (urge vs. stress incontinence, self-identified black person).
  • Transcript

    • 1. Rare Diseases Experience as a Model to Critically Affect Innovation in Biomarker Strategy and Precision Medicine
      Moderator
      Candida Fratazzi MD
      Speakers
      Claudio Carini, PhD, FRCPath
      GioraFeuerstein MD, MSc. F.A.H.A.
      Mark TrusheimPhD
      Colin Williams PhD
    • 2. Precision Medicine The Time is now
      Claudio Carini, MD, PhD, FRCPathPfizer Inc.
    • 3. Drug Development is a lengthy, high- attrition process
      More Spending – Less Apparent Productivity and Innovation?
    • 4.
    • 5. What is missing?
      Biomarkers
    • 6. Biomarker Definition
      A molecule that indicates an alteration of
      the physiological state of an individual in
      relationship to health or disease state,
      drug treatment, toxins etc
      Biomarkers are by virtue of their short
      term availability predictors of long term
      events
    • 7. Why Biomarkers are Important in Medicine?
      Staging or Severityof Disease
      Patient/Subject Selection
      Safety/Prediction of AE
      Prognosis of TX intervention
      Patient/Subject Selection
      Discriminate Health from Disease Stage
      Monitoring ClinicalResponse to Therapy
    • 8. The Elephant in the Room
      Putting it all together
      Understanding
      A multi
      -

      omics

      Qualified
      Biology
      Strategy
      Biomarkers
      Genechip
      Target
      n
      It

      s
      It

      s
      UC
      UC
      Efficacy
      n
      RT
      -
      PCR
      PK/PD
      n
      It

      s
      It

      s
      IHC
      RA
      RA
      Safety/
      /Tox
      It

      s
      It

      s
      n
      It

      s
      It

      s
      SLE
      SLE
      AS
      AS
      Flow
      Mechanism
      n
      cytometry
      Pharmacology
      n
      Molecular
      imaging
      Disease progression
      n
      It

      s
      It

      s
      It

      s
      It

      s
      Classification
      Protein
      n
      JIA
      JIA
      analysis
      CD
      CD
      Precision Medicine
      n
      Mass
      Understanding
      Spectrometry
      Drug PK/PD
      Proteomics
      profiling
    • 9. Biomarkers: Potential Guides to Effectiveness and Safety
      The -omics
      Clinical
      New study paradigms*
      Experimental human biology
      Imaging
      An Integrated Approach
      Proteomics
      Pharmacogenetics
      Metabonomics
    • 10. Building Bridges Between Research and Clinical Development
      Exchange of Information
      Biomarkers - PK - PG - Experimental CP
    • 11. Preclinical
      Animal
      Testing
      Biomarkers
      Compounds
      Biomarkers Connect Discovery and Clinical Research
      Clinical
      Medicine
      Clinical Research
      Phases
      Discovery & Preclinical Phases
      • Better
      Qualified
      Compounds
      • Patient
      Enrichment
      Strategies
      Omics,
      Screening
      Based on
      Cellular ,
      Physiologic
      Models,
      Driven by
      Target
      Population
      Analysis
      Diagnostic
      tests
      Patient samples
      Missing? Impact on clinical medicine
      Bench to Bedside
    • 12. What Patients Expect Today and More So in The Future?
      BIOMARKERS
      Drugs that work
      Drugs that are safe
      Doses that are right
      for me
      12
    • 13. A fit-for-Purpose Biomarker
      Qualified Biomarker
      Clinical endpoints
      Biology
      A qualified biomarker must link a biomarker with biology and clinical end-points
      13
    • 14. Why Do we Need Biomarkers?
      To treat diseases more effectively: Disease Biomarkers
      Disease BM will enable the:
      1. Differentiation/stratification of otherwise similar disease states
      2. Better identifies which disease states are more responsible to the study drug
      3. Evaluation of disease susceptibility
      4. Treat high risk pts before the onset of symptoms
      5. Tracking disease progression
      To predict clinical efficacy: Patient Selection BM
      Patient BM will provide:
      1. Explain why Pts are responding differently to different drugs
      2. Basis for differentiating “high responders” from “low responders”
      3. To target “ high responders” who stand better chances of success
    • 15. What is Personalized Medicine?
      15
    • 16. Major Drugs Ineffective for Many…
      Beneficial to Some
      16
    • 17. Harmful to Others
      17
    • 18.
      • Why do individuals respond differently to the same drug?
      • 19. Why do individuals require different doses?
      • 20. Why do some experience AE after taking the drug?
      • 21. Genetic variation of the drug target gene
      • 22. Genetic variation in the biochemical pathways affected by the drug
      • 23. Genetic and genomic factors related to the etiology of the disorder
      • 24. Other factors (age, sex, diet, environment ...)
      Pharmacogeneticslooks at inherited factors that may influence these differences.
    • 25. Responders
      Non-Responders
      Adverse Drug
      Events
      Current Treatments Take Little Account of Human Variation
    • 26. Personalized Medicine Foresees Greater Use of Diagnostics in Therapeutic Decision Making
      Responders
      Non-Responders
      Adverse Drug Events
      Choose the RIGHT DRUGat the RIGHT DOSEfor the RIGHT PERSON
      A
      B
      Dx
      Test
      C
    • 27. 21
      Why is Personalized Medicine Important?
      • To avoid adverse events:
      • 28. 2.2 million people are hospitalized and 100,000 deaths occur each year due to adverse effects of prescription drugs
      • 29. To better treat disease:
      • 30. Development of predictive markers would allow for earlier treatment
      • 31. To identify novel drug targets:
      • 32. Current drugs are based on less than 500 targets.
    • Why we Need Personalized Medicine in Research and Drug Development? Safer and more Effective Drugs
      22
    • 33. Six Blinded Scientists Examining an Elephant
      Translational Medicine: the lacking piece of the puzzle
      23
    • 34. 24
      Thank You
      Questions?
    • 35. Gene discovery and genomic prediction of Atherosclerosis disease states and susceptibility
    • 36. 26
    • 37. Biomarkers In Drug Discovery and Development: Orphan Diseases and Orphan Therapeutics
      Giora Feuerstein MD
      FARMACON LLC
      Washington DC
      June 28, 2011
    • 38. …and its getting worse
      Translational Medicine in Pharmaceutical Industry:
      from “nice to have” to “do or die”
    • 39. Translational Medicine in Pharmaceutical Industry: from “nice to have” to “do or die”
      • Aims at reducing the Attrition Rate – Increase Successful Deliveries by Rigorous Science
      • 40. From “Bench to Bed and Bed to Bench” (BB2)
      • 41. Identification, validation and implementation of Biomarkersin lieu of clinical end-points
      • 42. Harmonize and Rationalize Pre-clinical Research, Safety/ADME and Early Clinical Development
    • Target Validation
      • Biomarkers that validate the importance of the target in human disease
      • 43. Biomarkers that define the direct interaction of the compound with its discrete target
      • 44. Biomarkers that define consequencesof compound interaction with the target relative to PK
      • 45. Biomarkers that correlatewith disease
      (initiation, progression, regression, remission, relapse or modification)
      • Biomarkers that define likelihood of patients to respond (or not) to the compound
      Target/Compound
      Interaction
      Pharmacodynamic Activity (PK/PD)
      Disease Biomarker
      & Disease Modification
      Patient selection and
      Stratification
      Biomarkers: A Utilitarian Classification
    • 46. PK/PD Biomarkers in Orphan Disease
      show the way
      • Case Study 1: Muckle–Wells syndrome
      • 47. Rare genetic disorder provides biomarkers that ‘pave the way’ for target validation
      • 48. The case of anti-IL-1b development for RA
      • 49. PK/PD- Biomarkers
      • 50. Bayesian methodology
      • 51. Target validation in M-W syndrome
      • 52. Registration for Rheumatoid arthritis
    •                      
      Website for this image
      health.com
      • Full-size image - Same sizex larger
      This image may be subject to copyright.
      Target Validation: When Biology Trumps Chemistry
      • Case Study 2: Diabetes
      • 53. Diabetes drugs are available but unmet medical need high
      • 54. Insulin injection is the ultimate treatment in chronic diabetes
      • 55. Insulin sensitivity drugs (TZDs) of limited efficacy and carry safety issues
      • 56. 11beta-HSD-1 inhibitors have the potential to improve insulin sensitivity
      • 57. Neuro-endocrine liabilities observed with all HSD-1 inhibitors
    • ~
      -
      Hypothalamus
      Tissue
      Plasma
      ~
      Pituitary
      [Drug]
      [Drug]
      ~
      Adrenal
      [HSD-1]act
      ~
      [cortisol]n
      [cortisol]
      ~
      Cortisol
      ~
      IR
      Translational Medicine Case Study:When Biology “trumps” the compound, The 11bHSD1 Inhibitor saga
      PK
      PD
      Plasma AdiposeTissues
      Liver
    • 58. Visceral Fat
      SubQ Fat
      D4-Cortisol/D3-Cortisol
      Translational Medicine Issue: Can 11beta-HSD-1 inhibitors reduce peripheral tissue local cortisol and reduce tissue IR w/o activating the HPA
      The “Killer Study”
      HSD1 inhibitors can reduce IR w/o change in plasma cortisol
      • Translational Medicine study (Univ Edinburgh, B walker)
      • 59. Tissue cortisol production is significant
      • 60. In non-diabetics:
      • 61. Liver: Major source (~90%) of splanchniccortisol release into the circulation
      • 62. SubQ fat: Account for ~10% of cortisol release
      • 63. Visceral fat: does not appear to contribute to net cortisol output
    • Rare Diseases as Stratified Medicine Economic Models
      Mark Trusheim
      Visiting Scientist, MIT
      trusheim@mit.edu
      President, Co-Bio Consulting
    • 64. What We Mean by Stratified Medicine
      Matching therapies to patient sub-populations with clinical biomarkers
      Objective: Do more good (efficacy) or avoid ill (adverse reactions)
      Clinical Biomarkers -- beyond genotyping
      Molecular (gene expression, proteomic, biochemical)
      Imaging
      Clinical observation
      Patient self-reporting
      Clinical Biomarkers: Any information which shows a reliable, predictive correlation to differential patient responses
    • 65. The Patient Therapeutic Continuum: Stratified Medicines are not “Personalized”
      Nature Reviews Drug Discovery: April 2007
    • 66. Orphan Drugs Demonstrate Economic Potential
      Stratified
      Medicines
      Increasingly
      Approaching
      Orphan sizes
      (thousands of patients, average yearly price in $thousands)
    • 67. Comparing Orphan and Stratified Medicines
      Orphan
      Stratified
      Known mechanism & marker
      Small population
      Strong patient and provider networks
      Modest payer impact
      Known mechanism & marker
      May be small or large population
      Perhaps unrecognized strata and no networks
      Modest payer impact for one, but large if entire field (like oncology) stratifies
    • 68. When are Orphan Drugs Good Models for Stratified Economics?
      Stratification creates a small population
      Strong patient advocacy exists
      Clinical trial and regulatory models for small populationsBUT
      Market exclusivity and lower competition may not apply
      Payer concern that a large stratified condition is not ‘rare’10% of all Alzheimer’s patients is a lot of patients, and cost.
    • 69. Orphans Modeling Stratified Medicines: Expect Price and Profitability Premiums?
      Supporting Arguments
      Stratified medicines will perform substantially better for their target populations than alternative treatments (assumption)
      Recently introduced therapies have commanded price premiums: biologics, stratified medicines, adjuvant therapies
      Payers have formal or informal policies to “pay for performance”
      Counter Arguments
      Limited payer ability to afford increased costs
      Diagnostics will siphon profitability
      Multiple entrants in new “stratified” drug classes will lower prices
      Analytical Task
      Develop a Performance Differential/Price Premium curve by examining price premiums obtained in the market today by “classic” therapies LIKE ORPHAN DRUGS
      Price
      Premium
      Performance Differential
    • 70. Orphans Modeling Stratified Medicines: Development Processes
      Opportunities
      Strong patient and provider networks to enable clinical trials
      Novel clinical trial designs to accommodate few patients available can speed development and lower costs
      Potentially more rapid entry into man based on strong mechanism understanding and high need
      Challenges
      Need to develop and validate biomarker lower since embedded in diagnosis
      Regulatory skepticism that stratification is tactic to avoid ‘gold standard’ clinical trials
      Clinical
      Trial
      Size
      Biomarker Driven Performance Differential
      Potential: Lower Cost and Higher Success
      Probability of
      Regulatory
      Approval
    • 71. Orphans Modeling Stratified Medicines: Public Policy and Incentives?
      Federal Research and Development Support
      NIH grants for research, and even development (Bench to Bedside Awards)
      Expedited regulatory pathways
      Federal Financial Incentives
      Market exclusivity grants to INDICATION
      High value reimbursement
      R&D support above
      Registries to identify, monitor and involve patients and samples
      Role for Disease Foundations
      Awareness, network creation and dissemination
      Direct research support
      Expert science panels validates early, small company science
    • 72. Orphan Learnings in Stratified Medicine Examples
      Tysabri re-introduction for Multiple Sclerosis enabled by patient advocacy, patient registries and now, a biomarker
      Rare oncology sub-populations receiving Orphan level reimbursement
      Provenge autologous stem cell therapy: $93,000 for 3 course regimen
      Erbitux and Vectibis: Up to $80,000 for 18 week regimen
      Revlimid: Up to $10,000 per month for multiple myeloma
      Gleevec: Up to $54,000 per year for CML
      High market shares (>80%) are possible
    • 73. Conclusions
      Rare diseases and orphan drugs have blazed the trail for stratified medicine economic models
      From clinical development through regulatory to reimbursement and public policy, the lessons of rare diseases are being translated to stratified medicine
      However, the aggregate size of some stratified medicine markets may strain payers and induce skepticism by regulators that special treatment is appropriate
      An ‘integrated stakeholder chain” from research foundations to companies, regulators, payers and advocates is critical
    • 74. Information in Biomarker discovery
      How effective use of information resources can support innovation
      Dr. Colin Williams
      Thomson Reuters
    • 75.
    • 76. Why information?
      “In 1990, all the necessary data for the concept of feedback control of p53 function were available, although this function was recognized only recently.”
      Conceptual biology: Unearthing the gems, Nature 416, 373; 2001 Blagosklonny, M and Pardee, A
      • Knowledge differentiates organizations and delivers competitive advantage
      • 77. Decreases risk
      • 78. Enhances project level decision making
      • 79. Focuses resource allocation
      • 80. Empowers scientists to drive innovation
      • 81. Creates efficiencies by preventing wasted experimentation
    • The information challenge
      • Information overload
      • 82. Wide range of sources - Literature, Patents, Conferences and medical meetings, Press releases, Clinical trial reports
      • 83. Google 425k hits – Her2 and biomarker
      • 84. Highly variable terminology in Biology
      • 85. Lack of standard or Universal criteria on Biomarker development
      • 86. Variation in protocols, statistical analysis
      • 87. So many parameters not enough subjects
      • 88. It is estimated scientists spend ~35% time dealing with information
    • Mesothelioma
      • Mesothelioma is a form of cancer that affects the Mesothelium and can affect:
      • 89. the inner surface of the chest wall where it is known as the pleura
      • 90. the abdomen, where it is known as the peritoneum.
      • 91. Organs within those cavities eg lung, heart
      • 92. New diagnoses in US ~2,500 annually
    • 93.
      • Mesothelioma drug pipeline – 52
      • 94. Compared to 1104 drugs under development for Obesity
      • 95. Source: Thomson Reuters Integrity
      • Reported Biomarkers of Mesothelioma - 430
      • 96. 3,400 hits in Google search
      • 97. PubMed 1143 results
    • 98. Proof of efficacy with mesothelioma markers
      • Ranpirnase (activation of Caspase)
      • 99. Cisplatin
      • 100. Gemcitabine hydrochloride
      • 101. Pemetrexed disodium
      • 102. Troglitazone
      • 103. PPAT agonist inhibitors
      • 104. LenvatinibMesylate
      • 105. BEZ-235 (Novartis Phase I/II breast cancer, mTor inhibitor)
      • 106. Celecoxib
      • 107. AZD-1152-HQPA
      • 108. Do the targets associated to these drugs have a role in other disease?
    • 109.
    • 110. The Core cell cycle, Source MetaCore
    • 111. Gene Expression and Mesothelioma
      • Developing insights from experimental information is also a critical
      • 112. Analyzing gene expression data from mesothelioma can give a glance in to the mechanism of the disease
      • 113. Analyse publically available dataset from Geo (GDS2604)
      • 114. Explore expression profile in responders to previously identified drugs and identify differentially expressed genes
    • 115.
    • 116. Summary
      • Knowledge enhances decision making
      • 117. Improve efficiency in project design through researching the area
      • 118. Biomarker information is:
      • 119. published in a non standard way
      • 120. is fragmented way
      • 121. is expanding rapidly
      • 122. Disease segmentation based on molecular characteristics is going to create many new orphan diseases.
      • 123. Will the ophan disease ‘model’ become the life blood of pharmaceutical research
      • 124. There are many biomarkers available which can prove efficacy of a compound.
      • 125. Using Mesothlioma (or other orphan diseases) as a model can prove efficacy against a target quickly.
      • 126. Understanding the biological function of that target can open new indications for a therapeutic

    ×