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The Use of Biomarkers and Target Validation
                  Humanising Drug Discovery




                        Dr Har...
Dr H Parmar
Discovery Medicine, Astrazeneca
R & D Productivity
• What’s Increasing?
• What’s Increasing?
    ! R&D Cycle times at all
    ! R&D Cycle times at all
   ...
Main Reasons for Termination of Development
  for “Opportunity Cost” is LACK OF EFFICACY!

 Clinical Safety               ...
Dr H Parmar
Discovery Medicine, Astrazeneca
U.S. Drug Industry R&D Expenditures and
       Drug Approvals, 1963-2000
                     60                          ...
Readouts from the Human Genome Project




Dr H Parmar
Discovery Medicine, Astrazeneca
What are the Post Genomic Challenges ?
High-throughput technologies are being applied and
needed to identify and validate ...
How can we use HT technologies to address productivity
                 around Pharma R & D?
• Addressing traditional bott...
Human, Mouse & Primate Genomic Chart




!In these comparative genomic charts, it is easy to see why meaningful
   compari...
The comparison between Targets in the years 2001 and 2005.
    Shows the influence of Genomics on drug discovery.
 Dr H Pa...
Drug Targets in the Genome
       Assumption: wider phenotypic screening will identify
       a greater number of therapeu...
Why do we need to make better decisions
             faster in R&D?




                                  !Numerous target...
Human TV




Dr H Parmar
Discovery Medicine, Astrazeneca
Target Validation/PoP/PoC

 It would not be possible to overstate the value
     of in-vivo human validation. Most of what...
Some terminology around
                     biomarkers
    Pharmacology                   Pharmacology exists in “Proof o...
Benefit-Risk of Biomarkers in R & D
Benefits                                         Risks

1.    For NMEs with a novel me...
Dr H Parmar
Discovery Medicine, Astrazeneca
PoM: Chemokine Target
                  ex vivo CD11b upregulation
                Median Log DR30 (range) following oral ...
Discovery Medicine
                                                                               Utilize and Integrate Hu...
Pharmacodynamic Biomarkers
PRESENT                           Pharmacologic Effect
                                  Physio...
The Cellomics Concept




         DNA                  Messenger
        Genes                   RNA          Protein   W...
High Content Screening & Biomarkers




    “High Content Screening integrates fluorescence-based assays and
    novel ima...
Kinase Cascades




Dr H Parmar
Discovery Medicine, Astrazeneca
Pathway Analysis

               pJun                     pP38             κ
                                             ...
Disease Process Modelling




Dr H Parmar
Discovery Medicine, Astrazeneca
Focus on Biopathways
                                  What We Have:
•Maps for a variety of individual biochemical, signal...
Simulation & Prediction - rapidly emerging
                 technologies
                                     Discovery   ...
Modelling of Human Disease
                                  Disease in Whole Human Being
 Cell



      Nucleus


       ...
Human Tissue in Target Validation
                            Cross-functional Inputs
• Tissue acquisition - human tissue ...
Tools for Human Target Validation
       Also Potential Fast Track Therapeutics
              1.Monoclonal antibodies & Na...
Target Validation Experiments Already Established in Man

   1. HIV (Ribozymes, Antibodies, rHu P)
   2. Cancer (A/B’s, An...
No Targets                                              Attrition rate (%):
100
       initiated                          ...
Current cumulative success rates to market by product type



                    100%

                    90%
          ...
Number of Clinical Studies for Approved
   Biopharmaceuticals and NMEs
                    40
                            ...
Number of Subjects for Approved
     Biopharmaceuticals and NMEs
           4800                                          ...
Recombinant Proteins




Dr H Parmar
Discovery Medicine, Astrazeneca
Vascular Endothelial Growth Factor - 2 (VEGF-2)




Dr H Parmar
Discovery Medicine, Astrazeneca
Cooper, H. L., Healy, E., Theaker, J. M. & Friedmann, P. S.
Treatment of resistant pemphigus vulgaris with an anti-CD20 mo...
Human Skin
    As a Tool to Study Inflammation




Dr H Parmar
Discovery Medicine, Astrazeneca
Urate Crystal Skin Inflammation
• Need safe and malleable in      Biopsies                Clinical
    vivo inflammation m...
Urate crystals in skin chambers
•            Chamber applied to de-roofed vacuum blister
•            GMP crystals applied...
Intradermal urate crystals
  •    Graded doses 0- 2.5mg injected
  •    Quantitate inflammation with laser doppler
  •    ...
Psoriasis for assessing therapeutic effects
   • Cyclosporin A , anti-CD2, CTLA4-Ig and anti-TNFs are
     all clinically ...
Early concept testing in man-P2Y2
•     Experimental data suggested P2Y2 a good target for
      Psoriasis
•     Effect on...
Development of Concept testing for Inflammation
             Projects in Humans
                   Inflammation models in ...
Dermal Microdialysis & Microdosing




                        •Single Dose and/or
           •Mutiple Dose including Dose...
Asthma & COPD




Dr H Parmar
Discovery Medicine, Astrazeneca
Whole Blood PoM Markers
• The robustness of the CD11b and shape change responses on eosinophils to eotaxin-
  2 was assess...
Biomarkers for iNOS inhibition: exhaled NO
                                                           (SA Kharitonov, 2001...
COPD PoP: Biomarker Discovery
                  In Vivo                                  In Vitro

                       ...
Novel Markers-Proteomic analysis of plasma
                                                    Stable and Acute Exacerbati...
Core Problem:
    The migration of raw data into useable knowledge
   Current State of
  BioPharma Industry               ...
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Transcript of "Biomarkers & Tv Humanising Drug Discovery"

  1. 1. The Use of Biomarkers and Target Validation Humanising Drug Discovery Dr Harsukh Parmar Executive Director, Global Discovery Medicine, Respiratory & Inflammation Therapeutic Area harsukh.parmar@astrazeneca.com Dr H Parmar Discovery Medicine, Astrazeneca
  2. 2. Dr H Parmar Discovery Medicine, Astrazeneca
  3. 3. R & D Productivity • What’s Increasing? • What’s Increasing? ! R&D Cycle times at all ! R&D Cycle times at all • What’s Decreasing? phases phases ! ! Success rates at all phases Success rates at all phases ! Regulatory hurdles ! Regulatory hurdles ! ! Product Exclusivity Product Exclusivity ! Approval times ! Approval times ! Number of clinical ! Number of clinical trials/NDA trials/NDA ! Clinical trial size (# of ! Clinical trial size (# of patients) patients) ! R&D inflation (> 12 %) ! R&D inflation (> 12 %) ! Drug development costs ! Drug development costs ! R&D spending ! R&D spending The Result: ! Investors’ expectation for ! Investors’ expectation for – R & D productivity is down – R & D productivity is down growth growth across the industry! across the industry! ! Product liability ! Product liability ! Industry risk ! Industry risk Dr H Parmar Discovery Medicine, Astrazeneca
  4. 4. Main Reasons for Termination of Development for “Opportunity Cost” is LACK OF EFFICACY! Clinical Safety Toxicology 20.2% 19.4% Clinical Pharmacokinetics/ Bioavailability 3.1% Other 6.2% Preclinical efficacy 3.1% Preclinical Pharmacokinetcs/ Various Bioavailability 10% 1.6% Formulation Portfolio 0.8% Considerations Patent or Commercial 21.7% Clinical Efficacy Legal 0.8% 22.5% Regulatory 0.8% Dr H Parmar Discovery Medicine, Astrazeneca
  5. 5. Dr H Parmar Discovery Medicine, Astrazeneca
  6. 6. U.S. Drug Industry R&D Expenditures and Drug Approvals, 1963-2000 60 27 R&D Expenditures R&D Expenditures (Billions of 2000$) NCE Approvals 40 18 NCE Approvals 20 9 0 0 63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97 99 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 R&D expenditures adjusted for inflation Dr H Parmar Source: Tufts CSDD Approved NCE Database, PhRMA Discovery Medicine, Astrazeneca
  7. 7. Readouts from the Human Genome Project Dr H Parmar Discovery Medicine, Astrazeneca
  8. 8. What are the Post Genomic Challenges ? High-throughput technologies are being applied and needed to identify and validate molecular targets from the human genome. We have and need better: •Target Discovery & Disease Linkage •Biomarkers, Surrogates & Human Target Validation •Diagnostics-Pharmacogenetics-Personalised Medicine But we also need more Powerful •Bioinformatics-Computational Biology •Multiple Databases to Interrogate & Knowledge Mx Dr H Parmar Discovery Medicine, Astrazeneca
  9. 9. How can we use HT technologies to address productivity around Pharma R & D? • Addressing traditional bottlenecks in drug discovery » Making new chemical compounds » Screening the right mechanism, polymorphism etc » Identifying better targets, disease linkage & biomarkers • Changing the paradigm for drug discovery » High Content Biology allows Richer Human Integration- ”Humanizing Drug Discovery” » Greater throughput and more efficiency » More parallel, rather than linear drug discovery/development » Greater emphasis on molecular-mechanism-based targets (“treat the cause and not just the symptom”) » Reliance on Bioinformatics & Informatics as a partner Dr H Parmar Discovery Medicine, Astrazeneca
  10. 10. Human, Mouse & Primate Genomic Chart !In these comparative genomic charts, it is easy to see why meaningful comparisons between humans and other species is difficult. !The pink areas represent regions of high conservation !The blue areas represent the positions of protein-coding regions and !The purple areas represent the non-protein coding parts of a gene. Dr H Parmar Discovery Medicine, Astrazeneca
  11. 11. The comparison between Targets in the years 2001 and 2005. Shows the influence of Genomics on drug discovery. Dr H Parmar Discovery Medicine, Astrazeneca
  12. 12. Drug Targets in the Genome Assumption: wider phenotypic screening will identify a greater number of therapeutically-relevant genes? Therapeutically Predicted + Human genome relevant genes assumed ~30,000 ~6000 + 20% druggable overlap targets ~3000 +~3000 = ~6000 Small Mol 6000 Targets for Drug targets Large Molecule Therapeutics ~1200 Dr H Parmar Discovery Medicine, Astrazeneca
  13. 13. Why do we need to make better decisions faster in R&D? !Numerous targets !Limited target validation !Cost of development expensive !Regulatory Hurdles Dr H Parmar !Increasing Discovery Medicine, Astrazeneca
  14. 14. Human TV Dr H Parmar Discovery Medicine, Astrazeneca
  15. 15. Target Validation/PoP/PoC It would not be possible to overstate the value of in-vivo human validation. Most of what passes for target validation today is largely conjectural in relation to the disease in question. Diabetes Professor & Researcher Harvard Medical School A Revolution in R & D-The Impact of Genetics The Boston Consulting Group Dr H Parmar Discovery Medicine, Astrazeneca
  16. 16. Some terminology around biomarkers Pharmacology Pharmacology exists in “Proof of Mechanism” e.g. receptor, enzyme man, dose-exposure- (PoM) inhibition effect relationship on the target mechanism Disease relevant Mechanism related to “Proof of Principle” e.g. CRP, cartilage disease process and (PoP) breakdown products, alters some key disease tumour blood flow related parameters Clinical Endpoint Mechanism will treat “Proof of Concept” e.g. ACR20,50,70, the disease and alter (PoC) FEV1, symptom clinically recognised scores, tumour size, and relevant endpoints time to progression Dr H Parmar Discovery Medicine, Astrazeneca
  17. 17. Benefit-Risk of Biomarkers in R & D Benefits Risks 1. For NMEs with a novel mechanism of 1. Biomarkers that are nonspecific and action, biomarkers are key to do not correlate with clinical outcome understanding PoM and establishing may lead to incorrect conclusions. PoP/PoC. 2. Biomarkers associated with only a 2. Biomarkers should help contain the portion of the clinical outcome, may cost of drug development by allowing not identify all of the relevant effects of early termination or rapid progression the therapy, including adverse effects. to Launch. 3. Biomarker analysis can be expensive 3. Biomarkers may help pre-select and time-consuming. patient populations that are most likely 4. Biomarker-based decisions could to benefit. become biased unless a priori criteria 4. Biomarkers that predict the course of are set up for decision-making in disease may serve as a useful tool for addition to biomarker data. clinicians, health care systems. 5. Patient pre-selection using biomarkers 5. Diagnostic kits could be developed may reduce the potential market size. where appropriate patient segmentation may reduce the size of trials required Dr H Parmar Discovery Medicine, Astrazeneca
  18. 18. Dr H Parmar Discovery Medicine, Astrazeneca
  19. 19. PoM: Chemokine Target ex vivo CD11b upregulation Median Log DR30 (range) following oral administration of Novel NME 40 35 30 1 h post dose 25 Placebo 100 mg 20 300 mg 4/5 h post dose 400 mg 15 1000 mg 10 42/50 h post dose 5 0 -1 -0.5 0 0.5 1 1.5 2 Log DR30 •Similar level of inhibition of CD11b for all doses •Evidence of complete reversibility •PK/PD mismatch. Getting a better PD profile than predicted by PK Dr H Parmar Discovery Medicine, Astrazeneca
  20. 20. Discovery Medicine Utilize and Integrate Human Pathophysiology and Disease Models Median Log DR30 (range) following oral administration AZD8309 0 4 5 3 0 3 1 h post dose 5 2 Never smoked Placebo 100 or not 100 mg 0 2 susceptible 300 mg 4/5 h post dose to smoke 400 mg F E V (% o f v a lu e a t a g e 2 5 ) 5 1 75 1000 mg 0 1 Smoked regularly and 50 susceptible to Stopped 42/50 h post dose 5 its effects at 45 0 Disability -1 -0.5 0 0.5 1 1.5 2 1 25 Stopped at 65 Log DR30 Death † † 0 25 50 75 AGE (YEARS) Deliverables Platforms •Validated targets •Genetics Clinical Data •Pathophysiological •Genomics •Proteomics Experimental data understanding •Biological Mechanism •Metabonomics Bioinformatics and Informatics •Disease stratification •Imaging •Biomarkers •Epidemiology •PoP/PoC Methods •Physiology Dr H Parmar 09/08/2005 • Patient segmentation 15 Discovery Medicine, Astrazeneca
  21. 21. Pharmacodynamic Biomarkers PRESENT Pharmacologic Effect Physiologic Effect Biochemical Assays Enzymatic Assays In Vivo Challenge Tests Imaging From….. Single Variable To….. Multiple Variables FUTURE Genomics INCREASING Proteomics FUTURE FOCUS Metabonomics FOR BIOMARKER In Vivo Imaging DISCOVERY Dr H Parmar High Content Biology Discovery Medicine, Astrazeneca
  22. 22. The Cellomics Concept DNA Messenger Genes RNA Protein Whole Cell Dr H Parmar Discovery Medicine, Astrazeneca Image Processing
  23. 23. High Content Screening & Biomarkers “High Content Screening integrates fluorescence-based assays and novel image processing algorithms for automated analysis of sub- cellular events” Cellomics TM Dr H Parmar Discovery Medicine, Astrazeneca
  24. 24. Kinase Cascades Dr H Parmar Discovery Medicine, Astrazeneca
  25. 25. Pathway Analysis pJun pP38 κ NFκB pMAPK (Cellomics) (Cellomics) (Cellomics) (Cellomics) Compound HeLa/TNF HeLa/TNF HeLa/TNF HeLa/TNF V A A A A W A A N/A N/A X A N/A N/A N/A Y N/A N/A N/A A Z N/A N/A A N/A Dr H Parmar Discovery Medicine, Astrazeneca
  26. 26. Disease Process Modelling Dr H Parmar Discovery Medicine, Astrazeneca
  27. 27. Focus on Biopathways What We Have: •Maps for a variety of individual biochemical, signaling and gene regulatory pathways •A few examples of disease process models predicting likely targets and biomarkers What We Don’t Have: •Good understanding of relationships between individual targets, biomarkers and disease processes •General framework linking genomics, proteomics, and disease process evolution from biomarker changes to clinical outcomes Dr H Parmar Discovery Medicine, Astrazeneca
  28. 28. Simulation & Prediction - rapidly emerging technologies Discovery PreClinical Clinical Outcomes Molecular Structure Activity Subcellular Not appropriate Cellular Not currently addressed Tissues/Organs Under Development Whole Body (animals/humans) Products Available Clinical Trials Clinical Programs Drug Portfolios Medical Care Systems Dr H Parmar SOURCE: Price Waterhouse Coopers Discovery Medicine, Astrazeneca
  29. 29. Modelling of Human Disease Disease in Whole Human Being Cell Nucleus Chromosome DNA From molecules, mRNA pathways, cells, organs amino acids to integrated physiology Protein in health & disease Dr H Parmar Discovery Medicine, Astrazeneca
  30. 30. Human Tissue in Target Validation Cross-functional Inputs • Tissue acquisition - human tissue sources • Tissue banking - repository, logging and distribution • Histopathology - sectioning, staining and morphometry; diagnostic confirmation • Immunocytochemistry- bio markers (tagged antibodies, oligos enzyme markers etc) • Bio-analysis - mediators, enzymes, cytokines etc • Molecular biology - gene chip technology (Affymetrix, Taqman etc) • Bio-informatics - interrogation of integrated data bases Dr H Parmar Discovery Medicine, Astrazeneca
  31. 31. Tools for Human Target Validation Also Potential Fast Track Therapeutics 1.Monoclonal antibodies & Nanobodies 2.Antisense & siRNA 3.Viral Vectors 4.Gene therapy & Nucline Gene Silencing 5.Ribozymes & Aptamers 6.Recombinant proteins 7.Zinc Finger Proteins 8.Currently available drugs with multiple mechanisms 9.Lead Compounds in LO phase etc Dr H Parmar Discovery Medicine, Astrazeneca
  32. 32. Target Validation Experiments Already Established in Man 1. HIV (Ribozymes, Antibodies, rHu P) 2. Cancer (A/B’s, Antisense, GeneRx etc) 3. IHD & GI (AntiTNF,GeneRx, Viral Vectors) 4. RA (A/B’s, Cytokines etc) 5. Asthma (Anti IgE A/B, Anti IL-5) 6. Transplantation & Asthma (Zenapax) 7. Multiple Sclerosis (Anti-VLA4, Tysabri) Dr H Parmar Discovery Medicine, Astrazeneca
  33. 33. No Targets Attrition rate (%): 100 initiated •chemical •biological annually •selection of target •efficacy Target •safety & interactions •failure to meet target profile Hit Antibody 40 (2-3 years) Target & concept LC Small molecule validation (6-8 years) 20 Lead preCD CD IND discovery Lead 10 optimization 50% 50% 40% 15% 20% No 1 2 Year 4 4.5 5.5 CD prenomination Dr H Parmar Discovery Medicine, Astrazeneca
  34. 34. Current cumulative success rates to market by product type 100% 90% NCEs 80% Biotech/Gene therapy 70% Success rate 60% 50% 40% 30% 20% 10% 0% First human dose to market First patient dose to market First pivotal dose to market Submission to market Source: CMR International Dr H Parmar CONFIDENTIAL Discovery Medicine, Astrazeneca
  35. 35. Number of Clinical Studies for Approved Biopharmaceuticals and NMEs 40 37 Biopharmaceuticals (1994-2000, n=12) NMEs (1995-2000, n=23) MEAN NUMBER 21 11.8 10 5.1 5.2 6 1.3 0 Phase I Phase II Phase III Total Source: Reichert, Drug Inf J 2001;35:337-346 Dr H Parmar Discovery Medicine, Astrazeneca
  36. 36. Number of Subjects for Approved Biopharmaceuticals and NMEs 4800 4478 Biopharmaceuticals (1994-2000, n=12) NMEs (1995-2000, n=23) 3350 MEAN NUMBER 1014 696 598 441 307 107 0 Phase I Phase II Phase III Total Source: Reichert, Drug Inf J 2001;35:337-346 Dr H Parmar Discovery Medicine, Astrazeneca
  37. 37. Recombinant Proteins Dr H Parmar Discovery Medicine, Astrazeneca
  38. 38. Vascular Endothelial Growth Factor - 2 (VEGF-2) Dr H Parmar Discovery Medicine, Astrazeneca
  39. 39. Cooper, H. L., Healy, E., Theaker, J. M. & Friedmann, P. S. Treatment of resistant pemphigus vulgaris with an anti-CD20 monoclonal antibody (Rituximab). Clinical & Experimental Dermatology 28 (4), 366-368. Photos showing comparison between clinical condition pre- and post- Rituximab. ( N of 1 Trial) Dr H Parmar Discovery Medicine, Astrazeneca
  40. 40. Human Skin As a Tool to Study Inflammation Dr H Parmar Discovery Medicine, Astrazeneca
  41. 41. Urate Crystal Skin Inflammation • Need safe and malleable in Biopsies Clinical vivo inflammation models • for early PoP for novel Histology • Laser doppler inflammation targets • ICC • Systemic inflammatory Skin Chamber fluid markers (blood) • Skin is visible and safely accessible • Cell counts • Subjects assessment of discomfort • Monosodium urate crystals • Cell characterisation are a potent inflammatory • Soluble mediators • Investigators assessment of stimulus (gout) inflammation • Safety Dr H Parmar Discovery Medicine, Astrazeneca
  42. 42. Urate crystals in skin chambers • Chamber applied to de-roofed vacuum blister • GMP crystals applied 2 hours • Fluid for cells and mediators (20-plex Luminex) • Neutrophils, IL-8 and other chemokines 750 Control 300 Control 1.25mg 2.5mg Total cell count (103 ) UAX 1.25mg UAX 2.5mg IL-8 pg/ml 500 200 250 100 0 2 4 6 8 0 time (hr) 2hr 4hr 6hr 8hr Neutrophil exudate, #7 Luminex (IL-8), #7 Dr H Parmar Discovery Medicine, Astrazeneca
  43. 43. Intradermal urate crystals • Graded doses 0- 2.5mg injected • Quantitate inflammation with laser doppler • Biopsy shows neutrophil, then macrophage infiltrate • Safe, well tolerated, and with no lab changes • Some inter-patient subject variability (timecourse, intensity) 0 mg 0.63 1.25 Same model has been created in animals for full R & D Integration Dr H Parmar Discovery Medicine, Astrazeneca
  44. 44. Psoriasis for assessing therapeutic effects • Cyclosporin A , anti-CD2, CTLA4-Ig and anti-TNFs are all clinically validated in psoriasis • Accessibility of skin – Easily monitored clinical response – Sample collection to investigate mechanistic effects easy Infliximab CTLA4-Ig Dr H Parmar Discovery Medicine, Astrazeneca
  45. 45. Early concept testing in man-P2Y2 • Experimental data suggested P2Y2 a good target for Psoriasis • Effect on Keratinocytes & Neutrophils demonstrated • Progress in identifying good compounds (10nM) for the CDTP, however DMPK was still a problem • A fast track PoP/PoC was negotiated • Only 75 gms of GMP material for Tox, PARD, DMPK and Clinical PoP was produced. • A very limited Toxicology program agreed with MHRA • Ethics & Regulatory Approval CTX (IND) obtained • 26 patients with Psoriasis treated • Clear outcome, highly significant result 1. Human Stop/Go PoP data • Steroid >>Calcipitrol>>P2Y2=Placebo generated 3-5 years before traditional process 2. Limited cost < £200,000 for all PRD, Safety, DMPK, Clinical etc 3. Introduced the concept of Investigational Tracks to AZ 4. Process repeatable with new eIND and EU guidelines Dr H Parmar Discovery Medicine, Astrazeneca
  46. 46. Development of Concept testing for Inflammation Projects in Humans Inflammation models in humans • Quantification of inflammatory reactions • Investigation of inflammatory cell recruitment • Mediator analysis and the development of microdosing approaches to investigate Candidate Drug activity. Dr H Parmar Discovery Medicine, Astrazeneca
  47. 47. Dermal Microdialysis & Microdosing •Single Dose and/or •Mutiple Dose including Dose Ranging Possible In the same subject Dr H Parmar Discovery Medicine, Astrazeneca
  48. 48. Asthma & COPD Dr H Parmar Discovery Medicine, Astrazeneca
  49. 49. Whole Blood PoM Markers • The robustness of the CD11b and shape change responses on eosinophils to eotaxin- 2 was assessed in non-atopics • Shape more stable than CD11b in non-atopics Shape CD11b 550 10 525 9 500 8 475 450 7 Donor 3 425 6 400 375 5 350 4 325 300 3 -12 -11 -10 -9 -8 -7 -6 -11 -10 -9 -8 -7 -6 -5 550 10 525 9 500 8 475 450 7 Donor 5 425 6 400 375 5 350 4 325 300 3 -12 -11 -10 -9 -8 -7 -6 -11 -10 -9 -8 -7 -6 -5 Dr H Parmar Discovery Medicine, Astrazeneca
  50. 50. Biomarkers for iNOS inhibition: exhaled NO (SA Kharitonov, 2001) ASTHMA NORMAL 35 35 30 30 NO ppb 25 PLACEBO 25 20 20 15 15 10 10 PLACEBO SD3651 (L-NILTA) 5 5 0 SD3651 0 0 2 4 6 8 12 24 48 72 0 2 4 6 8 12 24 48 72 Hours Dr H Parmar Discovery Medicine, Astrazeneca
  51. 51. COPD PoP: Biomarker Discovery In Vivo In Vitro Elastin breakdown COPD Control specific peptides Differential Comparison Lung destruction Fraction 38, Mass 1286 Elastin degradation 500 products 400 Peptide Index Intensity 300 200 Exhaled breath condensate 100 Sputum 0 Control COPD Control COPD Blood Urine Dr H Parmar Discovery Medicine, Astrazeneca Size of peptide
  52. 52. Novel Markers-Proteomic analysis of plasma Stable and Acute Exacerbation, COPD % relative expression of total pooled sample Protein 1 Protein 2 100 100 80 80 60 60 40 40 20 20 0 0 Control Stable COPD AE Control Stable COPD AE Protein 3 Protein 4 100 100 80 80 60 60 40 40 20 20 0 0 Control Stable COPD AE Control Stable COPD AE Proteins identified by 2D Gel analysis – work on-going to validate and identify proteins Dr H Parmar Discovery Medicine, Astrazeneca
  53. 53. Core Problem: The migration of raw data into useable knowledge Current State of BioPharma Industry Knowledge User-Integrated Information • Predictive Modeling: Information – Disease progression models – Toxicity Models –Efficacy Models Data Raw Data: Integrated and • DNA Array Contextualized Data: • Sequence Data • Toxicity Data Sequence Data from multiple Databases DNA Array data derived throughout disease progression Integration of Orthogonal data types Dr H Parmar Discovery Medicine, Astrazeneca
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