Preston Hensley Skolkovo biotech vision

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Transcript of Preston Hensley Skolkovo biotech vision

  • 1. Vision for Skolkovo Biotech Sector Pharma Discovery Preston Hensley Lotus TranslationalMedicine, LLC 3 February 2011 Skolkovo Vision

2. What are the drivers?Chronic disease impacts US national economy 3 February 2011 Skolkovo Vision Combined treatment and productivity costs for US in 2003 Milken Institute 2008 Total: 1.3 T US$ 3. How Big is 1.3 T$ per Year?(US Numbers, $ per year)

  • 1/10 thof entire GDP 14 T US$
  • ~ 1000 Dallas Cowboys Football Stadiums(1.3 B$ ea) - 20 in each state of the USA
  • > 3X Dependence on foreign oil (420 B$)
  • > 6X Wars in Iraq and Afghanistan (190 B$)
  • ~ 2X Banking industry bailout (700 B$)
  • > 20 X Automotive industry bailout (60 B$)
  • > Economic stimulus package (~1,000 B$)

3 February 2011 Skolkovo Vision 4. What are the drivers?Unmet therapeutic need 3 February 2011 Skolkovo Vision Unmet Need Unrealized profit Adverse Events Cost Ineffective drugs - Waste 5. This is a big issue 3 February 2011 Skolkovo Vision Jerel Davis, McKinsey & Co http://www.dnapolicy.org/images/issuebriefpdfs/PGx%20IB.pdf Aspect Numeric 2008 Rx spend, US 292 B US$ (of 800 B US$ WW) Percent Rx not effective 20 90% (average 50%) Adverse events, US ~2,000,000 Fatal adverse events, US ~100-125,000 Cost adverse drug events, US 45-135 B US$ Percent events avoidable 20 35%

    • Percent of care decisions informed by diagnostics

70%

    • Diagnostics as percent of healthcare market

3-4% 6. US Drivers:Summary 3 February 2011 Skolkovo Vision 7. Confounding issue:High failure rate/cost to discover new medicines 3 February 2011 Skolkovo Vision High risk process 1/100 ideas get to market 12-15 years Fully amortized cost US$3.9B per drug 8. Productivity of pharma industry 3 February 2011 Skolkovo Vision ~20 NMEs / yr ~ 7 NMEs / yr Bernard Munos, NATURE REVIEWS | Drug Discovery VOLUME 8 | DECEMBER 2009 | 963 9. Discovery steps largely in good shape 3 February 2011 Skolkovo Vision HP Prang: Drug Discovery and Development 10. Reason for failure:complex biology of safety and efficacy is not well understood 3 February 2011 Skolkovo Vision

  • Reasons for failure:
  • 30% Efficacy
  • 30% Clinical Safety and Toxicology
  • 20% Commercial
  • 20% other reasons

I Kola, CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 2 | FEBRUARY 2008 11. US National Resource Committment

  • Efficacy NIH budget, ~30 B US$
  • Safety fraction of FDA budget, ~0.160 B US$
  • Safety/tox failure = efficacy failure
  • Safety/toxicology support off by a factor of nearly 200

3 February 2011 Skolkovo Vision 12. Outline of plan 3 February 2011 Skolkovo Vision 13. Where to focus? Causes of death (US, 2005) 3 February 2011 Skolkovo Vision Jernal, et al., CA Cancer J Clin 2008;58;71-96,Feb 20, 2008 14. Breast Cancer in Russia

  • 23,718.5 deaths per year
  • 16.5 deaths per 100,000 persons per year ( twice world average, 7.7 )
  • 288,048 life years lost per year
  • 200 life years per 100,000 persons per year

3 February 2011 Skolkovo Vision 15. What have we learned from cancer genomics?

  • GWAS
  • Although statistically compelling associations have been identified, there is anenormous gapin the ability to provide the biological explanation for why a genomic interval tracks with a complex trait.
  • Kelly A. Frazer
  • Scripps Translational Science Institute and The Scripps Research Institute
  • Cancer genomics
  • Therefore, these genetic analyses can only identify candidate genes that may play a role in cancer anddo not definitively implicate any genein the neoplastic process.
  • Bert Vogelstein
  • Johns Hopkins Kimmel Cancer Center

3 February 2011 Skolkovo Vision Cancer genomics What necessarily follows will be the detailed functional characterization of individual candidate cancer genes, to determine whether and how they contributeto a tumorigenic phenotype. Daphne Bell National Human Genome Research Institute, NIH 16. Global, unbiased, discovery technologies to more deeply understand biology 3 February 2011 Skolkovo Vision 100s 10,000s 1000s

  • Other Omics
  • Metabolomics
  • RNAi screens
  • Lipidomics
  • Global Protein
  • Turnover
  • Etc.

17. Global Unbiased Aceto-Proteomics Can Now Significantly Increase Resolution

  • Mouse adipocytes + insulin
  • > 100 proteins change acetylation state
  • Mostly non-histone

15 January 2010 Fraunhofer Center for Molecular Biotechnology Forest White, MIT 18. ResponseNet algorithm for identifying response networks 3 February 2011 Skolkovo Vision Ernest Fraenkel,Nat Genet.2009 March,41(3) : 316323 Assay Genomic Data Proteomic Data Probabilistic interactome Computational tools 19. Chip-Seq Data for Four Transcription Factors Ernest Fraenkel MIT 15 January 2010 Fraunhofer Center for Molecular Biotechnology 20. Study hepatotoxicity using LiverChip technology 3 February 2011 Skolkovo Vision Steve Tannenbaum, Linda Griffith, MIT 21. Phenotype-driven Rx and Dx discovery Drug Targets Are Proteins 3 February 2011 Skolkovo Vision Genome T T T T T T T T Complex Biology Phenotype-driven Drug Discovery In Cancer, Genome is Altered T Primary Cancer Targets Appear Proteome Drug Resistance Resistance Targets Appear X Proteome T T T T 22. Tamoxifen and Breast Cancer Resistance 3 February 2011 Skolkovo Vision Based on Narmanno et al.Endocrine-Related Cancer2005 23. Experimental approaches: Quantitative phosphoproteomics 3 February 2011 Skolkovo Vision Forest White, MIT Follow time course under multiple conditions 24. Globally follow many 100s of events Quantitative time courses 3 February 2011 Skolkovo Vision Forest White, MIT 25. New RTK signaling seen with Tamoxifen resistance directly defines a new target class 3 February 2011 Skolkovo Vision Forest White, MIT Indicates an increase in tyrosine phosphorylation as a result of acquiring Tamoxifen resistance. DefinesSRCas a potential resistance target.SRC-directed therapeutics may revert Tamoxifen resistance. 26. SRC-directed therapeutics revert Tamoxifen resistance functionally definea new target and therapy class 3 February 2011 Skolkovo Vision Forest White, MIT 27. Phenotype directs target/lead, toxicity pathway and biomarker identification 3 February 2011 Skolkovo Vision 28. Lack of therapeutic efficacy affects large populations 3 February 2011 Skolkovo Vision Unmet Need Unrealized profit Adverse Events Cost Ineffective drugs - Waste 29. Solution:Diagnostics to stratify populations by drug response 3 February 2011 Skolkovo Vision Diagnostic test positive Likely to benefit from therapy Diagnostic test negative Not likely to benefit from therapy Toxicity test positive Likely to have toxic response Dx+ Dx- Tx+ 30. Genomic Dx methods have had success: Oncotype DX segregates breast cancer populations 3 February 2011 Skolkovo Vision 31. Other Commercially Available Genomic Assays 3 February 2011 Skolkovo Vision Christos Sotiriou and Lajos Pusztai, n engl j med 360, february 19, 2009 32. Quantitative immunofluorescence tools can stratify patients 3 February 2011 Skolkovo Vision Recurrence score independent of grade and stage in multivariate analysis added value to histopathology Algorithm being optimised for AQUA technology Further validation in independent cohort from another institution David Harrison and Dana Faratian 33. Quantitative PTEN protein expression is associated with Trastuzumab resistancein vivo 3 February 2011 Skolkovo Vision AQUA fluorescent analysis of PTEN expression in a TMA core, showing mainly cytoplasmic localization of PTEN (red) and masking of tumor areas for quantification by cytokeratin (green) Kaplan-Meier survival curves for patients treated with Trastuzumab for low (blue) and high (red) protein expression of PTEN.Dana Faratian,et al ., Cancer Res 2009; 69: (16). August 15, 2009 Low PTEN High PTEN PTEN is a tumor suppresser 34. Stratification using aptamer-based serum proteomic platform

  • Highly multiplexed,>1000-plex today
  • Works on cells, tissues, serum
  • 300500 patient samples per day
    • Equivalent to 425,000 ELISAs per day
  • Needs ~14 l sample
  • 3-4 log unit dynamic range
  • 10 -14M lower limit of detection
  • Customizable Arrays 200 new aptamers in 2-3 months

3 February 2011 Skolkovo Vision SomaLogic 35. Aptamers Unlock Biomarker Discovery in The Human Proteome SomaLogic 3 February 2011 Skolkovo Vision 36. Multiplexed aptamer technology for clinical Dx discovery SomaLogic 3 February 2011 Skolkovo Vision 37. Example: Lung Cancer Diagnostic SomaLogic 3 February 2011 Skolkovo Vision 38. Aptamer-based diagnostics being developed

  • Oncology
    • Lung cancer
    • Pancreatic cancer
    • Ovarian cancer
    • Mesothelioma
  • Neurology
    • Amyotrophic lateral sclerosis (ALS)
    • Depression
    • Alzheimer's disease