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Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13
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Navigating the FDA: Getting to Market – CVG Second Thursday, 3/14/13

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  • 1. THANK YOU CVG SPONSORS B Round A RoundVenture Capital Sponsors Professional Service Firms
  • 2. Welcome Marketing at the Speed of LightKonstantine DrakonakisDirector, New HavenLaunchCapitalCTNEXT: New Haven HubDerek KochUsha Pillai
  • 3. Three Minute PitchesMarcia FournierJudson BrewerLew BenderJohn Bala SterileWave Medical Corp.
  • 4. Navigating the FDA: Getting to Market Marketing at the Speed of LightIntroductionPaul HughesPartnerWiggin and Dana LLPKeynoteEdison T. Liu, M.DPresident & CEOThe Jackson Laboratory
  • 5. Navigating the FDA orWhat is on the horizon? March 15,2013 Edison Liu, M.D. edison.liu@jax.org
  • 6. We discover precise genomic solutions for disease and empower the global biomedical community in our shared quest to improve human health.The Jackson LaboratoryTo discover precise genomic solutions forbetter medicine
  • 7. Biomarker Discovery in CancerThen: Single biomarker, spurred by a some laboratory findings, years of development before reaching clinicOne marker  many samplesNow: Interrogation of a cancer genome, in silico validation, identification of new therapeutic targetsMany markers  few samples Oct 1997
  • 8. HER2 and clinical trials Start of study CALGB 8869: 1989Ann Thor Don Berry Publication of final paper: 1998Soon Paik Mei HeLynn DresslerCraig HendersonHyman Muss In vitro observation: ARAC – RAS interactionJ Natl Cancer Inst. Koo, et al. Can Res 59:6057, 199990(18):1346-60 (1998) Patients with acute myeloid leukemia and RAS mutations benefit most from postremission treatment with high-dose cytarabine: a Cancer and Leukemia Group B study. Neubauer A, et al. J Clin Oncol. 26(28):4603-9, 2008. 9 years per marker, over 1,500 patients: There has got to be a better way
  • 9. Biomarker Discovery in CancerThen: Single biomarker, spurred by a some laboratory findings, years of development before reaching clinicOne marker  many samplesNow: Interrogation of a cancer genome, in silico validation, identification of new therapeutic targetsMany markers  few samples Oct 1997
  • 10. Sequenced Breast Cancers: focusing on  structural mutationsPET library construction PET sequences mapping Analysis of Cancer & sequencing to reference genome  Specific Mutations 1Kb 10Kb PET mapping span Concordant PET  tag density Automated cancer  genome assembly: Concordant PETs 7 month analysis to 4 days Discordant PETs SOLiD
  • 11. Structure variations Deletion Unpaired inversion (Inverted orientation)  Abnormal length Different strandTandem Duplication Translocation Incorrect order  Different chromosome Fusion points  predict fusion genes
  • 12. Structural Genomic Changes in Breast Cancer Genome Research 21(5):665-75 (2011)
  • 13. Cancer rearrangements are most often private and unique: Irrelevant mutations or part of the “long tail”Inaki K, et al. Transcriptional consequences of genomic structural aberrations inbreast cancer. Genome Res. 2011 May;21(5):676-87.
  • 14. Gene ontology (GO) analysis of genes with break points in cancer genomes: There is a higher organization to the collection of single structural mutations Breast cancer Gastric cancer 1) Genes with break points RefGen Expecte Obser RefGen Expecte ObserBiological Process3) +/‐ P value +/‐ P value e d ved e d vedCell adhesion‐mediated  386 20.88 51 + 2.22E‐06 Cell adhesion 592 31.61 73 + 2.62E‐09signaling Cell adhesion‐Cell adhesion 592 32.02 65 + 3.47E‐06 386 20.61 49 + 9.66E‐06 mediated signalingNeuronal activities 561 30.34 54 + 1.52E‐03 Signal transduction 3256 173.84 222 + 1.53E‐03Biological process unclassified 5972 322.97 269 ‐ 3.04E‐03 Synaptic transmission 275 14.68 33 + 3.24E‐03Electron transport 230 12.44 2 ‐ 1.05E‐02 Cell communication 1207 64.44 98 + 4.47E‐03Other intracellular signaling cascade 212 11.47 27 + 1.12E‐02 Neuronal activities 561 29.95 51 + 6.94E‐03Cell communication 1207 65.28 97 + 1.16E‐02 Biological process unclassified 5972 318.84 273 ‐ 2.36E‐02Chemosensory perception 204 11.03 1 ‐ 2.67E‐02 Chemosensory perception 204 10.89 1 ‐ 3.04E‐02Developmental processes 2065 111.68 144 + 2.97E‐02 Genes in recurrent high copy regions2) 2.35E‐ Chromatin packaging and  0.0024Signal transduction  3256 151.33 100 ‐ 194 2.21 11 +  05 remodeling  9Cell surface receptor mediated signal  2.05E‐ 1576 73.25 41 ‐transduction  03 7.74E‐Developmental processes  2066 96.02 65 ‐ 03 1.39E‐G‐protein mediated signaling  793 36.86 16 ‐ 02
  • 15. RPS6KB1‐TMEM49 fusion gene induced by tandem  replication is found in 30% of breast cancers.  5’ TMEM RPS6K (~100kb) 5’ TMEM RPS6K (~100kb)5’ TMEM RPS6K TMEM RPS6K (~100kb) (~100kb) 5’ TMEM RP EM RPS6K RPS6KB1-TMEM49 fusion gene
  • 16. Historical dataExpression of RPS6KB1‐VMP1 fusion Our datais correlated with:‐Poor prognosis‐Expression of neighboring oncogenes around the tandem duplication‐Expression of oncogenes in ~3Mb adjacent  region‐ Associated with gene amplification of locus The fusion gene is always associated with amplification of this region
  • 17. S6K‐TMEM Fusion Transcript is an indicatorof genomic instability in an “oncogenic region”  of the genome harboring at least 2 oncogenic  components miRNA21 TMEM 49 S6Kinase
  • 18. Indicator structural mutation:  S6K‐TMEM Fusion Transcript is an indicator of the amplification of an “oncogenic region” of the genome miRNA21 Oncogenic TMEM 49 S6Kinase bloc miRNA21 miRNA21 Tandem duplication S6 TMEM  TMEM 49 Kinase S6Kinase 49 GeneAmplification
  • 19. Genomic Organization and Cancer: Higher order organization of mutations in cancer genomes Chromosome as an oncogenic organizer Chromosomal “origami” to generate cancer gene cassettesEffect of the germline on cancer therapeutic outcome Focus on Structural Mutations in Cancer Systems Oncogenomics
  • 20. Chronic Myelogenous Leukemia (CML) Optimizing treatment for CML based on genetic makeup of the patient KP Ng, Axel Hillmer,… Yijun Ruan. Ong Sin Tiong Nat Med. 2012 Mar 18;18(4):521‐8.Imatianib (Gleevec) – primary and effective treatmentClinical Challenge: Drug resistance• Acquired resistance – resistance after long term  treatment ‐ due to second ABL mutation• Primary resistance – resistance at the beginning of  treatment. • In Asia, complete cytogenetic response rates are lower ‐ 50% vs. 74%.  Mechanism unknown   
  • 21. Question: is there a reason why 25% of CML cases do not respond to imatinib?Approach: Compared the genomes of three CMLcases with primary resistance to Imatinib with twoCML cases sensitive to Imatinib therapyResults:3/3 resistance caseshad the same 2.9kbdeletion in the BIMgene not seenin sensitive cases (0/2)Ng KP, Nat Med. 18(4):521-8(2012)
  • 22. BIM:• BIM is a gene that activates cell death (pro‐apoptotic). • Activated BCR‐ABL1, suppresses BIM function thus  allowing leukemia cells to survive. When CML cells are  treated with Imatinib, BIM expression goes up  cell  death Death of Bcr-ABL: CML Intact BIM Leukemia cells Imatinib
  • 23. How does it work?:    The 2.9kb BIM deletion polymorphism results an abnormal transcript (E3) that a produces a truncated and inactive BIM protein Normal Transcripts E3 Imatinib Death of Bcr-ABL: CML Intact BIM Leukemia cells Imatinib Deletion Polymorphism Bcr-ABL: CML BIM Primary E3 Drug Resistance
  • 24. BIM deletion polymorphism:• This deletion polymorphism is 3‐5X more common in  CML cases resistant to imatinib that sensitive cases• This 2.9 kb 2 deletion of BIM is not a mutation, but is a  polymorphism present in normal genomes (a germline polymorphism): 12% in Asian individuals 0% in Africans  0% in Caucasians
  • 25. We used this genomic intelligence to overcomethis resistance: ImatinibBcr-ABL: CML BIM 3 Primary Drug Resistance BH3 mimetics Imatinib Death of Bcr-ABL: CML BIM Leukemia cellsNg KP, Nat Med. 18(4):521-8 (2012)
  • 26. This genomic experiment with 5 patients explains the lower response rateIn North Asians to a life saving treatment in CML.Personalizing medicine in Asia Now: New ~50% cytogenetic response CML Patient in Asia Check for bcr-ABL YES rearrangement Check for 2.9kb deletion polymorphism in BIM YES NO Imatinib ? ? & BH3-mimetic Imatinib >75% cytogenetic 75% cytogenetic ? response response
  • 27. Translation InitiativeWe will construct avatars of your cancer: So that we can discover the best drugs for your cancer So that we can devise personalized and private diagnostic for your cancer So that we understand the nature of your cancer and explore the reasons for drug resistance So that we may project how your cancer might evolve
  • 28. PDX of patient = Patient “Avatar” of DrugResponse Drug 1 QuestionsSingle tumor Drug 2 Addressed:from a patient What drugs will be effective for Drug 3 my tumor? How to combine these drugs? Drug 4
  • 29. Predictive for TherapeuticsActivity of afatinib, cetuximab and erlotinib in LG703
  • 30. Cancer Avatar: General workflow Patient Tumor from Hartford Hospital JAX CT/BH JAX West Deep Sequencing PDX Model: Test Drugs predicted by genomics Genome Analysis: Extract the Source Code Future Treatments Immediate Personalized Treatment Plan Diagnostic
  • 31. Radiologist of the Genome Radiologist Interprets complex data rendered through Is the consultantscomputational algorithms to doctors
  • 32. What is the field looking for?• Tools and processes to enhance efficiency in the medical system• Life style enhancement: prolonging productive life and healthspan preventive therapeutics health monitoring performance enhancement mobility and independence• Personalization of information and medical care
  • 33. Navigating the FDA March 15,2013 Edison Liu, M.D.
  • 34. Navigating the FDA: Getting to Market Marketing at the Speed of LightPanelistsPamela BunesCEO, President & DirectorEpiEP, Inc.Harry PennerCo-founder, Executive ChairmanNew Haven PharmaceuticalsDr. Frank SciavolinoCo-founder, Board Member, ChiefScientific Officer & PresidentThetis Pharmaceuticals LLC
  • 35. Navigating the FDA: Getting to MarketMarch 2013 Crossroads Venture Group
  • 36. Overview  Pre-Clinical Requirements  Shift in Approval Requirements  Clinical Trial Sizing  Diagnostics  505(b)2 36
  • 37.  Premier Chemistry – Yale - Multiple Partners Pfizer – Schering Plough – Merck – Am. Home Anxiety / Alzheimers / Sleep / Obesity / Schiz. FDA Pre-Clinical Requirements Increased 37
  • 38.  Multiple Programs - Antibiotics Nobel Laureate Science – Tom Steitz (Yale) Premier Investors FDA Changed Approval Criteria After Phase II 38
  • 39.  In-Licensed Programs – Purdue + Yale Premier Investor Base – Domain / Canaan / FMP Epilepsy – Core Focus Equivocal Trial Results – Too Small “n” 39
  • 40. n  Diagnostic - CSF Detection  CI / Launch Capital / Management Financed  Ambitious Multi-antibody Strip Test  510k vs. PMA 40
  • 41.  In-licensed Programs – Flamel + Yale CI + Ironwood + Enhanced + Kuzari + EJ Funds Lead Product – Anti-Platelet 505(b)2 – Multiple FDA Interactions CMC + Approval Issues 41
  • 42. Closing Points Stay Abreast of All FDA Related Trends – Pre-clinical to Approval Maintain Strong Contact to FDA – Except When It Might Be Judicious Not To March to NDA - Process is Critical – The Longest Path to Approval Is a Short Cut 42
  • 43. THANK YOU CVG SPONSORS B Round A RoundVenture Capital Sponsors Professional Service Firms
  • 44. CVG Upcoming Events Boardroom Series Second Thursday 7:30 AM – 9:00 AM 4:30 PM – 7:00 PM March 20 April 11 Investment by Strategics Electronic Health Records (EHR) Hartford A Look at the Industry and Its Future March 27 HartfordEmployment and Immigration Issues Stamford May 9 April 3 Financial Services Stamford M&A: Legal Implications Stamford June 13 April 12 BioTech/Pharma M&A: Tax Considerations Hartford Glastonbury
  • 45. CVG 2013 CalendarOffering 60 Events Attendance to all Second Thursday events is free for members.

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