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  • 1. THANK YOU!Funding for this conference was made possible in partby Cooperative Agreement U13AG031125-05 from theNational Institute on Aging.The views expressed in written conference materials or publications and by speakers andmoderators do not necessarily reflect the official policies of the Department of Health and HumanServices; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

2. Thank You!MEETING SPONSORS BRONZE SPONSORS 3. SCIENTIFIC ADVISORY COMMITTEESCIENTIFIC ADVISORY COMMITTEEKurt R. Brunden, PhD, University of PennsylvaniaNeil S. Buckholtz, PhD, National Institute on AgingRebecca Farkas, PhD, National Institute of Neurological Disorders and StrokeHoward Fillit, MD, Alzheimers Drug Discovery FoundationBrian Fiske, PhD, Michael J. Fox Foundation for Parkinsons ResearchMark Frasier, PhD, Michael J. Fox Foundation for Parkinsons ResearchAbram Goldfinger, MBA, New York UniversityLorenzo Refolo, PhD, National Institute on AgingSuzana Petanceska, PhD, National Institute on AgingDiana Shineman, PhD, Alzheimers Drug Discovery FoundationEdward G. Spack, PhD, Fast Forward, LLCD. Martin Watterson, PhD, Northwestern University 4. ADDF Staff Diana Shineman, PhD Assistant Director, Scientific Affairs Rachel Lane, PhD Scientific Program Manager Filomena Machleder Assistant Director, Institutional Partnerships Natalie Romatz Partnerships Assistant, Institutional Partnerships Niyati Thakker Grants Assistant World Events Forum Conference Secretariat 5. NOTES Please remember to complete and submit the meeting survey!CME Certificates available at the Registration DeskA webcast of the conference will be available soon on our website: 6. SAVE THE DATE!13th International Conference onAlzheimers Drug DiscoverySeptember 10-11, 2012 Jersey City, NJ across from NYC on the Hudson River 7. Goals of the Meeting Knowledge: The principles and practice of drug discovery, with a focuson the unique aspects for neurodegenerative diseases Network: >190 attendees from 20 countries, ~40% from industry Exchange ideas, foster alliances, partnerships andcollaborations 8. Neurodegenerative Diseases Affect >22 Million Worldwide Some symptomatic agents, few disease modifying drugs Multiple Huntingtons, 30,sclerosis, 400,00 000 ALS, 30,0000 WHO estimatesneurodegenerative disorders willParkinsonsbe the major unmet disease, 1,000,00 0medical need of the 21stcentury, surpassing cancer as the Alzheimersdisease, 5,000,00worlds second leading cause of 0death by the year 2040 9. Drug Discovery is a Vital Stage in Drug DevelopmentWhen Innovation is CreatedProofSafety andProof Innovationof MechanismProof of Conceptof EfficacyANIMALBIOLOGY STUDIES andAND CHEMISTRY HUMAN STUDIESPHARMACOLOGY10,000 to1 FDA>1 millionApprovedchemicals Drug Developing a Drug is Risky, Takes 12-15 years and Costs Over $1.2B 10. Opportunity and Challenges for Success:A Perspective On The Origin of FDA Approved Drugs20,000 human genes~50M compounds in Chem Abstracts;100,000 proteins 1040-10100 possible small molecules ~10,000 approved drugsMost are variants onformulation and delivery Many anti-microbials Less than 500 distinct chemical entities Targeting ~266 human genome derived proteins Less than 50 unique chemical scaffoldsFrom: T. Bartfai and GV Lees, Drug Discovery from Bedside to Wall Street, 2006;Le Couteur, et al 2011 11. How a Biologist Thinks About Drug Discovery: Many Targets for Neurodegeneration? Deposits of Misfolded Protein -Amyloid, tau, -synuclein, TDP-43, poly-Q aggregates Oxidative stress Inflammation Mitochondrial dysfunction Synaptic and neuronal cell dysfunction Vascular ischemia and damage Other novel mechanisms (eg. epigenetics) 12. How a Chemist Thinks About Targets for Drug Discovery: Success Rates of Target Types Target types GPCR (small ligand) High Enzyme (small ligand) Ion channel Nuclear receptor ProteaseSuccess Enzyme (large ligand) GPCR (large ligand) Cytotoxic (other) Protein kinase Protein-protein Low 13. Why A Biological Network Approach to Drug Discovery isNeeded: Signaling in the Synapse is Complex 14. How Were New Drugs Discovered?Phenotypic Screening Vs. Target-based ScreeningSwinney, et al, Nature Reviews Drug Discovery, July, 2011 15. Case Studies: Routes to Drug Discoverybeta-secretase inhibitors gamma-secretase inhibitorsInhibitor DevelopmentRational design approach Screening approachAssay developmentgeneration ofprotein High throughput screen (500,000 cpds.)Identification of hits CrystalCom puterStructureModel Selection of leadsFocused Medicinal Chem istry Potency Medicinal ChemistrySpecificity PKTest for in v o activ ivity 16. Improving Success Rates?Drug Discovery in Academia Drug discovery is the interface between basic researchand clinical development Requires extensive resources and collaboration betweenteams of investigators Increasingly requires partnerships betweenpharma, biotechs, non-profits, andgovernment, especially for neurodegenerative diseases 17. Drug Discovery and Development RequiresMultidisciplinary Teams of ScientistsClinical Trialists Clinical Development IND enabling studies: ADMET,Pharamaceutical Scientists formulation and scale-up chemistry Animal TrialistsIn vivo Testing and Biomarker DevelopmentPreclinical Proof of MechanismMedicinal Chemistry, Pharmacology Lead Identification and optimizationAssay Development High Throughput Structure BasedChemical Libraries Screening ChemistryComputational Chemistry Basic Neurobiology Target identification 18. Feeding the Pipeline: The Alzheimers Drug Discovery Foundation The ADDF has granted over $55 million to >370Alzheimers drug discovery programs in academic centersand biotechnology companies in 20 countriesADDF funding has resulted in >$2 billion in follow-on commitments, and several novel drugs entering clinical trials 19. Drug Discovery: The Valley of Death?Or Welcome to An Amazing Journey! 20. Where is drug discovery going? Christopher A. LipinskiScientific Advisor, Melior Discoveryclipinski@meliordiscovery.comDDND 2012 Lipinski keynote 20 21. Outline Academic targets and the translational gapis it just a missing resource issue? Chemistry & attrition - worse with timereductionism , genomics, HTS to blame? Screening diverse compoundsthe worst way to discover a drugnovelty drive comes from patents and not science Biology and chemistry networks analysischemistry due diligence on leads is essential What to look for DDND 2012 Lipinski keynote21 22. Drivers for discovery changes Chemistry, 65% successful predictivity rules and filters, eg. phys chem, structural ADME predictivity worsens outside of RO5 space Safety, 50% successful predictivity Efficacy, 10% successful predictivity Tackle efficacy using academic collaborations systems biology still too new to save us target quality is most likely from rich biology DDND 2012 Lipinski keynote 22 23. Death Valley California DDND 2012 Lipinski keynote 23 24. Translational valley of death"curing disease is a byproduct of the [NIH] system and not a goal," saysFasterCures Simon. Most scientists dont want to and dont have the skills totranslate a discovery into a treatment; researchers at a dedicated center wouldtry to do that full-time. DDND 2012 Lipinski keynote 24 25. Death valley, politically correct causes? Academics lack drug discovery skills Requires industry / academic collaboration eg. medicinal chemists are mostly in industry No access to ADMET, drug met, pharm sci etc. critical disciplines not in academia No access to preclinical clinical interface skills eg. analytical, process chemistry, formulation No access to early development skills eg. toxicology, biomarkers, project management DDND 2012 Lipinski keynote 25 26. Death valley, politically incorrectcauses? Assumption - academic ideas on new targets areof high qualityWRONG Bayer analysis of validation of academic targets 50 % of academic targets are wrong 25% of academic targets are partially flawed Translational death valley exists (in part) becauseof poor quality academic target identificationDDND 2012 Lipinski keynote26 27. Why the academic target problem Culprit is primarily the pressure to publish tosupport both grant applications and careerdevelopment A people problem A government problem Exacerbated by hypothesis driven research The positive: infrastructure collaborationDDND 2012 Lipinski keynote27 28. Bayer observation in NRDDDDND 2012 Lipinski keynote 28 29. Has drug discovery gone wrong? Prevailing mantra: identify a mechanism anddiscover a selective ligand for a single target Counter responses: Phenotypic screening Drug repurposing Multi targeted drug discovery In-vivo screening Non target non mechanism screening DDND 2012 Lipinski keynote 29 30. Genomics Chemistry parallel Genome sequence deciphered in 2000 Automated chemistry starts in 1992 Misapplied, both impeded drug discovery The DNA reductionist viewpoint of the moleculargenetics community has set drug discovery backby 10-15 years Craig Venter quote In 1992-1997 if you had stored combinatorialchemistry libraries in giant garbage dumpstersyou would have much improved drug discoveryproductivity Chris Lipinski quoteDDND 2012 Lipinski keynote 30 31. Genomics / HTS science madness Collaborations to mine genomic targets Massive HTS campaigns to discover ligands 500 different targets, a million data points a wish to screen 100,000 compounds per day in a drug discovery factory and a wish to make a drug for each targetDrug discovery and development using chemical genomics. A. Sehgal, Curr Opin in Drug Disc & Dev (2002), 5(4), 526-531.The drug discovery factory : an inevitable evolutionary consequence of high throughput parallel processing. R. Archer, Nat Biotech (1999), 17(9), 834.DDND 2012 Lipinski keynote 31 32. Genomics financial madness1% success, NPV $34M, Decision