U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke American Society for Experimental Therapeutics Annual Meeting March 04-06, 2010 Therapeutic Development Resources at NINDS Bill Matthew Director, Office of Translational Research; NINDS 1 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Pipeline Principles: 101 Basic Research Therapeutics Raw Material & Pump Block Valve Station Final Delivery 2 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Translational Research: The process of using novel, basic research discoveries to develop clinical applications. T1 T2 T1 bench bedside community 3 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Office of Clinical Research Office of Translational Research NINDS Extramural Research 4 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Basic Research - Target ID Assay Hit to Lead Screen for Hit Proof of Principle Lead Optimization PreClincal Candidate – Safety/Tox First in Human Anti-Convulsant Screening Program Exploratory/Developmental Projects in Translational Research Cooperative Program in Translational Research Translational SBIR Blueprint Neurotherapeutics Grand Challenge CounterACT RAID: Rapid Access to Interventional Development Small Molecule Optimization Small Business Program: SBIR & STTR Spinal Muscular Atrophy Project Molecular Libraries (Roadmap) Assay Development (Roadmap) Drug Discovery for Nervous System Disorders NINDS/OTR Activities in Therapeutic Development: NINDS Multiple ICs 5 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program (ASP) Goal: To facilitate the development of drugs for patients with epilepsy, resistant epilepsy and related CNS conditions Screening performed via a contract mechanism using a battery of seizure models Compounds are submitted by a broad base of Investigators: > 500 total Industrial companies (~200) Academic institutions (~300) ASP Database > 29,000 small molecules – SAR chemistry & biology Compounds in clinical development: currently six Contributed to the development of ten marketed anti-convulsant drugs Jim Stables 6 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Exploratory/Developmental Projects in Translational Research Goal: Develop in vivo animal proof-of-concept for efficacy Program (R21) primarily targets four tasks: Creation and validation of screening assays Development of animal models of disease Identification of candidate therapeutics Development of preliminary animal efficacy data However, can be used for any preclinical development task Tom Miller 7 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Cooperative Program in Translational Research Tom Miller Goal: Bring novel compounds and devices to the clinic Cooperative Agreement, Milestone-driven program Significant staff involvement Reviewed by therapy development experts IND/IDE by the end of the research project period 6 filed INDs and 3 Clinical Trials 8 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Cooperative Program in Translational Research U44 Small Business Awards Goal: Facilitate Small Business development of neurotherapeutics Fast-Track (Phase I & II) and Phase II Applications accepted Phase I - identical scope as translational R21 Phase II - identical scope as translational U01 Randy Stewart Tom Miller For Translational 9 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke THE SMA PROJECT Goal: Develop a safe and effective drug for Spinal Muscular Atrophy Develop drugs that increase expression of SMN protein deficient in SMA patients A ‘Virtual Pharma’ network of contracts for industry-style drug development: medicinal chemistry in vitro testing pharmacological and toxicological studies animal model testing Industry-seasoned consultants and advisors to oversee programs Jill Heemskerk Coming Very Soon 10 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Blueprint Neurotherapeutics Grand Challenge Goal: Provide Medicinal Chemistry and Pharm/tox expertise for developing new drugs for nervous system disorders Investigator-initiated drug starting points “Virtual Pharma” model of drug development Provide access to industry-standard services: medicinal chemistry, pharm/tox, phase I clinical trials Provide industry expertise and guidance on committees Develop licensing opportunities Advance compounds through phase I trials Investigator retains IP Entry Requirements: - Hit compound(s) - Primary screening assay - Secondary assays for biological validation Jill Heemskerk Coming Very Soon 11 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Goal: To develop safe and effective therapies and diagnostic technologies for victims of emergency incidents involving exposure to highly toxic chemicals CounterACT Countermeasures Against Chemical Threats David Jett Research Centers of Excellence Individual research projects at academic, government and industry laboratories Cooperative Agreements, Milestone-driven Efficacy screening and preclinical services contracts Interagency Agreements with DoD laboratories 12 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Mark Scheideler Assay Development: Molecular Libraries and Imaging Roadmap Program Goal: Develop assays to identify small molecule interactions via high-throughput screening of compound libraries, and to chemically optimize active compounds as molecular probes 13 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke NIH-RAID NIH Rapid Access to Interventional Development Pre-IND studies All diseases Access to government expertise and contract resources –Production, bulk supply, GMP manufacturing –Pharmacokinetic/ADME studies –IND-directed toxicology, and more 6 successful IND submissions and 4 clinical trials to date Tom Miller Goal: To execute IND-enabling studies for extramural projects 14 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Basic Research - Target ID Assay Hit to Lead Screen for Hit Proof of Principle Lead Optimization PreClincal Candidate – Safety/Tox First in Human Anti-Convulsant Screening Program Exploratory/Developmental Projects in Translational Research Cooperative Program in Translational Research Translational SBIR Blueprint Neurotherapeutics Grand Challenge CounterACT RAID: Rapid Access to Interventional Development Small Molecule Optimization Small Business Program: SBIR & STTR Spinal Muscular Atrophy Project Molecular Libraries (Roadmap) Assay Development (Roadmap) Drug Discovery for Nervous System Disorders NINDS/OTR Activities in Therapeutic Development: NINDS Multiple ICs 15 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Please Contact us… Thank you 16 -Matthew

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke Activity Code R01 Research Project R21 Exploratory/Developmental Grants R41 Small Business Technology Transfer (STTR) Grants - Phase I R42 Small Business Technology Transfer (STTR) Grants - Phase II R43 Small Business Innovation Research Grants (SBIR) - Phase I R44 Small Business Innovation Research Grants (SBIR) - Phase II U01 Research Project--Cooperative Agreements U44 Small Business Innovation Research (SBIR) Cooperative Agreements U54 Specialized Center--Cooperative Agreements X01 Resource Access Award grants.nih.gov/grants/funding/funding_program.htm