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Workshop Agenda

Accelerating Therapeutic Development for Nervous System Disorders Toward First-in-Human Trials: A Workshop

April 8 and 9, 2013

National Academy of Sciences Building, Lecture Room 2101 Constitution Ave., NW, Washington, DC

Background: In March 2012, the Forum on Neuroscience and Nervous System Disorders hosted a public workshop called Improving Translation of Animal Models for Nervous System Disorders. This workshop explored strategies for improving the processes of discovery and development of effective therapies for nervous system disorders with a focus on translation of results from animal models to clinical practice. Two themes that emerged from the workshop were that many have lost confidence in the ability of animal models to predict efficacy and that current animal models may, in fact, be screening out potentially effective compounds. Another theme was the need to combine animal models with emerging translational tools and technologies in therapeutic development. Following on these themes, the goal of this workshop is to explore opportunities to accelerate the pathway from discovery to approval of new therapeutics for nervous system disorders.



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B Workshop Agenda Accelerating Therapeutic Development for Nervous System Disorders Toward First-in-Human Trials: A Workshop April 8 and 9, 2013 National Academy of Sciences Building, Lecture Room 2101 Constitution Ave., NW, Washington, DC Background: In March 2012, the Forum on Neuroscience and Nervous System Disorders hosted a public workshop called Improving Trans- lation of Animal Models for Nervous System Disorders. This workshop explored strategies for improving the processes of discovery and development of effective therapies for nervous system disorders with a focus on translation of results from animal models to clinical practice. Two themes that emerged from the workshop were that many have lost confidence in the ability of animal models to predict efficacy and that current animal models may, in fact, be screening out potentially effective compounds. Another theme was the need to combine animal models with emerging translational tools and technologies in therapeutic develop- ment. Following on these themes, the goal of this workshop is to explore opportunities to accelerate the pathway from discovery to approval of new therapeutics for nervous system disorders. 87

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88 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS Meeting Objectives:  Examine opportunities and challenges in neuroscience research for facilitating faster entry of potential treatments into first-in- human trials. o Discuss the role of new and emerging tools and technologies in accelerating therapeutic development. o Identify avenues for developing integrated strategies that utilize both animal and non-animal models. o Discuss potential benefits and risks of such an approach.  Explore how emerging neuroscience technologies and techniques may improve the efficiency of research and facilitate a more effective and efficient pathway to first-in-human trials (e.g., induced pluripotent stem cells, in vitro neuronal circuits, connectomics, brain imaging, etc.).  Consider regulatory mechanisms that may facilitate faster entry of potential treatments into first-in-human trials. o Discuss how new and emerging tools and technologies may accelerate progress toward first-in-human trials.  Consider mechanisms for integration and proliferation of new technologies and techniques to facilitate drug development and discovery. DAY ONE 8:30 a.m. Opening remarks JOHN DUNLOP, Co-Chair FRED GAGE, Co-Chair 8:40 a.m. Review of workshop on Improving Translation of Animal Models for Nervous System Disorders RICHARD HODES Director National Institute on Aging

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APPENDIX B 89 SESSION I: CURRENT THERAPEUTIC DEVELOPMENT PRACTICES Session Objectives: Discuss the benefits and risks of accelerating therapeutic development into first-in-human clinical trials. Consider the need for new molecular targets for nervous system disorders. Examine therapeutic development practices with a focus on challenges presented by current tools and technologies. 8:55 a.m. Overview and session objectives DAVID MICHELSON, Session Chair Vice President Clinical Neuroscience and Ophthalmology Merck Research Laboratories 9:00 a.m. The therapeutic development pathway: From the lab to the clinic WILLIAM POTTER Senior Advisor Office of the Director National Institute of Mental Health 9:15 a.m. Meeting the medical need: The benefits and risks of aggressively moving compounds forward JASON KARLAWISH Professor of Medicine, Medical Ethics, and Health Policy Perelman School of Medicine University of Pennsylvania 9:30 a.m. Evolutionary conservation and divergence: The utility of animal models in development of therapeutics DANIEL GESCHWIND Gordon and Virginia MacDonald Distinguished Professor Center for Autism Research and Treatment University of California, Los Angeles, School of Medicine

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90 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS 9:45 a.m. Developing new molecular and clinical targets for nervous system disorders SAMUEL GANDY Professor of Neurology and Psychiatry Associate Director Mount Sinai Alzheimer’s Disease Research Center 10:00 a.m. Therapeutic development practices: Challenges and limitations of current tools and technologies CHAS BOUNTRA Professor of Translational Medicine Head of Structural Genomics Consortium University of Oxford 10:15 a.m. Panel discussion with participants DAVID MICHELSON, Moderator and Session Chair 10:45 a.m. BREAK SESSION II: OPPORTUNITIES AND CHALLENGES FOR NEW AND EMERGING TOOLS AND TECHNOLOGIES Session Objectives: Examine the role of new and emerging tools and technologies in accelerating the development of therapeutics for nervous system disorders. Discuss the readiness of these tools and technologies for integration into therapeutic developmental pathways. Examine the utility of specific new and emerging tools and technologies in relation to nervous system disorders. 11:00 a.m. Overview and session objectives RAJESH RANGANATHAN, Session Chair Director Office of Translational Research National Institute of Neurological Disorders and Stroke Speakers will focus on the following questions:  How could this area of research speed therapeutic development?

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APPENDIX B 91  What would the qualification process look like for this area?  How long would it take for integration into therapeutic development pathways? 11:05 a.m. Induced pluripotent stem cells LARRY GOLDSTEIN Distinguished Professor, Department of Neurosciences Director, University of California, San Diego (UCSD) Stem Cell Program UCSD School of Medicine 11:25 a.m. Humanized animal models IRVING WEISSMAN Director, Institute of Stem Cell Biology and Regenerative Medicine Professor of Pathology and Developmental Biology Stanford University 11:45 a.m. Biomarkers/imaging SCOTT SMALL Herbert Irving Professor in Neurology The Neurological Institute of New York Columbia University Medical Center 12:05 p.m. Human models/experimental medicine JOHN KRYSTAL Robert L. McNeil, Jr., Professor of Translational Research Chair, Department of Psychiatry Yale University School of Medicine 12:25 p.m. Computational neuroscience READ MONTAGUE Director, Human Neuroimaging Laboratory Director, Computational Psychiatry Unit Virginia Tech Carilion Research Institute Professor, Wellcome Trust Centre for Neuroimaging, University College London

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92 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS 12:45 p.m. Panel discussion with participants  How would these new and emerging tools and technologies complement or replace current methods, including animal models?  How could these new and emerging tools and technologies aid in the identification of new molecular and clinical targets?  What are potential challenges for incorporation into current developmental pathways? RAJESH RANGANATHAN, Moderator 1:15 p.m. LUNCH 2:00 p.m. Opportunities and challenges around incorporation of new and emerging tools and technologies into current research programs.  Which tools and technologies show the most promise for the particular disease area?  How could these tools and technologies best be positioned to positively bolster current research programs? 1) Neurodevelopmental disorders: Autism and schizophrenia KEVIN EGGAN Associate Professor Harvard Stem Cell Institute Harvard University 2) Mood disorders: Depression WAYNE DREVETS Scientific Vice President Disease Area Leader in Mood Disorders Janssen Pharmaceuticals Companies of Johnson & Johnson

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APPENDIX B 93 3) Neurodegenerative disorders: Alzheimer’s and Parkinson’s PAUL AISEN Director, Alzheimer’s Disease Cooperative Study Professor, Department of Neurosciences UCSD 4) Traumatic brain injury RAMON DIAZ-ARRASTIA Director of Clinical Research, Center for Neuroscience and Regenerative Medicine Professor of Neurology Uniformed Services University of the Health Sciences 3:00 p.m. Panel discussion with participants RAJESH RANGANATHAN, Moderator 3:30 p.m. BREAK SESSION III: EVALUATING THERAPEUTIC DEVELOPMENT PATHWAYS Session Objectives: Explore mechanisms by which evidence is evaluated in decisions to commit to therapeutic development approaches. Discuss ways in which new and emerging tools and technologies could increase confidence in decision making. 3:45 p.m. Overview and session objectives MAGALI HAAS, Session Chair Chief Science & Technology Officer One Mind for Research 3:50 p.m. Decision processes for committing to a therapeutic development approach  What evidence is required for research programs to commit resources?  How is evidence evaluated in the decision pro- cess? What evidence is given greater weight?

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94 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS  When and how are decisions made to switch to a different approach? 1) Industry perspective KALPANA MERCHANT Chief Science Officer Tailored Therapeutics, Neuroscience Eli Lilly and Company 2) Government perspective STORY LANDIS Director National Institute of Neurological Disorders and Stroke 3) Academic perspective REISA SPERLING Director, Center for Alzheimer’s Research and Treatment Professor of Neurology Harvard Medical School 4:35 p.m. The contribution of animal models within the therapeutic development pathway  What is the spectrum of animal models used in the therapeutic development pathway?  How are research programs currently supplementing animal models in the development pathway? NICK BRANDON Senior Director, Neuroscience Innovative Medicines Unit (iMED) AstraZeneca 4:50 p.m. Panel discussion with participants  How can these tools and technologies help identify and validate molecular and clinical targets?

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APPENDIX B 95  Which of these tools and technologies show the best promise to help groups make these commitments?  What combinations of new and emerging tools, technologies, and animal models have the potential to accelerate therapeutic development? MAGALI HAAS, Moderator 5:20 p.m. Day one wrap-up JOHN DUNLOP, Co-Chair FRED GAGE, Co-Chair 5:30 p.m. ADJOURN DAY TWO 8:30 a.m. Welcome JOHN DUNLOP, Co-Chair FRED GAGE, Co-Chair SESSION IV: THE REGULATORY PATHWAY Session Objectives: Examine the current regulatory processes and the use of new and emerging tools and technologies in applications. Discuss common mistakes in applications as guidance for developing accelerated pathways into first-in-human trials. 8:35 a.m. Overview and session objectives WILLIAM POTTER, Session Chair Senior Advisor Office of the Director National Institute of Mental Health 8:40 a.m. Lessons learned: Accelerating therapeutic development through a look at current regulatory applications  What are key components of successful applications? What are common mistakes?

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96 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS  What uses of new and emerging tools and technologies are subject to regulatory processes across the phases of drug development: investigational new drug (IND)/Phase I; Phase II; Phase III; and new drug application (NDA)?  Are there mechanisms for moving into patients, children/adolescents faster? First? IMRAN KHAN Pharmacologist and Toxicologist Office of New Drugs, Center for Drug Evaluation and Research U.S. Food and Drug Administration 9:00 a.m. Potential challenges facing integration of new and emerging tools and technologies into the regulatory process  What potential challenges do these new and emerging tools and technologies face in the approval process? ROBERT CONLEY Distinguished Lilly Scholar Regulatory Leader, Biomedicines Eli Lilly and Company ERIC BASTINGS Deputy Director Division of Neurology Products, Center for Drug Evaluation and Research U.S. Food and Drug Administration NI KHIN Medical Team Leader Division of Psychiatry Products, Center for Drug Evaluation and Research U.S. Food and Drug Administration 9:30 a.m. Panel Discussion with Participants WILLIAM POTTER, Moderator

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APPENDIX B 97 SESSION V: ACCELERATING THERAPEUTIC DEVELOPMENT Session Objectives: Explore mechanisms by which evidence is evaluated to make commitments to invest in clinical trials. Discuss ways in which therapeutic development paradigms can be optimized and accelerated. Identify potentially innovative methods to accelerate development of new therapeutics. 10:00 a.m. Overview and session objectives DANIEL BURCH, Session Chair Global TA Head Neurosciences–Global Product Development (GPD) Pharmaceutical Product Development, LLC (PPDi) 10:05 a.m. Investment decisions in preclinical development and movement into clinical trials  What is the level of proof needed to justify investment in a preclinical project for IND enabling or a Phase I activity?  From an investment point of view, how attractive are neuroscience research areas when compared to other therapeutic areas? What could make it more attractive at the preclinical stage?  How important is it to fully understand mechanisms and molecular pathways of action prior to initiation of the IND enabling package? KIRAN REDDY Principal Third Rock Ventures STEVE ELMS Managing Partner Aisling Capital KAZUMI SHIOSAKI Managing Director MPM Capital

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98 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS 10:35 a.m. Panel discussion with participants  How would new and emerging tools and technologies affect the decision process? Would they increase confidence in decisions? DANIEL BURCH, Moderator 11:05 a.m. BREAK 11:20 a.m. Improving current therapeutic development approaches  How could new and emerging tools and technologies provide solutions for challenges currently facing development of drugs for nervous system diseases?  How could new and emerging tools and technologies be used in place of, or in addition to, animal models? 1) Discovery/basic research DAVID GOLDSTEIN Richard and Pat Johnson Distinguished University Professor Director, Center for Human Genome Variation Duke University 2) Target ID/validation DANIEL WEINBERGER Director and CEO Lieber Institute for Brain Development 3) Screening/optimization ADRIAN IVINSON Director, Harvard NeuroDiscovery Center Harvard University 4) Preclinical development MARK BEAR Picower Professor of Neuroscience Investigator, Howard Hughes Medical Institute Massachusetts Institute of Technology

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APPENDIX B 99 12:20 p.m. Panel discussion with participants  What balance between emerging tools and technologies and current methods (e.g., animal models) would be needed to increase confidence in selection of a particular development pathway? DANIEL BURCH, Moderator 12:45 p.m. LUNCH SESSION VI: NEW APPROACHES TO THERAPEUTIC DEVELOPMENT Session Objectives: Discuss workshop concepts in the context of nervous system disorders. Identify tangible next steps by which identified mechanisms might be rapidly incorporated into current practices. 1:45 p.m. Overview and session objectives STEVEN HYMAN, Session Chair Director, Stanley Center at the Broad Institute Distinguished Service Professor Professor of Stem Cell Biology and Regenerative Biology Harvard University 1:50 p.m. Imagining new therapeutic development pathways (with Q&A) CHRISTOPHER AUSTIN Director National Center for Advancing Translational Sciences National Institutes of Health 2:10 p.m. Next steps with workshop co-chairs and individual session chairs  How could workshop concepts be rapidly incorporated into current therapeutic development practices?

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100 THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS JOHN DUNLOP, Workshop Co-Chair AstraZeneca FRED GAGE, Workshop Co-Chair Salk Institute DAVID MICHELSON, Session I Chair Merck Research Laboratories RAJESH RANGANATHAN, Session II Chair National Institute of Neurological Disorders and Stroke MAGALI HAAS, Session III Chair One Mind for Research WILLIAM POTTER, Session IV Chair National Institute of Mental Health DANIEL BURCH, Session V Chair Pharmaceutical Product Development, LLC (PPDi) 3:30 p.m. Final comments JOHN DUNLOP, Co-Chair FRED GAGE, Co-Chair 3:45 p.m. ADJOURN