B

Workshop Agenda

Improving Translation of Animal Models for Nervous
System Disorders:
A Workshop

March 28-29, 2012

Institute of Medicine
Keck Building, Room 100
Washington, DC

Background: Nervous system disorders and diseases are highly prevalent and substantially contribute to the national disease burden. Animal models have significantly increased our understanding of nervous system disorders. Yet, in spite of these advances, there still remains a large gap in treatment options that are high in efficacy but low in side effects for many diseases. And for some diseases there are no treatment options. More than 80 percent of research projects fail to reach clinical trials. Of those nervous system drugs that do make it to clinical trials, only 8 percent end up being approved. These statistics translate to drug approval rates that are 50 percent lower than drugs for other therapeutic areas. Given the tremendous disease burden associated with nervous system diseases and disorders, the goal of this workshop is to bring together key stakeholders to discuss potential opportunities for maximizing the translation of effective therapies from animal models to clinical practice.



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B Workshop Agenda Improving Translation of Animal Models for Nervous System Disorders: A Workshop March 28-29, 2012 Institute of Medicine Keck Building, Room 100 Washington, DC Background: Nervous system disorders and diseases are highly prevalent and substantially contribute to the national disease burden. Animal models have significantly increased our understanding of nervous system disorders. Yet, in spite of these advances, there still remains a large gap in treatment options that are high in efficacy but low in side effects for many diseases. And for some diseases there are no treatment options. More than 80 percent of research projects fail to reach clinical trials. Of those nervous system drugs that do make it to clinical trials, only 8 percent end up being approved. These statistics translate to drug approval rates that are 50 percent lower than drugs for other therapeutic areas. Given the tremendous disease burden associated with nervous system diseases and disorders, the goal of this workshop is to bring together key stakeholders to discuss potential opportunities for maximizing the translation of effective therapies from animal models to clinical practice. 83

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84 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS Meeting Objectives: • Discuss key issues that contribute to poor translation of animal models in nervous system disorders. o Examine case studies that highlight successes and failures in the development and application of animal models. • Consider strategies to increase the scientific rigor of preclinical efficacy testing. o Explore the benefits and challenges to developing standardized animal and behavioral models. o Identify methods to facilitate development of corresponding animal and clinical endpoints. • Identify methods that would maximize bidirectional translation between basic and clinical research. • Determine the next steps that will be critical for improvement of the development and testing of animal models of disorders of the nervous system. DAY ONE 1:30 p.m. Opening Remarks RICHARD HODES, Co-Chair STEVEN PAUL, Co-Chair SESSION I: EVALUATION OF CURRENT ANIMAL MODELS Session Objective: Identify critical limitations impacting translation of therapies from animal models to clinical practice. Explore current expectations of animal models to predict therapeutic efficacy. Determine the impact of generalization of animal model capabilities. Examine the role of animal model–derived data in making decisions about moving therapeutics into clinical trials. 1:40 p.m. Overview and Session Objectives STEVIN ZORN, Session Chair

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APPENDIX B 85 1:45 p.m. Examination of Current Expectations for Animal Models STEVEN PAUL Director Helen and Robert Appel Alzheimer’s Disease Research Institute Weill Cornell Medical College 2:00 p.m. Choice and Validation of Animal Models for CNS Drug Discovery MARK TRICKLEBANK Director and Senior Research Fellow Eli Lilly and Co. 2:15 p.m. Impact of Publication Bias KATRINA KELNER Editor Science Translational Medicine 2:30 p.m. Q&A with Speakers SESSION II: CASE STUDIES Breakout Objective: Conduct in-depth analysis of six case studies in which animal models have ranged in translational success. Specifically, breakout groups will focus on three key questions: (1) Would this research area benefit from a new or improved standardized animal or behavioral models (e.g., testing conditions, reference standards)? (2) Do animal and human endpoints match for this case study? (3) What is needed to bridge the gap between animal models and clinical science? 3:00 p.m. Overview and Session Objectives RICHARD HODES and STEVEN PAUL Session Chairs 3:10 p.m. BREAK OUT INTO GROUPS

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86 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS 3:25 p.m. Breakout 1: Animal Models for Neurodegeneration ROBERT FERRANTE, Moderator Professor Departments of Neurological Surgery, Neurology, and Neurobiology University of Pittsburgh TIM COETZEE, Discussant Chief Research Officer National Multiple Sclerosis Society Breakout 2: Animal Models for Alzheimer’s Disease BRADLEY HYMAN, Moderator John B. Penny Jr. Professor of Neurology Harvard Medical School RICHARD HODES, Discussant Director National Institute on Aging SHARON ROSENZWEIG-LIPSON, Discussant IVS Pharma Consulting Breakout 3: Animal Models for Stroke CONSTANTINO IADECOLA, Moderator George C. Cotzias Distinguished Professor of Neurology and Neuroscience Weill Cornell Medical College WALTER KOROSHETZ, Discussant Deputy Director National Institute for Neurological Disorders and Stroke

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APPENDIX B 87 STEVEN PAUL, Discussant Director Helen and Robert Appel Alzheimer’s Disease Research Institute Weill Cornell Medical College Breakout 4: Animal Models for Schizophrenia: Cognition Enhancement and Antipsychotic Efficacy HOLLY MOORE, Moderator Associate Professor Clinical Neurobiology in Psychiatry Columbia University MARK GEYER, Discussant Professor Department of Psychiatry University of California, San Diego STEVIN ZORN, Discussant Executive Vice President Neuroscience Research Lundbeck USA Breakout 5: Animal Models for Addiction ATHINA MARKOU, Moderator Professor Department of Psychiatry University of California, San Diego ALAN LESHNER, Discussant Chief Executive Officer American Association for the Advancement of Science GERARD MAREK, Discussant Project Director Neuroscience Development Abbott Laboratories

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88 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS Breakout 6: Animal Models for Pain A. VANIA APKARIAN, Moderator Professor Neuroscience Institute Northwestern University DAVID SHURTLEFF, Discussant Acting Deputy Director National Institute on Drug Abuse 4:15 p.m. Breakout Groups Report Out and Panel Discussion with Participants (15 minutes per group) • What common themes were identified in: o standardization needs o endpoints o basic science/clinical research gap 6:00 p.m. ADJOURN DAY TWO Note: Continental breakfast will be available at 8:00 a.m. SESSION III: THE VALUE OF STANDARDIZATION Session Objective: Explore key components of animal model science that would benefit from standardization, such as behavioral paradigms. Examine the benefits and challenges to developing standardizations for animal and behavioral models. Discuss potential methods for dissemination of standards. 8:30 a.m. Overview and Session Objectives WALTER KOROSHETZ, Session Chair

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APPENDIX B 89 8:40 a.m. Standardization in Preclinical Models of Anxiety: Necessary But Not Sufficient ANDREW HOMES Chief Laboratory of Behavioral and Genomic Neuroscience National Institute on Alcohol Abuse and Alcoholism 8:55 a.m. Developing New Methods for Cognitive Translation from Rodent to Human TIM BUSSEY Professor Department of Experimental Psychology University of Cambridge 9:10 a.m. AD Models and the Risk/Benefit Ratio of Standardization LENNART MUCKE Director, Gladstone Institute of Neurological Disease Professor, Department of Neurology University of California, San Francisco 9:25 a.m. Discussion with Speakers and Participants 10:00 a.m. BREAK SESSION IV: CORRESPONDING ANIMAL AND CLINICAL ENDPOINTS Session Objective: Discuss methods to facilitate development of equivalent or surrogate animal research and clinical trial endpoints. Explore the value of surrogate endpoints for nervous system disorders. Identify components that require recapitulation in both animal studies and clinical trials.

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90 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS 10:15 a.m. Overview and Session Objectives SHARON ROSENZWEIG-LIPSON, Session Chair 10:30 a.m. Prepulse Inhibition: Corresponding Endpoints, But to What End? NEAL SWERDLOW Professor Department of Psychiatry University of California, San Diego 10:45 a.m. Choice of Endpoints—EAE to Approved Drug—One Huge Success; One Massive Failure LARRY STEINMAN Professor Department of Neurology and Neurological Sciences Stanford University 11:00 a.m. Improving Bidirectional Translation for Nervous System Disorders MICHELA GALLAGHER Krieger-Eisenhower Professor of Psychology and Neuroscience Department of Psychological and Brain Sciences Johns Hopkins University 11:15 a.m. Discussion with Speakers and Participants 11:45 a.m. LUNCH (will be provided for all participants) SESSION V: THE BASIC AND CLINICAL SCIENCE GAP Session Objective: Explore methods for increasing bidirectional application of research findings between basic and clinical researchers. Examine regulatory requirements that may either facilitate or impede translation of animal models. Identify methods to increase confidence in

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APPENDIX B 91 the movement from animal models to clinical trials, including replication of studies. 1:00 p.m. Overview and Session Objectives MARK GEYER, Session Chair 1:10 p.m. Developing Better Animal Models of Etiology and Pathophysiology RICHARD RANSOHOFF Director Neuroinflammation Research Center Cleveland Clinic 1:30 p.m. Panel Discussion on the Session Topic (15 minutes/speaker) DEANNA BARCH Professor of Psychology, Psychiatry and Radiology Washington University GERRY DAWSON Chief Science Officer P1vital HUGO GEERTS Scientific Liaison Officer In Silico Biosciences THOMAS STECKLER Senior Scientific Director Neuroscience Drug Discovery Johnson & Johnson 2:30 p.m. Discussion with Speakers and Participants 3:00 p.m. BREAK

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92 ANIMAL MODELS FOR NERVOUS SYSTEM DISORDERS SESSION VI: FUTURE DIRECTIONS AND NEXT STEPS Session Objective: Define important, yet practical, expectations for animal models in nervous system disorders. Identify opportunities and key stakeholders necessary for the success of improving translation of animal models. Identify key components of the infrastructure support that will be required for implementation. 3:15 p.m. Overview and Session Objectives RICHARD HODES and STEVEN PAUL Session Chairs 3:25 p.m. Session Synopsis and Next Steps STEVIN ZORN, Session I Chair RICHARD HODES, Session II Co-Chair STEVEN PAUL, Session II Co-Chair WALTER KOROSHETZ, Session III Chair SHARON ROSENZWEIG-LIPSON, Session IV Chair MARK GEYER, Session V Chair 4:25 p.m. Discussion with Speakers and Participants 5:00 p.m. ADJOURN