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C Agenda GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT FOR DISORDERS OF THE NERVOUS SYSTEM June 21 and 22, 2010 Institute of Medicine 500 Fifth Street, NW Keck Building, Room 100 Washington, DC 20001 Background: Dysfunction of glutamatergic neurotransmission has been implicated in many nervous system disorders, including neuropsychiatric disorders such as anxiety, schizophrenia and major depressive disorder, and neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis. Biomarkers that specifically measure glutamate signaling and related circuitry are a promising means to accelerate drug develop- ment for disorders associated with glutamatergic dysfunction by providing quantitative measures for diagnosis, patient stratification, and assessment of drug efficacy. The goal of the workshop is to present promising current and emerging technologies with potential as reliable glutamate biomarkers, and to outline strategies to accelerate development, validation, and implementa- tion of these biomarkers as powerful tools to advance drug development for nervous system disorders associated with glutamatergic dysfunction. Meeting Objectives: • B riefly outline the need for glutamate-related biomarkers both for understanding the causes of neuropsychiatric disorders and neuro- degenerative diseases associated with glutamatergic dysfunction, and for accelerating drug development for these disorders. 49

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50 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT • D iscuss the most promising current and emerging technologies and analytical methods for assessing glutamatergic neurotransmis- sion, and identify the research gaps for their development into biomarkers. • O utline approaches for biomarker validation in preclinical and clinical studies, including relevant animal models and translational challenges. • D iscuss the implementation and regulatory barriers to incorporat- ing glutamatergic biomarkers into drug development for neuropsy- chiatric disorders and neurodegenerative diseases and approaches to overcome them. • I dentify the next steps to establish principles and procedures to accelerate biomarker development, validation, and implementa- tion in clinical trials, including frameworks for partnerships and collaboration. June 21: Keck Center Room 100 1:00 p.m. Welcome, Introductions, and Workshop Objectives Chi-Ming Lee, Workshop Cochair Executive Director of Translational Science AstraZeneca Pharmaceuticals Daniel Javitt, Workshop Cochair Program Director Cognitive Neuroscience and Schizophrenia Nathan Kline Institute 1:10 p.m. Overview of the Glutamatergic System in the CNS: How Does a Single Neurotransmitter Result in So Many Diverse Functions? Darryle Schoepp Senior Vice President and Franchise Head Neuroscience Merck

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51 APPENDIX C SESSION I: GLUTAMATE DYSFUNCTION IN NERVOUS SYSTEM DISORDERS AND STATEMENT OF NEED Session Objective: • utline the current state of knowledge and the therapeutic gaps O in several nervous system disorders associated with glutamatergic dysfunction, focusing on neuropsychiatric disorders and neuro- degenerative disease. Discuss the needs and potential benefits of glutamate biomarkers for accelerating drug development for these diseases. 1:30 p.m. Schizophrenia: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Daniel Javitt Program Director Cognitive Neuroscience and Schizophrenia Nathan Kline Institute 1:45 p.m. Anxiety Disorders: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Jeffrey Conn Professor of Pharmacology Director, Vanderbilt Program in Drug Discovery Vanderbilt University 2:00 p.m. Major Depressive Disorder (MDD): Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Carlos Zarate Chief of the Mood and Anxiety Disorders Research Unit Associate Clinical Director of the Laboratory of Molecular Pathophysiology NIMH, NIH 2:15 p.m. Autism Spectrum Disorders: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Mark Bear Picower Professor of Neuroscience Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Scientific Founder, Seaside Therapeutics

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52 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT 2:30 p.m. Chronic Pain: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Brian Cairns Associate Professor and Canada Research Chair in Neuropharmacology Faculty of Pharmaceutical Sciences The University of British Columbia–Vancouver 2:45 p.m. BREAK 3:00 p.m. Alzheimer’s Disease: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Lennart Mucke Professor of Neurology Director and Senior Investigator Gladstone Institute of Neurological Disease University of California–San Francisco 3:15 p.m. Drug Addiction: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Peter Kalivas Co-Chair, Department of Neurosciences Medical University of South Carolina 3:30 p.m. Stroke and Ischemia: Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Dennis Choi Vice-President for Academic Health Affairs Woodruff Health Sciences Center Executive Director of the Strategic Neurosciences Initiative Emory University

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53 APPENDIX C 3:45 p.m. Amyotrophic Lateral Sclerosis (ALS): Glutamate Dysfunction, Treatments, and Need for Glutamate Biomarkers Jeffrey Rothstein Professor of Neurology Johns Hopkins University Director of the Robert Packard Foundation for ALS Research 4:00 p.m. Biomarkers and Biomarker Technologies for Glutamatergic Therapeutics: Progress, Opportunities, and Challenges Kalpana Merchant Chief Scientific Officer Translational Science Eli Lilly and Company 4:20 p.m. Discussion with Panelists and Attendees Chi-Ming Lee, Workshop Cochair Executive Director of Translational Science AstraZeneca Pharmaceuticals Daniel Javitt, Workshop Cochair Program Director Cognitive Neuroscience and Schizophrenia Nathan Kline Institute 5:00 p.m. ADJOURN June 22: Keck Center Room 100 SESSION II: CURRENT AND EMERGING TECHNOLOGIES TO ASSESS GLUTAMATERGIC FUNCTION Session Objectives: • iscuss current and emerging technologies and associated analyti- D cal methods for assessing glutamatergic function, their specificity for the glutamate system, their potential for translation into clinical biomarkers, and their validation status.

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54 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT • D iscuss biomarkers that act on specific glutamate receptor subtypes and their relative potential as robust biomarkers. • P resent biomarkers that assess three broad aspects of glutamatergic function: function of the glutamate system (e.g., imaging), muta- tions in genes involved in glutamate system function, and gene ex- pression (mRNA and protein) in the glutamate signaling pathway. Discuss their relative potential as robust biomarkers. • I dentify opportunities for increasing biomarker sensitivity us- ing combinatorial approaches (e.g., combining proteomics and imaging). • D iscuss approaches to standardize and optimize these approaches as glutamate biomarkers, including sample collection, data acquisi- tion, and analysis. • I dentify the scientific gaps and barriers to implementing these ap- proaches as biomarkers for clinical research, and strategies for overcoming them. 9:00 a.m. Welcome and Review of Day One Chi-Ming Lee, Workshop Cochair Executive Director of Translational Science AstraZeneca Pharmaceuticals Daniel Javitt, Workshop Cochair Program Director Cognitive Neuroscience and Schizophrenia Nathan Kline Institute 9:10 a.m. Panel Discussion: Sensory-Based Biomarkers Daniel Umbricht, Panel Chair Lead, Neuroscience Translational Medicine Hoffmann-La Roche Auditory Sensory Responses—Mismatch Negativity; N1; Auditory Steady-State Responses Gregory Light Associate Professor of Psychiatry University of California–San Diego

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55 APPENDIX C Visual Measures—Transient and Steady-State Visually Evoked Potentials (ssVEP); SPEM (Smooth Pursuit Eye Movements); Visual P1 Brian O’Donnell Professor of Psychology Indiana University Gating Measures—Auditory P50 Response, Prepulse Inhibition Bruce Turetsky Associate Professor of Psychiatry Associate Director, Neuropsychiatry Division Director, Neurophysiology and Brain Imaging Laboratory University of Pennsylvania 10:00 a.m. Discussion with Panelists and Attendees • hat potential targets have the potential for treatment and W what is their status? • hat biomarkers currently could be used to evaluate med- W ications that target the glutamatergic system? • hat biomarkers have the potential to be used clinically W to guide glutamatergic medications? Daniel Umbricht, Panel Chair Lead, Neuroscience Translational Medicine Hoffmann-La Roche 10:30 a.m. BREAK 10:45 a.m. Panel Discussion: Cognition-Based Biomarkers Mihaly Hajos, Panel Chair Neuroscience Department, CNS Discovery Pfizer Global Research and Development Error-Related Negativity (ERN) Cindy Yee-Bradbury Associate Professor Department of Psychology University of California–Los Angeles

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56 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT P300 (Auditory; Visual) Daniel Mathalon Associate Adjunct Professor Department of Psychiatry Codirector of the Brain Imaging and EEG Laboratory University of California–San Francisco Working Memory—Event-Related Potential (ERP); Functional MRI (fMRI); Gamma-Evoked Oscillations Angus MacDonald Associate Professor Department of Psychology University of Minnesota Hippocampal Function and Long-Term Potentiation (LTP) John Lisman Professor of Biology Brandeis University 11:45 a.m. Discussion with Panelists and Attendees • hat potential targets have the potential for treatment and W what is their status? • hat biomarkers currently could be used to evaluate med- W ications that target the glutamatergic system? • hat biomarkers have the potential to be used clinically W to guide glutamatergic medications? Mihaly Hajos, Panel Chair Neuroscience Department CNS Discovery Pfizer Global Research and Development 12:15 p.m. LUNCH 12:45 p.m. Panel Discussion: Genetic, Biochemical, and Metabolic- Based Biomarkers Nora Volkow, Panel Chair Director National Institute on Drug Abuse

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57 APPENDIX C Positron Emission Tomography (PET) Approaches to the Glutamatergic System (Pre-and Post-Synaptic Receptors, Transporters) Robert Innis Molecular Imaging Branch PET Neuroimaging Sciences Section NIMH, NIH An Integrated Imaging and Animal Models Approach to Identifying Schizophrenia Biomarkers Stephen Rayport Associate Professor of Clinical Neuroscience Department of Psychiatry Columbia University Medical Center Proton Magnetic Resonance Spectroscopy (MRS) Robert Mather Principal Scientist Pfizer Pharmaceuticals Pharmacogenomic and Epigenomic Markers (Disease-Specific) Anne West Assistant Professor Department of Neurobiology Duke University Metabolomics in the Study of Neuropsychiatric Diseases Rima Kaddurah-Daouk Associate Professor Department of Psychiatry Duke University

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58 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT 2:25 p.m. Discussion with Panelists and Attendees • hat potential targets have the potential for treatment and W what is their status? • hat biomarkers currently could be used to evaluate med- W ications that target the glutamatergic system? • hat biomarkers have the potential to be used clinically W to guide glutamatergic medications? Nora Volkow, Panel Chair Director National Institute on Drug Abuse 3:00 p.m. BREAK SESSION III: GLUTAMATE BIOMARKER VALIDATION: ANIMAL MODELS AND CLINICAL TRIAL DESIGN Session Objectives: • iscuss the key factors that will affect successful translation of D rodent and primate biomarkers. • xamine the advantages and limitations of rodent models in bio- E marker development and validation, and examine approaches to leverage rodent models for biomarker development and for biomarker-based preclinical trials. • xplore opportunities that were discussed that could facilitate com- E binatorial approaches (e.g., combining proteomics and imaging). • dentify the key principles that should be considered with bio- I marker validation in primate models, including most relevant tech- nologies for testing in primates. • dentify and discuss optimal principles of clinical trial design for I biomarker validation in humans. 3:15 p.m. Session Objectives and Introduction William Potter, Panel Chair Cochair Emeritus, Neuroscience Steering Committee, FNIH Biomarkers Consortium Former Vice President, Translational Neuroscience, Merck & Co., Inc.

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59 APPENDIX C 3:20 p.m. Biomarkers in Rodent Models: Challenges in Preclinical to Clinical Translation of Glutamate Biomarkers and Strategies to Overcome Them Mark Geyer Professor of Psychiatry University of California–San Diego 3:35 p.m. Biomarker Validation in Primates: Relevant Technologies and Translational Considerations Charles Schroeder Laboratory for Cognitive Neuroscience and Neuroimaging Nathan Kline Institute 3:50 p.m. Biomarker Validation in Humans: Roles of Healthy Volunteer and Patient Studies; Approaches to Cross-Site Standardization Gunvant Thaker Professor Department of Psychiatry University of Maryland School of Medicine 4:05 p.m. Discussion with Speakers and Attendees William Potter, Panel Chair Cochair Emeritus, Neuroscience Steering Committee, FNIH Biomarkers Consortium Former Vice President, Translational Neuroscience, Merck & Co., Inc. SESSION IV: NEXT STEPS FOR ACCELERATING GLATAMATE BIOMARKER DEVELOPMENT AND QUALIFICATION Session Objectives: • iscuss the current barriers to biomarker development in academia D and industry. • iscuss the opportunities for partnerships to advance glutamate D biomarker development (e.g., public–private partnerships in the precompetitive space) within existing or novel frameworks.

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60 GLUTAMATE-RELATED BIOMARKERS IN DRUG DEVELOPMENT • D iscuss strategies for pooling of resources and data, including failed clinical trial data. • I dentify a path forward to establish principles and procedures lead- ing to the qualification of glutamate biomarkers in order to address unmet medical needs in drug development for diseases associated with glutamatergic dysfunction. 4:35 p.m. Moderated Discussion: Steven Paul, Panel Chair Executive Vice President, Science (Former) Eli Lilly Panel Discussion: Dennis Choi Vice President for Academic Health Affairs Woodruff Health Sciences Center Executive Director of the Strategic Neurosciences Initiative Emory University Mark Bear Picower Professor of Neuroscience Department of Brain and Cognitive Sciences Massachusetts Institute of Technology Scientific Founder, Seaside Therapeutics Daniel Umbricht Lead, Neuroscience Translational Medicine Hoffmann-La Roche John Dunlop Senior Vice President and Chief Scientific Officer Neuroscience Research Unit Pfizer Stevin Zorn Executive Vice President, R&D Lundbeck

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61 APPENDIX C Darryle Schoepp Senior Vice President and Franchise Head Neuroscience Merck Discussion Questions: • hat are the most promising technologies and analytical methods W for assessing glutamatergic function with potential for development and translation into robust clinical biomarkers? • hat are the implementation barriers to incorporating glutamater- W gic biomarkers into drug development for neuropsychiatric disor- ders and neurodegenerative diseases and approaches to overcome them? • hat partnerships are needed to accelerate glutamate biomarker W research and development for translational medicine? • hat are the next steps toward establishing research principles and W guidelines for qualification of glutamatergic biomarkers? 5:15 p.m. Discussion with Speakers and Attendees 5:30 p.m. ADJOURN

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