Agenda: Workshop on Glutamate-related Biomarkers in Drug Development for Disorders of the Nervous System
Forum on Neuroscience and Nervous System Disorders
Board on Health Sciences Policy
Glutamate-related Biomarkers in Drug Development
for Disorders of the Nervous System
June 21, 2010
Institute of Medicine
500 Fifth St., NW
Keck 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 development 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 implementation of these biomarkers as powerful tools to advance drug development for nervous system disorders associated with glutamatergic dysfunction.
Meeting objectives:
• Briefly outline the need for glutamate-related biomarkers both for understanding the causes of neuropsychiatric disorders and neurodegenerative diseases associated with glutamatergic dysfunction, and for accelerating drug development for these disorders.
• Discuss the most promising current and emerging technologies and analytical methods for assessing glutamatergic neurotransmission, and identify the research gaps for their development into biomarkers.
• Outline approaches for biomarker validation in preclinical and clinical studies, including relevant animal models and translational challenges.
• Discuss the implementation and regulatory barriers to incorporating glutamatergic biomarkers into drug development for neuropsychiatric disorders and neurodegenerative diseases and approaches to overcome them.
• Identify the next steps to establish principles and procedures to accelerate biomarker development, validation, and implementation in clinical trials, including frameworks for partnerships and collaboration.
1:00 p.m. Welcome, Introductions, and Workshop Objectives
CHI-MING LEE, Workshop co-chair
Executive Director of Translational Science
AstraZeneca Pharmaceuticals
DANIEL JAVITT, Workshop co-chair
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
SESSION I: GLUTAMATE DYSFUNCTION IN NERVOUS SYSTEM DISORDERS AND STATEMENT OF NEED
Session Objective:
Outline the current state of knowledge and the therapeutic gaps in several nervous system disorders associated with glutamatergic dysfunction, focusing on neuropsychiatric disorders and neurodegenerative 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
2:30 p.m. Chronic pain: glutamate dysfunction, treatments, and need for glutamate biomarkers
BRIAN CAIRNS
Associate Professor & 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 (AD): 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 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
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
Senior Director
Biomarker Group
Eli Lilly
4:20 p.m. Discussion with panelists and attendees
CHI-MING LEE, Workshop co-chair
Executive Director of Translational Science
AstraZeneca Pharmaceuticals
DANIEL JAVITT, Workshop co-chair
Program Director
Cognitive Neuroscience and Schizophrenia
Nathan Kline Institute
5:00 p.m. ADJOURN
Glutamate-related Biomarkers in Drug Development
for Disorders of the Nervous System
June 22, 2010
Institute of Medicine
500 Fifth St., NW
Keck 100
Washington, DC 20001
SESSION II: CURRENT AND EMERGING TECHNOLOGIES TO ASSESS GLUTAMATERGIC FUNCTION
Session Objectives:
Discuss current and emerging technologies and associated analytical methods for assessing glutamatergic function, their specificity for the glutamate system, their potential for translation into clinical biomarkers, and their validation status.
Discuss biomarkers that act on specific glutamate receptor subtypes and their relative potential as robust biomarkers
Present biomarkers that assess three broad aspects of glutamatergic function: function of the glutamate system (e.g. imaging), mutations in genes involved in glutamate system function, and gene expression (mRNA and protein) in the glutamate signaling pathway. Discuss their relative potential as robust biomarkers
Identify opportunities for increasing biomarker sensitivity using combinatorial approaches (e.g. combining proteomics and imaging)
Discuss approaches to standardize and optimize these approaches as glutamate biomarkers, including sample collection, data acquisition, and analysis
Identify the scientific gaps and barriers to implementing these approaches as biomarkers for clinical research, and strategies for overcoming them
9:00 a.m. Welcome and Review of Day One
CHI-MING LEE, Workshop co-chair
Executive Director of Translational Science
AstraZeneca Pharmaceuticals
DANIEL JAVITT, Workshop co-chair
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
Visual measures – transient & steady-state visually evoked potentials (ssVER); 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
• What potential targets have the potential for treatment and what is its status?
• What biomarkers currently could be used to evaluate medications that target the glutamatergic system?
• What biomarkers have the potential to be used clinically to guide on 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
P300 (auditory; visual)
DANIEL MATHALON
Associate Adjunct Professor
Department of Psychiatry
Co-director of the Brain Imaging and EEG Laboratory
University of California, San Francisco
Error-related negativity (ERN)
CINDY YEE-BRADBURY
Associate Professor
Department of Psychology
University of California, Los Angeles
Working memory - Event Related Potential (ERP); functional MRI (fMRI); gamma evoked oscillations
ANGUS MACDONALD
Associate Professor
Department of Psychology
University of Minnesota
Hippocampal function & long-term potentiation (LTP)
JOHN LISMAN
Professor of Biology
Brandies University
11:45 p.m. Discussion with panelists and attendees
• What potential targets have the potential for treatment and what is its status?
• What biomarkers currently could be used to evaluate medications that target the glutamatergic system?
• What biomarkers have the potential to be used clinically to guide on 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 of Drug Abuse
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 Neuropsyhciatric Diseases
RIMA KADDURAH-DAOUK
Associate Professor
Department of Psychiatry
Duke University
2:25 p.m. Discussion with panelists and attendees
• What potential targets have the potential for treatment and what is its status?
• What biomarkers currently could be used to evaluate medications that target the glutamatergic system?
• What biomarkers have the potential to be used clinically to guide on glutamatergic medications?
NORA VOLKOW, Panel Chair
Director
National Institute of Drug Abuse
3:00 p.m. BREAK
SESSION III: GLUTAMATE BIOMARKER VALIDATION: ANIMAL MODELS AND CLINICAL TRIAL DESIGN
Session objectives:
• Discuss the key factors that will affect successful translation of rodent and primate biomarkers
• Examine the advantages and limitations of rodent models in biomarker development and validation, and examine approaches to leverage rodent models for biomarker development and for biomarker-based preclinical trials
• Explore opportunities that were discussed that could facilitate combinatorial approaches (e.g. combining proteomics and imaging)
• Identify the key principles that should be considered with biomarker validation in primate models, including most relevant technologies for testing in primates
• Identify and discuss optimal principles of clinical trial design for biomarker validation in humans
3:15 p.m. Session Objectives and Introduction
WILLIAM POTTER, Panel Chair
Co-Chair Emeritus,
Neuroscience Steering Committee, FNIH Biomarkers Consortium
former Vice President, Translational Neuroscience,
Merck & Co., Inc.
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
Co-Chair 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:
• Discuss the current barriers to biomarker development in academia and industry
• Discuss the opportunities for partnerships to advance glutamate biomarker development (such a public-private partnerships in the precompetitive space) within existing or novel frameworks
• Discuss strategies for pooling of resources and data, including failed clinical trial data
• Identify a path forward to establish principles and procedures leading 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 Office
Neuroscience Research Unit
Pfizer
STEVIN ZORN
Executive Vice President R&D
Lundbeck
DARRYLE SCHOEPP
Senior Vice President and Franchise Head
Neuroscience
Merck
Discussion questions:
• What are the most promising technologies and analytical methods for assessing glutamatergic function with potential for development and translation into robust clinical biomarkers?
• What are the implementation barriers to incorporating glutamatergic biomarkers into drug development for neuropsychiatric disorders and neurodegenerative diseases and approaches to overcome them?
• What partnerships are needed to accelerate glutamate biomarker research and development for translational medicine?
• What are the next steps toward establishing research principles and guidelines for qualification of glutamatergic biomarkers?
5:15 p.m. Discussion with speakers and attendees
5:30 p.m. ADJOURN
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