Strategic Research Institute, The Westin Princeton
April 11-12, 2005
Monday, April 11, 2005 (Day 1)
7:00 - 9:00
Pre-Conference Workshop Registration, Networking & Exhibits
PRE-CONFERENCE WORKSHOP
Pharma and Biotech Licensing Opportunities in Psychiatric Drug Discovery and Development
The purpose of the workshop is to identify and facilitate alliances and inlicensing opportunities between biotech and large pharmaceutical companies working in Psychiatry. CEOs and executives from biotech and pharmaceutical companies looking for partners will present their partnering goals and specific areas of interest. Senior industry representatives will be available to provide expert commentary and discussion from the customer perspective. The workshop is interactive, hence attendees will have the opportunity to participate during the session to ask questions and interject commentary. One on one networking appointments will then be facilitated throughout the conference between presenters and attendees.
Moderator John Reid, Ph.D.
Director, CNS Discovery
AstraZeneca Pharmaceuticals
PRE 703: A Novel mGluR Competitive Antagonist as Potential Anti-Anxiety Agent
Ken Curry, Ph.D.
CSO
Prescient Neuropharma
Ocaperidone, A New Profile Antipsychotic in Phase II
Cesare Mondadori
CSO
Neuro3d
Reactivate Quiescent Pathways : A New Way to Treat Depression
Dinah Weissman
CEO
Biocortech
Allosteric Modulators to Dopamine Receptors: the Next-Generation Stabilizers for Schizophrenia
Juan Ballesteros, Ph.D.
CEO
Novasite
Full D1 Agonists: Novel Treatment for Cognitive Deficits in Psychiatric Disorders
Prabhavathi Fernandes, Ph.D.
President and CEO
DarPharma Novel Approaches to Improve Target Selectivity of Neuro-Psychiatric Drugs using NP2 Technology Paul B. Bennett, Jr., Ph.D.
Vice President, Discovery
Neurion Pharmaceuticals
9:00 - 9:15
Opening Remarks
Session Chairs: Menelas N. Pangalos, Ph.D.
Vice President Neuroscience Research
Wyeth Research Darryle D. Schoepp, Ph.D.
Vice President Neuroscience Discovery Research
Lilly Research Laboratories, Eli Lilly and Company C. Anthony Altar, Ph. D.
Vice President, Research
Psychiatric Genomics, Inc.
9:15 - 10:00
KEYNOTE ADDRESS: What are the Targets, Clinical and Pharmacologic, for Psychotropic Drugs and How Shall we Find Them?
It has been estimated that current treatments of schizophrenia, bipolar disorder, and major depression, relieve, in aggregate, only 20-60% of the disability associated with these illnesses. The range of responses in individual patients is from worsening (inducing suicide?) to full remission, if not cure. The limited effectiveness of current treatments is a result of both lack of broad-spectrum efficacy, poor tolerability, and non-adherence which stems, in part, from the largely genetically driven diversity and overlap of these disorders. This talk will discuss some key concepts for developing better, if less universal, treatments, based upon understanding the disease processes and identifying the specific strengths and weaknesses of current treatments, focusing on schizophrenia and antipsychotic drugs as an example. Integrated clinical and basic research strategies which target the major unmet needs in this disorder, improving cognition and negative symptoms without causing metabolic side effects, will be stressed. Examples of pharmacologic, genetic, pharmacogenomic and biomarker strategies that have proven helpful to identify targets for more effective and tolerable drugs for schizophrenia and bipolar disorder will be presented. Herbert Y Meltzer, M.D.
Bixler Professor of Psychiatry and Pharmacology
Vanderbilt University School of Medicine
10:00 - 10:30
Gene Expression in Human Brain: Susceptibility Genes and the Neurobiology of Schizophrenia
This talk will focus on the use of postmortem human brains to elucidate the cellular and molecular mechanisms that lead to schizophrenia. Two of our objectives include the following: 1. To compare the expression of susceptibility genes in schizophrenic brains with normal controls; and 2. To examine the effects of allelic variations in susceptibility genes on the expression of these genes and related molecules. Although we have done a number of studies on ten of these genes to date, this talk will focus on the following three, COMT, GRM3 and DTNBP1, and to a lesser degree on three others, DISC1, GAD1 and NRG1. The neuroanatomical focus will be on dorsolateral prefrontal cortex, hippocampus and to a lesser degree, brainstem. Differences in expression of mRNA and/or protein levels have been found in three of these genes while effects of allelic variations on expression of these genes or related compounds have been found in all six genes. Hopefully, these findings and this approach will lead to improved understanding and targets for improved diagnosis and treatment. Joel E. Kleinman, M.D., Ph.D.
Chief, Section on Neuropathology and Deputy Chief
NIMH/NIH
10:30 - 11:00
Recent Progress in Glutamate Receptor Modulation to Treat Psychiatric Disorders
Glutamate is an important neurotransmitter involved in modulating excitability throughput cortical and subcortical circuits involved in the pathophysiology of psychiatric and neurological disorders. Pharmacological agents which target ionotropic and metabotropic (mGlu) receptor subtypes are now being investigated in patients based on very novel profiles in animal and human models of these illnesses. These include AMPA receptor modulators for cognition, neurodegenerative disorders and depression that alter the underlying plasticity of the nervous system, and mGlu receptor agonists and antagonists for anxiety, psychosis, and drug abuse disorders. This talk will review the most recent data and insights on these potential therapeutic agents. Darryle D. Schoepp, Ph.D.
Vice President, Neuroscience Discovery Research
Eli Lilly and Company
11:00 - 11:30
Refreshments, Networking & Exhibits
11:30 - 12:00
Bioaminergic Modulation and Approaches to Depression
The antidepressants currently in clinical practice modulate serotonergic and noradrenergic neurotransmitter systems. Despite the efficacy of these agents there is still unmet clinical needs in terms of efficacy parameters and side effects. In addition to bioaminergic strategies focusing upon subtype selective molecular targets (eg. 5-HT2C agonists), there are interesting novel combination mechanisms (eg. SSRI/5-HT1A antagonists) with intriguing scientific rationale based upon our understanding of monoaminergic neurochemistry and depression. Lee E. Schechter
Therapeutic Area Head/Director Depression and Anxiety Research Discovery Neuroscience
Wyeth
12:00 - 1:20
Networking Luncheon
1:20 - 1:40
Exploring the Use of Gene Expression-Based in vivo Pharmacodynamic Assays
A major component of the drug discovery process is the use of animal models to demonstrate in vivo efficacy and to optimize basic in vivo drug properties. Unfortunately, in many cases the number of compounds that can be tested is limited by the time and expense associated with the assays; this is especially true of CNS models with a behavioral readout. What is needed is a primary in vivo assay that employs a simple but reliable marker that measures a drug effect in the CNS. This assay can be used to establish many of the pharmacodynamic properties of the compound prior to in vivo functional testing. The use of both global and specific quantitative gene expression profiling platforms for the development and implementation of in vivo pharmacodynamic assays will be discussed. Michael Mallamaci, Ph.D.
Group Leader, CNS Discovery, Target Biology Department AstraZeneca
AstraZeneca
1:40 - 2:10
SmartCubeTM Analytical Systems: High Throughput Behavioral Screening Technology for Psychiatric Drug Discovery
SmartCubeTM, an automated high throughput behavioral testing system, is designed to overcome many of the limitations associated with standard in vivo testing and enable a behavior-driven approach to psychiatric drug discovery. The system employs robotics, computer-aided vision, and machine learning to measure over 2,000 features of mouse behavior and create a unique behavioral signature for each compound. SmartCubeTM automates and standardizes the process of collecting, analyzing and storing behavioral information, substantially increasing the throughput and accuracy of the data. A database of behavioral signatures for clinically effective reference compounds called SmartBaseTM has been established and bioinformatics tools have been developed to create a unique classification system to predict therapeutic potential. This therapeutic classification system has been validated for several classes of psychiatric medication, including antidepressants, anxiolytics and antipsychotics. Paul McGonigle, Ph.D.
CSO
Psychogenics CNS Drug Development
2:10 - 2:40
Biomarkers in Psychiatric Drug Development
Biomarkers have been widely but rarely systematically used in psychiatric drug development. As new drug candidates targeting novel mechanisms come to the clinic, they pose difficult challenges, particularly related to demonstrating on-target pharmacology, and require novel biomarker strategies. This presentation will focus on integrating biomarkers into early development for several novel compounds. David Michelson, M.D.
Executive Director, Neuroscience Medical Research
Lilly Research Laboratories
2:40 - 3:10
Application of Expression Signatures to Psychiatric Theranostics
Over many years scientists have searched in blood, urine and CSF for biomarkers of psychiatric disorders. A recent advance pioneered for cancer diagnostic uses patterns of gene or protein expression to identify certain types of cancer, predict outcomes and identify sub-groups of patients likely to benefit from specific treatments. There has been considerable progress in identifying patterns of gene and protein expression that may predict certain classes of mental illness, responses to drugs and side effects. Biomarkers can also be used to discover novel therapeutics. The presentation will cover the use of biomarkers in diagnostics and therapeutics (Theranostics) and discuss the opportunity they present for better disease management. Michael G. Palfreyman, Ph.D.
Principal
NOVACE Corporation
3:10 - 3:40
Networking, Refreshments & Exhibits
3:40 - 4:10
Neuroimaging in CNS Drug Development
Neuroimaging provides a powerful view into the brain, which has historically posed a "black box" challenge assessed via subjective means. While Magnetic Resonance Imaging (MRI) provides exquisite anatomical detail, PET imaging can be used to identify both the biochemical and functional characteristics of a drug. The PET image data can address key questions in the drug development process, including whether a compound has a central effect,
where that effect occurs, in what relationship to dose, with what behavioral implications, and in what relationship to other compounds. Neuroimaging provides value across all phases of clinical drug development, and as a translational model for preclinical development using nonhuman primates. Terry Brown, C.N.M.T.
Founder and EVP of Operations
MIICRO, INC
4:10 - 4:40
Obtaining Novel Indications in the Neurosciences: Developmental and Regulatory Challenges
Psychiatric syndromes are complicated, generally chronic conditions associated with a spectrum of symptomatology and functional impairment. Current pharmacological treatments, though, more frequently focus on short-term improvement as measured by scales capturing overall syndromal response. Though efficacy may be established and indication approval obtained, demonstration of improvement in some clinically relevant symptom domains may be lacking, and treatments may subsequently fall short of clinical goals and patient expectations. This talk will focus on some of the unique later phase development challenges and obstacles to obtaining novel indications in the neurosciences, incorporating examples of recent successful approvals. Steve Romano, M.D.
Therapeutic Area Head, Psychiatry Worldwide Medical
Pfizer, Inc.
4:40 - 5:45
Innovations in Clinical Research
Most often the outcome of a clinical trial hinges on the quality of the data and lowering of the placebo response. This symposium will focus on several innovations that attempt to achieve this goal. A roundtable discussion will follow where the participants are invited to expand on their perception of these issues and upon other innovations they have found useful. Moderator: Christopher D. Breder, M.D., Ph.D.
Director, Neuroscience Global Clinical Research
Bristol Myers Squibb Panelists: Michael Gendreau, M.D., Ph.D.
VP of Development
Chief Medical Officer
Cypress Bioscience Inc Alan Feiger, M.D.
Medical Director
Research Training Associates of Colorado Gary Sachs, M.D.
Director, Bipolar Clinical and Research Program
Massachusetts General Hospital
5:45 - 5:55
Chair’s Recap of Day One
5:55 - 7:15
Networking Reception
Tuesday, April 12, 2005 (Day 2)
7:30 - 8:30
Breakfast, Networking & Exhibits
8:30 - 8:45
Chairs’ Recap of Day One
NEW MOLECULAR TARGETS
8:45 - 9:30
Mining the Receptorome Reveals Validated Molecular Targets for CNS Drug Discovery
With the recently completed sequencing and annotation of the human genome it has become clear that much is devoted to encoding signal-tranduction molecules. Indeed, one estimate is that approximately 20% of the human genome is devoted to signal transduction and that many of these signal transducing molecules represent receptors of various types. Of the many classes of receptors, G-protein coupled receptors (GPCRs) represent the largest family representing nearly 4% of the human genome. Ion channels and transporters, which frequently function as 'receptors' for drugs and neurotransmitters, represent another 3% of the genome while non-GPCR receptors represent at least 1.5% of the genome. Taken together we have estimated that the receptorome, which we have defined as that portion of the proteome encoding 'receptors' represents more than 8% of the human genome (Armbruster and Roth, JBC 2004). I will review the receptorome and show how 'receptoromics' --the massively parallel screening of the receptorome via in silico and physical screening--provides novel insights into molecular target identification for psychiatric drug design and discovery. In particular, I will show how receptoromics facilitates the discovery of 'selectively-non-selective' drugs (Roth et al, Nature Rev Drug Discovery, 2004). Bryan Roth Ph.D.
Director
National Institute of Mental Health Psychoactive Drug Screening Program
Professor of Biochemistry
Case Western Reserve University Medical School
9:30 - 10:00
WAY-163909, a 5-HT2C Selective Agonist for the Treatment of Obesity, Depression and Schizophrenia: Lack of Tolerance
When developing agonists as potential therapeutics, a common concern is the development of tolerance to the therapeutic effects of an agonist following repeated administration. WAY-163909 is a highly selective 5-HT2C receptor full agonist that is efficacious in multiple models of obesity, depression, and schizophrenia. The neurochemical, electrophysiological, and behavioral effects of WAY-163909 have been evaluated following both acute and chronic administration (14-21 days) and the effects of WAY-163909 are unchanged following chronic dosing. Sharon Rosenzweig-Lipson, Ph.D.
Principal Research Scientist II
Wyeth Research
10:00 - 10:30
Genetic and Genomic Targets for Psychiatric Drug Discovery
Alterations in the sequence, and expression, of genes that encode for proteins involved in schizophrenia and bipolar disorder have been identified through their association with disease or its treatment with effective drugs or other therapies. Dr. Altar will describe the application of these novel forms of target identification to medicinal chemistry programs. These use both medium throughput conventional screening assays, and high content, mRNA-based screening assays. Each approach is being used to identify compounds for the treatment of negative and positive symptoms of schizophrenia, and has yielded a novel compounds that shows potent in vitro activity in an in vivo assay for mood stabilizing drugs. C. Anthony Altar, Ph.D.
Vice President, Research
Psychiatric Genomics, Inc
10:30 - 11:00
Networking, Refreshments & Exhibits
11:00 - 11:30
PDE10A Inhibitors as Potential Antipsychotics
PDE10A is a recently described cyclic nucleotide phosphodiesterase expressed at high levels in the brain and more specifically in the medium spiny neurons of the striatum and associated n. accumbens/ olfactory tubercle. Papaverine has been identified as a potent and selective inhibitor of recombinant rat PDE10A. This presentation will focus on the in vitro and in vivo effects of papaverine, including activity in animal models of antipsychotic activity. The neurochemical and behavioral characterization of PDE10A knockout mice will also be discussed. Judith A. Siuciak, Ph.D.
Senior Research Investigator - CNS Discovery Research
Pfizer Inc.
11:30 - 12:00
Allosteric Potentiators of Muscarinic Receptors and Metabotropic Glutamate Receptors as a Novel approach for Treatment of Schizophrenia.
Activators of M1 muscarinic receptors or mGluR5 metabotropic glutamate receptors may provide a novel approach for treatment of schizophrenia. We have developed a novel approach to allow selective activation of M1 or mGluR5 with compounds that target allosteric sites that to dramatically potentiate activation of the receptors by endogenous agonists. For mGluR5, we have developed highly selective allosteric potentiators that orally bioavailable and have robust behavioral effects in animal models predictive of antipsychotic efficacy. P. Jeffrey Conn, Ph.D.
Director, Department of Pharmacology, Program in Translational Neuropharmacology
Vanderbilt University Medical Center
12:00 - 1:30
Networking Luncheon
1:30 - 2:00
Characterization of Small Molecule CRF-1 Antagonists
Corticotropin-releasing factor (CRF) is a mediator of the nervous, endocrine, and immune responses to stress. It has been implicated in clinical disorders such as depression and anxiety. Preclinical data suggest that over-activation of the CRF1 receptor is involved in these clinical disorders. Long-standing efforts exist to identify small molecule CRF1 antagonists for evaluation in depression and anxiety. The in vitro characterization of several small molecule CRF1 antagonists suggests an allosteric mode of inhibition of CRF actions. However, recent studies demonstrate low potency inhibition of radiolabeled small molecule antagonist binding by CRF suggesting some overlap of binding domains. Small molecule CRF1 antagonists have been shown to be active in a number of rodent models that suggest efficacy in anxiety and depression. Efficacy in these models correlates well with CRF1 receptor occupancy in ex vivo binding experiments consistent with action through CRF1 blockade. Nicholas Lodge Ph.D.
Neuroscience Drug Discovery
Bristol Myers Squibb
2:00 - 2:30
The Truth About Trace Amines and their Receptors
Trace amines are endogenous substances related to the biogenic amine that occur at low levels in mammalian brain as well as other intriguing locations. They are considered to be potential neuromodulators in the nervous system. Interest in this field has begun to re-emerge due to the discovery, by our group and others of a family of G-protein Coupled Receptors some members of which have been shown to respond to trace amines. Although it is still early days, concepts of potential function of these receptors are emerging. Making use of a genetic strategy, we have been a knock-out animals that deletes one trace amine receptor: TA-1. These animals have deficits in Prepulse Inhibition and enhanced sensitivity to amphetamine, thus suggesting roles for this receptor in conditions such as psychosis, ADHD, and substance abuse Theresa A. Branchek, Ph.D.
Executive Vice President
Synaptic Pharmaceuticals
2:30 - 3:15
Brand Case Study: Clinical, Regulatory and Commercial Decisions Leading to Seroquel’s Success
Martin Brecher, M.D.
Medical Science Director
AstraZeneca
3:15 - 3:25
Chair’s Closing Remarks
3:25 - 3:30
Conference Concludes
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