BIOCHEMICAL PHARMACOLOGY DISCUSSION GROUP THE NEW YORK ACADEMY OF SCIENCES

JULIA N. HEINRICH, PhD CHARLES A. LUNN, PhD STEVEN S. GROSS, PhD ILDIKO ANTAL, PhD Secretary, BPDG Program Coordinator, BPDG Co-Chair, BPDG Co-Chair, BPDG Bristol-Myers Squibb (908) 874-8018 Weill Cornell Medical College Bristol-Myers Squibb (609) 818-4157 [email protected] (212) 746-6257 (609) 252-6600 [email protected] [email protected] [email protected]

EXECUTIVE COMMITTEE: 25 April 2014 Joshua Apgar, PhD Boehringer Ingelheim Colleagues: Mercedes Beyna, MS Pfizer

Lakshmi Devi, PhD Mount Sinai Medical School On behalf of the Biochemical Pharmacological Discussion Group (BPDG) steering Ruth Duffy, PhD Otsuka America Pharmaceutical, Inc. committee, I am pleased to present to you the New York Academy of Science BPDG

Ahmad Fawzi, PhD GPCR BioSciences Inc. proposals and ballot for the 2015 season. Please review the proposals, score the ballot with

Carolyn Foster, PhD your selections and return to me. This process will be used to select the final program for John Hambor, PhD Boehringer Ingelheim next year. Feel free to distribute the ballot and program proposals to other members of your Huiping Jiang, PhD Boehringer Ingelheim institution. Kenneth Jones, PhD Forest Research Institute

Kenneth LaMontagne, PhD Novartis Pharmaceuticals Score your 10 best programs from 1 to 10 with decreasing order of priority as follows: Scott M. MacDonnell, PhD Boehringer Ingelheim

Robert Martone Covance Biomarker Center of Excellence 1st choice 1

Martha Matteo, PhD 2nd choice 2 Jose Perez, PhD Broad Institute 3rd choice 3 Barbara Petrack, PhD Drew University ······ ···· Pat Rose, PhD

Esther Sabban, PhD 10th choice 10 New York Medical College

Pallavi Sachdev, MPH, PhD Eisai, Inc.

JoAnne Saye, PhD Please send the completed ballot to me as an e-mail attachment by EOB on Friday, 9 May ViroPharma Inc.

June Sonnenberg-Reines, PhD 2014. The only way we are able to identify and present high interest/high quality programs

Roland Staal, PhD Lundbeck Research USA is to obtain as much feedback from as many supporters as possible. If you need further

Edward Tamer, PhD assistance, don’t hesitate to contact me. Thank you. W. Ross Tracey, PhD Novartis Institutes for BioMedical Research

Lawrence Wennogle, PhD Charles A. Lunn Intra-Cellular Therapies Inc Program Coordinator, BPDG George Zavoico, PhD MLV [email protected]

PROPOSAL #1 FULL DAY BPDG 2015 Symposium Proposal Title: “Growing Pains: The Future of Cytokines as Immunotherapies for Oncology, Infection and Inflammatory Disease” Outline: Cytokines are small, short-lived proteins produced by a broad range of cells that play an important role in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction. Preclinical studies have shown that many cytokines have considerable clinical potential as antiviral and anticancer agents or to suppress inflammatory and autoimmune conditions. However, in the clinic substantial systemic toxicity associated with low dosing regimens prevents escalation to therapeutically active regimens. One strategy to circumvent this toxicity problem is the development of immunocytokines: cytokines fused to a binding module such as a scFv-antibody fragment or a nanobody to target them to selected cells and/or sites of disease. Targeted delivery of immune-stimulatory or immune- regulatory cytokines represents a promising strategy for the treatment of cancer and chronic inflammatory diseases, respectively, by improving the therapeutic index with acceptable side effects. As of 2012 there were over 40 immunocytokines tested in animal models which assessed biodistribution properties and/or therapeutic performance; 9 of these have entered clinical development. Although the use of antibodies as the delivery vehicle has improved the therapeutic index of cytokines, additional efforts are still being explored. One such effort; “activity-by-targeting”, utilizes mutated cytokines that alter receptor binding properties combined with selective targeting to cells or tissues. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Explore emerging strategies for how cytokines and immunocytokines can be applied in clinical practice. 2. Discuss limitations and toxicities with current marketed cytokine therapies. 3. Review aspects of cytokine and immunocytokine efficacy and safety in preclinical and clinical studies 4. Evaluate the application of targeted immunocytokine therapeutics for specific disease treatments

Suggested speakers, affiliations and topics: Speaker (Institution): Michael B. Atkins (Georgetown Lombardi Comprehensive Cancer Center, Wash.DC) Title: Approved Cytokine Therapies: History of Proleukin/aldesleukin [interleukin 2 (IL2)] in the Treatment of Melanoma Speaker (Institution): Paul M. Sondel (University of Wisconsin) Title: Immunocytokine Therapies Through Enhanced ADCC Activity: Anti-GD2 + IL2 for Treatment of Neuroblastoma and Melanoma Speaker (Institution): Julien Laurent (Merck KGaA, Germany) Title: Increasing Therapeutic Indices through Tissue Targeting: EMD 521873 (Selectikine; IL-2 Fusion Protein) in the Treatment Cancer Speaker (Institution): John G. McHutchison M.D. (Duke Clinical Research Institute) or Michael W. Fried MD (University of North Carolina) Title: Approved Cytokine Therapies: PEG-Interferon in the Treatment of Hepatitis C Infection Speaker (Institution): Gilles Uze (University Montpellier II, France) Title: Increasing Therapeutic Indices of Immunocytokines: High Efficiency Targeting of Interferon (IFN)2 Activity Speaker (Institution): Dario Neri (Philogen, Zürich, Switzerland) Title: Dekavil (F8-IL10): An Immunoregulatory “Armed Antibody” for the Treatment of Rheumatoid Arthritis

Proposal Submitted By: Name: Kerry Ralph, Boehringer Ingelheim Pharmaceuticals Inc. E-mail: kerry-leigh.ralph@boehringer- ingelheim.com Name: Scott Brodeur, Boehringer Ingelheim Pharmaceuticals Inc. E-mail: scott.brodeur@boehringer- ingelheim.com

BPDG Delegate(s) Submitting Proposal: Scott MacDonnell PROPOSAL #2 FULL DAY BPDG 2015 Symposium Proposal Title: Insight into GDF-11 and related proteins and their potential role in cardiomyocyte hypertrophy and fibrosis during diastolic heart failure Outline: Heart disease is one of the leading causes of mortality worldwide. The adult mammalian heart has very limited regenerative capacity. Indeed, the replacement of the damaged tissues after myocardial infarction with fibroblast and extracellular matrix generates a robust scar that does not conduct electricity or actively contract. Therefore, one of the greatest challenges is the redirection of the heart’s innate fibrosis repair program to generate new contractile muscle cells. Recently, a novel approach to reverse age-dependent cardiac hypertrophy has emerged with the observation that specific systemic factors are declining in an aging animal model. One factor identified, GDF-11 (or BMP-11), has been proposed to be a central negative regulator of age related diastolic heart failure. GDF-11 belongs to the BMP subfamily of TGF-β ligands, and is highly similar to myostatin (another BMP molecule involved in muscle growth). While the identification of a specific regulator is appealing from a therapeutic perspective, cardiac hypertrophy appears to be the result of a delicate balance between growth and inhibitory signals, including myostatin and GDF-11. The level of each of these signals either tips the balance to growth or potentially to regression. Future work needs to focus on understanding how distinct factors from the systemic environment control cellular outcome across tissues during aging. More specifically, it will be interesting to see whether and how circulating factors impact other aged phenotypes such as reduced skeletal mass, increased adiposity and reduced insulin sensitivity.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Gain a working knowledge of recent advances in the TGF-β/BMP receptors type I/II and signaling pathways (Smad and non Smad) 2. Understand the common features and differences between GDF-11 and GDF-8 (myostatin) (receptor sensitivity, expression and signaling pathway) 3. Understand the role of BMPs in heart hypertrophy, skeletal mass, increased adiposity and reduced insulin sensitivity 4. Understand the potential challenges and benefits of targeting TGF-β/BMP pathways

Suggested speakers, affiliations and topics: Speaker (Institution): Dr. Anthony Atala (Wake Forest Inst. for Regenerative Medicine, Winston-Salem, NC) Title: Cell therapy approach for Regenerative Medicine Speaker (Institution): David Glass (Novartis Institute for Biomedical Research, Cambridge, Boston, MA) Title: Targeting Activin type II receptor Speaker (Institution): Se-Jin Lee (JHU, Baltimore, MD) Title: Regulation of GDF-11 and myostatin by specific inhibitors Speaker (Institution): Thomas Thompson (University of Cincinnati, OH) Title: Interaction between Myostatin: follistatin and receptors Speaker (Institution): Anthony Rosenzweig (Beth Israel Deaconess Medical Cntr & Harvard Medical School) Title: Effect of MSTN deletion in aging mice Speaker (Institution): Kenneth Boheler (National Institute of Aging, Baltimore, MD) Title: Molecular mechanism of cardiomyocyte aging Speaker (Institution): Alan Schneyer (University of Massachusetts-Amherst, Springfield, MA) Title: Role of TGF-B superfamily in beta cells and glucose tolerance Speaker (Institution): Richard Lee (Harvard Stem Cell Institute, Brigham and Women’s, Boston, MA) Title: GDF-11 and therapeutic opportunity for cardiac aging

Proposal Submitted By: Name: Michael Franti, Boehringer Ingelheim, E-mail: [email protected] Name: Scott MacDonnell, Boehringer Ingelheim, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Scott MacDonnell

PROPOSAL #3 ½ DAY BPDG 2015 Symposium Proposal Title: New Insights into the Pathobiology of the Glomerular Filtration Barrier

Outline: The glomerular capillary is a unique structure that comprises a fenestrated endothelium, a basement membrane, and a specialized epithelial layer (podocytes). This structure, also called the glomerular filtration barrier, is able to filter molecules inversely proportional to size despite a high rate of filtration. Dysfunction of the filtration barrier allows for urinary excretion of albumin and other macromolecules and this derangement is strongly associated with the progression of chronic kidney disease (CKD). Numerous studies have focused on the contribution of the individual components of the filtration barrier in CKD. However, recent studies have highlighted the interaction between the components, notably the glomerular endothelial cell and the podocyte, in promoting filtration barrier integrity. This interaction, also known as endothelial-podocyte crosstalk, has been demonstrated to be altered in glomerular diseases. This symposium will examine the individual role of the fenestrated endothelium, basement membrane, and the podocyte in kidney disease. Furthermore, understanding how dysregulation between these components influences disease progression may enable the development of effective therapies to combat glomerular diseases.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand the structure and function of each of the glomerular filtration barrier components (fenestrated endothelial cells, glomerular basement membrane, and podocyte) 2. Discuss current knowledge regarding pathobiology of fenestrated endothelial cells, glomerular basement membrane and podocytes in chronic kidney disease 3. Discuss the endothelial-podocyte crosstalk in normal and disease setting 4. Discuss current and future therapeutic targets to modulate endothelial-podocyte cross-talk

Suggested speakers, affiliations and topics: (4or5 for ½ day symposia, 6-8 for full day symposia) Speaker (Institution): Alda Tufro (Yale University, CT) Title: Pathobiology of Glomerular Endothelium in CKD Speaker (Institution): John Ci-jiang He (Mt Sinai Hospital, NY) Title: Podocyte Dysfunction during CKD Speaker (Institution): Sue Quaggin (Northwestern University, IL) Title: Dysregulated Endothelial-Podocyte Crosstalk during CKD Speaker (Institution): Andrew Advani (St. Michael’s Hospital, Toronto, Canada) Title: Endothelial-Podocyte Mechanisms in Preclinical Models: Do Current Animal Models Bridge Cellular Mechanisms to Clinical Outcome? Speaker (Institution): Kevin Lemley (Children’s Hospital of Los Angeles, Univ. of Southern CA) Title: Clinical Translation of Endothelial-Podocyte Crosstalk: Current and Future Therapies to Restore Filtration Barrier Integrity in Patients?

Proposal Submitted By: Name: Jay Kuo, Boehringer Ingelheim Pharmaceutical, Inc. Name: Maria Fuentes, BMS

BPDG Delegate(s) Submitting Proposal: Scott MacDonnell

PROPOSAL #4 ½ DAY BPDG 2015 Symposium Proposal Title: Broad-spectrum anti-viral biotherapeutics: Re-engineering human cells' natural defense.

Outline: Infectious diseases caused by viral pathogens represent a constant threat to public health. With regards to some specific indications, e.g. HIV and Hepatitis C, new effective treatments have been recently developed and successfully launched. In addition, prophylactic vaccinations remain undoubtedly one of the most successful medical interventions. Nevertheless, viral pandemics still represent a major concern whenever they strike. The need to address such potentially occurring event is the availability of a generic treatment, i.e. a broad- spectrum anti-viral therapy which could be prescribed both as a post-infection treatment and a prophylactic agent. Human cells have specific features and are endowed with defense against viral pathogen that can be engineered to design such genetic anti-viral biotherapeutics.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Assert the relevance of broad-spectrum anti-viral strategies. 2. Be aware of the opportunity to create unprecedented therapies by making advantage of pre-existing human cell properties. 3. Learn innovative solutions using DNA recombinant and cell biology technologies.

Suggested speakers, affiliations and topics:

Speaker (Institution): Todd Rider, MIT Lincoln Laboratory. Lexington, MA Title: dsDNA sensor engineered with Caspase activator for broad-spectrum antiviral therapeutics

Speaker (Institution): Benhur Lee, Icahn School of Medicine at Mount Sinai, New York, NY Title: Broad-Spectrum Antivirals that Target Virus-Cell Fusion

Speaker (Institution): Michael Mathews, Rutger University, Newark, NJ Title: Reactivation of Apoptosis Abrogates HIV-1 Infection

Speaker (Institution): Mark Wainberg, McGill University AIDS Centre Jewish General Hospital, Montreal, Quebec, Canada Title: Therapeutic potential of host antiviral restriction factors

Proposal Submitted By:

Name: Manuel Duval, Boehringer Ingelheim, E-mail: manuel.duval@boehringer- ingelheim.com Name: Scott Tarone, Indegene Lifesystems Pvt. Ltd., E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Scott MacDonnell PROPOSAL #5 FULL DAY BPDG 2015 Symposium Proposal Title: GLP-1: Challenges and opportunities for treating diabetes and other diseases Outline: The launch of GLP-1 receptor agonists almost 10 years ago greatly improved the treatment options for type 2 diabetes. Currently, four GLP-1 receptor agonists are available as injectable treatments: Byetta (twice-daily), Bydureon (once-weekly), Victoza (once-daily) and Lyxumia (once-daily). This class of drug has received much attention based on its unique mechanism of action and pleiotropic effects. The GLP-1 receptor agonists potentiate insulin secretion, inhibit glucagon secretion, delay gastric emptying and reduce appetite thereby they not only improve glycemic control, but also induce weight loss. Despite the demonstrated efficacy of GLP-1 receptor agonists in lowering HbA1c, significant challenges remain as over a third of patients fail to reach target HbA1c goals. The promise of beneficial effects on pancreatic -cell health and cardioprotection have proved challenging to show in the clinic and the translatability of these pleiotropic actions remains controversial. In addition, novel insights suggesting that GLP-1 receptor agonists are neuroprotective have spurred a number of clinical trials for the treatment of neurodegenerative disorders, including Alzheimer’s disease. This symposium highlights emerging science for GLP-1 in the preclinical and clinical arena focusing on human genetics, novel cellular and molecular mechanisms for insulin secretion and weight loss, new indications and opportunities for drug development.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand GLP-1 effects on improving patient outcomes and potential to predict responders to treatment. 2. Review current developments in cellular mechanisms and efficacy of glucose metabolism. 3. Assess development opportunities and challenges for improved GLP-1 receptor agonist drugs. 4. Review neurological mechanisms of GLP-1 and discuss future indications for obesity and neurodegeneration. 5. Evaluate the emerging evidence for GLP-1 effects on cardiovascular health.

Suggested speakers, affiliations and topics: (4or5 for ½ day symposia, 6-8 for full day symposia) Session 1: GLP-1 and the treatment of diabetes Speaker (Institution): Dan Drucker, MD, FRCPC (University of Toronto, Toronto, Ontario, Canada) Title: GLP-1R agonists for the treatment of type 2 diabetes: Lessons from the past 10 years Speaker (Institution): Adrian Vella, MD (Mayo Clinic, Rochester, MN) Title: Common genetic variants and predicting treatment response in type 2 diabetes with GLP-1 analogues Speaker (Institution): Susumu Seino, MD, DM Sci (Kobe University, Kobe, Japan) or Meboob Hussain, MD (Johns Hopkins University, Baltimore, MD) Title: Novel insights into GLP-1R enhancement of glucose stimulated insulin secretion Speaker (Institution): Domenico Accili, MD (Columbia University, New York, NY) Title: Critical appraisal of the evidence for GLP-1 analogues in improving beta-cell health Session 2: Extrapancreatic effects of GLP-1 and new therapeutic opportunities Speaker (Institution): Chris Mantzoros, MD, DSc (Harvard University and Beth Israel Deaconess Medical Center, Boston, MA) Title: GLP-1 regulation of appetite in humans: insights from fMRI Speaker (Institution): Konrad Talbot, PhD (University of Pennsylvania, Philadelphia, PA) Title: Brain insulin resistance and Alzheimer’s disease: challenges and opportunities for GLP-1 analogues in the treatment of neurodegenerative diseases Speaker (Institution): Rick Shannon, MD (University of Pennsylvania, Philadelphia, PA) Title: Addressing the cardioprotection question and potential underlying mechanisms Speaker (Institution): Patrick Sexton, PhD (Monash University, Victoria, Australia) Title: Signal bias and allosterism at the GLP-1R: Implications for small molecule GLP-1R agonists Alternate Speaker (Institution): Kristina D. Chadwick, PhD (Bristol-Myers Squibb) Title: GLP-1-based therapeutics and pancreatic pathology

Proposal Submitted By: Name: Margaret Jackson, Pfizer, Cardiovascular and Metabolic Diseases, [email protected] Name: Brent Kuzmiski, Pfizer, Cardiovascular and Metabolic Diseases, [email protected]

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna, [email protected] PROPOSAL #6 FULL DAY BPDG 2015 Symposium Proposal Title: Revisiting calcium handling in the failing human heart - a target for therapy

Outline: Heart failure is one of the leading causes of morbidity and mortality in the world and is a major financial burden to health care systems. The worldwide prevalence of heart failure is increasing due to aging of the population and innovations in the care of cardiac patients. Despite improvements in therapy, the mortality rate in patients with heart failure is unacceptably and consistently high. Dysfunctional handling of calcium ions is critical to the pathogenesis of the failing heart, thus calcium cycling proteins are key potential targets for heart failure therapy. Calcium flux controls not only the cardiomyocyte contractile cycle, but also affects transcription and muscle growth, electrical excitability, cell survival and energy metabolism. Therefore, targeting defective components of the calcium regulatory cascade in cardiomyocytes might have therapeutic benefits in heart failure beyond solely improving cardiac contractile performance. Recent clinical studies have proven the feasibility of this therapeutic approach. This symposium brings together leading scientists and clinicians who translate our current understanding of cellular calcium management into potential treatments for heart failure and diseases that arise from abnormal calcium handling.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Review the importance and need for novel treatments for heart failure 2. Understand the role of calcium handling in the pathogenesis of cardiac diseases 3. Assess the potential for calcium cycling proteins as targets for therapeutic intervention 4. Discuss modern therapies that modulate intracellular calcium handling for the treatment of human heart failure.

Suggested speakers (affiliation) and topics: (4 - 5 for ½ day symposia, 6-8 for full day symposia) Speaker (Institution): Evangelia Kranias, PhD (University of Cincinnati, Cincinnati, OH) Title: Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome Speaker (Institution): Roger Hajjar, MD (Mt Sinai Hospital, New York, NY) Title: The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a target for cardiovascular diseases Speaker (Institution): Andrew Marks, MD (Columbia University, New York, NY) Title: Calcium cycling and new therapeutic approaches for heart failure Speaker (Institution): Marriell Jessup, MD (University of Pennsylvania, Philadelphia, PA) Title: AAV1/SERCA2a gene transfer as a treatment for patients with severe heart failure Speaker (Institution): David Kass, MD (Johns Hopkins University Medical Institutions, Baltimore, MD) Title: The role of nitric oxide synthases in the maintenance of myocardial Calcium homeostasis, relaxation and distensibility Keynote Speaker (Institution): Wilson S. Colucci, MD (Boston University Medical Center, Boston, MA) Title: Novel agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments Alternate: Lynne Warner Stevenson, MD (Harvard Medical School, Boston MA) Speaker (Institution): Evangelia Kranias, PhD (University of Cincinnati, Cincinnati, OH) Title: Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome Alternate: Steven R. Houser, PhD, FAHA (Temple University, Philadelphia, PA)

Proposal Submitted By: Name: Barry Ticho MD, PhDPfizer, External R&D Innovation, [email protected] Name: Albert Kim, MD, Pfizer CV MED Research Unit, [email protected] Name: Georgios Karamanlidis, PhD, Pfizer CVMED Research Unit, [email protected]

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna, [email protected]

PROPOSAL #7 FULL DAY BPDG 2014-2015 Symposium Proposal Title: The paradox of anti-obesity therapeutics: a new approach to harnessing melanocortin signaling Outline: In the last year obesity has been declared a disease by the American Medical Association. This landmark development clearly highlights the un-met medical need for therapeutics directed at weight loss and its associated co- morbidities. Obesity is associated with an increased incidence of diabetes and hypertension while weight loss often leads to decreases in blood glucose and blood pressure. Finding anti-obesity agents that are both efficacious and safe has proven difficult given that the most effective weight loss agents lead to blood pressure increases. Loss-of-function mutations in melanocortin 4 receptors (MC4R) have been strongly implicated in inherited human obesity, making targeting of the melanocortinergic pathways to reduce weight an attractive opportunity. However, preclinically pharmacological activation of the MC4 receptor is often associated with unwanted cardiovascular (CV) effects, and early clinical studies with prototype melanocortin receptor agonists have either shown lack of weight loss efficacy (MK-0493) or unwanted CV liability (LY2112688, bremelanotide). RM-483 is the only MC4R agonist currently being pursued clinically for obesity, and this compound is in Phase II clinical trials. Separation of CV effects from the weight loss profile of selective MC4R agonists is critical to the future clinical success of these agents. Understanding potential peripheral mechanisms of MC4R action along with identification of different pharmacologic modalities of activation could offer different routes to this goal. This symposium will explore novel mechanisms that control appetite and how they influence blood pressure, discuss emerging biology around the melanocortinergic pathways and will seek to initiate discussions aimed at incorporating this new knowledge for the development of safe and durable anti-obesity therapies. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Review current understanding of the mechanisms that control appetite and blood pressure. 2. Discuss the pros and cons of current treatment options for obesity. 3. Understand the contribution of the melanocortin system underlying inherited obesity in humans. 4. Discuss the effect of activating the melanocortin system in food reward and cardiovascular risk. 5. Evaluate current developments and challenges in MC4R agonism as an anti-obesity therapy.

Suggested speakers, affiliations and topics: ( 6-8 speakers for full day symposia) Session 1: Current state of obesity therapeutics Keynote Speaker (Institution): Marc Rietman, NIDDK, Bethesda, MD Title: Overview of current and potential therapies for obesity Speaker (Institution): Ruth J Loos, PhD Mount Sinai Hospital, NY Title: The genetics of human obesity Speaker (Institution): Joel Elmquist, DVM, PhD (UTSW, Dallas, TX) Title: Dissection of neural circuits in search of obesity therapies devoid of blood pressure modulation. Speaker (Institution): Lex H.T Van der Ploeg Rhythm Pharmaceuticals (Boston, MA) Title: RM-493 for Obesity Caused by Genetic Variants: Personalized medicine approach to treat obesity caused by MC4R genetic deficiency. Session 2: Modulating MC4R signaling as an anti-obesity therapy Speaker (Institution): John P. Mayer, PhD (Eli Lilly, IN, USA) Title: Why have MC4R receptor agonists not progressed in the clinic? Speaker (Institution): Roger Cone, PhD (Vanderbilt University Medical Center, Nashville, TN) Title: MC4R Positive allosteric modulators as novel treatment for severe obesity. Speaker (Institution): Giulia Baldini, PhD (University of Arkansas for Medical Science, AR, USA) Title: Complex regulation of MC4R intracellular trafficking: Therapeutic implications. Speaker (Institution): Carrie Haskell-Luevano (University of Florida) Or Michel Bouvier (Montreal University) Title: New approaches to rescue MC4R missense variant; from pharmacological chaperones to designer tetrapetides

Proposal Submitted By: Name: Magdalena Alonso-Galicia, PhD, [email protected] Name: John Dubinion, PhD, [email protected] Name: Margaret Jackson, Pfizer, Cardiovascular and Metabolic Diseases, [email protected] Name: Harveen Natarajan, Pfizer, Cardiovascular and Metabolic Diseases, [email protected] Name: Bhavik Shah, Pfizer, Cardiovascular and Metabolic Diseases, [email protected]

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna, [email protected] and Ken Jones, PhD, Allergan, [email protected] PROPOSAL #8 1/2 DAY BPDG 2014-2015 Symposium Proposal Title: GPCR Drug Discovery - Identification and Optimization of Positive Allosteric Modulators for Difficult Targets

Outline: The discovery of positive allosteric modulators (PAMs) for G protein-coupled receptors (GPCRs) presents unique challenges, from designing the right screens, choosing the most appropriate compound libraries to test, assessing polypharmacology profiles of hit compounds whose activity is probe dependent, and selecting the best pharmacological endpoint(s) to drive chemistry and optimize structure activity relationships (SAR). In this symposium, we will hear from speakers in both academics and industry who have worked on medicinal chemistry programs for GPCR PAMs from the discovery phase all the way to the identification of clinical candidate compounds. The topics to be covered include: a) novel pharmacological assays that utilize real time detection systems to assess functional endpoints; b) homology models based on GPCR crystal structures for identifying binding pockets of PAMs; and c) several case studies, illustrating key aspects of running an efficient medicinal chemistry program to advance chemical matter.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Design the right assay and select the right compounds for screening against a PAM target 2. Understand how to use GPCR homology models based on known GPCR crystal structures to optimize potency in PAM programs 3. Recognize the tactics and strategies in executing a PAM program 4. Be familiar with some strategies to set dose for human studies and transition smoothly into the clinic

Suggested speakers, affiliations and topics: (4 or 5 speakers suggested for ½ day symposia) Speaker (Institution): Corey Hopkins (Vanderbilt University, Nashville, TN) Title: Assay Development and HTS for Positive Allosteric Modulators

Speaker (Institution): Jeff Conn (Vanderbilt University, Nashville, TN) Title: Investigating mGluR5 Allosteric Modulator Cooperativity, Affinity, and Agonism

Speaker (Institution): Ron Dror (Stanford, Stanford, CA) (Formerly D.E. Shaw) Title: Structural Basis for Modulation of a GPCR by Allosteric Drugs

Speaker (Institution): Whitney Nolte (Pfizer, Cambridge, MA) Title: A GLP-1R PAM that acts through covalent modification of the 3rd intracellular loop: implications for closely related class B GPCRs

Speaker (Institution): Paul E. Harrington (Amgen, Thousand Oaks, CA) Title: Cinacalcet: Calcium Sensing Receptor which is the First Positive Allosteric Modulator on the Market

Proposal Submitted By: Name: Esther Lee, PhD Pfizer, CVMED Chemistry [email protected] Name: David Price, PhD Pfizer, CVMED Chemistry [email protected] Name: Phil Carpino, PhD Pfizer, CVMED Chemistry [email protected]

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna, [email protected] PROPOSAL #9 FULL DAY BPDG 2015 Symposium Proposal Title: Phenotypic Drug Discovery: from phenotype to targets or an alternative way to discover new medicines? Outline: Two types of strategies have dominated drug discovery so far: phenotypic- and target-based screens. The former looks at the effects, or phenotypes, that compounds induce in cells, tissues or whole organisms, whereas the latter measures the effect of compounds on a purified target protein via in vitro assays. Phenotypic screens used to be the mainstay of drug development but in the 1980s, advances in molecular biology and genomics led big pharma to target- based drug discovery. Today, phenotypic drug discovery (PDD) is making a comeback. Relevant scientific challenges, i.e., development of cancer resistance to approved medicines, have shown to the scientific community the limit of a strictly target-based or even pathway-based drug discovery. Nevertheless PDD as such still struggles to become an independent way to discover medicines, unclear hybrid between complementary way to discover new targets and true method for drug discovery. Why? Can combination of stem cell-based and -OMICS technologies allow creation of in vitro screenable disease phenotypes? How much translation is needed to succeed in identify new relevant molecular entities? What can be learned from specific case studies from pharmaceutical industry? How, when and which technology can be applied to follow up on interesting compounds aiming at molecular target identification (TID)?

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Explore emerging threats and strategies for PDD & TID 2. Discuss relevance of disease biology (biomarkers and translational medicine) for successful PDD 3. Discuss PDD case studies from Pharma (@ least 3 from different companies) & follow up actions aimed at target identification 4. Review current methods of TID : pros & cons Meeting is aimed @ deepen the science behind PDD & networking the PDD community fostering idea exchange between Pharma and Academia participants

Suggested Agenda: Morning: Phenotypic Drug Discovery Speaker (Institution): David C. Swinney (iRND3) Title: The mechanistic paradox of drug discovery Speaker (Institution): Jonathan Lee (Eli Lilly) – Title pending Speaker (Institution): Aravind Subramanian (Broad Institute) Title: Diving into molecular phenotype: implication for phenotypic drug discovery Speaker (Institution): Bryan Laffitte (Genomics Institute of the Novartis Research Foundation) Title: Phenotypic Screening for Novel Regulators of Pancreatic Beta Cells Afternoon: PDD, Target ID & regulatory perspective Speaker (Institution): Marco Prunotto & John Moffat (Roche group) Title: Blending molecular & cellular phenotype for screening NMEs Speaker (Institution): Steve Ludbrook (GSK) – Title pending Speaker (Institution): Alex Huang (Genentech) Title: Identification of tankyrase inhibitors through a pathway-based PDD Speaker (Institution): Speaker still to be defined (NIH Translational research center) Title: Approval of PDD-derived medicines: Truth & false received ideas on recently approved drugs Speaker (Institution): Giulio Superti-Furga (Research Center for Molecular Medicine - Austrian Academy of Sciences) – Title: Target identification strategies: method integration as a key to success

----PDD as critical path toward NMEs: panel discussion----

Proposal Submitted By: Name: Marco Prunotto, PhD, Hoffmann-La Roche AG, Basel,Switzerland E-mail: [email protected] Name: John Moffat, PhD

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna, [email protected] PROPOSAL 10 FULL DAY BPDG 2015 Symposium Proposal Title: Parkinson’s non-motor symptoms: unraveling the "invisible" face of the disease Outline: The “visible” face of PD, characterized by the cardinal motor features (tremor, rigidity, bradykinesia and postural instability) has attracted a large share of society’s drug discovery and development efforts. However, other symptoms exist which do not involve movement, coordination or physical tasks. Those non-motor symptoms (NMS), both CNS-related (such as depression, anxiety, psychosis, sleep disturbances, etc.) but also peripherally driven (such as gastro-intestinal dysfunctions, sexual, cardiovascular autonomic dysfunctions, etc.) are the “invisible” face of PD, and hitherto have remained somewhat less explored. As therapies dealing with motor deficits have evolved, NMS can actually be more troublesome for some people than the motor impairments of PD. Thus, treatment of NMS remains a critical need of Parkinson’s disease (PD) patients. Unravelling NMS is now a high priority in the field and will certainly be a main challenge faced by those working on the next generation of non-motor, non-dopaminergic Parkinson’s disease therapeutic treatments.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand the influence of CNS-related as well as peripherally driven non-motor disturbances on the daily life of affected individuals and their family. 2. Discuss the spectrum, frequency, evolution of NMS over the course of the disease from a clinical perspective and see current therapeutic options from a physician standpoint. 3. Evaluate preclinical progress made in recapitulating NMS in PD-like animals models and evaluate their translational value in the discovery of the next generation of therapeutic agents. A special focus will be given to CNS-related NMS in Parkinson’s disease. 4. Appreciate the challenges and opportunities faced current programs working on new drugs to treat NMS in PD.

Suggested speakers, affiliations and topics: Speaker (Institution): TBD (Parkinson’s disease Foundation or Parkinson’s association or the Michael J Fox Foundation) Title: NMS: The patient/caregiver view, focused on different NMS Ray Chaudhuri (National Parkinson Foundation Centre of Excellence, Kings College Hospital and Kings College, and University Hospital Lewisham, London, UK) Title: Non-motor symptoms in Parkinson’s disease: spectrum complexity, frequency and clinical scales for NMS assessment Paul Greengard (Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, NY) Title: Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems David Rye (Department of Neurology, Emory University, Atlanta, Georgia, USA) Title: Daytime REM sleep in Parkinson's disease. Warren Olanow (Department of Neurology, The Mount Sinai School of Medicine, New York, NY) Title: Current care management of non-motor symptoms in Parkinson’s disease Erwan Bezard (University of Bordeaux, France) Title: Non motor symptoms in experimental Parkinsonism Daniel Weintraub (University of Pennsylvania, USA) Title: Cognitive changes in Parkinson’s disease TBD (Acadia Pharmaceuticals) Title: Pimavanserin for the treatment of Parkinson’s disease psychosis?: from benchside to bedside Back-up speakers Jon Brotchie (Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada) Title: Non motor symptoms in experimental Parkinsonism Stephen Dunnett (Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, Wales, UK) Title: Cognitive dysfunctions and depression in Parkinson’s disease: what can be learnt from rodent models? Oliver Rascol (Toulouse University Hospital, France) Title: Current care management of non-motor symptoms in Parkinson’s disease David Burn (Clinical Ageing Research Unit Campus for Ageing and Vitality, Newcastle University, Newcastle Upon Tyne, UK) Title: Dementia in Parkinson’s and Alzheimer’s disease: the same?

Proposal Submitted By: Name: Dario Doller, Lundbeck Research USA, E-mail: [email protected] Name: Nathalie Bryesse, Lundbeck Research USA, E-mail: [email protected] Name: Elena Dale, Lundbeck Research USA, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Roland Staal, Lundbeck Research, USA, Inc. PROPOSAL 11 FULL DAY BPDG 2015 Symposium Proposal Title: Gene Network Changes in Alzheimer’s Disease: Potential Therapeutic Intervention Points Outline: Microglia, the resident innate immune cells of the central nervous system (CNS), have emerged as critical players in normal CNS function as well as in the progression of major disorders such as Alzheimer’s disease (AD). Although microglia have been traditionally categorized into either the pro-inflammatory ‘M1’ or the anti-inflammatory ‘M2’ phenotype, recent studies have uncovered a previously unappreciated range of microglial phenotypes involved in regulating specific immune responses, synaptic homeostasis, and neurotrophic support. A pressing question then is whether this continuum of microglial phenotypes is altered in AD and, if so, how might this contribute to disease initiation or progression? In order to address such critical issues it’s first necessary to elucidate the molecular signatures underlying these microglial phenotypes. Recent efforts have therefore applied next generation sequencing techniques and approaches such as weighted gene co-expression network analyses (WGCNA), a systems biology method for describing the correlation patterns among genes across samples, to better understand these signatures at the genomic level. Remarkably, the most perturbed gene networks identified in AD brains fall squarely within microglial pathways and these findings are consistent with previous genome wide association studies (GWASs) linking specific microglial genes to AD risk, further supporting the central role of microglia in AD. This symposium will focus on the implications of these gene networks for our understanding of microglia biology, the identification of molecular signatures specific to microglial phenotypes associated with AD, and how these phenotypes might be modulated to alter the course of AD pathology.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Discuss key emerging concepts surrounding the expanding range of known microglial phenotypes. 2. Review recent developments for identifying specific markers associated with specific microglial phenotypes. 3. Explore the relationship between specific phenotypes and Alzheimer’s disease pathology.

Suggested speakers, affiliations and topics: (6-8 speakers for full day symposia) Speaker (Institution): Steve Horvath, Ph.D. (UCLA) Title: Applying Weighted Gene Co-Expression Network Analyses (WGCNA) to the CNS Speaker (Institution): Howard Weiner, M.D. (Brigham and Women’s Hospital at Harvard) Title: Microglial Phenotypes Identified by Genomic Profiling and their Surface Marker Signatures Speaker (Institution): Jeremy Miller, Ph.D. (Allen Institute for Brain Science) Title: A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging Speaker (Institution): Erik Boddeke, Ph.D. (University Medical Center Groningen, Netherlands) Title: Parsing Microglial Phenotypes by Comparing Chronic and Acute Inflammatory Conditions Speaker (Institution): Eric Schadt, Ph.D. (Icahn School of Medicine at Mt. Sinai) Title: Integrated Systems Approach Identifies Genetic Networks in Late-Onset Alzheimer’s Disease Speaker (Institution): Joseph El Khoury, M.D. (Harvard Medical School, Mass. General Hospital) Title: RNA-Seq Reveals a Dynamic Microglial Sensome Speaker (Institution): Miriam Merad, M.D., Ph.D. (Icahn School of Medicine at Mt. Sinai; Immunological Genome Project) Title: Maintaining the Microglia Status Quo: CNS Signals that Determine Microglia Homeostasis Back Up Speakers: Speaker (Institution): Bruce Yankner, M.D., Ph.D. (Harvard Medical School) Title: No REST for the Weary: Neuronal Transcriptional Changes in MCI and Alzheimer’s Disease Speaker (Institution): Richard Ransohoff, M.D. (Cleveland Clinic) Title: Microglial Phenotypes Identified by Genomic Profiling and their Surface Marker Signatures Speaker (Institution): Oleg Butovsky, Ph.D. (Brigham and Women’s Hospital at Harvard) Title: Microglial Phenotypes Identified by Genomic Profiling and their Surface Marker Signatures Speaker (Institution): Bin Zhang, Ph.D. (Icahn School of Medicine at Mt. Sinai) Title: Applying Weighted Gene Co-Expression Network Analyses (WGCNA) to the CNS Speaker (Institution): Terrence Town, Ph.D. (Keck School of Medicine, USC) Title: Macrophages in Alzheimer’s Disease: The Blood-Borne Identity

Proposal Submitted By: Name: Sean Pintchovski, Ph.D., Lundbeck Research USA, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Roland Staal, Lundbeck Research, USA, Inc

PROPOSAL 12 FULL DAY BPDG 2015 Symposium Proposal Title: Novel Strategies for the Treatment of Neuropathic Pain: Smooth Sailing or Road to Agony? Outline: Neuropathic pain is caused by a lesion or disease affecting the somatosensory system and affects 2-5% of the general population. Current treatments relieve pain by only 20-30% and only one out of three patients perceives a 50% pain reduction. Thus, neuropathic pain is a major cause of suffering and disability. Causes may include but are not limited to trauma, diseases such as diabetes and cancer, chemotherapy, surgery (scarring), and infections such as shingles or HIV. In some neuropathic pain cases there is a persistent pain after the original cause has healed. In other neuropathic pain states, such as polyneuropathy pain, there is an ongoing pathological process. Current treatments for neuropathic pain include antidepressants, gabapentinoids, but also topical lidocaine or capsaicin. As second line, opioids and some anticonvulsants are used, as well as spinal cord stimulation. Thus, there remains a significant unmet need for new therapies with improved efficacy as well as reduced side effects. There are a number of challenges in developing new treatments, at all levels of the development value chain, despite a large number of targets being pursued. Some targets have safety related challenges, e.g. NGF, while others have shown to be efficacious in animals, but lacking effect on clinical pain. Translation of functional outcomes as well as genomics, transcriptomics, lipidomics, proteomics, etc. are some methodologies pursued to overcome these challenges. This symposium brings together researchers investigating novel approaches for the treatment of neuropathic pain. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand the challenges involved in developing new treatments for neuropathic pain 2. Discuss some of the novel approaches for treating neuropathic pain, including neuronal and glial targets and non-coding RNAs

Suggested speakers, affiliations and topics: Speaker (Institution): Märta Segerdahl Storck (Lundbeck, Denmark) Title: Intro: Challenges in drug discovery Speaker (Institution): Flaminia Pavone (Rome, Italy) Title: Botulinum toxin for the treatment of pain Speaker (Institution): McMahon SB (King’s College London, UK) Title: KV2 dysfunction Speaker (Institution): Michael Salter (Toronto, Canada) Title: Glutamatergic neurotransmission in the spinal cord in neuropathic pain Speaker (Institution): Philippe Séguéla (Montreal, Canada) Title: Post-translational regulation of P2X receptors by phospholipids Speaker (Institution): Yves De Koninck (Québec, Canada) Title: Microglial BDNF in the regulation of pain and opioid hyperalgesia Speaker (Institution): Niederberger E – (Frankfurt, Germany) Title: miRNAs in pain processing pathways as future therapeutic Speaker (Institution): Jeffrey Mogil (Algynomics, McGill U, Canada) Title: Genetics in NPP Alternate Speaker (Institution): Anthony Dickinson (UK) Title: Glutamatergic neurotransmission in the spinal cord in neuropathic pain Alternate Speaker (Institution): Tony Yaksh (UCSD, CA, USA) Title: Botulinum toxin for the treatment of pain

Proposal Submitted By: Name: Roland Staal, Lundbeck Research USA, Inc., E-mail: [email protected] Name: Märta Segerdahl Storck, Lundbeck, Denmark, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Roland Staal, Lundbeck Research, USA, Inc. PROPOSAL 13 FULL DAY BPDG 2015 Symposium Proposal Title: Leveraging Big Data and Predictive Knowledge to Fight Disease Outline: Drug development is entering an era of precision medicine centered on the analysis of massive amounts of big data. The ability to integrate, interrogate, model and interpret biological, chemical, pharmacological, genomic and clinical data holistically is key to making more effective and truly personalized medicines to fight disease. Researchers are using innovative technologies and computational techniques to develop predictive knowledge for the identification of promising new treatments, new therapeutic uses for existing molecules, patients that are good candidates for particular clinical trials or treatment protocols, and population signals of adverse drug reactions. An example of the successful use of big data to tailor treatments to specific patient populations using predictive analysis across genomic, clinical trial and anonymous Electronic Health Records (EHR) data is Pfizer’s Xalkori (crizotinib). Approved by the FDA in 2011, Xalkori was developed specifically for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have the ALK gene mutation. This symposium explores the many uses of big data and predictive knowledge to guide drug development and clinical studies.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Explore innovative approaches aimed at improving drug development. 2. Review the use of informatics in drug development 3. Discuss current developments in artificial intelligence to study disease. 4. Assess strategies to data mine EHRs and improve patient selection in clinical trials. 5. Evaluate knowledge-based drug discovery and repositioning.

Suggested speakers, affiliations and topics: Track 1: Informatics in drug development. Speaker (Institution): Keith Wilner, PhD (Pfizer) Title: Use of “big data” in the discovery and development of crizotinib (Xalkori) for non-small cell lung carcinoma. Speaker (Institution): Alex R. Pico, PhD (Gladstone Institutes) Title: Informatics Resources to Analyze, Visualize and Explore the Complex Networks that Make Up Biological Systems Speaker (Institution): Nicholas Tatonetti, PhD (Columbia University Medical Center) Title: Network Medicine: Integrating experimental data and clinical knowledge Track 2: Using artificial intelligence to study disease. Speaker (Institution): Niven Narain, PhD (Berg Pharma) Title: Using Artificial Intelligence to Develop Drugs Speaker (Institution): Jason Moore, PhD (Dartmouth) Title: Evaluating Genetic Variation with Imaging Technologies: An Artificial Intelligence Approach Track 3: Data mining Electronic Health Records and improving patient selection in clinical trials. Speaker (Institution): Joshua Denny (Vanderbilt University) Title: Mining Electronic Health Records in the Genomics Era Speaker (Institution): Chunhua Weng, PhD (Columbia University) Title: Sick Patients have More Data: Mining Clinical Trials Eligibility Criteria to Better Understand Patient Populations and Appropriate Treatments Track 4: Knowledge-based drug discovery and repositioning. Speaker (Institution): Jake Chen, PhD (Indiana University) Title: An Integrated Human Pathway Database to Build High-quality Disease Pathway Models Speaker (Institution): Anil Jegga, DVM, MRes (Cincinnati Children’s Hospital) Title: Computational Drug Repositioning

Proposal Submitted By: Name: Walter J. Jessen, PhD, Covance Informatics, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Robert Martone

PROPOSAL #14 ½ DAY BPDG 2015 Symposium Proposal Title: Use of Companion Diagnostics for Driving Precision Medicine in CNS Disorders Outline: CNS disorders, particularly those with a strong genetic component, show a lot of promise for the development of companion diagnostics (CDx). Biomarkers for CNS disorders, ranging from neurodegenerative, neuropsychiatry to neurological disorders, are being looked at for diagnostic development in terms of monitoring the progression of the disease as well as, for identifying the patient population that is most likely to benefit from the drug therapy. This symposium will bring together a panel of experts from academia and industry to discuss the opportunities and challenges associated with CDx for CNS disorders. The panel will discuss some case studies, tried and tested strategies, lessons learnt, and the possibilities now arising from better understanding of the pathophysiology of the disease and emergence of new diagnostic technologies. Topics that will be discussed include:  Knowledge Gaps and Unmet Needs  Using CNS Biomarkers for CDx  Emerging Technologies for CDx Development  Regulatory Concerns  Partnerships and Collaborations

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Discuss the challenges and opportunities surrounding companion dianostics for neurological disease 2. Understand the potential impact of CDx on success in clinical trials 3. Understand the impact of advances in diagnostic technologies on drug development & patient treatment

Suggested speakers, affiliations and topics: Speaker (Institution): Andreas Jeromin (Quanterix) Title: CNS biomarkers in the development of diagnostics and therapeutics: challenges and strategies to success Speaker (Institution): Kalpana Merchant (Lilly) Title: Biomarkers for patient classification and tailored medicines in neuropsychiatric disorders Speaker (Institution): Lon Schneider (USC, California Alzheimer’s Disease Center) Title: Clinical trial design in AD: real data and simulations Speaker (Institution): Patick Baithrop (Luminex) Title: Platform considerations in the Development of Companion Diagnostics Speaker (Institution): Steven Paul (Cornell) Title: Imaging Biomarkers in the Diagnosis and Treatment of Alzheimer’s Disease Speaker (Institution): Ken Marek (Institute for Neurodegenerative Disorders) Title: Imaging Biomarkers for Parkinson’s Disease Speaker (Institution): Michael Pacanowski (FDA) Title: Regulatory Considerations in the Development of Companion Diagnostics

Proposal Submitted By: Name: Andreas Jeromin, Quanterix, E-mail: [email protected] Name: Robert Martone, Covance Inc., E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Robert Martone

PROPOSAL #15 FULL DAY BPDG 2015 Symposium Proposal Title: Depression and Cardiovascular Disease – shared mechanisms, interactions and treatment implications Outline: There is new evidence that depression has somatic consequences, including an increased risk for cardiovascular disorders. Conversely, cardiovascular diseases, like myocardial infarction and cardiac insufficiency, increase the risk for developing depression. Both depression and cardiovascular disease share markers of metabolic syndrome, including inflammation and metabolic disturbances. Functional risk factors of cardiovascular dysregulation, including alterations in blood pressure (too high or too low) or the control of the heart beat, as measured by heart rate variability are present in patients with depression, while compounds, which control cardiovascular function exhibit antidepressant effects in animal models of depression. The potential implications of the associations between cardiovascular disease and depression for the prevention and treatment of these disorders will be discussed.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Identify the overlap between cardiovascular and mood disorders 2. Understand aspects of the mechanism of this overlap 3. Identify potential strategies to reduce risks of cardiovascular disease and depression, both as primary and secondary prevention 4. Understand the importance of the renin-angiotensin-aldosterone system, ,inflammation and metabolic dysfunction as mediating element.

Suggested speakers, affiliations and topics: (6-8 speakers for full day symposia) Speaker (Institution): Philip Gold (NIH) Title: Somatic Consequences of Depresion Speaker (Institution): Robert Carney (Washington University School of Medicine) Title: Psychiatric Consequences of Cardiovascular Disease Speaker (Institution): Steve Brannan (Takeda) Title: Depression and Cardiovascular Disorders: Overlapping Pharmacology Focusing on 5HT3 and PPAR Receptors Speaker (Institution): J Saavedra (NIMH) Title: The Role of the Renin-Angiotensin-Aldosterone System and Inflammation in Anxiety and Depression Speaker (Institution): T.A. Rummans (Mayo Clinic) Title: Cardiovascular Drugs for Psychiatric Diseases: Are Statins Useful for Depression? Speaker (Institution): Allen Kim Johnson (University of Iowa) Title: Why Salty Snacks Make Us Happy: The Role of Mineralcorticoids in Central Blood Pressure Regulation and Affective Behavior. Speaker (Institution): Eric G. Krause (University of Florida) Title: Oxytocin As Mediator of Stress, Anxiety and Cardiovascular Function Speaker (Institution): David Mischoulon (Harvard University) Title: Is Diet a Modulator of Efficacy in Clinical Trials for Depression

Proposal Submitted By: Name: Harald Murck, Covance Inc. E-mail: [email protected] Name: Robert Martone, Covance Inc. E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Robert Martone

PROPOSAL 16 FULL DAY BPDG 2015 Symposium Proposal Title: Microtubule Associated Protein Tau (MAPT): Pathogenic Mechanisms and Therapeutic Approaches in Alzheimer’s disease and other Taupathies

Outline: The Microtubule Associated Protein tau (MAPT or tau) is closely linked to Alzheimer’s disease (AD) and several other neurodegenerative diseases, especially the Fronto-temporal dementias (FTDs). Tau aggregates to form neurofibrillary tangles (NFTs), a hallmark pathological lesion in AD and other disorders, while mutations in the protein are linked to FTDs. Tau is expressed in multiple isoforms, and has a complex pattern of post translational modification, including phosphorylation, glycosylation, nitration and truncation, which influence tau function. Hyperphosphorylation of tau leads to aggregation into NFTs and, through loss of function is believed to destabilize microtubules: therefore there has been significant effort to inhibit tau phosphorylation and inhibit tau aggregation. However, recent studies in animal models demonstrate that tau knockout animals are viable suggesting that tau’s role in neurodegeneration is mechanistically complex . Tau is secreted in a regulated fashion, and extracellular tau forms toxic complexes which propagate pathology in a prion-like manner and stimulates neuroinflammation . Tau has multiple binding partners and interacts with the SH3 domain of proteins such as the Src-family kinase Fyn: these interactions have been linked to lethal cell-cycle re-entry for neurons. These recent finding suggest novel mechanisms and new therapeutic approaches for many devastating neurological disorders.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Discuss the relationship between tau mutations and post-translational modifications to neurological diseases 2. Review the emerging mechanistic role of tau in disease, and its significance for new therapeutic approaches 3. Discuss the merits and potential pitfalls of new therapeutic approaches

Suggested speakers, affiliations and topics: (6-8 speakers for full day symposia) Overview Speaker (Institution): Peter Davies (Albert Einstein College of Medicine) Title: Tau protein in Neurodegenerative Diseases Pathogenic Mechanisms Speaker (Institution): Khalid Iqbal (Institute for Basic Research, Staten Island) Title: Post-translational Modifications of tau: Pathogenic Mechanisms and Potential Targets Speaker (Institution): Nicole Leclerc (Université de Montréal) Title: Regulation of Tau Secretion Speaker (Institution): Marc Diamond (Washington University) Title: Prion-like propagation of Tau Pathology Speaker (Institution): George S. Bloom (University of Virginia) Title: A signals through Fyn Kinase to Activate Ectopic Cell Cycle Re-entry Speaker (Institution): Maria Figueiredo-Pereira (Hunter College) Title: The relationship between tau pathology and neuroinflammation in Alzheimer’s disease Therapeutic Approaches Speaker (Institution): Nancy Stagliano (iPierian, Inc.) Title: Targeting Extracellular Tau for the Treatment of Alzheimer’s Disease Speaker (Institution): HB Nygaard (Yale) Title: Fyn Kinase Inhibitors for the Treatment of Alzheimer’s Disease Speaker (Institution): Michael Hutton (Lilly) Title: Targeting Post-Translational Modification of Tau for AD Therapeutics: Kinase and OGlcNAcase Inhibitors

Proposal Submitted By: Name: Robert Martone, Covance Inc., E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Robert Martone

PROPOSAL 17 FULL DAY BPDG 2015 Symposium Proposal Title: Perchance to Dream: The Biology, Pathology and Pharmacology of Sleep

Outline: We spend nearly a third of our lives in slumber, we aspire to our dreams and dread our nightmares and the understanding of our sleep time behavior has been the focus of inquiry from the very origins of modern psychology, but the reason we need sleep is poorly understood. Sixty million Americans suffer at least occasional sleep disturbances, 40 million of these suffer chronic disorders, resulting in a $16 Billion industry for sleep aids. Moreover sleep disturbance are associated with nearly all psychological disorders, especially depression. Sleep manipulations, like therapeutic sleep deprivation, on the other hand, can lead to rapid, but short lived, improvements of depressive symptoms. This symposium will explore the role of sleep in cognition, its role in the metabolic homeostasis of the brain, the neuroimmune basis of sleep disorders, and the brain connectivity that underlies the link between sleep disorders and depression. We will also discuss sleep studies that inform an emerging understanding of consciousness and the emergence of a new class of hypnotics based on blocking orexin (the Dual Orexin Receptor Antagonists: DORAs) that are showing promise for pharmacological intervention in sleep disorders. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Discuss the impact of REM sleep on cognitive and affective behavior 2. Describe the manner in which sleep affects brain connectivity and metabolic clearance. 3. Discuss how anesthesia and induced states of unconsciousness are being used to model the structural correlates of consciousness 4. Describe the neuroinflammatory etiology of the sleep disorder narcolepsy. 5. Review new targets for therapeutic intervention insomnia. 6. Characterize sleep related changes as a window into brain plasticity

Suggested speakers, affiliations and topics: (6-8 speakers for full day symposia) Speaker (Institution): J. Allen Hobsen (Harvard) Title: The Cognitive Neuroscience of Sleep Speaker (Institution): CS Saper, (Harvard) Title: The Neurobiology of Sleep Speaker (Institution): Maiken Nedergaard (University of Rochester) Title: Sleep Drives Metabolic Clearance from the Brain Speaker (Institution): Mathew P. Waker (UC Berkeley) Title: REM Sleep Alters Functional Brain Connectivity and Alters Emotional Content of Experience Speaker (Institution): Gulio Tononi (University of Wisconsin, Madison) Title: Anesthesia and Consciousness Speaker (Institution): Emmanuel Mignot (Stanford) Title: Swine Flu Vaccine Causes Sleep Disorders: Narcolepsy as Neuroimmune Disorder Speaker (Institution): Neil Risch (UCSF) Title: The Genetics of Sleep Disorders Speaker (Institution): J.J. Renger (Merck, West Point, PA) Title: Orexin Receptor Antagonists as Therapeutic Class for Insomnia

Proposal Submitted By: Name: Robert Martone, Covance Inc., E-mail: [email protected] Name: Harald Murck, Covance Inc., E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Robert Martone

PROPOSAL #18 FULL DAY BPDG 2015 Symposium Proposal Title: Do we need a disease model for drug development in psychiatry Outline: Drug development in psychiatry is in a crisis. One reason for this is the overall absence of a theoretical concept of health and disease in psychiatry, which includes a deeply engrained bias toward separating mental and bodily functions in the western world. Animal models that are frequently used as screening instruments, such as the forced swim test, implicitly rely on the monoaminergic hypothesis of depression and therefore have no utility with fundamentally new mechanisms, such as glutamatergic approaches, which constitute a new paradigm for rapid acting antidepressant mechanisms. However, progress has been made in the characterization of the biological basis of psychiatric symptoms. For example, the detailed characterization of normal animal behavior and its alterations under stressful conditions, includes a new focus on biological underpinnings of resilience to stress. The focus on personalized medicine in psychiatry links back to the evolutionary advantages of diversity in behavior and its modifications by early life experiences. Epigenetic research provides a perspective on how to manipulate these settings in case they become dysfunctional. Our understanding of the brains architecture and connectivity provides another set of translatable markers, which can provide an unbiased insight into the activity of new compounds. Importantly, the link between these biological changes and the outcome variables in clinical trials in psychiatry, which are still based on the patients’ introspection and/or the raters assessment of the patients behavior and expression, is a fundamental gap. The understanding of how the patients’ emotionality is linked to the associated biological processes is a key area of improvement for clinical trial validity. Finally, the brain does not exist in isolation: emotional processing deeply involves a representation of the body and its function: heart rate changes, sweat, pain and stomach upset are only the most prominent examples, which show the close relationship between somatic and emotional states and deeply impact clinical practice. An integrated theory of psychiatric disease requires detailed attention and discussion.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Reflect on the organismic representation of emotion 2. Have insights into the evolutionary development of emotion and its disturbance. 3. Understand the CNS circuits of emotional regulation 4. Understand methodological approaches for the study of emotional circuits and there use in drug development 5. Understand new targets for pharmacological intervention in psychiatry

Suggested speakers, affiliations and topics: (6-8 speakers for full day symposia) Speaker (Institution): Toni Wolinsky, (Porsolt Inc, NJ.) Title: Use and limitations of screening tools for antidepressants. Speaker (Institution): Jaak Panksepp, (Washington State University) Title: The emotional Brain-Mind – evolutionary aspects of depression Speaker (Institution): Bruce McEwen, (Rockefeller University) Title: The Darwinian Concept of Stress – why diversity is an advantage Speaker (Institution): Georg Northoff, (University of Ottawa) Title: Can we learn from the brain's resting state for Psychopharmacology in depression? Speaker (Institution): Antonio Damasio/ Gil Carvalho, (University of Southern California Los Angeles) Title: Mind-Brain Split? On the bodily representation of feelings. Speaker (Institution): A.D. Craig, (Barrow Neurological Institute, Phoenix, AZ) Title: Can awareness be localized? The overlap between emotional and body-representation circuits. Speaker (Institution): Kurt Kroenke, (Regenstrief Center, Indianapolis) Titles: Why does depression hurt? Somatic complaints in depression and their impact on treatment outcome Speaker (Institution): Wayne Drevets, (Janssen Pharmaceutical) Title: Brain circuits and connectivity in affective processing and depression

------Panel Discussion------

Proposal Submitted By: Name: Harald Murck, Covance Inc. E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Robert Martone, [email protected]

PROPOSAL #20 FULL DAY BPDG 2015 Symposium Proposal Title: Treatment of Acute Heart Failure: Is there new hope in the horizon?

Outline:Despite substantial improvements in the treatment of chronic heart failure, morbidity and mortality for acute decompensated acute heart failure (ADHF) continues to rise. Current treatment of ADHF focuses on controlling acute symptoms. First-line management for ADHF, consisting of intravenous diuretic therapy and vasodilators such as nitric oxide donors, is recommended to relief symptoms of congestion in patients with acute pulmonary edema or severe hypertension. At present, there are no therapeutic strategies that improve long-term outcomes of ADHF patients and no new drugs have been approved for the treatment of ADHF in the US since 2001. Thus, therapies that improve not only hemodynamics and symptoms but also long-term outcomes are urgently needed. Compounds in development for the treatment of ADHF fall into the categories of inotropic, diuretic and vasodilator agents but the number of new therapeutics in the pipeline is remarkably low. Furthest along are serelaxin (a vasodilator peptide), ularitide (a natriuretic and vasodilating peptide) and the cardiac myosin activator omecamtiv mecarbil. This full-day symposium will review new data generated in current ADHF trials involving therapeutic drugs or strategies with emphasis on the pharmacology of the most promising agents such as natriuretic peptides, renin angiotensin-aldosterone system modifying agents, and serelaxin. In addition, the concept of biomarker-guided therapy in the setting of ADHF with the goal of improving outcomes will be explored.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Review current understanding of the pathophysiology of ADHF 2. Discuss the pros and cons of current strategies for ADHF management 3. Assess new and emerging data from ongoing Phase III trials in patients with ADHF 4. Evaluate the therapeutic benefits and liabilities of the most advanced agents in development 5. Review emerging biomarkers for the diagnosis and prognosis of patients with ADHF

Suggested speakers, affiliations and topics: (4 - 5 for ½ day symposia, 6-8 for full day symposia) Speaker (Institution): Biykem Bozkurt, M.D., Ph.D. Baylor College of Medicine, Houston, Texas Title: Pathophysiology, epidemiology and clinical characteristics of ADHF patients Speaker (Institution): G. Michael Felker, M.D., M.H.S., Duke Univ. School of Medicine, Durham, NC Title: New insights into management of volume overload in ADHF: Diuretics vs. Ultrafiltration Speaker (Institution): Michael M. Givertz, MD., Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Title: Existing Pharmacologic Therapies for ADHF: Clinical benefits and liabilities Speaker (Institution): Michelle D. Carlson, MD., Univ. of Minnesota Medical School, Minneapolis, MN Title: Novel Vasodilators for the treatment of ADHF Speaker (Institution): Fady I. Malik, PhD Cytokinetics, Inc., South San Francisco, CA Title: Cardiac myosin activation: a potential therapeutic approach for ADHF? Speaker (Institution): John R.Teerlink, MD., UCSF and San Francisco VA Medical Center, San Fran. CA Title: Effects of Serelaxin in ADHF patients Speaker (Institution): Jonathan Violin, PhD, Trevena, Inc. King of Prussia, PA Title: GPCR biased ligands as novel therapeutics for ADHF Speaker (Institution): John. C. Burnett Jr, MD., Mayo Clinic, Rochester, MN Title: Emerging biomarkers for the diagnosis and prognosis of patients with ADHF

Proposal Submitted By: Name: Magdalena Alonso-Galicia, PhD, Forest Res. Inst., Inc., E-mail: [email protected] Name: Christine G. Schnackenberg, PhD, GlaxoSmithKline, Inc., [email protected]

BPDG Delegate(s) Submitting Proposal: Name: Kenneth Jones, PhD, Allergan, [email protected] PROPOSAL #21 FULL DAY BPDG 2015 Symposium Proposal Title: Quantitative Systems Pharmacology: Progress Towards Integration into Drug Discovery and Development

Outline: Quantitative Systems Pharmacology (QSP) is a mathematical modeling approach to translational medicine that integrates quantitative knowledge about a compound with an understanding of its mechanism of action in the context of human disease. The goal of QSP modeling is “to understand, in a precise, predictive manner, how drugs modulate cellular networks in space and time and how they impact human pathophysiology.1” In the five years since the NIH QSP Working Group last met on this topic, there has been steady progress in both academic research and in the application to drug discovery and development. Despite these successes, full industry-wide adoption of QSP methods has yet to be realized. This symposium highlights advances in QSP applications in the continuum from preclinical exploration to clinical research and includes academic, government, and industry perspectives on the benefits and challenges of full adoption. Case studies from several therapeutic areas will be presented with applications to drug safety, efficacy, and precision medicine. 1. Sorger, PK, et al. Quantitative and Systems Pharmacology in the Post-genomic Era: New Approaches to Discovering Drugs and Understanding Therapeutic Mechanisms. An NIH White Paper, QSP Workshop Group R. Ward, Editor. 2011. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Describe the history, goals, and methodologies of Quantitative and Systems Pharmacology (QSP) 2. Evaluate the need for QSP approaches in the drug discovery & development process 3. Understand the academic, government, & industry perspectives on the challenges of adopting and implementing QSP 4. Discuss examples of successful applications of QSP modeling in several therapeutic areas Suggested speakers, affiliations and topics: Speaker: Peter Sorger, PhD (Harvard Medical School, Boston, MA) Title: QSP: The Vision and Current State of the Science Speaker: Paul Watkins, MD (The Hamner Institute, Research Triangle Park, NC) Title: QSP in Drug Safety Assessments Speakers: Richard Allen (Pfizer, MA) Joshuaine Toth (Boehringer Ingelheim, CT) Jesse Lyons (MIT, MA) Title: Three Vignettes from Early Career Scientists Speaker: Tim Rolph PhD (Pfizer Inc, Cambridge, MA) Title: A CSO’s Perspective on Integrating Quantitative Systems Pharmacology into Pharmaceutical R&D Speaker: John Burke (Applied BioMath, Winchester, MA) Title: Leveraging QSP to Reduce Late Stage Attrition in Drug Discovery and Development Speaker: Darrell R. Abernethy, MD, PhD (US FDA, Silver Spring, MD) Title: FDA Perspective on QSP Models in Regulatory Submissions Panel Discussion: The Present & Future of QSP in Drug Discovery and Development

Proposal Submitted By: Name: Cynthia Musante (Pfizer, MA) [email protected] Name: Nahor Haddish-Berhane (Pfizer, MA) [email protected] Name: John M. Burke (Applied BioMath, MA) [email protected] Name: Joshua F. Apgar (Applied BioMath, MA) [email protected] (BPDG Delegate)

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna (Pfizer, MA) [email protected]

PROPOSAL 22 FULL DAY BPDG 2014-2015 Symposium Proposal Title: Harnessing the potential of genome editing for drug discovery: Translational frontiers of in vitro and in vivo applications Outline: Until recently, the generation of precise alterations in mammalian genomes has been a challenging and cumbersome process. A rapid succession of technologies in the past several years has brought about a revolution in molecular biology: zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and then clustered regularly interspaced short palindromic repeats (CRISPR). Each successive advancement has brought us closer to a routine, bench-level method to modify endogenous genetic elements. Now proof-of-concepts abound and encompass exciting frontiers such as rapid animal model development in addition to knockout and knock-in human and mouse cell lines. More recently, the framework of TALEN and CRISPR has been extended to a vast array of applications including epigenetic modulation, stimulation of gene expression, and targeted repression of gene transcription. What do these advances mean for drug discovery and translational research? This symposium will cover the latest techniques and methodologies in genome editing and the potential they hold for therapeutic development. In particular, the union of CRISPR and TALEN with stem and iPS cell technologies is an avenue that holds promise in improving the physiological relevance of disease models. However, the application of TALEN and CRIPSR to drug discovery is still in a nascent stage and innovation will be a core theme as we explore opportunities and current limitations. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand the state-of-the-art tools, methodologies, and workflows in genome editing. 2. Be versed in both potential and realized applications of TALEN and CRISPR technologies in a translational/drug discovery setting. This will include assay design, high throughput screening, drug target validation, mechanism-of-action determination, functional genomics, and disease model generation. 3. Establish how genome editing can be used to synergistically improve the physiological relevance of drug discovery inputs such as isogenic control cell lines and iPSC-derived disease models. 4. Translate the key developments for both in vitro and in vivo utilization of genome editing and associated technique such as CRISPRi into practice. 5. Determine where the current limitations of genome editing technology are and the path forward to improving on existing techniques. Also, be informed of the potential therapeutic applications of genome editing and understand the technological hurdles that must be surpassed. 6. Act on opportunities to innovate beyond the existing CRISPR and TALEN applications to better serve the needs of the drug discovery community. Proposal coordination: In addition to being an excellent stand-alone NYAS symposium, we also welcome the idea of partnering with Marco Prunotto’s phenotypic drug discovery proposal symposium (Roche) for a 2-day comprehensive event. Adjoining the two symposia will ultimately lead to a synergy in scope and audience since the technology of genome editing goes hand-in-hand with phenotypic drug discovery principles.

Suggested speakers, affiliations and topics: (6-8 speakers for full day symposia) Speaker (Institution): George Church (Harvard University, Cambridge, MA) Title: A diverse array of RNA-guided tools for the manipulation of endogenous gene sequence, transcription, splicing, and epigenetic information Speaker (Institution): Feng Zhang (Massachusetts Institute of Technology, Broad Institute, Cambridge, MA) Title: CRISPR/Cas9 enables a new generation of genome-wide functional genomic platforms for drug discovery and target validation Speaker (Institution): James Inglese (National Institutes of Health, National Center for Advancing Translational Sciences, Bethesda) Title: Genome editing as a disruptive technology in assay design: the synergy of qHTS, endogenous reporters, and phenotypic drug discovery Speaker (Institution): Yi Yang (Novartis Institutes for Biomedical Research, Cambridge, MA) Title: CRISPR and TALEN in the trenches of drug discovery: How genome editing tools are changing early-stage discovery & development programs Speaker (Institution): J. Keith Joung (Massachusetts General Hospital, Boston, MA) Title: Beyond the nuclease: The frontiers of TAL and CRISPR/Cas9 in understanding epigenetic targets for therapeutic development Speaker (Institution): Lei (Stanley) Qi (University of California San Francisco, San Francisco, CA) Title: CRISPRi as the successor to RNAi: Flexible & high-throughput system to profile gene function & shape the differentiation of pluripotent cells Speaker (Institution): Chad Cowan (Harvard University, Cambridge, MA) Title: Building physiologically relevant, humanized disease models with TALEN and CRISPR-mediated genome editing: Human pluripotent stem cells as the gateway to better drug discovery

Proposal Submitted By: Name: Samuel A. Hasson, Pfizer Neuroscience, E-mail: [email protected] Name: Sandra J. Engle, Pfizer Primary Pharmacology Group, E-mail: [email protected] Name: Mi Cai, Pfizer Neuroscience, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna ([email protected]) PROPOSAL #23 FULL DAY BPDG 2015 Symposium Proposal Title: Solute Transporters (SLCs): Where Pharmacology and Disposition Merge

Outline: Solute Transporters are an important emerging gene family of membrane transport proteins with a strong connection to human disease. The pharmacology of SLCs has been demonstrated by approved drugs that target various SLCs, including the recently approved SGLT-2 class of anti-diabetic medications. In addition, there are another 12 SLC targets being pursued by putative drugs in the industry pipeline. However, with a gene family of over 370 members, this means less than 5% of potential targets are being pursued today, leaving a considerable proportion of the gene family untapped. Capitalizing on this opportunity requires building greater scientific understanding of the SLC families from genetic links to pathological processes, to a systems pharmacology understanding of the transporter and associated metabolomics pathways. Building the scientific understanding can then lead to de-orphanising strategies as well as the development of appropriate assays and chemical screening libraries, which are additional gaps in creating a platform approach to identifying SLC drugs. Only by filling these gaps can we turn this family into a gene family that can be successfully targeted, in a similar way to e.g. kinases. The goal of the symposia would be to develop further understanding of the gaps in our scientific approach to SLCs and identify opportunities for filling these gaps.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand the importance of SLC’s in disease processes and current state of SLC genetics 2. Identify and address the scientific gaps to successful targeting of SLCs in drug discovery 3. Share learning in the areas of structural biology, reagent and assay development, de-orphanising strategies and chemical lead generation. 4. Review current drug discovery approaches to targeting SLCs and discuss optimization opportunities

Suggested speakers (with affiliation) and topics: (4 - 5 for ½ day symposia, 6-8 for full day symposia)

Speaker (Institution): Eric Gouaux, PhD (Oregon Health & Science University, Portland, OR) Title: Molecular mechanism of ATP binding and ion channel activation in P2X receptors Speaker (Institution): Tim Rolph, PhD (Pfizer Inc, Cambridge, MA) Title: Loss-of-function mutations in SLC30A8 protect against type 2 diabetes Speaker (Institution): Dr. Gerhard Burckhardt (University of Gottingen, Germany) Title: Drug transport by Organic Anion Transporters (OATs) Speaker (Institution): Ming Zhou, PhD (Columbia University, New York, NY) Title: Understanding the mechanism of Kv1 channel modulation by cellular redox states Speaker (Institution): Anna Pajor, PhD (University of California, San Diego, La Jolla, CA) Title: Sodium-coupled dicarboxylate and citrate transporters from the SLC13 family Speaker (Institution): Kathy Giacomini, PhD (University of San Francisco, San Francisco CA) Title: SM. Transporters in drug development and clinical pharmacology

Proposal Submitted By: Name: Tony Wood, PhD Pfizer, Worldwide Medicinal Chemistry,[email protected] Name: Charlotte Allerton, MPhil Pfizer, Pharmacokinetics, Dynamics & Metabolism , [email protected] Name:Tim Rolph, PhD Pfizer, Cardiovascular and Metabolic Diseases Research Unit, [email protected]

BPDG Delegate(s) Submitting Proposal: Mercedes Beyna, [email protected] PROPOSAL 25 FULL DAY BPDG 2015 Symposium Proposal Title: Emerging Breakthroughs in Brain Research: The Ups, Downs and Abouts of Neuron Connectivity

Outline: The brain is a puzzle of remarkable genetic, structural and functional complexity. Ambitious projects significantly improve the map of the mammalian brain and define its circuitry on the ultrastructural level. They are complemented by conceptual advances into how development and experience shape the connectivity underlying its most basic functions. Our symposium will address both: the importance of synaptic changes in the modulation of neuronal activity and behavior, and technical advances in mapping brain circuitry and its functional output on a system-wide level. We will discuss the challenges of mapping the emerging functional circuitry, its relationship to behavior, and current and envisioned applications in therapy. Our full-day symposium will review how revolutionary tools help us to better understand the formation of thoughts and emotions as functional output of brain connectivity, and describe translational applications and therapeutic opportunities that result from our significantly improved understanding of neuronal connectivity. A clinical emphasis will be on the role that misdirected neuronal connectivity may play in emotional disorders, addiction, Alzheimer’s and Parkinson’s disease.

Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. Understand how neuronal connectivity is shaped during development and by life-long experiences. 2. Appreciate the challenge of understanding neuronal connectivity on a brain-wide level. 3. Expand consideration for the integrative function of structural neuroplasticity. 4. Gain insights into how processes underlying neuronal plasticity can be used to reverse neurodevelopmental and psychiatric disorders.

Suggested speakers, affiliations and topics: Speaker (Institution): Sebastian Seung (MIT) Title: The Brain Connectome: How the brain’s wiring makes us who are we Speaker (Institution): Rafael Yuste (Columbia University) Title: Brain mapping at the level of cortical circuits and dendritic spines Speaker (Institution): Bernardo Sabatini (Harvard University) Title: Postnatal recurrent activity drives synaptogenesis in the striatum Speaker (Institution): Wenbiao Gan (NYU School of Medicine) Title: Synaptic plasticity and stability in learning and memory Speaker (Institution): Eric Nestler (Mount Sinai School of Medicine) Title: Signaling pathways underlying drug of abuse-induced maladaptations in the mesolimbic system Speaker (Institution): Bruce McEwen (Mount Sinai School of Medicine) Title: Hormonal modulation of neural plasticity: a circuit-based analysis Speaker (Institution): Leonardo Cohen (NINDS/NIH) Title: Moving the world by thought: perspectives of brain-computer interfaces

Proposal Submitted By: Name: Thomas Franke, NYU School of Medicine, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: Barbara Petrack

PROPOSAL #26 FULL DAY BPDG 2015 Symposium Proposal Title: Pharmacologic Modulation of the Tumor Microenvironment to Treat Cancer Outline: There is increasing evidence that cancer cells are influenced by their surrounding microenvironment. Tumor cells are to a large extent dependent on surrounding non-tumor cells, the stroma, and the tumor vasculature, for their survival, proliferation, migration, and, ultimately, metastasis. By understanding the pathophysiology of the interplay between tumor cells and their microenvironment, potential drug targets may be identified. Clearly, as evidenced by vascular endothelial cell growth factor (VEGF) inhibitors like bevacizumab (Avastin®), choosing the right drug target can have a potent inhibitory effect on a wide variety of cancers. The objective of this symposium is to explore recent progress in the development of drugs for emerging new targets that modulate the tumor microenvironment or take advantage of its peculiar pathology. In particular, tumor hypoxia contributes to genetic instability and enables tumor cells to evade traditional chemotherapy, while the existing tumor vasculature (in contrast to new vasculature, or angiogenesis) and certain enzymes that remodel the tumor extracellular matrix sustain tumor cell proliferation and enable migration and metastasis. The potential for drugs that can penetrate hypoxic regions to kill tumor cells, disrupt existing tumor vasculature (vascular-disrupting agents), and inhibit extracellular remodeling enzymes have not been fully realized. The objective of this symposium is to present the opportunities for the development of drugs targeting the tumor vasculature and the clinical progress achieved to date. Scientific Learning Objectives: At the conclusion of this symposium, participants will be able to: 1. More fully understand the important role of the tumor microenvironment, the tumor vasculature, stroma, and hypoxia, in disease progression and metastasis. 2. Understand the potential benefit of targeting various aspects of the tumor microenvironment to treat cancer. 3. Evaluate the current state of the development of drugs targeting the tumor microenvironment, as well as the potential for activity in a wide variety of cancers, as monotherapy or in combination. Suggested speakers, affiliations and topics: Speaker (Institution): David Tuveson, MD, PhD (Cold Spring Harbor, NY) Title: The role of hypoxia, stroma, and tumor vasculature in pancreatic cancer progression and metastasis Speaker (Institution): Robert Bristow, MD, PhD (Princess Margaret Hosp., Toronto, ON, Canada) Title: Interplay between tumor hypoxia and genetic instability Speaker (Institution): Rolf Brekken, PhD (UT Southwestern, Dallas, TX) Title: Tumor extracellular matrix (ecm) signaling in disease progression Speaker (Institution): Michael F. Clarke, M.D. (Stanford Univ Cancer Institute, Palo Alto, CA) Title: The tumor microenvironment and cancer stem cell renewal and resistance Speaker (Institution): Dietmar Siemann, PhD, (Univ. of Florida College of Medicine, Gainesville, FL) Title: Unique characteristics of tumor vasculature and its selective destruction by vascular disrupting agents Speaker (Institution): Zena Werb, PhD. (Univ. of California, San Francisco, San Francisco, CA) Title: The tumor microenvironment in regulating metastasis Speaker (Institution): Frances Balkwill, PhD (Queen Mary Hospital, Univ of London, London, UK) Title: Targeting tumor-associated macrophages and cancer-related inflammation Speaker (Institution): Charles Hart, PhD (Threshold Pharmaceuticals, Inc., South San Francisco, CA) Title: TH-302, a hypoxia-activated prodrug, in late-stage clinical development for a variety of cancers. Speaker (Institution): David Chaplin, PhD (Oxigene, Inc., South San Francisco, CA) Title: Small molecule inhibitors of cathepsin L to prevent tumor cell migration and metastasis

Proposal Submitted By: Name: Peter Langecker, MD, PhD, Oxigene, Inc. E-mail: [email protected] Name: George Zavoico, PhD, HC Wainwright & Co. E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: George Zavoico, PhD PROPOSAL #27 FULL DAY BPDG 2015 Symposium Proposal Title: Cancer Epigenetics: Recent Advances and Emerging Therapeutic Approaches Outline: Epigenetics is the study of heritable changes based on global gene expression not encoded in DNA and epigenetic abnormalities are now recognized as being a common factor in both tumorigenesis and refractory disease. Translocations and/or mutations in chromatin-modifying machineries that perturb the timing and/or pattern of gene expression can result in the pathogenesis of cancer and other diseases. Recent studies demonstrate that the misregulation of several of the histone-modifying enzymes can contribute to changes in the epigenetic state leading to disease development and studies are underway to better understand the regulation of the nucleosome and subsequent modifications which alter the organization and function of the genome. Alterations of histone modifications tend to happen at specific locations either due to alternations in the DNA or inappropriate recruitment of histone modifying enzymes. When the inappropriate activity of these histone modifying enzymes occurs upstream of the genetic coding region, these changes contribute to cancer development or progression. The scientific and the pharmaceutical communities are working to identify the molecular function for many of the histone-modifying machineries and are in the process of developing small molecular inhibitors of their activities in the hope of their use for targeted therapeutics of cancer. Therapeutically targeted proteins involved in mediating epigenetic signaling include histone acetylases, deacetylases, demethylases, ATPases, DNA methyltransferases, and histone ligases. For example, dysregulation of histone deacetylases (HDACs) in both hematological and solid tumors is a common epigenetic abnormality in cancer, providing the rationale for the development of HDAC inhibitors. The objective of this symposium is to explore the therapeutic potential of pharmacologic modulation of epigenetic inhibitors. Scientific Learning Objectives. At the conclusion of this symposium, participants will be able to: 1. Understand the role of epigenetics in gene expression and silencing 2. Name the key biochemical and physiologic mechanisms underlying epigenetics. 3. Discuss how dysfunctional epigenetic mechanisms contribute to cancer pathogenesis and disease progression. 4. Explore the emerging field of epigenetic cancer therapies. Suggested speakers, affiliations and topics: Speaker (Institution): Craig B. Thompson, MD (Memorial Sloan-Kettering Cancer Center, NY, NY) Title: Cellular Metabolism and Epigenetic Changes in Cancer Speaker (Institution): C. David Allis, PhD (Rockefeller Univ., NY, NY) Title: Covalent histone modifications--miswritten, misinterpreted and mis-erased in human cancers Speaker (Institution): Stuart L. Schreiber, PhD (HHMI and Harvard University, Cambridge, MA) Title: Genetics of Human Cancers and Histone-Modifying Enzymes Speaker (Institution): Michael D. Cole, PhD (Dartmouth Medical School, Hanover, NH) Title: An Epigenetic Model for Myc Autoregulation and Gene Repression Speaker (Institution): Kevin G. McLure, Ph.D. (Zenith Epigenetics Corp., Calgary, AB, Canada) Title: BET bromodomain inhibitors abrogate cell cycle progression and induce apoptosis Speaker (Institution): Roberto Pili, MD (Roswell Park Cancer Institute, Buffalo, NY Title: HDAC Inhibitors: Advancing Therapeutic Strategies in Hematological and Solid Malignancies Speaker (Institution): Daniel Gold, PhD (MEI Pharma, San Diego, CA) Title: A Selective, Oral HDAC inhibitor, Pracoinostat, in Hematologic Malignancies Speaker (Institution): Patrick Trojer, PhD (Constellation Pharmaceuticals, Cambridge, MA) Title: Targeting Histone Lysine Methylation in Cancer

Proposal Submitted By: Name: Daniel Gold, Ph.D., MEI Pharma, Inc. E-mail: [email protected] Name: George Zavoico, Ph.D., H.C. Wainwright Co. E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: George B. Zavoico, PhD

PROPOSAL #28 ½ DAY BPDG 2015 Symposium Proposal Title: Emerging Novel Drug Targets for Eosinophilic Disorders of Many Organ Systems Outline: Many disorders, ranging from chronic common to orphan disorders, some life-threatening, are now recognized to be due to an overabundance of active eosinophils, including allergic rhinoconjunctivitis (hay fever), asthma (after an exacerbation), certain hematologic malignancies, atheroembolic disease, atopic dermatitis (eczema), bullous pemphigoid, drug/toxin-induced eosinophilic lung disease, inflammatory bowel disease (ulcerative colitis and Crohn's disease), enterocolitis, and an emerging class of eosinophilic gastrointestinal disorders such as eosinophilic esophagitis. Eosinophils are a normal cellular component of the blood and also of certain tissues, including spleen, lymph nodes, thymus, and the submucosal areas of the gastrointestinal, respiratory, and genitourinary tracts. When the body needs to attack a substance, such as food or airborne allergens, eosinophils respond by moving into the area and releasing a variety of toxins. If the eosinophil response is too strong, producing well over the normal level of eosinophils, then chronic inflammation resulting in tissue damage can occur at the site of insult. Despite the key role eosinophils are likely to play in these disorders, there are few drugs that specifically target eosinophils. Recent advances in our understanding of eosinophil biology has opened new avenues for drug development that may result in new and innovative medicines to treat eosinophilc disorders. A number of drug candidates have already advanced into clinical trials that could provide safe and efficacious treatment combinations or alternatives to existing therapies in this underserved clinical need. Scientific Learning Objectives. At the conclusion of this symposium, participants will be able to: 1. Understand the role of eosinophils in the pathogenesis of a variety of common and orphan diseases 2. Discuss mechanisms that may cause abnormal, robust, and chronic eosinophil activation. 3. Review therapeutic approaches and drug targets to stimulate resolution of eosinophilic inflammation. 4. Discuss the progress through clinical trials of drugs in development for eosinophilc disorders.

Suggested speakers, affiliations and topics: Speaker (Institution): Marc E. Rothenberg MD, PhD (Univ. of Cincinnati College of Medicine, Cincinnati, OH) Title: The Healthcare Burden of Eosinophilic Disorders and Emerging Treatment Options Speaker (Institution): Janet A. Fairley, MD, (Univ. of Iowa, Iowa City, IA) Title: Emerging treatment options for bullous pemphigoid, a orphan autoimmune disease: targeting IgE and eosinophils Speaker (Institution): Glenn T. Furuta, MD (Univ of Colorado Denver School of Medicine, Aurora, CO) Title: Role of eosinophils in inflammatory bowel and gastrointestinal diseases Speaker (Institution): Jonathan Corren, MD, (Allergy Medical Clinic, Los Angeles, CA) Title: Targeting severe exacerbations of asthma with IL-5 and IL-13 antagonists Speaker (Institution): Adam Foley-Comer, MD, Immune Pharmaceuticals, Inc. Title: Targeting eotaxin with an antibody, evidence of safety and efficacy

Proposal Submitted By: Name: Anna Baran, Immune Pharmaceuticals, Inc., E-mail: [email protected] Name: Marc E. Rothenberg MD, PhD, Cincinnati Children's Hospital Med. Ctr, Univ. Cincinnati College of Medicine E-mail: [email protected] Name: George B. Zavoico, PhD, H.C. Wainwright & Co., LLC, E-mail: [email protected]

BPDG Delegate(s) Submitting Proposal: George B. Zavoico