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Sara H. Beac Samue G. Johns ah chy, el son, Steve Olson, and d Adam C. Be A erger, Rappporteurs Roundta on Tra able anslating G Genomic-B Based Resear for Hea rch alth Bo oard on Hea Scienc Policy alth ces PREPUBLIC P CATION CO OPY: UNCORRECTED PROOFS

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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, NW • Washington, DC 20001 NOTICE: The workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This project was supported by contracts between the National Academy of Sciences and the American Academy of Nursing (unnumbered contract); American College of Medical Genetics and Genomics (unnumbered contract); American Heart Association (unnumbered contract); American Medical Association (unnumbered contract); American Society of Human Genetics (unnumbered contract); Association for Molecular Pathology (unnumbered contract); Blue Cross and Blue Shield Association (unnumbered contract); College of American Pathologists (unnumbered contract); Department of the Air Force (Contract No. FA7014- 0-P-0072); Department of Veterans Affairs (Contract No. VA248-P-1528); Eli Lilly and Company (unnumbered contract); Genetic Alliance (unnumbered contract); Health Resources and Services Administration (Contract No. HHSH250201100119P and Contract No. HHSH25034017T); International Society for Cardiovascular Translational Research (unnumbered contract); Johnson & Johnson (unnumbered contract); the Kaiser Permanente Program Offices Community Benefit II at the East Bay Community Foundation (Contract No. 20121257); Life Technologies (unnumbered contract); National Cancer Institute (Contract No. HHSN263201200074I, TO#5); National Coalition for Health Professional Education in Genetics (unnumbered contract); National Heart, Lung, and Blood Institute (Contract No. N01-OD-4-2139, TO#275); National Human Genome Research Institute (Contract No. N01- OD-4-2139, TO#264 and Contract No. HHSN263201200074I, TO#5); National Institute of Mental Health (Contract No. N01-OD-4-2139, TO#275 and Contract No. HHSN263201200074I, TO#5); National Institute of Nursing Research (Contract No. HHSN263201200074I, TO#5); National Institute on Aging (Contract No. N01-OD-4-2139, TO#275 and Contract No. HHSN263201200074I, TO#5); National Society of Genetic Counselors (unnumbered contract); Northrop Grumman Health IT (unnumbered contract); Office of Rare Diseases Research (Contract No. N01-OD-4-2139, TO#275); Pfizer Inc. (unnumbered contract); and PhRMA (unnumbered contract). The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity. International Standard Book Number-13:978-0-309-XXXXX-X International Standard Book Number-10:0-309-XXXXX-X Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2014. Drug repurposing and repositioning: Workshop summary. Washington, DC: The National Academies Press. PREPUBLICATION COPY: UNCORRECTED PROOFS

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PREPUBLICATION COPY: UNCORRECTED PROOFS C O

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The Na ational Academy of Sciences is a private, nonp s profit, self-perpe etuating society of y distingu uished scholars engaged in scie neering research dedicated to the entific and engin h, furthera ance of science and technology and to their use for the general welfare. Upon the a authorit of the charter granted to it by the Congress in 1863, the Acade ty emy has a mand date that req quires it to advis the federal go se overnment on sc cientific and tech hnical matters. D Dr. Ralph J. Cicerone is preesident of the Na ational Academy of Sciences. y The Nattional Academy of Engineering was establishe in 1964, unde the charter of the y ed er Nationa Academy of Sciences, as a pa al S arallel organizattion of outstandi engineers. It is ing t autonom mous in its adm ministration and in the selection of its members sharing with t i s, the Nationa Academy of Sciences the res al S sponsibility for advising the feederal governmeent. The Naational Academy of Engineerin also sponsors engineering p y ng s programs aimed at d meeting national needs, encourages edu g ucation and reseearch, and recoggnizes the super rior achievements of engine eers. Dr. C. D. Mote, Jr., is pres M sident of the Nattional Academy of y ering. Enginee The Insstitute of Mediccine was established in 1970 by t National Ac the cademy of Scienc ces to secur the services of eminent memb of appropri ate professions in the examinati re o bers ion of polic matters perta cy aining to the heealth of the pub blic. The Institu acts under t ute the responsibility given to the National Ac t cademy of Sciennces by its congr ressional charter to r be an ad dviser to the fed deral governmen and, upon its o nt own initiative, to identify issues of o s medical care, research, and education. Dr. Harvey V. Fi l D ineberg is presid ute dent of the Institu of Mediicine. The National Research Council was organized by the National Acade h o e emy of Sciences in s 1916 to associate the broad community of science and technology w the Academy o b y d with y’s purpose of furthering knowledge and advising the fe es ederal governme Functioning in ent. g accorda ance with genera policies deter al rmined by the AAcademy, the Co ouncil has become the prin ncipal operating agency of bo the Nationa Academy of Sciences and the g oth al Nationa Academy of Engineering in providing servic to the gover al E p ces rnment, the publ lic, and the scientific and engineering com e mmunities. The C Council is admiinistered jointly by both Ac cademies and the Institute of Me e edicine. Dr. Ralp J. Cicerone an Dr. C. D. Mo ph nd ote, Jr., are chair and vice ch c hair, respectively of the Nationa Research Cou y, al uncil. w www.national l-academies.o org PREPUBLIC P CATION CO OPY: UNCORRECTED PROOFS

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PLANNING COMMITTEE1 AIDAN POWER (Chair), Vice President and Head, PharmaTx Precision Medicine, Pfizer Inc., Groton, CT CHRISTINE COLVIS, Director, Extramural Therapeutics Discovery, National Center for Advancing Translational Sciences, Bethesda, MD ANDREW N. FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD GEOFFREY GINSBURG, Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC GABRIELA LAVEZZARI, Assistant Vice President, Scientific Affairs, PhRMA, Washington, DC THOMAS LEHNER, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD MICHAEL PACANOWSKI, Acting Associate Director for Genomics, Center for Drug Evaluation and Research, Office of Clinical Pharmacology, Food and Drug Administration Silver Spring, MD MICHELLE A. PENNY, Senior Director, Translational Medicine Group, Eli Lilly and Company, Indianapolis, IN ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; and Jefferson–Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology); Director, Deane Drug Discovery Institute; Senior Scholar, Fuqua School of Business, R. David Thomas Executive Training Center, Duke University, Durham, NC SHARON TERRY, President and Chief Executive Officer, Genetic Alliance, Washington, DC IOM Staff ADAM C. BERGER, Project Director TONIA E. DICKERSON, Senior Program Assistant 1 Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v PREPUBLICATION COPY: UNCORRECTED PROOFS

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Fellow SEAN P. DAVID, James C. Puffer, M.D./American Board of Family Medicine Fellow vi PREPUBLICATION COPY: UNCORRECTED PROOFS

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ROUNDTABLE ON TRANSLATING GENOMIC-BASED RESEARCH FOR HEALTH1 WYLIE BURKE (Co-Chair until June 2013), Professor and Chair, Department of Bioethics and Humanities, University of Washington, Seattle GEOFFREY GINSBURG (Co-Chair from June 2013), Director, Center for Genomic Medicine, Institute for Genomic Sciences and Policy, Duke University, Durham, NC SHARON TERRY (Co-Chair), President and Chief Executive Officer, Genetic Alliance, Washington, DC NAOMI ARONSON, Executive Director, Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL EUAN ANGUS ASHLEY, Representative of the American Heart Association; Director, Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Palo Alto, CA PAUL R. BILLINGS, Chief Medical Officer, Life Technologies, Carlsbad, CA BRUCE BLUMBERG, Institutional Director of Graduate Medical Education, Northern California Kaiser Permanente, Permanente Medical Group, Oakland, CA DENISE E. BONDS, Medical Officer, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD JOANN A. BOUGHMAN, Former Executive Vice President, American Society of Human Genetics, Bethesda, MD PAMELA BRADLEY, Staff Fellow, Personalized Medicine Staff, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD PHILIP J. BROOKS, Health Scientist Administrator, Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD ANN CASHION, Acting Scientific Director, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD 1 Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. vii PREPUBLICATION COPY: UNCORRECTED PROOFS

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C. THOMAS CASKEY, Professor, Baylor College of Medicine, Houston, TX SARA COPELAND, Former Acting Chief, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD ROBERT B. DARNELL, President and Scientific Director, New York Genome Center; Investigator, Howard Hughes Medical Institute, Heilbrunn Cancer Professor and Senior Physician, Head, Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, NY MICHAEL J. DOUGHERTY, Director of Education, American Society of Human Genetics, Bethesda, MD VICTOR DZAU, President and Chief Executive Officer, Duke University Health System; Chancellor for Health Affairs, Duke University, Durham, NC W. GREGORY FEERO, Contributing Editor, Journal of the American Medical Association, Chicago, IL ANDREW N. FREEDMAN, Branch Chief, Clinical and Translational Epidemiology Branch, Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD JENNIFER L. HALL, Representative of the International Society for Cardiovascular Translational Research; Associate Professor of Medicine, University of Minnesota, Minneapolis RICHARD J. HODES, Director, National Institute on Aging, Bethesda, MD SHARON KARDIA, Professor and Chair of Epidemiology; Director, Public Health Genetics Program; Director, Life Science and Society Program; Codirector, Center for Public Health and Community Genomics, University of Michigan School of Public Health, Ann Arbor MOHAMED KHAN, Representative of the American Medical Association; Leader of Radiation Oncology, Vancouver Cancer Centre, British Columbia Cancer Agency, Vancouver, BC, Canada MUIN KHOURY, Director, National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA GABRIELA LAVEZZARI, Assistant Vice President, Scientific Affairs, PhRMA, Washington, DC THOMAS LEHNER, Director, Office of Genomics Research Coordination, National Institute of Mental Health, Bethesda, MD DEBRA LEONARD, Representative of the College of American Pathologists; Professor and Chair of Pathology at the University of Vermont College of Medicine; Physician Leader of Pathology and viii PREPUBLICATION COPY: UNCORRECTED PROOFS

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Laboratory Medicine at Fletcher Allen Health Care, University of Vermont College of Medicine, University of Vermont, Burlington MICHELE A. LLOYD-PURYEAR, Representative of the Office of Rare Diseases Research; Former Senior Medical and Scientific Advisor, National Institute of Child Health and Human Development, Bethesda, MD TERI A. MANOLIO, Director, Division of Genomic Medicine, National Human Genome Research Institute, Rockville, MD ELIZABETH MANSFIELD, Director of the Personalized Medicine Staff, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, MD KATHRYN MCLAUGHLIN, Program Officer, National Hemophilia Program, Genetic Services Branch, Health Resources and Services Administration, Rockville, MD KELLY MCVEARRY, Former Senior Scientific Advisor, Health Solutions, Northrop Grumman Information Systems, Rockville, MD GARRY NEIL, Former Corporate Vice President, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ ROBERT L. NUSSBAUM, Chief, Division of Medical Genetics, Department of Medicine and Institute of Human Genetics, University of California, San Francisco, School of Medicine OLUFUNMILAYO F. OLOPADE, Walter L. Palmer Distinguished Service Professor of Medicine; Director, Center for Clinical Cancer Genetics; Associate Dean for Global Health, University of Chicago, IL MICHELLE A. PENNY, Senior Director, Translational Medicine Group, Eli Lilly and Company, Indianapolis, IN AIDAN POWER, Vice President and Head, PharmaTx Precision Medicine, Pfizer Inc., Groton, CT VICTORIA M. PRATT, Representative of the Association for Molecular Pathology; Associate Professor of Clinical Medical and Molecular Genetics and Director, Pharmacogenomics Diagnostic Laboratory, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis RONALD PRZYGODZKI, Associate Director for Genomic Medicine and Acting Director of Biomedical Laboratory Research and Development, Department of Veterans Affairs, Washington, DC ALLEN D. ROSES, President and Chief Operating Officer, Cabernet, Shiraz and Zinfandel Pharmaceuticals; and Jefferson–Pilot Professor of Neurobiology and Genetics, Professor of Medicine (Neurology); ix PREPUBLICATION COPY: UNCORRECTED PROOFS

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Director, Deane Drug Discovery Institute; Senior Scholar, Fuqua School of Business, R. David Thomas Executive Training Center, Duke University, Durham, NC KEVIN A. SCHULMAN, Professor of Medicine and Business Administration; Director, Center for Clinical and Genetic Economics; Associate Director, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC JOAN A. SCOTT, Chief, Genetic Services Branch, Division of Services for Children with Special Health Needs, Maternal and Child Health Bureau, Rockville, MD SAM SHEKAR, Chief Medical Officer, Health Information Technology Program, Northrop Grumman Information Systems, McLean, VA KATHERINE JOHANSEN TABER, Senior Scientist, Genetics and Molecular Medicine, American Medical Association, Chicago, IL DAVID VEENSTRA, Professor, Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle MICHAEL S. WATSON, Executive Director, American College of Medical Genetics and Genomics, Bethesda, MD DANIEL WATTENDORF, Deputy Chief, Medical Innovations, Department of the Air Force; Program Manager, Defense Advanced Research Projects Agency/Defense Sciences Office, Arlington, VA CATHERINE A. WICKLUND, Past President, National Society of Genetic Counselors; Director, Graduate Program in Genetic Counseling; Associate Professor, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL JANET K. WILLIAMS, Representative of the American Academy of Nursing; Professor of Nursing, University of Iowa, College of Nursing, Chair of Behavioral and Social Science, Iowa City IOM Staff ADAM C. BERGER, Project Director SARAH H. BEACHY, Associate Program Officer TONIA E. DICKERSON, Senior Program Assistant (until January 2014) MEREDITH HACKMANN, Senior Program Assistant (from January 2014) x PREPUBLICATION COPY: UNCORRECTED PROOFS

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Board on Health Sciences Policy Staff ANDREW M. POPE, Director DONNA RANDALL, Administrative Assistant Fellows SEAN P. DAVID, James C. Puffer, M.D./American Board of Family Medicine Fellow SAMUEL G. JOHNSON, American Association of Colleges of Pharmacy/American College of Clinical Pharmacy Anniversary Fellow xi PREPUBLICATION COPY: UNCORRECTED PROOFS

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Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its pub- lished report as sound as possible and to ensure that the report meets in- stitutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confi- dential to protect the integrity of the process. We wish to thank the fol- lowing individuals for their review of this report: Pankaj Agarwal, GlaxoSmithKline Russ Altman, Stanford University Don Frail, AstraZeneca Chris Watkins, U.K. Medical Research Council Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Elena Nightingale, The George Washington School of Medicine and Health Sciences and Georgetown University School of Medicine. Appointed by the Institute of Medicine, she was responsible for making certain that an independent examination of this report was carried out in accordance with institution- al procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the rapporteurs and the institution. xiii PREPUBLICATION COPY: UNCORRECTED PROOFS

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Acknowledgments The support of the sponsors of the Institute of Medicine Roundtable on Translating Genomic-Based Research for Health was crucial to the planning and conduct of the workshop on Genomics-Enabled Drug Repurposing and Repositioning and the development of the workshop summary report. Federal sponsors are the Department of the Air Force; Department of Veterans Affairs; Health Resources and Services Administration; National Cancer Institute; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Mental Health; National Institute of Nursing Research; National Institute on Aging; and Office of Rare Diseases Research. Nonfederal sponsorship was provided by the American Academy of Nursing; American College of Medical Genetics and Genomics; American Heart Association; American Medical Association; American Society of Human Genetics; Association for Molecular Pathology; Blue Cross and Blue Shield Association; College of American Pathologists; Eli Lilly and Company; Genetic Alliance; International Society for Cardiovascular Translational Research; Johnson & Johnson; the Kaiser Permanente Program Offices Community Benefit II at the East Bay Community Foundation; Life Technologies; National Coalition for Health Professional Education in Genetics; National Society of Genetic Counselors; Northrop Grumman Health IT; Pfizer Inc.; and PhRMA. The Roundtable wishes to express its gratitude to the expert speakers whose presentations helped outline the challenges and opportunities for genomics-enabled drug repurposing and repositioning. The Roundtable also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director xv PREPUBLICATION COPY: UNCORRECTED PROOFS

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xvi ACKNOWLEDGMENTS would like to thank the project staff who worked diligently to develop both the workshop and the resulting summary. PREPUBLICATION COPY: UNCORRECTED PROOFS

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Contents ABBREVIATIONS AND ACRONYMS xxi 1 INTRODUCTION AND THEMES OF THE WORKSHOP 1 Workshop Themes, 3 2 THE STATE OF THE SCIENCE 7 Industry Repurposing Efforts, 8 Rare Diseases, 10 Potential Opportunities for Drug Discovery, 11 3 ENABLING TOOLS AND TECHNOLOGY 17 Discovery Using Publicly Available Data, 18 Role of Basic Science for Translation, 19 Data Mining, 21 Repurposing at NCATS, 24 Patient-Reported Data, 27 4 VALUE PROPOSITIONS FOR DRUG REPURPOSING 31 Business Models, 32 Repurposing Drugs Currently in Development, 34 Thalidomide: Repurposing a Drug That Was Not Successful for Its First Indication, 37 5 POLICY APPROACHES AND LEGAL FRAMEWORK 39 Overcoming Barriers to Drug Repurposing at NCATS, 40 Overcoming Barriers to Drug Repurposing at the MRC, 43 Compound Availability, 45 Legal and Intellectual Property Issues, 46 xvii PREPUBLICATION COPY: UNCORRECTED PROOFS

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xviii CONTENTS 6 INCREASING THE EFFICIENCY AND SUCCESS OF REPURPOSING 49 The Role of Genomics, 49 Use of Electronic Medical Records, 51 Existing Barriers, 51 Possible Next Steps, 52 Future Repurposing Efforts, 54 REFERENCES 57 APPENDIXES A Workshop Agenda 65 B Speaker Biographical Sketches 73 C Statement of Task 89 D Registered Attendees 91 PREPUBLICATION COPY: UNCORRECTED PROOFS

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Boxes and Figure BOXES 1-1 Workshop Objectives, 3 6-1 Suggested Proposals Made by Individual Speakers, 55 FIGURE 4-1 Eroom’s Law in pharmaceutical R&D, 32 xix PREPUBLICATION COPY: UNCORRECTED PROOFS

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Abbreviations and Acronyms ACE angiotensin-converting enzyme ALS amyotrophic lateral sclerosis BMS Bristol-Myers Squibb CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator CMS Centers for Medicare & Medicaid Services CRO contract research organization DNA deoxyribonucleic acid EMR electronic medical record ENL erythema nodosum leprosum ERK extracellular-signal-regulated kinase FDA U.S. Food and Drug Administration GWAS genome-wide association studies HIV-1 human immunodeficiency virus-1 HPBCD 2-hydroxylpropyl-b-cyclodextrin ImmPort Immunology Database and Analysis Portal IOM Institute of Medicine IRB institutional review board xxi PREPUBLICATION COPY: UNCORRECTED PROOFS

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xxii ABBREVIATIONS AND ACRONYMS LINCS Library of Integrated Network-Based Cellular Signals LOD logarithm of odds MODDERN Modernizing Our Drug and Diagnostic Evaluation and Regulatory Network MRC Medical Research Council NCATS National Center for Advancing Translational Sciences NeuroNEXT Network for Excellence in Neuroscience Clinical Trials NIH National Institutes of Health NINDS National Institute of Neurological Disorders and Stroke R&D research and development TGF transforming growth factor TNF tumor necrosis factor TRND Therapeutics for Rare and Neglected Diseases U.K. United Kingdom U.S. United States PREPUBLICATION COPY: UNCORRECTED PROOFS