Cambridge University Press
9780521886451 - Translational Medicine and Drug Discovery - Edited by Bruce H. Littman and Rajesh Krishna
Frontmatter/Prelims

Translational Medicine and Drug Discovery

This book, edited by two leaders known for driving innovation in the field, focuses on the new discipline of translational medicine as it pertains to drug discovery and development within the pharmaceutical and biotechnology industries. Translational medicine seeks to translate biological and molecular knowledge of disease and how drugs work into innovative strategies that reduce the cost and increase the speed of delivering new medicines for patients. This book describes these general strategies, biomarker development, imaging tools, translational human models, and examples of their application to real-life drug discovery and development. The latest thinking is presented by researchers from many of the world's leading pharmaceutical companies, including Pfizer, Merck, Eli Lilly, Abbott, and Novartis, as well as from academic institutions and public–private partnerships that support translational research. This book is essential for anyone interested in translational medicine from a variety of backgrounds (university institutes, medical schools, and pharmaceutical companies) in addition to drug development researchers and decision makers.

Bruce H. Littman, MD, is the founder of Translational Medicine Associates, LLC, and was the Vice President and Global Head of Translation Medicine at Pfizer, Inc., where he worked for 19 years, first in Experimental Medicine and then in Translational Medicine before starting his own company. He has published and presented extensively in the areas of early drug development, biomarker qualification, and personalized medicine. He was former cochair and is a current member of the Inflammation and Immunity Steering Committee of the Biomarker Consortium. Prior to his pharmaceutical career, Dr. Littman was a faculty member of Virginia Commonwealth University School of Medicine for 13 years. He is a Founding Fellow of the American College of Rheumatology, former President of the Virginia Society of Rheumatologists, and a Fellow of the American College of Physicians.

Rajesh Krishna, PhD, FCP, FAAPS, is an area lead director in product value enhancement at Merck Research Laboratories. Dr. Krishna is the editor of three books on new drug development. In addition to authoring some 120 articles and oral/poster presentations, Dr. Krishna has served as a section editor for the Journal of Clinical Pharmacology, associate editor for BMC Clinical Pharmacology, and an editorial board member for BMC Medicine. He is a Fellow of the American College of Clinical Pharmacology and the American Association of Pharmaceutical Scientists, where he was the 2010 Chair of the Clinical Pharmacology and Translational Research section. He is an affiliate member of the Institute of Translational Medicine and Therapeutics at the University of Pennsylvania and an adjunct assistant professor in clinical pharmacology at Thomas Jefferson University.

Translational Medicine and Drug Discovery

Edited by

Bruce H. Littman

Translational Medicine Associates, LLC

Rajesh Krishna

Merck Research Laboratories

CAMBRIDGE UNIVERSITY PRESS
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© Cambridge University Press 2011

This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press.

First published 2011

Printed in the United States of America

A catalog record for this publication is available from the British Library.

Library of Congress Cataloging in Publication data

Translational medicine and drug discovery / [edited by] Bruce H. Littman, Rajesh Krishna.
 p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-521-88645-1 (hardback)
1. Drug development. 2. Molecular pharmacology. I. Littman, Bruce H., 1944–
II. Krishna, Rajesh. III. Title.
[DNLM: 1. Drug Discovery. 2. Translational Research – methods. QV 744]
RM301.25.T73 2011
615′.19–dc22 2010037116

ISBN 978-0-521-88645-1 Hardback

Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party Internet Web sites referred to in this publication and does not guarantee that any content on such Web sites is, or will remain, accurate or appropriate.

Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

Contents

Contributors
 xv
Preface
 xix
Section I:    Translational Medicine: History, Principles, and Application in Drug Development
 1
1.            Translational Medicine: Definition, History, and Strategies Bruce H. Littman
 3
1.1.          Biomarkers in Drug Development: A Common Understanding
 5
1.2.          Pharmacology: Testing the Target (POM)
 7
1.3.          Study Design Considerations for POM
 13
1.3.1.        Population
 13
1.3.2.        Risk
 14
1.3.3.        Feasibility
 14
1.3.4.        Endpoints
 15
1.3.5.        PK–PD and PD–PD Models
 16
1.4.          Confirming the Hypothesis That a Drug Target (Mechanism of Action) Will Be Efficacious (POC)
 17
1.5.          Study Design Considerations for POC
 17
1.5.1.        Population
 17
1.5.2.        Efficacy Endpoints
 19
1.5.3.        Dose Selection
 20
1.5.4.        Cost, Speed, and Risk
 20
1.5.5.        Multiple Indications (Serial or Parallel)
 21
1.6.          Human Indications Screening
 23
1.6.1.        Expl-IND Application
 24
1.6.2.        Low Cost Attrition and Portfolio Economics
 26
1.7.          Commercial Profile and Translational Medicine
 27
1.7.1.        Impact on Survival
 27
1.7.2.        Impact on Decision Making
 29
1.7.3.        Translational Medicine and the Personalized Medicine Option
 31
1.8.          Conclusion
 32
1.9.          References
 32
2.            Translational Medicine and Its Impact on Diabetes Drug Development Roberto A. Calle and Ann E. Taylor
 35
2.1.          Introduction
 35
2.2.          Primary Challenges
 37
2.2.1.        Efficacy
 37
2.2.2.        Safety
 46
2.3.          Case Studies
 49
2.3.1.        Case Study #1: Development of DPP-4i
 49
2.3.2.        Case Study #2: Development of 11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
 50
2.3.3.        Case Study #3: Effect of Weight Loss on HbA1c
 54
2.4.          Conclusions
 56
2.5.          Acknowledgments
 56
2.6.          References
 56
3.            Challenges in Atherosclerosis John S. Millar
 62
3.1.          Introduction
 62
3.2.          Prevailing Hypotheses of Atherosclerosis Development
 62
3.2.1.        The Lipid Hypothesis
 62
3.2.2.        The Response-to-Injury Hypothesis
 63
3.2.3.        The Response-to-Inflammation Hypothesis
 64
3.2.4.        The Response-to-Retention Hypothesis
 64
3.3.          Clinical Trials Supporting the Lipid Hypothesis
 65
3.4.          Where We Stand Today
 65
3.5.          Atherosclerosis and Drug Discovery and Development
 67
3.5.1.        Lipoprotein Metabolism
 67
3.5.2.        Antidyslipidemics
 69
3.6.          The Future Generation of LDL-Lowering Drugs
 73
3.6.1.        Thyroid Receptor-β Agonism
 73
3.6.2.        Lipoprotein-Associated-Phospholipase A2 Inhibitors
 73
3.6.3.        Secretory Phospholipase A2 Inhibitors
 74
3.6.4.        Microsomal Triglyceride Transfer Protein Inhibitors
 74
3.6.5.        Antisense/RNA Interference of apoB mRNA
 75
3.7.          Therapies to Increase HDL Cholesterol Levels and Improve HDL Function
 75
3.7.1.        CETP Inhibitors
 76
3.7.2.        PPAR-α Agonists
 76
3.7.3.        Reconstituted and Recombinant HDL/apoA-I Mimetic Peptides
 77
3.8.          Biomarkers Linked to Clinical Outcomes
 77
3.8.1.        Biomarkers
 78
3.8.2.        Measures of Vascular Function and Atherosclerosis
 78
3.9.          Case Study: CETP Inhibition with Torcetrapib – Mechanism versus Molecule
 80
3.10.         Conclusion
 82
3.11.         References
 82
4.            Obesity: New Mechanisms and Translational Paradigms Gregory Gaich and David E. Moller
 89
4.1.          Introduction
 89
4.1.1.        Medical Need and History of Failure
 89
4.1.2.        Pathophysiology and Principles of Energy Balance
 90
4.2.          Molecular Pathways and Associated Drug Targets
 90
4.2.1.        Central Regulation of Satiety–Thermogenesis
 92
4.2.2.        Modulating the Actions of Gut-Derived Peptide Hormones
 96
4.2.3.        Targeting Other Peripheral Pathways
 98
4.3.          Clinical Paradigm and Recent Clinical Experience
 100
4.4.          Translational Approaches
 102
4.4.1.        Target Engagement
 103
4.4.2.        Drug Pharmacology or Mechanism Biomarkers
 104
4.4.3.        Disease Process or Outcome Biomarkers and Mechanism Biomarkers Linked to Efficacy Outcomes
 105
4.4.4.        Subject Selection
 106
4.4.5.        Combination Therapy
 107
4.5.          Concluding Comments
 107
4.6.          References
 108
5.            Bone Disorders: Translational Medicine Case Studies S. Aubrey Stoch
 115
5.1.          Introduction
 115
5.2.          Challenges in Translational Research
 116
5.3.          Osteoporosis: Biomarker Considerations
 116
5.3.1.        Biochemical Biomarkers of Bone Turnover
 116
5.3.2.        Imaging Biomarkers (BMD)
 118
5.3.3.        Preclinical Models
 119
5.4.          Antiresorptives
 121
5.4.1.        Cat K Inhibitors
 122
5.4.2.        αvβ3 Integrin Antagonists
127
5.5.          Osteoanabolics
 130
5.5.1.        Selective Androgen Receptor Modulators
 131
5.5.2.        Calcium Receptor Antagonists (Calcilytics)
 136
5.5.3.        Dickkopf-1 (DKK-1) Inhibitors
 144
5.5.4.        Sclerostin Inhibitors
 149
5.6.          Conclusions
 155
5.7.          References
 158
6.            Case Studies in Neuroscience: Unique Challenges and Examples Gerard J. Marek
 168
6.1.          Why Is Neuroscience Not Tractable?
 168
6.2.          Why Have New Mechanisms Failed?
 169
6.3.          Can We Predict Efficacy in Short-Term Studies?
 173
6.4.          What Is the Role for Cognitive Biomarkers?
 174
6.5.          What Translational Medicine Approaches Will Drive Innovation in Neuroscience Drug Development?
 175
6.6.          References
 177
7.            Translational Medicine in Oncology Dominic G. Spinella
 180
7.1.          Pharmacodynamic Biomarkers
 180
7.1.1.        Traditional Phase 1 Dose Selection versus the Paradigm for Targeted Agents
 181
7.2.          Outcome Biomarkers
 183
7.3.          Patient Selection Biomarkers
 185
7.4.          Putting It All Together: The Translational Approach
 188
7.4.1.        Preclinical Work
 188
7.4.2.        The Phase 1 Study
 189
7.4.3.        The Phase 2 Study
 190
7.5.          Conclusions
 190
7.6.          References
 191
Section II:   Biomarkers and Public–Private Partnerships
 193
8.            Biomarker Validation and Application in Early Drug Development: Idea to Proof of Concept Pfizer Global Research and Development 2004
 195
8.1.          Definitions and Summary of Overarching Principles
 195
8.2.          Biomarker Validation Terminology
 197
8.3.          Stages of Biomarker Lifecycle
 198
8.4.          Why Biomarkers?
 200
8.5.          Biomarker Validation
 202
8.5.1.        Define the Specific Purpose(s) of the Biomarker
 202
8.5.2.        Examine the Business Impact of Making a Wrong Decision
 203
8.5.3.        Select Appropriate Technical Validation Attributes
 205
8.5.4.        Create the Biomarker MAC and Appropriate Decision Criteria
 209
8.5.5.        Summary
 214
8.6.          When and How to Apply Biomarkers in Drug Development: Biomarker Development Is Described for Each Stage of Drug Development
 215
8.6.1.        Biomarker Development Must Occur So That Biomarkers Are Validated for Their Purpose Prior to Application for Drug Development Decisions
215
8.6.2.        Biomarker Selection and Development between “Target Idea” and Decision on Drug Candidate Selection
 216
8.6.3.        Biomarker Best Practice between Drug Candidate Selection and First In-Human (FIH) Study
 216
8.6.4.        Biomarker Best Practice between FIH and Phase 2 Start
 218
9.            Imaging Biomarkers in Drug Development: Case Studies Johannes T. Tauscher and Adam J. Schwarz
 222
9.1.          Introduction
 222
9.2.          Molecular Imaging: PET “Receptor Occupancy” as a Marker for Target Engagement
 224
9.2.1.        A Brief History of Dopamine Receptor Occupancy with Antipsychotics
 224
9.2.2.        Serotonin Transporter Occupancy with Antidepressants
 226
9.2.3.        Case Study of a Translational PET Imaging Biomarker Strategy
 227
9.3.          Functional Imaging: fMRI as a Probe of Drug Effects in the CNS
 228
9.3.1.        fMRI Biomarkers and Mechanistic Models in Early Drug Development
 230
9.3.2.        Normalization of Brain Function: fMRI Studies in Patient Populations
 233
9.3.3.        Validation and Standardization of fMRI for Drug Development Applications
 234
9.4.          Imaging as a Biomarker to Enrich Study Populations
 235
9.5.          Oncology
 236
9.5.1.        Anatomical Imaging in Cancer Drug Development
 236
9.5.2.        Functional Imaging in Cancer Drug Development
 237
9.5.3.        Imaging the Tumor Vasculature
 239
9.5.4.        Imaging of Cellular Proliferation
 242
9.5.5.        Tumor Receptor Imaging
 244
9.5.6.        Imaging Apoptosis
 244
9.6.          Imaging Cardiovascular Disease
 245
9.6.1.        Clinical Trials in Atherosclerosis Using Imaging Endpoints
 246
9.6.2.        Practicality of Cardiovascular Imaging Trials and Application to Drug Development
 247
9.7.          Conclusions
 247
9.8.          Conflict of Interest Statement
 249
9.9.          References
 249
10.           European New Safe and Innovative Medicines Initiatives: History and Progress (through December 2009) Ole J. Bjerrum and Hans H. Linden
 265
10.1.         Introduction
 265
10.1.1.       The EU Research Funding System
 265
10.1.2.       Stakeholders
 266
10.2.         Toward the IMI
 267
10.2.1.       First Round: Establishment of the NSMF Project
 267
10.2.2.       Second Round: Incorporation of NSMF in FP 6
 269
10.2.3.       Third Round: The Rise of the IMI
 271
10.3.         Organizational Structure of the IMI
 272
10.4.         How Does the SRA of the IMI Address Predictive Markers of Efficacy and Safety?
 274
10.4.1.       Predictive Markers of Efficacy
 274
10.4.2.       Predictive Markers of Safety
 276
10.5.         How Is Off-Target Toxicity Addressed in the SRA?
 277
10.6.         How Will the IMI Consortium Help in Transforming Current Science?
 278
10.7.         The Topic Proposals in the First Call of the IMI
 280
10.7.1.       Predictive Safety
 281
10.7.2.       Predictive Efficacy
 282
10.7.3.       Knowledge Management
 283
10.7.4.       Education and Training
 283
10.8.         The Call Procedures
 285
10.9.         Future Perspectives
 285
10.10.        Acknowledgments
 287
10.11.        References
 287
11.           Critical Path Institute and the Predictive Safety Testing Consortium Elizabeth Gribble Walker
 289
11.1.         Introduction to the Critical Path in Medical Product Development
 289
11.2.         The Predictive Safety Testing Consortium
 290
11.3.         Regulatory and Public Health Impact of the PSTC
 292
11.4.         References
 293
12.           The Biomarkers Consortium: Facilitating the Development and Qualification of Novel Biomarkers Through a Precompetitive Public–Private Partnership David Wholley and David B. Lee
 295
12.1.         References
 300
Section III:  Future Directions
 301
13.           Improving the Quality and Productivity of Pharmacometric Modeling and Simulation Activities: The Foundation for Model-Based Drug Development Thaddeus H. Grasela, Jill Fiedler-Kelly, and Robert Slusser
 303
13.1.         Introduction
 303
13.1.1.       Chapter Overview
 304
13.2.         The Pharmacometric Analysis Process
 304
13.2.1.       The M&S Process in Pharmacometrics – Current Practice
 305
13.2.2.       The M&S Process in Pharmacometrics – Future Practice
 306
13.2.3.       The Central Role of the Franchise Disease–Drug Model
 307
13.2.4.       Implications of the Future Scenario
 310
13.3.         Challenges in the Delivery of M&S Results
 311
13.3.1.       Systematic Needs
 311
13.3.2.       Informatics Needs
 312
13.3.3.       Process Needs
 313
13.4.         Next Steps
 314
13.4.1.       Strategies for Improving the Quality and Productivity of the Pharmacometrics Process
 315
13.4.2.       Strategies for Improving the Quality and Robustness of the Informatics Infrastructure for Pharmacometrics
 318
13.4.3.       A Systematic Process for Assessing Franchise Disease–Drug Model Feasibility
 319
13.4.4.       Systematizing the Requirements Definition Management Process
 322
13.5.         Summary
 324
13.6.         References
 325
14.           Embracing Change: A Pharmaceutical Industry Guide to the 21st Century Mervyn Turner
 328
14.1.         Introduction
 328
14.1.1.       Toward a New Paradigm of Drug Development
 330
14.1.2.       Embracing Democratization: Partner or Perish
 331
14.2.         Toward a New Paradigm of Drug Development: It's a State of Mind
 331
14.3.         Fail Fast, Fail Cheap
 332
14.4.         Philosophy in Action: Merck's Clinical Pharmacology and Experimental Medicine Strategies
 334
14.4.1.       Embrace Democratization – Partner or Perish
 336
14.4.2.       Adapt Culture to Recognize the Benefits and Necessities of Diversifying Pathways to Knowledge
 337
14.4.3.       Advance Experimental Medicine through Acquisition and Partnering
 339
14.5.         A Blueprint for Change
 341
14.6.         References
 343
Index
 345


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