Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development: A Focus on Early Phase Clinical Studies PDF
Preview Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development: A Focus on Early Phase Clinical Studies
Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development A Focus on Early Phase Clinical Studies Andrew J. Krentz Lutz Heinemann Marcus Hompesch Editors 123 Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development Andrew J. K rentz (cid:129) L utz Heinemann Marcus Hompesch Editors Translational Research Methods for Diabetes, Obesity and Cardiometabolic Drug Development A Focus on Early Phase Clinical Studies Editors Andrew J. Krentz, MD, FRCP Marcus Hompesch, MD Profi l Institute for Clinical Research Profi l Institute for Clinical Research Chula Vista , CA Chula Vista , CA USA USA Lutz Heinemann, PhD Profi l Institute for Clinical Research Chula Vista , CA USA ISBN 978-1-4471-4919-4 ISBN 978-1-4471-4920-0 (eBook) DOI 10.1007/978-1-4471-4920-0 Springer London Heidelberg New York Dordrecht Library of Congress Control Number: 2014956922 © Springer-Verlag London 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Foreword This book provides an important contribution to the literature on the scientifi c basis of drug development and clinical trials in the general fi eld of metabo- lism. There is a worldwide epidemic of obesity, type 2 diabetes, and associ- ated cardiometabolic diseases, which have collectively emerged as one of the greatest public health problems we face. Consequently, there is a huge unmet medical need for improved therapeutic options. This has created the opportu- nity and incentive to test a number of new potential drugs for these disorders. Given the high level of interest in drug development in this fi eld, this book focuses exclusively on early phase (phase 1 and 2) clinical studies, rather than later-stage phase 3 development. As such, the chapters in this book discuss a variety of current methodologies in metabolic research, which focus on proof of mechanism, early indicators of effi cacy, biomarkers, and safety. A key goal of these early phase studies is to learn as quickly as possible whether a potential drug candidate works through the expected mechanism with the desired degree of effi cacy. This provides for earlier “go/no go” decisions, allowing biopharmaceutical companies to focus their resources on the most promising projects. By using the latest in vivo methodologies to measure physiologic variables such as insulin secretion, insulin sensitivity, thermogenesis, metabolomics, and a variety of other outputs, a great deal can be learned in the initial stages of drug testing, which has not been possible in the past. Thus, thoughtfully designed proof-of-mechanism studies are highly feasible and make current discussions and resource allocations in metabolic drug development far more effi cient and informative. The editors of this book, Andrew J. Krentz, MD, Lutz Heinemann, PhD, and Marcus Hompesch, MD, are all highly experienced experts in academic research and drug development, and they have recruited an expanded list of world leaders in metabolic research to cover a range of topics. Each chapter in part one chapter focuses on a specifi c approach or methodology, represent- ing the leading edge of knowledge in clinical research and early-stage drug development. To maintain uniformity, each chapter in the fi rst part of the book is organized in a comparable format, which greatly enhances its acces- sibility and usefulness to the reader. This includes an up-to-date summary of the latest scientifi c knowledge concerning each topic, coupled with practical information as to how the various methodologies can be best employed. The second part of the book considers emerging investigative approaches, regula- tory and practical issues of early phase cardiometabolic drug development. v vi Foreword T he intended readership includes industry-based scientists who are involved in the design and interpretation of fi rst-in-human effi cacy and proof- of-m echanism studies, as well as academic physicians engaged in metabolic research. This book should also be useful to a broader audience, including students and fellows who are just beginning or contemplating a career in this fi eld. San Diego, USA Jerrold M. Olefsky , MD Pref ace T his book is offered as a contribution to the complex quest for safe and effec- tive new drugs for the burgeoning global challenge of diabetes, obesity, and associated disorders. In creating the textbook, we hope to help fi ll what we perceive to be a gap in the scientifi c literature. Specifi cally, the focus is fi rmly on early phase (i.e., phase 1 and 2) safety, effi cacy, and proof-of-mechanism studies of relevant new therapies. As editors, we combine backgrounds anchored in the academic diabetes research environment with extensive experience of the professionalism of the biopharmaceutical industry. We hope that this dual – and, in our view, com- plementary – perspective is evident in our choice of topics. The primary for- mat is detailed reviews and critiques of the available methods along with illustrations of their use using examples derived from the literature. We are delighted to be joined in this venture by many renowned clinical investigators drawn from leading academic institutions and scientifi c service providers in the USA and Europe. We thank the contributors for their shared enthusiasm in providing chapters each of which we believe stands as a self- contained state-of-the-art review. In addition, where relevant we have pro- vided signposts that connect relevant sections of the book. The need to “fail early in appropriate subjects” has become a guiding prin- ciple in the development of new molecular entities for diabetes and obesity. In large part, this pressure refl ects the more stringent regulatory environment that was a response to recent high-profi le safety concerns of approved drugs. A new challenge facing the biopharmaceutical industry is fulfi lling the requirements for approval of biosimilar insulins, the pitfalls of which have already been demonstrated. For novel diabetes therapies, there is an increas- ing realization that blood glucose lowering to a similar degree to available therapies is no longer suffi cient. This realism recognizes the existence of an already crowded therapeutic arena that faces ever-increasing restrictions imposed by payers faced with cost-benefi t decisions. W e anticipate that the primary readership of the book will be industry- based clinical scientists involved in the design and interpretation of fi rst-in- human effi cacy and proof-of-mechanism studies. We hope that academic physicians engaged in clinical metabolic research will also fi nd the book of value. While we have assumed a high level of knowledge among readers, we have tried to provide relevant background science concerning the etiopatho- genesis of diabetes that informs the selection of the most appropriate vii viii Preface investigative methods. In addition to core methods for determining insulin action, time-action profi les of insulin formulations, body composition, etc., we review the ethics of early phase clinical research in diabetes and obesity, notably the move toward “fi rst-in-patient” studies that is increasingly accepted. The potential application of emerging disciplines such as the omics technologies and complex modelling techniques to diabetes drug develop- ment is also considered. M any clinicians, while familiar with the later stages of drug development, i.e., phases 3 and 4, may be rather less conversant with the aims of fi rst-in- human and proof-of-concept studies. Being mindful of this potential discon- nection, we have tried to bridge from the highly regulated early phase clinical research space to integrate new glucose-lowering drugs into clinical practice. For example, how does an improvement of X% of whole-body insulin sensi- tivity translate into glucose-lowering effi cacy? What “added value” do patients and prescribers want from a new diabetes drug, and conversely, what unwanted effects must be avoided? Perhaps a more developed dialogue between clinicians and clinical scientists would be of value when contemplat- ing the future of diabetes therapies. We wish to thank Diane Lamsback, Emma Sinclair, and Rebecca Owen of Springer for their unstinting assistance and support. Chula Vista, CA, USA Andrew J. Krentz, MD, FRCP Fall 2014 Lutz Heinemann, PhD Marcus Hompesch, MD Contents Part I Review of Clinical Investigation Methodologies 1 Methods for Quantifying Insulin Sensitivity and Determining Insulin Time-Action Profi les. . . . . . . . . . . . . 3 Andrew J. Krentz, Lutz Heinemann, and Marcus Hompesch 2 Assessment of β-Cell Function . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Andrew J. Krentz, Lutz Heinemann, and Marcus Hompesch 3 Isotopic Tracers for the Measurement of Metabolic Flux Rates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Carine Beysen, Marc K. Hellerstein, and Scott M. Turner 4 Imaging Techniques for the Assessment of Ectopic Fat in Liver and Skeletal Muscle . . . . . . . . . . . . . . . . . . . . . . . . 99 Gavin Hamilton, Michael S. Middleton, Elhamy R. Heba, and Claude B. Sirlin 5 Positron-Emission Tomography and Computed Tomography Measurement of Brown Fat Thermal Activation: Key Tools for Developing Novel Pharmacotherapeutics for Obesity and Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Monte S. Buchsbaum and Alex DeCastro 6 Assessment of Body Composition. . . . . . . . . . . . . . . . . . . . . . . . 139 Mark Punyanitya and Paul R. Clark 7 Measurement of Energy Expenditure . . . . . . . . . . . . . . . . . . . . 169 Klaas R. Westerterp 8 Omics: Potential Role in Early- Phase Drug Development. . . . 189 Harald Grallert, Carola S. Marzi, Stefanie M. Hauck, and Christian Gieger Part II Emerging and Complementary Research Methods; Ethical and Regulatory Considerations 9 Early Phase Metabolic Research with Reference to Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Linda A. Morrow and Andrew J. Krentz ix
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