Progress in Drug Research Founded by Ernst Jucker

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Progress in Drug Research

Founded by Ernst Jucker

Series Editors

Prof. Dr. Paul L. Herrling Alex Matter, M.D., Director

Novartis International AG Novartis Institute for Tropical Diseases CH-4002 Basel 10 Biopolis Road, #05-01 Chromos

Switzerland Singapore 138670

Singapore

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Birkhäuser Verlag Basel^•Boston^• Berlin

Progress in Drug Research

Imaging in Drug Discovery and

Early Clinical Trials

Vol. 62

Edited by

Markus Rudin

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Editor:

Prof. Dr. Markus Rudin

Institute for Biomedical Engineering University of Zürich/ETH Zürich Moussonstr. 18

CH – 8092 Zürich Switzerland

ISBN-10: 3-7643-7157-9 Birkhäuser Verlag, Basel – Boston – Berlin ISBN-13: 978-3-7643-7157-9

The Publisher and Editor cannot assume any legal responsibility for information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case.

The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws and regulations or free for general use.

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ISBN-10:7643-7157-9 e-ISBN: 3-7643-7426-8

ISBN-13: 978-3-7643-7157-9

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Foreword

Imaging techniques are undergoing a tremendous development. The clin- ically established methods such as X-ray computerized tomography (CT), magnetic resonance imaging (MRI), ultrasound imaging, and nuclear imaging provide structural and functional data of ever increasing quality. Today, the speed of data acquisition allows making efficient use of the measure- ment time; the collection of multiple complementary datasets during a sin- gle imaging session enhances the reliability of the diagnostic/prognostic information. Improved image processing tools enable three-dimensional visualization of imaging data as well as the derivation of biomedical relevant information from the primary imaging data. In the recent years, target-specific, so-called molecular imaging approaches have been developed at a rapid pace. Information such as target expression, target function, path- way activities (e.g., protein-protein interactions), or cell migration can meanwhile be studied in the intact organism with reasonable spatial and temporal resolution. While most of these methods are currently confined to animal studies, they will be translated in a not too distant future also to the clinical arena. The value of these techniques, which allow visualizing the underlying molecular mechanism associated with disease, as a basic research tool and, most importantly, for diagnostics will be enormous. In addition, the use of multiplexed imaging methods will enable the compre- hensive characterization of a therapeutic intervention, visualizing and mea- suring the biodistribution of both the drug and the drug target, the drug- target interaction, the activation of signal transduction pathways, and ultimately the morphological and physiological consequences of these molecular events.

It is obvious that aside from the already established relevance in medical diagnostics, imaging techniques will play a major role in the development of novel therapies. As non-invasive modalities they are readily translatable from a preclinical to a clinical setting. There is considerable hope that imaging methods, in conjunction with other bio-analytical techniques, will provide early information of drug efficacy, much earlier than conventional pharmacological readouts. Drug development resources could then be focused on the most promising development candidates, for which pilot clinical trials using imaging readouts have demonstrated proof of the therapeutic concept. This

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potentially would save considerable resources and might expedite transla- tional and clinical studies, from which ultimately the patient would profit.

Non-invasive imaging enhances the diagnostic accuracy, enabling medical personnel to select and tailor the therapy strategy in an optimal way; monitoring the patient’s therapy response will allow optimizing the treatment reg- imen.

The objective of this volume is to illustrate the role of non-invasive imaging for modern drug discovery and development. There is considerable expec- tation by many different stakeholders that investments in imaging technol- ogy will add value to the process of developing a novel drug: for biomedical researches imaging should enhance the basic understanding of the disease process, for the drug development it should yield unambiguous information that facilitates proper decision making allowing to focus resources, for man- agement it should expedite the development process and thus reduce costs, for marketing it should provide compelling visual evidence of drug effi- ciency that would convince prescribers to choose this drug, for the regula- tors validated imaging data might replace softer endpoints that are currently used for many indications. Most importantly, patients would profit from better monitoring and better medicine.

The layout of the book follows the drug discovery process, from the target selection/validation (molecular imaging) to the clinical drug evaluation and ultimately to the approval by regulatory authorities. Chapter 1 by Paul L Herrling gives an overview of the drug discovery process from the selection of a potential drug target to the handover to the clinical development. The layout of the volume essentially follows this process. In Chapter 2, Tobias Schäffter discusses the basic principles of the individual non-invasive imaging techniques that are used as clinical diagnostic tools.

The information provided by modern imaging techniques extends far beyond the structural-anatomical readouts obtained from the first X-ray studies. Today, information on molecular and cellular events, physiological and metabolic processes can be gathered in the intact organism, which complements structural information. Molecular and cellular imaging approaches translate many assays developed for molecular and cell biological studies into paradigms suited for in vivo visualization. These aspects are discussed in Chapters 3 by David Sosnovik and Ralph Weissleder focusing on MRI and optical (fluorescence) imaging techniques, and in Chapter 4 by Olivier Gheysens and Sam Gambhir with special emphasis on nuclear and

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optical (bioluminescence) methods. Molecular imaging approaches will impact drug discovery at all phases: from the visualization of the target expression and target function, to the molecular proof-of-therapeutic mechanism at a molecular level in the intact organism – ultimately in the patient.

The use of genetically modified organisms, and in particular mice, for testing biological hypotheses or as models of human diseases has become indispensable in modern biomedical research. This demands tools for rapid and efficient characterization of such animals with the intention to link molecular, physiological, metabolic or structural peculiarities to genetic modifications (phenotyping). Transgene insertion is a random process, correspondingly large numbers of mice have to be analyzed to identify the desired phenotypes. Non-invasive methods play an important role in this task; these aspects are addressed by R. Mark Henkelman et al.

in Chapter 5.

Following target identification and validation and the screening of large compound libraries, potential drug candidates have to be optimized with regard to efficacy, pharmacokinetic properties, and safety. This lead opti- mization phase involves the qualitative and quantitative evaluation of drug effects in models of human disease, as discussed by Markus Rudin et al. in Chapter 6. Mark Tengowski and John Kotyk illustrate the role of imaging, and in particular MRI for the evaluation of potential safety issues and toxicolog- ical effects.

A prerequisite for clinical drug evaluation is knowledge of the drug’s pharmacokinetic (PK) properties. In vivo PK studies are based on positron- emission tomography (PET) using radiolabeled drug molecules. Aspects of tracer synthesis, PET experiments, and the extraction of quantitative information from PET data are topic of Chapter 8 by Mats Bergström and Bengt Langström. Clinical drug evaluations, in particular when targeting chronic diseases require large patient populations, are time consuming and there- fore expensive. To optimize the chances for success, pilot studies aiming to demonstrate proof of the pharmacological concept would be of outmost importance. Such studies depend on the availability of biomarkers that are indicative of treatment outcome. Biomarkers would also be of value for stratifying patient groups, a higher homogeneity of the population, increasing the relevance of the study. In Chapter 9 Janet Miller and Greg Sörensen discuss the potential of imaging biomarkers for diagnosis and prognosis of

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human stroke as well as for the evaluation of therapeutic interventions. In particular, the concept of using the patient as its own control is highly attractive. Finally, Chapter 10 is devoted to the use of imaging readouts for clinical drug trials. David Lester puts special emphasis on regulatory aspects, discussing efforts by the regulatory authorities regarding the use of innov- ative methodologies such as imaging in drug approval process.

Zürich, May 2005 Markus Rudin

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Progress in Drug Research Founded by Ernst Jucker

Progress in Drug Research

Progress in Drug Research

Imaging in Drug Discovery and

Early Clinical Trials

Vol. 62

Edited by

Markus Rudin

Contents

Foreword