Drug Repositioning E-Book

Michael J. Barratt

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 880

Veröffentlichungsjahr: 2012

Beschreibung

The how's and why's of successful drug repositioning Drug repositioning, also known as drug reprofiling or repurposing, has become an increasingly important part of the drug development process. This book examines the business, technical, scientific, and operational challenges and opportunities that drug repositioning offers. Readers will learn how to perform the latest experimental and computational methods that support drug repositioning, and detailed case studies throughout the book demonstrate how these methods fit within the context of a comprehensive drug repositioning strategy. Drug Repositioning is divided into three parts: * Part 1, Drug Repositioning: Business Case, Strategies, and Operational Considerations, examines the medical and commercial drivers underpinning the quest to reposition existing drugs, guiding readers through the key strategic, technical, operational, and regulatory decisions needed for successful drug repositioning programs. * Part 2, Application of Technology Platforms to Uncover New Indications and Repurpose Existing Drugs, sets forth computational-based strategies, tools, and databases that have been designed for repositioning studies, screening approaches, including combinations of existing drugs, and a look at the development of chemically modified analogs of approved agents. * Part 3, Academic and Non-Profit Initiatives & the Role of Alliances in the Drug Repositioning Industry, explores current investigations for repositioning drugs to treat rare and neglected diseases, which are frequently overlooked by for-profit pharmaceutical companies due to their lack of commercial return. The book's appendix provides valuable resources for drug repositioning researchers, including information on drug repositioning and reformulation companies, databases, government resources and organizations, regulatory agencies, and drug repositioning initiatives from academia and non-profits. With this book as their guide, students and pharmaceutical researchers can learn how to use drug repositioning techniques to extend the lifespan and applications of existing drugs as well as maximize the return on investment in drug research and development.

Leseprobe

Table of Contents

Cover

About the Cover

Title page

Copyright page

ABOUT THE EDITORS

ACKNOWLEDGMENTS

CONTRIBUTORS

Introduction

PART I: DRUG REPOSITIONING: BUSINESS CASE, STRATEGIES, AND OPERATIONAL CONSIDERATIONS

CHAPTER 1 Drug Repositioning: The Business Case and Current Strategies to Repurpose Shelved Candidates and Marketed Drugs

1.1. INTRODUCTION

1.2. IS PHARMACEUTICAL R&D FAILING?

1.3. WHY ARE DRUGS FAILING?

1.4. OVERCOMING FAILURES

1.5. DRUG REPURPOSING

1.6. EXAMPLES OF SUCCESSFUL REPURPOSING

1.7. REPURPOSING EXISTING DRUGS

1.8. ORPHAN DRUGS

1.9. CONCLUSIONS

CHAPTER 2 Opportunities and Challenges Associated with Developing Additional Indications for Clinical Development Candidates and Marketed Drugs

2.1. INTRODUCTION

2.2. THE VALUE PROPOSITION

2.3. MANAGING THE RISK: ORGANIZATIONAL CHALLENGES

2.4. PRACTICAL CONSIDERATIONS, REAL RISKS, AND MITIGATION STRATEGIES WHEN DEVELOPING ADDITIONAL INDICATIONS FOR A CANDIDATE OR MARKETED DRUG

2.5. CONCLUSION

CHAPTER 3 Clinical and Operational Considerations in Repositioning Marketed Drugs and Drug Candidates

3.1. INTRODUCTION

3.2. CHALLENGES AND OPPORTUNITIES IN ESTABLISHING A DRUG REPOSITIONING PORTFOLIO: MARKETED DRUG, LEAD CANDIDATE, OR BACKUP?

3.3. PROOF-OF-MECHANISM (POM) FOR REPOSITIONED COMPOUNDS AND THE USE OF CLINICAL PROBES

3.4. IMPLICATIONS OF DRUG REPOSITIONING FOR CLINICAL PLANNING AND OPERATIONS

3.5. CONCLUSION

ACKNOWLEDGMENTS

CHAPTER 4 Regulatory Considerations and Strategies for Drug Repositioning

4.1. INTRODUCTION

4.2. HISTORY/BIRTH OF THE 505(b)(2)

4.3. SOURCES OF INFORMATION CITED IN 505(b)(2) SUBMISSIONS

4.4. WHERE TO FIND THE PUBLIC INFORMATION NEEDED FOR 505(b)(2) SUBMISSIONS

4.5. INTELLECTUAL PROPERTY AND DATA EXCLUSIVITY

4.6. 505(b)(2) CASE STUDIES

4.7. PRODRUGS

4.8. SUMMARY

PART II: APPLICATION OF TECHNOLOGY PLATFORMS TO UNCOVER NEW INDICATIONS AND REPURPOSE EXISTING DRUGS

CHAPTER 5 Computational and Bioinformatic Strategies for Drug Repositioning

5.1. INTRODUCTION

5.2. KNOWLEDGE MINING AND INTEGRATION STRATEGIES

5.3. CASE STUDY: APPLICATION OF COMPUTATIONAL DRUG REPOSITIONING APPROACHES IN THE VAN ANDEL RESEARCH INSTITUTE PERSONALIZED MEDICINE INITIATIVE

5.4. SUMMARY AND FUTURE DIRECTIONS

CHAPTER 6 Mining Scientific and Clinical Databases to Identify Novel Uses for Existing Drugs

6.1. INTRODUCTION

6.2. DATA SOURCES

6.3. ONTOLOGIES

6.4. LITERATURE CORPORA AND MINING

6.5. STRATEGIES TO INFER NOVEL ASSOCIATIONS BETWEEN DRUGS, DRUG TARGETS, AND HUMAN DISEASES: CASE STUDIES

6.6. FURTHER READING

6.7. CLOSING REMARKS

CHAPTER 7 Predicting the Polypharmacology of Drugs: Identifying New Uses through Chemoinformatics, Structural Informatics, and Molecular Modeling-Based Approaches

7.1. INTRODUCTION

7.2. THE CONCEPT OF POLYPHARMACOLOGY AND ITS RELATIONSHIP TO DRUG RESISTANCE, SIDE EFFECTS, AND DRUG REPOSITIONING

7.3. THE IMPORTANCE OF DRUG REPOSITIONING IN THE PHARMACEUTICAL INDUSTRY

7.4. CHEMICAL AND PROTEIN STRUCTURE-BASED APPROACHES

7.5. MOLECULAR ACTIVITY SIMILARITY-BASED METHODS

7.6. OTHER APPROACHES THROUGH DATA AND TEXT MINING

7.7. CONCLUSION

CHAPTER 8 Systematic Phenotypic Screening for Novel Synergistic Combinations: A New Paradigm for Repositioning Existing Drugs

8.1. INTRODUCTION

8.2. FUNDAMENTAL APPROACHES

8.3. KEYS TO SUCCESS

8.4. OPPORTUNITIES AND CHALLENGES IN COMBINATION DRUG DEVELOPMENT

8.5. CASE STUDIES

8.6. CONCLUDING REMARKS

ACKNOWLEDGMENTS

CHAPTER 9 Phenotypic In Vivo Screening to Identify New, Unpredicted Indications for Existing Drugs and Drug Candidates

9.1. INTRODUCTION

9.2. SETTINGS FOR IN VIVO DRUG REPOSITIONING

9.3. IN VIVO MODELS

9.4. ADVANTAGES OF COMPOUND SCREENING IN PHENOTYPIC IN VIVO MODELS

9.5. DESIGN OF AN OPTIMAL DRUG REPOSITIONING PLATFORM

9.6. RESULTS FROM PHENOTYPIC SCREENING STUDIES

9.7. COMPOUND SELECTION FOR DRUG REPOSITIONING

9.8. EXCLUSIVITY STRATEGIES FOR REPOSITIONED DRUGS IDENTIFIED BY PHENOTYPIC SCREENING

9.9. SUMMARY

CHAPTER 10 Old Drugs Yield New Discoveries: Examples from the Prodrug, Chiral Switch, and Site-Selective Deuteration Strategies

10.1. INTRODUCTION

10.2. PRODRUG APPROACH

10.3. CHIRAL SWITCH APPROACH

10.4. SITE-SELECTIVE DEUTERATION APPROACH

10.5. CONCLUSION

PART III: ACADEMIC AND NONPROFIT INITIATIVES AND THE ROLE OF ALLIANCES IN THE DRUG REPOSITIONING INDUSTRY

CHAPTER 11 Repurposing Drugs for Tropical Diseases: Case Studies and Open-Source Screening Initiatives

11.1. INTRODUCTION

11.2. DRUG DEVELOPMENT FOR NEGLECTED DISEASES

11.3. DRUG REPURPOSING IN MALARIA

11.4. DRUG REPURPOSING IN LEISHMANIA

11.5. DRUG REPURPOSING IN AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS)

11.6. OPEN-SOURCE SCREENING INITIATIVES—A SYSTEMATIC APPROACH TO IDENTIFYING NEW USES FOR EXISTING DRUGS

11.7. HIGH-THROUGHPUT SCREENING OF EXISTING DRUGS FOR TROPICAL DISEASES: THE JOHNS HOPKINS CLINICAL COMPOUND SCREENING INITIATIVE

11.8. IDENTIFICATION OF ASTEMIZOLE AS AN ANTIMALARIAL AGENT BY SCREENING A CLINICAL COMPOUND LIBRARY

11.9. SCREENING OF EXISTING DRUG LIBRARIES FOR OTHER TROPICAL DISEASES

11.10. CONCLUSIONS AND FUTURE DIRECTIONS

CHAPTER 12 Drug Repositioning Efforts by Nonprofit Foundations

12.1. INTRODUCTION

12.2. REPOSITIONING OF DRUGS FOR HEMATOLOGICAL MALIGNANCIES: PERSPECTIVE FROM THE LEUKEMIA & LYMPHOMA SOCIETY

12.3. REPOSITIONING DRUGS FOR PARKINSON’S DISEASE: PERSPECTIVE FROM THE MICHAEL J. FOX FOUNDATION

12.4. REPOSITIONING DRUGS FOR POLYCYSTIC KIDNEY DISEASE: PERSPECTIVES FROM THE POLYCYSTIC KIDNEY DISEASE FOUNDATION

CHAPTER 13 Business Development Strategies in the Repositioning Industry

13.1. INTRODUCTION

13.2. LARGE PHARMACEUTICAL COMPANIES

13.3. FRANCHISE GROWTH FOR SPECIALTY PHARMACEUTICAL COMPANIES

13.4. SMALL BIOTECHNOLOGY COMPANIES—REDUCING THE RISK OF COMPANY FAILURE

13.5. EXPANDING THE VALUE PROPOSITION FOR VENTURE CAPITAL

13.6. SPEED AND SAFETY FOR PATIENT ADVOCACY GROUPS

13.7. ACADEMIA—ACCESS TO DRUGS FOR RESEARCH USE

13.8. FUTURE PROSPECTS FOR BUSINESS DEALS IN THE REPOSITIONING INDUSTRY

CHAPTER 14 A Case Study in Drug Repositioning: Sosei

14.1. INTRODUCTION

14.2. HISTORICAL PERSPECTIVE

14.3. DRP®

14.4. ACCESSING HALTED COMPOUNDS

14.5. ESTABLISHING A STRONG SCREENING NETWORK

14.6. PATENTING

14.7. LIMITATIONS

14.8. LONG-TERM PERSPECTIVE—FUTURE OF REPOSITIONING

14.9. CONCLUSION

APPENDIX: Additional Drug Repositioning Resources and Links

Index

About the Cover

Drug repositioning can be a daunting challenge, but one filled with possibility. There is a story in The Art of Possibility by Rosamund Stone Zander and Benjamin Zander of a man who comes upon a woman on a beach, surrounded by starfish that have washed ashore. She picks up individual starfish and throws them back into the water, in an almost “ritualistic dance.” The man approaches her: “There are stranded starfish as far as the eye can see. What difference can saving a few of them possibly make?” Smiling, she bends down and once more tosses a starfish out over the water, saying serenely, “It certainly makes a difference to this one.”

Like the woman, drug repositioning sifts through many compounds, particularly those “washed up,” failed compounds, to find the one that makes a difference to patients.

Art of Possibility: Transforming Professional and Personal Life by Rosamund Stone Zander and Benjamin Zander. Harvard Business Press Books, 2000.

Cover image by Rachel Frail

Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permissions.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at [phone], outside the United States at [phone] or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

Drug repositioning : bringing new life to shelved assets and existing drugs / edited by Michael J. Barratt, Donald E. Frail.

p. ; cm.

 Includes bibliographical references and index.

 ISBN 978-0-470-87827-9 (cloth)

 I. Barratt, Michael J. II. Frail, Donald E.

 [DNLM: 1. Drug Repositioning. 2. Computational Biology–methods. 3. Drug Industry–economics. 4. Pharmaceutical Preparations–economics. QV 55]

 338.4'76151–dc23

2011044253

ISBN: 9780470878279

ABOUT THE EDITORS

Michael J. Barratt was a founding member and Senior Director of Pfizer’s Indications Discovery Unit, where he led the Biomarker, Computational Biology, and Screening initiatives and later took on responsibility for academic alliances, a key ele­ment in the Unit’s external drug repositioning efforts. Previously, Michael has held positions as Head of Molecular Pharmacology and Head of Dermatology Molecular Sciences for Pfizer in Ann Arbor, Michigan, and Skin Research Platform Leader for Unilever in New Jersey. With broad experience in drug discovery technologies and preclinical/early clinical drug development spanning multiple therapeutic, Michael has been involved in bringing more than 15 drug candidates into the clinic. In addition, he has fostered and led numerous strategic alliances in both the pharmaceutical and consumer health industries. Michael earned a degree in Biochemistry from Exeter College, Oxford University and obtained his PhD in Molecular Sciences from King’s College London, where he also completed a postdoctoral fellowship.

Donald E. Frail is currently Vice President, Science, in the New Opportunities iMED at AstraZeneca, a research unit focused on identifying developing new medicines through external partnerships and drug repositioning. Prior to this, Don founded and led the Indications Discovery Unit at Pfizer, a dedicated research unit focused on drug repositioning, and was an architect of the groundbreaking partnership between Washington University School of Medicine and the Indications Discovery Unit. He has also held positions as Site Head for Pfizer’s St. Louis Laboratories, Head of Biology for the St. Louis Laboratories, Head of Central Nervous Systems Research at Pharmacia, and positions at Women’s Health at Wyeth and Neuroscience at Abbott. He has been involved in bringing more than 20 potential new medicines into the clinic across multiple indications. He obtained his PhD in Biochemistry from McGill University and completed a postdoctoral fellowship at Washington University School of Medicine.

ACKNOWLEDGMENTS

This book is dedicated to the many scientists who have worked tirelessly to produce the outstanding drug candidates that provide opportunities for drug repositioning and hope for patients. We thank all of our authors for sharing their expertise through insightful contributions. We also thank our colleagues in industry and academia, who have provided incredibly thoughtful perspectives and debates over the past few years. Our appreciation and gratitude are also extended to Lauren Frail for her expertise in indexing this first comprehensive work on this subject. Finally, none of this would have been possible without the understanding and patience of our families, to whom we are indebted for affording us the time to work on this project.

CONTRIBUTORS

Christos Andronis, Biovista Inc., Charlottesville, Virginia, USA

Makiko Aoyama, Sosei R&D Ltd., London, UK

John Arrowsmith, Thomson Reuters, London, UK

Michael J. Barratt, Washington University School of Medicine, St. Louis, Missouri, USA

Philip E. Bourne, University of California, San Diego, La Jolla, California, USA

Curtis R. Chong, Massachusetts General Hospital, Boston, Massachusetts, USA

Kuldip D. Dave, Michael J. Fox Foundation for Parkinson’s Research, New York, New York, USA

Spyros Deftereos, Biovista Inc., Charlottesville, Virginia, USA

Louis DeGennaro, The Leukemia & Lymphoma Society, White Plains, New York, USA

Donald E. Frail, AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA

Scott L. Harbeson, Concert Pharmaceuticals, Lexington, Massachusetts, USA

Richard Harrison, Thomson Reuters, Philadelphia, Pennsylvania, USA

James Kasper, The Leukemia & Lymphoma Society, White Plains, New York, USA

Sarah L. Kinnings, University of California, San Diego, La Jolla, California, USA

Ourania Konstanti, Biovista Inc., Charlottesville, Virginia, USA

Margaret S. Lee, Zalicus Inc., Cambridge, Massachusetts, USA

Christopher A. Lipinski, Melior Discovery, Inc., Waterford, Connecticut, USA

Craig E. Masse, Nimbus Discovery, Inc., Cambridge, Massachusetts, USA

Richard Mazzarella, Appistry, Inc., St. Louis, Missouri, USA

John McCall, Polycystic Kidney Disease Foundation, Kansas City, Missouri, USA

Maria L. Miller, BioMed-Valley Discoveries, Inc., Kansas City, Missouri, USA

Mark A. Mitchell, Pfizer Inc., St. Louis, Missouri, USA

Akinori Mochizuki, Sosei Group Corporation, Tokyo, Japan

Adam J. Morgan, Concert Pharmaceuticals, Lexington, Massachusetts, USA

Damian O’Connell, Bayer HealthCare Pharmaceuticals, Berlin, Germany

Bhaumik A. Pandya, Concert Pharmaceuticals, Lexington, Massachusetts, USA

Jill Panetta, Polycystic Kidney Disease Foundation, Kansas City, Missouri, USA

Andreas Persidis, Biovista Inc., Charlottesville, Virginia, USA

Aris Persidis, Biovista Inc., Charlottesville, Virginia, USA

Ken Phelps, Camargo Pharmaceutical Services, LLC, Cincinnati, Ohio, USA

Andrew G. Reaume, Melior Discovery, Inc., Exton, Pennsylvania, USA

Michael S. Saporito, Melior Discovery, Inc., Exton, Pennsylvania, USA

Aaron Schimmer, Ontario Cancer Institute, Toronto, Ontario, Canada

David J. Sequeira, Upsher-Smith Laboratories, Maple Grove, Minnesota, USA

Anuj Sharma, Biovista Inc., Charlottesville, Virginia, USA

Todd B. Sherer, Michael J. Fox Foundation for Parkinson’s Research, New York, New York, USA

Elizabeth T. Stark, Pfizer Inc., St. Louis, Missouri, USA

Alison Urkowitz, Michael J. Fox Foundation for Parkinson’s Research, New York, New York, USA

Vassilis Virvilis, Biovista Inc., Charlottesville, Virginia, USA

Craig Webb, Van Andel Research Institute, Grand Rapids, Michigan, USA

Richard Winneker, The Leukemia & Lymphoma Society, White Plains, New York, USA

Lei Xie, University of California, San Diego, La Jolla, California, USA; and Hunter College, the City University of New York, New York, New York, USA

Li Xie, University of California, San Diego, La Jolla, California, USA

Introduction

MICHAEL J. BARRATT and DONALD E. FRAIL

Drug repositioning, also commonly referred to as drug reprofiling or repurposing, has become an increasingly important part of the drug development process for many companies in recent years. The process of identifying new indications for existing drugs, discontinued, or “shelved” assets and candidates currently under development for other conditions—activities we refer to as “indications discovery”—is an attractive way to maximize return on prior and current preclinical and clinical investment in assets that were originally designed with different patient populations in mind. It is widely appreciated that the business impetus to recoup the vast investments in pharmaceutical research and development (R&D) is enormous. As discussed by Arrowsmith and Harrison in Chapter 1, output of new medical entities (NMEs) approved by the U.S. Food and Drug Administration (FDA) has remained steady at around 25 per year over the last decade, while pharmaceutical R&D expenditure has increased over 50% in the same time frame [1, 2]. Against this backdrop of escalating costs associated with increased development timelines and requirements, along with growing regulatory and reimbursement pressures, drug repositioning has emerged as a lower cost and potentially faster approach than de novo drug discovery and development. The objective of Part I of this book is to examine in detail the medical and commercial drivers underpinning the repositioning industry, and to highlight the key strategic, technical, operational, and regulatory considerations for drug repositioning programs.

Among the numerous case studies that are described throughout this book, perhaps the best known example of successful implementation of drug repositioning is that of the blockbuster and first approved treatment for erectile dysfunction (ED), Viagra® (sildenafil citrate). The story of the development of this drug, which was originally being developed by Pfizer for the treatment of angina, offers a fascinating insight into how keen observation and good science can unlock the full potential of safe biotherapeutics that are either already marketed or, as was the case for sildenafil, under development for other indications [3]. This example serves to highlight some of the essential elements that underpin the rationale behind, and opportunities that exist in, drug repositioning.

At its core, drug repositioning takes advantage of three fundamental principles. First is the reality of biological redundancy, namely that “druggable” biological targets can contribute to the etiologies of seemingly unrelated conditions, due to common underlying pathology and/or shared biological signaling networks. In the mid-1980s, the biological target of Viagra®, an enzyme called phosphodiesterase 5 (PDE5), was being studied for its involvement in regulating nitric oxide (NO) signaling in smooth muscle cells associated with coronary blood vessels. NO activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation, increased blood flow, and the associated hemodynamic effects characteristic of nitrates. cGMP PDE enzymes such as PDE5 inactivate cGMP by converting it into guanosine monophosphate (GMP), and attenuate NO signaling. With this underlying biology in mind, sildenafil was at the time being considered as an antiangina therapy. After initial clinical trials in angina indicated modest hemodynamic effects (i.e., efficacy) but dose-limiting adverse events including erections, attention turned to ED, where the role of NO/cGMP was emerging at the time; but the role of PDE5 in the corpus cavernosum of the penis had not previously been appreciated [3]. New biology was thus uncovered and the rest, as they say, is history.

A second key driver for drug repositioning, which is also highlighted by the Viagra® story, is that the pharmaceutical drug discovery process is typically therapy area–focused and sequential, meaning that a candidate is usually designed and developed single-mindedly for one disease, regardless of whether the drug target may have roles in other diseases in different therapy areas. Because of this focus—though less frequent now than in the past—consideration of alternative therapeutic applications for a candidate may not occur until it either succeeds in the primary indication (typically in Phase III or beyond), or fails. Even then, repositioning or “indications discovery” efforts are not guaranteed and certainly rarely systematic, due to potential stigma associated with a failed asset, or risk aversion in a successful primary project team that “owns” the candidate, or simply lack of cross-therapeutic expertise/ mindset. As described in Chapter 2 of the book, one consequence of this for a pharmaceutical company’s pipeline is that valuable patent life may be lost by delaying exploration of other opportunities, particularly if the candidate’s safety, pharmacokinetics (PK), and pharmacology have been adequately demonstrated—often several years previously—in Phase I studies. Thus, repositioning applies not only to previously shelved candidates or marketed drugs, but increasingly to candidates that are still under clinical development in a primary indication.

Among the key elements of any repurposing program are the unique clinical, regulatory, and logistical considerations of conducting patient studies with candidates in secondary indications. The purpose of Chapter 3 is to outline some of the requirements for generating a robust data package for a second indication, as well as to highlight some of the often underappreciated challenges of repositioning candidates to different patient populations, where the safety package, route of administration, site of action, and PK/pharmacodynamic (PD) requirements can all differ. Part I concludes with a review of some unique regulatory and market exclusivity opportunities that can be applied to repositioned candidates (Chapter 4).

Fortunately, for both companies and the patients they serve, the traditional, sequential approach to drug discovery is changing. Increasingly, companies are leveraging internal expertise and external collaborators in a more cross-therapeutic manner to assess the applicability of pipeline or shelved candidates (and in some cases, external opportunities) in alternative indications that may be in noncore areas, in a more systematic and intentional way. A key component of a systematic approach to repositioning is the application of bio- and chemoinformatics-based approaches to interrogate vast amounts of internal and published preclinical/ clinical data (both on the drug candidates themselves and their cognate biological targets/pathways) to generate new hypotheses for experimental testing. Part II of this book—“Application of Technology Platforms to Uncover New Indications and Repurpose Existing Drugs”—addresses this aspect and outlines a number of computational strategies, tools, and databases that have been developed or successfully applied to repositioning studies. Authors in this section have been drawn from large pharmaceutical and biotechnology companies, as well as academia, in order to provide a wide spectrum of perspectives. Chapters in this section include descriptions and case studies using the numerous information sources that are publicly available to facilitate repositioning.

Also covered in Part II of the book is the topic of screening approaches for drug repositioning. As a complementary strategy to “hypothesis-driven” indications discovery, screening clinical candidates or marketed drugs in disease-relevant in vitro assays or animal models in an unbiased manner increases the probability of uncovering not only previously unknown connections between drug targets and diseases, but also the potential to reveal pharmacologically important “off-target” effects of a candidate. Off-target biology—the elicitation of useful pharmacology by a drug that was not intended or appreciated at the time of development—is a third and important driver for drug repositioning, particularly for older compounds that were less extensively profiled than present day candidates. For example, amantadine, originally developed for influenza through its ability to interfere with the viral M2 protein [4], was later found to have, among other activities, dopaminergic and noradrenergic effects and was subsequently repurposed for Parkinson’s disease [5]. Another well-known example is thalidomide. Originally prescribed as sedative, it was found to have antiemetic effects leading to its use by pregnant women in the late 1950s and early 1960s with tragic teratogenic consequences for the developing fetus [6]. Despite these tragic beginnings, thalidomide has since been found to have a number of pharmacologically beneficial effects including antitumor necrosis factor (TNF) and antiangiogenic activities and has been approved for use in erythema nodosum leprosum (ENL) and multiple myeloma [7].

From the perspective of drug repositioning, phenotypic, disease-relevant in vitro screening assays, or animal models are unbiased with respect to “on-target” or “off-target” effects; any activity that modulates the endpoint being measured will be detected, regardless of cause. Although often more complex to prosecute and automate than conventional target-based biochemical assays used in the drug discovery process, such models provide the significant benefit of enabling an investigator to probe all the possible activities of a candidate, or cohort of candidates, across a wide therapeutic spectrum of disease models. Examples of cell-based screening approaches, including searching for novel synergistic combinations of marketed drugs, are described in the Chapter 8 by Lee, while the application of “multiplexed” in vivo screening platforms to identify new indications clinical candidates is described in Chapter 9 by Saporito et al.

The final chapter in Part II by Morgan et al. addresses a common strategy employed for drug repositioning or “drug salvaging,” namely the development of chemically modified analogs of approved agents which are either metabolized in vivo into the parent drug molecule (prodrugs), or may themselves be viewed essentially as NCEs, in the case of deuterium-labeled analogs. Also covered in this chapter is the “chiral switch” approach, namely single enantiomer variants of previously approved chiral drug mixtures. Collectively, such strategies have yielded numerous clinically relevant, enhanced drug properties including increased bioavailability, improved PK profiles, more convenient dosing regimens, dramatic changes in tissue distribution, and decreased adverse events. A number of case studies are provided to illustrate these concepts.

It is noteworthy that many of the strategies covered in Part II have been driven by specialist companies that have developed and validated technology platforms to provide unique and cost-effective screening/repurposing services to the pharmaceutical/biotechnology industry. In many cases, these same companies have utilized their own platforms together with strategic alliances with large pharmaceutical companies to build internal pipelines of repurposed drugs of their own.

In Part III of the book, we turn our attention to repositioning approaches being pursued outside the industry, but often in partnership with it; specifically some of the efforts being championed in academia and by not-for-profit organizations/foundations. One of the increasingly important contributions that academic investigators and foundations provide in the field of drug discovery in general—and repositioning in particular—is their advocacy for rare or neglected diseases (sometimes collectively termed orphan diseases), which are frequently overlooked by big pharmaceutical companies due to lack of commercial return. In the United States, the Rare Disease Act of 2002 [8] defines rare disease strictly according to prevalence, specifically as “any disease or condition that affects less than 200,000 persons in the United States,” or about 1 in 1500 people. A similar definition exists in Europe [9]. Neglected diseases [10] generally refer to a group of tropical infections prevalent in developing countries of Africa, Asia, and south/central America but essentially nonexistent in developed nations (e.g., parasitic trypanosomal and helminth infections, bacterial infections such as cholera, and viral episodes such as dengue fever). Chapter 11, written by Curtis Chong, describes several examples of repositioned candidates for diseases of the developing world that have been identified through open source screening campaigns such as the Johns Hopkins Clinical Compound Screening Initiative. Chapter 12 provides case studies from several different patient advocacy groups/foundations to highlight the unique work these organizations perform, as well as the tremendous potential advantages afforded by repositioning for patients suffering from rare diseases whose existing treatment options are often extremely limited. The book concludes with an overview of some of the business thinking that is currently being applied to drug repositioning within the pharmaceutical and biotechnology sectors with an emphasis on partnerships between the various stakeholders that are engaged in this sector. Chapter 13 highlights the increasing use of strategic alliances and risk-sharing partnerships as approaches to increase the industry’s clinical development capacity and number of successful proof-of-concepts and recoup value on otherwise stalled assets. This chapter examines the various drivers for each party in such alliances and assesses the potential of current and future repositioning joint ventures between industry, academia, and not-for-profit organizations. Finally, Chapter 14 exemplifies some of the key considerations for drug repositioning partnerships through a case study on the Japanese biopharmaceutical company Sosei, which pioneered a unique business platform for reprofiling previously shelved drug candidates using a sophisticated shared risk partnership model.

The Appendix at the end of the book seeks to provide a compilation of valuable resources for the prospective repositioner, providing information on drug repositioning and reformulation companies, databases, relevant government resources and organizations, links to regulatory agency guidance, along with academic and nonprofit organization initiatives related to repositioning.

We hope that the book is as informative to the reader as it has been enlightening to compile.

REFERENCES

 1. DiMasi, J.A., Grabowski, H.G. (2007). The cost of biopharmaceutical R&D: Is biotech different? Managerial and Decision Economics, 28, 469–479.

 2. DiMasi, J.A., Feldman, L., Seckler, A., Wilson, A. (2010). Trends and risks associated with new drug development: Success rates for investigational drugs. Clinical Pharmacology and Therapeutics, 8, 272–277.

 3. Bell, A. (2005). The Viagra Story: From Laboratory to Clinical Discovery. Medicinal and Bioorganic Chemistry Foundation Winter Conference, January 24, 2005. http://www.mbcfoundation.org/pdfs/Blockbuster%20Drug%20Symposium%20Final.pdf

 4. Wang, C., Takeuchi, K., Pinto, L.H., Lamb, R.A. (1993). Ion channel activity of influenza A virus M2 protein: Characterization of the amantadine block. Journal of Virology, 67(9), 5585–5594.

 5. Verma, U., Sharma, R., Gupta, P., Kapoor, B., Bano, G., Sawhney, V. (2005). New uses for old drugs: Novel therapeutic options. Indian Journal of Pharmacology, 37(5), 279–287.

 6. Mekdeci, B. How a commonly used drug caused birth defects. http://www.birthdefects.org/research/bendectin_1.php

 7. Teo, S.K., Stirling, D.I., Zeldis, J.B. (2005). Thalidomide as a novel therapeutic agent: New uses for an old product. Drug Discovery Today, 10(2), 107–114.

 8. Rare Disease Act of 2002. Public Law 107–280. November 6, 2002. 107th U.S. Congress. http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=107_cong_public_laws&docid=f:publ280.107

 9. Use Information on Rare Diseases from an EU Perspective. European Commission Health & Consumer Protection Directorate General. http://ec.europa.eu/health/ph_information/documents/ev20040705_rd05_en.pdf

10. Wikipedia. Neglected diseases. http://en.wikipedia.org/wiki/Neglected_diseases

PART I: DRUG REPOSITIONING: BUSINESS CASE, STRATEGIES, AND OPERATIONAL CONSIDERATIONS

CHAPTER 1

Drug Repositioning: The Business Case and Current Strategies to Repurpose Shelved Candidates and Marketed Drugs

JOHN ARROWSMITH and RICHARD HARRISON

1.1. INTRODUCTION

Drug repositioning or “repurposing” has become one of the major sources for revenue growth within the pharmaceutical industry [1]. Repurposing encompasses everything from new indications for failed compounds to line extensions for existing drugs and is expected to generate up to $20 billion in annual sales in 2012 [2]. This opportunity for revenue generation has led to an increase in companies such as Biovista, Melior, Marco Polo Pharma et al., consortia such as CTSA (http://www.ctsapharmaportal.org), and specialist units within major pharmaceutical companies that are dedicated to bringing new life to existing compounds, as well as summit meetings specifically designed on this topic [3].

It is easy to understand why repurposing drugs is so attractive since those that failed have been through much of the preclinical and some early human clinical trials and in many cases have been found to be safe. In general, drugs that have been approved for an indication have a greater likelihood of being safe in a new indication and different patient population. This increased knowledge of a drug shortens its development cycle relative to new molecular entities (NMEs1), bringing significant savings and lower risk to the cost of development. In addition, the continually evolving knowledge of targets and pathways means that developing drugs for rare diseases or stratified populations of common diseases has become a more technically viable research and development (R&D) strategy.

This chapter will begin with a historic overview of why drugs fail and will explore the reasons for failures at each stage in the development paradigm, highlighting differences in success rates between therapeutic areas. Next, we will discuss how some of these failures led to the drugs that are on the market today. Finally, we will identify some of the common themes of repurposing failed—or “shelved” compounds—with the goal of highlighting some of the key learnings from these failures.

1.2. IS PHARMACEUTICAL R&D FAILING?

The only time you don’t fail is the last time you try anything—and it works

—William Strong

Failure is a common problem in any research environment. Yet it is from these failures that many of the greatest successes are born. When Thomas Edison’s experiments failed to produce a storage battery, he simply muttered, “I have just found 10,000 ways that won’t work.” Failure is a fundamentally inherent property in the pharmaceutical research and development process. It is due to the difficult nature of the problems being solved that makes it so, and is not reflective of the work that goes into the process. Despite the working of some of the most creative scientific minds, most drug candidates fail. Statistically, after testing up to one million potential candidates, one is picked to enter clinical trials, and only 1 out of 20 compounds that enter into clinical trials goes on to be a marketed product [4, 5]. Put another way, 95% of new drug candidates entering human clinical trials fail. Furthermore, pharmaceutical research data [6] suggest that drug candidates are failing more often. As shown in Figure 1.1, the success rate for compounds progressing through clinical development from Phase II to Regulatory Submission actually decreased over the period from 2004 to 2009.

Success is not final, failure is not the end. It is the guts to carry on that counts.

—Winston Churchill

FIGURE 1.1. Average success rates for compounds successfully advancing to the next phase of clinical trials for the years 2004 through 2009 for a cohort of 40 large and mid-sized pharmaceutical companies.

Source: CMR International 2010 Global R&D Performance Metrics Programme. Reproduced with permission.

The pharmaceutical industry faces unprecedented challenges in its R&D productivity. Despite the continued increase in R&D investment up to 2008, with a slight flattening in 2009–2010, the number of NMEs approved globally per annum has fallen and cycle times for candidate development have risen [7] (Figure 1.2). The sales figures in Figure 1.2 would at first glance suggest a fairly optimistic future for R&D-based pharmaceutical companies; however the growth in sales of branded drugs is more than offset by patent expiry such that the majority of future sales growth comes from generic drugs and emerging markets. Generic sales are expected to be worth $400 billion by 2015. The shift from branded to generic drugs has a major negative impact on the profitability of traditional pharmaceutical companies [8].

FIGURE 1.2. The percent change in pharmaceutical investment in R&D, drug development times, and global NME output over a 10-year period indexed to 2000 for a cohort of 40 large and mid-sized pharmaceutical companies.

Source: CMR International 2011 Pharmaceutical Fact Book [7]. Reproduced with permission.

Despite the steady increase in pharmaceutical R&D budgets over the last ∼15 years, the number of new drug applications (NDAs) approved per annum has remained reasonably constant (Figure 1.3). The only exception to this trend in output was in the period from 1995 to 1997 when output spiked to more than 50 NDAs per annum; the industry mistakenly thought that this was the dawn of a new and sustainably high output, but by 1998 output had fallen back to historic levels. Forecasts predict that the investment in R&D has no obvious signs of major decline [7], but the need to discover drugs to address unmet medical needs is even more urgent [9].

FIGURE 1.3. The number of NMEs approved in the United States by the FDA for the years 1996 to 2009 targeting a novel mode of action, and the total NMEs approved for a cohort of 40 large and mid-sized pharmaceutical companies.

Source: Thomson Reuters Integrity database.

The consequences of the unchanging NDA output and the rise in R&D budgets results in an average cost per launch that has been estimated at as high as $3 billion [10]. To add insult to injury, fewer approved drugs will recoup their R&D costs. Data from the Centre for Medicines Research (CMR) International [6] for the number of pharmaceutical projects at each stage of clinical development for the years 2002 through 2009 are shown in Figure 1.4. It can be seen from these data that despite a nearly 70% increase in the number of Phase II projects between 2002 and 2007, there has not been a commensurate rise in the number of Phase III starts or NDA submissions. Based on this analysis of attrition in early clinical development, the problem of stagnant NME output is unlikely to be reversed in the near term.

FIGURE 1.4. The number of NMEs entering each stage of clinical development from 2002 to 2009 for a cohort of 40 large and mid-sized pharmaceutical companies.

Source: CMR International Global R&D Performance Metrics Programme. Reproduced with permission.

Many explanations are offered for this productivity decline, but in reality, it results from a combination of multiple factors. From a biological standpoint, “breakthrough” drugable targets are often elusive, particularly for complex multigenic diseases such as Alzheimer’s, cancer, and diabetes. There is also increased understanding of and attention to the safety risk–benefit profile of candidate therapeutics by the industry and regulatory authorities. Changes in strategic focus and cost reductions within corporate portfolios and ensuing reorganizations can halt entire therapeutic areas and delay progress in others. In addition, there is growing pressure from payers to reimburse only those new medicines that are clearly differentiated from existing standards of care, which themselves in many areas are increasingly dominated by lower cost generics as patents on branded medicines expire.

It is perhaps ironic that the current challenges are in part the result of past success. The pharmaceutical industry had a period of extraordinary growth in the mid-1990s, producing a far greater number of NDAs per year between 1995 and 1997 than ever before. In addition, a significant proportion of this cohort became blockbuster drugs, such as Lipitor®, Norvasc®, Zocor®, and Zoloft®. The underlying assumption at the time was that the discovery of new targets and new drugs was a “scalable commodity,” and to increase drug launches one simply needed to increase the number of compounds entering clinical trials. Thus, if it required 10 first-in-human (Phase I) starts to get one blockbuster drug then, according to this logic, 20 Phase I starts would produce two launches. What followed was a major increase in R&D spending and capacity, and in addition research groups within these compa­nies began to be incentivized to produce more drug development candidates; the number of new drug candidates became a primary goal. This flawed basis for improved productivity was built around a “shots on goal” philosophy. Since the average research and development time for a new drug is nearly 12 years, it took a while for the industry to recognize that more early clinical programs per se was not resulting in the anticipated number of late stage programs and launches. The increased attrition of candidates in development and the flat NDA approval rates was not an aberration. It became apparent that pharmaceutical R&D productivity could not be enhanced solely by increasing the number of candidates, but rather by producing quality candidates based on fundamental understanding of the human disease processes they are designed to affect. In this context, quality is defined in terms of appropriate toxicolo­gical, physicochemical, and pharmacological properties against a biological target(s) that has a validated role in causation of human disease/symptoms. Furthermore, a quality drug development program will evaluate such a drug candidate in well-defined patient populations in order to demonstrate that it is meaningfully superior to currently available therapies.

Declining productivity has been exacerbated by, or perhaps in part resulted from, the fact that few of the drugs launched over the last 10 years work via a new mode of action (Figure 1.3). The majority of new approvals are line extensions or “follow-on” compounds, including some that were not considered to be sufficiently differentiated from current therapies to receive reimbursement at a level that would make them commercially successful. Based on an analysis of Center for Drug Evaluation and Research NME Calendar Year Approvals [11], the number of NDAs approved for drugs that target unprecedented molecular mechanisms remains fairly steady at about 3–4 per annum. New regulatory hurdles now mandate that new drugs show superiority over existing therapies; the effectiveness of a drug (as measured in the United States) and the cost-effectiveness of a drug (as measured in the European Union) is the new standard for assessing drug value, further compounding the decline of drugs that are perceived to be only equal to or marginally more effective than currently available therapies. This greater need to differentiate from current therapy to enable reimbursement is driving the industry to a mantra of being “first and/or best in class” for each new drug candidate that it invests in. However in this regard, the concentration of research effort among companies working on the same mechanisms for the same or similar indications is a concern, since only a few of the drugs that come from this work will ever be approved and reimbursed. For example, according to an analysis by the authors in the Thomson Reuters Integrity database, 71 different organizations are listed as working beta-secretase as a drug target for Alzheimer’s disease. It is reasonable to assume that, at best, only a very small number of these efforts will result in a medically beneficial and commercially successful product; and even this is assuming that the target turns out to be a viable therapeutic approach.

In summary, new targets for the complex diseases that remain poorly served are elusive, as are the drugs to safely and effectively modulate their activity. Biological complexity and redundancy will likely mean that in many cases a single “magic bullet” will not be found. These factors have combined to contribute to the progressive decrease in drug candidate survival in most phases of development and along with it, the probability of success to market. To make matters worse, many of the blockbuster drugs launched in the 1990s reach the end of their period of exclusivity in the period from 2005 to 2013 and there are not enough new drugs of high value to replace these revenue streams for their innovators. Even the emergence of high cost per treatment biologics is insufficient to bridge the revenue gap across the industry. The consequence of lower Pharma revenues, coupled with the higher cost of development, has led to reduction in R&D footprints, increased use of outsourcing, and a need to refill development pipelines using strategies such as company mergers and acquisitions, in-licensing, orphan drug approaches, and repurposing.

1.3. WHY ARE DRUGS FAILING?

Remember the two benefits of failure. First, if you do fail, you learn what isn’t working and second, the failure provides you the possibility to try a new approach.

—Roger Von Oech

Data collected by Thomson Reuters have uncovered the reasons for failure from Phase I to submission over the last 6 years for a cohort of 20 pharmaceutical companies (Figure 1.5). The data highlight the fact that the causes of failure change during the course of development. Early in the process, compounds fail primarily for safety reasons. Compounds that successfully navigate Phase I increasingly drop out due to lack of efficacy in Phase II/III. As noted previously, this decrease in pharmaceutical industry productivity (as judged by the number of products approved per money invested) appears to have no obvious signs of an immediate upward inflection. Attrition is not just increasing in early development but also in Phase III and at the approval stage [12]. Despite being the most expensive phase of development, more than half of the compounds fail to move from Phase III to approval. Table 1.1 lists some of the more notable failures of 2009.

TABLE 1.1. Phase III Project Terminations Reported in 2009 and Reasons for Termination [12]

MAA, marketing approval authorization; NBE, new biological entity; NCE, new chemical entity; NDA, new drug application; Hep B, hepatitis B; Hib, Haemophilus influenzae type B; OA, osteoarthritis.

FIGURE 1.5. A retrospective analysis of the reasons for a compound failing to advance to the next stage of clinical trials for the year 2009 as reported by a cohort of large and mid-sized pharmaceutical companies that represent approximately 70% of global R&D expenditure.

Source: CMR International 2010 Global R&D Performance Metrics Programme. Reproduced with permission.

The failures at this late stage of development fall into a small number of categories, either lack of efficacy (defined as undifferentiated from current standard of care, no advantage as add-on therapies, or no advantage vs. placebo) or an unacceptable safety or risk-to-benefit ratio. The decrease in late-stage candidate survival seems to apply to both and large and small molecules and also occurs more frequently in complex, multigenic disorders such as neurodegenerative disease and cancer, where early promise in Phase II does not always translate into positive outcomes in larger Phase III trials (Figure 1.6). Another area of concern for cancer drug development is that the previously approvable endpoint of progression-free survival is being questioned for some tumor types where current therapies exist, and the higher hurdle of overall survival is now seen as the gold standard approvable clinical endpoint [13, 14]. This change in approval criteria has even impacted drugs that had previously been approved and marketed against the original endpoint of progression free survival.

FIGURE 1.6. Phase III and submission failures: 2007–2010, by therapeutic area (A) and reason for failure (B).

Modified from Reference [12].

To exacerbate the problem, even if a drug candidate successfully navigates its way through the R&D maze, the probability of it becoming a blockbuster drug has become increasingly difficult [15]. To maximize the potential for differentiated efficacy, it has also become increasingly important to stratify patient groups, which further compounds the challenge of producing a rapid rise in revenue after the initial launch of a new drug. Some companies have attempted to address this issue through launch of “incremental blockbusters,” whereby they focus on the drug target, leverage an understanding of disease pathways that are dependent on modulating that drug target, and then target the responder groups across numerous diseases. In this way, only those patients that are likely to be high responders are selected, thus avoiding some of the major reasons for late-stage failure. The value of this approach is based on sound science where only those patients whose disease etiology is dependent on the pathway under investigation are included in trial. This is particularly true for rare diseases (see later sections) as well as for subpopulations of large disease groups such as breast cancer (e.g., BRCA1 vs. BRCA2), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), and hypertension [16]. In the past, patients in trials for these diseases have often been treated as large homogeneous groups with similar symptoms but in practice may have differing underlying etiologies. The approach of sub-grouping patient populations in clinical trials has been demonstrated eloquently by Novartis with their novel IL-1β monoclonal antibody, canakinumab (Ilaris®) for a spectrum of rare autoinflammatory syndromes, termed cryopyrin-associated periodic syndromes (CAPS).

1.4. OVERCOMING FAILURES

Failure is success if we learn from it.

—Malcolm Forbes

Pharmaceutical companies have adopted a number of strategies in order to offset the issues caused by the fall in R&D productivity, price constraints, reimbursement issues, and generic intrusion. At a macro scale, companies are trying to maintain revenue streams and decrease a heavy reliance on a flow of novel drugs for the United States and Western European markets by moving more aggressively into emerging markets, building or buying generic drug capability, diversifying the business into animal health or consumer health, and focusing on rare diseases. There has been consolidation in the industry through mergers and acquisitions; there has been downward pressure on costs through staff reductions, outsourcing, and in-licensing. Many of the traditional “small molecule” companies have invested heavily in vaccines and biologics (“large molecules”). In addition, companies have increasingly extracted more value from their assets through life cycle management as seen in new indications (often related to the original indication), new formulations, combination products, and targeting new patient groups for previously approved products. Typically, this type of life cycle management used to occur as a product matured and the end of its period of exclusivity came closer, but in recent years the trend has been to advance these types of life cycle activities earlier in the period of patent protection. Clearly, life cycle management is dependent on a flow of new NMEs and so this practice will become more challenging as the flow of new products slows and exclusivity is lost. While biologics have remained relatively immune to generic intrusion, the recent introduction of legislation (U.S. Patient Protection and Affordable Care Act; European Medicines Agency guideline on similar biological medicinal products) [17, 18] will allow biosimilar production; and so this area is now under threat. Thus premium pricing that drives the value of biologics is expected to face challenges. However, the cost of entry into biosimilar development remains very high compared with small molecules, so it cannot be assumed that market share for biologic innovator drugs will be eroded as quickly as has been seen for small molecules.

Fundamentally the industry needs more strategies from which it can develop new and commercially attractive drugs at reasonable cost. Traditional life cycle management was discussed above; however, one area that still remains relatively underexploited is drug repurposing. With better understanding of drug targets and disease pathways, there are potentially significant opportunities to take existing drugs, or previously discontinued candidates, and repurpose them in new indications with high unmet medical need and so complement the usual de novo approach to R&D.

1.5. DRUG REPURPOSING

Failure is a back road, not a dead-end street.

—Zig Ziglar

1.5.1. The Case for Repurposing

Table 1.1 provides a summary of the Phase III program terminations in the pharmaceutical industry in 2009. Although not exhaustive, the data clearly show that compounds are failing in Phase III primarily for efficacy reasons. While the detailed causes for each of these failures are beyond this chapter, the following points are noteworthy:

The majority of these compounds were safe at the doses administered in the Phase II and Phase III trials.

The compounds have desirable pharmacokinetic (PK) and pharmacodynamic properties.

It is estimated that around 2000 failed drugs are sitting on companies shelves and that this number grows at the rate of 150–200 drugs per annum [19].

The drivers for repurposing highlighted in this chapter are:

Pharmaceutical companies need to have additional strategies that will bring new and reimbursable drugs to market quickly.

There is much substrate available on which to build a repurposing strategy.

The science to evaluate or re-evaluate new diseases continues to evolve so that science-led repurposing (rather than random screening) is a viable business model.

The risk of failure is decreased.

The cost of a repurposing program is significantly cheaper than

de novo

R&D.

The cycle time of a repurposing program is significantly shorter than

de novo

R&D.

With repurposing strategies, companies are going back to re-examine these failed drug candidates with an eye toward new indications. Current estimates suggest that around 2000 failed drugs are sitting on companies’ shelves and this number grows at the rate of 150–200 drug candidates per annum [19]. Clearly not all of these failed drugs are amenable to repositioning; some were shown to be unsafe or have poor PK properties, but there are a large number of molecules that could be considered for science-led re-evaluation.

Drug repositioning offers an attractive route to halt the declining pro­ductivity trend. An analysis of the reasons for a compound’s failure—particularly where safety was not the primary cause—can be used to turn these failures into insights into how to be successful in the future. There is a growing list of examples of drugs that were initially designed for one indication and have either been discontinued or gone on to be successful after repurposing in additional indications. Some of these examples are shown in Table 1.2.

TABLE 1.2. Examples of Repurposed Drugs and Their Original Indications

And why wouldn’t the pharmaceutical industry want to build on this model? The time and cost to re-evaluate shelved drugs is less than the time and cost required to create NMEs, and can be a highly effective approach to developing new or better drugs that meet medical needs and that are also reimbursable [1, 2]. With a robust rationale in place, including confidence in the target and its relationship to the disease state in humans, a drug candidate can get a “second chance” to make it to market or extend the franchise of an existing approved drug. This second chance will benefit from the continually evolving science on targets and pathways, which not only elucidates new pathways of disease, but also enables the repositioning of drugs to them.

Understanding why a drug fails will help identify whether it can potentially be repurposed and, if so, the most likely therapeutic applications based on its known mechanism of action. Clearly when a drug has been shown to be unsafe in humans (e.g., TeGenero TGN1412, [20]) it would not be considered for repurposing. However, when a drug is dangerous in specific populations (e.g., thalidomide in women of child bearing potential) it has been demonstrated that carefully selected alternative populations can benefit from such drugs [21]. The definition of a “safe drug candidate” can therefore be indication/patient population specific. There are also drugs that express pharmacology in humans but do not translate into meaningful clinical outcomes (e.g., thromboxane synthetase inhibitors) yet may be synergistic with other pharmacologically active agents. Finally there are potential repositioning candidates among assets dropped from a company’s portfolio for strategic reasons (e.g., Roflumilast, a phosphodiesterase 4 [PDE4] inhibitor for COPD that was dropped by Pfizer but subsequently launched by Nycomed/Forest). Therefore, a thorough understanding of the reasons for termination provides a basis for rational decision making on future investments.

As will be discussed in greater detail in subsequent chapters of this book, a number of technologies have been employed in drug repurposing, including computational approaches [22–26], in vitro and in vivo methods [27–29], and screening for synergies among combinations of existing drugs [30]. Success stories can be found in diverse therapeutic areas such as HIV [31], cancer [21, 32], diabetes, [33] and erythema nodosum leprosum (ENL) [21] among numerous others.

1.6. EXAMPLES OF SUCCESSFUL REPURPOSING

A discussed, repurposing or repositioning is a smart way to capitalize on the cost of developing a new drug or resurrecting a shelved candidate. It has become a major driver for increased revenue within the industry [2]. Numerous small companies have been started with the sole purpose of repurposing drugs, but increasingly larger companies are building this capability into their R&D function. Successful repurposing can result in three potential outcomes: (1) new indications for shelved candidates, (2) line extension for existing drugs, and (3) new targets and new indications for existing drugs. The first category, shelved drugs, can be further subdivided into those that failed for efficacy, safety, and strategic reasons. We will examine each of these in greater detail with examples.

1.6.1. Drug Candidates That Lacked Efficacy in their Primary Indications

1.6.1.1. Sildenafil 

Perhaps the most frequently cited example of drug repurposing is Viagra® (sildenafil), a phosphodiesterase 5 (PDE5) inhibitor that was under development for the treatment of angina in the 1990s. Clinical trials for the drug were suspended after it was shown that the compound had PK properties that were inconsistent with the prolonged control of angina in patients [34]. However, in these trials, researchers identified a striking side effect that helped define a new disorder—erectile dysfunction (ED). The poor PK properties that made the compound unsuitable as an antiangina treatment were ideal for a drug prescribed for ED. This case also exemplifies the point that some diseases are only considered as targets for therapeutic intervention when an efficacious drug is discovered, as was also the case for migraine prior to Imigran (sumatriptan). Subsequent to their use for ED, PDE5 inhibitors have been tested in a variety of other indications and found to be effective in pulmonary arterial hypertension (PAH) [34] for which sildenafil is now approved and marketed as REVATIO®.

1.6.1.2. Canakinumab 

Another recently discontinued drug that was repurposed provides a good example of a new paradigm for drug discovery. Canakinumab, (trade name, Ilaris®) is a recombinant monoclonal antibody developed by Novartis that works by blocking an immune system protein known as interleukin-1beta (IL-1β), It was originally tested as a therapy for RA in a Phase II trial, where the drug failed to reach its clinical endpoints and was discontinued. Subsequently, a separate group of researchers at Novartis knew of a rare disease, termed Muckle–Wells syndrome, in which patients were genetically predisposed to high levels of IL-1β [35]. Although this rare and potentially life-threatening illness affects only a few thousand patients worldwide, the researchers successfully argued for additional trials. The results of these showed that Ilaris® produced rapid and sustained remission of symptoms in up to 97% of patients, with most of them responding within hours of the first injection [36]. The U.S. Food and Drug Administration (FDA) has approved and given orphan drug status to the drug for two forms of cryopyrin-associated periodic syndrome (CAPS): Muckle–Wells and familial cold autoinflammatory syndrome. It has also received priority approval in the EU. Novartis is now conducting trials to extend the drug to other inflammatory indications such as COPD, gout, RA, ostheoarthritis (OA), and vasculitis in stratified groups of patients whose disease is highly dependent on IL-1β overproduction. The lesson here is that a clear understanding of the disease pathway is an extremely important factor in de novo drug discovery and is essential to unlocking the full potential of the many thousands of drugs that are available for repurposing.

1.6.1.3. Pertuzumab 

Another recent example from Genentech involves pertuzumab, a first-in-class monoclonal antibody that acts as a “HER dimerization inhibitor”, which was intended to be the successor to Herceptin®. In 2005, the Phase II clinical trials of pertuzumab in prostate, breast, and ovarian cancers met with limited success [37]. However, when evaluated in newly diagnosed early stage HER-2 positive breast cancer, pertuzumab used in combination with other chemotherapeutic agents caused cancers to disappear in 49% of patients, compared with 29% of patients receiving Herceptin® and chemotherapy [38].

1.6.2. Drugs That Failed for Safety Reasons in the Primary Patient Populations

1.6.2.1. Thalidomide 

Thalidomide, launched by Grünenthal in 1957, was found to act as an effective tranquilizer and painkiller [21]. It was also found to be an effective antiemetic and had an inhibitory effect on morning sickness during pregnancy. Soon after launch, severe side effects began to be noticed as thousands of children were born with severe developmental abnormalities of the limbs and face (phocomelia) as a consequence of thalidomide use. The drug was withdrawn in 1962. Subsequent studies revealed the compound was an enantiomer, and only one of the two optical isomers was responsible for the teratogenic effects [39]. Unfortunately the two isomers interconvert in humans, so it is impossible to separate the risk from the benefit in women of childbearing age. However, despite the catastrophic effects on the developing fetus, thalidomide has since been used successfully in the treatment of ENL, a painful complication of leprosy, and tuberculosis [21]. Mechanistic studies have revealed that the efficacy observed may be due to its ability to inhibit tumor necrosis factor (TNF) alpha signaling. Further studies have been carried out to develop the potential for thalidomide in Kaposi’s syndrome (a complication of AIDS) and multiple myeloma [21, 40]. Sales of thalidomide produced $550 million in revenue for Celgene in 2008. There is, therefore, renewed interest in thalidomide and its derivatives, and a recent literature search by these authors (Thomson Reuters Integrity database) has revealed investigation into its use in more than 30 alternative indications.

1.6.2.2. Plerixafor 

Plerixafor was initially developed at the Johnson Matthey Technology Centre for potential use in the treatment of HIV because of its role in the blocking of CXCR4, a chemokine receptor that acts as a co-receptor for certain strains of HIV. Development of this indication was terminated because of poor oral bioavailability, cardiac disturbances, and its teratogenic potential. Plerixafor (Mozobil®) was subsequently repurposed as an immunostimulant used to multiply hematopoietic stem cells in cancer patients and the stem cells are subsequently transplanted back to the patient [41]. Hence the limitations that resulted in failure as an oral drug were not relevant for this innovative application.

What all of these compounds have in common is that they previously failed to meet safety and/or efficacy goals for their original indication. Additional studies brought about by keen observations of the clinical data or a deeper understanding of disease pathways led them to this innovative application.

1.6.3. Drug Candidates That Were Discontinued for Strategic Reasons

There is a category of drugs that were discontinued during clinical development for commercial or strategic reasons. These include drugs:

In therapeutic areas that were exited by a company.

That were “backups” or “follow-ons” to lead candidates.

Where the likelihood of getting a return on investment was low either because the target population is small or because the development costs were very high.

That, based on data generated or timelines, were not going to be first- or best-in-class.

Drug candidates that have been discontinued during development for strategic reasons may be offered for out-licensing if a company assesses that there is no impact on their retained portfolio.

One example of a strategic discontinuation was Pfizer’s Factor Xa inhibitor eribaxaban, which was shelved when a competing, but more advanced Factor Xa inhibitor, apixiban, was licensed-in from BMS.

Other examples of strategic terminations can be found in Table 1.3.

TABLE 1.3. Examples of Drug Development Candidates Discontinued for Strategic Reasons

1.7. REPURPOSING EXISTING DRUGS

1.7.1. Line Extensions

A line extension is a variation of an existing product. The variation can be a new formulation of an existing product or an additional indication of an existing molecular entity [42].

It has been estimated that over half of the top 50 pharmaceutical companies expect to increase revenue by implementing some form of line extension on current products. This is clearly one of the best ways to maximize the potential of a compound, and this has not gone unnoticed by the pharmaceutical industry. One example of a drug that was extended beyond the original indication is bevacizumab, sold under the trade name Avastin®. The drug is a monoclonal antibody raised against vascular endothelial growth factor (VEGF), one of the primary mediators of blood vessel growth (angiogenesis). It was approved by the FDA in 2004 for use alongside the chemotherapeutic drug 5-fluorouracil in patients with advanced colorectal cancer and in Europe in 2005 as a first-line treatment of patients with colorectal cancer in combination with chemotherapy. Since the initial approval, Avastin® has been approved for a variety of indications both as a first-line treatment and in combination with existing therapies. Table 1.4 lists a few other examples of line extensions to expand the monopoly that these drugs gained.

TABLE 1.4. Examples of Line Extensions and the Increased Years of Monopoly

The advantages of a line extension are many. Approval rates are greater for line extensions than for first-in-class molecules. While a new development project has a 10% chance of going from Phase II to approval, a line extension or repurposed candidate at the same stage (excluding reformulations or new combinations) has a 25% chance of approval (Figure 1.7). Similarly increased approval rates are also seen for compounds from Phase III to submission. Line extensions also expand patient populations and increase revenues with lower development costs than a new drug.

FIGURE 1.7. Probability of success to market for new development projects versus repurposed drugs for decisions made between 2004 and 2009. Repurposed drugs are defined as those drugs that have entered Phase II after the parent drug has been launched; it excludes reformulations, combinations, or same indications.

Source: