The Textbook of Pharmaceutical Medicine

The Textbook of Pharmaceutical Medicine

EDITED BY John P. Griffin BSc, PhD, MBBS, FRCP, FRCPath, FFPM Director, Asklepieion Consultancy Ltd; Visiting Professor, University of Surrey Postgraduate Medical School; Former Director, ABPI; Formerly Professional Head of the Medicines Division, DOH (now MHRA), London, UK John Posner BSc, PhD, MBBS, FRCP, FFPM Independent Consultant in Pharmaceutical Medicine John Posner Consulting Beckenham, Kent, UK; Visiting Professor, School of Biomedical Sciences, King’s College London, UK Geoffrey R. Barker TD, BSc, MSc, MBBS, FDSRCS, FRCS, FFPM Independent Consultant in Pharmaceutical Medicine Limited Partner, Pappas Ventures, NC, USA; Board Member, Trustee and Registrar Faculty of Pharmaceutical Medicine of The Royal Colleges of Physicians UK Former Adj. Professor Immunology, Duke University Medical Center, NC, USA Formerly Chief Medical and Scientific Officer, Quintiles Transnational Corp, NC, USA

7TH EDITION

A John Wiley & Sons, Ltd., Publication This edition first published 2013, © 2013 by John Wiley & Sons, Ltd; 1993, 1994, 1998 © The Queen’s University Belfast; 2002, 2006, 2009 © Blackwell Publishing Ltd BMJ Books is an imprint of BMJ Publishing Group Limited, used under licence by Blackwell Publishing which was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the authors to be identified as the authors of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. 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 or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data The textbook of pharmaceutical medicine / edited by John P. Griffin, John Posner, Geoffrey R. Barker. – 7th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-65987-8 (cloth : alk. paper) I. Griffin, J. P. (John Parry) II. Posner, John. III. Barker, Geoffrey R. [DNLM: 1. Drug Approval. 2. Clinical Trials as Topic. 3. Pharmacology. QV 771] 615.1–dc23 2012037180 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Cover design by Sarah Dickinson Set in 8.5/11 pt Minion by Toppan Best-set Premedia Limited

1 2003 Contents

Contributors, vii 11 Pharmacovigilance, 235 Stephen F. Hobbiger, Bina Patel and The editors, x Elizabeth Swain Acknowledgements, xiii 12 Vaccines, 254 List of abbreviations, xiv John Beadle Preface, xix 13 Drugs for cancer, 270 James Spicer and Johann De Bono Part I Research and development, 1 14 Ethics of human experimentation, 286 1 Discovery of new medicines, 3 Jane Barrett Yves J. Ribeill 15 Drug development in paediatrics and 2 Pharmaceutical development, 32 neonatology, 295 Michael Gamlen and Paul Cummings Nazakat M. Merchant and Denis V. Azzopardi

3 Preclinical safety testing, 42 16 Due diligence and the role of the Lutz Müller and Elisabeth Husar pharmaceutical physician, 306 Geoffrey R. Barker 4 Exploratory development, 82 John Posner

5 Clinical pharmacokinetics, 113 Part II Regulation, 317 Paul Rolan and Valéria Molnár 17 A history of drug regulation in the UK, 319 6 Biological therapeutics, 132 John P. Griffin Peter Lloyd and Jennifer Sims 18 The Clinical Trials Directive, 347 7 Objectives and design of clinical trials, 143 Fergus Sweeney and Agnès Saint Raymond John Posner and Steve Warrington 19 Human medicinal products in the 8 Conduct of clinical trials: Good Clinical European Union: Regulations, Directives Practice, 155 and structures, 360 Kate L.R. Darwin Agnès Saint Raymond and Anthony J. Humphreys

9 Medical statistics, 189 20 Human medicinal products in the European Andrew P. Grieve Union: Procedures, 379 Agnès Saint Raymond and Anthony J. Humphreys 10 Development of medicines: full development, 219 21 European regulation of medical devices, 418 Peter D. Stonier Shuna Mason

v vi Contents

22 Paediatric regulation, 435 31 The supply of unlicensed medicines for Heike Rabe and Agnès Saint-Raymond individual patient use, 610 Ian Dodds-Smith and Ewan Townsend 23 Technical requirements for registration of pharmaceuticals for human use: The ICH 32 Legal and ethical issues relating to medicinal process, 447 products, 632 Dean W.G. Harron Nick Beckett, Sarah Hanson and Shuna Mason 24 The regulation of drug products by the US Food and Drug Administration, 461 33 Medical marketing, 653 Peter Barton Hutt David B. Galloway and Bensita M.V. Thottakam

25 The US FDA in the drug development, 34 Information and promotion, 670 evaluation and approval process, 501 Charles De Wet Richard N. Spivey, Judith K. Jones, William Wardell and William W. Vodra 35 Economics of health care, 692 Carole A. Bradley and Jane R. Griffin 26 Future prospects of the pharmaceutical industry and its regulation in the USA, 518 36 Controls on NHS medicines prescribing and Richard N. Spivey, William W. Vodra, expenditure in the UK (a historical perspective) Judith K. Jones and William Wardell with some international comparisons, 707 John P. Griffin and Geoffrey R. Barker 27 Regulatory and clinical trial systems in Japan, 537 37 Pharmaceutical medicine in the emerging Mamiko Satake and Natsuko Hosoda markets, 728 Nadarajah Sreeharan, Jennie A. Sykes and 28 The regulation of therapeutic products in Richard B. Nieman Australia, 554 Elizabeth de Somer, Deborah Monk and 38 Biosimilars, 744 Janice Hirshorn Raymond A. Huml and John Posner

Appendix 1 Declaration of Helsinki, 751 Appendix 2 Agreements and Guidelines for Part III Health care marketplace, 587 Implementation of Clinical Trials, 755 29 An Introduction to life cycle management of Appendix 3 Directive 2001/20/EC of the medicines, 589 European Parliament and of the Council David Gillen of 4 April 2001, 771 Appendix 4 PharmaTrain Syllabus 2010, 783 30 Availability of medicines online and counterfeit medicines, 597 Ruth Diazaraque and David Gillen Index, 788 Contributors

Denis V. Azzopardi, F MedSci Johann De Bono, MBChB, MSc, PhD, FRCP, Professor of Neonatal Medicine FMedSci Institute of Clinical Sciences Professor of Experimental Cancer Medicine Imperial College London Drug Development Unit London, UK Institute of Cancer Research; Honorary Consultant Medical Oncologist Geoffrey R. Barker, TD, BSc, MSc, MBBS, Royal Marsden NHS Foundation Trust FDSRCS, FRCS, FFPM Sutton, UK Independent Consultant in Pharmaceutical Medicine Limited Partner, Pappas Ventures, NC, USA; Elizabeth de Somer, BN, MMedSc Board Member, Trustee and Registrar Faculty of Director, Health Policy & Research Pharmaceutical Medicine of The Royal Colleges of Physicians Medicines Australia UK Deakin, ACT, Australia Former Adj. Professor Immunology, Duke University Medical Center, NC, USA Charles De Wet, MBChB, MPharMed, FFPM, Formerly Chief Medical and Scientific Officer, Quintiles FIoD Transnational Corp, NC, USA Medical Director UK and Ireland Jane Barrett, MBBS, FFPM, LLM Boehringer Ingelheim Ltd The Barrett Consultancy Bracknell, UK Gawsworth, Cheshire, UK Ruth Diazaraque, MD, PhD, MBA, MSc John Beadle, MBBCh, MBA Research Method, MSc Pharm Med Chief Executive Officer, Sr Director Medical Affairs PsiOxus Therapeutics Limited Gilead Sciences Ltd Abingdon, Oxfordshire, UK Uxbridge, UK

Nick Beckett, BSc (Hons) Ian Dodds-Smith, MA (Cantab) Partner, CMS Cameron McKenna LLP Partner, Arnold & Porter (UK) LLP London, UK London, UK

Carole A. Bradley, MSc David B. Galloway, MB, ChB, DRCOG, FRCP, Boehringer Ingelheim Canada Ltd Burlington, ON, Canada FRCPE, FFPM Medical & Scientific Director Paul Cummings, BSc(Hons), CBiol, FSB, Cytosystems Ltd EurProBiol, FRI Aberdeen, Scotland Director of Pharmaceutical Development Michael Gamlen, BSc, PhD, MRPharmS, FRSC Pharmaceutical Development Services Ltd Managing Director Nottingham, UK Pharmaceutical Development Services Ltd Kate L.R. Darwin, BA, DPhil, MRQA, MICR, Nottingham, UK CSci David Gillen, BSc, MRCGP, FFPM Hammersmith Medicines Research Ltd Senior Director London, UK Head of Medical Affairs Celgene UK and Ireland London, UK

vii viii Contributors

Andrew P. Grieve, BSc, MSc, PhD, DSc Peter Barton Hutt, LLB, LLM Senior Vice President Clinical Trials Methodology Senior Counsel, Covington & Burling; Aptiv Solutions GmbH Lecturer on Food and Drug Law, Harvard Law School; Cologne, Germany Former Chief Counsel, US Food and Drug Administration Washington, DC, USA Jane R. Griffin, BA(Hons), MSc Director, Market Access, Pricing and Outcomes Research Judith K. Jones, MD, PhD, FISPE Boehringer Ingelheim Ltd President, The Degge Group, Ltd. Bracknell, Berkshire, UK President, The Pharmaceutical Education & Research Institute, Inc. John P. Griffin, BSc, PhD, MBBS, FRCP, & Adjunct Professor of Pharmacology, Georgetown University FRCPath, FFPM School of Medicine Director, Asklepieion Consultancy Ltd; and University of Michigan School of Public Health Visiting Professor, University of Surrey Postgraduate Medical Arlington, VA, USA School; Former Director, ABPI; Peter Lloyd, BSc, PhD Formerly Professional Head of the Medicines Division, DOH Executive Director; Head PKPD Biologics Safety and (now MHRA), London, UK Disposition, Novartis Novartis Institutes for Biomedical Research Sarah Hanson, MA Horsham, UK Partner, CMS Cameron McKenna LLP London, UK Shuna Mason, BA (Hons) Solicitor, Head of Regulatory Dean W.G. Harron, PhD, FRPharmS, MPSNI CMS Cameron McKenna LLP School of Pharmacy London, UK Queens University Belfast, Northern Ireland Nazakat M. Merchant, MBBS, CFM, DCH, MRCPCH Judith Hirshorn, BSc (Hons), PhD, FAICD Academic Clinical Lecturer, Neonatology Consultant Centre for the Developing Brain Rose Bay Perinatal Imaging and Health NSW, Australia King’s College St Thomas’ Hospital Stephen F. Hobbiger, BSc, FRCP(E), FFPM London, UK Vice President and European Qualified Person for Pharmacovigilance Valéria Molnár, MScPharm GlaxoSmithKline R&D Director Stockley Park Clinical Pharmacology Consulting Ltd Uxbridge, UK Beaumont, Australia

Natsuko Hosoda Deborah Monk, BPharm, Dep Hosp BA Medical & Regulatory Affairs Innovation and Industry Policy Quintiles Transnational Japan KK Medicines Australia Tokyo, Japan Deakin, ACT, Australia

Raymond A. Huml, MS, DVM, RAC Lutz Müller, PhD Quintiles Lead Late Stage Projects Toxicology Durham, NC, USA F. Hoffmann-La Roche Ltd Basel, Switzerland Anthony J. Humphreys, BSc (Pharm), MSc (Pharmaceutics), MPSI Richard B. Nieman, MB BS, FRCP Head of Regulatory, Procedural and Committee Support Vice President and Head of Medical Affairs, Asia Patient Health Protection Bayer Healthcare Pharmaceuticals European Medicines Agency Beijing, China London, UK Bina Patel, BSc (Hons) Elisabeth Husar, DVM, MAS (Toxicology) Director, International Safety Affiliates (EEMEA) Head Toxicology Project Leads Amgen F. Hoffmann-La Roche Ltd Uxbridge, UK Basel, Switzerland Contributors ix

John Posner, BSc, PhD, MBBS, FRCP, FFPM Nadarajah Sreeharan, MD, PhD, FRCP, FACP, Independent Consultant in Pharmaceutical Medicine FFPM John Posner Consulting Senior Partner, Transcrip-Partners LLP Beckenham, Kent, UK; Visiting Professor, King’s College London, London, UK Visiting Professor, School of Biomedical Sciences, King’s Senior Visiting Professor, UITM Medical School, Malaysia College London, UK Peter D. Stonier, MBChB, BSc, PhD, FRCP, Heike Rabe, MD, PhD, FRCPCH FFPM Senior Clinical Lecturer Visiting Professor of Pharmaceutical Medicine Brighton and Sussex Medical School; School of Biomedical Sciences Honarary Consultant Neonatologist King’s College London Brighton and Sussex University Hospitals NHS Trust London, UK Brighton, UK Elizabeth Swain, MRPharm.S Yves J. Ribeill, PhD, CChem, MRSC Director Pharmacovigilance Advocacy and Policy President and CEO GlaxoSmithKline R&D SCYNEXIS, Inc. Stevenage, UK Research Triangle Park, NC, USA Fergus Sweeney, PhD Paul Rolan, MB, BS, MD, FRACP, FFPM, Head of Compliance and Inspection DCPSA Patient Health Protection Professor of Clinical and Experimental Pharmacology European Medicines Agency Medical School London, UK University of Adelaide Adelaide, Australia Jennie A. Sykes, MBChB, MRCP, FFPM Vice President, Global Medical Centre of Excellence Agnès Saint Raymond, MD Head, GSK Academy of Pharmaceutical Medicine Head of Human Medicines Special Areas GlaxoSmithKline Member of the UN Commission on Life-Saving Commodities London, UK for Women and Children Human Medicines Development and Evaluation Bensita M.V. Thottakam, B Pharm, M Pharm, European Medicines Agency Msc London, UK Clinical Research Scientist Department of Research and Development Mamiko Satake Cytosystems Ltd Corporate Development Aberdeen, Scotland Quintiles Transnational Japan KK Tokyo, Japan Ewan Townsend, MA (Cantab) Arnold & Porter (UK) LLP Jennifer Sims, BSc, PhD London, UK Integrated Biologix GmbH Basel, Switzerland William W. Vodra, JD Senior Partner (Retired), Arnold & Porter LLP James Spicer, MA, FRCP, PhD Washington, DC, USA Reader in Experimental Oncology and Consultant in Medical Oncology William Wardell, MA (Oxon), MD, PhD Cancer Early Phase Trials Unit President, Wardell Associates International King’s Health Partners at Guy’s Hospital Ponte Vedra, FL, USA London, UK Steve Warrington, MA, MD, FRCP, FFPM Richard N. Spivey, PharmD, PhD Consultant, Hammersmith Medicines Research Ltd Senior Vice President London, UK Global Regulatory Affairs Allergan Irvine, CA, USA The editors

Professor John P. Griffin, BSc, PhD, MBBS, FRCP, ments on the development of a pharmaceutical FRCPath, FFPM graduated in medicine at the Royal policy, and to national trade associations and indi- London Hospital, where he was also in clinical prac- vidual companies. John P. Griffin was Visiting Profes- tice. He was a lecturer in Physiology at King’s College, sor in Pharmaceutical Medicine at the University of London and held the post of Head of Clinical Surrey for 6 years and was also Honorary Consultant Research at Riker Laboratories from 1967 to 1971. Clinical Pharmacologist at the Lister Hospital in Professor Griffin joined the then Medicines Division Hertfordshire, UK. of the Department of Health, now Medicines Health- Professor Griffin was on the Board of the Faculty care Agency (MHRA) London, as a Senior Medical of Pharmaceutical Medicine for 12 years, was Chair- Officer, in 1971, and was subsequently appointed man of the Board of Examiners of the Faculty of Medical Assessor to the Committee on Safety of Pharmaceutical Medicine of the Royal College of Medicines. From 1977 to 1984, Professor Griffin was Physicians for 7 years, and was Academic Registrar Senior Principal Medical Officer and Professional and served on the Task Force on Specialist Medical Head of Medicines Division in addition to being Training in Pharmaceutical Medicine. He has served Medical Assessor to the Medicines Commission. As on a number of Royal College of Physicians, London the Professional Head of Medicines Division he also Working Parties including that on the ‘Development attended the Scientific Sub-Committee of the Veteri- of Clinical Pharmacology and Therapeutics in a nary Products Committee of the Ministry of Agricul- Changing World’. ture, Food and Fisheries. During this time he was a Professor Griffin is the author and co-author of member of the EC committee on Proprietary Medici- over 250 publications on adverse drug reactions and nal Products and Chairman of the CPMP’s Working iatrogenic disease, aspects of neurophysiology and Party on Safety Requirements. clinical pharmacology and toxicology and drug regu- From 1976 to 1984 John P. Griffin served on the lation. Notable among his publications are the fol- Joint Formulary Committee of the British National lowing four standard texts: Formulary, during which period the first eight issues • Iatrogenic Diseases. Oxford University Press, 1st edn of the current format were produced. 1972, 3rd edn 1986; jointly with Professor P.F. D’Arcy. John P. Griffin was the director of the Association • A Manual of Adverse Drug Interactions. John Wright, of the British Pharmaceutical Industry from 1984 to Bristol, 1st edn 1975; Elsevier Press, Amsterdam, 5th 1994. During this time he was a member of the Exec- edn. 1997; jointly with Professor P.F. D’Arcy. utive Board of the European Federation of the Phar- • The Textbook of Pharmaceutical Medicine. The maceutical Industries’ Associations and IFPMA. He Queen’s University of Belfast Press, 1st edn 1993, 2nd chaired the ICH Safety Working Group from 1988 to edn 1994, 3rd edn 1998, 4th edn 2002 published by 1994 and presented papers at ICH1 and ICH2 in the the BMJ Publishing Group in 2002, 5th edn 2006 and plenary sessions. 6th edn 2009, Blackwell. In 1992 he was invited to deliver the Thomas • Medicines, Research, Regulation and Risk. The Young Lecture and was awarded the Thomas Young Queen’s University of Belfast Press, 1st edn 1989, 2nd Gold Medal at St George’s Hospital Medical School, edn 1992. University of London. From 1991 to 2003 he served as Editor in Chief of Since June 1994, John P. Griffin has run his own Adverse Drug Reactions and Toxicological Reviews, a independent consultancy company, which has pro- peer-reviewed journal produced quarterly by Oxford vided independent and impartial advice to govern- University Press.

x The editors xi

In 2005 he was awarded the Faculty of Pharmaceu- physicians and scientists in pharmaceutical compa- tical Medicines Commemorative Medal for outstand- nies and academia. He has been a long-standing, ing services to the Faculty. active member of the Board of Examiners of the Faculty of Pharmaceutical Medicine of the Royal Professor John Posner, BSc PhD MBBS FRCP FFPM College of Physicians and served as its Chair for a gained a BSc and PhD in pharmacology at King’s period of 3 years. John established a Diploma and College London and qualified in medicine at King’s Certificate in Human Pharmacology for the Faculty; College Hospital in 1974. After holding various the Diploma is now a recognised qualification for medical posts in London, he completed a residency Principal Investigators. He continues to serve as in Internal Medicine at the Soroka Medical Centre in Director of these programmes and has responsibility Beer Sheva, Israel. He subsequently worked as an for a number of MSc modules at King’s College, Attending Physician at Soroka and Lecturer at Ben London, where he is a Visiting Professor in the School Gurion University of the Negev. of Biomedical Sciences. John has published exten- With the desire to spend more time in clinical drug sively and is an Executive Editor of the British Journal research, John returned to the UK in 1982, joining the of Clinical Pharmacology. Wellcome Research Laboratories. He developed and validated models of analgesia in healthy volunteers Professor Geoffrey R. Barker, TD, BSc, MSc, and applied these to the evaluation of novel, periph- FDSRCS, FRCS, FFPM graduated from Guy’s Hospi- erally acting opioids. He also used a variety of phar- tal Dental and Medical Schools with a 1st class macodynamic tests in the evaluation of drugs for honours degree in physiology, a distinction and epilepsy, stroke and migraine. Other areas of in­­ honours in dental surgery and MBBS medicine in vestigation included drugs for allergy, asthma depres- 1973. He held assistant lecturer posts in Dental sion and anti-infectives. Studies in patients included anatomy, Physiology and Restorative Dentistry at investigation of a novel agent for sickle cell disease Guy’s Hospital Medical and Dental Schools and sub- and one of the first biologics for lymphoma. sequently completed his training to become a Princi- In 1986, John was appointed Head of Clinical pal in Medical Practice. Over the next several years Pharmacology at Wellcome, becoming responsible Professor Barker continued to pursue his interests in for the evaluation of all new molecular entities ema- clinical research, medical and surgical practice and nating from Wellcome’s discovery research in the UK. gained a Masters in Medicine from Manchester Uni- He negotiated the design and build of a new clinical versity and Fellowships in London (FDSRCS) and research facility at King’s College Hospital Medical Edinburgh (FRCS). School, where his department subsequently con- In 1987 he was awarded the Chair in Oral Surgery ducted their phase I studies. He continued to practise Medicine and Pathology for the University of Wales. medicine and teach students on a part-time basis as In this role Professor Barker specialised in major Honorary Senior Lecturer in Medicine at King’s. With reconstructive surgery, cleft lip and palate surgery, the acquisition of Wellcome by Glaxo in 1995, John and the clinical development of osseo-integration for was appointed an International Director of Clinical the replacement of lost bone with titanium implants. Pharmacology at GlaxoWellcome. By application of oral pathology he also advanced the After a period with a consultancy and contract understanding of oral manifestations of underlying research organisation, John started working as an systemic diseases and their management. independent consultant in 1999. He continues to In 1990, his continued interest in the translation of work in a wide range of therapeutic areas, assisting new treatment concepts from the laboratory bench companies with their strategic planning, design, into clinical practice resulted in the opportunity to conduct and reporting of exploratory studies of join the pharmaceutical industry while continuing to novel compounds from ‘first-in-human’ to ‘proof of hold a position as a consultant surgeon. As Medical concept’. His work also includes preparation of clini- Director for Astra Pharmaceuticals UK, Professor cal overviews, summaries and briefing documents for Barker played a key part in the development of acid regulatory submissions worldwide, serving on data proton pump inhibitors to treat and prevent gastro- monitoring and governance committees and advising esophageal reflux disease and peptic ulceration and on licensing opportunities. was able to advance the use of once-daily inhaled John has extensive postgraduate teaching commit- steroids for respiratory disease and new management ments, organising and participating in courses for regimens for cardiovascular disease. xii The editors

In 1997 Professor Barker joined the Medicines medicines. In 2004 he was appointed Adjunct Profes- Control Agency working with product licensing. In sor in Immunology at Duke University Medical 1999 he was appointed Global Head of Medical Center, North Carolina. On retiring from Quintiles, Affairs at Actelion Pharmaceuticals and, as a member Professor Barker joined Pappas Ventures, a leading of the senior management team, successfully steered health care venture capital fund investing in the the company through its IPO and the launch and development of new medicines and he continues to marketing of its new treatment for pulmonary consult for several venture capital and pharmaceuti- hypertension. cal companies In 2001 Professor Barker moved to North Carolina Professor Barker became a Member of the Faculty to serve as Chief Medical and Scientific Officer for of Pharmaceutical Medicine in 1995 and Fellow in Quintiles Translational Corp, overseeing worldwide 1998 and was elected Registrar and a Member and clinical trials and the continued development of new Trustee of the Board of the Faculty in 2009. Acknowledgements

This is the 7th edition of The Textbook of Pharmaceu- who died in 2011. His expertise will be missed tical Medicine in the 20 years since its first publica- greatly. tion. The size of the book has progressively increased It is fitting to thank our publishers, Wiley- and, with it, the breadth of expertise of its contribu- Blackwell, for their exceptional continuing support tors. For example, there were 22 contributors to the over many years, particularly Adam Gilbert, Elisabeth 1st edition; 44 to the 6th edition and 54 to the current Dodds and Rebecca Huxley, whose patience, courtesy edition. The increase in expertise that this represents and expertise have been outstanding. We are grateful has changed the Textbook from being a good book to Aileen Castell for the invaluable help she provided targeted at pharmaceutical physicians to a one-stop during the production stage of this edition. We would shop and the outstanding information source in this like to thank Jan East for her exemplary copyediting field of medicine. skills on this and the 6th edition. We also wish to The success of a book depends on the quality of thank Mary Banks, who retired in September 2011 contributors and the editors would like to thank all but was a pillar of strength in preparing previous of them for their delivery of high quality manu- editions and in the early stages of the current edition. scripts. In particular we wish to acknowledge the dili- Finally, thanks are due to the World Medical Asso- gence of those contributors who have contributed to ciation (WMA) and the European Medicines Agency all seven editions. (EMA) for permission to publish key documents as We would also like to thank those who have gener- Appendices. Others have allowed us to quote or use ously given permission to reproduce figures and their material and this generosity is acknowledged in documents; this is acknowledged in the appropriate the text; however, a general thanks is appropriate at places in the Textbook. this point. It is fitting to pay tribute to Professor John O’Grady, co-editor of the first five editions of the Textbook,

xiii List of abbreviations

ABPI Association of the British ATMP advanced therapy medicinal product Pharmaceutical Industry AUC area under the curve ACE angiotensin converting enzyme AUSFTA Australia–US Free Trade Agreement AChE acetylcholinesterase AusPAR Australian Public Assessment Report ACPM Advisory Committee on Prescription AWMSG All Wales Medicines Strategy Group Medicines BACE beta-secretase AD Alzheimer’s disease BCS Biopharmaceutics Classification System ADA antidrug antibody BER base excision repair ADEC Australian Drug Evaluation Committee BLA Biological Licence Application ADME absorption, distribution, metabolism BMA British Medical Association and elimination BNF British National Formulary ADMET absorption, distribution, metabolism, BP British Pharmacopoeia excretion and toxicological properties BPCIA Biologics Price Competition and ADR adverse drug reaction Innovation Act AEFI adverse event following immunisation BPR Business Process Reform AF atrial fibrillation cAMP cyclic adenosine monophosphate AFR annual financial return CAT Committee for Advanced Therapies AHEC Australian Health Ethics Committee CBA cost–benefit analysis AHMAC Australian Health Ministers’ Advisory CBER Center for Biologics Evaluation and Council Research AIMD active implantable medical device CCA cost–consequence analysis AMWG Access to Medicines Working Group CCDS Company Core Data Sheet ANCOVA analysis of covariance CCG clinical commissioning group ANDA abbreviated New Drug Application CDER Center for Drug Evaluation and ANVISA Brazil’s National Health Surveillance Research Agency CDISC Clinical Data Interchange Standards ANZTPA Australia New Zealand Therapeutic Consortium Products Agency CDR Common Drug Review API active pharmaceutical ingredient CDSM Committee on Dental and Surgical ARB angiotensin II receptor blockers Materials ARGPM Australian Regulatory Guidelines for CEA cost-effectiveness analysis Prescription Medicines cGMP cyclic guanosine monophosphate ARR absolute rate reduction CHM Commission on Human Medicines ARSAC Administration of Radioactive CHMP Committee on Medicinal Products for Substances Advisory Committee Human Use ARTG Australian Register of Therapeutic CI confidence interval Goods CIOMS Council for International ARU attack rate in the unvaccinated Organization of Medical Science population CJEU Court of Justice of the European ARV attack rate in the vaccinated population Union

ASA Advertising Standards Authority Cmax maximum concentration

xiv List of abbreviations xv

CMD(h) Coordination Group for Mutual EAG expert advisory group Recognition and Decentralised EC ethics committee Procedures for Human Medicinal ECG electrocardiogram Products ECMO extracorporeal membrane CMD(v) Coordination Group for Mutual oxygenation Recognition and Decentralised eCRF electronic case report form Procedures for Veterinary Medicines ECSC European Coal and Steel Community CMI Consumer Medicine information ED exploratory development CML chronic myeloid leukaemia EDC electronic data capture CMS Concerned Member State EDTA ethylene diamine tetra acetic acid COFEPRIS Mexico’s Federal Commission for the EEA European Economic Area Protection against Sanitary Risks EEG electroencephalography COMP Committee for Orphan Medicinal EFPIA European Federation of Products Pharmaceutical Industries and COPD chronic obstructive pulmonary disease Associations CPAB Code of Practice Appeal Board EFTA European Free Trade Association CPMP Committee on Proprietary Medicinal EGFR epidermal growth factor receptor Products ELA Establishment Licence Application CPP Certificate of Pharmaceutical Product ELD Evaluation and Licensing Division CPP Code of Practice Panel EMA European Medicines Agency CRD clinically relevant difference EMC electromagnetic compatibility CRF case report form EMEA European Medicines Evaluation CRO contract research organisation Agency CRS cytokine release syndrome EPC European Patent Convention CSD Committee on Safety of Drugs ESG Expert Scientific Group CSI Core Safety Information EU European Union CSM Committee on Safety of Medicines EUFEPS European Federation for CT computed tomography Pharmaceutical Sciences CTA clinical trial agreement EURATOM European Atomic Energy Community CTA clinical trial authorisation FBDD fragment-based drug discovery CTC Clinical Trial Certificate FD full development CTD Common Technical Document FDA Food and Drug Administration CTFG Clinical Trials Facilitation Group FDC fixed drug combination CTM Community Trade Mark FD&C Act Food, Drug, and Cosmetic Act CTN clinical trial notification FHSA Family Health Service Authority CTS common technical specification FIH first-in-human study CTX clinical trial exemption FOIA Freedom of Information Act CUA cost–utility analysis FPC Family Practitioner Committee CVMP Committee for Medicinal Products FPS Family Practitioner Service for Veterinary Use FTC Federal Trade Commission DALY disability adjusted life year GAVI Global Alliance for Vaccines and DESI Drug Efficacy Study Implementation Immunization DH Department of Health GCG Global Cooperation Group DHSS Department of Health and Social GCP Good Clinical Practice Security GDP gross domestic product DISK dry powder inhaler GFR glomerular filtration rate DLT dose limiting toxicity GLP glucagon-like peptide DPP dipeptidyl peptidase GLP Good Laboratory Practice DRF dose-range-finding GM genetically modified DSMC Data Safety Monitoring Committee GMC General Medical Council DSUR Development Safety Update Report GMP Good Manufacturing Practice DTC direct-to-consumer GP general practitioner xvi List of abbreviations

GPS general product safety KFDA Korea Food and Drug Administration GPSP Good Post-Marketing Study Practice LA Licensing Authority GQP good quality practice LCM life cycle management GRAS generally recognised as safe (drug) LDC least developing country GSK glycogen synthase kinase MAA Marketing Authorisation Application GSL general sales list mAB monoclonal antibodies GVP Good Vigilance Practice MABEL minimal anticipated biological effect HCV hepatitis C virus level HED human equivalent dose MAH marketing authorisation holder hERG human ether-a-go-go related gene MALDI matrix-assisted laser desorption/ HESC human embryonic stem cells ionisation HHS Department of Health and Human MAOI monoamine oxidase inhibitor Services MAP minimum acceptable profile HLA human leucocyte antigen MC Medicines Commission HMAC Herbal Medicines Advisory MCA Medicines Control Agency Committee MCCT multinational cooperative clinical HMPC Herbal Medicinal Products trial Committee MCDA multicriteria decision analysis HPB Health Policy Bureau MDD medical devices Directive HREC human research ethics committee MDI metered-dose inhaler HTA Health Technology Assessment MDU Medical Defence Union HTS high-throughput screening MedDRA Medical Dictionary for Regulatory IATA International Air Transport Association Activities IB investigator’s brochure MHLW Ministry of Health, Labour and Welfare ICF Informed Consent Form MHRA Medicines and Healthcare products ICH International Conference on Regulatory Agency Harmonisation MID minimum intolerated dose IDMC independent data-monitoring MOT margin of tolerance committee MPD medicinal products Directive IEC independent ethics committee MPS Medical Protection Society IES Integrated Efficacy Summary MRA Mutual Recognition Agreement IFN-α interferon α MRC Medical Research Council Ig immunoglobulin MRD maximum repeatable dose IMP investigational medicinal product MRI magnetic resonance imaging IMPACT International Medical Products mRNA messenger RNA Anti-Counterfeiting Taskforce MRSA methicillin-resistant Staphylococcus IMPD Investigational Medicinal Product aureus Dossier MRSD maximum recommended starting IMS international medical statistics dose IND investigational new drug MRUS maximum rate of urea synthesis INR international normalised ratio MS multiple sclerosis INTERPOL International Criminal Police MTD maximum tolerated dose Organization MW molecular weight IP intellectual property MWTD maximum well-tolerated dose IPS indicative prescribing scheme NAS National Academy of Sciences IRB institutional review board NBE new biological entity ISS Integrated Safety Summary NCA national competent authorities ITP immune thrombocytopenic purpura NCE new chemical entity ITT intention to treat NDA New Drug Application IVD in vitro diagnostic device NEAF National Ethics Application Form IVRS interactive voice randomisation system NHI National Health Insurance IVRT interactive voice response technology NHMRC National Health and Medical Research JFC Joint Formulary Committee Council List of abbreviations xvii

NHS National Health Service PFSB Pharmaceutical and Food Safety NICE National Institute for Health and Bureau Clinical Excellence PGx pharmacogenomic NIH National Institutes of Health PhVWP Pharmacovigilance Working Party NK natural killer PI product information NMDA N-methyl-d-aspartic acid PIL patient information leaflet NME new molecular entity PIP paediatric investigation plan NMR nuclear magnetic resonance PK pharmacokinetic NNT number needed to treat PK-PD pharmacokinetic–pharmacodynamic NOAEL no observed adverse effect level PL Product Licence NOEL no observed (non-toxic) effect dose PLA Product Licence Application level PLM pre-launch marketing NRES National Research Ethics Service PLR Product Licences of Right NRG Name Review Group PMCPA Prescriptions Medicines Code of NSAID non-steroidal anti-inflammatory drug Practice Authority NSCLC non-small cell lung cancer PMDA Pharmaceuticals and Medical Devices NTD neglected tropical disease Agency OCSC oversulfated chondroitin sulfate PMSB Pharmaceutical and Medicine Safety OECD Organisation for Economic Bureau Cooperation and Development PoC proof of concept OFT Office of Fair Trading POM prescription only medicine OMA Office of Medicines Authorisation PPA Prescription Pricing Authority OPG osteoprotegerin PPC prescription prepayment certificate OR odds ratio PPE personal protective equipment OTC over-the-counter PPP public–private partnership PAC Pharmaceutical Affairs Committee PPRS Pharmaceutical Price Regulation PAD pharmacologically active dose Scheme PADER periodic adverse drug experience PRAC Pharmacovigilance Risk Assessment report Committee PAFSB Pharmaceutical Affairs and Food PSD Public Summary Document Safety Bureau PSUR Periodic Safety Update Report PAFSC Pharmaceutical and Food Sanitation PTL Product Team Leader Council PTSC Predictive Safety Testing Consortium PAGB Proprietary Association of Great PUMA Paediatric Use Marketing Britain Authorisation PAGE poly-acrylamide gel electrophoresis PV pharmacovigilance PAL Pharmaceutical Affairs Law QA quality assurance PARP poly-ADP-ribose polymerase QALY quality-adjusted life-year PBAC Pharmaceutical Benefits Advisory QbD Quality by Design Committee QC quality control PBPA Pharmaceutical Benefits Pricing QoL quality of life Authority QPPV Qualified Person for PBRER Periodic Benefit Risk Evaluation Report Pharmacovigilance PBS Pharmaceutical Benefits Scheme R&D research and development PCG primary care group RANKL receptor activator of nuclear factor-kB PDCO Paediatric Committee ligand PDE phosphodiesterase RBC red blood corpuscle PDG pharmacopoeial discussion group RECIST response evaluation criteria in solid PDUFA Prescription Drug User Fee Act tumours PEG polyethylene glycol REMS Risk Evaluation and Mitigation peg-IFN-α peg-interferon α Strategies PET positron emission tomography RHA Regional Health Authority PFS progression-free survival RMP risk management plan xviii List of abbreviations

RMS Reference Member State SUSMP Standard for the Uniform Scheduling ROC return on capital of Medicines and Poisons RP2D recommended phase II dose SVR sustained virological response RPW randomised-play-the-winner TdP torsade de pointes RR relative risk TFT trifluorothymidine RR response rate TGA Therapeutic Goods Administration RTK receptor tyrosine kinase TGP therapeutic group premium SAD single ascending dose Th1 T-helper 1 SAE serious adverse event Th2 T-helper 2 SAG scientific advisory group TK thymidine kinase SAL sterility assurance level TKI tyrosine kinase inhibitor SAR structure–activity relationship TLR toll-like receptor SAS special access scheme TMA tissue microarrays

SAWP Scientific Advice Working Party tmax time to maximum concentration siRNA small interfering RNA TMDD target mediated drug disposition SMC Scottish Medicines Consortium TNF tumour necrosis factor SME small and medium-sized enterprises TPN total parenteral nutrition SMO site management organisation TPPA Trans Pacific Partnership Agreement SmPC Summary of Product Characteristics TRIP trade-related aspect of intellectual SMT Safety Matrix Team property rights SMW small molecular weight TTC Threshold of Toxicological Concern SOP standard operating procedure UDS unscheduled DNA synthesis SPA special protocol assessment USDA US Department of Agriculture SPC Summary of Product Characteristics VAS visual analogue scale SPC Supplementary Protection VDR virtual data room Certificate VE vaccine efficacy SSAR suspected serious adverse reaction VEGF vascular endothelial growth factor ssRNA single-stranded RNA WFI water for injection STB Scientific and Technical Branch (of WHA World Health Assembly the DHSS) WHO World Health Organization SUSAR suspected unexpected serious adverse WMA World Medical Association reaction WOCBP women of child-bearing potential Preface

The 7th edition of the ‘Textbook’ reflects the enor- for the professional qualification of the Diploma in mous changes in the environment in which the phar- Pharmaceutical Medicine and for Membership of the maceutical industry and the pharmaceutical physician Faculty of Pharmaceutical Medicine of The Royal operate, many of which have occurred since 2009 Colleges of Physicians of the UK. Over subsequent when the 6th edition was published. editions, the scope of the book has broadened and The arrangement of the material is now in three much of its content should now be pertinent to the parts: wide range of personnel involved in the development, Part I: Research and Development; regulation and marketing of medicines. This includes Part II: Regulation; clinical trial investigators and their research teams as Part III: Healthcare Marketplace. well as those in the industry. We have attempted to There are fundamental changes in all three areas make this book a ‘first stop shop’ for all these readers, with new chapters on topics that have not featured in with sufficiently generous referencing to guide further previous editions. These include biological therapeu- detailed study included in each chapter. tics, vaccines, drugs for cancer, drug development in It is to be hoped that the broad international scope paediatrics and neonates, pharmacovigilance, the will make the book of interest to those in the devel- European clinical trials directive, lifecycle manage- oped markets of Europe, North America, Japan and ment of medicines, availability of medicines on-line Australasia and also to those in the developing and counterfeits and the supply of unlicensed medi- markets. cines. Several pre-existing chapters have undergone Whilst recognising that it is impossible for all its major revision, often by new authors. New chapters content to remain up to date, we thank the publisher on the ethics of human experimentation in Part I Wiley-Blackwell for permitting late changes to some and legal and ethical issues in Part III reflect a text where regulations have been updated very recently greater emphasis on ethical issues, which are of such so that information is as up to date as it can be. critical importance to the pharmaceutical industry as a whole. John P. Griffin The ‘Textbook’ started 20 years ago as essential John Posner reading for the pharmaceutical physician preparing Geoffrey R. Barker

xix

Part I Research and development

1 Discovery of new medicines

Yves J. Ribeill Scynexis Inc., Research Triangle Park, NC, USA

Introduction ‘leads’ via cycles of altering the structure and proper- ties of the molecules followed by iterative screening. Patients rely on discovery researchers to embrace During this process, lead compounds are further innovation, make advances and deliver new therapies optimised for the desired absorption, distribution, that will improve their lives. The discovery of drugs metabolism, excretion and toxicological (ADMET) is a complex, costly and lengthy process involving properties. ADMET optimisation supplies the ‘lead several distinct stages on the path towards delivery compound’, which advances to later stages of drug of a marketable drug (Figure 1.1). It is becoming development. increasingly important in the ever competitive enter- A case study around the investigation of phos- prise of drug discovery for researchers to develop phodiesterase (PDE) inhibitors illustrates the suc- innovative drug discovery strategies in order to fill cessful applications of the principles of contemporary their pipelines. This chapter is designed to highlight drug discovery and development. Based on the dis- these modern approaches to drug discovery and the covery of an endothelium-derived relaxing factor changing therapeutic landscape for the currently and the interplay of nitric oxide, cyclic guanosine available drugs. monophosphate (cGMP) and PDEs in vasodilation, Progress in drug discovery relies on fundamental researchers at Pfizer reasoned that a PDE inhibitor biological research in pharmaceutical and biotech- might be advanced for the treatment of angina [1]. nology companies as well as academia to identify new Their comparison of the structure of cGMP, with biological targets, to implement target validation consideration of how it may bind to PDEs, with that strategies and to confirm target relevance in a disease of the weak vasodilator Zaprinast, also a PDE inhibi- state. Initially, drug discovery researchers select a tor, further supported their hypothesis. The screen­­ target that can interact with a modulator, such as ing of existing compound collections as well as the a protein or small molecule. After a target has rational design of analogues produced active mole- been chosen, researchers must demonstrate that the cules that targeted PDE-5, a cGMP-specific PDE target is relevant to a disease in both living cells and located in coronary smooth muscle. Further optimi- animal models. The promise of determining the sation of these compounds for the desired potency whole genome sequence, new insights into molecular and ADMET properties led to a clinical candidate for sources of disease, technological advances in both angina; the compound was found to be ineffective, target and lead validation, and high-throughput and its development as a cardiovascular drug was screening (HTS) strategies all provide potentially halted. During the clinical trials, however, some novel opportunities for target validation in drug dis- patients reported experiencing enhanced penile erec- covery. After such validation, the search begins for a tions. Subsequently, PDE-5 was identified as the main ‘hit’ molecule that interacts with the desired target. cGMP-degrading enzyme in the corpus cavernosum. These ‘hits’ may originate from nature, de novo design Thus, efforts were redirected toward proving the or HTS but, in most cases, require optimisation to effectiveness of the lead compound as a treatment for

The Textbook of Pharmaceutical Medicine, Seventh Edition. John P. Griffin, John Posner, and Geoffrey R. Barker. © 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

3 4 Chapter 1

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Figure 1.1 Drug discovery pipeline.

O O O H CH3 CH3 N N HN HN O O N O O N N S S N N N N N N H O N H C N O 3 O CH3 CH3 O CH CH 3 3 O

^ŝůĚĞŶĂĮů sĂƌĚĞŶĂĮů dĂĚĂůĂĮů Figure 1.2 Structures of PDE-5 inhibitors for erectile dysfunction. erectile dysfunction and the eventual approval of ment (R&D), clinical trials and marketing to intro- sildenafil (Viagra) in 1998 as a prescription medicine duce drugs to market. However, fewer than one in 50 for erectile dysfunction [2,3]. drug discovery projects results in the delivery of a Important parts of drug discovery and develop- drug to market [4], and the average time from ment are intellectual property protection and the concept to market is 15 years, at a cost of nearly a ability to navigate around prior art. Pfizer filed patent billion dollars per drug [5]. Further, since 2008, new applications proactively around the lead compound/ drug approvals have declined sharply despite an series, as well as its therapeutic use, to deter competi- increase in R&D spending [6]. The observed high tors from achieving success in the PDE arena in attrition rate is unsustainable and researchers must similar chemical space. Others interested in advanc- constantly reassess their tactics in order to translate ing compounds in this therapeutic area became faced discovery research into clinical success. with searching for gaps in the patent coverage or pur- Despite the steady decline in overall new drug suing alternative structural classes. Implementation approvals there has been a steady increase of new of a ‘patent busting’ strategy enabled the discovery of products in the therapeutic areas of anti-infective, vardenafil (Levitra). Analogues outside of the Pfizer metabolic and orphan diseases, as well as a shift patents were identified, optimised and evaluated in into specialty-care therapies (Tables 1.1, Table 1.2, clinical trials ahead of product launch in 2003. Con- Table 1.3 and Table 1.4) [7–9]. The majority of versely, Icos and Lilly investigated an unrelated mol- new molecular entities (NMEs) continue to be small ecule as a longer-acting PDE-5 inhibitor that led to molecules; however, vaccines and non-biological oli- the approval of tadalafil (Cialis), also in 2003. Figure gonucleotides employed as macromolecular thera- 1.2 highlights the structural similarities, and differ- peutics are directed at enzymes and receptors that ences, of these three medicines. have been classically modulated by small molecule drugs. In response to the decline in new drug approvals, Medicines marketed in the years new approaches have been put in place: 2008–2011 1. drug combinations that target multiple pathways continue to increase in drug discovery to modulate The pharmaceutical and biotechnology industries the interplay of complex chemical pathways involved spend billions on cutting-edge research and develop- in diseases; Discovery of new medicines 5

Table 1.1 New molecular entities (NME) approved 2008. Reproduced from Hegde S, Schmidt M. To Market, To Market Annual Reports in Medicinal Chemistry 2009; 44: 577 with permission from Elsevier [8]

Proprietary Established Applicant Treatment/indication

Entereg Alvimopan GlaxoSmithKline/Adolor Oral treatment of postoperative ileus following bowel resection surgery Biomatrix Biolimus drug-eluting stent Biosensors Antiresenotic Lonasen Blonanserin Dainippon-sumitomo Dual antagonist of dopamine D2 and serotonin 5-HT2 for schizophrenia Zeftera Ceftobiprole medocaril Basilea/Johnson&Johnson New injectable cephalosporin antibiotic

Cimzia Certolizumab pegol UCB TNF-α blocker for Crohn’s disease Trilipix Choline fenofibrate Abbott/Solvay PPARα dyslipidaemia Cleviprex Clevidipine The Medicines Co. IV treatement for hypertension Pradaxa Dabigatran Boehringer Ingelheim Oral administered anticoagulant Pristiq Desvenlafaxine Wyeth SNRI for antidepression Intelence Etravirine Tibotec NNRT antiviral for HIV Toviaz Fesoterodine Pfizer Orally active pro-drug from treatment of overactive bladder Ivemend Fosapreptiant dimeglumine Merck Anti-emetic Firazyr Icatibant Jerini Hereditary angiodema (HAE) Vimpat Lacosamide Schwarz Pharma Anticonvulsant Relistor Methylnaltrexone bromide Wyeth/Progenics Opiod-induced constipation Pirespa Pirfenidone Shinogi Idiopathic pulmonary fibrosis (IPF) Arcalyst Rilonacept Regeneron Recombinant fusion protein for symptoms of inherited auto-inflammatory syndrome Xarelto Rivaroxaban Bayer/Ortho-McNeil Anticoagulant Nplate Romiplostim Amgen Recombinant fusion protein for treatment of thrombocytopenia Gracevit Sitafloxacin hydrate Daiichi Sankyo Antibacterial Bridion Sugammadex Schering-Plough Reversal of neuromuscular blockade Taflotan Tafluprost Santen/Asahi Glass Antiglaucoma Recothrom Thrombin alfa Zymogenetics Recombinant human protein for haemostat Recomodulin Thombomodulin Asahi Kasei Pharma Recombinant human protein as an anticoagulant

NNRT, non-nucleoside reverse transcriptase; PPAR, peroxisome proliferator-activated receptor; SNRI, serotonin– norepinephrine reuptake inhibitor; TNF, tumour necrosis factor.

2. drug repurposing has accounted for two-thirds 3. collaboration strategies between pharmaceutical of new drug applications. Increased focus on re­­ companies and academic research institutions have purposing existing drugs for orphan indications contributed to the drug discovery process [10,11]. emanates from disease-focused philanthropic groups; While academic research is focused principally on the and underlying mechanistic components of a disease and 6 Chapter 1

Table 1.2 NME approved 2009. Reproduced from Hegde S, Schmidt M. To Market, To Market Annual Reports in Medicinal Chemistry 2010; 45: 467 with permission from Elsevier [9]

Proprietary name Established name Applicant Treatment/indication

Nuvigil Aromodafinil Cephalon Sleep disorder, α1-adrenoceptor agonist Saphris Asenapine Merck/Schering-Plough Schizophrenia and bipolar 1, dual antagonist dopamine D2 and serotonin 5-HT2 Besivance Besifloxacin Baush & lomb Antibacterial, ophthalmic use Ilaris Canakinumab Novartis Recombinant monoclonal antibody, anti-inflammatory Removab Catumaxomab Trion Trifunctional monoclonal antibody, anticancer Priligy Dapoxetine Janssen-Cilag Premature ejaculation Firmagon Degarelix acetate Ferring Pharmaceutical Antagonist of GNRH, anticancer Kapidex Dexlansoprazole Takeda Gastroesophogeal reflux disease Multaq Dronedarone Sanofi-Aventis Anti-arrhythmic Promacta Eltrombopag GlaxoSmithKline Antithrombocytopenic Zebinx Eslicarbazepine Eisai Anti-epileptic Adenuric Febuxostat Takeda/Teijin/Ipsen Antihyperuricaemic, selective xanthine oxidase inhibitor Simponi Golimumab Centocor Ortho Recombinant monoclonal antibody, anti-inflammatory Onbrez breezhaler Indacaterol Novartis/Skye Pharma Chronic obstructive pulmonary disease, inhaled β2 adrenoceptor agonist Victoza Liraglutide Novo Nordisk Antidiabetic Recalbon, bonoteo Minodronic acid Ono/Astella Pharma Osteoporisis Remitch Nalfurafine hydrochloride Toray/Japan Tobacco Pruritus (chronic itching) Arzerra Ofatumumab Genmab/GlaxoSmithKline Recombinant monoclonal antibody, anticancer Votrient Pasopanib GlaxoSmithKline VEGF, anticancer Mozobil Plerixafor Genzyme Haematological malignancies, autologous haemtopoietic stem cell transplantation Folotyn Pralatrexate Allos Injectable DHFR inhbitior, anticancer Effient Prasugrel Daiichi Sankkyo/Eli Lilly Antiplatelet therapy Onglyza Saxagliptin Bristol-Myers-Squibb/ Antidiabetic Astrazeneca Nucynta Tapentadol Ortho-McNeil-Janssen Analgesic, pain intervention

Arbelic, vibativ Telavancin Theravance/Astellas Pharma Antibiotic Samsca Taolvaptan Otsuka America Hyponatraemia

Ellaone Ulipristal acetate HRA Pharma Contraceptive, progesterone receptor antagonist Stelara Ustekinumab Janssen-Ortho Humanized IGG1K monoclonal antibody, antipsoriatic

DHFR, dihydrofolate reductase; GNRH, gonadotrophin-releasing hormone; VEGF, vascular endothelial growth factor. Discovery of new medicines 7

Table 1.3 NME approved 2010. Reproduced from Bronson J, Dhar M, Ewing W, Lonberg N. To Market, To Market Annual Reports in Medicinal Chemistry 2011; 46: 433 with permission from Elsevier [7]

Proprietary name Established name Applicant Treatment/indication

Lastacaft Alcaftadine Vistakon Pharmaceuticals Ophthalmologic, histamine antagonist Nesina Alogliptin Takeda/Furiex Pharmaceuticals Antidiabetic, DPP-4 Bilaxten Bilastine Faes Farma, Menarini, Pierre Antiallergy, histamine antagonist Fabre, Merck-Serono Jevtana Cabazitaxel Sanofi-Aventis Anticancer, tubulin inhibitor Teflaro Ceftaroline fosamil Forest Laboratories Antibacterial, bacterial cell wall synthesis inhibitor Elonva Corifollitropin Merck Infertility, FSH agonist Ampyra Dalfampridine Acorda Therapeutics Multiple sclerosis, potassium channel blocker Prolia / xgeva Denosumab Amgen Osteoporosis, recombinant monoclonal antibody Diquas Diquafosol Santen Ophthalmologic dry eye, P2Y2 purinergic receptor agonist Kalbitor Ecallantide Dyax Corp Angiodema, plasma kallikrein inhibitor Halaven Eribuline Eisai Anticancer, tubulin inhibitor Gilenya Fingolimod Novartis Multiple sclerosis, S1P receptor agonist Inavir Laninamivir Daiichi-Sankyo Antiviral, neuraminidase Lurasidone Lurasidone Dainippon Sumitomo Pharma Schizophrenia, dopamine 5-HT receptor antagonist Junovan Mifamurtide Takeda Anticancer Rapiacta Peramivir Biocryst Pharmaceuticals Antiviral, neuraminidase inhibitor Daxas Roflumilas Nycomed Chronic obstructive pulmonary disorder, PDE4 inhibitor Istodax Romidepsin Celgene Anticancer, histone deacetylase inhibitor

Provenge Sipuleucel-t Dendreon Anticancer, therapeutic cancer vaccine Egrifta Tesamorelin Theratechnologies HIV lipodystrophy, growth hormone- releasing factor Brilique Ticagrelor Astra-Zeneca Antithrombotic, P2Y12 antagonist Brinavess Vernakalant Merck/Cardiome Pharma Anti-arrhythmic, atrial potassium channel blocker Javlor Vinflunine Pierre Fabre Anticancer, tubulin inhibitor Civanex Zucapsaicin Winston Analgesic, TRPV1 channel activator

FSH, follicle stimulating hormone; PDE4, phosphodiesterease 4; TRPV1, transient receptor potential cation channel subfamily V member 1. 8 Chapter 1

Table 1.4 NME approved 2011. Reproduced with permission from U.S. Food and Drug Adminstration, ‘How Drugs are Developed and Approved?’, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ DrugandBiologicApprovalReports/ucm121136.htm. Last accessed 13 Aug 2012

Proprietary name Established name Applicant Treatment / indication

Zytiga Abiraterone J&J Advanced prostate cancer Eylea Aflibercept Regeneron/Bayer Wet AMD Edarbi Azilsartan Takeda Hypertension angiotensin II receptor blocker Nulojix Belatacept Bms Renal transplant Benlysta Belimumab HGSI, GSK Lupus Victrelis Boceprevir Merck Hepatitis C Adcetris Brentuximab vedotin Seattle Genetics Hodgkin lymphoma, anaplastic large cell lymphoma Teflaro Caftaroline Cerexa Acute bacterial skin infections and pneumonia Erwinaze Crisantaspase Eusa ALL Xalkori Crizotinib Pfizer NSCLC Promacta Eltrombopag GSK Chronic immune (idiopathic) thrombocytopenic purpura Potiga Ezogabine GSK, Valeant Epilepsy Corifact Factor xiii Behring Prevention of bleeding with genetic defects in factor XIII Horizant Gabapentin enacarbil GSK, Xenoport Restless legs syndrome Firazyr Icatibant Shire Hereditary angioedema Arcapta neohaler Indacaterol Novartis COPD Yervoy Ipilimumab Bms Metastatic melanoma Tradjenta Linagliptin Lilly, Boehringer Ingelheim Type 2 diabetes Edurant Rilpivirine J&J HIV Xarelto Rivaroxaban Bayer, J&J Blood clot prevention Daliresp Roflumilast Forest COPD Jakafi Ruxolitinib Incyte, Novartis Myelofibrosis Natroba Sphinosad Parapro Head lice Incivek Telaprevir Vertex, J&J, Mitsubishi Tanabe Hepatitis c Brilinta Ticagrelor Astra Zeneca Blood clot prevention Caprelsa Vandetanib Astra Zeneca Medullary thyroid cancer Zelboraf Vemurafenib Roche, Daiichi Sankyo Melanoma Zictifa Vendetanib Astra Zeneca Thyroid cancer Viibryd Vilazodone Forest, Merck KGAA Major depressive disorder

ALL, acute lymphocytic leukaemia; AMD, acute macular degeneration; COPD, chronic abstructive pulmonary disease; NSCLC, non-small cell lung cancer. Discovery of new medicines 9 the pharmaceutical industry focuses on pro­gressing by the compatibility of that target with an HTS discovery projects, a willingness to share expertise approach to enable rapid and cost-effective evalua- through these research alliances has resulted in tion of hundreds of thousands of compounds from advances in poorly funded rare diseases. screening collections. Much debate continues around the relative effec- tiveness of the two models outlined earlier. The Impact of high throughput premise that high-affinity binding to a single biologi- screening in drug discovery cal target that is associated with a disease state will afford a therapeutic benefit in humans [13,14] has A judicious choice of therapeutic area and biological been countered by opinions that pharmaceutical target, along with an acceleration of development products developed pre-HTS in fact do not act on a time through scientific innovation, are critical to a single target, and are actually more promiscuous than successful R&D drug discovery programme. Pharma- previously thought, thereby exposing a deficiency in ceutical companies often engage in economic balanc- the HTS approach. Off-target binding could have an ing when choosing therapeutic areas in which to important role in the efficacy of a drug candidate begin research by weighing the probability of deliver- that: (i) underscores not only the importance of ing a product against potential sales of this product. target selection, but also the choice of the R&D stra- Additionally, companies must consider development tegic model; and, (ii) provides one plausible explana- costs and regulatory hurdles when choosing their tion for the success of the in vivo screening model in research path. As an example, since 2000, the propor- delivering NMEs. tion of R&D projects from available corporate port- folios in the area of antineoplastic agents has increased by about 7% [12]. The average sales per year for an Impact of combinatorial chemistry antineoplastic agent developed since 2000 was 92 on drug discovery million dollars, among the highest of the major thera- peutic classes. However, the probability of success for The paradigm of drug discovery experienced changes reaching the market from the preclinical phase for an at the end of the last century. The acceptance of HTS antineoplastic development project is quite low due methodologies reinforced opinions to prepare larger, to project attrition [12]. diverse collections of test compounds, especially pep- The drug discovery paradigm has evolved in recent tides and small molecules. Solid-phase chemistry [15] times. In the simplest example, the mode of action enabled the assembly of complex polypeptides on a of a compound (drug) centres on its binding to polymer support, simultaneously providing access to a receptor (target) that influences a biochemical previously unattainable molecules and foreshadow- pathway, which is relevant to a physiological process, ing the use of automation. The overarching features and the sum of these events provides a therapeutic of this approach were the use of substrates covalently benefit to a disease state. In many cases the reality bound to a solid-support (polypropylene, polysty- is not that simple, thus additional approaches have rene or other polymeric beads) and an excess of rea- become necessary. Prior to 1990, the standard gents to drive reactions to completion that could be approach to small molecule drug discovery relied washed away, thus eliminating the need for tradi- on iterative, low-throughput in vivo screening and tional purifications [16]. Means of accessing larger optimisation of compounds to improve chemical or numbers of polypeptides as well as complex arrays of biochemical parameters (e.g. potency, selectivity or polypeptides naturally emerged [17,18]. Another pharmacokinetic properties). Antihypertensive beta- methodology used in combination with automated blockers were developed through this process from parallel synthesis equipment enabled the synthesis of adrena­­line (epinephrine) [12] where analogues were sets of compounds (libraries) containing literally mil- synthesised individually and evaluated in concurrent lions of members. This ‘split-and-mix’ [19–21] meth- assays (often in vivo) and optimised via medicinal odology relied on a three-step regimen to build chemistry to progress compounds to clinical trials. libraries of compounds on a solid support: perform- With the advent of HTS and the availability of large ing the initial reactions on the beads, mixing the collections of compound libraries, this model was beads and then partitioning the beads for the next criticised for being slow, expensive and obsolete. reaction. This process could be repeated many times, Target selection has since become heavily influenced limited only by the targeted size of the final products. 10 Chapter 1

As the number of final products increases by mul­ [23]. Also, the recognition of relationships between tiplication whereas the number of reagents and compound structure and biological activity has reactions used increases only by addition, this com- enabled enhancements towards library design based binatorial approach could rapidly provide libraries on physicochemical properties (properties that can be of more complex compounds. Of course the inherent measured such as logD or solubility) and constitutive difficulty of assigning specific structures to the syn- properties (features that can be derived, or calculated, thesised molecules became an issue, in terms of relat- from the arrangement of atoms in a compound) [33]. ing a chemical structure to a ‘hit’ from a biological A popular example of the usage of constitutive prop- assay. The use of inert chemical ‘tags’ (or labels) as an erties was first described by Lipinski et al. [34,35] encoding strategy to describe the chemical reagents who developed a guide widely known as the ‘Rule of used for any member of a library offered a method to Five’ that states drug-like molecules should have: a decipher structures associated with ‘hits’ [22]. molecular weight (MW) of ≤500; ≤5 hydrogen bond Large investments in drug discovery, along with the donors; ≤10 hydrogen bond acceptors and a logP of advent of HTS methodologies and the ability to syn- ≤5. The ‘Rule of Five’ has helped guide library design thesise very large libraries led to a mistaken sense of to bias a set of molecules towards having properties exuberance in the field based on the founding (but similar to known drugs. flawed) principle that, ‘given a sufficiently large and The realisation that making large libraries alone diverse set of compounds to test, the discovery of an would not necessarily provide chemical leads for drug ideal drug for any given disease state would be statis- discovery programmes was intimately associated with tically unavoidable’ [23]. Combinatorial libraries of advances in computational methods. During this peptides/nucleotides did not readily translate to func- time, computational chemists were developing tools tional and commercial drugs for a variety of reasons: to assist with the design and selection of compounds (i) although millions of molecules were made, they for synthesis and screening. Chemists were equipped represented only a minute fraction of the possible to engineer focused libraries with drug-like proper- compounds that could be made [24]; (ii) the de- ties, and arguably a higher chance of success, as well convolution of large libraries is not practical because as libraries to address specific questions or probe spe- the split-and-mix method requires the concomitant cific structure–activity relationships during a lead resynthesis (or partial resynthesis) to relate a ‘hit’ to optimisation programme. a discrete chemical structure; and (iii) combinatorial chemistry produced libraries of compounds with physicochemical properties that deviated substan- tially from either drug-like or natural product- Fragment-based design like compounds [25]. Despite these shortcomings, combinatorial chemistry efforts have produced one Fragment-based drug discovery (FBDD) is a recent success story. The preparation and testing of approxi- addition to the set of tools available to pharmaceuti- mately 200,000 compounds in a HTS assay for Raf1 cal scientists. In FBDD, collections of low molecular kinase inhibition [26] identified a weak inhibitor of weight compounds, or ‘fragments’, are screened using Raf1 kinase that was optimised to sorafenib, approved biophysical methods to identify weak, as character- for the treatment of renal cell carcinoma after just 11 ised by dissociation constants in the micromolar years of R&D. to millimolar range, but efficient binders to a target Although the desire for drug discovery pro- of interest, usually a purified protein. The fragments grammes to produce large [>10,000 new chemical thus identified serve as starting points for further entity (NCE)] libraries by the split-and-mix method optimisation with the goal of producing potent drugs eventually waned, medicinal chemists have developed with favourable properties. Herein we discuss the a repertoire of tools for parallel synthesis. The key concepts of FBDD, the biophysical techniques advances in the use of parallel platforms have been involved, recent advances in the area and some FBDD employed to prepare smaller collections to enhance successes. medicinal chemistry hit-to-lead programmes [27– Fragment criteria as well as the properties of col- 32]. Furthermore, the skill sets developed by medici- lections are topics often debated in this field. A frag- nal chemists have been adopted by the fields of ment in the context of FBDD is smaller and more agricultural chemistry, chemical biology, catalyst polar than most drug molecules. Fragments are discovery, process chemistry and material science often filtered by a ‘Rule of Three’ [36] (analogous to Discovery of new medicines 11

Lipinski’s ‘Rule of Five’ [34,35]), to have MW <300, resonance is observed for every 1H-15N pair in the hydrogen bond donors or acceptors ≤3, the number protein; chemical shift changes in the presence of of rotatable bonds ≤3 and ClogP ≤3 (there has been fragments reveal the area of the protein involved in success, however, with a ‘non-Rule of Three’ compli- binding. Recent work describes the use of 19F-NMR ant library [36]). Fragments bind to their targets in screening fragments [44,45]. Regardless of the weakly but very efficiently relative to their size. The techniques selected, more than one technique should concept of ligand efficiency stems from a better be used to validate fragment binding, preferably in an understanding of the free energy changes involved orthogonal fashion [40,46] prior to further develop- in the binding of a ligand to a protein. In fact, the ment of a FBDD programme. free energy increases steadily as the number of non- Various strategies are employed subsequently hydrogen ligand atoms approaches 15, and plateaus to transform a selected fragment into a viable lead as the number of non-hydrogen atoms in the ligand compound. The earliest approaches, fragment continues to rise [37]. linking, advocated connecting multiple fragments Another often cited advantage of FBDD is the that bind in different areas of the binding pocket. ability to sample diverse chemical space. The number However, fragment linking has struggled to maintain of possible fragments has been estimated at around the stringent distance and angular requirements 108 [38] as opposed to 1060 for discrete drug-like com- between fragments while preserving their original pounds with MW 500. Thus, a collection of even a binding modes. More common approaches have been few thousand fragments samples a relatively larger described as fragment elaboration or fragment proportion of the available pool of entities, thereby growth, where functional groups are added iteratively increasing the chances of identifying hits. to assess potency and other properties [40]. Impor- Optimising a library toward a particular target is tantly, the growth of the fragment is guided by the also feasible when dealing with only a few thousand structural information obtained from the biophysical fragments; for example, rigid fragments and those techniques described previously. with aromatic rings may target protein–protein The success of FBDD can be measured in several interactions [39]. Recent work demonstrates that ways. Many companies have been founded on FBDD additional key factors to consider when selecting platforms or have incorporated fragment-based fragments include solubility, reactivity and the ten- approaches into their discovery programmes. How­ dency to aggregate in solution; these characteristics ever, the real success of any drug discovery paradigm can confound data analysis and hinder the ability to is the ability to deliver marketed drugs and improve identify successful binders correctly [40]. patient outcomes. At last count, 17 compounds that A range of biophysical techniques has been used to originated from FBDD programmes had reached identify compounds that bind target proteins. The clinical trials, including seven that reached phase II most popular techniques for FBDD are X-ray crystal- and one, vemurafenib, that reached phase III [40]. lography, nuclear magnetic resonance (NMR), Vemurafenib, a selective inhibitor of the B-Raf kinase surface plasmon resonance and isothermal calorim- for the treatment of malignant melanoma, was etry [40]. X-ray crystallography both identifies frag- recently approved as Zelboraf by both the FDA and ments that bind to the target and provides detailed the European Commission and represents the first structural information in a single experiment; success for FBDD. however, expense precludes the use of X-ray crystal- lography as a primary screening tool. NMR can be utilised effectively to screen fragments against a Examples in drug discovery target protein and has become a workhorse of FBDD. Saturation transfer difference [41] and WaterLOGSY Hepatitis C virus [42] experiments can identify binding interactions Hepatitis C virus (HCV) is a positive sense RNA virus between the fragment and protein. Isotopically of the family Flaviviridae which was first identified in labelled protein is not required, and these methods 1989 [47] and causes an infection of the liver that is are more effective for larger protein targets. When the transmitted via blood and mother-to-child transmis- target protein is relatively small (<30,000 Da), tech- sion. HCV does not kill the cells it infects, but it niques such as structure–activity relationships by instead triggers an immune-mediated inflammatory NMR [43] can be used to acquire a 2D 1H-15N HSQC response that either rapidly clears the virus or slowly NMR spectrum of a 15N labelled protein. A separate destroys the liver. It is estimated that 130–170 million 12 Chapter 1 people are chronically infected with HCV, with 3–4 4. mutagenesis resulting in reduced virion million newly infected people each year, and that infectivity. more than 350,000 people die from hepatitis C-related Despite the success of this therapy, less than 50% of liver diseases each year [48]. The nucleotide sequence the patient population exhibit sustained virological of HCV is variable and has been grouped into six response (SVR). main genotypes, each with multiple subtypes, based Since 2008, the FDA has approved two drugs for on sequence data [49]. HCV genotypes/subtypes and treating HCV infection: boceprevir (2011) and tel- areas of prevalence are as follows: aprevir (2011), both of which are serine NS3/4A pro- North America – genotype 1a; tease inhibitors. Boceprevir has been approved for South America – genotype 1a, 1b, and 3; treating HCV genotype 1 in combination with peg- Europe, Asia – genotype 1b; IFN-α/ribavirin [54,55]. Boceprevir covalently, yet Egypt, Zaire – genotype 4; reversibly, binds to the active site of NS3 protease at South Africa – genotype 5; and a serine residue (S139) via an α-ketoamide, inhibiting Hong Kong – genotype 6 [50,51]. the activity of HCV genotype 1a and 1b NS3/4A pro- HCV infects a liver cell by first binding to surface tease [56]. In clinical trials with genotype 1 HCV, receptors on the host cell membrane [50,51]. boceprevir taken in combination with peg-IFN-α/ Receptor-mediated endocytosis promotes entry of ribavirin exhibited a SVR higher (63–66%) than the virion into the cell, where it is uncoated and those subjects taking peg-IFN-α/ribavirin alone releases its positive single-stranded RNA (ssRNA) (38%). Telaprevir has also been FDA-approved for genome. This ssRNA is then translated by host cell treating HCV genotype 1 in combination with peg- ribosomes via an internal ribosome entry site into IFN-α/ribavirin [57,58]. Telaprevir inhibits protease a polypeptide that codes for 10 proteins including NS3/4A in the same manner as described for bocepre- four structural proteins: capsid protein C (genome vir. In clinical trials involving patients with genotype encapsidation), envelope proteins E1 and E2 (glyco- 1 HCV infection, telaprevir taken in combination proteins) and p7 (ion channel). In addition, six non- with peg-IFN-α/ribavirin exhibited an SVR higher structural proteins are part of this replication: NS2 (79%) than those subjects taking peg-IFN-α/ribavi- (cysteine protease); NS3 (serine protease, RNA heli- rin alone (46%). case); NS4A (serine protease co-factor); NS4B (mem- HCV drug discovery is relatively young, with the brane altercations); NS5A (phosphoprotein); and first enzyme-targeting drugs being approved by the NS5B (RNA-dependent RNA polymerase). The FDA in 2011. While these new drugs provide alterna- polypeptide is then cleaved into these 10 functional tives to what has been the standard of the care, they proteins. The NS5B protein then catalyses the replica- both still require co-administration of peg-IFN-α/ tion of HCV RNA. ribavirin and are limited to treating only those with Unlike hepatitis A and B, there is currently no genotype 1 HCV infection. Hence, there is still a great vaccine to prevent HCV infection [52]. Until 2011, need for new therapeutics with different modes of the only FDA-approved treatment of HCV infection action that, it is hoped, can treat all genotypes of consisted of peg-interferon alpha (peg-IFN-α) and HCV, either alone or in combination with one ribavirin for 48 weeks. IFN-α does not act directly on another, but in the absence of peg-IFN-α/ribavirin. the virus or replication complex. Instead it induces Promising targets include NS5A and B inhibitors, IFN-stimulated genes, which establish a non-virus- entry/fusion inhibitors, nucleosides and inhibitors of specific antiviral state within the cell, mediated by host targets that are integrated in the HCV life cycle, IFN cell surface receptor subunits, JAK1, TYK2, such as cyclophilin. STAT1 and STAT2, and IFN-regulatory factor 9 (IRF- 9), which leads to the expression of multiple IFN- HIV stimulated genes, many of which are related to Human immunodeficiency virus (HIV) is a positive antiviral activity [53]. Ribavirin is thought to inhibit sense RNA retrovirus of the family Retroviridae HCV by four proposed mechanisms: which was first identified in 1981. It is transmitted via 1. immunomodulation of T-helper-1 (Th1) over sexual contact, blood and mother-to-child transmis- T-helper-2 (Th2) phenotype; sion and primarily infects T-helper cells (CD4 Th 2. inhibition of inosine monophosphate dehydroge- cells) [59]. HIV kills T cells by directly killing infected nase leading to guanosine diphosphate depletion; cells, increasing the rate of apoptosis in infected cells 3. direct inhibition of HCV RNA polymerase; and and killing infected cells by cytotoxic CD8 TC cells Discovery of new medicines 13 that recognise infected cells. When the CD4 Th cell ine exhibited anti-HIV activity (83% virologic re­­ number decreases below 200 cells/μL, the condition sponse) comparable to efavirenz (80% virologic is categorised as acquired immunodeficiency syn- response) and superior to etravirine (60% virologic drome (AIDS), during which cell-mediated immu- response), but offers a more favourable safety and nity is lost, and the body becomes progressively more tolerability profile. The other two drugs, nevirapine susceptible to opportunistic infections [60]. Accord- XR (extended release) and Complera, are composed ing to a 2009 UNAIDS report, 60 million people have of previously approved drugs. contracted the HIV virus since its discovery in 1981, HIV drug discovery is a significantly mature field, of whom 25 million have died from AIDS-related with 35 FDA-approved drugs over 25 years that span causes, and 33.3 million people are currently infected six mechanisms of action, and many of these can be by HIV/AIDS [61]. There are two types of HIV: taken in combination with one another in order to HIV-1 and HIV-2. HIV-1 is the more virulent and combat resistance. Challenges that remain include the infective of the two, and is the predominant HIV further development of drugs with high barriers to virus globally, while HIV-2 is largely restricted to resistance such as second generation non-nucleoside West Africa [62]. reverse transcriptase inhibitors and, due to failure to HIV infects a T cell by first binding to CD4 surface cure, a strong safety profile that can be taken for a receptors on the host cell membrane [63]. Fusion long period of time. Ultimately, the ability to achieve between the HIV virion and the host is mediated by cure and not simply stasis of the disease is desired. a fusogenic domain in gp41 and CXCR4, a G-protein- linked receptor in the target cell membrane. The Central nervous system therapeutic area nucleocapsid-containing viral genome and proteins Multiple sclerosis then enter the host cell and are released following the Multiple sclerosis is an autoimmune disease affecting removal of core proteins. Viral reverse transcriptase the brain and spinal cord of people typically between catalyses the reverse transcription of ssRNA, forming the ages of 20 and 40, although it can be diagnosed RNA-DNA hybrids. The original RNA template is at any age. Caused by damage to the myelin sheath, it then partially degraded, and the synthesis of a second remains a significant unmet medical need and the DNA strand affords HIV double-stranded DNA. The subject of research at many pharmaceutical and viral double-stranded DNA is then translocated to biotechnology companies. The majority of patients the nucleus and integrated into the host cell DNA by (85%) suffer from the so-called relapsing-remitting the viral enzyme integrase. form of MS in which acute flare-ups are followed by Currently, there is no cure for HIV infection, nor symptom-free periods, often progressing to the sec- is there any vaccine that protects individuals from ondary progressive form. HIV infection, thus the search continues for new The management of MS consists of two lines of therapies. Current treatment entails highly active therapy. In the first, symptoms associated with muscle retroviral therapy, which typically consists of com­ spasms and acute flare-ups are treated. Use of muscle binations of drugs that inhibit different proteins in relaxants for spasms and high doses of steroids for the HIV life cycle. These drugs are categorised as vision loss are two of the common treatments. Drugs fusion/entry inhibitors, reverse transcriptase inhibi- used to slow the progression of MS have seen varying tors, integrase inhibitors and protease inhibitors degrees of success. Most of the currently used thera- [64,65]. Since 2008, the FDA has approved four drugs pies involve modulation of the immune system. for treating HIV [64]. Three of these are non- There are a number of different versions of IFN nucleoside reverse transcriptase inhibitors: etravirine β-1b, which work by limiting the effects of anti- (2008), nevirapine XR (2011) and rilpivirine (2011), inflammatory cytokines. There is also evidence that while the fourth is a multi-class combination product they improve the integrity of the blood–brain barrier Complera (a single tablet, fixed dose combination of which is generally compromised in MS patients. emtricitabine/rilpivirine/tenofovir disoproxil fuma- Mitoxantrone is a known anticancer drug prescribed rate) (2011). Etravirine [66–69] has been approved for MS based on its immunomodulatory effects. for treating HIV-1 in combination with other antiret- Another approved therapy is glatiramer acetate which roviral agents [70]. Likewise, rilpivirine [71,72] has is a random polymer of four amino acids found in been approved for treating HIV-1 in combination myelin basic protein. The mechanism of action is with other antiretroviral agents, and it has the same unknown but several proposals have been put forth. mechanism of action as etravirine [73]. Rilpivir­­ One proposal has shown that glatiramer converts 14 Chapter 1 pro-inflammatory Th1 cells into regulatory Th2 cells which targets the B-cell component of the immune that are immunosuppressive [74]. Another proposal system. The mechanism is currently unclear, but is that the resemblance to myelin basic protein causes ocrelizumab appears to target a B-cell surface protein, glatiramer to decoy the autoimmune response to CD20, which primes T cells for myelin attack [82]. myelin in the myelin sheath [75]. Glatiramer acetate, Continued forward progress in the management of unlike the other treatments, has shown no effective- symptoms and disease progression will allow patients ness in halting disability progression and thus has to optimise treatment on an individual basis. Drugs been approved only for reducing the frequency of that actually repair damage to the myelin sheaths and relapses [76]. permit some level of neurological restoration will be One of the more significant advances occurred in the next desirable addition to the MS pipeline. 2004 with the approval of natalizumab (Tysabri). Natalizumab is a humanised monoclonal antibody Alzheimer’s disease that acts against the cellular adhesion molecule α4- Alzheimer’s disease (AD) is the most common form integrin to prevent penetration of the blood–brain of dementia. Prevalence increases dramatically with barrier by inflammatory cells. It has shown efficacy age, with up to 50% of patients over the age of 85 in preventing relapse, vision loss and cognitive having been diagnosed with AD. Onset is slow and decline. Serious side effects are known, especially if insidious; progression is gradual with the average co-dosed with interferon, and have muted enthusi- time from onset of symptoms to death being 8–10 asm for natalizumab. However, it has shown a signifi- years [83]. cant improvement in quality of life for those MS Although the exact pathophysiology is unknown, patients who can tolerate it. there are prominent findings that are characteristic The success of these medications, and their limita- of AD, including amyloid plaques, neurofibrillary tions, continue to drive efforts to identify novel treat- tangles and neuronal degeneration [84]. Amyloid ments that are efficacious and orally bioavailable. plaques are deposits of beta-amyloid and are believed Two such drugs approved in 2010 are first in class to disrupt neuronal activity by increasing the produc- molecules that extend the mechanism-based approach tion of free radicals, resulting in oxidative cell damage to MS treatments. Dalfampridine is the first drug and eventual death of the affected cells. The second approved by the FDA to improve walking in patients most prominent finding in the brains of patients with with MS. A voltage-gated potassium channel blocker, AD is the formation of neurofibrillary tangles. These it acts by readily penetrating the blood–brain barrier tangles are primarily composed of tau protein which and increasing the conduction and duration of action is essential for the growth and development of the potential across nerve fibres. The result is improved axons of strong healthy neurones. Tau proteins can functionality of the damaged myelinated fibres and become hyperphosphorylated and form tangles, thus improved locomotion [77]. making it more difficult for neurones to maintain The second new drug to be released in 2010 was their normal formation of microtubules. It is interest- fingolimod hydrochloride. A series of studies [78,79] ing to note that the number of neurofibrillary tangles showed that fingolimod is converted to fingolimod can be correlated with the severity of dementia (i.e. phosphate by sphingosine kinase-2 and this phos- impaired cognition and memory loss) [83,84]. The phate binds to multiple sphingosine-1-phosphate third characteristic of neuronal degeneration (as well (S1P) receptors. Binding to the S1P1 receptor leads to as subsequent synapse loss) can be directly correlated internalisation of the receptor and sequestration of with the formation of neurofibrillary tangles. The autoimmune reactive T cells in the lymph nodes. death of cholinergic neurones ultimately leads to a Because these T cells are believed to be responsible loss of acetylcholine, necessary for synaptic transmis- for the inflammation and myelin sheath damage sion, which, in turn, leads to progressive memory observed in MS, their reduced circulation leads to decline. improved symptom management and significant The loss of cholinergic synapses along with dimin- reduction in disease progression [80,81]. ished acetylcholine activity led to the initial develop- Despite these advances, MS remains a debilitating ment of acetylcholinesterase (AChE) inhibitors to disease and an active area of research in both academia treat patients with AD. AChE inhibitors help prevent and industry. Indeed, several new drugs are in various the breakdown of the neurotransmitter acetylcholine stages of clinical trials and are utilising new concepts (by the enzyme acetylcholinesterase) in the synapses in the biology of MS. One such drug is ocrelizumab of cholinergic neurones, thus improving cholinergic Discovery of new medicines 15 transmission in the surviving neurones [83]. AChE protein to form beta-amyloid peptides. It is believed inhibitors were the first agents to be approved by the that inhibition of this enzyme would decrease beta- FDA in the treatment of AD and include donepezil, amyloid production. Past research strategies have rivastigmine, galantamine and tacrine. All of these focused on selective inhibitors of gamma-secretase, are indicated for mild-to-moderate symptoms of AD. but these have resulted in the accumulation of a Donepezil is also indicated for moderate-to-severe potential neurotoxin; therefore, much of the focus symptoms and is available as an orally disintegrating has shifted to BACE. Some research findings involv- tablet for patients who have trouble swallowing. A ing BACE inhibitors have found that when covalently transdermal patch is an alternative to oral dosing in linked to a peptide that promoted transport into the patients taking rivastigmine. Tacrine is rarely used in brains of mice, levels of beta-amyloid in plasma and current therapeutic regimens due to its rigid dosing brain were significantly lower post-intraperitoneal schedule and potential for causing hepatotoxicity administration. Such a result suggests that an orally [83,85]. active BACE inhibitor able to cross the blood–brain N-methyl-d-aspartic acid (NMDA) antagonists barrier would lower beta-amyloid levels in the brain. have been the most recent agents to be approved for The key feature of the most active BACE inhibitors is treating AD. The drug memantine is indicated in the the ability to mimic a transition state at the active site, treatment of moderate-to-severe symptoms of AD. It thus conferring low nanomolar potency [83,88]. is surmised that by blocking the NMDA receptor, Glycogen synthase kinase-3 (GSK-3) is a proline- over-stimulation of the glutamatergic system is pre- directed serine/threonine kinase that is involved in vented. Because excess glutamate has been shown the phosphorylation of a number of substrates affect- to lead to destruction of cholinergic neurones, the ing numerous cellular functions. GSK-3 inhibition reduced levels of glutamate may prevent neurotoxic- has become a subject of interest because of its role in ity without interfering with the role of glutamate in the phosphorylation of tau protein which, in turn, is normal memory [83,85]. directly involved in beta-amyloid formation. Chal- It is important to note that existing therapies do lenges involved in developing an effective GSK-3 not reverse the progression of AD, but only slow the inhibitor will be those of selectivity and the ability worsening of symptoms and improve quality of life. to cross the blood–brain barrier. Because GSK-3 is A principal thrust of current research seeks to inves- involved in many cellular processes, the issue of selec- tigate ways to prevent, slow or possibly cure AD. tivity will be very important, especially to avoid toxic- Muscarinic agonists (especially M1 muscarinic ity in a clinical setting. Two classes of compounds that receptor agonists) have been of interest in the fight have been prominent in the literature surrounding against AD because they may prevent beta-amyloid GSK-3 inhibition are the indirubins and maleimides. formation via activation of alpha-secretase. If ulti- While both classes have shown activity in kinase inhi- mately effective, these agents would have the potential bition, finding a GSK-3 specific inhibitor has been to treat memory deficits as well as halt the disease challenging work. To date, neither class has a repre- process itself. Although none is currently marketed sentative GSK-3 specific agent ready to enter the for AD, several muscarinic agonists have shown market. It is interesting to note that other established promise and are under investigation. Xanomeline, drugs may have the added mechanism of GSK-3 inhi- CDD-0102A, cevimeline and talsaclidine are M1 bition as part of their pharmacological activity. agonists currently under investigation. In 2009, the Donepezil, currently marketed as an AChE inhibitor, FDA allowed further clinical development of CDD- was shown to reduce tau phosphorylation in a study 0102A to take place. At last report, the compound using primary cortical neurone cultures treated with was in clinical trials and re-designated as MCD-386. donepezil and challenged with beta-amyloid. This Cevimeline has been used in the treatment of xeros- result suggests GSK-3 inhibition as a potential mech- tomia (i.e. dry mouth) associated with Sjögren’s syn- anism. Olanzapine, an atypical antipsychotic agent, drome, but its selectivity for muscarinic receptors is has demonstrated GSK-3 inhibition in the brains of of great interest in AD. Interestingly, both cevimeline mice and has since been shown to be a potent inhibi- and talsaclidine have shown the ability to promote tor of GSK-3 (beta isoform). Other existing drugs clearance of beta-amyloid from the cerebrospinal of interest as GSK-3 inhibitors include cimetidine, fluid of AD patients [86,87]. hydroxychloroquine and gemifloxacin [88,89]. Beta-secretase (BACE) is an aspartic protease that To date, current therapies in the treatment of AD cleaves the type I transmembrane amyloid precursor have only been able to address the symptoms of the 16 Chapter 1 disease rather than its underlying aetiology. Contin- Angiotensin converting enzyme (ACE) inhibitors ued research and emphasis on development of com- and angiotensin II receptor blockers (ARBs) have pounds that can combat the biological mechanisms long been prescribed for management of hyper­ seen in AD are of greatest importance. Specifically, tension. The renin–angiotensin–aldosterone system research focused on medicinal agents that can prevent regulates blood pressure; ACE inhibitors interrupt the the formation of neuritic plaques or neurofibrillary conversion of angiotensin I to angiontesin II to mini- tangles (or hasten their clearance) is key in the fight mise vasoconstriction and prevent high blood pres- against AD. sure. Aliskiren, introduced in 2007, represents a first-in-class treatment for its direct suppression of Cardiovascular disease renin upstream of the ACE/ARBs [97,98]. Aliskiren is Two new medicines were approved for treatment of differentiated from existing treatments by its long atrial fibrillation (AF) which accounts for approxi- duration of action (24-hour half-life) and reduction mately 35% of arrhythmia-related hospitalisations in in the incidence of side effects (e.g. angioedema and the USA annually. In combination with electrical car- coughing). However, high doses of aliskiren can result dioversion, anti-arrhythmic drugs are used to main- in diarrhoea. By contrast, clevipidene is a very short tain a normal sinus rhythm. The standard of care for duration vasodilator used primarily for urgent treat- AF is amiodarone, whose efficacy is believed to arise ment of hypertension during surgery [99,100]. Intro- from a combination of effects. It has been shown to duced is 2008, clevipidine is a calcium channel prolong certain cardiac action potentials, possess ion blocker administered intravenously and is so rapidly channel effects – both sodium and potassium – and eliminated from the bloodstream that the dose can be bind to the nuclear thyroid receptor. Undoubtedly, titrated against the patient’s blood pressure. In prac- these combinations of activities contribute to its use- tice, the target blood pressure is reached within 30 fulness, but also to its side effects. These include inter- minutes of administration. Common side effects stitial lung disease, pulmonary fibrosis and abnormal include nausea, vomiting and headaches. thyroid function, due to high iodine content. Dron- Hereditary angioedema is a rare but potentially edarone , an analogue of amiodarone, was introduced life-threatening disorder when swelling occurs in the in 2009. It is a potassium ion channel blocker that upper airway. Two new drugs for treatment of heredi- has lower efficacy but fewer side effects than amio- tary angioedema were introduced: ecallantide (2010, darone [90]. The reductions in side effects are related a 60 amino acid recombinant protein) [101,102] to reduced lipophilicity, reduced half-life and the and icatabant (2008, a peptidomimetic) [103,104]. absence of iodine in dronedarone. Vernakalant is also Both work to control bradykinin which, when present a potassium channel blocker which was introduced in elevated concentrations, leads to vasodilation for treatment of AF in Europe in 2010 [91–94]. Ver- and hypotension. Icatabant is a selective β2 receptor nakalant has been used successfully to treat 51% of antagonist while ecallantide inhibits plasma kal- patients with short duration paroxysmal AF (up to 7 likrein, an immediate precursor of bradykinin, in the days) but is far less effective (8% of patients) in treat- renin–angiotensin–aldosterone system system. ment of persistent AF. Three new treatments have recently been launched In the field of lipidaemia there has been relatively for the treatment of atherothrombotic events associ- little progress in terms of newly approved drugs. ated with acute coronary syndrome. Rivaroxaban Choline fenofibrate was introduced in 2008 and is (2008) is a highly potent inhibitor of factor Xa which used in combination with a statin to increase levels is responsible for the conversion of prothrombin to of high-density lipoprotein cholesterol and lower thrombin during coagulation [105,106]. Prasugrel concentrations of triglycerides in patients with mixed (2009) is employed for antiplatelet therapy and is a dyslipidaemia and coronary heart disease [95,96]. As third generation thienopyridine following in the a stand alone treatment it is indicated for patients footsteps of clopidogrel [107,108]. Prasugrel inhibits with severe hypertriglyceridaemia. Choline fenofi- platelet aggregation and is 10 times more efficacious brate is a salt form of fenofibric acid, an active metab- than clopidogrel. Thienopyridine drugs irreversibly olite of fenofibrate which was previously marketed bind to the P2Y12 receptor. Ticagrelor (2010) differs for treatment of hypercholesterolaemia. As such, the in that it is reversibly bound to the same receptor and mechanism of action of choline fenofibrate is consist- as such the risk for uncontrolled bleeding is reduced ent with fenofibrate. [109,110]. Discovery of new medicines 17

Chronic obstructive pulmonary disease inflammatory process. Roflumilast is indicated for Chronic obstructive pulmonary disease (COPD) is a maintenance treatment of severe COPD associated chronic inflammatory disease that is characterised with chronic bronchitis in adult patients with a by increased numbers of neutrophils, macrophages history of frequent exacerbations as an add on to and T lymphocytes [111] present in the proximal bronchodilator treatment [131,132]. airways, lung parenchyma and lung vasculature Pharmacological therapy is used to prevent and [112]. Repeated injury and repair leads to progressive control symptoms, reduce the frequency and severity structural changes that increase with disease severity of exacerbations, improve health states and improve [113]. COPD was ranked as the sixth leading cause of exercise tolerance in patients with COPD. While death worldwide in 1990 and is projected to be the existing drugs do not modify the long-term decline fourth leading cause of death by 2030 because of an in lung function or disease progression [133], these increase in smoking rates and demographic changes shortcomings should not preclude efforts to use med- in many countries [114]. ications to prevent or reduce symptoms. Bronchodilator medications are central to the symptomatic treatment of COPD [115–118]. They Diabetes are given either on an as-needed basis for relief of Diabetes mellitus is a group of metabolic diseases for persistent or worsening symptoms or on a regular which there is no true cure; however, all forms of the basis to prevent or reduce symptoms. Acute applica- disease are treatable. The administration of insulin tion of inhaled glucocorticosteroids is appropriate through external sources, the preferred treatment for for patients with severe COPD accompanied by type 1 diabetes, aids the body in processing blood repeated exacerbations [119–122]; however, chronic glucose levels by providing a source of the hormone treatment is discouraged because of a plethora of that is, in many cases, no longer secreted by the potential side effects including neutrophilia, hyperg- pancreas. Because of the structural nature of insulin lycaemia, immunodeficiency and steroid myopathy, and the related peptidic hormone amylin, oral which contributes to respiratory failure in advanced administration of hormone-based drugs is ineffec- COPD cases [123–125]. Recently, two new molecular tive: peptide-based drugs typically have poor phar- entities received regulatory approval from the FDA macokinetic and ADMET properties. Therefore, and European Medicines Agency (EMA). A new drugs in this class are chiefly injectables, although bronchodilator approved for COPD, indacaterol acts recent years have seen advances in formulations that as an agonist on the β2-adrenoceptor. This agonism offer hope for the development of oral insulin [134]. causes smooth muscle relaxation resulting in dilation The vast majority of diabetes patients present with of bronchial passages [126,127]. Indacaterol is an type 2 disease, where insulin levels may be insufficient ultra-long-acting agent with duration of action suit- to diminish the blood sugar concentration of patients. able for once-a-day dosing. It is supplied as the Those with type 2 diabetes are treated with a variety maleate salt in an aerosol formulation and is admin- of pharmaceuticals developed specifically to combat istered via a dry powder device [128]. Recently the disease, which include combinations of newer approved for COPD, the anti-inflammatory roflumi- medications with older therapeutics [135]. Attributes last is a selective, orally active PDE-4 inhibitor. The of non-related classes of therapeutics have positioned selectivity observed with roflumilast is in contrast these entities for the treatment of type 2 diabetes as to long-used theophylline, a non-selective PDE in­­ well. For example, colesevelam, a bile acid seques- hibitor, and is reflected in the improved side effect trant, proved to lower blood sugar levels and was profile of roflumilast. Interestingly, the improvement approved by the FDA in 2008; the orally administered observed with roflumilast may be brought about by drug is not absorbed by the body and therefore must an appropriate balance between binding at low- and function within the digestive tract [136]. Another high-affinity sites on PDE-4 and not simply isozyme such example, approved in 2009, is bromocriptine, a specificity [111,129]. PDE-4 is expressed in several powerful D2 dopamine receptor agonist that lowers tissue types involved in diseases of the airway and is blood sugar levels in patients. [137]. known to have a role in inflammation [130]. Inhibi- Glucagon-like peptide 1 (GLP-1) is a digestive pro- tion of PDE-4 blocks the hydrolysis of cyclic adeno- hormone secreted by L cells found in the intestinal sine monophosphate (cAMP), leading to elevated wall and metabolised into the active forms GLP-1- levels of cAMP, which in turn downregulates the (7-37) and GLP-1-(7-36), all of which are under 18 Chapter 1 investigation as therapeutics for type 2 diabetes. during testing of saxagliptin [141]. Linagliptin, GLP-1 seems to retard apoptosis of pancreatic β-cells another DPP-4 inhibitor, emerged in 2011. Again, thereby increasing the secretion of insulin, as needed, based upon studies of the toxicity of linagliptin, during postprandial periods; unfortunately, the active the beneficial affects outweighed the small risk of forms of GLP-1 are very short-lived in the body with tumour development associated with the class of an estimated half-life of less than 2 minutes [138]. molecules [142]. GLP-1 (and its active forms) not only upregulate insulin secretion, but they also slow ‘gut emptying’ Osteoporosis which delays the digestion and uptake of carbohy- Osteoporosis is a disease characterised by low bone drates after eating. This effect promotes satiety thus mass and structural deterioration of bone tissue delaying the desire to eat and subsequent need for that gradually weakens bones and often leads to insulin production. In 2010, a GLP-1 mimic, liraglu- painful and debilitating fractures. [143–148] Bone tide, was approved by the FDA for use in patients with remodelling, the process through which bone tissue type 2 diabetes in the USA; it had been previously continuously renews and changes, is essential for approved for use in Europe in 2009. Liraglutide is a adult bone homeostasis. The remodelling cycle con- mimetic of human GLP-1-(7-37) that has been modi- sists of two distinct stages: bone resorption and bone fied through the addition of a fatty acid residue to the formation. During bone resorption, surface osteo- peptidic backbone of the hormone. This change pro- clasts dissolve bone tissue and create small cavities. motes binding with albumin in the bloodstream and During bone formation, osteoblasts then refill these subcutaneous tissues resulting in sequestration that cavities with new bone tissue. The failure or disrup- extends the half-life of the drug to nearly 12 hours. tion of this process often leads to the development of Liraglutide is released from the albumin at a slow osteoporosis [149]. Progress in understanding the steady pace to maintain insulin concentration at effi- bone remodelling process has been at the core of cacious levels [139]. efforts leading to the discovery of drugs for the treat- Entities with modes of action related to human ment of osteoporosis [150]. These drugs may stimu- GLP-1 are also of interest. Exenatide is a synthetic late bone formation, such as teriparatide, or may form of exendin-4, a hormone found in the saliva of retard bone resorption, such as the selective oestro- Gila monsters, which stimulates pancreatic activity. gen receptor modulator raloxifene and salmon calci- Exenatide has approximately 50% amino acid homol- tonin products. ogy to human GLP-1 and displays a prolonged in vivo Bisphosphonates have been the drugs of choice for half-life. In 2005, exenatide was approved as an inject- preventing and treating osteoporosis over the last 20 able medication for the treatment of type 2 diabetes; years [151]. Studies indicate that these drugs are it was originally used in conjunction with other oral effective and safe for at least 10 years but note that drugs for the control and treatment of elevated blood bone loss does continue, albeit at a reduced rate. This glucose concentration. continued loss is believed to result from the interrup- While increasing the amount of GLP-1 or mimick- tion of bone remodelling which ultimately impairs ing its mode of action in the body achieves the desired the bone formation portion of the process [152]. affects for treatment of type 2 diabetes, another tactic Complications have been reported with prolonged that has gained momentum is to prevent the metabo- use of bisphosphonate drugs. The most serious, but lism of GLP-1. It has been shown that dipeptidyl rare, side effects are bone loss in the jaw (osteonecro- peptidase-4 (DPP-4) is critical in the degradation of sis) [152], a possible increase in the risk of unusual GLP-1 and inhibitors of DPP-4 therefore prolong the fractures of the thigh bones (femur) and atrial fibril- half-life of active forms of GLP-1 in the bloodstream. lation [153,154]. In general, the benefits of bisphos- Recently, small molecules that modulate DPP-4 have phonates outweigh the risks they present. Nonetheless, been developed to delay the breakdown of hormones the FDA continues to monitor the long-term effects crucial to the stimulation of pancreatic β-cells. These of this important class of therapeutics. drugs not only increase serum GLP-1 levels, but they Denosumab was approved by the FDA in 2010 for also can be administered orally [123–125]. The first the treatment of osteoporosis. It has a novel mecha- of the DPP-4 inhibitors, sitagliptin, was released in nism of action, improved dosing convenience and 2006 [140], with saxagliptin following in 2009. While provides an alternative to bisphosphonate drugs. there is a risk that DPP-4 inhibitors do promote pro- Denosumab is the first human monoclonal antibody gression of some cancers, few side effects were noted that inhibits the formation, function and survival of