Attrition in the Pharmaceutical Industry – Reasons ,Implications, and Pathways Forward

<p>Contributors xiii<br /><br />Introduction 1<br />Alexander Alex C. John Harris and Dennis A. Smith<br /><br />References 4<br /><br />1 Attrition in Drug Discovery and Development 5<br />Scott Boyer Clive Brealey and Andrew M. Davis<br /><br />1.1 The Graph 5<br /><br />1.2 The Sources of Attrition 7<br /><br />1.3 Phase II Attrition 9<br /><br />1.3.1 Target Engagement 11<br /><br />1.3.2 Clinical Trial Design 11<br /><br />1.4 Phase III Attrition 12<br /><br />1.4.1 Safety Attrition in Phase III 14<br /><br />1.5 Regulation and Attrition 17<br /><br />1.6 Attrition in Phase IV 19<br /><br />1.7 First in Class Best in Class and the Role of the Payer 32<br /><br />1.8 Portfolio Attrition 34<br /><br />1.9 Avoiding Attrition 36<br /><br />1.9.1 Drug Combinations and New Formulations 36<br /><br />1.9.2 Biologics versus Small Molecules 37<br /><br />1.9.3 Small –Molecule Compound Quality 38<br /><br />1.10 Good Attrition versus Bad Attrition 39<br /><br />1.11 Summary 40<br /><br />References 42<br /><br />2 Compound Attrition at the Preclinical Phase 46<br />Cornelis E.C.A. Hop<br /><br />2.1 Introduction: Attrition in Drug Discovery and Development 46<br /><br />2.2 Target Identification HTS and Lead Optimization 50<br /><br />2.3 Resurgence of Covalent Inhibitors 55<br /><br />2.4 In Silico Models to Enhance Lead Optimization 56<br /><br />2.5 Structure –Based and Property –Based Compound Design in Lead Optimization 59<br /><br />2.5.1 Risks Associated with Operating in Nondrug –Like Space 62<br /><br />2.6 Attrition Due to ADME Reasons 64<br /><br />2.6.1 Metabolism Bioactivation and Attrition 68<br /><br />2.6.2 PK/PD Modeling in Drug Discovery to Reduce Attrition 69<br /><br />2.6.3 Human PK Prediction Uncertainties 70<br /><br />2.7 Attrition Due to Toxicity Reasons 72<br /><br />2.8 Corporate Culture and Nonscientific Reasons for Attrition 75<br /><br />2.9 Summary 76<br /><br />References 76<br /><br />3 Attrition in Phase I 83<br />Dennis A. Smith and Thomas A. Baillie<br /><br />3.1 Introduction 83<br /><br />3.2 Attrition in Phase I Studies and Paucity of Published Information 84<br /><br />3.3 Drug Attrition in not FIH Phase I Studies 85<br /><br />3.4 Attrition in FIH Studies Due to PK 86<br /><br />3.4.1 Attrition due to Pharmacogenetic Factors 88<br /><br />3.5 Attenuation of PK failure 90<br /><br />3.5.1 Preclinical Methods (In Vivo) 90<br /><br />3.5.2 Preclinical Methods (In Vitro) 91<br /><br />3.5.3 Phase 0 Microdose Studies in Humans 92<br /><br />3.5.4 Responding to Unfavorable PK Characteristics 94<br /><br />3.6 Phase I Oncology Studies 95<br /><br />3.7 Toleration and Attrition in Phase I Studies 97<br /><br />3.7.1 Improving the Hepatic Toleration of Compounds 98<br /><br />3.7.2 Rare Severe Toxicity in Phase I Studies 98<br /><br />3.8 Target Occupancy and Go/No ]Go Decisions to Phase II Start 99<br /><br />3.9 Conclusions 102<br /><br />References 102<br /><br />4 Compound Attrition in Phase II/III 106<br />Alexander Alex C. John Harris Wilma W. Keighley and Dennis A. Smith<br /><br />4.1 Introduction 106<br /><br />4.2 Attrition Rates: How Have they Changed? 107<br /><br />4.3 Why do Drugs Fail in Phase II/III? Lack of Efficacy or Marginal Efficacy Leading to Likely Commercial <br />Failure 108<br /><br />4.4 Toxicity 111<br /><br />4.5 Organizational Culture 112<br /><br />4.6 Case Studies for Phase II/III Attrition 112<br /><br />4.6.1 Torcetrapib 112<br /><br />4.6.2 Dalcetrapib 113<br /><br />4.6.3 Onartuzumab 114<br /><br />4.6.4 Bapineuzumab 115<br /><br />4.6.5 Gantenerumab 115<br /><br />4.6.6 Solanezumab 116<br /><br />4.6.7 Pomaglumetad Methionil (LY ]2140023) 116<br /><br />4.6.8 Dimebon (Latrepirdine) 117<br /><br />4.6.9 BMS ]986094 117<br /><br />4.6.10 TC ]5214 (S ]Mecamylamine) 118<br /><br />4.6.11 Olaparib 118<br /><br />4.6.12 Tenidap 119<br /><br />4.6.13 NNC0109 ]0012 (RA) 120<br /><br />4.6.14 Omapatrilat 120<br /><br />4.6.15 Ximelagatran 121<br /><br />4.7 Summary and Conclusions 122<br /><br />References 123<br /><br />5 Postmarketing Attrition 128<br />Dennis A. Smith<br /><br />5.1 Introduction 128<br /><br />5.2 On –Target Pharmacology –Flawed Mechanism 130<br /><br />5.2.1 Alosetron 130<br /><br />5.2.2 Cerivastatin 130<br /><br />5.2.3 Tegaserod 133<br /><br />5.3 Off –Target Pharmacology Known Receptor: An Issue of Selectivity 135<br /><br />5.3.1 Fenfluramine and Dexfenfluramine 135<br /><br />5.3.2 Rapacuronium 136<br /><br />5.3.3 Astemizole Cisapride Grepafloxacin and Thioridazine 138<br /><br />5.4 Off –Target Pharmacology Unknown Receptor: Idiosyncratic Toxicology 142<br /><br />5.4.1 Benoxaprofen 142<br /><br />5.4.2 Bromfenac 142<br /><br />5.4.3 Nomifensine 143<br /><br />5.4.4 Pemoline 144<br /><br />5.4.5 Remoxipride 144<br /><br />5.4.6 Temafloxacin 145<br /><br />5.4.7 Tienilic acid 145<br /><br />5.4.8 Troglitazone 146<br /><br />5.4.9 Tolcapone 146<br /><br />5.4.10 Trovafloxacin 147<br /><br />5.4.11 Valdecoxib 148<br /><br />5.4.12 Zomepirac 148<br /><br />5.5 Conclusions 150<br /><br />References 151<br /><br />6 Influence of the Regulatory Environment on Attrition 158<br />Robert T. Clay<br /><br />6.1 Introduction 158<br /><br />6.1.1 How the Regulatory Environment has Changed Over the Last Two Decades 159<br /><br />6.1.2 Past and Current Regulatory Attitude to Risk Analysis and Risk Management 161<br /><br />6.2 Discussion 162<br /><br />6.2.1 What Stops Market Approval? 162<br /><br />6.2.2 Impact of Black Box Warnings 166<br /><br />6.2.3 Importance and Impact of Pharmacovigilance 167<br /><br />6.2.4 Prospects of Market Withdrawals for New Drugs 168<br /><br />6.2.5 What are the Challenges for the Industry Given the Current Regulatory Environment? 173<br /><br />6.2.6 Future Challenges for Both Regulators and the Pharmaceutical Industry 174<br /><br />6.3 Conclusion 175<br /><br />References 176<br /><br />7 Experimental Screening Strategies to Reduce Attrition Risk 180<br />Marie –Claire Peakman Matthew Troutman Rosalia Gonzales and Anne Schmidt<br /><br />7.1 Introduction 180<br /><br />7.2 Screening Strategies in Hit Identification 183<br /><br />7.2.1 Screening Strategies and Biology Space 183<br /><br />7.2.2 Screening Strategies and Chemical Space 187<br /><br />7.2.3 High –Throughput Screening Technologies 191<br /><br />7.2.4 Future Directions for High –Throughput Screening 194<br /><br />7.3 Screening Strategies in Hit Validation and Lead Optimization 194<br /><br />7.4 Screening Strategies for Optimizing PK and Safety 197<br /><br />7.4.1 High –Throughput Optimization of PK/ADME Profiles 198<br /><br />7.4.2 Early Safety Profiling 202<br /><br />7.4.3 Future Directions for ADME and Safety in Lead Optimization 204<br /><br />7.5 Summary 205<br /><br />References 206<br /><br />8 Medicinal Chemistry Strategies to Prevent Compound Attrition 215<br />J. Richard Morphy<br /><br />8.1 Introduction 215<br /><br />8.2 Picking the Right Target 216<br /><br />8.3 Finding Starting Compounds 216<br /><br />8.4 Compound Optimization 218<br /><br />8.4.1 Drug –Like Compounds 218<br /><br />8.4.2 Structure –Based Drug Design 219<br /><br />8.4.3 The Thermodynamics and Kinetics of Compound Optimization 220<br /><br />8.4.4 PK 220<br /><br />8.4.5 Toxicity 222<br /><br />8.5 Summary 225<br /><br />References 226<br /><br />9 Influence of Phenotypic and Target ]Based Screening Strategies on Compound Attrition and Project Choice 229<br />Andrew Bell Wolfgang Fecke and Christine Williams<br /><br />9.1 Drug Discovery Approaches: A Historical Perspective 229<br /><br />9.1.1 Phenotypic Screening 229<br /><br />9.1.2 Target –Based Screening 230<br /><br />9.1.3 Recent Changes in Drug Discovery Approaches 231<br /><br />9.2 Current Phenotypic Screens 233<br /><br />9.2.1 Definition of Phenotypic Screening 233<br /><br />9.2.2 Recent Anti –infective Projects 233<br /><br />9.2.3 Recent CNS Projects 235<br /><br />9.3 Current Targeted Screening 237<br /><br />9.3.1 Definition of Targeted Screening 237<br /><br />9.3.2 Recent Anti –infective Projects 237<br /><br />9.3.3 Recent CNS Projects 239<br /><br />9.4 Potential Attrition Factors 241<br /><br />9.4.1 Technical Doability and Hit Identification 241<br /><br />9.4.2 Compound SAR and Properties 246<br /><br />9.4.3 Safety 248<br /><br />9.4.4 Translation to the Clinic 250<br /><br />9.5 Summary and Future Directions 252<br /><br />9.5.1 Summary of Impact of Current Approaches 252<br /><br />9.5.2 Future Directions 254<br /><br />9.5.3 Conclusion 255<br /><br />References 255<br /><br />10 In Silico Approaches to Address Compound Attrition 264<br />Peter Gedeck Christian Kramer and Richard Lewis<br /><br />10.1 In Silico Models Help to Alleviate the Process of Finding Both Safe and Efficacious Drugs 264<br /><br />10.2 Use of In Silico Approaches to Reduce Attrition Risk at the Discovery Stage 265<br /><br />10.3 Ligand –Based and Structure –Based Models 265<br /><br />10.4 Data Quality 268<br /><br />10.5 Predicting Model Errors 270<br /><br />10.6 Molecular Properties and their Impact on Attrition 272<br /><br />10.7 Modeling of ADME Properties and their Impact of Reducing Attrition in the Last Two Decades 275<br /><br />10.8 Approaches to Modeling of Tox 276<br /><br />10.9 Modeling PK and PD and Dose Prediction 276<br /><br />10.10 Novel In Silico Approaches to Reduce Attrition Risk 278<br /><br />10.11 Conclusions 280<br /><br />References 280<br /><br />11 Current and Future Strategies for Improving Drug Discovery Efficiency 287<br />Peter Mbugua Njogu and Kelly Chibale<br /><br />11.1 General Introduction 287<br /><br />11.2 Scope 288<br /><br />11.3 Neglected Diseases 289<br /><br />11.3.1 Introduction 289<br /><br />11.3.2 Control of NTDs 290<br /><br />11.3.3 Drug Discovery Potential of Neglected Diseases 290<br /><br />11.4 Precompetitive Drug Discovery 292<br /><br />11.4.1 Introduction 292<br /><br />11.4.2 Virtual Discovery Organizations 293<br /><br />11.4.3 Collaborations with Academic Laboratories 295<br /><br />11.4.4 CoE and Incubators 296<br /><br />11.4.5 Screening Data and Compound File Sharing 297<br /><br />11.5 Exploitation of Genomics 297<br /><br />11.5.1 Introduction 297<br /><br />11.5.2 Target Identification and Validation 298<br /><br />11.5.3 Target –Based Drug Discovery 298<br /><br />11.5.4 Phenotypic Whole –Cell Screening 301<br /><br />11.5.5 Individualized Therapy and Therapies for Special Patient Populations 302<br /><br />11.6 Outsourcing Strategies 304<br /><br />11.6.1 Introduction 304<br /><br />11.6.2 Research Contracting in Drug Discovery 305<br /><br />11.7 Multitarget Drug Design and Discovery 305<br /><br />11.7.1 Introduction 305<br /><br />11.7.2 Rationale for Multitargeted Drugs 306<br /><br />11.7.3 Designed Multitarget Compounds for Neglected Diseases 307<br /><br />11.8 Drug Repositioning and Repurposing 315<br /><br />11.8.1 Introduction 315<br /><br />11.8.2 Cell Biology Approach 317<br /><br />11.8.3 Exploitation of Genome Information 318<br /><br />11.8.4 Compound Screening Studies 318<br /><br />11.8.5 Exploitation of Coinfection Drug Efficacy 318<br /><br />11.8.6 In Silico Computational Technologies 319<br /><br />11.9 Future Outlook 319<br /><br />References 319<br /><br />12 Impact of Investment Strategies Organizational Structure and Corporate Environment on Attrition and Future Investment Strategies to Reduce Attrition 329<br />Geoff Lawton<br /><br />12.1 Attrition 329<br /><br />12.2 Costs 331<br /><br />12.2.1 The Costs of Creating a New Medicine 331<br /><br />12.2.2 The Costs of Not Creating a New Medicine 332<br /><br />12.3 Investment Strategies 334<br /><br />12.3.1 RoI 334<br /><br />12.3.2 Investment in a Portfolio of R&amp;D Projects 335<br /><br />12.3.3 Asset –Centered Investment 335<br /><br />12.3.4 Sources of Funds 336<br /><br />12.4 Business Models 337<br /><br />12.4.1 FIPCO 337<br /><br />12.4.2 Fully Integrated Pharmaceutical Network (FIPNET) 338<br /><br />12.4.3 Venture –Funded Biotech 339<br /><br />12.4.4 Fee –for –Service CRO 339<br /><br />12.4.5 Hybrids 339<br /><br />12.4.6 Academic Institute 340<br /><br />12.4.7 Social Enterprise 341<br /><br />12.5 Portfolio Management 341<br /><br />12.5.1 Portfolio Construction 341<br /><br />12.5.2 Project Progression 343<br /><br />12.5.3 The Risk Transition Point 343<br /><br />12.6 People 344<br /><br />12.6.1 Motivation 344<br /><br />12.6.2 Culture and Leadership 344<br /><br />12.6.3 Sustainability 344<br /><br />12.7 Future 345<br /><br />12.7.1 Business Structures 345<br /><br />12.7.2 Skilled Practitioners 347<br /><br />12.7.3 Partnerships 348<br /><br />12.7.4 A Personal View of the Future 349<br /><br />References 351<br /><br />Index 353&nbsp;</p>