With a focus on case studies of R&D programs in a variety of disease areas, the book highlights fundamental productivity issues the pharmaceutical industry has been facing and explores potential ways of improving research effectiveness and efficiency.
* Takes a comprehensive and holistic approach to the problems and potential solutions to drug compound attrition
* Tackles a problem that adds billions of dollars to drug development programs and health care costs
* Guides discovery and development scientists through R&D stages, teaching requirements and reasons why drugs can fail
* Discusses potential ways forward utilizing new approaches and opportunities to reduce attrition
Autorentext
Alexander Alex, Dr. rer. nat., is director of Evenor Consulting and has over 20 years' experience as consultant and as director and research fellow in drug discovery in the pharmaceutical industry.
C. John Harris, PhD, is the director of cjh Consultants and has a successful track record in drug discovery, research management, small company fund-raising and start-ups.
Dennis A. Smith, PhD, is an independent consultant with a long track record in drug discovery and development with an emphasis on metabolism and safety. He has published four books, including Pharmacokinetics and Metabolism in Drug Design (1st and 2nd editions) and Reactive Drug Metabolites published by Wiley.
Inhalt
Contributors xiii
Introduction 1
Alexander Alex C. John Harris and Dennis A. Smith
References 4
1 Attrition in Drug Discovery and Development 5
Scott Boyer Clive Brealey and Andrew M. Davis
1.1 The Graph 5
1.2 The Sources of Attrition 7
1.3 Phase II Attrition 9
1.3.1 Target Engagement 11
1.3.2 Clinical Trial Design 11
1.4 Phase III Attrition 12
1.4.1 Safety Attrition in Phase III 14
1.5 Regulation and Attrition 17
1.6 Attrition in Phase IV 19
1.7 First in Class Best in Class and the Role of the Payer 32
1.8 Portfolio Attrition 34
1.9 Avoiding Attrition 36
1.9.1 Drug Combinations and New Formulations 36
1.9.2 Biologics versus Small Molecules 37
1.9.3 Small?-Molecule Compound Quality 38
1.10 Good Attrition versus Bad Attrition 39
1.11 Summary 40
References 42
2 Compound Attrition at the Preclinical Phase 46
Cornelis E.C.A. Hop
2.1 Introduction: Attrition in Drug Discovery and Development 46
2.2 Target Identification HTS and Lead Optimization 50
2.3 Resurgence of Covalent Inhibitors 55
2.4 In Silico Models to Enhance Lead Optimization 56
2.5 Structure?-Based and Property?-Based Compound Design in Lead Optimization 59
2.5.1 Risks Associated with Operating in Nondrug?-Like Space 62
2.6 Attrition Due to ADME Reasons 64
2.6.1 Metabolism Bioactivation and Attrition 68
2.6.2 PK/PD Modeling in Drug Discovery to Reduce Attrition 69
2.6.3 Human PK Prediction Uncertainties 70
2.7 Attrition Due to Toxicity Reasons 72
2.8 Corporate Culture and Nonscientific Reasons for Attrition 75
2.9 Summary 76
References 76
3 Attrition in Phase I 83
Dennis A. Smith and Thomas A. Baillie
3.1 Introduction 83
3.2 Attrition in Phase I Studies and Paucity of Published Information 84
3.3 Drug Attrition in not FIH Phase I Studies 85
3.4 Attrition in FIH Studies Due to PK 86
3.4.1 Attrition due to Pharmacogenetic Factors 88
3.5 Attenuation of PK failure 90
3.5.1 Preclinical Methods (In Vivo) 90
3.5.2 Preclinical Methods (In Vitro) 91
3.5.3 Phase 0 Microdose Studies in Humans 92
3.5.4 Responding to Unfavorable PK Characteristics 94
3.6 Phase I Oncology Studies 95
3.7 Toleration and Attrition in Phase I Studies 97
3.7.1 Improving the Hepatic Toleration of Compounds 98
3.7.2 Rare Severe Toxicity in Phase I Studies 98
3.8 Target Occupancy and Go/No?]Go Decisions to Phase II Start 99
3.9 Conclusions 102
References 102
4 Compound Attrition in Phase II/III 106
Alexander Alex C. John Harris Wilma W. Keighley and Dennis A. Smith
4.1 Introduction 106
4.2 Attrition Rates: How Have they Changed? 107
4.3 Why do Drugs Fail in Phase II/III? Lack of Efficacy or Marginal Efficacy Leading to Likely Commercial
Failure 108
4.4 Toxicity 111
4.5 Organizational Culture 112
4.6 Case Studies for Phase II/III Attrition 112
4.6.1 Torcetrapib 112
4.6.2 Dalcetrapib 113
4.6.3 Onartuzumab 114
4.6.4 Bapineuzumab 115
4.6.5 Gantenerumab 115
4.6.6 Solanezumab 116
4.6.7 Pomaglumetad Methionil (LY?]2140023) 116
4.6.8 Dimebon (Latrepirdine) 117
4.6.9 BMS?]986094 117
4.6.10 TC?]5214 (S?]Mecamylamine) 118
4.6.11 Olaparib 118
4.6.12 Tenidap 119
4.6.13 NNC0109?]0012 (RA) 120
4.6.14 Omapatrilat 120