Preface xvii Part I General Aspects 1 1 New Trends in Drug Discovery 3 Gerd Schnorrenberg 1.1 Introduction 3 1.1.1 Analysis of New Molecular Entities Approved in 2015 3 1.2 New Trends in NCE Discovery 7 1.3 Enhanced Lead Generation Strategies 7 1.3.1 Analogue Approach 9 1.

3.2 High Throughput Screening (HTS) 9 1.3.3 Structure-Based Design 11 1.3.4 Virtual Screening 12 1.3.5 Fragment-Based Lead Discovery 13 1.

3.6 Repositioning 14 1.3.7 Additional New Trends in Hit/Lead Generation 15 1.4 Early Assessment of Development Aspects during Drug Discovery 16 1.4.1 DMPK 17 1.4.

2 Assessment of Physicochemical Parameters 18 1.4.3 Tolerability Assessment 19 1.5 New Biological Entities (NBEs) 19 1.5.1 Antibody Engineering to Reduce Immunogenicity 23 1.5.2 Progress in Antibody Production and Engineering of Physicochemical Properties 24 1.

5.3 Engineering to Improve Efficacy 25 1.5.4 New Formats 26 1.5.4.1 Antibody-Drug Conjugates 26 1.5.

4.2 Bispecific Antibodies 28 1.6 General Challenges in Drug Discovery 30 1.7 Summary 31 Acknowledgments 31 List of Abbreviations 31 References 32 2 Patenting Small and Large Pharmaceutical Molecules 41 Uwe Albersmeyer, Ralf Malessa, and Ulrich Storz 2.1 The Role of Patents in the Pharmaceutical Industry 41 2.2 Classification of Active Pharmaceutical Ingredient Grouping 42 2.3 Patentability Criteria and Patentable Embodiments 43 2.3.

1 Patent Eligibility and Patentability 43 2.3.2 Patent Eligibility of Molecules 43 2.3.2.1 Small Molecules and Peptides 44 2.3.2.

2 Molecules Isolated from Nature 44 2.3.3 Novelty 44 2.3.3.1 Novelty of Molecules that are More or Less Identical to Molecules from the Human Body 46 2.3.4 Inventive Step/Non-Obviousness 47 2.

3.5 Patentability Criteria and Patentable Embodiments in Biopharmaceutics 47 2.3.5.1 Different Types of Biopharmaceutics 47 2.3.5.2 Monoclonal Antibodies 48 2.

3.5.3 Nucleic Acid-Based Therapeutics 49 2.4 Patent Term Extensions and Adjustments, Supplementary Protection Certificates, and Data Exclusivity in Biopharmaceutics 49 2.4.1 Introduction 49 2.4.2 Patent Lifetime 49 2.

4.2.1 Patent Term Adjustment (PTA) 50 2.4.2.2 Patent Term Extension (PTE) and Supplementary Protection Certificates (SPC) 50 2.4.2.

3 Pediatric Investigations (EU) 52 2.4.3 Exclusivity Privileges Related to Regulatory Procedures 53 2.4.3.1 Data Exclusivity and Market Exclusivity 53 2.4.3.

2 Orphan Drugs 54 2.5 Patent Lifecycle Management 57 2.5.1 Formulations and/or Galenics 57 2.5.2 Combination Products 57 2.5.3 Second or Higher Medical Indication 58 2.

5.4 New Dosage Regimens 59 2.5.5 Further Options for Small Molecules 59 2.5.6 Divisional Applications 60 2.6 Conclusion 60 List of Abbreviations 60 References 61 Part II Drug Class Studies 65 3 Kinase Inhibitor Drugs 67 Peng Wu and Amit Choudhary 3.1 Introduction 67 3.

2 Historical Overview 70 3.2.1 Before 1980 70 3.2.2 1980s 70 3.2.3 1990s 70 3.2.

4 After 2000 72 3.3 Approved Kinase Inhibitors 72 3.3.1 FDA-Approved Non-Covalent Small-Molecule Kinase Inhibitors 74 3.3.1.1 Bcr-Abl Inhibitors 74 3.3.

1.2 ErbB Family Inhibitors 77 3.3.1.3 VEGFR Family Inhibitors 77 3.3.1.4 JAK Family Inhibitors 78 3.

3.1.5 ALK Inhibitors 78 3.3.1.6 MET Inhibitors 78 3.3.1.

7 B-Raf Inhibitors 79 3.3.1.8 MEK Inhibitors 79 3.3.1.9 PI3K Inhibitor 79 3.3.

1.10 CDK Inhibitor 80 3.3.2 FDA Approved Covalent Small Molecule Kinase Inhibitors 80 3.3.3 FDA-Approved Rapalogs 80 3.3.4 Other Approved Kinase Inhibitors 81 3.

4 New Directions 82 3.5 Conclusion 83 List of Abbreviations 83 References 83 4 Evolution of Nonsteroidal Androgen Receptor Antagonists 95 Arwed Cleve and Duy Nguyen 4.1 Introduction 95 4.2 Flutamide (Eulexin®) 96 4.3 Nilutamide (Anandron®) 98 4.4 Bicalutamide (Casodex®) 99 4.5 Enzalutamide (Xtandi®) 102 4.6 Outlook 106 4.

7 Conclusion 106 List of Abbreviations 106 References 107 Part III Case Studies 111 5 Development of T-Cell-Engaging Bispecific Antibody Blinatumomab (Blincyto®) for Treatment of B-Cell Malignancies 113 Patrick A. Baeuerle 5.1 Introduction 113 5.1.1 Brief History of Bispecific Antibodies 114 5.1.2 History of T-Cell-Engaging Antibodies 115 5.1.

3 History and Design of Blinatumomab 116 5.1.4 Blinatumomab Mode of Action 117 5.1.5 Manufacturing of Blinatumomab 118 5.1.6 Clinical Development of Blinatumomab 118 5.1.

7 Administration of Blinatumomab 120 5.1.8 Side Effects of Blinatumomab 121 5.2 Discussion 122 5.2.1 Other BiTETM Antibodies in Development 124 5.2.2 Blinatumomab versus CD19 CAR-T Cell Therapy 125 5.

3 Summary 126 List of Abbreviations 126 References 127 6 Ceritinib: A Potent ALK Inhibitor for the Treatment of Crizotinib-Resistant Non-Small Cell Lung Cancer Tumors 131 Pierre-Yves Michellys 6.1 Introduction 131 6.2 Drug Design and Strategy 134 6.3 Synthesis of Ceritinib 135 6.4 In Vitro Evaluation of Ceritinib 136 6.5 In Vitro ADME Evaluation of Ceritinib 137 6.6 Preclinical Pharmacokinetic Evaluation of Ceritinib 138 6.7 In Vivo Evaluation of Ceritinib 138 6.

8 Evaluation of Ceritinib in Crizotinib-Resistance Mutations 140 6.9 Mouse Model of Crizotinib-Resistant Tumors 141 6.10 Clinical Phase I Evaluation of Ceritinib 143 6.11 Conclusion 146 List of Abbreviations 146 References 146 7 Discovery, Development, and Mechanisms of Action of the Human CD38 Antibody Daratumumab 153 Maarten L. Janmaat, Niels W.C.J. van de Donk, Jeroen Lammerts van Bueren, Tahamtan Ahmadi, A.

Kate Sasser, Richard K. Jansson, Henk M. Lokhorst, and Paul W.H.I. Parren 7.1 Introduction 153 7.2 CD38: The Target 154 7.

2.1 CD38 as a Therapeutic Target 154 7.2.2 CD38 Function 154 7.2.3 CD38 Expression in Normal Tissue 155 7.2.4 CD38 Expression in Cancer 155 7.

3 Discovery of Daratumumab 156 7.4 Daratumumab Combines Multiple Mechanism of Actions 157 7.4.1 Complement-Dependent Cytotoxicity (CDC) 157 7.4.2 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) 158 7.4.3 Antibody-Dependent Cellular Phagocytosis (ADCP) 158 7.

4.4 Programmed Cell Death (PCD) 159 7.4.5 Enzymatic Modulation 159 7.4.6 Immunomodulation 160 7.5 Single-Agent Antitumor Activity of Daratumumab in Multiple Myeloma 160 7.5.

1 Monotherapy Studies with Daratumumab 163 7.5.2 Factors That Predict Response to Daratumumab 164 7.5.3 Daratumumab in Other Plasma Cell Dyscrasias 164 7.5.4 Subcutaneous Delivery of Daratumumab 165 7.5.

5 Interference of Daratumumab in Clinical Laboratory Assays 165 7.6 Daratumumab-Based Combination Therapies in Multiple Myeloma 166 7.6.1 Preclinical Combination Studies 167 7.6.2 Clinical Combination Studies 168 7.7 Potential of Daratumumab Outside Multiple Myeloma 171 7.7.

1 Other Hematologic Malignancies 171 7.7.2 Solid Tumors 171 7.7.3 Autoimmune Disorders 172 7.8 Conclusions and Future Perspectives 173 7.9 Summary 175 List of Abbreviations 176 References 178 8 The Discovery of Obeticholic Acid (OcalivaTM): First-in-Class FXR Agonist 197 Roberto Pellicciari, Mark Pruzanski, and Antimo Gioiello 8.1 Introduction 197 8.

2 Bile Acids in Health and Disease 197 8.2.1 Structure and Properties of Natural Bile Acids 197 8.2.2 Physiology 200 8.2.3 Bile Acids as Therapeutic Agents 202 8.3 The Early Bile Acid Medicinal Chemistry Program at the University of Perugia 204 8.

4 The Breakthrough (1999): Bile Acids Are the Endogenous Ligands of the Farnesoid X Receptor (FXR) 210 8.5 Discovery of 6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA, INT-747, Obeticholic Acid) 214 8.5.1 Design, Synthesis, and Structure-Activity Relationships of C6-Modified CDCA Derivatives 214 8.5.2 Scale-Up Synthesis of Obeticholic Acid 220 8.6 Properties and Preclinical Studies of Obeticholic Acid 222 8.6.

1 Physicochemical Properties, Pharmacokinetics, and Metabolism 222 8.6.2 OCA in Preclinical Models of Liver Diseases 225 8.7 Obeticholic Acid (OcalivaTM) for the Treatment of Primary Biliary Cholangitis (PBC): Phases I-III Clinical Studies to Establish Clinical Efficacy 228 8.8 Conclusions and Future Directions 230 List of Abbreviations 231 References 232 9 Discovery and Development of Obinutuzumab (GAZYVA, GAZYVARO), a Glycoengineered Type II Anti-CD20 Antibody for the Treatment of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia 245 Christian Klein, Ekkehard Mössner, Marina Bacac, Günter Fingerle-Rowson, and Pablo Umaña 9.1 Introduction 245 9.2 Preclinical Experience with Obinutuzumab 246 9.2.

1 Characteristics and Mechanisms of Action of Type I and Type II CD20 Antibodies 246 9.2.2 Obinutuzumab Development, Chemistry, and Production 247 9.2.3 CD20 Binding by Obinutuzumab 248 9.2.4 Complement-Dependent Cytotoxicity 249<.