János Fischer is a Senior Research Scientist at Richter Plc., Budapest, Hungary. He received his MSc and PhD degrees in organic chemistry from the Eotvos University of Budapest under Professor A. Kucsman. Between 1976 and 1978, he was a Humboldt Fellow at the University of Bonn under Professor W. Steglich. He has worked at Richter Plc. since 1981 where he participated in the research and development of leading cardiovascular drugs in Hungary. His main interest is analogue based drug discovery. He is the author of some 100 patents and scientific publications. Since 2014 he is Chair of the Subcommittee on Drug Discovery and Development of IUPAC. He received an honorary professorship at the Technical University of Budapest.

Christian Klein is Head of Oncology Programs at the Roche Innovation Center Zurich, specialized in the discovery, validation and preclinical development of antibody based cancer immunotherapies and bispecific antibodies. During his 15 years at Roche he has made major contributions to the development and approval of obinutuzumab, the preclinical development of eight clinical stage bispecific antibodies/immunocytokines that are currently at the clinical stage, as well as the development of Roche's novel proprietary bispecific antibody platforms, e.g., the CrossMAb technology.

Wayne E. Childersis Associate Professor of Pharmaceutical Sciences at Temple University, Philadelphia, USA. Wayne received his BA (1979) degree from Vanderbilt University in chemistry and PhD (1984) in organic chemistry from the University of Georgia under the direction of Harold Pinnick. He served as an assistant adjunct professor at Bucknell University before accepting a position as a postdoctoral fellow at the Johns Hopkins University School of Medicine in the laboratories of Dr. Cecil Robinson. He then joined Wyeth, working in numerous therapeutic areas, including psychiatric diseases, stroke, and Alzheimer's disease, and the treatment of chronic pain. He stayed with Wyeth for 22 years, before joining the faculty of Temple University in 2010.

Preface xvii

Part I General Aspects 1

1 New Trends in Drug Discovery 3Gerd 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 AntibodyDrug 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 41Uwe 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 67Peng 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 BcrAbl 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 95Arwed 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 113Patrick 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 131Pierre-Yves Michellys

6.1 Introduction 131

6.2 Drug Design and Strategy 134

6.3 Synthesis of Ceritinib 135

6.4In Vitro Evaluation of Ceritinib 136

6.5In Vitro ADME Evaluation of Ceritinib 137

6.6 Preclinical Pharmacokinetic Evaluation of Ceritinib 138

6.7In 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 153Maarten 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 197Roberto 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 6-Ethyl-Chenodeoxycholic Acid (6-ECDCA, INT-747, Obeticholic Acid) 214

8.5.1 Design, Synthesis, and StructureActivity 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 IIII 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 245Christian 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

9.2.5 Direct Cell Death Induction 249

9.2.6 FcR Binding 249

9.2.7 Antibody-Dependent Cellular Cytotoxicity and Antibody-Dependent Cellular Phagocytosis 250

9.2.8 Whole Blood B-Cell Depletion 250

9.2.9 Activity of Single-Agent Obinutuzumab in Human Xenograft Models of B-Cell Lymphoma 251

9.2.10 Activity of Obinutuzumab Combined with Chemotherapy and Novel Agents in Human Xenograft Models of B-Cell Lymphoma 251

9.2.11 Conclusions from Preclinical Studies 252

9.3 Clinical Experience with Obinutuzumab 253

9.3.1 Non-Hodgkin Lymphoma 253

9.3.1.1 Early Clinical Experience (Phase I/II) 253

9.3.1.2 Phase III Studies 262

9.3.1.3 Ongoing Clinical Studies of Novel Combinations, Including Chemotherapy-Free Regimens 269

9.3.2 Chronic Lymphocytic Leukemia 270

9.3.2.1 Early Clinical Experience (Phase I/II) 270

9.3.2.2 Phase III Studies 272

9.3.2.3 Ongoing Clinical Studies of Novel Combinations, Including Chemotherapy-Free Regimens 273

9.3.3 Obinutuzumab in Non-tumor Indications 273

9.4 Conclusions 274

Acknowledgments 274

List of Abbreviations 275

References 276

10 Omarigliptin (MARIZEVTM, MK-3102) 291Tesfaye Biftu

10.1 Introduction 291

10.1.1 Discovery of Omarigliptin 293

10.1.2 X-ray and Modeling Studies 297

10.1.3 Synthesis of Omarigliptin 298

10.1.4In Vitro Pharmacology 302

10.1.4.1In Vivo Pharmacology in Preclinical Species 302

10.1.4.2 Pharmacokinetics (PK) in Preclinical Species 303

10.1.4.3 Pharmaceutical Properties 304

10.1.4.4 Preclinical Safety Pharmacology 304

10.1.4.5 Clinical Data 305

10.1.5 Add-On Studies 308

10.1.5.1 Add-On to Metformin and Sitagliptin 308

10.1.5.2 Add-On to Glimepiride 310

10.1.5.3 Safety and Tolerability 311

10.2 Summary 311

List of Abbreviations 312

References 313

11 Opicapone, a Novel Catechol-O-Methyltranferase Inhibitor (COMT) to Manage the Symptoms of Parkinsons Disease 319László E. Kiss, Maria João Bonifácio, José Francisco Rocha, and Patrício Soares- da-Silva

11.1 Introduction 319

11.2 COMT Inhibitors Used in l-DOPA Treatment 320

11.3 The Discovery of Opicapone 322

11.3.1 Early Pyrazole Analogues 322

11.3.2 Modulation of the Central Heterocyclic Core 325

11.3.3 Optimization of Oxadiazolyl Nitrocatechols 327

11.3.4 Identification of Opicapone 330

11.4 Opicapone Preclinical Profile 332

11.5 Clinical Studies with Opicapone 333

11.5.1 Phase I and Phase IIStudies 333

11.5.2 Phase III Studies 334

11.6 Conclusion 335

List of Abbreviations 336

References 336

12 The Discovery of Osimertinib (TAGRISSOTM): An Irreversible Inhibitor of Activating and T790M Resistant Forms of the Epidermal Growth Factor Receptor Tyrosine Kinase for the Treatment of Non-Small Cell Lung Cancer 341Michael J. Waring

12.1 Introduction 341

12.2 Discussion 346

12.3 Summary 353

List of Abbreviations 354

Acknowledgment 355

References 355

13 Discovery of Pitolisant, the First Marketed Histamine H3-Receptor Inverse Agonist/Antagonist for Treating Narcolepsy 359C. Robin Ganellin, Jean-Charles Schwartz, and Holger Stark

13.1 Introduction 359

13.2 Chemical Background 360

13.3 Generation of a Chemical Lead 362

13.4 Pharmacological Screening Methods 366

13.5 StructureActivity Optimization 367

13.6 Generation of Pitolisant 369

13.7 Preclinical Development Studies 371

13.8 Clinical Development Studies 373

13.9 Conclusion 374

Acknowledgment 375

List of Abbreviations 375

References 375

14 Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinsons Disease 383Paolo Pevarello and Mario Varasi

14.1 Introduction 383

14.1.1 Parkinsons Disease 383

14.1.2 From James Parkinson to l-Dopa 385

14.1.3 Pharmacotherapy of Parkinsons Disease 386

14.2 Discovery of Safinamide 387

14.2.1 From Milacemide to Safinamide 388

14.2.2 SAR Efforts on 2-Aminoamide Analogues Provide Lead Molecules 391

14.2.3In Vivo Antiepileptic Efficacy Assessment Identifies Safinamide 395

14.3 Mechanisms of Action of Safinamide 396

14.3.1 Safinamide Inhibits MAO-B 396

14.3.2 Safinamide Blocks Voltage-Dependent Sodium Channels (VDSCs) 398

14.3.3 Safinamide Modulates Voltage-Dependent Calcium Channels (VDCCs) 399

14.3.4 Safinamide Inhibits Glutamate Release 399

14.4 PreclinicalIn Vivo Pharmacological Characterization of Safinamide 399

14.4.1 Preclinical Epilepsy Models 400

14.4.2 Preclinical PD Models 401

14.5 Pharmacokinetics and Metabolism (PKM) 402

14.5.1 Preclinical PKM 402

14.5.2 Clinical PKM and Safety 403

14.6 Clinical Efficacy of Safinamide 403

14.6.1 Clinical Studies in Early PD 403

14.6.2 Clinical Studies in Advanced PD 406

14.6.3 Clinical Trials for Other Indications 407

14.7 Safety and Tolerability in Clinical Studies 408

14.8 Summary of Clinical Trials and Marketing Authorization 408

14.9 Conclusion 408

List of Abbreviations 409

References 410

15 Discovery and Development of Trifluridine/Tipiracil (LonsurfTM) 417Norihiko Suzuki, Masanobu Ito, and Teiji Takechi

15.1 Introduction 417

15.2 A Concept to Maximize the Antitumor Effect of 5-FU 419

15.3 A Concept to Maximize the Antitumor Effect of FTD 420

15.3.1 Medicinal Chemistry:In Vitro and Pharmacokinetic Studies 420

15.3.2 PreclinicalIn vivo Efficacy Studies 425

15.4 The Mechanism Underlying the Antitumor Effect of Trifluridine 427

15.5 Characterization of the Pharmacologic Effect of FTD/TPI 429

15.6 Clinical Pharmacology and Determination of the Optimal Dosing Scheme of FTD/TPI 430

15.7 Clinical Efficacy, Safety, and Approval 432

15.8 Summary 434

List of Abbreviations 435

References 435

Index 443