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Drug Discovery in Japan: Investigating the Sources of Innovation
ISBN-13: 9789811389085 / Angielski / Miękka / 2020 / 333 str.
Drug Discovery in Japan: Investigating the Sources of Innovation
ISBN-13: 9789811389085 / Angielski / Miękka / 2020 / 333 str.
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Foreword
Acknowledgement
Chapter 1: Introduction
1.1 Objectives
1.2 Drugs discussed in the case studies
References
Chapter 2: Compactin
The discovery of statin, “penicillin” for cholesterol
Abstract
2.1 Introduction
2.2 Timeline of the discovery and development of compactin
2.3 Statin discovery program
2.4 Novelty of the Endo’s discovery program
2.5 Collaboration with academia
Box 2.1 Academic–industrial collaboration to understand the mechanism of action of statin
2.6 Crises and discontinuations
2.6.1 First crisis: failure in rats
2.6.2 Second crisis: suspected hepatotoxicity
2.6.3 Third crisis: discontinuation of clinical development
2.7 Science sources that supported the discovery of compactin
2.8 Responses to discontinuation of the clinical trial
2.9 "Invisible" discovery competition
2.10 Compactin is the basis for all statins
2.11 Statin sales
2.12 Conclusion
References
Chapter 3: Pravastatin (Pravachol, Mevalotin) “Blockbuster” statin discovered from the metabolites of compactin
Abstract
3.1 Introduction
3.2 Characteristics of pravastatin
3.3 Timeline of R&D for pravastatin
3.4 Discovery of pravastatin: from the metabolites of compactin
3.5 Pre-clinical studies using WHHL rabbits
3.6 Development of a two-step fermentation production process
3.7 Five yeas from initiating clinical trials to the approval for human use
3.10 Global large-scale and long-term clinical studies
3.12 Clinical development through collaboration between industry and academia
3.11 Toward a blockbuster drug
3.12 Partnership with Bristol-Myers Squibb
Box 3.1 Statin development competition: Sankyo vs Merck3.13 Conclusion
References
Chapter 4: Rosuvastatin(Crestor) “Super statin” which became a global block buster despite its late entry
Abstract
4.1 Introduction
4.2 Timeline of rosuvastatin synthesis and development
4.3 Discontinuation of the Clinical Trial by Shionogi4.4 AstraZeneca resumed clinical trials
4.5 Sources of discovery: fluvastatin as the lead compound
4.6 Crestor sales: Peak sales exceed 7.1 billion USD
4.7 Rosuvastatin vs atorvastatin
4.8 Properties of commercially available statins
4.9 Economic value of follow-on innovation
Box 4.1 Contribution of follow-on drugs to innovation4.10 AstraZeneca’s resumption of the suspended project
4.11 Conclusion
References
Chapter 5: Leuprorelin (Leuplin, Lupron, Viadur) A prostate cancer drug with dual innovations in mechanism of action and drug delivery system
Abstract
5.1 Introduction
5.2 R&D timeline of Leuplin5.3 Leuprorelin mechanism of action
5.4 Academia provides the “seed”
5.5 Challenges and luck in the synthesis of derivatives
5.6 The start of microencapsulation
5.7 Discovery of downregulation and a change in the target disease
5.8 Commercialization challenges
5.9 Scientific theory behind Leuplin: Application of Nobel Prize-winning compounds
5.10 DDS: Optimizing drug therapy
5.11 Scientific foundation of Takeda Pharmaceutical
5.12 Scientific contributions to Leuplin R&D
5.13 Market success of Leuplin
5.14 R&D competition
5.15 Competition after the launch
5.16 Conclusion
References
Chapter 6: Oflaxacin and levofloxacin (Tarivid/Cravit)Best-in class antimicrobial agents
Abstract
6.1 Introduction
6.2 Mechanism of action of fluoroquinolones
6.3 Ofloxacin R&D
6.4 Efficient mass production of ofloxacin
6.5 Ofloxacin clinical research
6.6 Levofloxacin R&D process
6.7 Increased competition for ofloxacin and the discovery of levofloxacin
6.8 Development of the mass production process of levofloxacin
6.9 Levofloxacin clinical development
Box 6.1 Optical activity and drug discovery
6.10 Technological advances since sulfa-based antimicrobials
6.11 Ofloxacin and levofloxacin R&D team6.12 Scientific contributions to the development of ofloxacin and levofloxacin
6.13 Sales of levofloxacin: approximately 300 billion yen at peak
6.14 Fluoroquinolone development competition
6.15 Levofloxacin gains half the fluoroquinolone market share
6.16 Conclusion
References
Abstract
7.1 Introduction
7.2 Tamsulosin R&D timeline
7.3 Development history of tamsulosin
7.5 Basic Research: Amosulalol R&D and the creation of tamsulosin7.6 Application to prostatic hyperplasia
7.7 Clinical trial program: Overcoming side effects with extended-release formulations
7.8 Scientific contributions to the development of tamsulosin
7.9 Yamanouchi's R&D structure
7.10 Scientific contributions to tamsulosin’s basic research
7.11 Scientific contributions to tamsulosin's clinical research
7.12 Sales of tamsulosin7.13 Competition with other companies: First α1-blocker to treat prostate hypertrophy
7.14 Conclusion
References
Chapter 8: Pranlukast (Onon) An anti-asthmatic drug realized by intensive investment in the arachidonic acid cascade
Abstract
8.1 Introduction
8.2 Timeline from discovery to launch8.3 Prostaglandins (PGs) and the arachidonic acid cascade
8.4 History of prostaglandin research
8.5 Discovery and development of PG drugs by Ono Pharmaceutical
8.6 Discovery of leukotrienes
8.7 Ono Pharmaceutical started development of LT antagonists
8.8 Technology transfer from Corey’s laboratory and clinical development challenges
8.9 Concentrating on PG research
8.10 High efficacy for bronchial asthma
8.11 Onon earned one-quarter of Ono Pharmaceutical's sales
8.12 LT antagonist development competition
8.13 Exploring global expansion
8.14 Conclusion
References
Chapter 9: Tacrolimus (Prograf) An immunosuppressant of global standards
Abstract
9.1 Introduction9.2 Transplant immunology
9.3 Timeline of tacrolimus development
9.4 The history of organ transplantation is the history of immunosuppression
9.5 Natural products drug discovery in Fujisawa Pharmaceutical
9.6 Discovery research started at the newly established research laboratory
9.7 Scientific contributions to exploratory research
9.8 The world authority in liver transplantation led clinical trials
9.9 Tacrolimus is more effective than cyclosporine
9.10 Contributing to the creation of chemical biology
9.11 Annual sales exceed 2 billion dollars
9.12 R&D competition and the first-mover advantage
9.13 Conclusion
References
Chapter 10: Pioglitazone (Actos, Glustin) A drug that transformed diabetes therapy
Abstract
10.1 Introduction
10.2 Pioglitazone mechanism of action
10.3 Timeline of the development of pioglitazone
10.4 Discovery of lead compounds through animal models
10.5 Balancing potency and side effects
10.6 Clinical development
10.7 Diabetes treatment before pioglitazone10.8 Insulin mechanism of action
10.9 Scientific basis for research and development
10.10 Market success
10.11 World's largest market share of insulin sensitizers
10.12 Conclusion
References
Chapter 11: Donepezil (Aricept) The world's first drug for Alzheimer's disease 236
Abstract
11.1 Introduction
11.2 Mechanism of action of donepezil
11.3 Timeline of donepezil R&D
11.4 Science basis for R&D
11.5 Exploratory research of tacrine derivatives
11.6 Lead compound derivation and project discontinuation
11.7 "Yami Research," project restart, and derivation of donepezil11.8 Clinical trials
11.9 Science basis of donepezil: The acetylcholine hypothesis
11.10 Development of tacrine based on the choline hypothesis
11.11 Donepezil R&D team members
11.12 Interactions between science and donepezil
11.13 Sales of Aricept: Over 300 billion yen sold worldwide annually
11.14 Entries and Failures of Other Companies in R&D of Anti-Alzheimer Drugs
11.15 Competition in the anti-Alzheimer's drug market
Box 11.1 Innovations in diagnosing Alzheimer's disease by Magnetic Resonance Imaging
11.16 Conclusion
References
Chapter 12: Candesartan (Blopress, Atacand) Antihypertensive drug with a new mechanism of action
Abstract
12.1 Introduction
12.2 Mechanism of action
12.3 Timeline of the candesartan R&D process
12.4 Start as diuretic research
12.5 A new synthesis method and serendipitous findings
12.6 Drug lacked efficacy in the clinical trial
12.7 The discovery of losartan
12.8 Resumption of Takeda's ARB research and the discovery of candesartan12.9 The Scientific basis of candesartan
12.10 Drug development era
12.11 Contributions of scientific knowledge
12.12 Impact of candesartan
12.13 Global competition for ARB R&D
12.14 Over $20 billion markets worldwide
12.15 Conclusion
References
Chapter 13: Tocilizumab (Actemra,Ro-actemra) First antibody drug developed in Japan 283
Abstract
13.1 Introduction
13.2 Time line of the R&D process of tocilizumab
13.3 The mechanism of action: Inhibition of IL-6 signaling
13.4 Scientific basis for exploratory research
Box 13.1 The discovery of IL-6.
13.5 Joint research with Osaka University
13.6 Humanized antibodies
13.7 Efficacy and safety of tocilizumab were confirmed.
13.8 Mass production of tocilizumab
13.9 Tocilizumab for multiple myeloma
13.10 Return to autoimmune diseases as the disease target
13.11 Drug prices determined by the cost calculation method
13.12 Scientific sources of tocilizumab13.13 Tocilizumab development through successful academic-industrial alliances
Box 13.2 Contribution of drug discovery to science: The role of IL-6 revealed by tocilizumab.
13.14 Tocilizumab sales - exceeded two billion USD
13.15 Competition among antibody drugs
13.16 Comparison with R&D process of Remicade (infliximab)
13.17 ConclusionReferences
Chapter 14: Nivolumab (Opdivo) Science-based antibody drug, which opened a new category of cancer treatments
Abstract
14.1 Introduction
14.2 Overview of nivolumab R&D
14.3 Mechanisms of action and characteristics of nivolumab
14.4 Timeline from the start of basic research to the market launch
14.5 Background to discovery research
14.6 Discovery and isolation of PD-1 and generation of PD-1 knockout mice
14.7 International collaboration to discover the ligands of PD-1
14.8 Pursuing the applicability of anti-PD-1 antibodies as cancer therapeutic agents
14.9 Application for method-of-use patents and creation of nivolumab through collaboration with Medarex
14.10 Conducting Phase I clinical studies14.11 Late-stage clinical studies and approval
14.12 Scientific basis for the discovery of nivolumab
14.13 Use of public research grants, KAKEN, and other grants
14.14 Sales of Opdivo
14.15 Major immune checkpoint inhibitors and combination therapy
Box 14.1 Exploiting frontier science for drug development: a comparison with ipilimumab (Yervoy) nivolumab
14.15 ConclusionReferences
Chapter 15: Sources of innovation of drug discovery in Japan and its implications
Abstract
A. Knowledge sources
15.1 Knowledge sources inspiring discovery projects
15.2 Transfer of knowledge through direct collaboration among researchers
15.3 Research tools and the discovery of the new use of a compound15.4 Survey evidence on knowledge sources for drug inventions
B. Dynamic relationship between drug discovery and scientific progress
15.5 Status of science when the discovery research begins
15.6 Survey evidence on incomplete science when drug discovery begins
15.7 Dynamic relationship between drug discovery and scientific progress
C. Coping with uncertainty
15.8 Unexpected difficulties
15.9 Overcoming unexpected difficulties
15.10 Capturing serendipity and unexpected luck
D. Uniqueness and competition in discovery research
15.11 Uniqueness of discovery research
15.12 Emergence of within-mechanism competition and knowledge spillover
E. Implications on management and policy
15.13 Absorptive capability and incomplete science
15.14 Encouraging Individual initiative and long-term perspective
15.15 Global clinical development capabilities
15.16 Patent system that encouraged challenges to uncertainty
15.17 Science and R&D infrastructure in Japan
15.18 Regulations that facilitate drug innovationsReferences
Dr. Sadao Nagaoka is a Professor of economics at Tokyo Keizai University (Japan). Before this position, he was a professor at the Institute of Innovation Research of Hitotsubashi University (Japan). He has been the Program Director for research on innovation in the Research Institute of Economy, Trade and Industry (RIETI). He worked in the MITI, the World Bank and in the OECD. He has been an economic advisor for the JPO and was a member of the Economic and Scientific Advisory Board of the EPO. He has a Ph.D. in Economics from Massachusetts Institute of Technology. His scientific interests are economics of innovation, especially R&D, intellectual property, standards and science. His recent publications appeared in Journal of Economics & Management Strategy, International Journal of Industrial Organization, Research Policy, Economics of Innovation and New Technology, Journal of Technology Transfer, Journal of the Japanese and International Economies and the US National Academies.
This book analyzes the drug-discovery process in Japan, based on detailed case studies of 12 groups of 15 innovative drugs. It covers the first statin in the world up to the recent major breakthrough in cancer therapy, the recent immune checkpoint inhibitor, the scientific discovery for which a 2018 Nobel Prize in Physiology or Medicine was awarded to Prof. Tasuku Honjo, Kyoto University. The book shows the pervasive high uncertainty in drug discovery: frequent occurrences of unexpected difficulties, discontinuations, serendipities, and good luck, significantly because drug discovery starts when the underlying science is incomplete. Thus, there exist dynamic interactions between scientific progress and drug discovery. High uncertainty also makes the value of an entrepreneurial scientist high. Such scientists fill the knowledge gaps by absorbing external scientific progress and by relentless pursuit of possibilities through their own research, often including unauthorized research, to overcome crises. Further, high uncertainty and its resolution significantly characterize the evolution of competition in the drug industry. The patent system promotes innovation under high uncertainty not only by enhancing appropriability of R&D investment but also by facilitating the combination of knowledge and capabilities among different firms through disclosure. Understanding such a process significantly benefits the creation of innovation management and policy practices.
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