Drug Discovery in Japan: Investigating the Sources of Innovation

338 Pages·2019·6.361 MB·English

by  Sadao Nagaoka

Sadao Nagaoka Editor
Drug
Discovery
in Japan
Investigating the Sources of Innovation
Drug Discovery in Japan
Sadao Nagaoka
Editor
Drug Discovery in Japan
Investigating the Sources of Innovation
123
Editor
Sadao Nagaoka
Department ofEconomics
Tokyo KeizaiUniversity
Kokubunji, Tokyo,Japan
ISBN978-981-13-8905-4 ISBN978-981-13-8906-1 (eBook)
https://doi.org/10.1007/978-981-13-8906-1
©SpringerNatureSingaporePteLtd.2019
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar
methodologynowknownorhereafterdeveloped.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom
therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, expressed or implied, with respect to the material contained
hereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregard
tojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.
ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,
Singapore
Preface
This book investigates the sources of drug-discovery innovation in Japan through
detailed case studies of the 12 groups of 15 innovative drugs discovered in Japan.
Japan is a major contributor to the global drug-discovery industry, as is illustrated
by its breakthrough discoveries, such as the first statin and the recent immune
checkpoint inhibitor against cancer. This book discusses the knowledge sources
ofthedrug-discoveryprojects,theinteractionbetweendrugdiscoveryandscientific
progress, causes of unexpected difficulties, capturing serendipities, and uniqueness
and competition in drug discovery, focusing on the sources of innovation.
Case studies of the following drugs are covered: compactin/pravastatin
(Mevalotin, Pravachol), rosuvastatin (Crestor), leuprorelin (Leuplin, Lupron,
Viadur), ofloxacin (Tarivid, Floxin) and levofloxacin (Cravit, Levaquin), tamsu-
losin (Harnal, Flomax), pranlukast (Onon), tacrolimus (Prograf), pioglitazone
(Actos, Glustin), donepezil (Aricept), candesartan (Blopress, Atacand, Amitas),
tocilizumab(Actemra),andnivolumab(Opdivo).Manyofthesedrugsofferednew
treatments to diseases that had been previously intractable and significantly
increased the patient length of life and/or quality of life. Most of these drugs are
globally available, and their values are recognized internationally. The drugs dis-
cussed in thisbook covered not only those discovered throughchemical synthesis,
including peptides, but also those screened from natural products and antibody
drugs.
Each case has unique features so that the book as a whole provides diverse and
rich information on drug-discovery processes in Japan. Across the cases, one
commonfindingisthepervasivehighuncertaintythatdrug-discoveryprojectsface.
Manyoftheprojectsfacedthedangersofdiscontinuationbecauseoftheemergence
of unexpected difficulties. Serendipitous discoveries also played major roles in a
number of drug-discovery projects. The major source of such uncertainty is the
incompleteness of science. Over the past century, there has been significant sci-
entific progress in the medical sciences, and some believed that such scientific
progresswouldmake drugdiscoverylessrandom andmorerational. However,the
drug-discoveryprocesscontinuestofacesignificantuncertaintyasdemonstratedby
thehigh failurerate ofclinical trials. Thisislargelycaused by theextensivelist of
v
vi Preface
unknownswithregardtothespecificdiseasemechanisms,thepotentialtargets,and
the drug candidate’s mechanism of action. As a result, even today, drug-discovery
projects by pharmaceutical firms often start when the underlying science for such
projects is incomplete. Such major uncertainty makes the progress of science and
drug discovery by a firm mutually reinforcing. A drug discovered provides a tool
for a scientist to analyze how the target molecule functions in a body, thereby
increasing understanding of the disease mechanism.
High uncertainty makes the value of an entrepreneurial scientist high. Such
scientists are the gap fillers as defined in the theories of entrepreneurship put
forward by Leibenstein (1968).1 The case studies described in this book highlight
the role that entrepreneurial researchers have played in drug discovery. These
scientistsfilledtheknowledgegapsbyabsorbingandcombiningexternalscientific
progressandbyarelentlesspursuitofpossibilitiesthroughtheirownresearch,often
including unauthorized research to overcome crises. Furthermore, high uncertainty
and its resolution significantly characterize the evolution of competition.
Competition is initially rare for a pioneer who engages in discovery projects for
drugs with new mechanisms of action because uncertainty is very high. However,
once the clinical trials by a successful pioneer credibly show that the new specific
mechanism of action works, there emerges strong intra-mechanism competition
(competition among drugs with the same mechanism discovered by the pioneer).
Finally, the case studies described also highlight the contribution of policy and
institutionstoinnovations,whicharenotoftenrecognized.Forexample,thepatent
system promotes innovation under high uncertainty not only by enhancing appro-
priability of such research and development investment but also by facilitating the
combinationofknowledgeandcapabilitiesbetweendifferentorganizationsthrough
disclosure.
As the editor of this book, I thank Dr. Yoshiyuki Ohsugi (Chairman, Ohsugi
BioPharmaConsultingCo.,formerglobalprojectleaderfortocilizumab(Actemra))
and Dr. Hideo Kawabe (Patent Attorney at Hiraki & Associates/IP Counsel in
ManufacturingTechnologyAssociationofBiologics)fortheirvaluableprofessional
adviceoncasestudiesintermsofmedicalscienceandpatentlaw;andYasushiHara
(Michelin Fellow, CEAFJP/EHESS, Paris, France/Adjunct Associate Professor,
Faculty of Economics, Hitotsubashi University, Tokyo, Japan) who serves as a
secretariatfortheresearchprojectsdescribedinthisbookandhelpedtocompletethe
case studies. Dr. Akira Nagumo (Medical Science Liaison, MSD K.K.) provided
useful comments for the introductory and final chapters of the English draft of the
book. I also express my gratitude to the Institute of Innovation Research of
Hitotsubashi University for assisting in many research tasks that lead to this book.
Withouttheassistanceofthecenter’sresearchsupportstaff,theimplementationof
suchlarge-scaleempiricalprojectswouldbedifficult.IalsothankJunoKawakamiof
Springer for facilitating the publication of this book and thank Osami Kono of the
BiotechEditorialDepartmentofNikkeiBP(then)forenablingthecompilationofthe
first editionof this volume in Japanese.
1ThereferenceisindicatedattheendofChap.1.
Preface vii
In the case-based investigations, it was indispensable to interview the principal
researchers for each drug-discovery project. I express my deep gratitude to the
followingresearchersfortheirtimeandsupporttothisproject(theirtitlesappearin
the corresponding chapters, while some researchers are not named in accordance
with their company policy):
Akira Endo (compactin), Kazuo Nakamura (pravastatin; Mevalotin, Pravachol),
HaruoKoike(rosuvastatin;Crestor),HiroakiOkada(leuprorelin;Leuplin,Viadur),
IsaoHayakawa(ofloxacin;Tarivid,Floxin;levofloxacin;Cravit,Levaquin),Toichi
Takenaka (tamsulosin; Harnal, Flomax), Hisao Nakai (pranlukast; Onon), Toshio
Goto(tacrolimus;Prograf),HiroyukiOdaka(pioglitazone;Actos,Glustin),Hachiro
Sugimoto (donepezil; Aricept), Youichi Iimura (donepezil; Aricept), Yoshiyuki
Kawakami (donepezil; Aricept), Koji Shimizu(donepezil; Aricept), Toshio Hirano
(tocilizumab; Actemra), Tetsuya Taga (tocilizumab; Actemra), Kiyoshi Yasukawa
(tocilizumab; Actemra), Kazuyuki Yoshizaki (tocilizumab; Actemra), and Tasuku
Honjo (nivolumab; Opdivo).
Finally, I acknowledge that the views expressed in this book are those of the
authors and are published under the responsibility of the authors and the editor.
March 2019 Sadao Nagaoka
Professor, Faculty of Economics
Tokyo Keizai University
Kokubunji, Japan
Former Professor, Institute of Innovation Research
Hitotsubashi University
Kunitachi, Japan
Acknowledgements
Thepapersconstitutingthisbookarebasedonthefindingsfromaresearchproject:
“Science Origins of Innovations and its Economic Effects” (Principal Investigator:
Sadao Nagaoka), supported by the Research Institute of Science and Technology
for Society of the Japan Science and Technology Agency (JST/ RISTEX). The
authors thank the Japan Science and Technology Agency for its support. We also
thank the Office of Pharmaceutical Industry Policy Research (OPIR) of the Japan
Pharmaceutical Manufacturers Association for their cooperation in conducting the
interviews with the principal researchers of the drug-discovery projects as well as
the complementary large-scale surveys for the drug discovery and development
projectsinJapan. Theeditor thanks theJapan SocietyofthePromotionofScience
for grants (26285055, 18H00854, and 17H00963) in advancing the research to the
current version published in English. The editor also thanks the Research Institute
ofEconomy,TradeandIndustry(RIETI),wheretheeditorhasorganizedanumber
ofresearchprojectsoninnovation,whichhavecontributedtothisresearchproject.
ix
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Sadao Nagaoka
2 Compactin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Sadao Nagaoka and Yasushi Hara
3 Pravastatin (Pravachol, Mevalotin). . . . . . . . . . . . . . . . . . . . . . . . . 35
Yasushi Hara and Sadao Nagaoka
4 Rosuvastatin (Crestor) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Yasushi Hara, Sadao Nagaoka and Koichi Genda
5 Leuprorelin (Leuplin, Lupron, Viadur) . . . . . . . . . . . . . . . . . . . . . 65
Naoki Takada and Hideo Kawabe
6 Ofloxacin and Levofloxacin (Tarivid/Cravit). . . . . . . . . . . . . . . . . . 85
Yasushi Hara and Yuji Honjo
7 Tamsulosin (Harnal, Flomax, OMNIC). . . . . . . . . . . . . . . . . . . . . . 111
Yasushi Hara, Akira Nagumo and Hajime Oda
8 Pranlukast (Onon) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Kenta Nakamura
9 Tacrolimus (Prograf) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Kenta Nakamura
10 Pioglitazone (Actos, Glustin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Naoki Takada and Koichi Genda
11 Donepezil (Aricept) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Yasushi Hara and Hideo Kawabe
12 Candesartan (Blopress, Atacand) . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Naoki Takada, Koichi Genda and Akira Nagumo
xi
xii Contents
13 Tocilizumab (Actemra, RoActemra) . . . . . . . . . . . . . . . . . . . . . . . . 223
Yasushi Hara, Yoshiyuki Ohsugi and Sadao Nagaoka
14 Nivolumab (Opdivo) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Yasushi Hara and Sadao Nagaoka
15 Sources of Innovation of Drug Discovery in Japan
and Its Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Sadao Nagaoka
Index .... .... .... .... .... ..... .... .... .... .... .... ..... .... 331