Strengthening the Competitiveness of Japan’s Pharmaceutical Industry: Analysis of Country Differences in the Origin of New Drugs and Japan’s Highly Productive Firm

Abstract

Improving the new drug discovery and development capability of the Japanese pharmaceutical industry, which shows a huge trade deficit, is an urgent issue. To tackle this issue and propose remedies, this study analyzed the originators and characteristics of new drugs approved by the Food and Drug Administration (FDA) from 2017 to 2022 and examined the contributions of Japanese companies. Analysis of the establishment year of the companies that created the approved drugs showed that bio-ventures established in the 1990s and 2000s highly contributed to the creation of the approved drugs in regions other than Japan (particularly in the US), whereas, in Japan, all approved drugs were created by old incumbent pharmaceutical companies. This suggests the presence of an urgent need in Japan to foster start-ups that link scientific discoveries and technologies in academia to drug discovery. The novelty of approved drugs measured by the ratio of first-in-class, orphan drug, and recent drug modalities did not differ between Japan and other countries, suggesting that Japanese pharmaceutical companies follow the technological trends of new drugs. A case analysis of Kyowa Kirin, the Japanese company that created the largest number of the drugs approved by the FDA from 2017 to 2022 among Japanese companies, suggests that focused investment in modality technology development, strengthening collaboration with academia in biology, and the reutilization of small-molecule drug discovery capabilities are important for improving drug discovery productivity.

INTRODUCTION

This study was designed to compare the innovation system for drug discovery in Japan with that in other countries and to explore ways to improve the international competitiveness of Japanese drug discovery. Japan’s ability to develop new drugs is weak compared with that of other countries worldwide. Japan has a longstanding trade deficit in pharmaceuticals, with an excess of $30 billion in 2021.¹⁾ Of the top 20 drugs in global sales in 2021, only one drug, opdivo, was discovered by a Japanese company.²⁾ It is indicated that this is attributed to Japanese companies’ low research and development (R&D) spending and lagging in biopharmaceuticals.³⁾ It has also been pointed out that bio-ventures and academic drug discovery as a mechanism to link university drug seeds to pharmaceutical products have not functioned well in Japan.⁴⁾

The pharmaceutical industry is the most representative science-based industry. New biological discoveries and inventions of pharmaceutical modality technologies at universities and public research institutions are transferred to companies, resulting in the development of new drugs.⁵⁾ A study reported that half of the innovative drugs approved by the Food and Drug Administration (FDA) from 1998 to 2007 were developed by small biotechnology companies, many of which were university start-ups.⁶⁾ This trend was more pronounced in the US and less so in Japan.⁶⁾ In contrast, in Japan, the 1000 University-Originated Ventures Plan was announced in 2001, and since then, the number of venture companies has significantly increased.⁷⁾ One of the most common industries of established ventures is biotechnology,⁷⁾ and recently, drug discovery ventures with an international presence have emerged.⁸⁾ Given this background, quantitatively analyzing the role of drug discovery ventures in more recent new drugs and the differences between countries is worthwhile. Therefore, in this study, I conducted a comprehensive survey of companies that created new FDA-approved drugs from 2017 to 2022 to identify their characteristics according to country.

Recently, the trend for new drugs has shifted from follow-on drugs for common diseases to first-in-class drugs aimed at orphan diseases.⁹⁾ The increased reimbursement pressure for drugs poorly differentiated from existing drugs and the growing need for personalized medicine have raised the demand for innovative drugs.^10,11) The emergence of new modalities that can control drug targets that have been difficult to control with small-molecule drugs has also significantly contributed to the development of new drugs recently.^12,13) Many “druggable” targets were already pursued, and several companies develop drugs against the same promising drug targets.¹⁴⁾ Therefore, there is growing emphasis on drug discovery for targets that were previously considered “undruggable,” and the importance of new modality technologies that make this possible is increasing. From the international competitiveness perspective, investigating whether Japanese drug discovery follows these trends or pursues old-fashioned drug discovery is important. In this study, I examined the novelty of recent drugs from Japan by making an international comparison of the ratio of first-in-class drugs, orphan drugs, and modalities other than small molecules.

If Japan’s innovation system for drug discovery differs from that of the US and Europe, considering unique measures to strengthen Japan’s competitiveness is also important. Japan’s social systems and business practices are different from those in the West, such as less investment money,¹⁵⁾ low mobility of human resources,¹⁶⁾ and low entrepreneurship¹⁷⁾; therefore, pursuing the same innovation model as those of other countries is not always the right solution. Conversely, if some Japanese companies have shown high productivity in drug discovery recently, exploring the direction in which the Japanese pharmaceutical industry is heading based on their R&D practices would also be important. For this purpose, this study identified a Japanese company with high R&D productivity that has recently created many FDA-approved drugs and conducted case analyses of their R&D activities. Based on these analyses, this study discusses the direction that Japan should aim for in drug discovery.

MATERIALS AND METHODS

All new drugs approved by the FDA from 2017 to 2022 were identified from New Drugs at the FDA (https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products). Imaging agents and new fixed-dose combinations of existing drugs were excluded. Then, originator firms or academic institutions of listed drugs were searched through the “Asu no Shinyaku (Tomorrow’s New Drug)” website (https://technomics-info.com/jsp/top.jsp), a database that provides originator information of approved and clinically developed drugs. “Asu no Shinyaku” is the database which records drug discovery and development information collected from press releases, news reports, scientific meetings and scholarly papers. Each record is sorted by the drug name and includes the name of the organization that conducted the drug research as “originator” and the name of the company that conducted the clinical development as “developer,” therefore the originator firms or academic institutions of a certain drug can be identified as distinct from the company that developed the drug. If there were more than one originator listed for a drug, all companies and institutions listed were included in the analysis. The headquarter location of the listed firms and academic institutions were searched on the Internet. The established year of the listed firms were identified in the company’s homepage or the information on the Internet. If an originator company does not currently exist due to merger and acquisition, the headquarter location and established year of the initial company that actually created the drug (“Asu no Shinyaku” database refers to the company as an originator even if the company does not exist anymore) were used for the analysis. The molecular target of each approved drugs was identified using DrugBank Online (https://go.drugbank.com/). DrugBank Online has a unique function that can search for other drugs that target the same molecule. If no other drugs target the same molecule and were previously approved, the drug was identified as first-in-class, otherwise identified as follow-on. It was identified from FDA Search Orphan Drug Designations and Approvals (https://www.accessdata.fda.gov/scripts/opdlisting/oopd/) whether each drug received orphan designation or not. The drug modality of each drug was identified in DrugBank Online. The drug discovery cases of Kyowa Kirin (Tokyo, Japan) were analyzed from literature referred in the case analysis section of Results.

RESULTS

Distribution of Countries of Origin of FDA-Approved New Drugs

From 2017 to 2022, 258 compounds were identified for new drugs approved by the FDA. Of these, the originator of three compounds was unknown. Twelve compounds had two originators, and one compound had three originators. Thus, 269 originators were identified. Of these, 259 were companies and 10 were universities (data not shown). The countries where these companies and universities are located (in the case of companies, the location of their headquarters) were identified, and the numbers are shown for each country or region in Fig. 1. The nationality of the originator companies was overwhelmingly US, with 148 (55%) of the 269 companies being US companies and universities. European countries accounted for 28% of these originator companies and universities (n = 75). There were 26 Japanese companies and universities, accounting for 10% of the total.

Fig. 1. Location of Firm/Academia That Created New Drugs Approved by the FDA from 2017 to 2022

Each column represents the number of originator companies or academic institutions of the drugs that were approved by the FDA from 2017 to 2022 in each country/region in which the originator companies or academic institutions are located.

Distribution of the Establishment Period of Originator Companies of FDA-Approved Drugs in Each Region

The distribution of the establishment periods of the 259 companies that created new drugs approved by the FDA from 2017 to 2022 is shown by region (Fig. 2). In the US, companies founded in the 2000s accounted for 26%, the largest share of new drug originators along with companies founded before 1980. Then, 21% of the companies were founded in the 1990s and 6% in the 2010s, indicating that relatively young companies with a history of approximately 30 years or less are the most common source of new drugs. In Europe, companies established before 1980 accounted for 60% of new drug discoveries, whereas young companies established after 1990 accounted for approximately one-third. In contrast, in Japan, all approved new drugs were created by companies established before 1980. Areas outside the US, Europe, and Japan showed similar distribution of the establishment periods of originator companies as that of the US. These results indicate that relatively young companies founded after 1990 contribute significantly to the discovery of new drugs in regions other than Japan, particularly in the US, whereas, in Japan alone, existing pharmaceutical companies founded before 1980 are responsible for creating all newly approved drugs. Japan is a country with an internationally unique innovation system in which all new drugs were created by old incumbent pharmaceutical companies.

Fig. 2. Distribution of Established Age of Originator Firms of the FDA-Approved Drugs from 2017 to 2022 in Each Region

The distribution of the year of establishment of originator firms of the drugs that were approved by the FDA from 2017 to 2022 is shown by region. The total number of originator firms in each region is set as 100%, and the percentage of each founding year is represented by the height of the column. Light blue represents the percentage of firms founded before 1980, orange represents firms founded in the 1980s, gray represents firms founded in the 1990s, yellow represents firms founded in the 2000s, and blue represents firms founded in the 2010s.

Novelty of New Drugs Created by Japanese Companies

The trend of new drugs is shifting toward first-in-class drugs for orphan diseases because of the increasing reimbursement pressure and the rise of personalized medicine. Additionally, the development of various modalities has increased the number of new drugs for molecular targets that were previously considered “undruggable.” To determine whether Japanese drug discovery matches these global trends, this study examined the percentage of first-in-class drugs, the percentage of drugs receiving orphan designation, and the distribution of modalities used for FDA-approved drugs created by Japanese companies. The results were compared with those of drugs discovered outside Japan (Tables 1–3). Of the approved drugs created by Japanese companies, 25% were first-in-class, and the proportion of first-in-class drugs among approved drugs discovered in other countries was 37% (Table 1); however, no significant difference was observed between the two distributions (chi-square test, p = 0.24). Half of the approved drugs created by Japanese companies received orphan designation (Table 2), and the distribution was not significantly different from that of drugs discovered in other countries (chi-square test, p = 0.75). The distribution of the four modalities (i.e., small-molecule, antibody, protein/peptide, and nucleic acid) was compared between the FDA-approved drugs created by Japanese companies and by foreign companies (Table 3), and no significant difference was found (chi-square test, p = 0.35). These results suggest that the trend of the novelty of recent Japan-originated drugs in terms of first-in-class, orphan drugs, and modality is not different from that of recent drugs discovered in other countries, suggesting that Japanese pharmaceutical companies are responding to technological trends in new drugs.

Table 1. Number of First-in-Class and Follow-on Drugs in the FDA-Approved Drugs from 2017 to 2022 Depending on the Region of Originator Companies

	First-in-class	Follow-on
Japan	6 (25%)	18 (75%)
Non-Japan	87 (37%)	147 (63%)

Table 2. Number of Drugs Receiving and Not Receiving Orphan Designation in the FDA-Approved Drugs from 2017 to 2022 Depending on the Region of Originator Companies

	Orphan	Non-orphan
Japan	12 (50%)	12 (50%)
Non-Japan	125 (53%)	109 (47%)

Table 3. Number of Drugs Using Each Indicated Modality in the FDA-Approved Drugs from 2017 to 2022 Depending on the Region of Originator Companies

	Small molecule	Antibody	Protein/Peptide	Nucleic acid
Japan	16	7	0	1
Non-Japan	146	53	27	8

Analysis of a Japanese Firm with High R&D Productivity

If any Japanese company has demonstrated high R&D productivity in new drug development recently, its R&D strategy probably indicates the direction to which the Japanese pharmaceutical industry should be heading. Therefore, I listed all new drugs approved by the FDA in the 2017–2022 period that were created by Japanese companies (Table 4). Of these, the company that created the most approved drugs was Kyowa Kirin, which created five drugs. Kyowa Kirin ranks approximately 10th among Japanese pharmaceutical companies in terms of R&D expenditure, and this ranking has not changed from at least 2005 to 2020.¹⁸⁾ Thus, the fact that Kyowa Kirin, which does not have a large R&D scale among Japanese pharmaceutical companies, has created the largest number of approved drugs suggests that Kyowa Kirin’s drug discovery productivity is extremely high. Therefore, this study conducted a case analysis of the R&D history of the five approved drugs and the surrounding R&D process of Kyowa Kirin.

Table 4. List of Drugs That Were Originated from Japanese Companies and Approved by the FDA from 2017 to 2022

Originator	Active ingredient	Modality	Market entry
Astellas	Avatrombopag	Small molecule	Follow-on
Astellas/Seagen	Enfortumab vedotin	Antibody-drug conjugate	First-in-class
Astellas/Kotobuki	Gilteritinib	Small molecule	Follow-on
Chugai	Satralizumab	Monoclonal antibody	Follow-on
Chugai	Emicizumab	Bispecific antibody	Follow-on
Daiichi Sankyo	Trastuzumab deruxtecan	Antibody-drug conjugate	Follow-on
Daiichi Sankyo	Pexidartinib	Small molecule	First-in-class
Eisai	Lemborexant	Small molecule	Follow-on
FUJIFILM Toyama Chemical	Ozenoxacin	Small molecule	Follow-on
Kyowa Kirin	Tivozanib	Small molecule	Follow-on
Kyowa Kirin	Istradefylline	Small molecule	Follow-on
Kyowa Kirin	Mogamulizumab	Monoclonal antibody	First-in-class
Kyowa Kirin	Burosumab	Monoclonal antibody	First-in-class
Kyowa Kirin	Benralizumab	Monoclonal antibody	First-in-class
Mitsubishi Tanabe	Edaravone	Small molecule	Follow-on
Nippon Shinyaku/National Center of Neurology and Psychiatry	Viltolarsen	Antisense oligonucleotide	Follow-on
Shionogi	Cefiderocol	Small molecule	Follow-on
Shionogi	Baloxavir marboxil	Small molecule	First-in-class
Shionogi	Lusutrombopag	Small molecule	Follow-on
Shionogi	Naldemedine	Small molecule	Follow-on
Taiho	Futibatinib	Small molecule	Follow-on
Takeda	Relugolix	Small molecule	Follow-on
Takeda	Duvelisib	Small molecule	Follow-on
Wakunaga	Delafloxacin	Small molecule	Follow-on

Case Analysis of a Highly Productive Company: Kyowa Kirin

Of the five drugs that were created by Kyowa Kirin and approved by the FDA from 2017 to 2022, two small-molecule compounds were created by Kyowa Hakko and Kirin Pharma from their respective small-molecule drug discovery efforts before the merger.

Tivozanib

Tivozanib is a small-molecule vascular endothelial growth factor receptor (VEGFR) antagonist discovered by Kirin Pharma. This compound was synthesized as a compound that shows advantages over other VEGFR tyrosine kinase inhibitors. First, it has stronger receptor inhibitory activity than other compounds and is a potent and specific inhibitor of all three VEGFR subtypes.¹⁹⁾ It was also designed to have a long plasma half-life after oral administration and to minimize off-target toxicity.²⁰⁾

Istradefylline

Istradefylline was originally designed as a small-molecule adenosine receptor antagonist in the 1980 s when the former Kyowa Hakko began exploratory studies. The pharmacological concept was established through animal experiments using experimental Parkinson’s disease models, and the prevention of wearing-off with long-term levodopa treatment was selected as an application.²¹⁾ In the 1990s, the company succeeded in developing a clinical candidate by modifying side chains, screening derivatives, evaluating efficacy in animal models of catalepsy, and obtaining structure–activity relationships.²²⁾

Kyowa Kirin was established in 2008 through a strategic alliance between the Kyowa Hakko Group and Kirin Group. The synergies in biotechnology, particularly in the antibody medicine technology possessed by both parties, was expected.²³⁾ Kirin Brewery’s pharmaceutical division had developed a method for producing transchromosomic mice using human chromosomes as vectors and had succeeded in establishing human antibody-producing mice (KM mice) in collaboration with Medarex.²⁴⁾ Kyowa Hakko (Tokyo, Japan) had developed potelligent technology to increase antibody-dependent cellular cytotoxicity (ADCC) activity by removing fucose from the Fc region of immunoglobulin G (IgG) antibodies.²⁵⁾ Kyowa Kirin has built its strength in the R&D of biopharmaceuticals with antibody technology at its core and has succeeded in the successive creation of innovative new drugs, benralizumab, burosumab, and mogamulizumab, all of which are first-in-class drugs.²⁶⁾

Burosumab

Researchers at the former Kirin Brewery, in collaboration with the School of Medicine of the University of Tokyo, discovered FGF23 as a causative factor for rickets and osteomalacia in 2000. Kyowa Kirin created burosumab, an antibody that binds to FGF23 and suppresses its function, and initiated clinical trials.²⁷⁾ Burosumab was developed as a treatment for two rare diseases: X chromosome-linked hypophosphatemia and tumor-induced osteomalacia.²⁷⁾ The FDA approved the drug in 2018.

Benralizumab

Interleukin-5 (IL-5) and IL-5 receptor were discovered by Prof. Takatsu at the Institute of Medical Science, University of Tokyo. Takatsu and Nakajima also found that IL-5 is involved in the proliferative differentiation of eosinophils and causes severe asthma.²⁸⁾ Takatsu and Kyowa Kirin created benralizumab, an antibody that binds to the IL-5 receptor and suppresses its function. Benralizumab has strong ADCC activity because of the application of potelligent technology and shows strong anti-asthma effects not only by suppressing IL-5 signaling but also by injuring and eliminating eosinophils.²⁹⁾

Mogamulizumab

Prof. Matsushima and colleagues at the University of Tokyo identified CCR4 as a chemokine receptor that is selectively expressed in T-helper 2 (Th2) cells.³⁰⁾ Subsequently, Prof. Ueda and colleagues at Nagoya City University found that CCR4 is highly expressed in adult T-cell leukemia/lymphoma (ATL).³¹⁾ Kyowa Hakko began collaborative research with Prof. Matsushima in 1996 and obtained an antibody against CCR4. The antibody was later switched into IgG1 type and modified using potelligent technology, becoming mogamulizumab. In 2001, Kyowa Hakko started collaboration with Prof. Ueda to investigate the efficacy of mogamulizumab in treating ATL, which led to the development of mogamulizumab as a first-in-class drug for ATL.³²⁾

Of the five new drugs approved by the FDA in the 2017–2022 period and created by Kyowa Kirin, two were small-molecule drugs. Both were follow-on drugs created by the former company’s organic synthesis technology before the merger and increased focus on biopharmaceuticals. The remaining three drugs are first-in-class antibody drugs created using Kyowa Kirin’s proprietary antibody medicine technologies. Additionally, all three drugs were created through collaborative research with academic researchers who had discovered novel drug targets.

DISCUSSION

The most interesting finding of this study was that the profile of companies that recently created approved drugs was markedly different between Japan and other countries. Approximately half and one-third of approved drugs were created by biopharmaceutical companies with a short history established after 1990 in the US and in Europe, respectively (Fig. 2). In contrast, in Japan, all approved drugs were created by old incumbent pharmaceutical companies established before 1980 (Fig. 2). Academic scientific discoveries and inventions related to biology and drug discovery technologies are highly used in the discovery of new drugs. Therefore, the rapid application of basic research conducted at universities and public institutions to drug discovery through the establishment of start-ups is an important pathway for new drug R&D. This study suggests that in Europe and the US, particularly in the US, this pathway is well established. Many venture companies that apply academic discoveries to practical use are established, and new drugs are continuously produced through this pathway. In contrast, in Japan, no drug discovery ecosystem via venture entrepreneurship was confirmed. Clearly, there is a lack of a mechanism to translate cutting-edge scientific knowledge from universities and public institutions into drug discovery on a continuous basis via venture companies. Japan’s longstanding weakness of international competitiveness in new drug discovery may be attributed to this lack of a translating mechanism. Although the number of university start-ups is increasing and promising bio-ventures are emerging, they have not yet contributed to the discovery of approved drugs. Therefore, nurturing high-quality bio-ventures that can create approved drugs for the improvement of Japan’s international competitiveness in new drug discovery is an urgent issue. The number of university start-ups peaked in 2022,³³⁾ and the 2019 survey of domestic bio-ventures showed active venture entrepreneurship over the past 5 years, particularly in the fields of drug discovery and digital health.³⁴⁾ Japanese bio-ventures might increase their presence in the future, and I look forward to their development.

In contrast, the novelty of the FDA-approved drugs created by Japanese companies were not significantly different from that of drugs created outside Japan in terms of the percentage of first-in-class drugs (Table 1) and orphan designation (Table 2) and the distribution of modalities (Table 3). This indicates that Japanese pharmaceutical companies are responding to the recent global trends in drug discovery, such as the creation of first-in-class drugs for orphan diseases and the shift to newer modalities, such as antibody and nucleic acid drugs. In contrast, the number of new drugs created by Japanese companies accounts for 10% of the world’s total (Fig. 1), which is almost the same as the number of FDA-approved drugs created between 1998 and 2007. Therefore, the international competitiveness of Japan in terms of the number of new drugs created has not changed.

What direction, then, is desirable for drug discovery in Japan? As mentioned above, there is an urgent need to nurture start-ups. However, because the promotion of university start-up establishment and academic drug discovery activity has not been sufficiently effective so far,^35,36) the reality of this direction is questionable. Rather, enhancing the innovation of old incumbent pharmaceutical companies, which are the main players in new drug discovery in Japan, could be another direction. There are three possible directions for Japanese pharmaceutical companies to pursue based on the analysis of Kyowa Kirin, a company with high R&D productivity that created five of the drugs approved by the FDA from 2017 to 2022.

The first is to invest heavily in the R&D of modality technologies and create strengths there. Many drug targets once considered “druggable” have already been pursued, leaving hard targets that are difficult to control with drugs. New modalities are attracting attention as drug discovery methods for such hard targets. By merging companies with strengths in antibody drugs, Kyowa Kirin further strengthened its antibody-drug-manufacturing technology and created a series of new drugs for target molecules that are difficult to control with small molecules. More recently, novel modalities for challenging drug targets, such as, medium-sized molecules and proteolysis-targeting chimera, are emerging as promising technologies. The diversification of technologies has become the key to creating new drugs, and the development and improvement of new technologies ahead of competitors will continue to give pharmaceutical companies a competitive edge. Takeda (Tokyo, Japan), which has the largest R&D budget in Japanese companies, created only two drugs approved by the FDA between 2017 and 2022 and both were small-molecule drugs (Table 4). Takeda has a history of producing small-molecule blockbuster drugs and this legacy might have delayed the shift to new modalities.

The second point is that collaborative research with universities should be actively used to identify drug targets. In recent years, new drug development of pharmaceutical companies has shifted to first-in-class orphan drugs due to decreased viability of blockbuster model focusing on common diseases with large patient population.⁹⁾ Large Japanese pharmaceutical companies succeeded in the production of best-in-class blockbuster drugs in life-style related diseases in the past. These companies showed lower productivity in the creation of new drugs approved by the FDA between 2017 and 2022 (Table 4), implying delayed shift to this recent drug development trend. In the first-in-class drug development for specific patient population, the access to academic discovery of new molecules is important to identify novel drug targets. In the case of Kyowa Kirin, all three antibody drugs were first-in-class against novel targets discovered by academia researchers. With the strength of modality technology, pharmaceutical companies can quickly develop a drug candidate for a novel target molecule discovered by an academic researcher. By strengthening modality technology development in-house and facilitating academic collaboration regarding drug target identification, pharmaceutical companies could increase their capability to create innovative drugs. Kyowa Kirin is leveraging its existing antibody medicine technology platform to further develop next-generation antibodies.³⁷⁾ This continuous enhancement of antibody modalities will help build sustainable competitiveness.

The third point is to reuse the small-molecule drug discovery capabilities that Japanese companies once had as a strength. Even after focusing on antibody drugs, Kyowa Kirin leveraged its past achievements in small-molecule drug discovery and successfully launched small-molecule drugs. Kyowa Hakko began antibody-related research in approximately 1995. Before that, Kyowa Hakko had a strong track record in small-molecule drug discovery and built strength in synthetic organic chemistry.³⁸⁾ Before the 2000 s, Japanese pharmaceutical companies had strength in creating small-molecule drugs mainly for lifestyle-related diseases, and leveraging this legacy led to the approval of multiple drugs in Kyowa Kirin’s case. The reuse of organic synthesis capability is also effective for future modality technology development. Kyowa Kirin is focusing on developing small-molecule antibodies and is attempting to integrate antibody technology with organic synthesis technology.³⁷⁾ Modalities that can use the strengths of both antibodies and small molecules, such as antibody–drug conjugates,³⁹⁾ and small-molecule-based modalities, such as medium-sized molecules⁴⁰⁾ and proteolysis-targeting chimera,^41,42) have emerged. Focusing on the development of proprietary modality technologies while leveraging technological capabilities cultivated in small molecules and strengthening collaboration with biology research in academia will be effective in improving the drug discovery competitiveness of Japanese companies.

Conflict of Interest

The author declares no conflict of interest.

REFERENCES

• 1) National Institute of Science and technology Policy. “Japanese Science and Technology Indicators 2022.”: ‹https://www.nistep.go.jp/research/science-and-technology-indicators-and-scientometrics/indicators›, accessed 10 January, 2023.
• 2) Dunleavy K. “The top 20 drugs by worldwide sales in 2021.”: ‹https://www.fiercepharma.com/special-reports/top-20-drugs-worldwide-sales-2021›, accessed 10 January, 2023.
• 3) NIKKEI. 12 December, 2021: ‹https://www.nikkei.com/article/DGXZQOUF015SZ0R01C21A0000000/›, accessed 10 January, 2023.
• 4) Okuyama R, Tsujimoto M. Background and current status of academic drug discovery—analysis from standing points of industry, universities and government—. J. Jpn. Soc. Intel. Prod., 13, 127–134 (2017).
• 5) Okuyama R. Chapter 1. Science-based Innovation. Jichosha, Tokyo, pp. 27–45 (2020)
• 6) Kneller R. The importance of new companies for drug discovery: origins of a decade of new drugs. Nat. Rev. Drug Discov., 9, 867–882 (2010).
• 7) Ministry of Economy, Trade and Industry. Database of university start-up.: ‹https://www.meti.go.jp/policy/innovation_corp/univ-startupsdb.html›, accessed 10 January, 2023.
• 8) Morita S. “FEATURE. NIKKEI BP.”: ‹https://project.nikkeibp.co.jp/behealth/atcl/feature/00019/022000005/›, accessed 10 January, 2023.
• 9) Lanthier ML, Kerr KW, Miller KL. An analysis of follow-on development in new drug classes, January 1986–June 2018. Clin. Pharmacol. Ther., 106, 1125–1132 (2019).
• 10) Eichler HG, Bloechl-Daum B, Abadie E, Barnett D, König F, Pearson S. Relative efficacy of drugs: an emerging issue between regulatory agencies and third-party payers. Nat. Rev. Drug Discov., 9, 277–291 (2010).
• 11) Dugger SA, Platt A, Goldstein DB. Drug development in the era of precision medicine. Nat. Rev. Drug Discov., 17, 183–196 (2018).
• 12) Mullard A. FDA approves 100th monoclonal antibody product. Nat. Rev. Drug Discov., 20, 491–495 (2021).
• 13) Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB. The growth of siRNA-based therapeutics: updated clinical studies. Biochem. Pharmacol., 189, 114432 (2021).
• 14) Agarwal P, Sanseau P, Cardon LR. Novelty in the target landscape of the pharmaceutical industry. Nat. Rev. Drug Discov., 12, 575–576 (2013).
• 15) NIKKEI. 7 May, 2022 ‹https://www.nikkei.com/article/DGKKZO60565180W2A500C2TB0000/›, accessed 10 January, 2023.
• 16) Ministry of Economy, Trade and Industry. “4th innovation meeting document.”: ‹https://www8.cao.go.jp/cstp/tyousakai/seidokadai/2kai/sanko1.pdf›, accessed 10 January, 2023.
• 17) Global Entrepreneurship Monitor. “GEM 2021/2022 global report: OPPORTUNITY AMID DISRUPTIO.”: ‹https://gemconsortium.org/report/gem-20212022-global-report-opportunity-amid-disruption›, accessed 10 January, 2023.
• 18) Japan Pharmaceutical Manufacturers Association. “DATA BOOK 2022. 58.”: ‹https://www.jpma.or.jp/news_room/issue/databook/ja/lofurc000000ybyo-att/DATABOOK2022_J_ALL.pdf›, accessed 10 January, 2023.
• 19) Nakamura K, Taguchi E, Miura T, Yamamoto A, Takahashi K, Bichat F, Guilbaud N, Hasegawa K, Kubo K, Fujiwara Y, Suzuki R, Kubo K, Shibuya M, Isae T. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res., 66, 9134–9142 (2006).
• 20) Kyowa Kirin. Press release.: ‹https://www.kyowakirin.co.jp/pressroom/news_releases/2019/pdf/20190801_01.pdf›, accessed 10 January, 2023.
• 21) Kyowa Kirin. Homepage.: ‹https://medical.kyowakirin.co.jp/neuro/info/nrt/001/index.html›, accessed 10 January, 2023.
• 22) Shimada S, Mori A, Kanda T, Toyama K. Discovery of Istradefylline, a novel adenosine A_2A receptor antagonist, as a therapeutic agent for Parkinson’s disease. MEDCHEM NEWS, 24, 37–43 (2014).
• 23) Kirin Holdings. Press release.: ‹https://www.kirinholdings.com/jp/newsroom/release/2007/1022_02.pdf›, accessed 10 January, 2023.
• 24) Takahashi N, Niwa R, Nakano R, Tomizuka K. Strategy for technology development of antibody therapeutics. Nihon Yakurigaku Zasshi (Folia Pharmacologica Japonica), 147, 235–240 (2016).
• 25) Shitara K, Satoh M, Uchida K, Nakamura K. Improvement of effector function of antibody by modification of its oligosaccharide. B&I, 64, 11–16 (2006).
• 26) Kyowa Kirin. Company presentation.: ‹https://pdf.irpocket.com/C2503/vTQq/idan/TvVe.pdf›, accessed 10 January, 2023.
• 27) Hashimoto M. “Focus 20. NIKKEI BP.”: ‹https://business.nikkei.com/atcl/gen/19/00022/032500018/›, accessed 10 January, 2023.
• 28) Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr. Opin. Immunol., 20, 288–294 (2008).
• 29) Nagase H. The role of eosinophils in allergic inflammation indicated by the effect of anti-IL-5 therapy to asthma. Nihon Naika Gakkai Zasshi, 108, 587–593 (2019).
• 30) Imai T, Nagira M, Takagi S, Kakizaki M, Nishimura M, Wang J, Gray PW, Matsushima K, Yoshie O. Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine. Int. Immunol., 11, 81–88 (1999).
• 31) Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, Takeuchi G, Shimizu S, Ito M, Komatsu H, Wakita A, Eimoto T, Matsushima K, Ueda R. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin. Cancer Res., 9, 3625–3634 (2003).
• 32) Ishii T. Development of an anti-CCR4 antibody, mogamulizumab, the first approved antibody made by POTELLIGENT^® technology. Nihon Yakurigaku Zasshi (Folia Pharmacologica Japonica), 142, 167–171 (2013).
• 33) Ministry of Economy, Trade and Industry. “Survey of university start-up.”: ‹https://www.meti.go.jp/press/2022/05/20220517001/20220517001.html›, accessed 10 January, 2023.
• 34) Suzuki N. “Report.”: ‹https://www.jst.go.jp/tt/journal/journal_contents/2019/06/1906-05_article.html›, accessed 10 January, 2023.
• 35) Japan Bioindustry Association. “Report 2015.”: ‹https://www.jba.or.jp/link_file/publication/15_innovation_statistic_summary.pdf›, accessed 10 January, 2023.
• 36) Okuyama R, Tsujimoto M. Issues in academic drug discovery -Analysis for applied drug discovery research capability-. Iryo To Shakai (J. Health Care Soc.), 27, 237–250 (2017).
• 37) Takahashi N. Strategy for technology development of low molecular weight antibody therapeutics. MEDCHEM NEWS, 27, 19–24 (2017).
• 38) Ohshima E. Drug discovery research at Kyowa Hakko Kirin Co., Ltd. MEDCHEM NEWS, 19, 2–6 (2009).
• 39) Yamada K, Ito Y. Recent chemical approaches for site-specific conjugation of native antibodies: technologies toward next-generation antibody-drug conjugates. ChemBioChem, 20, 2729–2737 (2019).
• 40) Ikeda K, Maezawa Y, Yonezawa T, Shimizu Y, Tashiro T, Kanai S, Sugaya N, Masuda Y, Inoue N, Niimi T, Masuya K, Mizuguchi K, Furuya T, Osawa M. DLiP-PPI library: an integrated chemical database of small-to-medium-sized molecules targeting protein-protein interactions. Front. Chem., 10, 1090643 (2023).
• 41) Moon S, Lee BH. Chemically induced cellular proteolysis: an emerging therapeutic strategy for undruggable targets. Mol. Cells, 41, 933–942 (2018).
• 42) Ohoka N, Ujikawa O, Shimokawa K, Sameshima T, Shibata N, Hattori T, Nara H, Cho N, Naito M. Different degradation mechanisms of inhibitor of apoptosis proteins (IAPs) by the specific and nongenetic IAP-dependent protein eraser (sniper). Chem. Pharm. Bull., 67, 203–209 (2019).