Points of View Suggestions for future "co-creation drug discovery Lessons Learned from Research and Development of COVID-19 Therapeutics and Vaccines

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Yuji Takasago, Senior Researcher, National Institute of Biomedical Innovation Policy

Introduction

Since 2020, a pandemic of infectious disease (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) has been raging, causing serious health problems throughout the world. Looking back over the past two decades, emerging infectious disease pandemics such as Severe Acute Respiratory Syndrome (SARS), H1N1 influenza, Middle East Respiratory Syndrome (MERS), and Ebola have occurred, but COVID-19 is the most widespread and the most infectious emerging infectious disease to date (Table 1).

Under these circumstances, the pharmaceutical industry, which plays a role in the development of human health and medical care, has been working with various stakeholders, including academia, drug discovery ventures, and governments around the world to overcome COVID-19, and since last year has continued the challenge of research and development of therapeutic agents and vaccines. The Institute for Pharmaceutical Industry Policy Research (IPIPR) has been working with a wide range of stakeholders, including academia, drug discovery ventures, and governments around the world, in the research and development of therapeutic drugs and vaccines since last year.

While the Pharmaceuticals and Industrial Policy Research Institute (PIIPRI) has previously reported on R&D for COVID-19 therapeutics and other products from a variety of ^{perspectives1)-3)}, this paper compares R&D trends in emerging infectious diseases and COVID-19 therapeutics and vaccines over the past 20 years and presents progress in this area. In addition, we define "co-creation drug discovery" as "drug discovery through collaboration with various stakeholders" or "rapid drug discovery through collaboration." We will also present the challenges that pharmaceutical companies face in co-creation drug discovery for COVID-19 therapeutics and vaccines, and discuss the key points of co-creation drug discovery that can be applied to drug discovery for emerging and reemerging infectious diseases or other disease areas that may occur in the future. The key points of co-creation-type drug discovery that can be applied to drug discovery for emerging and reemerging infectious diseases or other disease areas that may arise in the future will be summarized.

Global R&D Trends in Emerging Infectious Disease Therapeutics and Vaccines

We surveyed global R&D trends of therapeutics and vaccines for SARS/MERS, influenza, Ebola, and COVID-19, which have been prevalent for the past 20 years, using Pharmaprojects, which mainly contains pipeline information from pharmaceutical companies.

Table 2 summarizes the number of drugs and vaccines that have been developed or launched for these emerging infectious diseases. Compared to Table 1, it can be seen that the number of items for the infectious disease correlates to some extent with the number of infected patients and the expansion of endemic areas.

The number of drugs and vaccines for SARS/MERS, influenza, and Ebola were selected from those with development stage records in Pharmaprojects, and the number of drugs and vaccines for SARS/MERS, influenza, and Ebola was examined from 2000 (Fig. 1). The figure shows that the development of both drugs and vaccines has been active during the infectious disease epidemic periods indicated by the colored backgrounds in the figure. In addition, the development of emerging infectious diseases other than COVID-19 is on the rise again in 2020, but it is thought to be associated with COVID-19, which is the main indication, as many of the diseases are in the preclinical stage.

A survey of the number of COVID-19 drugs and vaccines by development stage shows that several items have already been launched, as evidenced by media reports (Figure 2). The average time from preclinical to market was calculated to be 326 days for therapeutics (3 items) and 293 days for vaccines (8 items), by extracting items for which preclinical stage records exist. With more than a year having passed since the spread of the disease, it is evident that pharmaceutical companies have launched numerous projects and are rapidly conducting research and development with concerted efforts.

The percentage of nationalities of companies developing therapeutics and vaccines was surveyed by emerging infectious disease (Figures 3 and 4). For both emerging infectious diseases, U.S.-based companies are involved in the development of the largest number of both therapeutics and vaccines. Japanese companies are in the top three to six positions for therapeutics and three to four for vaccines. In addition, a characteristic point is that, unlike the nationalities of companies creating NME-approved products in Japan, the U.S., and ^{Europe7) that} were previously surveyed by the Pharmaceuticals and Industrial Policy Institute, relatively high rankings for products in the emerging infectious disease field are held by countries with past epidemics of infectious diseases and by China, South Korea, and Russia, which regard infectious disease control as part of their national security measures. It can be inferred that in these countries, the state is strategically leading the research and development of infectious disease drugs and vaccines in a contingency.

Trends in the number of acquired pipelines and in-licensing agreements at the time of acquisition by pharmaceutical companies in the field of infectious diseases

In recent years, as the difficulty of creating innovative drugs has been increasing, pharmaceutical companies are increasingly required to engage in drug R&D through collaboration with various stakeholders, including academia and drug discovery ventures. In response, EvaluatePharma, which collects information based on each company's news releases, financial announcements, and other public materials, conducted a survey of the number of products and license-in agreements acquired by pharmaceutical companies through acquisitions in the field of infectious diseases.

Figure 5 shows the number of companies acquired globally since 2000 and the number of pipelines in the infectious disease area acquired through acquisitions. On the other hand, the number of pipeline acquisitions in the infectious disease area in 2020 is increasing compared to 2019. To confirm the details, there seems to be a certain increase in acquisition momentum to overcome emerging infectious diseases that may occur in the future, including COVID-19, such as Merck & Co.'s acquisition of Themis Bioscience, which is developing the COVID-19 vaccine, in June 20208 ⁾ COVID-19. Although the largest number of pipeline acquisitions in the infectious disease area occurred in 2013, there were no top deals for the acquisition of a therapeutic or vaccine for MERS, which was in the midst of an epidemic at the time of the acquisition. The number of deals for MERS in the emerging infectious disease epidemic period other than COVID-19 is not high throughout the entire period.

Figure 6 shows the number of in-licensing agreements in the all disease area and the infectious disease area. The number of agreements in the all disease area has been on a declining trend since 2019. On the other hand, the number of contracts in the infectious disease area is on a gradual downward trend from 2003 to 2019, but is increasing significantly in 2020.

A look at the number of licensed-in contracts by emerging infectious disease shows that the number of contracts related to COVID-19 is increasing rapidly in 2020 (Figure 7). On the other hand, the number of license-in contracts does not increase as much as COVID-19 during other emerging infectious disease epidemics, suggesting that pharmaceutical companies have been vigorously promoting R&D using license-in contracts since the COVID-19 outbreak.

Case Studies of "Co-Creation Drug Discovery" in COVID-19 Therapeutics and Vaccines

As mentioned above, pharmaceutical companies have been actively engaged in research and development of therapeutic drugs and vaccines for emerging infectious diseases in accordance with the epidemics that have occurred. In response to COVID-19, a number of therapeutic drugs and vaccines are being researched and developed around the world based on "drug discovery through collaboration with various stakeholders" or "rapid drug discovery through collaboration. We define such efforts as "co-creation drug discovery" and introduce some of the characteristics and summarize key points for future "co-creation drug discovery.

1. Co-creation with venture companies in mRNA vaccine R&D

Pfizer and BioNTech announced on December 2, 2020 (U.S. local time) that the UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted the first-ever emergency use of an mRNA vaccine candidate (BNT162b2) against ^COVID-199). On March 17 of the same year, less than a year after the two companies ^announced10) that they had agreed to joint development, they obtained permission to use an mRNA vaccine, a novel technology that has never been commercialized before. Since it takes a very long time to develop conventional vaccines against various infectious diseases, Philip Ball's report shows that the development of the COVID-19 vaccine has been put into practical use with unprecedented speed. ¹¹⁾ Research on mRNA-based vaccines has been conducted by drug discovery companies such as Moderna and The development of mRNA-based vaccines has been actively pursued mainly by drug discovery ventures such as Moderna and BioNTech. In this section, we will summarize the trends of mRNA vaccine research and development, focusing on the initial R&D activities by drug discovery ventures and pharmaceutical companies, to understand how new technologies could be put to practical use so quickly.

Using EvaluatePharma, we examined licensing agreements between major drug discovery ventures and pharmaceutical companies involved in mRNA vaccine R&D that were announced prior to the COVID-19 epidemic period, before 2019. Table 3 shows the license-in agreements related to mRNA vaccine items from drug discovery ventures to pharmaceutical companies, and Table 4 shows the technology licensing agreements related to mRNA from drug discovery ventures to pharmaceutical companies. From these tables, it can be seen that as early as 2011, megapharmaceutical companies in Europe and the U.S. have started to acquire mRNA vaccine technologies in the infectious disease and oncology fields in large numbers. Noteworthy is the development stage of each project at the time of contracting. Most of the projects were in the "research project" or "preclinical" stage before entering clinical development. It can be inferred that these megapharmaceutical companies focused on mRNA vaccine technology at an early stage when practical application was not foreseeable, and took the risk of embarking on research and development. And there is no doubt that the fact that Pfizer and BioNTech had already started working together on influenza infection as of 2018 is one of the factors that led to the rapid and successful research and development of the COVID-19 mRNA vaccine.

While Western megapharmaceutical companies have been focusing on mRNA vaccines since the early 2010s, Japanese pharmaceutical companies, although some of them have been promoting collaboration with domestic academia and other organizations, unfortunately, no evidence of contact with Western drug discovery ventures that are actively engaged in mRNA vaccine development was found in this survey. Unfortunately, the survey found no evidence of contact with European or U.S. drug discovery ventures that are vigorously developing mRNA vaccines. As reported by ^Hashimoto12) and ^{Kagii3) of the} Pharmaceutical and Industrial Policy Research Institute (PIIPRI), Japanese companies have not been so active in bringing in products from outside in the early clinical stages, not only in the field of infectious diseases but also in various other disease areas. In comparison with European and U.S. pharmaceutical companies, there are many cases where products that have already been launched overseas are introduced in the late clinical stage and developed in Japan. This situation has surfaced in the development of the COVID-19 vaccine, and it is believed that the company is lagging behind foreign competitors.

However, Pfizer and Sanofi are the only Western megapharmaceutical companies listed in Tables 3 and 4 that are involved in COVID-19 mRNA vaccine development. Other megapharmaceutical companies are, for example, Johnson & Johnson with its own proprietary ^{technology13)} and Merck & Co. with the technology of Themis Bioscience, which it acquired in ^202014), both of which are classified as viral vectors for COVID-19 vaccine Both companies have been working on the development of a COVID-19 vaccine, which is classified as a viral vector.

Not all megapharmaceutical companies that approached mRNA technology prior to the COVID-19 epidemic have begun developing mRNA vaccines for COVID-19. Why? The reason is not clear, but one can imagine that perhaps there has been some breakthrough in mRNA vaccine technology since around 2018, when Pfizer and Sanofi each signed a license agreement with a drug discovery venture, that has led directly to practical applications. Sanofi licensed the technology from CureVac in 2011, but was unable to commercialize it due to the immaturity of the technology at that time, but re-entered the market in June 2018 through a licensing agreement with Translate Bio and will begin commercialization in March 2021. In June 2018, the company re-entered the market through a license agreement with Translate Bio, and in March 2021 began clinical trials of an mRNA vaccine against COVID-19, also in collaboration with Translate ^Bio15).

From the above, it can be seen that in order for domestic pharmaceutical companies to introduce promising new external technologies and lead them to commercialization, it is necessary to approach them at the appropriate timing, keeping an eye on the progress of the relevant technologies as much as possible. However, it is extremely difficult to precisely identify the right timing. It will be increasingly necessary for domestic pharmaceutical companies to keep an eye on cutting-edge science and technology outside the company, including overseas projects, and to actually come into contact with these technologies and experience their capabilities firsthand. In addition, as in the case of Sanofi, whose core business has been vaccines for many years, it will be necessary to continue to monitor technologies that were once abandoned from a long-term perspective.

In addition, while BioNTech obtained know-how for large-scale clinical trials and mass production technology from Pfizer while obtaining private funding, Moderna succeeded in commercializing mRNA vaccines by obtaining government funding from the National Institutes of Health (NIH) and the U.S. Biomedical Advanced Research and Development Authority (BARDA). ³⁾. A system like that of the U.S., in which a nation can strategically support drug discovery ventures, is thought to have played an important role in the development of mRNA vaccines.

As described above, a comparison of the efforts of each pharmaceutical company with regard to mRNA vaccine R&D during the COVID-19 epidemic clearly reveals points that can be used for the introduction of any external new seeds and technologies in the future.

2. Global co-creation by multiple competing companies

On March 4, 2020, Takeda announced the start of development of a plasma fractionated formulation for the treatment of COVID-19. Relevant developments since then are shown in Table 5.

Since April 2020, 10 of the world's top manufacturers of plasma-fractionated products have gathered one after another, as well as members from other industries, in an initiative called the CoVIg-19 Alliance, to conduct research and development to rapidly deliver a therapeutic agent to patients amid the widespread prevalence of COVID-19. In April 2021, although the results of the Phase III clinical trial were announced and development was reported to be discontinued, many competing companies quickly promoted therapeutic drug development through co-creation. Table 6 shows the top global companies by number of blood products. Of the top 15 companies, more than half (8) are participating in the Alliance, and in addition, all 10 participating companies are of different nationalities. One of the reasons why the alliance of many top plasma fractionation companies from different nationalities was able to move forward so quickly is due in part to the unique environment of an infectious disease pandemic. Normally, when many companies participate in an alliance, the delineation of competitive and non-competitive areas and various rights must be thoroughly discussed prior to the development of a therapeutic drug, and a considerable amount of time is required before an agreement is concluded. On the other hand, in this alliance, the companies were able to proceed with discussions quickly and smoothly without giving priority to profit (business).

In addition, in promoting the project, it is thought that co-creation was practiced in order to bring together the resources, technologies, and other strengths of each participating company and combine them to develop the project more quickly. Specifically, the use of Microsoft's digital technology to efficiently collect plasma from people recovered from COVID-19, the manufacture and provision of advanced intravenous immunoglobulin (H-Ig) for clinical trials by four companies including CSL Behring and Takeda Pharmaceutical Company, and other factors contributed to the speed and efficiency of the project. The four companies, including CSL Behring and Takeda, manufactured and provided the advanced intravenous immunoglobulin (H-Ig) for the clinical trials. Takeda's strong initiative in spearheading this alliance should also be highly evaluated. In addition, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) funded and collaborated in the Phase III clinical trials, providing strong support not only in terms of funding, but also in patient recruitment, and this is believed to have helped the project move forward quickly.

Although it may be difficult to utilize the experience gained through this alliance under normal circumstances from a rights perspective, we expect that the know-how gained through this alliance will be utilized for therapeutic drugs and vaccines of various modalities, including plasma fractionated drugs, in the infectious disease pandemics that may occur in the future.

3. Co-creation for the entire disease spectrum, from treatment to prevention, diagnosis, and control of severe disease

On June 1, 2020, Shionogi announced its new mid-term business plan through FY2024, in which the company reported that it aims to care for the entire spectrum of diseases, including diagnostic, preventive, and unwell, through a diverse approach that includes partnering strategies, with the core strength of the pharmaceutical company, therapeutic drugs (Figure 8).

The company is using the COVID-19 epidemic as an opportunity to push forward with co-creation in areas other than therapeutics at an unprecedented speed. The company's collaborative efforts in response to COVID-19 are shown in Table 7. It shows that the company is working to achieve total care for COVID-19 in the non-therapeutic Disease Journey, including epidemic forecasting, prevention, diagnosis, and control of severe disease, as well as drug discovery research, in collaboration with various stakeholders, including academia, pharmaceutical companies, and non-pharmaceutical industries.

In addition, the company has concluded a license agreement with a joint research team from Nihon University, Gunma University, and Tokyo Medical University that has developed a completely new and innovative nucleic acid amplification method (SATIC method) for rapid virus diagnosis, and has licensed out a DP1 receptor antagonist discovered in-house to BioAge for the prevention of severe COVID-19 disease. The company effectively utilizes a variety of partnerships by acquiring assets it does not have from outside sources and providing its existing assets to outside parties, depending on the project. Diversity of human resources is one of the key factors in creating innovation, and this will increase opportunities for new innovations to be created not only in ongoing projects but also in future projects.

The impact of the company's disease-wide work on COVID-19 on the pharmaceutical industry is significant, as many in the healthcare industry, including pharmaceutical companies, are working to shift healthcare from treatment to prevention and disease prevention in a variety of disease areas, We hope that the company's disease-wide efforts to address COVID-19 will have a significant impact on the pharmaceutical industry.

Summary

In this paper, we compare the R&D trends of emerging infectious diseases and COVID-19 therapeutics/vaccines over the past 20 years, and present the challenges that pharmaceutical companies face from co-creation of COVID-19 therapeutics/vaccines, and discuss the future co-creation of therapeutics that can be used for drug discovery for emerging and reemerging infectious diseases or other disease areas that may occur in the future. The following is a discussion of the key points of future co-creation-type drug discovery that can be used for drug discovery in emerging and reemerging infectious diseases or other disease areas that may arise in the future.

Points that can be utilized for future co-creation drug discovery

Although the database used in this survey is based on publicly available information, it is assumed that more COVID-19-related projects are being undertaken globally if unpublished projects are included. The pharmaceutical industry is now working as an industry to respond to the COVID-19 pandemic, either by concentrating all of its resources or by collaborating with a variety of stakeholders.

In addition, although it deviates from the category of co-creation drug discovery as defined in this paper, the success of mRNA vaccine development as described above is supported by the government and pharmaceutical companies, which have provided strategic financial and other support for mRNA technologies developed in academia for various target diseases other than COVID-19, such as Ebola hemorrhagic fever, influenza, and cancer. There is a background of strategic financial and other support from the government and pharmaceutical companies. A mechanism to continuously foster drug discovery ventures with novel technologies is also important.

In addition, unless new seeds and technologies are created by basic research in academia, drug discovery ventures will naturally not be born. As the Japan Business Federation ⁽ Keidanren) ²⁰⁾ suggests, it is difficult for companies to directly invest in basic research by academia, etc., which aims to create disruptive innovations through diversity and fusion, without setting any issues or short-term goals, because it is extremely difficult to obtain targeted results. In Japan in particular, the government should invest funds widely and over the long term in this area as well to further enhance basic research in Japan.

On May 25, 2021, the Japanese government held a meeting of the Council on Drug Development under the Health and Medical Care Strategy Headquarters, and compiled issues and measures for strengthening the domestic vaccine development and production system as ^{recommendations21)}. The "Strategy for Strengthening Vaccine Development and Production Systems," formulated based on these recommendations, was approved by the Cabinet on June 1, ^202122). It is necessary for industry, academia, government, and medical institutions to work together to quickly establish a domestic vaccine development environment that will enable rapid response in the event of an infectious disease outbreak, even in normal times. It is our earnest hope that this strategy will not become mere idealism, and that it will be put into action immediately.

In the wake of the COVID-19 outbreak, I strongly hope that collaboration among various stakeholders will be increasingly promoted, and that co-creation drug discovery will make further progress not only in the area of emerging infectious diseases but also in other disease areas.

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