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

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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 has been the most widespread and the most infectious emerging infectious disease to date. COVID-19 is the most widespread and the most frequently infected emerging infectious disease to date. Therefore, in this newsletter, we introduce "co-creation drug discovery" as seen in the research and development of COVID-19 therapeutics and vaccines, which was discussed in Policy Research Institute News No. 63*1.

Introduction

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 since 2020, and has been involved in the research and development of drugs and vaccines for emerging infectious diseases in a way that has been rare in the past. The Covidien Institute has also been involved in the research and development of COVIDA, a unique approach that has been rare among past research and development efforts in the field of emerging infectious diseases.

In this report, we define "co-creation drug discovery" as "drug discovery through collaboration with various stakeholders" or "rapid drug discovery through collaboration", and we will discuss how pharmaceutical companies have been involved in the co-creation of COVID-19 therapeutics and vaccines. The report also outlines key points of co-creation drug discovery that can be applied to the discovery of drugs for emerging and reemerging infectious diseases and other disease areas that may arise in the future.

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

There are many therapeutic drugs and vaccines being researched and developed around the world for COVID-19. Some of the most notable examples of such "co-creation-type drug discovery" are introduced below.

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

Pfizer and BioNTech announced on December 2, 2020 (U.S. local time) that the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) had granted the first-ever emergency use of an mRNA vaccine candidate (BNT162b2) against COVID-19*5 On March 17, 2020, the two companies announced an agreement to co-develop 5 On March 17 of the same year, less than a year after the two companies announced*6 that they had agreed to jointly develop an mRNA vaccine, a novel technology that has never been put to practical use before, the two companies obtained permission to use the mRNA vaccine. 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 to practical use in an unprecedentedly rapid manner*7. mRNA-based vaccine research has been conducted by drug discovery companies such as Moderna and BioNTech. 7 Research on mRNA-based vaccines has been actively conducted 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 find out how a new technology could be commercialized so quickly.

Using EvaluatePharma, we examine 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 1 shows license-in agreements from drug discovery ventures to pharmaceutical companies related to mRNA vaccine products, and Table 2 shows technology licensing agreements from drug discovery ventures to pharmaceutical companies related to mRNA. 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. It can be inferred that these megapharmaceutical companies focused on mRNA vaccine technology from the early stage, when its commercialization was not foreseeable, and embarked on research and development, taking the risk. Pfizer and BioNT were the first to develop mRNA vaccine technology in the early stages. And there is no doubt that the fact that Pfizer and BioNTech had already started working together on influenza infections as of 2018 is one of the factors that led to the rapid and successful research and development of the COVID-19 mRNA vaccine.

Table 1 Licensing-in Agreements from Major Venture Companies Engaged in mRNA Vaccine R&D (~2019)
Note: Arbutus Biopharma, Arcturus Therapeutics, Argos Therapeutics, BioNTech, CureVac, eTheRNA immunotherapies, Ethris, Eukarys, Moderna, Translate Research Bio
Source: EvaluatePharma (as of May 2021)

Table 2: Major Venture-Backed Technology Licensing Agreements Involving mRNA Vaccine R&D (~2019)
Note: Arbutus Biopharma, Arcturus Therapeutics, Argos Therapeutics, BioNTech, CureVac, eTheRNA immunotherapies, Ethris, Eukarys, Moderna, Translate Research Bio
Source: EvaluatePharma (as of May 2021)

While European and US 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 others, unfortunately we could not find any evidence of contact with European and US drug discovery ventures that are vigorously engaged in mRNA vaccine development in this survey. Unfortunately, we were unable to find any evidence of contact with Western drug discovery ventures that are actively engaged in mRNA vaccine development. As previously reported by Eriko Hashimoto*8 and Hideyuki Kagii*4 of the National Institute for Policy Studies, 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 domestically. This situation has surfaced in the development of the COVID-19 vaccine, and it is believed that the company is lagging behind its overseas competitors.

However, Pfizer and Sanofi are the only Western megapharmaceutical companies listed in Tables 1 and 2 that are involved in COVID-19 mRNA vaccine development. Other megapharmaceutical companies, for example, Johnson & Johnson using its own proprietary technology*9 and Merck & Co. using the technology of Themis Bioscience acquired in 2020*10, are both working on developing COVID-19 vaccines that are classified as viral vectors 10 Both companies are 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 is this? 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 licenses with drug discovery ventures, that 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. 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 Bio*11.

The above indicates that in order for domestic pharmaceutical companies to introduce and commercialize promising new external technologies, it is necessary to approach them at the appropriate timing while keeping an eye on the progress of the technology as much as possible. However, it is extremely difficult to accurately 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 also be necessary to continuously watch 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). The U.S. system of strategically supporting drug discovery ventures as a nation also played an important role in the development of the mRNA vaccine. 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.

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 3.

Table 3: CoVIg-19 Alliance Trends
Source: Takeda Pharmaceutical Company News Release*12

After April 2020, ten of the world's top manufacturers of plasma-fractionated drugs came together one after another, and members from other industries joined them in the CoVIg-19 Alliance, an initiative to rapidly deliver therapeutic drugs to patients in the midst of the COVID-19 epidemic. 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 moved forward with therapeutic drug development through co-creation. Table 4 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 this alliance of top plasma fractionation companies of different nationalities was able to move forward so quickly is due to the unique environment of an infectious disease pandemic. When many companies participate in an alliance, it usually takes a considerable amount of time to conclude an agreement because the line between competitive and non-competitive areas and various rights must be thoroughly discussed prior to the development of a therapeutic drug. On the other hand, in this alliance, each company was able to proceed with discussions quickly and smoothly without giving priority to profit (business).

Table 4 Top Global Companies by Number of Blood Fractionation Products
Note: Companies highlighted in gray are CoVIg-19 Alliance participants (or related companies)
Source: Pharmaprojects(R) | Informa, 2021 (as of May 2021)

In addition, in promoting the project, each participating company brought its resources, technology, and other strengths to the table, and co-creation was practiced in order to combine them for faster development. Specifically, the use of Microsoft's digital technology to efficiently collect plasma from people recovering from COVID-19, the manufacture and supply of advanced intravenous immunoglobulin (H-Ig) for clinical trials by four companies including CSL Behring and Takeda, 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 is also to be commended. 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 trial, which provided strong support not only in terms of funding but also in patient recruitment, and 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 hope that the know-how gained through this alliance will be utilized in the treatment of various modalities of drugs and vaccines, including plasma fractionated drugs, in the event of an infectious disease pandemic that may occur in the future.

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 its pharmaceutical company, therapeutic drugs ( Figure 1 ).

Figure 1: Shionogi's "Approach to Disease Strategy
Source: Shionogi's new medium-term business plan*13

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 5. It shows that the company is working to realize 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. The COVID-19 is a new and innovative product that has never been seen before.

Table 5 Shionogi's Collaborative Efforts for COVID-19
Source: Shionogi press release*14, based on FY2020 financial results*15

In addition, we have 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 we have licensed out a DP1 receptor antagonist discovered and developed by our company to BioAge For example, we have out-licensed a DP1 receptor antagonist discovered in-house to BioAge, Inc. for the inhibition of COVID-19 severity of disease, and we make effective use of various partnering arrangements by acquiring assets that we do not have from external sources and providing existing assets that we do have to external parties for each project. Diversity of human resources is one of the most important factors in creating innovation, and it is believed to increase opportunities for new innovations to be created not only in ongoing projects but also in future projects that the company is involved in.

The company's disease-wide commitment to COVID-19 will have a significant impact on the pharmaceutical industry, 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 expect that the company's disease-wide commitment to COVID-19 will have a ripple effect on the pharmaceutical industry, not only on COVID-19-related projects, but also on industry-wide R&D in a wide variety of diseases.

Summary

In this report, we present the challenges that pharmaceutical companies face from co-creation of COVID-19 therapeutics and vaccines, and discuss the following points for future co-creation of drugs that can be used for the discovery of drugs for emerging and reemerging infectious diseases or other disease areas that may arise in the future.

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. And the pharmaceutical industry is trying to respond to the COVID-19 pandemic with an industry-wide effort, either by each company focusing all its resources or by collaborating with various 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 due to the strategic financial support provided by the government and pharmaceutical companies for mRNA technologies developed in academia for a variety of target diseases other than COVID-19, including Ebola, influenza, and cancer. The government and pharmaceutical companies have provided strategic financial and other support for the development of mRNA technology. We believe that it is also important to have a mechanism to continuously nurture drug discovery ventures with novel technologies.

In addition, unless new seeds and technologies are created through basic research in academia, drug discovery ventures will naturally not be born. As the Japan Business Federation has proposed*16, it is difficult for companies to directly invest in basic research by academia, etc., which aims to create disruptive innovation through diversity and fusion without setting issues and 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 Strategic Headquarters, and compiled issues and measures for strengthening the domestic vaccine development and production system as recommendations*17. It is necessary for industry, academia, government, and medical institutions to work together to promptly establish a domestic vaccine development environment that will enable rapid response in the event of an infectious disease outbreak, even in normal times. I sincerely hope that this strategy will not be merely idealistic, and that it will be put into action immediately.

I strongly hope that the COVID-19 outbreak will promote collaboration among various stakeholders and further advance co-creation drug discovery, not only in the area of emerging infectious diseases but also in other disease areas.

( Yuji Takasago, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute)

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