Topics Global R&D Trends of Drugs for Prevention and Treatment of Novel Coronavirus Infections (COVID-19)

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Hideyuki Kagii, Senior Researcher, Pharmaceutical Industry Policy Institute

1. Introduction

On December 31, 2019, a new type of coronavirus (SARS-CoV-2, the disease caused by which was named COVID-19), reported as a new type of pneumonia of unknown cause in Wuhan, China, quickly spread throughout the world. according to the WHO ^website1), as of June 8, 6.9 million people were infected and more than 400,000 people have died. Countries around the world have imposed legally binding lockdowns, and national emergency declarations have been issued, which have had a tremendous impact on the economy, including restrictions on the movement of people. Although the impact in Japan was less than in Western countries due to the efforts of many people, including government and medical personnel, it was a reminder of the important role of pharmaceuticals in supporting people's health, safety, and security.

As of the end of May, about six months after the report of the new coronavirus case, development of vaccines and therapeutic drugs is proceeding at a rapid pace in countries around the world. In Japan, Lemdecivir (brand name: Becluri) was urgently approved, and clinical trials for Avigan and Actemra are underway. National authorities are also supporting the development of vaccines/therapeutics for coronaviruses from various aspects, including science, regulation, review, and funding.

While there is a global need for a vaccine/treatment against COVID-19, this report examines the movement of authorities in Japan, the U.S., and Europe, as well as the pipeline of COVID-19-related drugs.

2) Movements of governments and authorities in each country, international cooperation, etc.

(1) U.S.

In the U.S., the U.S. Food and Drug Administration (FDA) launched the Coronavirus Treatment Acceleration Program (CTAP), a public-private partnership to accelerate the development of COVID-19 drugs, on March 31, ²⁰¹²²⁾. Under this partnership, the FDA provides immediate scientific or regulatory advice to researchers and pharmaceutical companies. In addition, on May 11, the agency issued a pre-IND consultation on COVID-19 drug development and guidance to assist in conducting clinical trials. The National Institutes of Health (NIH) funds a wide range of topics, from basic research on the molecular mechanisms of novel coronaviruses to the diagnosis, prevention, and treatment of COVID-19, and conducts its own clinical trials. The U.S. government has provided approximately $1.8 billion in additional COVID-19-related funding to the NIH, of which more than $1.5 billion is related to the National Institute of Allergy and Infectious Diseases (NIAID) ^.3 On April 17, the NIH led a global public-private partnership, Accelerating (ACTIV), a global public-private partnership led by the NIH, was launched on April 17 to create a mechanism for advancing COVID-19-related research and development and to prioritize ^projects4). The ACTIV is comprised of five organizations: the FDA, NIH, ASPR (U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, which is responsible for emergency operations functions during a pandemic), CDC (Centers for Disease Control and Prevention), and EMA (European Medicines Agency) from the "government" sector, and global megapharmaceutical companies from the "private sector" sector. In addition to global megapharmaceutical companies, biotech companies such as Evotec, KSQ Therapeutics, and Vir Biotechnology, and Takeda Pharmaceutical Company Limited, a domestic company, are participating from the "private sector. Furthermore, on April 29, the NIH organized the Rapid Acceleration of Diagnostics (RADx) to accelerate the diagnostic technology of COVID-19, with the goal of commercialization by the fall of this ^year5). In addition, the U.S. Biomedical Advanced Research and Development Authority (BARDA) ^{6), which} belongs to the U.S. Department of Health and Human Services, has awarded approximately $430 million to the U.S. company Moderna, which is developing an mRNA vaccine, and $150 million to Janssen Research & Development (drug against SARS-CoV-2 screening for SARS-CoV-2) for a total of more than $1.2 ^billion7).

(2) Europe

The European Medicines Agency (EMA) waived COVID-19 drug development advisory and GMP site visit fees for one year. In addition, the EMA has stated that it will accelerate the development of COVID-19-related products by shortening the review ^period8). As examples from other countries, in the United Kingdom, the National Institute for Health Research (NIHR) and the UK Research and Innovation Agency issued a research call for new corona-related research totaling 20 million euros. In France, REACTing, a national consortium run by the National Institute for Health and Medical Research (Inserm), has funded 20 research themes on a wide range of basic and epidemiological studies on novel ^{coronaviruses9)}.

(3) Japan

In Japan, Lemdesivir was granted special exception approval on May 7, just three days after the application (May 4) (emergency use authorization was granted in the U.S. on May 1 and compassionate use in Europe). According to the MHLW's notification, clinical trials for the development of new corona-related drugs can be conducted within 30 days of the submission of a notification of clinical ^trial10), review and investigation will be conducted with the highest ^priority11), and if a certain level of efficacy and safety has been confirmed through public research, clinical trials and other study results may be submitted and As for AMED's efforts, a total of approximately 8.4 billion yen has been invested in research and development on emerging infectious diseases such as COVID-19 in phases since February 13, 2011. In addition, the second supplementary budget approved by the Cabinet on May 27 allocated a total of 60.9 billion yen for research and development related to novel coronaviruses. This includes 50 billion yen for projects to promote vaccine development, including support for phase II and III trials, and 5 billion yen for research and development of therapeutic agents with new mechanisms of ^action13).

(4) International collaboration

In terms of international coordination, the International Collaboration of Medicinal Regulatory Authorities (ICMRA) has pledged to provide regulatory support for medical device and drug development in response to the global COVID-19 pandemic. ¹⁴⁾

The International Collaborative Partnership (ACT Accelerator) ¹⁵⁾, in which WHO plays a central role, is responsible for accelerating innovation and equitable access to diagnosis, prevention, and treatment related to COVID-19. Participating organizations include many international organizations such as CEPI (Coalition for Pandemic Preparedness Innovation), GAVI (Global Alliance for Vaccines and Immunization), the Global Fund (Global Fund to Fight AIDS, Tuberculosis and Malaria), UNITAID (UnitAID), as well as industry organizations such as IFPMA (International Federation of Pharmaceutical Manufacturers and Associations, Japan Pharmaceutical Manufacturers Association, Inc. The Global Fund (Global Fund to Fight AIDS, Tuberculosis and Malaria), UNITAID (UnitAid), and many other international organizations. As of June 9, CEPI, a public-private partnership launched in January 2017 in Davos to promote vaccine development through global collaboration, has funded research on nine themes, including Oxford University's project on recombinant protein nanoparticles (up to $38.8 billion). ¹⁶⁾

The above are just a few examples of the efforts of individual countries and international collaboration. In emergency situations such as pandemics, in addition to governments taking leadership in promoting drug development, international collaboration is actively used to promote the development of therapeutic drugs and vaccines, speed up the review process, and share information on regulations and technologies. In addition, international collaboration is actively taking place to promote therapeutic drug and vaccine development, expedite the review process, and share information on regulations and technologies.

Trends in drug development

3.1 New coronavirus infection mechanisms and drug targets

Coronaviruses are RNA viruses, consisting of genomic RNA and an envelope that envelopes the RNA. The S protein on the surface of the coronavirus envelope recognizes angiotensin-converting enzyme 2 (ACE2) on the human cell membrane, and activation of the enzyme TMPRSS2 causes the envelope and cell membrane to fuse, allowing the genomic RNA in the envelope to enter the cell, Proteins and genomic RNAs necessary for viral replication are synthesized (see Figure 1).

Approaches to COVID-19 drug development include vaccines to induce immunity against the virus, antibodies against S proteins and other viral component proteins, regulation of ACE2 and related proteins, inhibition of virus-related enzymes (RNA polymerase), and others. Remdecivir and favipiravir (brand name: Avigan) are RNA polymerase inhibitors. Clinical trials are also underway for anti-inflammatory agents such as anti-IL-6 antibodies and JAK inhibitors, as cytokine storm, an excessive immune response in COVID-19, has a significant impact on patient prognosis.

3.2 Pipeline analysis

(1) Number of COVID-19 products in development and development stage

• Number of items analyzed

  In this study, using the drug database EvaluatePharma, pipeline data from each company that is developing COVID-19 for prevention (mainly vaccines) and treatment were extracted and organized by ^compound18). The number of items analyzed in this study is shown in Table 1. Data as of May 19, 2020 were used for this analysis. ¹⁹⁾

• Number of items by development stage

  Table 2 (top) shows the number of COVID-19-related ²⁰⁾ items in development by stage of development. The numbers in parentheses indicate items approved or under development for indications other than COVID-19 (referred to here as "drug ^{repositioning21)} items. Seven of the 65 items for prophylactic use and 89 of the 138 items for therapeutic use were drug repositioning items. In addition, 2 out of 6 items for prophylactic use and 54 out of 60 items for therapeutic use were drug repositioned items. In other words, the majority of the clinical stages for therapeutic purposes are drug repositioning, indicating that drug repositioning may play an important role in providing therapeutic drugs at an early stage.

  Table 2 (below) shows a breakdown of the development stages of drug repositioned products for indications other than COVID-19 (hereafter referred to as "other indications"). The most common development stage for other indications is launch (including approval), with a total of 33 products, but a wide range of development stages including Phase II (P2: 21 products) and preclinical stages (12 products) were also observed for COVID-19.

(2) Drugs utilized in COVID-19 therapeutics

As mentioned earlier, 89 of the 138 products being developed for COVID-19 therapeutic purposes were drug repositioning products, so we surveyed those 89 products. Table 3 shows which disease areas drugs are being deployed for COVID-19 therapeutic purposes, with the majority of drugs in the oncology, infectious disease, and immunology areas. Diversions from the oncology area identified included kinase inhibitors, TLR agonists, and anti-PD-1 antibodies.

In addition, 33 of the 89 drugs were already approved for other indications, and when we checked the year of launch of these drugs, we found that many of them were relatively new, having been launched in 2010 or later (Figure 2). (Figure 2)

(3) Breakdown of COVID-19 development products (for therapeutic use) by drug type

Figure 3 shows a breakdown of the 138 products in development for the treatment of COVID-19 by drug classified by mechanism of action. They can be broadly classified into symptom improvement (37% of the total) and inhibition of coronavirus infection/proliferation (46% of the total). Symptom amelioration mainly targets anti-inflammatory effects against cytokine storms and includes anti-IL-6 antibodies, IFN-γ modulators, and JAK inhibitors. Those expected to inhibit infection and proliferation are under development at various drug targets, including neutralizing antibodies with affinity for the S protein of novel coronaviruses, as well as those targeting ACE2 and RNA polymerase virus-related enzymes.

(4) Modality classification of COVID-19 development products

• COVID-19 development products: prophylactic purposes

  The modality classification of the 65 products developed for prophylactic purposes is shown in Figure 4. Vaccines account for more than 80% of the total. When further subdivided by vaccine technology type, inactivated or recombinant vaccines (the major vaccines currently on the market, and together classified here as "conventional technology") account for the largest share at approximately 60% of all vaccines, while the remaining 40% are The remaining 40% were relatively new technologies such as plasmid/viral vectors, mRNA, and peptide vaccines. In vaccines using plasmid/viral vectors and mRNA, nucleic acids encoding viral proteins are administered to the human body, which then produces proteins constituting the novel coronavirus and antibodies against them. Peptide vaccines synthesize a portion of the protein that constitutes the virus and administer it to cause the body to produce antibodies against the novel coronavirus. Thus, the basic principle of vaccines is to produce antibodies against the virus in the human body, and various technological platforms are being utilized. Note that small molecules and antibodies other than vaccines were mainly prophylactic administration of compounds being developed as therapeutic agents.

(5) Classification of development companies and nationality

The nationalities (top of Table 4) and company classifications (bottom of Table 4) ²²⁾ of companies (including government and non-profit organizations) that are developing COVID-19 prophylactic and therapeutic drugs were surveyed. Regarding nationality, the U.S. was by far the leading country for both prophylaxis and treatment, with China and the U.K. in second and third place. In terms of prophylaxis, seven products were identified from Norway, all of which were involved in the aforementioned CEPI (Coalition for Pandemic Preparedness Innovation).

In terms of company classification, Biotechnology companies accounted for the majority in both prophylaxis and treatment, but universities, non-profit organizations such as CEPI, and government agencies were also involved.

Discussion and Summary

In this paper, we focus on COVID-19 prophylactic and therapeutic drugs currently under development, and investigate the characteristics of drug repositioning, modalities, and development companies. (R&D started at about the same time around the world). (2) The impact of the disease on life and health is extremely large. (3) No effective drugs have been identified. (3) No effective drugs have been identified. This survey is a snapshot of the current situation (using data from May 19), and it is necessary to first consider that many more products will be added to the development pipeline in the future, and that the global R&D pipeline will change as the above environment changes.

Drug repositioning of existing drugs is important in order to respond quickly to new diseases; for COVID-19 therapeutics, many approved drugs were utilized and their disease areas varied. In the case of prophylactic drugs (vaccines), on the other hand, drug repositioning is less common, possibly because the highly specific nature of vaccines makes it difficult to deploy them against novel coronaviruses (or perhaps it is the ineffectiveness of existing vaccines against novel coronaviruses that has led to their worldwide spread). mRNA.

In vaccines, mRNA vaccines and DNA vaccines with viral vectors are attracting attention as new platform technologies. The advantages of using nucleic acids in vaccines include the following: nucleotide sequences can be freely designed based on the amino acid sequence of the protein to be used as antigen; nucleic acids themselves are substances that exist in living organisms, so there are few safety concerns; and stability in blood is one of the issues in the development of nucleic acid drugs, whereas in vaccines In the case of vaccines, it is desirable for the target protein to be degraded after expression, and the generally accepted weakness of nucleic acid drugs may be a strength in the case of vaccine development. In the case of mRNA, artificial synthesis using enzymes, and in the case of plasmid vectors, production by E. coli is possible, and it is also expected to be provided early and at an affordable ^price23).

The development of COVID-19 prophylaxis and treatment is led by the U.S. in terms of nationality and biotech companies in terms of company classification. The contributions of non-profit organizations such as CEPI, government agencies, and academia are also seen as an indication of society's overall commitment to the recent pandemic. As an example of how vaccines are being developed with a sense of speed, the history of vaccine development by the U.S. company ^Moderna24), ²⁵⁾ is presented here.

Since then, Moderna has been eyeing emergency use in the third quarter of 2020, the start of Phase III trials in the second half of 2020, and commercialization in 2021.

Factors that enabled Moderna to proceed with development this quickly include the technical characteristics of the vaccine, which, as mentioned earlier, can be designed with nucleotide sequences (the candidate product was ready two days after the publication of the genome sequence of the novel coronavirus), as well as the fact that the start-up company was financially able to bear the difficulty of the mass production process, which was In addition to the technological features of the vaccine design (the candidate product was ready two days after the publication of the genome sequence of the novel coronavirus), the company was able to obtain funding for the process of mass production, which is difficult for start-ups to bear financially, and the technical and regulatory support from the regulatory authority (NIH). Another important factor in the practical application of the drug is the partnership with Lonza, a world-class pharmaceutical manufacturing company, which has secured a manufacturing system capable of responding to a global pandemic.

In Japan, companies are also using the latest science to develop COVID-19 therapeutics and ^vaccines26). In addition to the efforts of pharmaceutical companies, it is hoped that the development of drugs to control novel coronaviruses will be further accelerated with the support of the government, regulatory authorities, NPOs, and society.

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