Points of View Survey on Development Trends of New Modalities - mRNA and microbiome

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Yosuke Takahashi, Senior Researcher, National Institute of Biomedical Innovation Policy

Introduction

In recent years, various drug discovery modalities (hereafter referred to as "modalities") have begun to be commercialized as pharmaceuticals, and the Pharmaceuticals and Industrial Policy Research Institute (PIIPRI) has reported on the latest trends in various publications1), 2). In particular, in the Policy Research Institute News No. 55, we reported the latest trends with emphasis on the three modalities of nucleic acid medicine, gene therapy, and cell therapy3). In this article, we will focus on mRNA as a modality that has been newly commercialized since then, and on the microbiome as a modality that will soon be commercialized, and introduce the latest trends.

Although mRNA can be interpreted as a modality of nucleic acid medicine in a broad sense, most nucleic acid medicines currently in practical use (antisense nucleic acids, siRNA, etc.) are produced by chemical synthesis and have molecular weights in the thousands to low tens of thousands, while mRNA is produced by biological methods and has molecular weights in the tens of thousands to hundreds of thousands. mRNA, on the other hand, is a molecule with a molecular weight of several tens to hundreds of thousands, produced by biological methods. In addition, microbiome is a term originally used to refer to the microflora and not necessarily to pharmaceuticals. In this article, we will take a broad view of things that have various effects on the microbiome.

Chapter 1. mRNA

mRNA (messenger RNA) is a type of RNA (ribonucleic acid), which is a genetic information transmitter commonly conserved in many organisms, including humans. The application and administration of mRNA as a drug is similar to the approach of replenishing protein in view of the central dogma. The application and administration of mRNA as a drug is similar to the approach of trying to replenish proteins in view of central dogma. If a certain protein is depleted in quantity due to some factor that leads to the onset of a disease, mRNA can be used as a gene therapy, so to speak. On the other hand, when a protein that does not exist in the body is supplied to the body, the protein is easily recognized as a foreign substance in the body, and as a result, the immune system is activated (acquired immunity), which opens up the possibility of application as a vaccine.

During the COVID-19 pandemic, mRNA technology was put to practical use as a vaccine and contributed greatly to the improvement of public health, making it a modality that is attracting a great deal of attention. In this paper, we will review the research and development trends of mRNA-related drugs and look ahead to the future of mRNA drugs. Next, two mRNA vaccines approved in Japan, Cominati intramuscular injection from Pfizer/Biontec and SpikeVax intramuscular injection from Moderna, are discussed and compared to naturally occurring mRNA in the body, to analyze what kind of innovative science and technology is incorporated. The following is an analysis of the innovative science and technology incorporated in Spikebux myoinjection and Modelana's Spikebux myoinjection in comparison to naturally occurring mRNA in vivo.

Using Pharmaprojects, a pharmaceutical database, we conducted an exhaustive search on the current status of the development pipeline of mRNA drugs (excluding those that have been discontinued4). Figure 1 shows the number of pipelines at each stage, categorized into vaccines against COVID-19, vaccines against infectious diseases other than COVID-19, and others (mainly therapeutic drugs, but cancer vaccines are also categorized here). There are a total of 14 mRNA drugs in Phase III, 11 of which are vaccines against COVID-19. In Phase III, there were a total of 14 vaccines, 11 of which were against COVID-19 (vaccines against mutant strains were counted separately), accounting for a high percentage. The percentage of vaccines against COVID-19 was lower for early-stage products, and there were many other infectious disease vaccines in development and in the pipeline that were classified as Others. 5) In the future, mRNA technology is expected to be applied not only as a vaccine to prevent infectious diseases, but also to a wide range of other diseases.

Figure 1 Number of mRNA development pipelines by stage

The development pipelines of these mRNA drugs are categorized by originator company or originator company nationality and are shown in Figures 2 and 3. The company with the largest pipeline was ModernaTherapeutics (Moderna, USA), followed by BioNTech (Biontec, Germany). These two companies are considered to have particularly strong R&D capabilities in the mRNA drug area, as they have commercialized the COVID-19 vaccine and have many more products in their pipelines that have advanced to the late-stage clinical stage than their competitors. The top two countries by nationality were the U.S. and Germany, where the two aforementioned companies are located. The next highest ranked countries were China, South Korea, and Belgium, in that order, and Japanese companies were not well represented (as of August 3, 2022, there was only one product in the pipeline that originated from a Japanese company).

Figure 2 Number of mRNA drug development pipelines by company of origin
Figure 3 Number of mRNA drug development pipelines by nationality of company originating development

However, in reality, there are various challenges to overcome, and there is a dramatic story of peaks and valleys on the way to practical application. The story is described in detail in other articles6), so we will avoid introducing it in this paper and focus on the various elements incorporated in the mRNA vaccines of Pfizer/Biontec (hereafter referred to as Pfizer, the manufacturer and distributor in Japan) and Moderna, which were commercialized first, respectively. The following is an overview of the various elements incorporated in the mRNA vaccines of Pfizer/Biontec (hereafter referred to as "Pfizer") and Moderna, and their respective attachments7), 8), 9), 10) and interview forms11) and 12), and a discussion of what kind of optimization studies are possible for each of these elements. In addition, at the time of this writing, on September 12, 2022, the bivalent vaccine for Omicron strain BA.1 from Pfizer and Moderna was approved (special exception approval). Hereafter, unless otherwise noted, references will be made to the monovalent vaccine (conventional vaccine) against the strain of origin, and some changes from the conventional vaccine to the bivalent vaccine will also be mentioned.

Modified nucleic acid

Both vaccines are modified at the base site by replacing the U (uridine) in the base portion of the RNA (AGCU) with N1-methyl pseudouridine. This modification was adopted to avoid the excessive immune response (side effect) that occurs when wild-type mRNA is administered, and is based on the research results13 of Dr. Catalin Carrico, currently Senior Vice President of Biontec, and his colleagues. While this groundbreaking research result is undoubtedly a turning point in the application of mRNA as a drug, there may exist room for further improvement here. Requirements for modified nucleic acids include (1) high safety (avoidance of spontaneous immunity), (2) highly efficient and accurate transcription from DNA vectors to mRNA (reactivity of RNA polymerase), and (3) highly efficient and accurate translation from mRNA to target proteins (reactivity in ribosomes) (4) High efficiency and high precision transcription (reactivity of RNA polymerase). It is not easy to find the optimal modified nucleic acid while balancing these factors, but now that it has been demonstrated that mRNA can actually be applied as a medicine, there is room for thorough and precise optimization research.

Manufacturing/formulation/storage method

Normally mRNA is based on DNA vectors and synthesized by biological methods using transcription enzymes (RNA polymerase). In fact, the interview forms for Cominati intramuscular injection (Pfizer) and SpikeVax intramuscular injection (Moderna) indicate that mRNA is produced by a biological method, although the specific type of RNA polymerase used cannot be determined. There may be room for further technological development, such as modifications to the DNA vector as the raw material for production (e.g., modifications to increase transcription efficiency), modifications to the transcription enzyme (e.g., to increase transcription efficiency, transcription accuracy and purity), mRNA purification methods, and development of highly stable storage methods. The two companies' vaccines differ in terms of additive ingredients and content, as well as in terms of preparation methods for administration (i.e., directly administered after dissolution or diluted with saline solution before administration). In addition, both companies have made changes to the formulations/additives of their conventional vaccines and bivalent vaccines. Pfizer's vaccine no longer requires dilution with saline when preparing the administration solution, and the composition of the additives has also changed. In the case of Modela's vaccine, the dosage volume has been changed based on changes in the concentration of the active ingredient in the formulation, and the concentration of the additive has also been changed. Although the reasons for these changes are not clear, it is likely that improvements were made to improve the vaccine by reflecting various research results and information accumulated after the commercialization of the conventional vaccine, as well as the opinions of medical professionals and other vaccine users. When vaccines are used as vaccines, it is more important to consider mass production, storage, and distribution methods than for ordinary drugs, and it will be necessary to optimize these factors one by one.

DDS method

Both Pfizer's and Moderna's vaccines use LNPs (Liquid Nano Particles) as transport carriers, which not only enable control of pharmacokinetics (tissue and intracellular translocation), but also stabilize the mRNAs themselves and contribute to the adjuvant effect of the vaccine. Although LNPs themselves have been put to practical use in nucleic acid medicine (On Patro), they are still in the developmental stage, and there may be room for further optimization research. which are composed of different components. Pfizer has not made any major changes to the LNPs in their vaccines, while Moderna has made a slight change in the concentration of one of the LNP components (PEG-lipid). The reason for this change is not clear, but it may be that improvements were made based on accumulated information.

On the other hand, if mRNA is to be used not as a vaccine but as a gene therapy, LNPs with different characteristics from those of vaccines, such as target tissue directivity, will be needed. Or, if the DDS of mRNA is to be broadened to include the entire process, we can look forward to the discovery of a superior DDS method that will replace LNPs in the future, and the advancement of research and development.

Other

In addition to the above, there is room for research improvements in various other respects. For example, design of antigenic site (amino acid sequence), codon optimization of mRNA (for example, whether CCU, CCC, CCA, or CCG should be used for proline), cap structure, setting of optimal dosage (depending on the purpose such as vaccine or gene therapy), administration site and method (consideration of optimal administration site, development of dosage formulations, etc.), and establishment of a manufacturing method by chemical synthesis.

mRNA Overall Consideration

In the event of a COVID-19 pandemic, the results of various basic research results accumulated up to that point and the experience of practical mRNA research14) will be brought together and used to create a revolutionary vaccine, The fact that an epoch-making vaccine was promptly created by combining the results of various basic research and experience in mRNA application research14) during the COVID-19 pandemic was a remarkable event, but it also reminded us of the importance of promoting basic research and practical application research as preparedness measures in times of peace.

Although the COVID-19 pandemic is far from over, it is highly likely that various emerging infectious diseases will continue to attack humans in the future, and we must be prepared to create even better vaccines. As mentioned earlier, the presence of Japanese companies in the mRNA field is still limited, but in order to protect the health of the Japanese people, it is important from the perspective of economic security to establish a foundation that enables Japanese companies to create innovative vaccines, rather than relying on foreign companies. In the area of mRNA vaccines, which include a variety of elemental technologies, one idea is to advance research and development in areas where Japan can take advantage of its strengths. For example, since LNP is composed of several types of small to medium-sized molecules, this may be an area where Japanese pharmaceutical companies with a track record in small molecule drug discovery can show their strengths. However, for non-competitive areas or areas where collaboration is possible (peripheral technologies such as DDS methods, safety enhancement methods, and manufacturing methods), an all-Japan consortium could promote basic research and establish Japan's own technologies. It is also possible to establish Japan's own technologies by promoting basic research in an all-Japan consortium, for example. If intellectual property rights for Japan's unique technology can be secured, it will be available for common use by consortium member companies, and in case of emergency, the consortium will be prepared to apply the technology to the development of domestically produced vaccines in a coordinated manner. In addition, granting licensing rights to foreign companies could contribute to Japan's economic growth as well as to international contributions in the healthcare field. In addition, as mentioned above, mRNA has potential for applications other than vaccines, especially in gene therapy for the purpose of protein replenishment. In the case of gene therapy, the DDS method for delivering mRNA to target tissues/cells that differ according to the disease indication may be a competitive area, but even in this case, there are certain areas where collaboration is possible.

Chapter 2 Microbiome

It is said that there are approximately 1,000 species and 100 trillion intestinal bacteria in the human gut15), and since the total number of cells that make up a human being is said to be 37 or 60 trillion, we are in a situation where we coexist with a large number of intestinal bacteria, more than the total number of human cells. The microbiome is defined as the environment in which a variety of microorganisms coexist, and research on the microbiome on various mucosal surfaces, such as the oral cavity and nasal cavity, as well as in the gut, has been active. The intestinal bacteria can be roughly classified into three categories: good bacteria, bad bacteria, and intermediate bacteria, and the balance of the presence of these intestinal bacteria is closely related to the state of health. The balance of intestinal bacteria is said to be affected by diet, age, and living environment, as well as by suffering from diseases such as obesity, diabetes, colorectal cancer, atherosclerosis, and inflammatory bowel disease16). In recent years, various research approaches have been underway with the idea that restoring a disrupted gut bacterial balance (dysbiosis) may lead to disease treatment, and these are outlined in this paper.

Gulliver et al. classify research on the microbiome into two areas as shown in Figure 4: the BIOMARKERS area (left side), which utilizes the microbiome to diagnose diseases and stratify patients, and the THERAPEUTICS area (right side), which seeks to intervene in human and patient health to promote health and treat disease. The microbiomes are classified into two areas: the BIOMARKERS area (left side) and the THERAPEUTICS area (right side) 17). In this paper, each of the elements classified into the THERAPEUTICS area will be explained.

  1. (1)
    DIETARY INTERVENTION: This can be described as a diet, and refers to a diet that takes into account the intestinal environment in certain diseases. This includes liquid diets and diets that do not contain certain ingredients (additives, gluten, FODMAPs18, etc. ).
  2. (2)
    PREBIOTICS: Foods that increase specific bacteria (especially good bacteria) present in the intestine, such as dietary fiber and oligosaccharides.
  3. (3)
    PROBIOTICS: Foods that contain bacteria that have a positive effect on the organism (such as lactobacilli and bifidobacteria), typical examples of which are yogurt and natto (fermented soybeans). These are foods that have historically been inoculated by humans as foods or supplements and whose safety has been fully confirmed.
  4. (4)
    SYNBIOTICS: Refers to a combination of PREBIOTICS and PROBIOTICS inoculated as a food, intended to maximize the effect of PROBIOTICS.
  5. (5)
    ANTIBIOTICS: drugs that affect gut bacteria and are included in microbiome-related drug discovery in the broad sense.
  6. (6)
    FECAL MICROBIOTA TRANSPLANTATION (FMT): refers to fecal transplantation, a technique in which donor stool containing beneficial bacteria is transplanted into the digestive tract of a patient in a state of dysbiosis.
  7. (7)
    PHAGE THERAPY: This is a method of killing specific bacteria with high specificity using bacteriophages. Phage therapy is a promising new technology for the treatment of AMR (multidrug-resistant bacteria), which has become a major issue in the international community. Although it is a therapy that acts on the microbiome, some consider it as a modality of PHAGE THERAPY in a narrow sense.
  8. (8)
    LIVE BIOTHERAPEUTICS: drug/drug candidates composed of a single or multiple bacterial species, although they have not been used adequately as drugs or food (genetically modified microorganism; could include GMM, etc.), The definition of PROBIOTICS is often ambiguous. As a category of drugs, clinical trials are considered necessary for medical use, and the FDA website states that IND or regulatory approval is required under the jurisdiction of the Center for Biologics Evaluation and Research19). Almost synonymously, they are often collectively referred to as Live Biotherapeutic Products (LBPs), and the FDA uses this expression.
  9. (9)
    MICROBIOME MIMETICS: Refers to mimicked interactions between the microbiome and the host (human), and includes components of bacterial origin (e.g., proteins, polysaccharides), food metabolites (e.g., short-chain fatty acids), and host-derived components.
Fig. 4 Application of microbiome in healthcare

For the purpose of investigating research trends in the microbiome area, a search limited to original papers was conducted using Web of Science (Clarivate) with the setting of "topic: microbiome. Figure 5 shows the annual trends in the number of original papers found, and the number of papers has been rising steadily since 2010, with even steeper growth in recent years, indicating that this field is attracting increasing attention. The fields of papers were further classified using a function on the Web of Science20). The results are shown in Fig. 6, and the number of papers classified into Medicine Research Experimental and Pharmacology Pharmacy, which are considered to be directly related to pharmaceuticals, was limited, but the number of papers in Microbiology and other basic research fields related to the fundamentals of the microbiome area was very high. However, there were a large number of papers in basic research fields related to the foundation of the microbiome, such as Microbiology. In the future, we hope that the results of such basic research will lead to applied research for pharmaceuticals and other products. We also conducted a survey on the nationality of the research institutes to which the authors belonged for the papers hit by the above search criteria. The results are shown in Fig. 7, with the U.S. and China in descending order, and Japan ranked 11th. Although Japan is far behind the top two countries, the number of countries after Germany in third place is relatively close, suggesting that Japan is able to maintain a certain level of research in the microbiome field.

Fig. 5 Number of microbiome-related papers per year
Fig. 6 Number of microbiome-related papers by field
Fig. 7 Number of microbiome-related papers by nationality of author's institution

The microbiome has attracted attention as a modality, most notably because of the high efficacy of FMT in the treatment of refractory C. difficile infection (CDI) 16). The mechanism of CDI development (recurrence) is that pathogenic C. difficile grows and colonizes in the intestine triggered by dysbiosis of the intestinal microbiota due to antibiotic administration, etc. FMT restores the normal intestinal microbiota and is effective in treatment and prevention of the disease. Since those reports, research and development of FMT and LBPs as applied drugs has been activated. A survey of drug candidates in development21) related to the microbiome by Pharmaprojects, a drug database, shows the number of products in development at each stage as shown in Figure 8.

Fig. 8 Number of microbiome-related drug development pipelines by stage

As of August 2022, no drugs have been launched (Launched), and the most advanced are the eight products in Phase III. Two of the most advanced in development are RBX2660 from Rebiotix (acquired by Ferring in 2018) and SER-109 from Seres Therapeutics, both of which started Phase III in 2017 for the indication of CDI, and which are discussed in detail in a separate Please refer to a separate section as a column for more information on these two products. As for the remaining six products, one started Phase III in 2019, two started Phase III in 2021, and three started Phase III in 2022, and as of this writing (September 2022), no specific information on Phase III trial results has been disclosed. The number of Phase II and earlier products in the pipeline is not very large at this point, and the modality is probably just at the dawn of its development.

Figure 9 shows the results of the analysis of the nationality of the developing companies (HQ) for Phase III and Phase II pipelines. Many of the products were developed by U.S. and European companies, and none of them originated from Japanese companies.

Fig. 9 Nationalities of originators of microbiome-related development pipelines

Figure 10 shows an analysis of trends in the indications for a total of 39 pipeline products in Phase II or higher stages. Of these, six were developed for CDI, for which the level of evidence is considered to be the highest based on past clinical studies, and three were developed for the treatment of other infectious diseases.

Fig. 10 Target disease areas of microbiome-related drugs

After infectious diseases, oncology was the second most common area of development, with seven items. The microbiome affects the host immune system in various ways, and several basic research results have been reported, such as increasing the anti-tumor effects of immune checkpoint inhibitors24), and there were many development pipelines that actually applied the effects in the field of cancer immunology.

In addition, there were many development cases in diseases in the intestine, where intestinal bacteria take root (e.g., ulcerative colitis), and diseases in which the immune system is deeply involved in the pathogenesis (e.g., atopic dermatitis, food allergy, graft-versus-host disease). There are also products targeting the nervous system, such as insomnia, although the number of products is not large. The fact that the brain and intestines closely influence each other via the autonomic nervous system and humoral factors has been well known for a long time as the "brain-gut correlation," but in recent years, attention has begun to focus on the involvement of intestinal bacteria in this brain-gut correlation25), and the fact that intestinal bacteria are involved in various diseases and symptoms (eating disorders, anxiety disorders, autism spectrum disorder, Parkinson's disease, etc.) has become a focus of attention. 26), 27). Thus, the scope of drug discovery related to the microbiome is expanding, and the future progress of basic research should be closely watched.

The above is an overview of the status of drug research and development related to the microbiome area. Although Japan is considered to have a certain level of basic research, it is still lagging behind the rest of the world in drug development research. However, although Japan is behind in the practical application of LBPs and FMTs that match the properties of pharmaceuticals, there are many examples of practical application in the health food field due to the cultural background of eating a variety of fermented foods historically. It is clear that microbiome control is important to improve human health, and it is important to be able to rationally determine whether development should be promoted as a pharmaceutical product or a food/supplement, depending on the specific application and purpose. It is important to be able to make a rational decision on whether a drug should be developed as a pharmaceutical product or be put to practical use as a food or dietary supplement, depending on the specific application and purpose.

The microbiome has large racial, individual, and environmental differences even among healthy people, and it is expected that racial differences in efficacy may be even larger than with low-molecular-weight pharmaceuticals. Therefore, when applying the microbiome as a pharmaceutical product, it is likely to be difficult to apply drugs that have been put to practical use overseas to Japanese people, and research and development of drugs suitable for Japanese people will need to be conducted in Japan. In Japan, regulatory development and other aspects have yet to catch up, but a microbiome subcommittee has been established within the PMDA, and discussions on drug discovery issues and regulations/guidance are progressing28). In addition, the Japan Microbiome Consortium (JMBC) was established in 2017, with 31 companies and organizations participating as of April 2022, and activities are underway to promote industrialization through industry-academia collaboration29). Thus, various attempts toward the practical application of the microbiome have been initiated in Japan.

There are reports that the COVID-19 pandemic has had a significant impact on the promotion of research and development in the microbiome area (especially in the FMT area, which involves transplantation from donor to recipient30), but we hope that as humanity overcomes this pandemic, research and development in the microbiome area will progress. However, it is hoped that humanity will overcome this pandemic and that research and development in the microbiome field will progress.

Column.

Two of the leading medical products in the microbiome area, RBX2660 and SER-109, are particularly well ahead of their development. Both have reported positive results in Phase III and may soon be approved by the FDA. In this column, we will discuss these two developments. RBX2660 is an enterobacterial cocktail purified and extracted from donor feces and stored under freezing conditions. It is stored under freezing conditions. According to information on Ferring's website, RBX2660 can be used to normalize the intestinal microbiota of patients in a state of dysbiosis and prevent recurrence of C. Difficile infection (CDI), RBX2660 has Fast Track, Orphan Drug, and Breakthrough Therapy designations from the FDA, and is currently in the submission stage following positive results from a Phase III study (PUNCH CD3 study; a placebo-controlled, multicenter, randomized, double-blind, parallel group study conducted in the United States and Canada). On September 22, 2022, the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) met to review the RBX2660 data and concluded that RBX2660 is safe and effective in reducing recurrence of CDI. The majority of the VRBPAC members expressed a positive opinion regarding the efficacy and safety of RBX2660 in preventing recurrence of CDI, which should support the upcoming approval of RBX2660. Ferring also has RBX7455, its next drug candidate for CDI, which is currently in the clinical stage (Phase III starting in 2021), and RBX7455 has improved formulation, specifically a lyophilized, enteric soluble formulation for oral administration and room temperature storage. RBX7455 is a lyophilized, enteric-soluble formulation for oral administration and can be stored at room temperature.

According to the Seres Therapeutics website, the Phase III study (ECOSPOR III; a placebo-controlled, multicenter, randomized, double-blind, parallel-group, placebo-controlled, placebo-controlled, multicenter, randomized, double-blind study conducted in the U.S. and Canada) reported that SER-109 showed a reduction in the rate of CDI recurrence, among other things. ECOSPOR III; a placebo-controlled, multicenter, randomized, double-blind, parallel-group, placebo-controlled study conducted in the U.S. and Canada), which showed a reduction in the recurrence rate of CDI, and the company plans to submit a BLA (Biologics License Application) rolling submission by September 7, 2022. Like RBX2660, RBX2660 is an enterobacterial cocktail purified and extracted from donor feces, but it has been developed as an enteric soluble formulation that can be administered orally and stored at room temperature. SER-109 is an enterobacterial cocktail purified and extracted from donor feces as well. In the commercialization process of SER-109, a business alliance agreement has already been concluded with Nestle of Switzerland, with a view to global development after approval.

Ferring's enterally administered RBX2660 is being followed by orally administered SER-109, which in turn is being followed by RBX7455. In the near future, we hope that several microbiome drugs will be put to practical use and contribute to the improvement of people's health.

Summary

In this paper, we have discussed mRNA as a modality that has recently been put to practical use and the microbiome as a modality that will be put to practical use in the near future, and have given an overview of the latest status and future prospects.

Although mRNA has reached practical application at an exceptional speed, partly due to external factors such as the COVID-19 pandemic, it is undeniable that the practical application of mRNA vaccines was achieved in a rush. In addition, the mRNA vaccine has yet to be utilized for gene therapy purposes. In addition, there are no examples of practical applications for gene therapy, and several issues remain to be addressed. In order to utilize mRNA technology for a variety of applications, we hope that research on the refinement and optimization of mRNA as a modality will progress, and the contribution of Japanese companies will expand.

As for the microbiome, while its practical application as a pharmaceutical product is imminent in other countries, the development of the microbiome in Japan is lagging behind. Although the significance and marketability of this field are expected to continue to grow, it will be necessary for pharmaceutical companies to carefully consider the environmental factors unique to Japan and make a decision on how far they should go and whether they should collaborate with health food companies and IT companies to contribute to the improvement of the health of the Japanese people. To this end, we will need to make a careful decision on whether or not to collaborate with health food companies and IT companies to contribute to the health of the Japanese people. To this end, it is important to promptly establish regulations in Japan to encourage Japanese companies to enter the market. It will also be important to actively promote basic research in the microbiome area, including industry-academia collaboration.

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