Points of View Current Status and Future Prospects of Gene Therapy in Practical Use

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

Introduction

In recent years, drug discovery modalities (hereinafter referred to as "modalities") have been diversifying, and a variety of modalities, including not only small molecule drugs but also recombinant proteins, antibody drugs, nucleic acid drugs, gene therapy, and cell therapy, have begun to be put into practical use as actual ^drugs1). This paper focuses on gene therapy, and provides an overview of marketed products, development pipeline trends, technology development trends, and various R&D issues (safety, manufacturing/quality control, regulatory issues, etc.). In particular, each country has its own unique approach to this field, and by comparing and discussing these differences, the author would like to examine the future prospects for gene therapy in Japan.

The term "gene therapy" seems to be used in various definitions in various information media, including academic papers and books. In a broad sense, the term "gene therapy" is used to refer to all methods of treating or preventing diseases using genes, including methods of introducing genes by means of viral vectors, plasmid vectors, mRNA, etc., or methods of achieving genome editing, and includes both those directly administered in vivo and those in which cells using these methods are injected into the body (ex vivo). Some are administered directly in vivo, while others are administered ex vivo. On the other hand, in the case of drugs for rare diseases caused by a single gene mutation, gene therapy is defined only in the case of supplementation of a gene originally possessed by a human, and is not defined as gene therapy in the case of introduction of a foreign gene (DNA vaccine, mRNA vaccine, etc.). In fact, the FDA classifies gene therapy (Cellular& Gene Therapy Products) and vaccines (Vaccines) as separate categories, even though they are drugs that use similar viral vectors for gene transfer as a ^modality2). In this paper, we will focus on the similarity in terms of modality and define/notate gene therapy in a broad sense as "gene therapy," and analyze and discuss it. In addition, when subdividing and analyzing the elemental technologies of gene therapy, we classify them into three categories: "in vivo gene therapy," "ex vivo gene therapy (gene-cell therapy)," and "tumor lysing virus.

Status of Gene Therapy R&D

According to the website of the National Institute of Health Sciences, Department of Gene Medicine, as of January 2022, three in vivo gene therapy products and four ex vivo gene therapy products (gene cell therapy products) have been approved (including conditional approval) ³⁾ in Japan. As of January 2022, three vaccines against COVID-19 have been ^approved4). All of these were approved after 2019, and more and more gene therapy products are expected to be put into practical use in the future.

Using Pharmaprojects, a drug database, we analyzed the number of development pipelines for gene cell therapy and in vivo gene therapy, respectively, as shown in Figure 1. The number of gene cell therapy pipelines has increased exponentially since the 2010s, and multiple successes have emerged, including the approval of two CAR-T cell products in the United States in 2017. The number of in vivo gene therapy pipelines has been relatively large since the 1990s, but the number of pipelines stagnated for a while in the 2000s. Around 2010, clinical efficacy was demonstrated for Parkinson's disease, AADC deficiency, Leber's congenital melanoma, hemophilia, and spinal muscular atrophy, ⁶⁾ which triggered a steady increase in the number of pipelines.

Next, using EvaluatePharma, we analyzed the ^originator7) nationality and type of originator for gene cell therapy, in vivo gene therapy, and tumor lysing virus, as shown in Figure 2. Note that there is a discrepancy in the number of items with the results of Figure 1, which was surveyed using Pharmaprojects, but this is due to differences in the criteria for classification and the scope of data inclusion in the two databases. In gene cell therapy, about 50% of the pipeline originates from the U.S., and about 26% from China, with these two countries accounting for about 3/4 of the total. China has a number of anti-tumor drugs in the pipeline, including various CAR-T and CAR-NK cells, etc. In the "China Manufacturing 2025" promulgated by China in 2015, biopharmaceuticals are positioned as one of the 10 priority areas, and the country is making efforts to develop various anti-tumor drugs utilizing this modality. In in vivo gene therapy, about 57% of the pipeline originates from the U.S., followed by European countries such as France, the U.K., and the Netherlands, and it can be assumed that these countries are focusing on in vivo gene therapy. In tumor lysing virus, the overall number of products is not yet large, with about 42% of the pipeline originating in the U.S., followed by 11% in China and 9% in Canada. It can be assumed that China is focusing on this modality, which is expected to have anti-tumor effects as well as gene cell therapy. In Japan, tumor-dissolving virus accounts for about 7% of the total, but only about 2% for both gene-cell therapy and in vivo gene therapy, and it must be said that Japan is lagging behind other countries in these modalities.

The originator type of these modalities tended to be similar, with few pipelines originating from major pharmaceutical companies, such as those classified as Global or Regional, and the majority originating from Biotechnology. Also, compared to other modalities, the percentage of University is relatively high. In particular, the proportion of Others or #N/A is relatively high in in vivo gene therapy, which is attributed to the large number of pipelines originating from hospitals and non-profit organizations. In addition, many in vivo gene therapy development pipelines are for rare diseases with few patients (detailed data is omitted), indicating that entities other than pharmaceutical companies are making important contributions to the discovery of drugs for these diseases.

In many cases, gene therapy seeds created by startup companies and academia are being licensed out to or co-developed with larger pharmaceutical companies for commercialization. In order to understand this situation, we conducted a survey on the number of deals (Figure 3), amount of deals (Figure 4), and international trends of deals (Figure 5) related to gene therapy based on the database of Clarivate Cortellis Competitive Intelligence. ⁹⁾ The survey on the amount of deals was conducted by using the database of Clarivate Cortellis Competitive Intelligence. The survey was limited to transactions involving the transfer of product ^rights10), and the average value for each year was calculated for Total Projected Current (the total amount of contracts (current forecast)). As shown in Figure 3, the number of deals related to gene therapy is increasing every year, indicating that the focus on this modality is growing every year. The average value of deals shown in Fig. 4 is the average value of deals that have been publicly announced, but the average value has been rising year by year, and in recent years, the average value has been close to 1 billion dollars. The high average transaction value of the products in the "Product" category (excluding individual data) is not only due to the high evaluation of the product itself, but also the high evaluation of the basic technology related to the product, indicating that investment in promising seeds and basic technology is heating up.

Figure 5 shows the international trends of deals (top 50 ^pathways11), with the U.S. accounting for the majority of both the nationalities of the principal companies (seed generators) and partner companies (seed adopters). The U.K. follows the U.S. both as a principal company and as a partner company, and is characterized in particular by the fact that it actively incorporates seeds from a variety of countries as a partner company. In Japan, most of the deals were made in Japan or with the U.S.

Next, we investigated trends in patent applications, which are the source of pipeline creation, by extracting PCT applications related to gene therapy based on the database of Clarivate Cortellis Competitive Intelligence, as well as those related to genome editing technology, which has been the focus of attention in recent years. We also investigated PCT application trends related to CRISPR-Cas, a genome editing technology that has been attracting attention in recent years. Specifically, patent applications related to gene therapy were extracted using the search formula Any Action (Gene therapy) AND Technologies (Gene transfer system), and PCT applications among them were included in the analysis. As for the number of patents by year (classified by first priority date), those containing the word "CRISPR" in the Target-based Actions section of the search results were also extracted, and the number of patent applications related to genome editing using the CRISPR-Cas system was also included in the analysis. The results are shown in Figure 6. Table 1 shows the ranking of owner companies based on the number of patent applications. If there were multiple applicants for a single patent application, each was counted as one application.

As shown in Figure 6, the number of patent applications related to gene therapy was almost nonexistent around 1990, but it increased significantly around 2000, reaching about 200 applications/year. The number remained constant from there for a while, but has been increasing even more rapidly in recent years against the backdrop of the 2010s, when significant results began to be reported in clinical trials of gene therapy. The number of patent applications related to the CRISPR-Cas system, which was developed in 2012, has shown remarkable growth since then, and it can be inferred from the number of patent applications that research and development applying this technology is flourishing. Table 1 shows that most of the top applicants are companies and research institutes in the U.S., followed by France, which has three applicants ranked in the top 20. One Chinese company is also ranked in the top 20. On the other hand, Japan's presence is relatively small when analyzed from this angle, with only two companies ranked in the top 100.

Challenges for Gene Therapy in Japan

As we have seen, gene therapy has been rapidly put to practical use in recent years, but various issues have been pointed out regarding the fact that research and development in Japan has lagged behind that of other countries. At the 5th Advisory Board for the Promotion of Genomic Medicine held by the Health and Medical Care Strategic Headquarters, various issues and measures were presented and discussed by the ^members12). 12) The author has categorized and organized the various issues based on the content of the discussions and presented them in Table 2.

As shown in Table 2, various issues are piling up in the promotion of gene therapy research and development. In terms of enhancing basic research, modalities need to be further refined in order to further improve efficacy and safety and promote the industrialization of gene therapy. This is not a challenge unique to Japan, but one that is common worldwide. However, the number of researchers involved in gene therapy is relatively small in Japan, and as a result, the country is lagging behind foreign countries in basic research, which is a significant challenge in Japan. To overcome this situation, it will be important to raise public awareness of the importance of gene therapy research, stimulate government support and investment from funds, etc., to enhance research funding over the long term, and expand the number of researchers engaged in basic research. If research progresses in this way, and Japan's first practical applications begin to emerge, a path to industrialization in the health and medical fields will be established, triggering further investment and ultimately leading to a virtuous cycle that will further invigorate research.

In gene therapy, the importance of patent strategies specific to the biopharmaceutical field has also been pointed out. Unlike low-molecular-weight drugs, for which substance patents can comprehensively claim pharmaceutical rights, it is important for biopharmaceuticals to secure pharmaceutical rights through a combination of multiple patents, and to maintain international competitiveness through strategic patent strategies such as cross-licensing, including patent applications by the companies themselves, It is necessary to secure and expand resources (especially human and financial resources). In this regard, there are many cases where it is difficult for academia and start-ups, which are expected to be the source of seeds, to respond individually. In some cases, it will be important to create a mechanism for sharing patents among players.

Although it has been mentioned that there is a mountain of issues to be addressed, in reality, these issues are not left unaddressed and measures are being taken to address them. Furthermore, the fact that this modality can be applied to vaccines in the field of infectious diseases after the Corona disaster has provided a tailwind, and measures to deal with these issues are beginning to progress at an accelerated pace. In the following sections, we will present specific trends in "development and relaxation of regulations (especially related to the Cartagena Act)," "expansion of manufacturing facilities," and "enhancement of basic research (especially safety issues).

Regulatory Trends Surrounding the Cartagena Act

In many cases, the development of gene therapy in Japan will require measures related to the "Law Concerning the Conservation of Biological Diversity through Regulations on the Use of Living Modified Organisms (Cartagena Act)".

The Cartagena Act was enacted in Japan based on the international rules of the Cartagena Protocol on Biosafety to the Convention on Biological Diversity (Cartagena Protocol), which was adopted in January 2000. The following is a summary of the measures necessary for promoting gene therapy research and development in Japan in relation to the Cartagena Protocol. When a genetically modified organism is used in a closed system under nonproliferation measures (e.g., when plasmid vectors are produced using E. coli), it falls under "Type 2 Use, etc." and requires ministerial confirmation (or internal agency approval). In the case of "Type 1 Use, etc.", the use of recombinant organisms (recombinant viruses, etc.) in an open system, such as administration to humans, requires ministerial approval. For more details, please refer to the PMDA's website page on "Applications under the Cartagena Act" for an easy-to-understand ^{explanation13)}. In addition, the Japan Pharmaceutical Manufacturers Association (JPMA) has published "Points to Consider before Conducting Clinical Trials on Gene Therapy Products and Recombinant Live Vaccines for the Prevention of Infectious Diseases" as a product of the Biopharmaceutical Committee on its ^website14). It is organized in a very easy-to-understand manner, including the knowledge necessary for research and development of gene therapy and information on how to promote efficient development.

The Cartagena Protocol is an international rule established for the purpose of preserving biological diversity, and as an idea, it is considered very significant. On the other hand, however, some countries such as the United States have not ratified the Cartagena Protocol, and international alignment has not been achieved. The reason for this is that it has been difficult to find a balanced landing point between the benefits of genetically modified organisms and the risks of adverse effects on the ecosystem, and to reach an international consensus. Despite these circumstances, the above measures, which are unnecessary in the U.S., have become indispensable for the development of gene therapy in Japan, and this has led to delays in development and impediments to R&D in Japan.

Against this background, there are some who argue that the Cartagena Act is a stumbling block to research and development of gene therapeutic products in Japan. However, discussions on this issue have been conducted based on a common understanding among industry, academia, and government, and steady progress is being made toward resolving this issue. The fact that it was previously necessary to apply for a full package that anticipated the actual scale of production after approval from the stage prior to the start of clinical trials has been clarified as a de facto partial change procedure. In addition, industry, academia, and government are studying cases in Europe, which has ratified the Cartagena Protocol similar to Japan, to enable approval with the minimum necessary data before the start of clinical trials and then to prepare the necessary data step by step while conducting the ^trials15). The point at which it was necessary to obtain approval for Type 1 Use Regulations before submitting a notification of clinical trial was changed to "it is now sufficient to obtain approval by the date of commencement of the clinical trial (specifically, "by the first domestic subject incorporation (clinical trial participant registration) for the clinical trial of the drug concerned, etc. " ¹⁶⁾. These matters are summarized in an easy-to-understand manner in a document submitted by the MHLW at the 6th Regenerative Medicine, Cell Medicine, and Gene Therapy Development Council, as shown in Fig. 7 ^.17)

In addition, it has been clarified that products manufactured for research purposes that have been confirmed for Type 2 use (confirmed by the Minister of Education, Culture, Sports, Science and Technology) do not need to be confirmed again by the Minister of Health, Labor and Welfare when manufactured for industrial purposes, as long as there are no changes in the manufacturing location, manufacturing method, manufacturing quantity, etc. ¹⁸⁾.

Thus, based on the knowledge accumulated to date and the regulatory situation overseas, various operational improvements have been made while respecting the basic concept of the Cartagena Act, and the period required for research and development is being shortened. It is hoped that further discussions will lead to a more ideal landing point for promoting R&D in Japan.

Challenges in Expanding Manufacturing Facilities

The following are some examples of efforts in Japan to address the issue of the shortage of manufacturing facilities and professional personnel involved in the production of gene therapy products.

The Next Generation Biopharmaceuticals Manufacturing Technology Research Association (MAB Association) is a technical association established in 2013, in which researchers from universities and companies are participating to develop manufacturing technology for biopharmaceuticals. Previously, MAB Kumiai focused on the development of manufacturing technology for antibody drugs, but in FY2018 it was selected by AMED for its "Fundamental Technology Development Project for the Industrialization of Regenerative Medicine and Gene Therapy (Development of Gene Therapy Manufacturing Technology)" and has started the R&D project "Development of New Mass Production Technology for Vectors for Gene and Cell Therapy". It is hoped that the results of this research will establish Japan's strengths in the future, such as mass production/analysis technology for gene therapeutic vectors, which is currently a bottleneck, and regulatory compliance methods for conducting clinical trials.

In addition, the policy recommendations of the Pharmaceutical Manufacturers Association of Japan led to the establishment of the Biologics Research and Training Center (BCRET) in 2017, utilizing the GMP-compliant manufacturing facilities owned by Kobe University and the MAB association. training, and training for inspectors and others involved in inspections and GMP conformity investigations, and plays a role in promoting research and development of gene therapy products, especially from the perspective of human resource development.

One of the government's largest projects, with a budget of 227.4 billion yen in the fiscal 2021 supplementary budget, is the "Project to Establish Biopharmaceutical Production Bases to Strengthen the Vaccine Production System. As the name suggests, this project aims to develop manufacturing facilities that can promptly produce vaccines in times of emergency (e.g., in the event of an infectious disease outbreak), but the facilities are to be dual-use facilities that can also manufacture biopharmaceuticals in normal times. It is hoped that when this manufacturing facility goes into operation, the new coronavirus infection will be under control and the facility will be maximally utilized for the production of biopharmaceuticals, including gene therapy products.

How are overseas countries addressing issues related to manufacturing in the field of gene therapy and promoting research and development? We would like to take up the cases of the U.K. and the U.S. as examples for reference.

In the U.K., the "Catapult Initiative" was proposed in 2010, and a state-led project to establish industry-academia collaboration centers (catapults) in key fields that will drive future economic growth in the U.K., and to invest funds intensively in each field, is being promoted. The Cell and Gene Therapy Catapult (CGT Catapult) was established in 2018 as an extension of the Cell Therapy Catapult, which was established in 2012 as one of these projects, and is playing a central role in research and development in this area. ¹⁹⁾.

The vision and mission of the CGT Catapult is to (1) achieve innovation by building industry-academia networks, (2) commercialize innovation, (3) complement industry-academia collaboration with unique research and manufacturing facilities and expertise, and (4) collaborate with industry, research institutions, government, healthcare organizations, industry associations, international organizations, etc. (4) promote the growth of the UK ecosystem through collaboration with industry, research institutions, government, healthcare organizations, industry associations, international organizations, and others. A particular feature of this project is the construction of a large-scale GMP manufacturing facility at its Stevenage site. This manufacturing facility was built with an investment of approximately 60 million pounds by the UK government, and the facility has been expanded intermittently since ^{then19), 20)}. The CGT Catapult is strongly aware of this point, and has been working on the development of a clinical trial system that is tailored to the needs of the users. The CGT Catapult is very conscious of this point and intends to develop cell and gene therapy into a major industry in the UK in the future by establishing a system that allows flexible joint use of manufacturing facilities, including the manufacturing of investigational drugs, according to the needs of users, and by employing and training a large number of human resources by regarding it as a place to foster human resource development. According to Catapult's Annual Review 2021, the most recent report indicates that the program has contributed to the upskilling of 3,800 professional personnel and that 132 projects are underway (Figure 8) ^.21)

We would like to highlight PaVe-GT (Platform Vector Gene Therapy) ^{22) and} BGTC (Bespoke Gene Therapy Consortium) ²³⁾ as notable US initiatives.

PaVe-GT is a project led by NCATS, which is located within the NIH, and is designed to develop genes for four different rare diseases (two types of organic acidemia (PCCA deficiency, MMAB deficiency), two types of congenital myasthenia syndrome (DOK7 deficiency, COLQ The project will conduct research and development of gene therapy for two rare diseases (two types of organic acidemia (PCCA deficiency) and two types of congenital myasthenic syndromes (DOK7 deficiency and COLQ deficiency). In this project, the objective is to create a candidate formulation using a common capsid (AAV9) and common manufacturing and purification methods, and to verify the possibility of improving the efficiency of gene therapy R&D by using standardized methods, such as common non-clinical studies, adoption of CMC evaluation methods, and efficient clinical trials using master protocols. The objective of the project is to verify the potential of this approach. Furthermore, the BGTC intends to bring useful insights to the future development of AAV gene therapy technologies by widely disclosing a variety of information, including the results of a series of studies and correspondence with the U.S. Food and Drug Administration (FDA).

The BGTC is a consortium involving a total of 27 various stakeholders, including several NIH institutes such as the aforementioned NCATS, the FDA, 10 pharmaceutical companies, and patient organizations, and was launched with a press release in October 2021. ²⁴⁾ With a budget size of $76.5 million over 5 years, the BGTC will conduct AAV The consortium will conduct four to six clinical trials using AAVs to establish rational and effective standard endpoints and evaluation methods, as well as to examine regulatory requirements, uniform manufacturing processes, etc. The consortium will then conduct research on gene therapy for rare diseases. The project also aims to explore the possibility of reducing the cost of research and development of gene therapy for rare diseases and to create a path to commercial viability and sustainability.

One of the lessons to be learned from these overseas examples is that many players are participating and organically collaborating on projects to solve bottlenecks in the promotion of R&D, with active investment under the leadership of the government. The formation of such an ecosystem, where many players gather under a common vision and work together in close psychological proximity, rather than merely gathering in close spatial proximity, is a characteristic and important point of this project.

Safety Challenges

In the history of gene therapy research and development, safety issues have always accompanied the development of gene therapy, and although the hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency (X-SCID) initiated in 1999 was the first in the world to show a clear efficacy of gene therapy alone, a series of patients who received the therapy subsequently reported developing leukemia. However, the development of leukemia in a series of patients who subsequently received the treatment was reported, which seriously affected the research and development of gene therapy in general. Subsequent studies clarified the toxicity mechanism, and it became clear that the retroviral vector used at that time increased the risk of carcinogenesis due to gene insertion at unintended sites. In recent years, improved retroviral vectors have been developed, and it has been reported that this risk has been significantly ^reduced6).

In recent years, research and development of in vivo gene therapy using adeno-associated virus (AAV) vectors has been actively conducted, because AAV vectors are derived from non-pathogenic viruses and have high safety, relatively high gene transfer efficiency even to non-dividing cells, and multiple serotypes with different tissue-directedness. AAV vectors are widely used as in vivo gene therapy vectors because they are derived from non-pathogenic viruses and are safe, they show relatively high gene transfer efficiency to non-dividing cells, and they can target various organs in the body. However, AAVs have also shown some toxicity in clinical trials, and safety issues remain. In September 2021, the FDA convened the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting was held at the FDA in September 2021, where intensive discussions were held on the safety risks of ^AAVs25). In addition to Oncogenicity Risk, Hepatotoxicity, TMA (Thrombotic Microangiopathy), and Neurotoxicity, shown in Table 3, were discussed as serious adverse reactions observed in clinical ^{trials26), 27)}. Although various hypotheses have been proposed regarding the mechanisms of these toxicities, no clear conclusion has yet been reached. However, further progress in basic and applied research is expected to overcome these safety issues and further accelerate the research and development of gene therapy. However, it is hoped that further progress in basic and applied research will overcome these safety issues and accelerate gene therapy research and development.

Conclusion

We have reviewed trends in basic research, practical application research, and clinical trials related to gene therapy, and discussed Japan's current status, issues, and measures to address them in comparison with overseas countries. While it is clear that Japan is lagging behind foreign countries, it is also clear that various measures are being taken in Japan to make up for this lag. The need for progress and enhancement of basic research remains a common challenge worldwide, and further scientific and technological breakthroughs are required to refine gene therapy into a more reliable modality for medical applications. Specifically, these include improving the efficiency of gene expression (reducing dosage), controlling gene expression (optimizing expression levels and expression time), clarifying toxicity mechanisms and establishing methods to avoid toxicity, providing target-directedness (systemic action and tissue-selective delivery), establishing high-quality manufacturing methods including cell culture methods, and developing new drugs that can be manufactured in a comprehensive manner by solving these issues. The cost of manufacturing drugs for therapeutic use must be significantly reduced by comprehensively resolving these issues. If these hurdles can be overcome, the results of basic research will become a source of competitiveness in the industry and, in some cases, may lead to gaining an advantage over other modalities, such as replacing drugs that currently must be taken throughout life with gene therapy that can be treated with a single administration. This may lead to the acquisition of superiority over other modalities. In light of the above, the promotion of gene therapy R&D may be a key driver for the growth of pharmaceutical companies and the development of the pharmaceutical industry as a whole.

The first point is that "Japan needs to develop its own gene therapy for diseases based on genetic mutations unique to Japan. The first point is that "Japan needs to develop its own gene therapy for diseases based on genetic mutations that are unique to Japan. The second point is that "gene therapy technology can be applied not only to rare diseases but also to various other diseases. The second point is that "gene therapy technology can be applied to a variety of diseases, not only rare diseases. If it is applied only to rare diseases, the profits may not be commensurate with the investment in research and development, which entails a significant risk of failure. However, in the R&D of therapeutic drugs for rare diseases, it is possible to keep the scale of manufacturing and clinical trials relatively small, and the flow of scaling up/step up to the creation of drugs for a larger patient population based on the experience of this series of R&D is rational/effective from a business perspective. It would also be rational/effective from a business perspective. One particularly important point is that "this technology can be applied to the development of vaccines for emerging infectious diseases. Using the delay in the development of domestically produced vaccines against novel coronavirus infections as a reminder, technological development should be promoted so that the development of domestically produced vaccines can be started promptly in case of emergency, and the protection of the lives and health of Japanese citizens using Japanese technology would be an important measure from the perspective of national security.

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