The founders are nephrologists, but at the time of the foundation, there were very few therapeutics for kidney diseases. Since our company was founded with the goal of developing medicines for kidney diseases, it was named Renascience, meaning “renal + science”. Renascience also means “renaissance or renascence”.

Drugs are not always developed in the medical fields requiring them, and the development of drugs in areas such as kidney diseases (difficult diseases to develop pharmaceuticals since it takes time to evaluate efficacy) and rare diseases (diseases with a small number of patients and low sales) is lagging behind. Therefore, we are now actively working on drug development in difficult-to-develop therapeutic areas and rare diseases.

The head office is in Sendai (Miyagi). Research and development center is located at Tohoku University Graduate School of Medicine Medicinal Hub (School of Medicine Building No. 5, 2-1 Seiryocho, Aoba-ku, Sendai City, Miyagi Prefecture, Japan).

We hope to solve medical problems and create new medical treatments that will enable humans to enjoy lifelong health, both physically and mentally. We are not a biotech company specializing in a particular technology, so any modality is acceptable.

The pharmaceutical industry is diversifying from the development of traditional small molecule drugs to biopharmaceuticals. Furthermore, recent advances in engineering and information technologies have led to a search for new medical treatments that integrate information and engineering technologies, and major pharmaceutical companies in Europe, the U.S., and Japan have already shifted from the business of pharmaceuticals alone to the business of medical solutions in general. Treatment options in medicine are expanding to include pharmaceuticals, medical devices, and even software as a medical device and applications that utilize artificial intelligence (AI).

Therefore, in addition to the chemical and biological research that has been our focus, we would like to broaden our vision to include engineering and information research to create a diverse and attractive research and business portfolio.

The World Health Organization (WHO) identifies important diseases associated with aging and lifestyle (aging-related diseases) as “non-communicable diseases (NCDs)” and covers four disease areas: cancer, diabetes, respiratory diseases, and cardiovascular diseases. These diseases caused 74% of all deaths worldwide in 2023. Our development items target all four of these disease areas.

Another important social issue is the declining birthrate, but not many pharmaceutical companies focus on the issue of declining birthrates. We focus on medical issues specific to women (premenstrual dysphoric disorder, menopausal disorders, AI diagnosis for breast cancer) and pediatric diseases (rapid diagnosis for phenylketonuria).

The role of public research institutions such as universities and medical institutions in creating medical innovations is expanding. Unlike traditional small molecule synthetic pharmaceuticals, the technological foundations and seeds for biopharmaceuticals that utilize genetic engineering and other technologies belong to universities and other public research institutions. In addition, medical institutions possess the medical data necessary for the development of software as a medical device utilizing artificial intelligence (AI).

Since Renascience collaborate with multiple departments at many medical institutions to conduct investigator-initiated clinical trials, we have many opportunities to understand medical issues in the medical field and can easily acquire the medical data necessary for AI development in a relatively short period of time. Rather than sticking to our own resources and research environment, we would rather focus on proactively utilizing external resources and the external environment to build a framework for efficient innovation.

We conceive concepts and ideas for treatments from basic research and “create” pharmaceuticals and medical devices. We then complete non-clinical studies using appropriate animals and cells and demonstrate the efficacy and safety in necessary clinical studies (clinical trials). We would like to develop them in-house to the point close to applying for regulatory approval to receive marketing authorization.

For example, the medical device (ultrafine endoscope) that received approval in December 2022 was developed in collaboration with several universities, starting from creation of the product to conducting non-clinical trials and completing clinical trials (investigator-initiated trials conducted by the physicians who did research on the product), and was submitted for regulatory approval after being licensed out to a foreign medical device company. In addition, we are currently conducting Phase III trials, the last clinical trials required for application for approval, for a treatment for chronic myeloid leukemia, a type of hematological cancers, and we intend to continue conducting Phase III trials in-house for other rare diseases. The reason is that it is sometimes difficult for major pharmaceutical companies to focus on drugs for rare diseases.

By developing drugs in-house up to the point of approval, we can ensure that important seeds will be implemented in society. In addition, we believe that outlicensing a drug at a late stage of development allows us to receive greater compensation, which we can pass on to our shareholders.

We emphasize collaborative research with physicians (called “physician-scientists”) who conduct a wide range of research from basic research to clinical trials; that is, the researcher conducting basic research jointly with us is also a physician, and is able to conduct investigator-initiated clinical trials as a coordinating investigator (principal investigator). In this manner, the researchers conducting basic research and clinical research are the same in many cases, allowing us to conduct both basic research and investigator-initiated clinical trials in a single integrated manner for efficient development.

In the past, many pharmaceutical companies and drug discovery biotechs have focused on increasing the business value by building the entire pipeline value chain (the buildup of all development processes) in-house. However, in areas such as pharmaceuticals, where the probability of success is extremely low, development time is long, and investment is significant, R&D and business risks are high, so it is essential to form a portfolio combining many pipelines and diversifying risks. Large pharmaceutical companies, backed by abundant funds, are often able to develop pipelines within the existing framework of forming their own value chain, but this is difficult when funds are not plentiful, as in the case of biotech companies.

We have been practicing development with high development efficiency including cost by utilizing resources of external organizations (research institutes and medical institutions). We consider building many value chains based on alliances with external institutions, and our strategy, R&D, and human resource management are different from those of existing biotech companies. We have been expanding many pipelines and developing modalities with fewer internal human resources and expenses, and we are beginning to see the outcomes . Rather than focusing solely on our own resources and internal environment, we would rather focus on actively utilizing external resources and external environment to build a framework for efficient innovation. We promote open innovation based on partnerships and collaborations with universities and companies from various different industries and develop our pipelines efficiently.

In January 2022, we opened Tohoku University Renascience Open Innovation Labo (Tohoku University x Renascience = TREx) in the Medicinal Hub of Tohoku University Graduate School of Medicine (Building No. 5, School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi).

Renascience used to have a research laboratory, including a facility for breeding animal models of kidney diseases, in the Kawasaki Biotechnology Special Zone in Kanagawa, when founded. Later, as the scope of research expanded from kidney diseases to many other disease areas and the research stage progressed from basic to clinical trials, the original laboratory, which mainly focused on animal models of kidney diseases, was closed. However, we decided to open TREx because we believe there is a need for a “place” to leverage cutting-edge scientific and technological achievements in many disease areas, a “place” for face-to-face interactions with physicians and researchers, and a “place” for open innovation with the government and medical industry companies.

TREx is the first base location project based on the “Agreement on Regional Economic Development between Sendai City and Tohoku University” concluded in April 2021. TREx will 1) accelerate collaboration among different categories, like researchers at Tohoku University Graduate School of Medicine, physicians at Tohoku University Hospital, companies participating in the Medicinal Hub, and government agencies, and 2) promote research in the existing development pipeline and introduce several new seeds, 3) efficiently and promptly perform investigator-initiated clinical trials, accession to medical data, acquisition of public funds, and planning of licensing strategies, and 4) develop and secure human resources. We have been able to further accelerate the high efficiency of R&D, which is one of our strengths.

In April 2023, we concluded a comprehensive collaboration agreement with Hiroshima University and established the Hiroshima University Renascience Open Innovation Lab (Hiroshima University x Renascience = HiREx) following TREx. HiREx will be utilized to conduct investigator-initiated clinical trials for pharmaceutical products such as non-small cell lung cancer and cutaneous hemangiosarcoma, and clinical performance tests for various software as a medical device (SaMD) utilizing artificial intelligence (AI) including diabetes treatment support and medical support for maintenance hemodialysis medical support.

Research and development of pharmaceuticals, especially clinical trials, requires a large amount of R&D expenses. Since our business model is based on developing seeds through investigator-initiated clinical trials and licensing them out to pharmaceutical companies, we are required to bear a large amount of R&D costs ourselves.

However, by proactively utilizing public research grants (competitive research fund), we can reduce our own R&D expenses required for these high-risk investigator-initiated clinical trials. We will continue to actively obtain and utilize public research grants in the future.

In order to make efficient and prompt management decisions, and furthermore, in light of our company’s size, we have examined the optimal governance structure and determined that it is appropriate to introduce a company with an Audit and Supervisory Committee and have changed the design of the organization. We believe that we can now reflect the objective opinions of outside directors in our decision-making process and manage our company with greater transparency than ever before.

The declining birthrate is an important social issue. We focus on medical issues for women (premenstrual dysphoric disorder, menopausal disorder, and AI diagnosis of breast cancer) and children (rapid diagnosis of phenylketonuria). We therefore consider that it is our corporate social responsibility (CSR) to support the social activities of children and women. In addition to the specific example below , we will continue to support educational activities for the health of children and women.

□Presentations on the software as a medical device (SaMD) for supporting maintenance hemodialysis that has been developed in collaboration with several universities/medical institutions including Tohoku University

・Japanese Society for Apheresis on October 22, 2023

At the symposium “Toward Safe Apheresis Therapy” (on October 22) of the 44th Japanese Society for Apheresis (October 20-22, 2023, Iwate Prefectural Information Exchange Center “Aiina”), Dr. Mariko Miyazaki, Associate Professor of Tohoku University Graduate School of Medicine, gave a presentation at the symposium.

・Eastern Regional Meeting of the Japanese Society of Nephrology on September 17, 2023

At the 53rd Eastern Regional Meeting of the Japanese Society of Nephrology (September 16-17, 2023, Sendai International Center), Dr. Toshio Miyata, Professor of Tohoku University Graduate School of Medicine (Director Chairman of Renascience) gave a presentation at the symposium “Digital Nephrology – Future Treatment of Renal Diseases Created from Medical-Engineering Cooperation and Artificial Intelligence” on September 17, 2023.

□Presentations on our plasminogen activator inhibitor-1 (PAI-1) inhibitor

・Annual Meeting of the Japanese Lung Cancer Society on November 3 & 4, 2023

Renascience entered into a collaboration agreement with Hiroshima University on October 31, 2022, to conduct joint research on the PAI-1 inhibitor as a novel treatment for non-small cell lung cancer, and Renascience also executed the agreement on comprehensive research collaboration with Hiroshima University on April 24, 2023 to jointly conduct not only the development of pharmaceuticals but software as a medical device (SaMD). On September 26, 2023, a phase II investigator-initiated clinical trial was initiated to evaluate the efficacy and safety of RS5614 in combination with nivolumab, an immune checkpoint inhibitor, in patients with unresectable advanced or recurrent non-small cell lung cancer.

In the 64th Annual Meeting of the Japanese Lung Cancer Society (November 2-4, 2023, at the Makuhari Messe), our collaborator, Dr. Takeshi Masuda, Lecturer & Head, Hospitalized Patient Treatment at the Department of Respiratory Medicine, Hiroshima University Hospital, gave a presentation on “Investigation of the Involvement of PAI-1 in the Development of Non-Small Cell Lung Cancer -Initiative of the Investigator-Initiated Clinical Trial Using the PAI-1 Inhibitor-“ in the workshop entitled “Frontiers of Translational Research for Drug Discovery” on November 3, and Dr. Masahiko Sumii, Department of Respiratory Medicine, Hiroshima University Hospital, gave a presentation on “Overcoming Early Resistance to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer -Development of Novel Treatment Targeting PAI-1-” in the general session entitled “Drug Resistance and Overcoming the Drug Resistance” on November 4, 2023.

・Bio Asia-Taiwan Asian Biotechnology Conference 2023 on July 28, 2023.

At the Bio Asia-Taiwan Asian Biotechnology Conference 2023 held in Taipei, Taiwan from July 26 to 30, 2023, Professor Toshio Miyata, Tohoku University Graduate School of Medicine (Director Chairman of Renascience), discussed the novel role of PAI-1 in cancer and aging, and the research and development of the PAI-1 inhibitor for the treatment of these diseases. The content of the lecture is published in the August 25, 2023 issue of Global Bio Investment, a monthly magazine, as one of the innovative medical researches from Japan at Bio Asia (Notice of Publication of Article on Our Pipeline in Global Bio Investment Magazine).

It is important to confirm safety and efficacy of the drug candidates in drug development. Safety can be assessed in accordance with pharmaceutical regulation in the tests such as general toxicity and genotoxicity, and the tests can be done with the right amount of time and money. On the other hand, evaluating efficacy is not as simple, and finding out which diseases a drug is effective against is a difficult task.

Even if a drug is not effective in the disease for which it was originally intended, it may be effective in another disease. It is difficult to consider a wide range of indications for a given drug (drug repositioning), and it is practically impossible to consider the drug in all diseases.

We provide our pipeline compounds as “open resources” to researchers who belong to public research institutes in Japan and overseas. Our framework, which allows us to collaborate with researchers in various fields who are conducting cutting-edge basic research, enables us to conduct drug repositioning research far more efficiently and extensively than if we were to conduct basic research only with our own limited resources.

Our clinical trials are investigator-initiated by physician scientists who are researchers and physicians simultaneously.

The overwhelming advantages of investigator-initiated clinical trials are “quality” and “speed,” that is, “efficiency. In an investigator-initiated clinical trial, physicians who are at the forefront of research, with access to the latest research results, and who treat patients daily in the medical field, can draw up appropriate patient populations and study plans. It is a suitable clinical trial framework for early-stage trials of unapproved drugs (the stage in which the usefulness and safety of a drug are first confirmed, known as exploratory clinical trials), since physicians can conduct clinical trials themselves. In addition, orphan diseases (rare diseases; the number of patients is small, so large sales cannot be expected.) may have to be conducted from beginning to finish in investigator-initiated clinical trials, as pharmaceutical companies are not often engaged in drug development for these diseases due to low profitability. Almost the large part of R&D costs is spent in the clinical development phase, not the basic research phase.

Investigator-initiated clinical trials can reduce development costs because the results of cutting-edge science and technology from universities and other institutions can be quickly utilized, and investigators can appropriately select patients to be treated. Unlike other companies, we give priority to this form of clinical trials because, when appropriate coordinating investigators are named and the support of several large medical institutions such as universities can be obtained, investigator-initiated clinical trials have a significant advantage over industry-sponsored clinical trials, and large trials can be conducted in a short period of time.

The 2003 revision of the Pharmaceutical Affairs Law opened the way for investigator-initiated clinical trials, in which physicians themselves conduct clinical trials. However, it is still difficult for physicians to prepare all the necessary drugs for clinical trials by themselves, including safety tests and drug formulations.

At the time of the revision of the law, there were many new drugs that had been approved overseas but not domestically or for off-label use in Japan (so-called drug lag), so the main target of investigator-initiated clinical trials was the expansion of indications for drugs that had not been approved in Japan or for off-label use. In terms of ease of conducting clinical trials (existing data can be used from manufacturing to safety tests), many physicians at medical institutions, including those at universities, conducted investigator-initiated clinical trials for new drugs approved overseas (but not yet approved in Japan) and drugs for off-label use. In addition, there were cases where investigator-initiated clinical trials were conducted using existing drugs for rare diseases that pharmaceutical companies do not work on. Because of this background, there seem to be still a strong impression that investigator-initiated clinical trials are for drugs approved overseas (not yet approved in Japan) or for the expansion of indications for existing drugs.

However, all our clinical trials are for unapproved drugs (first-in-human), not for drugs approved overseas (unapproved in Japan) or for the expansion of indications for existing drugs. Since our drugs are unapproved drugs and we have secured the intellectual properties, we are able to commercialize them on an exclusive basis and earn sufficient profits.

In our drug development, non-clinical studies are conducted in compliance with Good Laboratory Practice (GLP) and investigational new drug manufacturing is conducted in compliance with Good Manufacturing Practice (GMP) for investigational new drugs. In addition, investigator-initiated clinical trials are conducted in compliance with GCP (Good Clinical Practice), as are industry-sponsored clinical trials. Therefore, the results of investigator-initiated clinical trials can be used in regulatory filing and in obtaining regulatory approval.

We have succeeded in increasing our pipeline of numerous drugs by providing our development compounds as open resources to researchers at universities and other public research institutions in Japan and overseas, and by efficiently conducting a wide range of studies on the possibility of expanding the indications for our drugs (drug repositioning).

Our compounds that are not candidates for clinical development are provided under a material transfer agreement (MTA), while the clinical candidate compounds are provided under a collaboration agreement (an agreement that encompasses the grant of license for research and development, handling of intellectual properties of the new discovery, and compensation after commercialization). Since our founding, more than 100 research institutions have conducted research on our projects using the compounds provided under MTAs as open resources. These numerous domestic and international collaborations have produced seeds (concepts) that we never would have thought of.

We make the decisions of pipeline development, based on a comprehensive consideration of the four factors listed in the table below: science, medicine, profitability (business), and time frame.

Since we conduct collaborations with universities and other public research institutions, intellectual property is basically filed together with the university or other institution (joint application of the patent). We are required to file, manage, and operate intellectual property applications in accordance with the university’s internal rules through repeated consultations with the university’s department of industry-academia collaboration (intellectual property department), while complying with the regulations on employee inventions of the university or other institution. In addition, the applications of intellectual properties are filed after agreeing on the inventor, applicant, ownership percentage of rights, cost burden, and licensing conditions (scope, consideration). Since these negotiations and agreements take a considerable period of time (several months), it is necessary to formulate an IP application plan that takes these periods into account.

In addition to substance patents, we file, maintain, and manage multiple related patents, such as use patents and dosage patents, in an appropriate and continuous manner.

We provide our compounds as open resources to researchers belonging to public research institutes in Japan and overseas.

The laboratories of researchers at public research institutions have research facilities and unique animal models of diseases in their specialized fields, but these researchers specialize in medicine and biology and do not have drug candidate compounds. Due to the open resource policy of Renascience, we have received an increasing number of requests from many domestic and foreign researchers who have learned the information on these compounds. After filing a patent application, our collaborators are free to present their work at academic conferences and scientific papers, and we have also agreed to allow them to apply for research funding based on our compounds.

Our framework, which allows us to develop compounds jointly with researchers conducting cutting-edge basic research, is far more efficient and far-reaching than conducting basic research with only our own limited resources.

The application of artificial intelligence (AI) to the medical field is a theme with great potential, but the stakeholders who play an important role in research and development of medical AI face individual challenges.

Although physicians (medical institutions) are well versed in medical issues and problems (needs) and possess a wealth of medical data and ideas, they lack AI technologies and networks with IT vendors, making it difficult for them to launch specific R&D projects. On the other hand, IT vendors with AI technologies are interested in applying them to the medical field, which is expected to grow, but practical application is not easy because they have little network with physicians (medical institutions), making it difficult to access medical needs and medical data, and they lack experience in pharmaceutical administration and regulations, including the Pharmaceutical and Medical Device Act. Furthermore, pharmaceutical and healthtech companies at the exit that wish to commercialize medical applications of AI often find it difficult to handle everything from research to business development on their own, in terms of time and resources.

Therefore, it is important to have a framework in which physicians (medical institutions) who totally knows medical issues, IT vendors with AI technologies, and exit pharmaceutical/healthtech companies can collaborate from the beginning to promote the development of AI-based software as a medical device.Therefore, it is essential to plan from the early stages of development with an eye toward regulatory approval and the exit to actual clinical implementation. For this reason, open innovation among different fields is important, and in addition to physicians, data scientists, AI researchers, and pharmaceutical affairs experts must work together.

In the process of conducting many investigator-initiated clinical trials, Renascience has established networks with numerous medical institutions and multiple medical departments, and have easy access to medical issues and medical data (medical support), has concluded collaborative business agreements with multiple IT companies through open innovation (technological support), and are able to comply with pharmaceutical regulations in the process of conducting investigator-initiated clinical trials for pharmaceuticals.

The essential elements for research and development of medical AI are 1) medical issues, 2) medical data (quality and quantity), and 3) AI algorithms (engines). In many cases, even excellent technologies are difficult to put to practical use because they do not meet the needs of the medical field and there are challenges in using them in the medical field, and many companies that possess the technologies often face the problem.

In recent years, the “Biodesign” method attracts substantial interest, in which solutions to problems are developed starting from the needs of the medical field and optimized by envisioning the final product in the medical field. The same method can be applied to software as a medical device that use AI as its core technology, but it is important to note that the medical data is obtained from a patient with individual differences but not from a machine, though AI technology is of course important. Therefore, it is crucial to customize the AI based on medical issues, medical data, and the advice of physicians in the medical field. The essential material for AI research is medical data, and a sufficient amount of data is definitely needed because AI finds rules from a large amount of data (inductive inference), In addition to the quantity of data, the quality of data is also important.

Furthermore, the optimal AI algorithm should be selected based on the medical problem to be solved and the type of medical data to be utilized. It is necessary to “select (or in some cases, develop independently) the optimal AI algorithm” to solve a specific medical issue, rather than looking for a medical field where a specific AI algorithm can be utilized. In addition, after the AI algorithm has been determined, data scientists can analyze it with AI as long as they have data, but only physicians can interpret and evaluate whether the results are correct. Therefore, without physician involvement, good quality medical data cannot be used to train AI to solve problems.

Collaboration among physicians, data scientists, and AI researchers is important, and active involvement of the medical field (physicians), where medical issues, medical data, experience, and knowledge exist, is the key to success in solving medical issues through AI.

To promote research and development on medical applications of AI, we signed a memorandum of understanding (MOU) with NEC Solution Innovator in November 2022 and a comprehensive collaboration agreement (MOU) with NEC in June 2023.

We efficiently conduct a wide range of studies on the possibility of expanding the range of indications for our drugs (called drug repositioning) within our limited resources, by providing our developed compounds as open resources to researchers affiliated with universities and other public research institutions in Japan and overseas. Since we do not require any specific in-house resources, there are no restrictions on the number of projects for non-clinical studies (studies on animal models of diseases). Clinical development is conducted utilizing investigator-initiated clinical trials, and the use of contract research organizations (CROs) reduces the need for in-house human resources.

The number of clinical trials in FY2022 was 7 , 9 in FY2023 , and 10 in FY2024 (including 2 clinical performance studies), showing a gradual increase.

We have set a goal of conducting at least 5 investigator-initiated clinical trials per year. With regard to software as a medical device (SaMD) utilizing artificial intelligence (AI), we consider the development of about 10 seeds per year at the exploratory level to be an appropriate number based on our resources. Of these, we believe that about 30% will move to the development and commercialization level (conducting clinical trials such as clinical performance studies).

Development of pipelines, which are at an advanced clinical stage, is of high priority.

In pharmaceuticals, we focus on the development of a plasminogen activator inhibitor-1 (PAI-1) inhibitor in the oncology and respiratory fields. In the oncology area, a Phase III study for chronic myeloid leukemia is ongoing; Phase II studies for malignant melanoma is completed;and non-small cell lung cancer, and cutaneous angiosarcoma have been conducted. In the respiratory field, Phase II trials have been completed for novel coronavirus lung injury, and Phase II trial has been conducted for interstitial lung disease associated with systemic scleroderma.

Development of a medical device (ultrafine endoscope) is almost completed. The main part of the ultrafine endoscope, fiberscope, was approved in December 2022, and development of the accessory part, guide catheter, is almost complete, and we plan to proceed with preparation for regulatory filing.

As for software as a medical device (SaMD) utilizing artificial intelligence (AI), development of SaMD for supporting diabetes treatment and supporting maintenance hemodialysis go in advance among other SaMD projects, and we plan to conduct clinical performance tests for these SaMD to file for regulatory approval.

PAI-1 is a protein required for fibrinolysis of blood clots but is also deeply involved in inflammation and tissue fibrosis. Based on these actions, we have been developing the PAI-1 inhibitor for respiratory diseases. Specifically, projects in progress include novel coronavirus lung injury (Phase II completed), interstitial lung disease associated with systemic scleroderma (Phase II), and interstitial pneumonia (non-clinical study).

It is known that cancers with high expression of PAI-1 have higher malignancy and poorer prognosis (‘PAI-1 paradox’). In our collaboration, we found that PAI-1 promotes the expression of immune checkpoint molecules (such as PD-L1) in cancer cells. We have also shown in mouse models of colorectal cancer and malignant melanoma that administration of our PAI-1 inhibitor reduces expression of immune checkpoint molecules in cancer cells, increases infiltration of cytotoxic T cells within tumors, and suppresses tumor-associated macrophages.

Based on the results of these non-clinical studies, Phase II clinical trial has been conducted for malignant melanoma and the evidence of the expected efficacy was obtained. Treatment with nivolumab plus RS5614 for 8 weeks in patients with malignant melanoma refractory to nivolumab resulted in a response rate of 24.1% (7/29 patients), which was higher than the existing response rate of nivolumab plus ipilimumab (13.5% in Japan). Phase II investigator-initiated clinical trials for non-small cell lung cancer, and cutaneous angiosarcoma are being conducted. “PAI-1 paradox” is actually involved in the cancer treatment, and the concomitant use of the PAI-1 inhibitor with other tumor medicines has been confirmed to be effective synergistically in some types of cancer.

Based on the crystal structure of the human PAI-1 molecule, we obtained 96 PAI-1 inhibitory candidate compounds from the search of approximately 2 million virtual compound library using computer engineering. Using the inhibition of the PAI-1 activity as an index, over 1,400 novel inhibitory compounds have been synthesized to date over more than 10 years and screened for drug efficacy. By further evaluating the efficacy and safety of the compounds, we obtained RS5275, a lead compound with excellent safety profile that can be orally administered. From RS5275, we further synthesized new compounds and obtained four clinical candidates, RS5441, RS5484, RS5509, and RS5614. Among them, RS5614 was finally selected as a candidate for clinical development.

In the past, many pharmaceutical and biotech companies, including domestic and foreign giants, have worked to develop small molecule PAI-1 inhibitors. Several drugs were reported to be effective in animal models in mice and rats, and PAI-749 (Diaplasinin) among them advanced to the clinical stage, but development was halted after Phase I clinical trials, since it showed no efficacy.

Non-clinical studies have been conducted including safety pharmacology studies (hERG study, central nervous system in rats, cardiovascular and respiratory studies in monkeys), general toxicity studies (26-week oral repeated-dose study in rats, 39-week oral repeated-dose study in monkeys), genotoxicity studies, phototoxicity studies, reproductive and developmental toxicity studies, and we have confirmed that there are no problems for clinical trials and regulatory applications. In a Phase I single-dose study, up to 240 mg of RS5614 was found to be safe, and in a Phase I oral repeated-dose study, all adverse events that occurred at 120 mg for 7 days were mild. RS5614 has been administered to over 200 subjects (healthy volunteer, chronic myeloid leukemia, novel coronavirus lung injury, and malignant melanoma). In chronic myeloid leukemia, 180 mg/day for 48 weeks was administered to 33 patients, and no serious adverse events related to the investigational drug were reported. Therefore, RS5614 is considered to be a safe medicine.

Chronic myeloid leukemia (CML), a type of hematological cancers, is caused by an abnormality in the chromosomes of hematopoietic stem cells that results in the unrestricted growth of cancerous leukemia cells (CML cells).

The most common treatment for CML is the tyrosine kinase inhibitors (TKIs, such as imatinib), but the TKIs do not work on CML stem cells present in so-called the bone marrow niche, from which CML cells differentiate and proliferate.Therefore, after discontinuation of the therapy with the TKIs, CML cells again proliferate from the CML stem cells, and the disease recurs.

The PAI-1 inhibitor has been shown to enhance the action of the TKIs by acting on the CML stem cells, resulting in the complete cure of CML. In fact, the PAI-1 inhibitor RS5614 in combination with TKI markedly reduced the number of CML stem cells in bone marrows and significantly prolonged the survival compared to TKI alone. Although the development of the TKIs has greatly improved the prognosis of CML patients, long-term, expensive TKI treatment must be continued for a long period of time to cure CML. Side effects caused by long-term continuous use of the TKIs are also a problem.

RS5614 is expected to be a safe medicine with a new mechanism of action that can lead many CML patients to treatment-free remission (TFR) as early as possible.

RS5614 120 mg/day was administered for 4 weeks (TKI continued for 12 weeks) to CML patients who had been receiving TKI therapy for at least 2 years, and the rate of DMR (deep molecular response: the highest therapeutic response) after 12 weeks was evaluated as the primary endpoint in the early Phase II investigator-initiated clinical trial conducted at Tohoku University, Akita University and Tokai University. Twenty-one patients were enrolled in the study, and all were eligible for analysis with no dropouts or discontinuations. Results of the primary endpoint showed that 4 of the 21 patients achieved DMR, with a cumulative DMR achievement rate of 20.0% at 12 weeks (the average cumulative DMR achievement rate at 3 months with TKI alone to date is 2.0% when patients are treated with TKI alone (called historical control)). In the safety evaluation, no side effects were observed in all 21 patients in the analysis.

In the late Phase II study, TKI and RS5614 (starting at 150 mg/day, dose can be increased to 180 mg/day) were administered in combination in CML patients to confirm that a cumulative DMR of 33.0% could be expected at 48 weeks after the start of RS5614 treatment compared to 8.0% in the historical control, and to confirm the pharmacokinetics and safety of RS5614 in the long-term concomitant use of RS 5614 and TKI. As the results, 11 of 33 patients achieved DMR, and the cumulative DMR achievement rate at 48 weeks was 33.3% (the data was comparable to the expected, and therefore POC was established). As for the safety, there were no serious adverse events causally related to the study drug.

Based on the results of the late Phase II study, a placebo-controlled, double-blind, investigator-initiated Phase III clinical trial to evaluate the efficacy of the combination of TKI and RS5614 in patients with chronic phase CML is underway in collaboration with 12 universities and medical institutions, including Tohoku University, Tokai University, and Akita University. This study was adopted by the Japan Agency for Medical Research and Development (AMED) under the Research Program of the “Practical Application for Innovative Cancer Therapy” in fiscal 2022  (Tohoku University is the representative research organization and Renascience participates as a sharing research organization). In November and December 2021, we held face-to-face consultations with the Pharmaceuticals and Medical Devices Agency (PMDA), and in May 2022, we submitted a notification of the clinical trial plan to the PMDA and started a multicenter Phase III study. Sixty (60) patients with chronic stage CML who had been treated with TKI for more than 3 years will be enrolled in the study, and the study will evaluate whether the combination of RS5614 significantly increases the maintenance rate of DMR for more than 2 years compared to TKI alone in 60 patients with chronic CML who have been treated with TKI for more than 3 years.

Currently, there are four major cancer treatments: (1) surgery, (2) radiation therapy, (3) chemotherapy (anticancer drugs), and (4) immunotherapy. Immunotherapy is a treatment method that attacks cancers utilizing the body’s own immune system. Various immunotherapies have been proposed, but among the immunotherapies that have proven to be effective, immune checkpoint inhibitors, which inhibit the brakes of the immune system, are the mainstay. Since an excessive immune response is harmful, the body has mechanisms to suppress it. The molecules responsible for such a braking function are called immune checkpoint molecules. In fact, cancers abuse these immune checkpoint molecules to prevent the immune system from attacking against themselves.

Immune checkpoint inhibitors release this brake by blocking immune checkpoint molecules, thereby activating the immune response against cancers. We discovered that PAI-1 inhibits cancer immunity via immune checkpoint molecules. In animal model studies, we also found that malignant melanoma (melanoma), colorectal cancer, and other cancers regress in animals treated with RS5614, and that cancer immunity was synergistically and strongly enhanced when RS5614 was combined with an immune checkpoint inhibitory antibody.

We hope the checkpoint inhibitory activity of the PAI-1 inhibitor RS5614 is confirmed in the phase 2 study of malignant melanoma.

（What is malignant melanoma?)

Malignant melanoma is a type of skin cancer when melanocytes, skin cells that produce melanin pigment, which is related to skin color, become malignant. Among skin cancers, malignant melanoma has a high rate of metastasis and is considered to be extremely malignant. In Japan, the number of patients with malignant melanoma is as low as 0.6 per 100,000 people, but in the U.S. the number is 12.7 and in Australia 33.6, several tens of times higher than that of Japanese. Malignant melanoma is an extremely malignant cancer (5-year survival rate is about 50% when the size of the cancer exceeds 4 mm, 40% when there are metastases in the regional lymph nodes, and a few percent when there are distant metastases). Furthermore, the degree of progression of malignant melanoma in Japan is reported to be about three times higher than in the United States. This may be due to the fact that most malignant melanoma in Japan is of the acral lentiginous type, which is not major in Europe and the United States, making it difficult to respond to therapeutic agents.

The first treatment for malignant melanoma is surgical resection. However, the cancer is already advanced at the time of detection in many cases, and drug therapy (pharmaceuticals) is required for cases that are not radically resectable. Radiation therapy is not very effective for malignant melanoma. With the advent of antibody drugs (immune checkpoint inhibitors) such as nivolumab that target immune checkpoint molecules, drug therapy has made revolutionary progress. However, the response rate of nivolumab for malignant melanoma is 22.2% in Japan. Furthermore, the combination therapy of nivolumab and ipilimumab is approved for the patients refractory to nivolumab, and the response rate is 21% overseas and 13.5% in Japan. The combination therapy with nivolumab and ipilimumab causes serious side effects in more than half of patients, and the incidence of severe immune-related side effects that result in discontinuation of treatment is four times higher than that with the nivolumab therapy, requiring several months of hospitalization or interruption of cancer treatment. In addition, due to the challenge of high medical costs, there is a long-awaited need for a concomitant medication that can be orally administered differently from antibody therapeutics, have fewer side effects, and increase the response rate.

(Results of the Phase II study)

A Phase II investigator-initiated clinical trial to evaluate the efficacy and safety of the combination of RS5614, a PAI-1 inhibitor, and nivolumab, an immune checkpoint inhibitor, in the patients with malignant melanoma that is difficult to surgically resect was conducted in collaboration with six medical institutions including Tohoku University Hospital.

The results showed that the combination of nivolumab and RS5614 was as effective as or more effective than the reported combination of nivolumab and ipilimumab, which is an existing treatment (the response rate of nivolumab + RS5614 is 24.1%; the response rate of nivolumab + ipilimumab is 13.5%). The safety of the combination of nivolumab and ipilimumab has been a concern due to serious immune-related side effects, but no problematic side effects were observed with the combination of nivolumab and RS5614. The clinical study report was completed in Feb 2024, and we will prepare the next phase study in order to file an application for regulatory approval.

Currently, the combination of nivolumab and ipilimumab has been approved for patients with malignant melanoma refractory to nivolumab and covered by insurance, but the serious side effects of the nivolumab-ipilimumab combination have become a problem. The Japan Clinical Oncology Group (JCOG) conducted a phase III study (JCOG2007) at 59 centers nationwide from April 2021 to compare the efficacy of nivolumab-ipilimumab combination therapy and found that about 7.4% (11 out of 148 patients) of the patients in the nivolumab-ipilimumab combination group had treatment-related death, which was higher than expected. The study was terminated on March 30, 2023. So, the nivolumab-ipilimumab combination is problematic for several types of cancer.

The combination of RS5614 and nivolumab is as effective as or more effective than the combination of nivolumab and ipilimumab in the patients refractory to nivolumab, and the combination of RS5614 and nivolumab is safer than the combination of nivolumab and ipilimumab. The development of the novel therapeutics for unresectable malignant melanoma refractory to immune checkpoint inhibitors alone is an urgent issue. The combination of nivolumab and RS5614 is expected to be a highly effective and safe drug therapy for the patients with malignant melanoma refractory to the monotherapy with immune checkpoint inhibitors.

The preclinical studies in animal models have shown that oral administration of RS5614, the PAI-1 inhibitor, regresses malignant melanoma as well as colorectal and lung cancers, and that this beneficial effect significantly increases when combined with immune checkpoint inhibitory antibodies. Therefore, we have started Phase II investigator-initiated clinical trials for non-small cell lung cancer and for cutaneous hemangiosarcoma.

It has long been reported that many cancers with high PAI-1 expression have high malignancy and poor prognosis, which has been called the “PAI-1 paradox”. Through collaboration with many universities in Japan and overseas, we have discovered that cancer cells produce PAI-1 and enhance the expression of immune checkpoint molecules such as PD-L1, thereby evading attacks by the immune system. In the preclinical studies using animal models, we have demonstrated that oral administration of RS5614, the PAI-1 inhibitor, can regress malignant melanoma, colorectal cancer, lung cancer, and others. The clinical trial confirmed the response in 7 of 29 patients with malignant melanoma who were not eligible for complete surgical resection and were refractory to nivolumab, when administered in combination of RS5614 with nivolumab for 8 weeks. The efficacy of RS5614 for chronic myeloid leukemia (CML), a hematological cancer, has already been demonstrated in the early and late Phase II studies, and a Phase III trial is currently ongoing. We have confirmed in humans that the “PAI-1 paradox” is indeed important in cancer therapy, that PAI-1 is a target of therapy in some types of cancer, and that the PAI-1 inhibitor is effective as a drug therapy.

Since we have confirmed the efficacy in the Phase II study, we will discuss with the regulatory authorities and clarify the roadmap for the future, including the next phase of clinical trials and application for regulatory approval. Also, since Renascience does not have a marketing license for pharmaceuticals, we would like to clarify the path for commercialization through collaboration with other companies.

All traditional immune checkpoint inhibitors are antibody drugs that require hospitalization and administration by injection and are also expensive. In addition, existing antibody drugs are known to have various side effects. RS5614 will be a highly safe and convenient drug that can be taken at home. Unlike antibodies, RS5614 is chemically synthesized, so its price is expected to be lower than that of antibodies.

The standard treatment for non-small cell lung cancer is platinum-based chemotherapy and immunotherapy using anti-PD-1/anti-PD-L1 antibodies, but only small number of patients are cured. In the event of failure, chemotherapy such as docetaxel is administered as second-line treatment, but the survival period is as short as 3 months, requiring third-line treatment. But there are few effective third-line treatments, and so new drugs are eagerly awaited. In the collaboration, we discovered that PAI-1 is involved in the progression and proliferation of lung cancer, and confirmed that cancer cells that become resistant to anti-PD-1 antibodies express extremely high levels of PAI-1. In fact, we confirmed that the combination of an anti-PD-1 antibody and the PAI-1 inhibitor showed higher anti-cancer activity than the anti-PD-1 antibody alone in a lung cancer model mice. Based on these findings, we have been conducting a phase II study to confirm the efficacy and safety of the PAI-1 inhibitor RS5614 for non-small cell lung cancer at Hiroshima University Hospital and other hospitals.

Cutaneous angiosarcoma is a rare soft-tissue tumor (about 300 cases per year in Japan), and taxane anticancer agents, which induce apoptosis* in tumor cells, are the first-line drugs. However, a study of the prognosis of 90 cutaneous angiosarcoma patients treated with taxane anticancer agents showed that the overall survival was 649 days, with limited therapeutic efficacy, and research and development of new therapeutic agents is urgently needed. PAI-1 is produced primarily in the vascular endothelium. In our analysis of cutaneous angiosarcoma samples, we found that high PAI-1 expression is strongly correlated with poor prognosis. The finding that cancer cells that express high levels of PAI-1 are resistant to apoptosis strongly suggests that the PAI-1 inhibitor, when combined with taxane anticancer drugs, can enhance the therapeutic effect of taxanes in angiosarcoma. Therefore, a phase II study (investigator-initiated clinical trial) is being conducted at Tohoku University and other institutions to confirm the efficacy of the PAI-1 inhibitor RS5614 in patients with cutaneous angiosarcoma who have failed the taxane anticancer drug paclitaxel.

*Apoptosis: A phenomenon in which the cell’s own death program is activated and leads to cell death, unlike necrosis (or necrosis) in which cells are damaged and die.

Systemic scleroderma (SSc) (designated as Intractable Disease 51 in Japan) is a systemic autoimmune disease characterized by vasculopathy and fibrosis of the skin and many organs, the etiology of which is still unknown. It is an intractable disease that causes symptoms such as skin hardening, fibrosis of the lungs (Interstitial lung disease, ILD), gastroesophageal reflux disease, cardiac involvement, and hand ulcers.

It is estimated that there are more than 30,000 patients with SSc in Japan. ILD is a serious disorder that accounts for more than 30% of deaths among SSc patients. Even when ILD is not the direct cause of death, fibrosis impairs lung function, resulting in severe cough and breathing difficulties that significantly limit daily life. Current therapies may not be effective enough, and even though the treatment of autoimmune diseases has advanced, disease-related deaths account for 70% of all deaths in SSc while for less than 10% of all deaths in rheumatoid arthritis and systemic lupus erythematosus. Therefore, the development of effective therapies is highly desirable.

RS5614 may suppress the progression of SSc symptoms, since SSc is mainly caused by inflammation, fibrosis, and vascular damage associated with autoimmunity, since RS5614 ameliorates all the symptoms. In fact, the efficacy of RS5614 in suppressing lung fibrosis has been demonstrated in animal models of SSc. Although many current SSc medicines have strong side effects, such as steroids and immunosuppressants, RS5614 is expected to be useful as a treatment for ILD associated with SSc due to its high safety profile.

Therefore, a Phase II study to investigate the efficacy and safety of the PAI-1 inhibitor RS5614 for SSc-ILDs has been conducted at several medical institutions in Japan, including Tohoku University Hospital. The project is funded by Japan Agency for Medical Research and Development (AMED).

The global spread of novel coronavirus infection (COVID-19) is a significant societal challenge. About 80% of infected patients only have mild symptoms, but the disease can deteriorate, especially in the elderly and patients with underlying medical conditions, leading to severe pneumonia and acute respiratory distress syndrome (ARDS). In mild cases, patients are treated at home or stay overnight in hotels, but there is a problem with some patients who are mildly ill at the onset of illness but rapidly become severely ill. Vaccination and mutation of the virus strain (Omicron strain) have made the disease less severe than before, but the possibility of further mutation of the virus strain causing severe disease must be closely monitored. In addition, with the lowering of the classification of novel coronavirus from “Class 2” to “Class 5” under the Infectious Disease Control Law, an even greater number of patients may receive treatment at home or as outpatients. We prepare to conduct the next phase of clinical trials as soon as possible in the event of an outbreak of a new strain that causes pneumonia.

We hope to develop a medicine that prevents deterioration of pneumonia, especially a safe and convenient preventive/treatment (oral medicine) that can be prescribed on an outpatient basis and taken at home, thereby not only prolonging the lives of patients but also reducing the burden on medical facilities and contributing to the effective use of medical resources. Patients with severe pneumonia caused by novel coronavirus exhibit rapid progression of lesions such as inflammation and fibrosis, and characteristic findings of enhanced blood coagulation. Very characteristic findings in novel coronavirus lung injury are fibrin microthrombi, inflammation, and fibrosis in the lungs.

RS5614 suppresses inflammation, fibrosis, and vascular damage, and may be effective in the treatment of new-type coronavirus lung injury.

The early Phase II investigator-initiated clinical trial (open-label) was conducted from the fall of 2020, and the clinical trial report was completed in June 2021. There were no significant side effects, and all 26 patients who were hospitalized for lung injury and administered the investigational drug were discharged safely.

Based on the results of the early Phase II investigator-initiated clinical trial, a placebo-controlled late Phase II investigator-initiated clinical trial was conducted in patients with novel coronavirus lung injury (moderate disease, hospitalized patients) in collaboration with 20 universities and medical institutions in Japan, including Tohoku University, Kyoto University, Tokyo Medical and Dental University, and Tokai University. This trial was adopted in March 2021 by the AMED’s “Research Program for Emerging and Re-emerging Infectious Diseases”(with Tohoku University as the representative research organization and Renascience as a sharing research organization), and started in June 2021 after the study protocol was finalized based on a preliminary consultation with the PMDA in April 2021. The clinical trial was extended until the end of October 2022 (finally 75 patients were enrolled) due to the decrease in the number of eligible patients with novel coronavirus lung injury (moderate disease, hospitalized patients) as a result of the sharp decrease in the number of infected patients and the emergence of Omicron strain. The clinical study report was finalized in April 2023.

The primary efficacy endpoint showed no statistically significant difference between the two groups, but there was a reduction in deterioration in the RS5614 group versus the placebo group, suggesting efficacy, especially in patients with relatively mild disease. In addition, the proportion of patients requiring oxygen therapy was lower in the RS5614 group in the first 3-5 days after hospitalization, suggesting the effectiveness of RS5614 in early treatment. The RS5614 group also showed improvement in pneumonia imaging findings, but not in the placebo group. The incidence of side effects was similar in the RS5614 and placebo groups, confirming the safety of this investigational drug (RS5614) in patients with COVID-19-related lung injury.

On December 25, 2020, we entered into an option agreement with Daiichi Sankyo Company, Limited for preferential negotiating rights for the pulmonary use of RS5614, such as novel coronavirus lung injury and other lung injuries. In November 2022, we signed a memorandum of understanding to extend the option period to March 2025 with a view to conducting clinical trials to confirm the efficacy of RS5614 not only for novel coronavirus lung injury but also for interstitial pneumonia caused by anticancer drug therapy.

Non-clinical studies have shown that our RS5614 inhibits thrombosis, inflammation, and fibrosis, suggesting that it may be effective against interstitial pneumonia. Lung injury can be caused not only by viruses but also by various other causes, such as anticancer drugs, autoimmune diseases, and idiopathic diseases of unknown cause, and we will conduct clinical studies to evaluate the efficacies on these lung injuries.

As part of these efforts, we have initiated a collaboration with the Department of Respiratory Medicine, Kyoto University Hospital, with a view to conducting clinical trials for acute exacerbations of idiopathic interstitial pneumonia. Acute exacerbation of idiopathic interstitial pneumonia is a condition with a poor prognosis, accounting for approximately 40% of all deaths from idiopathic interstitial pneumonia. We have also extended our agreement with Daiichi Sankyo Company, Limited, with a view to conducting clinical trials to confirm the efficacy of this drug in interstitial pneumonia arising from anticancer drug therapy and other treatments. Furthermore, the Phase II study to investigate the efficacy and safety of RS5614, a PAI-1 inhibitor, in the treatment of interstitial pneumonia associated with systemic scleroderma was conducted at several hospitals in Japan, including Tohoku University Hospital (funded by Japan Agency for Medical Research and Development, AMED).

We have been conducting research on “PAI-1 and aging” in collaboration with Northwestern University in the United States.

Cells of living organisms cannot proliferate without limit due to a phenomenon called cellular senescence. This phenomenon involves the shortening of telomere length of genome, as well as cellular senescence factors such as p53. Senescent cells have been found to have extremely high expression of PAI-1 in addition to p53. In fact, it has become clear that the phenomenon of cellular senescence can be inhibited by suppressing p53 or PAI-1. It was reported that PAI-1 expression is high not only in cells but also in aged tissues and individuals (klotho mice and humans with Werner’s syndrome, a well-known form of premature aging). In klotho mice, a well-known model of aging, it was shown that all major symptoms of aging can be ameliorated by inhibiting PAI-1 expression and activity at the gene or protein level. Furthermore, in a study of people from the Amish community, a Christian sect living in the Midwest, we found that those without the PAI-1 gene lived 10 years longer than those who had it. We also found that deficient people are less susceptible to diseases such as diabetes.

These facts were reported in the New York Times and many other newspapers in November 2017. The principal investigator of the study, the Chair, Professor of Medicine at the Department of Medicine at Northwestern University, said “They are not only living longer. They are living healthier .” He also added, “This is the ideal type of longevity.” This epidemiological study in humans is consistent with the results of experiments in cells and mice. Diseases such as cancer, vascular (atherosclerosis), pulmonary (emphysema, chronic obstructive pulmonary disease), metabolic (diabetes, obesity), renal (chronic kidney disease), bone and joint (osteoporosis, osteoarthritis), and brain (cerebrovascular disease, Alzheimer’s disease and dementia) develop with aging. Interestingly, PAI-1 expression is extremely high in the tissues of these diseases. Furthermore, it has been confirmed that administration of PAI-1 inhibitors to animal models of these diseases markedly improves their symptoms.

Recently, it is reported that senescent cells express PD-L1, a protein that acts as “the brake” for immunity (immune checkpoint molecule) and allows themselves to escape immune attack. Therapeutics inhibiting immune checkpoint molecules (immune checkpoint inhibitors) can activate immune system in aged mice and lifestyle-disease mice. The activated immune system eliminates the aged cells, and ameliorates senile change of various organs and tissues and life-style diseases in the mice.

We have discovered that PAI-1 is involved in the expression of immune checkpoint molecules in cancer cells and promotes cancer cell proliferation, and that our PAI-1 inhibitor has immune checkpoint inhibitory effects. Thus, PAI-1 promotes cancer and aging, and our PAI-1 inhibitor may be effective against cancer and other aging-related diseases.

These are just a few of the interesting findings that are emerging regarding PAI-1 and aging. However, it is not known whether PAI-1 inhibitors are effective in preventing aging, as clinical trials to prove this are not feasible at this moment.

The Phase II investigator-initiated clinical trial of RS8001 for PMS/PMDD is ongoing in collaboration with Kinki University, Tohoku University, Tokyo Medical and Dental University, and Tokyo Women’s Medical University (placebo lead-in* double-blind, placebo-controlled, 3-arm comparative study; target number of patients, 105). This clinical trial was adopted by the AMED’ under the ” Cyclic Innovation for Clinical Empowerment (CiCLE)” (Renascience is the representative research organization) in FY2019 .

The clinical trial started in November 2020, earlier than the originally scheduled February 2021, but the number of patient visits decreased due to the impact of the spread of novel coronavirus infection, so two new study sites were added in FY2021 to promote the enrollment of the patients, posters and educational booklets were created in the hospital, and the coordinating investigator conducted Web seminars for pharmacists. In November 2022, three additional study sites were added, and measures are being taken to utilize volunteer panels and hold public lectures by investigators. As the results, the target number of the enrollment was achieved in September 2023. AMED has decided to continue the project at the interim evaluations. A report was compiled in June 2024. We are currently in discussions with AMED regarding future development directions.

*Placebo lead-in method: Placebos do not contain active ingredients, but they may improve disease symptoms due to psychological effects (placebo effect). Therefore, we adopt a study design in which subjects are asked to take a placebo for a certain period of time prior to administration of the active drug, and subjects with a large placebo effect are not asked to participate in the study.

Insulin therapy is required to strictly control blood glucose levels in diabetes and prevent diabetic complications. However, the safe dose range of insulin is narrow, and the optimal type and dosage must be selected for each patient because overdosing results in hypoglycemia. On the other hand, since diabetologists account for less than 2% of all physicians and are geographically unevenly distributed, diabetic patients currently do not always see their primary care physician as a diabetologist, but rather see a non-diabetologist.

Therefore, we have been developing an AI DM-SAiL (SAiL stands for Skill Acquisition Learning) in collaboration with Tohoku University and NEC Corporation to assist non-diabetologists to perform diabetologist-level insulin therapy.We have completed the analysis on data from approximately 1,000 patients (about 1,080,000 clinical parameters) admitted to Tohoku University Hospital, and have been able to develop an AI that predicts insulin dosage with an error margin of about 2 units from the dosage prescribed by diabetologists.The correct rates in the patients hospitalized at Tohoku University Hospital are extremely high, with an overall rate of approximately 90% and the error rates (difference in insulin units) were 0.65 to 0.95 units from the prescription by the diabetologists for both rapid-acting and long-acting insulins. We are currently developing a system to use this SaMD on the cloud with NEC Solution Innovator and have completed the development of a demo system.

In April 2022, the project was adopted by the AMED under the “Commercialization Promotion Project for Medical-engineering Collaboration (Support for small and medium-sized enterprises development and commercialization) in FY2022″ (our company is the representative research organization). We are now moving forward with development toward practical application. The PMDA pre-development consultation was completed in December 2022, the PMDA protocol consultation (pre-consultation) was completed in May 2023, proceed with development toward practical application, and start clinical performance testing in August 2024.

Patients with chronic renal failure undergo hemodialysis three times a week for life to replace the crippled kidneys and remove waste products. Insufficient dehydration causes cardiopulmonary dysfunction such as heart failure and hypertension, while excessive dehydration results in hypotension during dialysis and adverse events such as bad mood and loss of consciousness. Insufficient or excessive water removal due to inappropriate water volume settings can cause adverse events, placing a heavy burden on healthcare professionals who are forced to deal with the patient.

To achieve safe hemodialysis, we have been developing an AI (Dual-Channel Combiner Network, DCCN) to predict the appropriate total volume of water removal in collaboration with Tohoku University and NEC Corporation. DCCN learns from 725,000 dialysis records (patient information, dialysis information, and laboratory information) obtained from St. Luke’s International Hospital and other private dialysis treatment facilities, and predicts the target amount of water removal, based on the patient’s last 5 dialysis records and pre-dialysis data on the day of dialysis: it can now predict sudden drop of blood pressure during hemodialysis (less than 20 mmHg) with the accuracy of AUC 0.91, and can predict total amount of water removal with an error of about the volume of ‘one cup’ from one empirically set by the nephrologists.

In April 2023, we completed a pre-development consultation with the PMDA and the development have been proceeding toward practical application.

This project was adopted by AMED under the Program of the “Research on Development of New Medical Devices” in February 2023. In May 2021, we concluded a collaboration agreement with Nipro Corporation regarding the development of this AI. In December 2023, we started development of an AI equipped hemodialysis medical device that can control water removal and blood flow rate in hemodialysis, in collaboration with Toray Medical Co. Ltd.

Early diagnosis and appropriate treatment of the deterioration of oral function (oral frailty) with aging are important because the deterioration, if left untreated, can lead to many physical and social impairments such as eating disorders and dysarthria (speech) disorders, as well as generalized muscle weakness (frailty). In an aging society, eating and swallowing disorders, a form of oral functional decline, have been increasing, and it has been reported that aspiration is the cause of approximately 70% of pneumonia, which is considered a cause of death. Early detection of swallowing dysfunction and therapeutic intervention such as rehabilitation are important to prevent aspiration pneumonia, but currently there are only swallowing evaluation methods such as swallowing endoscopy and fluoroscopy, which are burdensome to patients.

Since the organs used in swallowing and speaking have many parts in common, such as the tongue, oral cavity, and pharynx, we have focused on the possibility of evaluating swallowing function from conversation, and are developing an AI that can evaluate swallowing dysfunction from speech data during conversation. In collaboration with several departments at Tohoku University (Department of Otorhinolaryngology, Department of Dentistry, Rehabilitation Medicine, and Graduate School of Biomedical Engineering) and NEC Corporation, all frequencies of speaking sounds of patients visiting the Tohoku University Hospital Swallowing Treatment Center are analyzed by an AI engine (time series model-free analysis) specialized for analysis of time series data, We have been able to develop an AI that confirms the baseline (gender, age, individual differences, etc.) of voice of healthy people, detects the differences between the pronunciation of healthy people and that of the patients, and diagnoses the decline in swallowing function.

In the future, we will develop an AI for practical use by training it on data from elderly people with impaired swallowing function. If this program medical device is put into practical use, it can diagnose patients with impaired swallowing function who may develop aspiration pneumonia easily and at an early stage. In March 2023, we filed a patent application jointly with Tohoku University for intellectual property rights.

Spirometry is a physiological test of respiratory function that measures the amount of breath a subjects exhale and the duration of exhalation. It is an important test for the diagnosis of chronic obstructive pulmonary disease (COPD) and other lung diseases, but it is not widely used. In addition to requiring the subject’s (patient’s) cooperation (breathing efforts), it is difficult for non-specialists to determine if the test was performed correctly and to interpret the output (flow volume curve). The development of a system that allows non-specialists to easily interpret the results is considered an important medical issue for the diagnosis and early treatment of respiratory diseases.

We have been developing an AI to interpret flow volume curves in collaboration with Kyoto University and NEC Solution Innovator, Ltd. Medical data from approximately 1,900 subjects has been obtained, and development toward practical application is ongoing. We executed a collaboration and commercialization agreement (license agreement) with Chest M.I. Inc in July 2020.The milestone payments were received in October 2021 and June 2023 under the agreement.

As an initiative related to women’s diseases, one of our priority areas, we have been developing an AI to detect lesions from pathological images of breast cancer in collaboration with Tohoku University. In the verification using pathological images, the detection model was classified into three classes (benign, non-invasive cancer, and invasive cancer) or two classes (benign and malignant), and achieved diagnostic accuracy of 88.3% and 90.5%, respectively. In the future, we plan to work on AI diagnosis with “specimen for intraoperative pathology” in the area of breast cancer.

In addition, as an initiative related to aging-related diseases, we have been developing an AI to predict the occurrence of arrhythmia and heart failure using information from cardiac implantable devices, in collaboration with Tohoku University.

A collaboration agreement was executed with HI-LEX Corporation and HI-LEX Medical in September 2022, and we work with HI-LEX Medical and Tohoku University to develop an AI to predict the occurrence of thrombi in the auxiliary artificial hearts.

Software as a medical device (SaMD) utilizing AI requires AI as its core technology and the development of a system to run the AI in the medical settings. The most appropriate AI algorithm must be selected based on the medical issue to be solved and the type of medical data to be utilized. We have licensed some basic AI algorithms (engines) from NEC Corporation and have been customizing them for medical use with medical data and physicians’ advice at medical fields. The development of the system for the medical AI is outsourced to NEC Solution Innovator, Ltd. (NES).

A tube is placed into the peritoneum of peritoneal dialysis patients to inject dialysis fluid. We have developed an ultra-thin endoscope (about 1 mm in diameter) that is inserted through this thin tube to non-invasively observe the abdominal cavity without laparotomy or laparoscopy in collaboration with Tohoku University, Juntendo University and Jikei University School of Medicine. 

In August 2022, the main part of the fiberscope was submitted to the PMDA for approval, and in December of the same year, the Ministry of Health, Labour and Welfare (MHLW) granted the regulatory approval.

In September 2022, we entered into a collaboration agreement with HI-LEX Corporation and its subsidiary HI-LEX Medical, Inc. for the development of medical devices including the guide catheters.

In May 2024, we entered into a license agreement with HI-LEX Medical, Inc. for this endoscope for medical applications including peritoneal dialysis.

Phenylalanine is one of the amino acids that make up proteins in the body, and is metabolized by enzymes in the body to another amino acid called tyrosine. Phenylketonuria is a disease in which phenylalanine is not metabolized and accumulates in the body because the enzyme activity is congenitally low. It is designated as an intractable pediatric disease.Without proper treatment, this disease may cause severe symptoms such as mental retardation and convulsions.Mass postnatal screening was introduced in 1977, and almost all affected children are now detected at an early age.

However, affected children need to be on a proper diet to limit phenylalanine, and regular checkups at a medical facility are necessary, but blood samples taken every few months do not allow for meticulous dietary management. The self-management of phenylalanine diet is currently difficult since there is no home blood glucose monitoring system available at home like self-monitoring blood glucose for diabetics. 

We have been developing a system to measure blood phenylalanine concentration easily and accurately at home in collaboration with Tohoku University. We aim to integrate this new testing system into a kit and take it to insurance reimbursement for self-management. If self-measurement can be performed at home at any time, as in the case of self-glucose control in diabetics, detailed dietary management for patients with phenylketonuria can be achieved.

There are many cases where medical application (implementation) is difficult even for excellent technology because the technology does not meet the issues and needs of the medical field or is inappropriate for the specifications of the medical field. Many companies that possess the technologies face this problem. We try to develop a medical device and software as a medical device based on the concept of “Biodesign,” in which solutions to problems are developed starting from the needs of the medical field, and then the process is optimized by imagining the final product at the medical field to realize innovation.

For the fiscal year ending March 31, 2024, we reported business revenue of 194 million yen and a net loss of 258 million yen. On the revenue, in addition to the payments under the contracts with companies, we received a funding from the Japan Agency for Medical Research and Development (AMED), but the timing of recording the upfront payment for a collaboration agreement was changed from the fiscal year ending March 31, 2024 to the fiscal year ending March 31, 2025, resulting in 78% of the planned amount.

In terms of expenses, the net loss was smaller than originally planned due to the use of public funds from AMED for pipeline development of interstitial lung disease associated with systemic scleroderma and software as amedical device such as support for maintenance hemodialysis.

Although our out-of-pocket R&D expenses decreased, the pipeline development (number and stage) progressed as planned as a result of efficient R&D activities, that are our strengths.

First quarter: mid-August, second quarter: mid-November, third quarter: mid-February, and announcement of financial results: mid-May.

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Although it is difficult to state clearly when we will be able to achieve stable profitability, we believe that we may achieve profitability in a single year within a few years. One of the reasons for this is the income from out-licensing of pipelines (upfront payments, milestone payments based on the development stage, royalty payments based on product sales, etc.).

Renascience is still in the stage of promoting research and development of pipelines for the next several years and plans to use cash and cash equivalents on hand for this purpose. Renascience has received grants from public funds such as AMED (Japan Agency for Medical Research and Development), so the out-of-pocket expense for R&D has remained at a lower level than planned. We do not plan to raise funds from the general financial market for the near term until new business capital needs arise in the future.

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