The Neglected Tropical Disease (NTD) Drug Discovery Booster is a collaborative project in early small molecule drug discovery running since 2015 between Drugs for Neglected Diseases initiative (DNDi) and pharmaceutical partners across the globe, including Astellas Pharma Ltd., Eisai Co., Ltd., Shionogi & Co., Ltd. and Takeda Pharmaceutical Company Ltd. in Japan, along with AbbVie Inc., Merck KGaA, AstraZeneca plc and Celgene Corporation. The Booster engages these partners to share both their experience with in silico screening as well as their proprietary chemical libraries to further develop new starting points for NTDs such as visceral leishmaniasis and Chagas disease. This collaborative approach allows DNDi to access new chemical space and elaborate the structure activity relationships (SAR) around phenotypic screening hits against the causative parasites of these diseases (Trypanosoma cruzi, Leishmania donovani and infantum) as well as access new starting points via innovative scaffold hops proposed by the partners. Since 2015 the Booster has probed over 20 new starting point “hits” for these diseases, successfully converting over half into new series for further exploitation. These series were developed further in partnership with the booster collaborators to enable in vivo proof of concept studies, with series from the booster progressing into lead optimization. Our efforts in the NTD Discovery Booster have demonstrated clear advantages of this precompetitive sharing mechanism and the synergistic value of exploring multiple proprietary compound libraries in parallel. The most advanced of these Booster projects is projected to deliver a preclinical candidate for leishmaniasis within the next 2 years.

Overcoming serious infectious diseases such as malaria, tuberculosis, and other neglected tropical diseases (NTDs) that threaten human life around the world is an important issue in global health. Most of these diseases are concentrated in developing and low-income countries, and in order to reinforce drug discovery activities, pharmaceutical companies are actively promoting industry-academia-government partnerships and utilizing funds to stimulate global health activities. In this presentation, three examples of our drug discovery activities are introduced. The first is participation in the Booster project led by Drugs for Neglected Diseases initiative (DNDi) aimed at creating therapeutic agents for leishmaniasis and Chagas disease, an effort supported by the Global Health Innovative Technology (GHIT) Fund. As domestic and overseas pharmaceutical companies participate in the project and provide their own compounds, it is possible to obtain structure-activity relationship information in a short period of time and improve compound potency. We collaborated with DNDi to create a lead compound from one hit compound, and contributed to further enhancement of its activity. The remaining two are collaborations with academia for the creation of new therapeutic agents or vaccines: a joint research project with Hokkaido University Research Center for Zoonosis Control for emerging viral diseases, and a collaboration with Nagasaki University in malaria. In each case, our researchers were based at the university, establishing close working collaborations with the university researchers. Novel solutions for serious infectious diseases are expected by the combination of the high-level basic research capabilities of academia and the drug discovery know-how and original compound libraries possessed by pharmaceutical companies.

Delivering new medicines to patients suffering from Neglected Tropical Diseases (NTD) is a major challenge. There are various hurdles to be overcome, such as the large number of patients in a large number of different regions, the lack of marketability, and resistance to medicines. Takeda Pharmaceutical Company Limited (Takeda) is following a corporate mission of “striving towards better health for patients worldwide though leading innovation in medicine”. These guiding principles lead to the values of Integrity, Fairness, Honesty and Perseverance that make up what we call “Takeda-ism”. As part of its contribution to R&D for NTDs, Takeda collaborates with global Product Development Partnerships (PDPs). In this symposium, the “Drug Discovery Booster” project to accelerate and expand discovery of new drugs for Leishmaniasis and Chagas disease with Drugs for Neglected Diseases initiative (DNDi) and other pharmaceutical companies is introduced. Proprietary compound libraries and the drug discovery expertise of various partners was applied to this new drug discovery approach. An overview of our research projects in malaria, tuberculosis, and NTD is also presented. In addition to these, Takeda's Access to Medicines (ATM) strategy and activities are introduced. Lastly, we discuss a new open innovation model which is accelerated by partnership with a variety of organizations and how Takeda achieves its sustainable development goal (SDG) targets.

Neglected tropical diseases (NTDs) are communicable diseases that are uncommon in developed countries but epidemic in developing countries of the tropical and subtropical regions around the world. One of the important contributions expected of pharmaceutical companies is the development and provision of drugs effective against NTDs. Firstly, Eisai has distributed at price zero to endemic countries worldwide diethylcarbamazine (DEC) tablets for patients suffering with lymphatic filariasis (LF). Eisai's efforts toward improving global health have resulted in a rich portfolio of assets addressing six infectious diseases: malaria, tuberculosis, Chagas disease, LF, leishmaniasis, and mycetoma. As the most advanced project, Eisai has developed E1224, which is available in both intravenous and oral formulations, and delivers ravuconazole, the active form of fosravuconazole, with a long plasma half-life. The first clinical trials of E1224 for Chagas disease have already been completed, led by the Drugs for Neglected Diseases initiative (DNDi). As a result, parasite clearance was observed with E1224 during the treatment phase, but parasite regrowth was observed after the end of drug administration. On the other hand, a clinical trial for eumycetoma in collaboration with DNDi is ongoing supported by the Global Health Innovative Technology (GHIT) Fund. In this manner, Eisai will continue its Medicine Creation research projects in collaboration with various Product Development Partnerships (PDPs) and academia.

The number of clinical trials investigating the use of nucleic acid drugs, including DNA/RNA-based vaccines, immunostimulatory/modulatory DNA/RNA and cyclic dinucleotides, for immuno-prophylaxis and -therapy has been increasing exponentially in recent years. These new drugs have revealed their therapeutic potential not only as vaccines or adjuvant therapies, but also as monotherapies for use in immuno-therapy of cancer and allergic disease. I will present an overview of their current R&D taking place in this field, then describe our recent progress, particularly regarding CpG oligodeoxynucleotides (ODNs), such as K3, K3-SPG, and D35 as either vaccine adjuvants or mono-immunotherapeutic agents for tropical diseases including malaria and leishmaniasis.

Astellas regards the situation where there still remain barriers for many people who have difficulty accessing the healthcare they need due to the lack of available treatments, poverty, healthcare system challenges and insufficient healthcare information. Astellas recognizes this problem as the Access to Health issue. To improve Access to Health, Astellas has identified four areas where we can leverage our strengths and technologies, and is working to solve issues, making full use of external partnerships. These areas are “creating innovation”, “enhancing availability”, “strengthening healthcare system” and “improving health literacy”. In March 2018, Astellas participated in the Neglected Tropical Diseases Drug Discovery Booster, a consortium whose purpose is to identify lead compounds for leishmaniasis and Chagas disease, both of which are neglected tropical diseases (NTDs). Moreover, within the pediatric praziquantel consortium, involving pharmaceutical companies, research institutions and international non-profit organizations, Astellas has developed a pediatric formulation of praziquantel for the treatment of schistosomiasis. In this report, we will introduce concretely how Astellas has promoted new drug development projects for NTDs in collaboration with various external partners, giving the projects as examples.

The industrial application of mammalian cells can be divided into two categories, where (1) the cells are mediators (i.e., the cell produces a desired product), or (2) the cells themselves are the product. The main application of cell-produced products is in biopharmaceuticals (biologics), and these include therapeutic enzymes, cytokines, antibodies, vaccines, and vectors for gene therapy. Among the 291 biopharmaceuticals launched in Europe and the United States by 2018, the number of products produced using mammalian cells exceeded 60%, with Chinese hamster ovary (CHO) cells being used for 131 products. The production of mammalian cells requires a comprehensive approach, including cell line development, cell culture, culture media, bioreactors, scale-up, separation and purification, process development, quality analysis and control, and research and development related to safety. In this manuscript, the activities of the “Manufacturing Technology Association of Biologics (MAB)” are introduced. MAB is a research organization composed of several companies, organizations, and academics that focuses on advanced manufacturing research for the production of biologics.

In the development of therapeutic monoclonal antibodies (mAbs), it is essential to characterize the modifications causing structural heterogeneity because certain modifications are associated with safety and efficacy. However, the rapid structural analysis of mAbs remains challenging due to their structural complexity. The multi-attribute method (MAM) is a structural analytical method based on peptide mapping using LC/MS, and has drawn attention as a new quality control method for therapeutic mAbs instead of conventional structural heterogeneity analyses using several chromatographic techniques. Peptide mapping, which is regarded as an identification test method, is used to confirm that the amino acid sequence corresponds to that deduced from the gene sequence for the desired product. In contrast, MAM is used for simultaneously monitoring the modification rates of individual amino acid residues of therapeutic mAbs, indicating that MAM is used as quantitative test rather than identification test. In this review, we summarized the typical structural heterogeneities of mAbs and the general scheme of MAM. We also introduced our optimized sample preparation method for MAM, and examples of simultaneous monitoring of several modifications including deamidation, oxidation, N-terminal pyroglutamination, C-terminal clipping and glycosylation by our MAM system.

Continuous Manufacturing is a manufacturing method in which raw materials enter the manufacturing process continuously, and products are discharged continuously throughout the duration of the process including multiple unit operations. Continuous Manufacturing includes various options: Those with all stages of processing from charging raw materials to discharging final products that are continuous, and those with only certain parts of the manufacturing process that are continuous. It can be introduced in an appropriate range in consideration of the characteristics of products, manufacturing processes, robustness of processes, etc. Continuous Manufacturing is expected to have the following advantages: A wide range of manufacturing scales are available by adjusting the continuous operation time of the process; it is possible to use the same manufacturing equipment from the development stage to commercial production, eliminating the need to change to large scale manufacturing equipment; and it is possible to reduce the equipment installation area (footprint). While Continuous Manufacturing can be a major manufacturing technique of the pharmaceutical industry in the future, official documents such as guidelines for Continuous Manufacturing are limited. In particular, no official documents such as guidelines specialized in manufacturing of biotechnological drug products have been issued yet. In Japan Agency for Medical Research and Development (AMED) research project, we summarized the key points to consider for investigation of the control strategy for Continuous Manufacturing of biotechnological products as a document. In this paper, we introduce the document.

In recent years, the development of biologics such as therapeutic antibodies has increased. Around 1980, Japan was the world's leading country in terms of research and development on biologics. However, after that, the development of biologics in Japan has become stagnant. Especially, research and development of therapeutic antibodies, which are critical medical products, is compared to that being conducted in Europe and the United States. The products distributed in Japan are developed and manufactured overseas. Furthermore, related emerging technologies are developed overseas. Therefore, to improve this situation, Biologics Center for Research and Training (BCRET) was established in August 2017 in Kobe city to develop human resources for biologics with the cooperation of Japan Pharmaceutical Manufacturers Association, Japan Agency for Medical Research and Development, Kobe University, and related ministries and agencies. BCRET will develop human resources by providing useful information and experience related to the development and manufacture of biologics in the form of classroom lectures and practical training for process and analysis developers and pharmaceutical affairs related to manufacturing, quality control, and approval applications in the biologics field of pharmaceutical companies, along with reviewers and inspectors of Pharmaceuticals and Medical Devices Agency and inspectors from countries belonging to Asia-Pacific Economic Cooperation (APEC). This is the first attempt in the world to develop human resources in a field of chemistry, manufacturing and control and Good Manufacturing Practice of biologics for inspectors in countries belonging to APEC, and it is expected to contribute internationally for human resources for biologics.

Naldemedine (Nal) is widely used as a therapeutic drug against opioid-induced constipation. However, patients in phase III trials are limited to those with good performance status (PS). Cancer patients may have inferior PS owing to progression of symptoms and adverse events from chemotherapy. Therefore, it is important to survey the efficacy of Nal in patients with poor PS. This study aimed to evaluate Nal efficacy in patients with poor PS. We retrospectively investigated patients from July 2017 to June 2019 and compared Nal efficacy between patients with good and poor PS. The efficacy of Nal was evaluated using changes in the number of spontaneous bowel movements 7 days before and after the introduction of Nal with reference to previous reports. Multivariate analysis was performed to reveal whether poor PS affects Nal efficacy. In total, 141 patients at the Hokkaido University Hospital were analyzed. The effective rate of Nal from day 1 to day 7 of administration was 71.7% and 71.4% in the patients with good and poor PS, respectively, that from day 1 to day 2 of administration was 61.1% and 57.1%, respectively, and that from day 3 to day 7 of administration was 60.2% and 71.4%, respectively, suggesting an absence of significant differences. Furthermore, results of multivariate analysis showed that “best supportive care” and “body weight (55 kg and above)” reduced Nal efficacy. In conclusion, Nal showed similar effectiveness in patients with poor PS as that in those with good PS.

The pharmacovigilance activities of new drugs are usually planned and conducted based on the clinical safety information obtained at approval. Revealing pre- and post-marketing drug characteristics associated with post-marketing safety-related regulatory actions (PSRAs) would help facilitate pharmacovigilance activities as these activities are not sufficient for early detection of safety signals that require warning. Therefore, we investigated the association between PSRAs and characteristics of new drugs in Japan. New active substances approved in Japan between fiscal year 2005 and 2015 were analyzed. PSRAs were defined as “revisions of precautions in drug package insert” instructed by the regulatory authority within the first 5 years after the initial approval (up to 2021). Drug characteristics included therapeutic area, number of Japanese subjects in clinical trials, dose-response study in Japanese subjects, approval lag between Japan and the United States or Europe (US/EU), novelty of the drug, estimated number of target patients, and number of supplemental approvals. Negative binomial regression and path analyses were performed to investigate the association between PSRAs and drug characteristics. PSRAs were more common among antineoplastic agents and drugs with a larger estimated number of target patients and were less common among drugs with a longer approval lag between Japan and the US/EU. Supplemental approval was more common among antineoplastic agents, and there were fewer target patients for novel drugs. For new drugs with the characteristics identified in the present study, it is important to proactively collect post-market safety information by intensifying patient monitoring.

We report a haemodialysis patient with end-stage renal failure whom a pharmacist aided in the management of acyclovir (ACV) encephalopathy, which may have been related to valacyclovir hydrochloride (VACV) administered without sufficient dose reduction. The patient 78 years was admitted with a tentative diagnosis of varicella zoster viral meningitis. A pharmacist suspected ACV encephalopathy related to excessive VACV administration and raised a query with the attending physician. According to the pharmacist's proposal, ACV administration was discontinued and continuous hemodiafiltration (CHDF) was performed. On day 5 of hospitalisation, the consciousness disorder was improved. In this report, we showed the detailed CHDF conditions of the present case, and the contribution of a pharmacist to treating and avoiding ACV encephalopathy was discussed.