Since 1982, The Japanese Society of Neurological Therapeutics has promoted (1) publication of treatment guidelines for rare diseases, (2) industry–government–academia collaboration, (3) globalization, and (4) support of clinical trials. In the future its role will be expanded focusing on clinical trial support and drug recovery/development. In 2021, the committee for promotion of drug discovery has been launched. The committee will activate (1) research and development, advices on the trial protocol and participating institutes, (2) support for collection of participants (patients), matching of industry and academia, (3) development of trial–ready registry, and (4) patient and public involvement. So far, the committee has supported 5 clinical trials by pharmaceutical industries. The Japanese Society of Neurological Therapeutics should play an important role in the promotion of drug recovery and clinical trials.

Additionally, Department of Neurology, Chiba University Hospital has performed development of new treatment for POEMS syndrome, myasthenia gravis, amyotrophic lateral sclerosis, and Guillain–Barré syndrome. Among them, thalidomide for POEMS syndrome was approved in 2021, and currently autologous peripheral blood stem cell transplantation has been established as a standard therapy for this syndrome. Clinical trials for other diseases are on–going or planned.

In the field of rare and intractable diseases, patients and families face numerous unmet needs due to limited medical resources, insufficient understanding, and social isolation. To address these challenges, intermediary organizations can play a key role in facilitating collaboration among diverse stakeholders.

This study highlights a collaborative research initiative on hereditary transthyretin amyloidosis (ATTRv), conducted by NPO ASrid in cooperation with clinicians, patient groups, and industry partners. Using mixed methods—including standardized QOL assessments and in-depth interviews—this project explored the health-related quality of life (HRQOL), psychological burden, family dynamics, and care experiences of patients and families.

The findings revealed significant variation in patient experiences depending on treatment availability and disease progression, as well as the importance of tailored support and communication strategies. Following the study, ASrid organized feedback sessions and a symposium involving all major stakeholders to disseminate findings and promote co-creation of solutions.

This case underscores the importance of intermediary organizations in integrating patient perspectives into research and policy, and in building inclusive frameworks for evidence-based advocacy.

At Alnylam, we believe that patients are experts in their own disease and the experiences that come with it, and that they are the key decision makers in their own treatment and care. Patients are at the centre of everything we do and every decision we make.

Patient Advocacy & Engagement team works with patient advocacy groups around the world, including in Japan, to raise awareness of the patient communities we serve and to ensure that their needs are met. Through collaboration and partnership, we provide information and support to patients and families living with rare genetic diseases. We also actively listen to patients and their families, incorporating their perspectives into all aspects of our business.

To understand the unmet needs of a disease, it is necessary to understand what it means to live with a disease and to find out where and what gaps exist in the current medical environment. For this purpose, anecdotes and data generated from the experiences of patients and their families, such as the path to diagnosis, the burden of the disease, and issues with access to treatment, become important. This is the essence of Evidence Based Advocacy, and collaboration and cooperation between multi–stakeholders, including patient advocacy groups and healthcare professionals, makes it possible to collect, interpret and understand such anecdotes and data.

Based on these beliefs, we have conducted a survey of patients and families with hereditary ATTR (ATTRv) amyloidosis in Japan in collaboration and cooperation with stakeholders from different backgrounds, including patient advocacy groups, and would like to introduce it as an example of Evidence Based Advocacy.

Clinical research conducted in academia faces various challenges, such as limited research funding, time constraints, manpower shortages, and insufficient knowledge with increasingly complex regulations. To overcome these challenges, Academic Research Organizations (AROs) provide support to researchers affiliated with universities and research institutions. Recently, digital transformation (DX) has been advancing in clinical research, with the use of digital tools expanding in areas such as informed consent, clinical evaluation, and data collection. AROs are working on building operational frameworks and systems to introduce DX–driven clinical research methods and decentralized clinical trials (DCT). It is the important mission of ARO to lead research to success while maximizing the benefits of DX and DCT within limited resources. This paper introduces the ARO's initiatives in these areas.

In recent years, the digital transformation (DX) of clinical research and clinical trials in Japan has played a crucial role in shaping the future of the medical field, marking a significant turning point. This paper explores the current state and forefront initiatives of clinical trial DX tailored to Japan's medical environment, focusing on the utilization of clinical trial support platforms, the introduction of artificial intelligence (AI), and the adoption of decentralized clinical trials (DCT).

First, the foundation of Japan's clinical trial DX lies in the implementation of clinical trial support platforms. A representative example is Buzzreach Inc.'s StudyWorks Platform, which leverages DX to provide innovative solutions addressing challenges in clinical trials. This platform facilitates seamless information sharing among stakeholders, enhances process efficiency, and improves transparency. By digitalizing communication among sponsors, trial sites, and participants, the platform enables centralized data management, contributing to the rapid execution and improved quality of clinical trials.

Next, this paper discusses Japan's strategic advantage of having the world's largest number of medical institutions and its application to patient recruitment. Japan's extensive network of medical institutions can significantly enhance recruitment efficiency. The use of partner (satellite) sites allows certain trial activities to be conducted at these facilities, increasing patient convenience and improving enrollment rates. This approach is closely linked to DCT implementation, allowing patients to participate in trials from home or nearby medical institutions, thereby reducing geographical and time constraints while ensuring diverse data collection.

Furthermore, AI integration plays a critical role in various trial processes. AI–driven data analysis of electronic health records (EHRs) and patient registries accelerates patient identification, improving the efficiency of patient enrollment. Additionally, AI is utilized for document generation and workflow optimization, enhancing the overall quality and outcomes of clinical trials.

Through this paper, we examine the current state and challenges of clinical trial digitization in Japan, explore potential solutions, and discuss how DX can be promoted within the country's unique environment. Finally, we identify the key elements essential for the success of clinical research and trial DX, aiming for more efficient and reliable clinical studies.

The Drug Information Association (DIA) is a global non–profit organization that supports innovation in the research, development, and life cycle management of pharmaceuticals, medical devices, regenerative medicine products, and other medical products through educational activities and the exchange of information and discussion between regulatory authorities, industry, academia, and patients. It is a global non–profit organization with more than 10,000 members worldwide.

DIA's activities involve stakeholders from industry, government, and academia involved in the development of medical products in a variety of professional communities, drawing on their experience in their areas of expertise to improve the healthcare industry in Japan.

A collaborative session with the Japanese Society for Neurotherapeutics, which conducts industry–government–academia exchanges, clinical trial support, and clinical research education with the goal of establishing superior therapies, was also planned at the meeting, where industry, government, and academia collaborated to discuss drug discovery and patient and citizen involvement. And the collaboration between the Japanese Society for Neurotherapeutics and DIA, which will not be limited to the Japan Annual Conference, is expected to promote the development of treatments for neurological diseases.

Many new drugs have been approved in the field of neurological diseases over the past decade, including the recent approval of lecanemab (genetical recombination) for Alzheimer disease. On the other hand, “drug loss” (no development of a new drug in Japan, resulting in no access of Japanese patients to the new drug) has recently become more serious. Academia, industry and government have worked to improve the situation but more collaborative efforts among various stakeholders may promote correct understanding of the situations and facilitate a process for improvement. A neutral platform (e.g., Drug Information Association) will play an important role for promoting collaborations among various stakeholders and for constructive discussions toward problem solving. In this article, current situation of drug development in Japan is described and the role of the neutral platform in strengthening collaboration for continuously providing new drugs to patients is discussed, including my personal perspective.

DIA (Drug Information Association) was established in 1964 to support the research and development of pharmaceuticals and medical devices. DIA Japan activities started in 1994. Since then, pharmaceutical companies, regulatory authorities, and academia have exchanged information. The author has participated in DIA Japan events since 2015, especially in project management training for medical institutions, statistical workshops, and the Japan Annual Meeting. 2023 and 2024, as a program committee member, the author organized sessions on neurological diseases and post–marketing surveillance. The author also participated in the Patient Engagement community, conducting sessions on the importance of patient and public involvement (PPI). In addition, the author has been a member of the Contents Committee since 2024, proposing and supporting programs. Through DIA activities, the author has been exposed to the latest drug development and hopes that more neurologists will join.

I had the opportunity to present at the DIA Japan Annual Meeting from November 5–7, 2023. DIA founded in the U.S., provides a platform for stakeholders―regulatory authorities, industry, academia, and patients―to exchange information. Although physician participation was limited, particularly among neurologists, the event was a large–scale conference supported by Japan's Ministry of Health, Labour and Welfare, AMED, and PMDA. The 2023 DIA Japan Annual Meeting, themed “Fusion of Knowledge and Skills Beyond Time and Space : Reconstructing Drug Development in Society 5.0,” covered diverse topics, including AI in healthcare, decentralized clinical trials, rare disease research, and regulatory science. While neurology–focused discussions were sparse, advanced initiatives in oncology and infectious diseases provided valuable insights applicable to neurology. I presented in a session on rare disease drug development alongside patient representatives, pharmaceutical companies, and MHLW officials. A patient's plea, “Are you truly committed to saving patients?” was deeply moving. Regulatory discussions included concerns about Japan's pharmaceutical competitiveness if Phase 1 trials were bypassed for global studies. The MASTER KEY Project for rare cancers demonstrated a sustainable registry model through industry–academia collaboration, providing a reference for neurological disorders like ALS. Strengthening ties between the Japanese Society of Neurological Therapeutics and DIA Japan could enhance collaboration with global regulators, industry, and patients, accelerating drug development in neurology.

We developed voice biomarkers for depression, Parkinson disease, dementia, and mild cognitive impairment. For depression, Parkinson disease, and dementia, we tested our original index, multiple regression analysis, logistic analysis, and machine learning, all of them were sufficiently accurate. In the case of mild cognitive impairment, good accuracy was obtained by comparing the change of voice in a single task. The voice biomarkers for mild cognitive impairment were made publicly available on the Web. In addition, voice biomarkers for depression and Parkinson disease can also be used to differentiate between these two disorders. In the future, it is necessary to study voice acquisition methods for differentiation of the three diseases including mild cognitive impairment.

In the clinical development of drugs in Neurology, there are clinical development issues such as the lack of established the efficacy endpoint, the number of patients is small, controlled comparative studies are difficult, and so on. Therefore, it is hoped that industry, government, and academia will collaborate to organize issues and ideas based on the knowledge of current scientific findings accumulated to date and formulate guidelines for clinical evaluation in drug development, so that drug development and review can be conducted appropriately and promptly.

Clinical trials for neurological diseases such as amyotrophic lateral sclerosis (ALS) face numerous challenges due to disease–specific characteristics and the significant burden on patients. In Japan and overseas, guidelines for clinical trial design and evaluation have been established for some neurological diseases, contributing to the implementation of high–quality trials. Recently, the utilization of real–world data (RWD) and decentralized clinical trials (DCT) has gained attention, offering the potential to reduce patient burden and improve trial efficiency. These efforts play a crucial role in advancing the development of new drugs for neurological diseases.

The revised ALS clinical practice guidelines were published for the first time in a decade in 2023, emphasizing pharmacological treatment, particularly riluzole and edaravone, supported by accumulating evidence. However, Japan faces a growing concern over “drug loss,” where innovative therapies developed abroad fail to reach domestic markets due to high clinical trial costs and low drug pricing.

ALS drug development has accelerated globally, with over 50 clinical trials in progress. North American and European consortia, such as NEALS, ENCALS, and TRICALS, have adopted adaptive and platform trials to streamline drug approval. Japan, however, remains largely excluded from these global trials.

Despite the success of Japan's JaCALS registry and significant contributions to ALS research, only two out of 11 ongoing phase III trials include Japan. Additionally, 143 drugs approved overseas remain unavailable in Japan, with 86 yet to be pursued domestically. To address this, the ALS Clinical Trial Project Team (ACT–PT) is conducting feasibility studies to enhance trial participation.

Establishing ALS clinical trial guidelines and fostering international collaboration are crucial to mitigating Japan's drug loss and promoting domestic drug development. By integrating global trial networks, Japan aims to improve access to cutting–edge ALS treatments.

Prion diseases represent rapidly progressive, fatal neurodegenerative disorders with an exceptionally short clinical course, typically culminating in death within three months of symptom onset. While no effective therapeutic interventions currently exist, the imminent launch of an international investigator–initiated clinical trial within the next triennium underscores the urgent need for refined early diagnostic criteria. Previous investigations have demonstrated the diagnostic utility of diffusion–weighted magnetic resonance imaging (DW–MRI) combined with cerebrospinal fluid (CSF) biomarker analysis, particularly through our research group's development of the RT–QUIC assay, which has exhibited remarkable specificity.

Although these advances have facilitated novel biomarker–driven diagnostic criteria, the substantial reliance on biomarkers for early–stage diagnosis presents challenges, as certain markers may introduce diagnostic ambiguity. Current diagnostic frameworks, while incorporating clinical manifestations and biomarker profiles, remain suboptimal in their comprehensiveness.

This investigation aims to validate new diagnostic criteria through systematic evaluation of biomarkers in conjunction with clinical symptomatology, electroencephalographic patterns, neuroimaging findings, and CSF analyses. Our primary objective is enhancing differential diagnosis between prion diseases and other neurodegenerative disorders. We endeavor to optimize early diagnostic accuracy, thereby maximizing the potential efficacy of future therapeutic interventions. The development of a sophisticated multimodal diagnostic approach will be instrumental in establishing a comprehensive diagnostic and therapeutic framework for prion diseases, ultimately contributing to improved patient outcomes and effective treatment strategies.

Medical chaperone (MC) specifically binds to the normal conformation of the prion protein (PrP^C) and inhibits its conversion to the pathogenic conformation (PrP^Sc). By peripheral intravenous administration, MC penetrates the blood brain barrier, spreads to the brain, and inhibits the prion's pathogenic conversion. MC is removed from the blood within a week, whereas the half–time of MC in the brain is more than one month, thereby enabling the regulation of brain concentration of MC by controlling the concentration and the time schedule of the peripheral administration. The pharmacological effect of MC is only the anti–prion effect and no other function nor side effect has been found. IC50 of MC is about 500 nM for Fukuoka–1 strain (GSS). Prion is completely eradicated once incubated at the concentration of four times of IC50, 2µM, i.e. prion never proliferate even after the removal of MC. Symptom suppression and the life extension effects of MC were proved for the Fukuoka–1 infected mice and for the BSE infected macaques. Furthermore MC suppresses the quaking induced conversion (QuIC) of a prion in vitro. In short, MC has a strain– and host–independent anti–prion effect. Molecular weight of MC is about 500 and is stable for at least ten years when stored in powder form at room temperature. Since preclinical tests of MC have been completed, the clinical trial will start shortly, through the efforts of those who involved.

In prion diseases, normal prion protein is transformed into the abnormal protein which propagates and accumulates in the brain, rapidly leading to neurodegeneration. The therapeutic strategy of normal prion gene knockdown in the brain using nucleic acid drugs is expected to be an effective disease modifying therapy from the early clinical stages. In fact, antisense oligonucleotide drugs, the most prevalent type of nucleic acid drugs, have begun to be utilized in a clinical trial.

A major challenge in the treatment of brain diseases using nucleic acid drugs is the requirement for frequent and invasive intrathecal administration. An ideal solution would involve the systemic administration of nucleic acid drugs, enabling their delivery into the brain across the blood–brain barrier (BBB).

Here we introduce two types of our original BBB–crossing drug delivery system. One is a nano engineering–based system for a variety of drug modalities, that allows the delivery through the transcellular route of brain microvascular endothelial cells, the chief components of the BBB, in response to the change in blood glucose concentration. The other system is a recombinant peptide–based system, that modulates the tight junctions at the points where the corners of three brain microvascular endothelial cells meet, allowing the delivery of antisense oligonucleotide through the paracellular route into the brain.

On July 30, 2024, the Prime Minister's Office hosted the Drug Discovery Ecosystem Summit, where Prime Minister Kishida announced a five–year numerical target to eliminate uninitiated drug development by 2026. This initiative aims to revive Japan's pharmaceutical industry amidst growing dependency on overseas drugs, which has worsened the trade deficit. ALS is no exception to this “drug loss” issue.

ALS drug development has surged globally, with approximately 50 clinical trials ongoing. However, “pipeline pressure” due to excessive trials relative to patient numbers has become a concern in Western countries, prompting initiatives like NEALS, ENCALS, and TRICALS. Asia–Pacific established PACTALS in 2014, but regional trial infrastructure remains underdeveloped. While North America and Europe have embraced adaptive and platform trials, Japan has yet to participate. To address this, the Department of Neurology at Toho University launched an ALS clinic in 2017 and became Asia's first NEALS–certified site in 2020.

Japan's ALS registry, JaCALS, has contributed significantly to global research. However, only 2 of 11 ongoing Phase III trials listed in ClinicalTrials.gov include Japan. The lack of participation in adaptive trials exacerbates drug loss. Additionally, Japan's drug approval system and high trial costs deter venture firms.

To integrate with global trials, Japan is developing an English–language ALS clinical trial guideline. Efforts are also underway to harmonize ALSFRS–R standards and streamline trial site selection through ACT–PT. Strengthening international collaboration is essential for Japan to mitigate drug loss and enhance ALS drug development.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with limited therapeutic options. Clinical trials play a crucial role in evaluating potential treatments, and selecting appropriate endpoints and biomarkers is essential for their success. This review examines the current status and challenges of endpoints and biomarkers in ALS clinical trials, focusing on their utility in efficacy assessment and regulatory decision–making. Traditionally, ALS clinical trials have relied on survival and functional measures, particularly the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS–R). However, concerns regarding its variability and the absence of a standardized international approach have prompted efforts toward global harmonization and the development of alternative assessment methods. Concurrently, the role of biomarkers in ALS trials has expanded. Neurofilament light chain (NfL) has emerged as a key biomarker applicable across different disease stages. It has potential applications as a susceptibility/risk biomarker in high–risk populations, a prognostic biomarker in early–stage ALS, and a pharmacodynamic biomarker for evaluating treatment response in clinical trials. The recent accelerated approval of tofersen, an antisense oligonucleotide targeting SOD1 mutations, was primarily based on NfL reduction as a surrogate marker of therapeutic efficacy. However, whether NfL qualifies as a “reasonably likely surrogate endpoint” remains under debate, as its predictive validity for clinical benefit may vary depending on the stage of intervention. As regulatory agencies, including the FDA, continue to refine their frameworks for biomarker qualification, ongoing discussions continue regarding the formal recognition of NfL as a biomarker in ALS. This review highlights the need for further research and regulatory clarity to optimize biomarker–driven ALS clinical trials, with implications for both therapeutic development and broader neurodegenerative disease research.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder with limited treatment options, underscoring the need for efficient trial designs to accelerate drug development. Traditional randomized controlled trials (RCTs), which focus on a single investigational treatment per study, are often inadequate for ALS due to slow enrollment and high costs. Adaptive platform trials (APTs) provide a transformative approach, enabling multiple treatments to be tested simultaneously under a master protocol. This structure supports the shared use of control groups and allows treatments to enter or exit the trial based on interim analysis. The HEALEY ALS Platform Trial exemplifies this model, utilizing a Bayesian approach for integrated assessment of treatment efficacy and survival outcomes, thus enhancing efficiency and flexibility. By sharing a control arm across treatment groups and employing adaptive randomization, the HEALEY trial reduces sample size requirements and accelerates results. Despite initial setup complexity and substantial upfront investment, APTs hold great potential for advancing ALS research and could become standard in neurology and rare disease studies. The HEALEY ALS Platform Trial serves as a model for future neurodegenerative disease trials, offering a sustainable and patient–centered approach to rapid therapeutic evaluation.

Alzheimer disease (AD) is the main cause of dementia worldwide. Extracellular deposition of amyloid β–protein (Aβ) in the brain is a primary event for the pathogenesis of patients with AD. Currently, the development of anti–Aβ monoclonal antibodies is at the center of AD treatment. This article discusses the therapeutic efficacy of lecanemab, which is a pioneer of anti–Aβ monoclonal antibody medication, based on the Aβ cascade hypothesis.

In the development of anti amyloid β (Aβ) antibody therapy for Alzheimer disease patients, amyloid–related imaging abnormality (ARIA) is increasingly recognized as the major side effect. ARIA has been classified to ARIA–E (edema/effusion) and ARIA–H (microhemorrhage/hemosideros). In Japan lecanemab has been approved in 2023, and subsequently donanemab in 2024. The both antibodies bind aggregates of Aβ with varying affinity to some extent ; lecanemab preferrentially with protofibril, and donanemab with aggregated pyroglutamyl Aβ. For the early and sensitive detection of ARIA, optimal use guidelines for lecanemab and donanemab request regular examination with head MRI especially until 6 months, during which most ARIA cases are encountered. The risk of ARIA increases with APOE ε4 gene dosage, the severity of cerebral amyloid angiopathy (CAA) and dosage of antibodies. Therefore, appropriate use criteria in the US strongly recomended a pretest with APOE genotyping, whereas in Japan, it is not mandatory at present. The severity of CAA is also the risk of ARIA, which is prescribed as the number of cerebral microbleeds and cortical superficial siderosis. This review overviews an update of ARIA, including the pathophysiology and practical use recommendations for anti Aβ antibody therapy.

Anti–amyloid therapies for Alzheimer disease (AD), lecanemab and donanemab, are now available in clinical practice. We described the flow of anti–amyloid therapy for patients with early AD in actual clinical practice. We examined 107 patients between January 2024 and January 2025 and completed testing to determine whether anti–amyloid therapy was feasible. Seventy–two of the 107 patients (67%) started anti–amyloid therapy, but 35 patients could not receive treatment due to amyloid–β pathology negative or many cerebral microbleeds etc. or it was not recommended due to the use of anti–platelet or anticoagulant therapies or concerns about side effects of amyloid related imaging abnormality (ARIA) due to apolipoprotein E (APOE) ε4 homozygotes. The incidence rates of ARIA, a side effect of anti–amyloid therapies, clearly differs depending on whether APOE ε4 is present, and management of ARIA is considered to be very important to reduce concerns about anti–amyloid therapies. We also touch on regional collaboration between hospitals where the anti–amyloid therapies begin (the facility which had many specialists) and the treatments will be continued (the facility which located near the patient's home), which is important for continuing treatment for patients.