Folia Pharmacologica Japonica最新文献

Hereditary angioedema (HAE) is a rare life-threatening disease with recurrent edema. We outline the pharmacological characteristics and study results of a new drug, garadacimab (human anti-activated factor XII [FXIIa] monoclonal antibody), which has novel mechanism of action and suppresses acute HAE attacks. In HAE, excessive bradykinin production, an inflammatory mediator increasing vascular permeability, causes edema, and activation of factor XII initiates bradykinin production. Garadacimab suppresses bradykinin production by inhibiting FXIIa. HAE attacks include fatal laryngeal edema, and overall severity varies substantially among patients. There is an unmet medical need for treatment to reduce its frequency and severity. For prophylactic treatment, a convenient drug with long-administration interval is desired to reduce patients' burden. Based on results of Phase I study in healthy subjects and Phase II study of multiple doses in patients, efficacy and safety of monthly administration of 200 mg garadacimab were compared in 64 patients (ITT: 39 in garadacimab and 25 in placebo) in Phase III study. The primary endpoint, monthly attack frequency was significantly lower in garadacimab than placebo (0.27 vs. 2.01; P < 0.001), with relative reduction rate 87%. Monthly subcutaneous administration of 200 mg garadacimab showed favorable safety profile. The proportion of patients who remained attack-free during the 6-month was 62% in garadacimab and 0% in placebo, and effect after the first dose was maintained throughout the study period. Since this drug is administered subcutaneously once a month with autoinjector, reduction of patients' burden is also expected.

The treatment of recurrent or metastatic cervical cancer has entered a new era, with immune checkpoint inhibitors now being used as first-line standard of care options. Meanwhile, there is a lack of second-line and subsequent treatment options that can adapt to this changing treatment landscape, highlighting the need for the development of new treatments with novel mechanisms of action. Tisotumab vedotin (recombinant) is an antibody-drug conjugate (ADC) consisting of tisotumab, an anti-human tissue factor (TF) monoclonal antibody (IgG1κ), the microtubule inhibitor monomethyl auristatin E (MMAE), and a valine-citrulline linker. When the linker is cleaved by a protease in a tumor cell, MMAE is released to induce cell cycle arrest and apoptosis via disruption of the microtubular network. In non-clinical studies, tisotumab vedotin demonstrated concentration-dependent cytotoxic and anti-tumor activities. Tisotumab vedotin also mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activities. In a global Phase III study of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer (Study SGNTV-003/innovaTV 301), the drug demonstrated higher efficacy than the investigator's choice of chemotherapy. Although some eye-related adverse events occurred as unique toxicities, the safety profile of tisotumab vedotin was generally manageable. The results of analysis in the Japanese subpopulation of the SGNTV-003 (innovaTV 301) study were consistent with those of the overall population. Based on these results, tisotumab vedotin received regulatory approval in Japan in March 2025 for the indication of "advanced or recurrent cervical cancer that has progressed after cancer chemotherapy".

Difelikefalin (KORSUVA^® IV Injection Syringe for Dialysis) is a novel kappa opioid receptor (KOR) agonist. In September 2023, difelikefalin was approved for the treatment of pruritus in hemodialysis patients. Pruritus is a major symptom that significantly reduces the quality of life of hemodialysis patients, even with improved dialysis techniques, dialysis membranes, and dialysate solutions. The factors that contribute to pruritus include dry skin, accumulation of uremic toxins, overproduction of chemical mediators and altered immune function, and disruption of the opioid balance. In nonclinical studies, difelikefalin showed highly selective for KOR and antipruritic effects in animal models of histamine- and substance P-induced itching. It also showed anti-inflammatory effects by suppressing cytokine release in human monocyte-derived macrophages and TNFα and IL-1β induced by lipopolysaccharide administration in mice. In the phase 3 clinical trial in Japanese hemodialysis patients, difelikefalin showed significant improvement compared to placebo in the primary endpoint of the change from baseline in the weekly mean NRS score at week 4. It also improved sleep disturbance and itch-related quality of life, and the improvement in itch was sustained up to 58 weeks. Furthermore, there was no increase in adverse drug reactions with long-term treatment, and no delayed adverse events were observed. In conclusion, the novel KOR agonist difelikefalin is expected to be a new treatment option for pruritus on dialysis.

Pharmaceuticals used for pregnant women must be safe for the babies while therapeutic to the mothers. To ensure the safety of drugs, developmental neurotoxicity should be evaluated although it is currently not a mandatory requirement in the US and Europe at the regulatory level. Organisation for Economic Co-operation and Development (OECD) has constituted the test guideline (TG426) to assess developmental neurotoxicity. TG426 requires various assessments using animals (assuming rats), including the brain weight, neuropathology, locomotion, sensorimotor function, and learning ability of dams from the mother treated with the chemical during pregnancy. Due to the huge burden of the cost, time, and labor, the number of chemicals evaluated for developmental neurotoxicity by TG426 remains around 200. To boost the pace of the assessment, OCED has constituted a novel guideline (No. 377) adopting in vitro test batteries. OCED has also evaluated the utility of the neurobehavior of zebrafish larvae in the assessment of developmental neurotoxicity. In this review, I focus on valproic acid, a therapeutic drug to treat epilepsy and bipolar disorder and a well-known developmental neurotoxicant, and summarize the studies using zebrafish neurobehavior to assess the developmental neurotoxicity of valproic acid. The utility and validity of zebrafish neurobehavior for developmental neurotoxicity testing are discussed by comparing the findings from rodents and humans.

Fetal thyroid hormones (THs), essential for brain development, largely depend on maternal supply. Clinical studies have shown that TH alterations in pregnant mothers can lead to permanent neurodevelopmental effects in their children, suggesting that chemicals causing maternal TH disruption may require regulation. However, the quantitative relationship between chemical-induced maternal TH reductions and fetal brain TH disruption, as well as fetal brain developmental abnormalities, is not fully understood. Thus, there is a need for methods that can precisely, rapidly, and quantitatively evaluate TH-disrupting effects of test chemicals that may cause brain abnormalities. Currently, multiple molecular initiating events (MIEs) in the adverse outcome pathways (AOPs) of TH disruption are known, and tests using New Approach Methodologies are being developed to investigate the effects of chemicals on these MIEs. Additionally, the Comparative Thyroid Assay (CTA) is expected to be utilized to comparatively evaluate the decrease in blood TH concentrations, commonly observed as a result of actions on multiple MIEs, in maternal rats along with their offspring. Recently, due to the increasing need for more precise and efficient evaluations and the reduction of animal testing, we have worked on improving the CTA. We proposed a modified CTA that adds new test items: brain TH concentrations and heterotopia (a histological marker of brain TH deficiency), while reducing the number of animals used by 50%. Feasibility studies confirmed that it can detect approximately 20-30% TH disruption in the offspring brain. This review outlines the current efforts to develop new evaluation methods for perinatal TH disruption effects.

Aging serves as a risk factor for various age-associated disorders, such as cancer and type 2 diabetes. The study of aging is linked with metabolic research, due to the metabolic changes associated with aging. For example, chronic inflammation and the accumulation of DNA damages associated with aging lead to a decrease in NAD⁺ levels and mitochondrial dysfunction, resulting in cells becoming irreversibly cell cycle arrested, known as senescent cells. Senescent cells exhibit metabolic changes distinct from normal cells, along with distinct phenotypic characteristics, such as the senescence-associated secretory phenotypes (SASP), characterized by the excessive secretion of bioactive molecules such as inflammatory cytokines and chemokines. The accumulation of senescent cells has been observed in the pathology of age-related diseases, and their characteristics are thought to contribute to disease progression. Recent research has focused on the characteristics of senescent cells, such as their resistance to apoptosis, and aims to eliminate these cells from the body through pharmacological inhibition. Indeed, experimental evidence has demonstrated improvements in age-related phenotypes following the removal of senescent cells. Here, we review how age-related changes in cell metabolism induce cellular senescence, what are the metabolic characteristics of senescent cells, and how they affect the organism. Additionally, we also review our recent findings on the elimination of senescent cells by pharmacological inhibition of glutaminolysis rate-limiting enzyme GLS1, and outline the prospects for drug discovery targeting senescent cells.

Inspired by my experiences working in research at an overseas biotech venture, I founded GenAhead Bio Inc. in 2018. GenAhead Bio adopts a unique dual-business structure, providing contract services for generating genetically modified cells using highly efficient CRISPR/Cas9 genome editing technology for researchers, while simultaneously pursuing a nucleic acid drug business aiming to develop nucleic acid drugs such as antisense oligonucleotides and siRNAs. Based on the emerging delivery system called Antibody-Nucleic acid Conjugate, where an antibody is covalently linked to a nucleic acid as a targeting ligand, we are conducting drug developmental research by delivering nucleic acids to the organs where antibodies accumulate. Our ultimate goal is to apply this technology to genome editing for gene modification in specific cell types. In this review, we will introduce some case studies of genome editing, including single nucleotide substitutions, as well as the delivery of siRNA to the skeletal muscle using anti-transferrin receptor (CD71) antibody and its therapeutic effects on muscular diseases.

This study evaluated the utility of an integrated drug discovery strategy that combines three emerging data-driven approaches: real-world data analysis, in silico screening, and network pharmacology. First, transcriptomic data from public gene expression databases and adverse event reports were analyzed to address myocarditis induced by immune checkpoint inhibitors. The findings suggested a preventive effect of non-steroidal anti-inflammatory drugs, particularly those targeting the arachidonic acid metabolism pathway. Second, to identify therapeutic options for trastuzumab-resistant HER2-positive breast cancer, a cheminformatics approach was applied. A machine learning classification model and structure-based docking simulations enabled efficient in silico screening of approved drugs, identifying novel YES1 kinase inhibitors. Third, network-based analysis evaluated the topological distance between disease-associated gene modules and statin-induced gene modules in drug-induced peripheral neuropathy. This analysis indicated that certain statins may protect against drug-induced peripheral neuropathy through modulation of shared targets and neurodegenerative pathways. These findings demonstrate that integrating heterogeneous data modalities-from transcriptomics and chemical structure to protein-protein interaction networks and real-world clinical observations-can enable the discovery of repositioning candidates and risk-mitigating therapies. The study highlights the potential of multi-layered, data-driven strategies in constructing translational drug discovery frameworks aimed at both efficacy and safety.

With Japan's aging population, the number of individuals diagnosed with dementia has been steadily rising, creating significant social and economic challenges. Dementia is caused by various underlying conditions that lead to acquired brain injury. It is characterized by a progressive decline in cognitive function, which can impair activities of daily living (ADLs) and social interactions. However, current medical interventions for neurodegenerative dementias remain insufficient to achieve a complete cure.