Astellas Pharma (China)

ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo , PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.

Background: Mismatch negativity (MMN) is a component of the auditory event-related potential (ERP) that is elicited during a passive oddball paradigm where task-irrelevant infrequent deviants are presented in a stream of more frequent standard stimuli. MMN is believed to index a pre-attentive stage of auditory information processing closely linked to N-methyl-D-aspartate receptors (NMDAR). Ketamine is thought to act primarily as an NMDAR antagonist, has been used in clinical trials to model the symptoms of schizophrenia and is increasingly used in the clinic to treat depression. Various studies have reported that ketamine reduces MMN amplitude which, in turn, might reflect reduced function of NMDAR-mediated neurotransmission. Nonetheless, there is growing evidence showing MMN amplitude either having high variability or, paradoxically, moving in the opposite direction after ketamine in different individuals. Methods: In here, we analyzed results from three independent ERP studies to test the hypothesis of a cross-over interaction (″disordinal″ drug effect) between the duration-deviant MMN at baseline (without ketamine) and the direction and magnitude of the ketamine effect. To rule out regression to the mean (RTM), a statistical phenomenon that may also partially explain this cross-over interaction, we separately estimated RTM using a drug-free test-retest study. Results: Our results are the first to statistically demonstrate the existence of a disordinal drug response to ketamine, where the direction and magnitude of ketamine-induced changes in MMN amplitude can be predicted by baseline MMN amplitude. Conclusions: These new insights may contribute to novel precision medicine approaches to treatment of CNS disorders.

Inherited and complex retinal degenerative diseases, such as retinitis pigmentosa, age-related macular degeneration, and glaucoma, represent a significant global burden of irreversible vision loss. Due to immense genetic and clinical heterogeneity and complex underlyingmechanisms, these diseases still lack safe and effective disease-modifying treatments. This review summarizes the current landscape of gene therapeutic approaches to develop novel treatments for these blinding conditions. Specifically, we provide an update on several ongoing or completed clinical trials on gene-specific or gene-agnostic approaches, including recombinant adeno-associated viral vector-mediated delivery of the full gene or gene editing and antisense oligonucleotide components into the eye. We also discuss the initial clinical trial results of the use of the different approaches to ocular delivery, including subretinal, intravitreal, and suprachoroidal delivery. While long-term clinical trial data and refined clinical endpoints are essential to assess the efficacy, safety, and durability of these strategies, the data so far underscore the immense potential of gene therapy to revolutionize the management of retinal diseases in patients living with these debilitating conditions.

Aim This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China. Methods A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes. Results In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer–related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer–related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50–1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50–818.50]). Limitations EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden. Conclusions A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer–related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.

We conducted cost-effectiveness analysis and budget impact analysis for androgen deprivation therapy (ADT) plus enzalutamide (ENZ) on patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the publicly-funded healthcare system perspective. Using a partitioned survival model, lifetime costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) of ADT＋ENZ were estimated against ADT alone, ADT plus abiraterone (ADT＋ABI), and ADT plus apalutamide (ADT＋APA). Total healthcare cost differences with and without ENZ in mHSPC therapy were estimated for the period from 2022 to 2026. Based on cost-effectiveness analysis, the ICER of ADT＋ENZ versus ADT alone was estimated as ￥7.18 million/QALY gained. ADT＋ABI and ADT＋APA were dominated options (extended dominance). Budget impact analysis showed that incorporation of ENZ had a net budget impact of ￥57.19 billion, an 8.4% increase, over these 5 years. This amounted to a budgetary impact of ￥16,000 per patient per month at year 5. However, the number of patients with disease progressed to metastatic castration-resistant prostate cancer (mCRPC) would be reduced from 79,000 (without ENZ) to 65,000 (with ENZ), resulting in a 17% cost reduction within the mCRPC phase. In conclusion, ADT＋ENZ would be a cost-effective option, at the willingness to pay threshold of ￥7.5 million/QALY gained. Introduction of ENZ in the mHSPC treatment would result in a marginal increase in the total budget. However, ENZ is also expected to provide clinical benefits in reducing the number of patients with disease that would otherwise progress to mCRPC during these 5 years, resulting in cost savings in this phase.

IntroductionMenopause generates different symptoms, among which vasomotor symptoms are especially prevalent and bothersome. The aim of this work was to determine their impact and the treatment patterns and perceptions in Spain by analyzing the opinions of physicians and patients with moderate-to-severe vasomotor symptoms (MS-VMS). MethodsDescriptive cross-sectional study of the Spanish subpopulation from the Adelphi-VMS™ Disease-Specific Program. Primary Care and Gynecology and Obstetrics physicians selected the patients. These patients were invited to complete a survey and the MENQOL and WPAI:SHP questionnaires. Data are presented as percentage or mean±standard deviation. ResultsOverall 32 Primary Care and Gynecology and Obstetrics physicians participated in the study, enrolling 241 women, of whom 143 experienced MS-VMS. Despite the reported impact on global work (24.84%±17.49 presentism) and quality of life (3.37±1.52 MENQOL score), only 53.85% of women with MS-VMS were treated. Menopausal hormone treatment was the most prescribed (77.92%), followed by serotonin reuptake inhibitors (32.47%). Fifty-nine percent of clinicians were very or completely satisfied with hormone treatment, whereas only 19% had this level of satisfaction with selective serotonin reuptake inhibitors. Less than 38% of patients and physicians were satisfied with the control of VMS. ConclusionsMenopause-associated MS-VMS have an important impact on quality of life. Increased awareness about their management and better therapeutic options would significantly contribute to improving women's health and well-being during their climacteric period.

Inclusion of advocates as partners in research is now required by numerous international funding agencies. The role of advocates has expanded in recent years to include all areas of research, including basic cancer research, translational research, and clinical trial design and development. The involvement of advocates as partners in cancer research can be challenging for the advocate and for the researchers, but this collaboration is beneficial to all involved. Herein, we will define patient advocacy, explore advocate engagement, and share information on programs that train advocates and researchers to work together as partners.

This document illustrates the results of the work of two interdisciplinary and multistakeholder panels (researchers, public institutions, and industry representatives) on drug territorialization and digitalization, organized as part of a residential seminar held on 30 September and 1st October 2021. Arising from some considerations about the demand for health and the provisions of the National Recovery and Resilience Plan (PNRR), the discussion touched various aspects of managing the transition from current to future management models. The importance of identifying criteria for prioritizing interventions in the area emerged: different methods of drug delivery, scientific information and measurement, re-evaluation of pathologies that can be managed in this area. Finally, the role of digitization within this change was explored. The opinions provided by the experts move towards making the most of the opportunities arising from PNRR, in terms of investments in healthcare and data application, with a view to improve health system efficiency, patient care and related outcomes.