Astellas Pharma (United States)

Abstract Background and Aims Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is approved in multiple countries for the treatment of anemia of chronic kidney disease (CKD). Previous pooled analyses have reported that roxadustat was non-inferior to erythropoiesis-stimulated agents (ESAs) for time to first major adverse cardiovascular event (MACE) and MACE plus congestive heart failure (CHF) or unstable angina requiring hospitalization in patients with dialysis-dependent (DD) or non–dialysis-dependent (NDD) CKD; however, these analyses were not stratified by history of CHF. The current post hoc analysis was conducted to evaluate time to first hospitalization for CHF in patients with DD or NDD CKD with or without a history of CHF treated with roxadustat compared with ESA. Method Patients with anemia of CKD from four phase 3, multicenter, randomized, open-label, active-comparator studies (HIMALAYAS, ROCKIES, SIERRAS, and PYRENEES) were pooled for the DD CKD group, and patients from a phase 3, multicenter, randomized, open-label, active-comparator study (DOLOMITES) were analyzed as the NDD CKD group. Data were analyzed for the time to first occurrence of hospitalization for CHF during and up to 7 days after the treatment period (ie, on-treatment plus 7 days) using a separate model for each of the four groups (DD CKD with a history of CHF, DD CKD without a history of CHF, NDD CKD with a history of CHF, and NDD CKD without a history of CHF). Hazard ratios (HRs) were estimated with a Cox proportional hazards model adjusted for baseline age as a continuous covariate. The non-inferiority margin was set at 1.8, as recommended by industry guidance provided by health authority bodies regarding the assessment of cardiovascular risk in clinical studies. Results Of the 4714 patients with DD CKD (roxadustat: n = 2354; ESA: n = 2360), 1122 had a history of CHF (roxadustat: n = 562; ESA: n = 560). Of the 616 patients with NDD CKD (roxadustat: n = 323; ESA: n = 293), 158 had a history of CHF (roxadustat: n = 81; ESA: n = 77). In the DD CKD group, treatment with roxadustat demonstrated noninferiority to ESA treatment in patients with no history of CHF (HR [95% CI]: 0.85 [0.64, 1.14]) and in patients with a history of CHF (0.97 [0.67, 1.39]; Table 1), both with the upper limit of the confidence limit less than the non-inferiority margin of 1.8. In the NDD CKD group, treatment with roxadustat demonstrated noninferiority to ESA treatment in patients with a history of CHF (0.62 [0.25, 1.51]). The noninferiority margin was not achieved (upper limit of the confidence interval ≥1.8) in patients with NDD CKD with no history of CHF (1.31 [0.57, 2.99]; Table 1). These results are difficult to interpret due to the low number of events included in the analysis; this increased uncertainty is evident in the wider confidence interval. Conclusion In patients with DD CKD, regardless of history of CHF, and in patients with NDD CKD with a history of CHF, the results from this post hoc analysis suggest that treatment with roxadustat is non-inferior to ESA for the risk of hospitalization for CHF. In patients with NDD CKD without a history of heart failure, the results should be interpreted cautiously due to the low number of events included in this analysis.

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.

This 2‐part, randomized, placebo‐controlled, double‐blind, Phase 1 study analyzed the pharmacokinetics, safety, and biomarker profile of fezolinetant in healthy Japanese individuals. Part 1: male participants received single doses of placebo or fezolinetant 15 or 60 mg. Part 2: male and premenopausal and postmenopausal female participants received a single dose of placebo or fezolinetant 180 mg, followed by a 2‐day washout, and multiple dosing once daily for 10 days. Fezolinetant was rapidly absorbed with peak concentrations 1‐2 hours after single‐dose administration; plasma levels subsequently declined (half‐life range, 3.29‐7.24 hours). Only slight accumulation (area under the concentration–time curve accumulation ratio, 1.46‐1.57) was observed after once‐daily multiple‐dose administration. No serious/severe treatment‐emergent adverse events were observed; the only fezolinetant‐related treatment‐emergent adverse event was mild uterine bleeding in 1 premenopausal woman and 1 postmenopausal woman. Concentration‐QT analysis showed that fezolinetant does not have a clinically significant effect on QT interval. Fezolinetant produced dose‐dependent reductions in luteinizing hormone and slight reductions in follicle‐stimulating hormone; levels subsequently returned to baseline 48 hours or fewer after dosing. This analysis shows that fezolinetant doses up to 180 mg had an acceptable safety, pharmacokinetic, and biomarker profile. This study clarifies the safety, pharmacokinetic, and biomarker profiles of fezolinetant in Japanese individuals.

PURPOSEMaster protocols represent transformations, enabling multiple therapies or diseases under a single protocol. These designs streamline therapeutic development by reducing redundancies. Suited for evolving fields such as oncology and global emergencies such as the COVID-19 pandemic, master protocols have been exemplified by studies such as RECOVERY, Solidarity, and I-SPY 2, which accelerated effective treatment identification (with I-SPY 2 focused on molecular subtypes). Recent oncology examples, such as MORPHEUS, evaluate immunotherapy combinations with shared controls. Despite advantages, their application in early-phase oncology remains underutilized amid growing regulatory emphasis on randomization for robust evidence.METHODSUS Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) initiatives, such as Project Optimus and Project FrontRunner, emphasize randomization in early-phase oncology trials. However, these initiatives pose challenges, including larger sample sizes, patient and physician reluctance to randomization, and high failure rates from poor accrual. To address these, this article adapts master protocol designs to consolidate early-phase trials for novel therapeutics sharing a common backbone therapy, integrating hybrid controls from published standard-of-care data to minimize randomization to the control arm.RESULTSBy consolidating trials under a shared standard-of-care control arm, the proposed master protocol design reduces total sample size by as much as 55% when compared with independent trials (with control arm sizes 2.4-2.9 times lower), lowers costs and duration, and enhances enrollment through reduced randomization to controls. Incorporating hybrid controls from prior studies and sharing information among arms with common background standard-of-care further improve efficiency, increasing power (reaching 90% overall) while controlling type I error rates acceptable levels.CONCLUSIONMaster protocol designs with hybrid controls and Bayesian information sharing enable the efficient integration of randomization into early-phase oncology trials, enhancing efficiency, cost-effectiveness, and patient-centricity while aligning with FDA OCE initiatives.

The implementation of the Internet of Things (IoT) technologies into data center (DC) infrastructures is a highly relevant topic amid the increasing volumes of processed information, rising energy consumption, and the development of cloud and AI-based services. The integration of IoT enables the design of multi-layered architectures comprising distributed sensor networks, edge computing, advanced analytics, and automated infrastructure management. This study analyzes a typical architecture, the role of key components (sensors, actuators, gateways, edge nodes), and summarizes the practical experience of leading companies in optimizing energy consumption and enhancing infrastructure resilience. It is demonstrated that the use of IoT components contributes to achieving significant performance improvements across key KPI metrics, including reduced mean time to detect and resolve deviations, improved energy efficiency, and enhanced anomaly detection accuracy. Particular attention is paid to the analysis of security threats within IoT-based DC infrastructures, including MQTT protocol vulnerabilities, lack of TLS encryption, open APIs, and other issues. The necessity of implementing a secure IoT architecture based on the security-by-design principle is emphasized, incorporating network segmentation, access control, and the use of advanced intrusion detection and prevention systems (IDS/IPS). The obtained results confirm the potential of IoT applications in building flexible, energy-efficient, and cyber-resilient next-generation data centers.