Lundbeck Inc.

The efficacy and tolerability of vortioxetine tablets for depression is established, but prospective data for the oral drop formulation were unavailable. This analysis compared the effectiveness, tolerability and dosing patterns of vortioxetine tablet and drop formulations for the treatment of major depressive episodes in Swiss real-world practice. A post hoc analysis of a prospective, non-interventional study in adults experiencing a major depressive episode (MDE) was conducted. Depression symptoms, functioning, dosing patterns and tolerability were assessed using unanchored Montgomery–Åsberg Depression Rating Scale items, the Clinical Global Impression-Severity (CGI-S) scale, a four-point functioning scale, and incidence of adverse drug reactions (ADRs). Statistical tests included two-sample t-tests, Fisher’s exact test, Chi-square test and general linear modelling. Of 225 patients, 60 (26.7

The Unified Multiple System Atrophy Rating Scale (UMSARS) is widely used as an outcome measure in MSA trials, but it has limitations for clinical trial use. To address these, we developed the Multiple System Atrophy Combined Outcome Assessment (MuSyCA), a comprehensive multimodal tool for disease-modifying MSA trials. The purpose of this manuscript is to describe the development and validation plan for MuSyCA, with emphasis on its structure, intended use, and assessment of reliability, validity, and sensitivity in tracking disease progression. The development of MuSyCA followed a multistep process. Candidate outcome assessments were identified through systematic literature review and analysis of longitudinal data from large MSA cohorts. Content was refined through multiple Delphi-like consensus rounds involving MSA experts, patient advocacy groups representatives, and industry stakeholders. Cognitive interviews conducted in 20 patients with MSA evaluated the clarity and clinical relevance of patient- and clinician-reported outcomes; feedback was incorporated into a subsequent version of the MuSyCA. Validation is ongoing and includes assessment of construct validity, internal consistency, test–retest reliability, and responsiveness. Longitudinal analyses to determine sensitivity to change over time are ongoing. MuSyCA combines patient- and clinician-reported outcomes, biomarkers (neurofilament light chain, neuroimaging), and performance-based measures to capture subjective and objective aspects of MSA progression, enhancing its utility to detect treatment effects in clinical trials. MuSyCa is not intended to be used in clinical practice. MuSyCA offers a multidimensional approach to MSA assessment, supporting precise, disease-relevant evaluations in trials of putative disease-modifying therapies. Its validation will provide a standardized multimodal outcome measure, advancing MSA therapeutic development.

This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer’s disease, on the basis of pooled clinical trial data. Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer’s disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing. In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0

To assess evolving practices in Investigative Toxicology (I-Tox) across the pharmaceutical industry, a 30-question survey was conducted in 2025, following earlier editions in 2015 and 2020. Seventeen mid- to large-sized pharmaceutical companies participated, all active in both traditional (NCEs, NBEs) and emerging modalities. Respondents included in vitro toxicologists from the Investigative Toxicology Leadership Forum, providing company-level input on team structure, objectives, assay capabilities, and future outlook. Most companies reported a dedicated I-Tox function embedded within nonclinical safety organizations. While I-Tox teams remain lean—around 1% of R&D staff—their focus has shifted toward high-impact project support, with greater reliance on CROs and GLP-compliant outsourcing. Internal laboratory activities have become more streamlined, but scientific scope remains broad, with growing emphasis on general toxicology and in silico approaches. I-Tox involvement now occurs earlier in discovery to enable proactive safety de-risking. Core I-Tox contributions span the R&D continuum, from target selection to clinical support. Compared to 2015, greater emphasis is placed on early-phase activities, including SAR guidance, off-target risk assessment, and chemistry support. In later phases, I-Tox focuses on elucidating mechanisms of toxicity, translational relevance, and signal interpretation in both nonclinical and clinical settings. The growing proportion of GLP work managed by I-Tox prompted further exploration of adjacent disciplines. Safety Pharmacology (SP) and Genetic Toxicology (GT) are now integrated into I-Tox functions in 50% and 75% of companies, respectively. These functions are supported by GLP-compliant assays conducted internally (25%), at CROs (58%), or through a combination of both (17%). Notably, one-third of respondents reported incorporating SP into I-Tox within the past five years. Assay availability has improved over the past decade, particularly for in vitro and in silico platforms targeting key organ systems. However, translational confidence remains a limiting factor. Technologies such as iPSC models and high-content imaging are now routinely applied, while others—like organ-on-chip and metabolomics—are still maturing. Respondents also highlighted emerging tools with near-term disruptive potential. Overall, I-Tox continues to evolve as a strategic enabler of drug safety, increasingly contributing to early de-risking, mechanistic insight, and the integration of innovative, non-animal technologies across pharmaceutical R&D.

Abstract Drug-induced seizures remain a major safety concern in drug development, yet human seizure liability is difficult to predict using conventional preclinical models. Here, we evaluated whether spontaneous calcium network activity in human induced pluripotent stem cell-derived CNS-3D Brain Organoids could predict clinically observed seizure risk across a pharmacokinetically anchored drug set. CNS-3D organoids contained neuronal and astrocytic populations, expressed neuroactive receptor and ion-channel gene programs that aligned with human cortical tissue, and exhibited reproducible spontaneous calcium oscillations across production batches. A retrospective drug panel of 66 small-molecule drugs was assembled from human clinical evidence, including 30 seizure-associated drugs and 36 comparator drugs without documented clinical seizure liability. Drugs were tested across concentration ranges anchored to reported clinical C max , and calcium time-series responses were integrated with chemical structure features using a machine-learning workflow. The final model predicted clinical seizure liability with an AUROC of 0.872, achieving 83.3% sensitivity and 88.9% specificity in drug-level cross-validation. Model scores also stratified seizure-associated drugs by clinical context and prevalence, suggesting that CNS-3D activity profiles capture clinically meaningful differences in seizure risk. Compared with published in vitro and preclinical seizure-liability models, CNS-3D organoid-based predictions showed improved balanced sensitivity and specificity. These findings support high-throughput calcium profiling in human CNS-3D organoids as a scalable, exposure-aware platform for predicting human seizure liability and contributing functional human data to neuro-safety assessment.