Jazz Pharmaceuticals (United States)

The cuprizone (CPZ) lesioned mouse is a widely used model of demyelination and remyelination, but most studies rely on histology at terminal timepoints, limiting understanding of disease dynamics. Here, we present a longitudinal multimodal magnetic resonance imaging and spectroscopy (MRI/MRS) study of CPZ-induced pathology, pooling control arms from three independent experiments (n=40). Mice were imaged at baseline, then exposed to 0.2% cuprizone for 5 weeks and repeatedly imaged at days 24, 35, 49, 63 and 77 after the start of CPZ. Imaging included multiparametric mapping (MPM), diffusion tensor imaging (DTI), tensor-based morphometry (TBM), and single-voxel MRS in the corpus callosum. Histology (MBP, silver, GFAP, Iba1) was performed at selected timepoints for validation. Additional group of 18 CPZ-lesioned mice were imaged ex vivo using a different higher resolution MRI protocol and compared against 19 non-CPZ controls. MPM-derived MTsatδ and R1 reductions indicated robust demyelination in the corpus callosum and deep cerebellar nuclei by day 24, expanding to cortex and hippocampus by day 35. Partial recovery was observed by day 77 but changes persisted, consistent with histological evidence. TBM revealed dynamic volumetric alterations, including hippocampal and cerebellar expansion alongside cortical and subcortical shrinkage, persisting beyond CPZ cessation. DTI demonstrated early (days 24-35) decreases in FA and MD, followed by complex trajectories consistent with microstructural disruption and partial repair. MRS detected early increases in GABA, glutamine, taurine, and glutathione, with corresponding decreases in NAA, while inositol showed a biphasic decrease-increase profile, likely reflecting acute astrocytic dysfunction followed by gliosis – neuroinflammatory processes that were corroborated by immunohistochemistry. Together, these results demonstrate that multimodal MRI/MRS sensitively captures widespread, dynamic, and only partially reversible pathology in CPZ-treated mice. Longitudinal imaging provides a non-invasive, translational approach to characterising demyelination, gliosis, and remyelination, offering a powerful alternative to histology for preclinical studies and longitudinal therapeutic screening.

Prolonged nighttime sleep is a prominent symptom in many patients with idiopathic hypersomnia. The only US Food and Drug Administration-approved treatment for idiopathic hypersomnia is low-sodium oxybate (LXB; Xywav®), for which efficacy and safety were established in a double-blind, placebo-controlled, randomized-withdrawal study (NCT03533114). This post hoc analysis evaluated the effect of LXB treatment on sleep time. Eligible participants (aged 18-75 years, primary diagnosis of idiopathic hypersomnia) began LXB treatment in an open-label titration and optimization period (10-14 weeks), entered a stable-dose period (SDP; 2 weeks), and were randomized to continue LXB or placebo in a double-blind, randomized-withdrawal period (DBRWP; 2 weeks). Sleep parameters, including 24-hour self-reported total sleep time (TST), nocturnal TST, and total nap duration, were analyzed using daily electronic sleep diary data collected ≥2 weeks during 3 different study periods. In total, 3917 daily records from 148 participants were analyzed. During open-label LXB treatment, from baseline to the end of SDP, there were decreases in median 24-hour TST (from 513.3minutes to 468.8minutes), nocturnal TST (from 495.0minutes to 454.3minutes), and total nap duration (from 16.3minutes to 7.8minutes). During DBRWP, estimated median differences between LXB and placebo in 24-hour TST, nocturnal TST, and total nap duration were -25, -9, and -12minutes, respectively. Common treatment-emergent adverse events (≥10% of participants) were nausea, headache, dizziness, anxiety, and vomiting. Open-label LXB treatment in adults with idiopathic hypersomnia was associated with reductions in 24-hour TST, nocturnal TST, and total nap duration.

Background:Essential tremor (ET) is one of the most common movement disorders. Previous estimates of ET prevalence vary due to multiple factors. This study estimated the prevalence of diagnosed ET.Methods:The prevalence of diagnosed ET was estimated among adults with continuous enrollment in 2022 and ≥1 additional year of prior baseline enrollment in the Merative™ MarketScan® Research Databases, a US administrative claims database. ET was defined as ≥2 ET claims within 12 months of one another during the 2016–2022 study period. The proportion of patients receiving treatment was defined as having a claim for possible medication for ET in 2022 among those with diagnosed ET who had an additional 6 months of follow-up following the first ET diagnosis claim. Age-standardized estimates of the number of US adults with diagnosed ET were calculated using 2024 US population census projections.Results:The prevalence of diagnosed ET was 0.28% before age standardization, ranging from 0.06% (18–40 years) to 1.61% (≥75 years); 74% of patients overall received possible treatment. After standardization, prevalence was 0.42%; in 2024, 1.1 million US adults were estimated to have diagnosed ET. Estimates of the prevalence of diagnosed ET in the US were susceptible to the choice of case definition, nearly doubling (ie, 2.1 million US adults) with a more sensitive definition.Discussion:ET affects a substantial proportion of the US adult population. Selecting appropriate case definitions and using methods such as standardization are critical for estimating valid and generalizable chronic condition prevalences with real-world data.HighlightsThis study found that 1.1 million US adults were estimated to have been diagnosed with essential tremor, with the sensitivity analyses yielding additional estimates. Estimating reliable and generalizable prevalences of diagnosed chronic conditions requires selection of appropriate case definitions and standardization to the general population.

There are no validated measures to assess hyperphagia associated with rare MC4R pathway diseases, such as Bardet-Biedl Syndrome (BBS). Symptoms of Hyperphagia© (SoH) and Impacts of Hyperphagia© (IoH) are novel questionnaires designed to assess signs and symptoms of hyperphagia and their impacts on patients and caregivers. We evaluated the psychometric performance of the caregiver-versions of the SoH: Caregiver (Observer-reported) and IoH: Caregiver (Observer-reported and Self-reported subscales). Reliability and validity were evaluated using data from a multi-country cross-sectional survey of adult caregivers of patients with BBS experiencing hyperphagia and obesity. Other instruments included were Impact of Weight on Quality of Life (IWQOL)-Kids (Parent Proxy), PROMIS Scale Global Health of Caregiver, Revised Impact on Family Scale (RIOFS), and Work Productivity and Activity Impairment. 242 eligible caregivers completed the survey. Exploratory factor analysis identified 1 factor per subscale. Strong internal consistency was observed for IoH: Caregiver (Observer) (Cronbach's a = 0.66) and IoH: Caregiver (Self) (a = 0.72) and moderate for SoH: Caregiver (Observer) (a = 0.40). Moderate-to-strong correlations were observed with school days missed and all domains of IWQOL-Kids except Physical Comfort (range = 0.315-0.573, p's < 0.001). Known-groups indicated significantly worse SoH: Caregiver subscores for patients using appetite suppressants or implementing more weight management approaches (6-10 vs. ≤5 or > 10). Caregivers reporting greater strain on RIOFS items and worse mental health had worse IoH subscores. The SoH: Caregiver and IoH: Caregiver demonstrated preliminary validity, reliability, and consistency in a real-world setting. Research is underway to further validate these measures for use in clinical trials for BBS and other MC4R pathway-related diseases associated with obesity.

Chronic stress has been linked with higher risk of ovarian cancer and one posited pathway is through altered metabolism of amino acids, lipids, and other small molecule metabolites. However, the types of alterations that occur may not be uniform across tissue types. We aim to examine and compare the impacts of chronic stress on metabolomic changes in circulation and ovarian tissue. Twelve-week-old, healthy, female, C57 black mice were randomly assigned to three-week of chronic stress using daily restraint (2-hours/day; n = 9) or normal care (n = 10). Metabolomic profiling was conducted on plasma and ovarian tissues via mass spectrometry. We utilized Wilcoxon Rank Tests, Metabolite Set Enrichment Analysis, Differential Network Analysis and a previously derived metabolite-based distress score to identify metabolomic alterations under restraint stress. We used the false discovery rate to account for testing multiple correlated comparisons. In plasma, individual lysophosphatidylcholines and the metabolite class carnitines were positively associated while diacylglycerols and triacylglycerols were inversely associated with restraint stress (adjusted-p < 0.2). In contrast, in ovarian tissue, diacylglycerols and triacylglycerols were positively associated while carnitines were inversely associated with restraint stress (adjusted-p < 0.2). Other metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were inversely associated with restraint stress in both plasma and ovarian tissue (adjusted-p < 0.2). A previously developed human metabolite-based distress score was higher in restraint stress mice compared to controls, with a larger difference observed in ovarian tissue than in plasma. These findings suggest research to understand the metabolic impact of chronic stress needs to consider both systemic and tissue-specific alterations.

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) assessing the effectiveness of low-sodium oxybate (LXB; Xywav®) treatment on daytime and nighttime symptoms in participants with narcolepsy (type 1 [NT1] or 2 [NT2]) or idiopathic hypersomnia. Data presented are from the narcolepsy cohort. Methods DUET included a screening period (with 2-week washout for current oxybate users), 8-day baseline (BL) period, 2- to 8-week LXB titration period, 2-week stable-dose period, 8-day end-of treatment (EOT) period, and 2-week safety follow-up. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Key secondary endpoints for the narcolepsy cohort included change in polysomnography parameters: total shifts from deeper to lighter sleep stages, stage N3 sleep duration (minutes), and number of awakenings. Additional endpoints included Patient Global Impression of Change (PGIc)–overall narcolepsy disease. Primary and key secondary endpoints were controlled for multiplicity with sequential testing; other P-values are considered nominal. Results Fifty-five narcolepsy participants enrolled and were dosed with LXB (NT1, n=26; NT2, n=29); 13 transferred to another cohort and 34 were completers (NT1, n=16; NT2, n=18). Enrolled participants were mostly female (72.7%) and White (80.0%); mean (SD) age was 33.4 (12.9) years (NT1=34.6 [12.6]; NT2=32.4 [13.2]). For completers, least-squares mean (LSM) (SE) changes in ESS score were −7.7 (0.9), P&amp;lt;.0001, overall; NT1=−6.5 (1.4), P&amp;lt;.0001; NT2=−8.8 (1.3), P&amp;lt;.0001. Compared with BL, sleep architecture at EOT showed fewer deeper to lighter sleep stage shifts (LSM [SE]: −13.1 [2.9], P&amp;lt;.0001, overall; NT1=−13.9 [4.3], P=0.0029; NT2=−12.3 [4.1], P=0.0050); increased stage N3 sleep (minutes) (45.0 [8.8], P&amp;lt;.0001, overall; NT1=49.8 [13.0], P=0.0006; NT2=40.8 [12.3], P=0.0023); and fewer awakenings (−3.2 [0.9], P=0.0015, overall; NT1=−4.1 [1.4], P=0.0056; NT2=−2.3 [1.3], P=0.0771). Most participants (93.3%, n=30; NT1, 86.7%, n=15; NT2, 100%, n=15) reported improvement (very much, much, minimally) in overall narcolepsy disease on PGIc. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion Participants with NT1 and NT2 taking open-label LXB showed improvements in daytime sleepiness (decreased ESS scores) and reduced symptom burden (improved PGIc), which paralleled improvements in sleep architecture and disruption. Support (if any) Jazz Pharmaceuticals