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Abstract Rationale Low-sodium oxybate (LXB; Xywav®) is FDA approved for treatment of cataplexy and excessive daytime sleepiness (EDS) in people ≥7 years of age with narcolepsy, and for idiopathic hypersomnia in adults. LXB Prescribing Information includes a Warning and Precaution for respiratory depression and sleep-disordered breathing; therefore, data on safety of LXB in people with obstructive sleep apnea (OSA; a common comorbidity among people with narcolepsy or idiopathic hypersomnia) are needed. This post hoc analysis of DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974), a prospective, open-label phase 4 study, evaluated respiratory parameters in participants taking LXB with or without comorbid OSA, in 3 cohorts: narcolepsy or idiopathic hypersomnia (LXB ≤9 g/night), or narcolepsy (LXB >9 g/night). Methods Participants underwent the following study periods: screening, 8-day baseline (BL; off-LXB for narcolepsy and idiopathic hypersomnia cohorts; on-LXB 9 g/night for >9 g cohort), 2-8-week dose titration, 2-week stable-dose, 8-day end-of-treatment (EOT; on optimized total nightly dosage; ≤12 g for the >9 g cohort), and 2-week safety follow-up. Participants with BL apnea-hypopnea index (AHI) >10 (treated/untreated OSA) were excluded from the study. Overnight polysomnography assessments conducted at BL and EOT included respiratory parameters: AHI, central apnea index (CAI), and percentage of total sleep time spent with oxygen saturation (SpO2) <90% (T90). Treatment-emergent adverse events (TEAEs) were assessed by OSA group. Least squares mean changes were adjusted for BL values. Results Fifty-five participants enrolled in the narcolepsy cohort, 9% (5/55) had comorbid OSA; 22% (10/46) and 31% (15/48) had comorbid OSA in the idiopathic hypersomnia and narcolepsy >9 g cohorts, respectively (3, 9, and 12 were on OSA treatment throughout the study). Most participants (narcolepsy, idiopathic hypersomnia, narcolepsy >9 g) were female (72.7%, 80.4%, 62.5%) and White (80.0%, 84.8%, 77.1%). No worsening of sleep-disordered breathing was observed during LXB treatment, as evidenced by respiratory parameters AHI, CAI, and T90 assessed at BL and EOT in either participants with or without OSA (Table 1). Percentages of participants with/without OSA reporting ≥1 TEAE were 60.0%/62.0% (narcolepsy), 80.0%/72.2% (idiopathic hypersomnia), and 66.7%/78.8% (narcolepsy >9 g). Most TEAEs were mild or moderate; 1 serious TEAE each occurred in the idiopathic hypersomnia cohort (with OSA) and the narcolepsy >9 g cohort (without OSA). Conclusions No worsening respiratory signals were observed with LXB treatment in participants with or without comorbid (mild or treated) OSA in the narcolepsy, idiopathic hypersomnia, or narcolepsy taking >9 g LXB dosage cohorts. This abstract is funded by: Jazz Pharmaceuticals

Abstract Introduction Low-sodium oxybate (LXB; Xywav®), the only FDA-approved treatment for idiopathic hypersomnia in adults, was evaluated in the phase 4, open-label DUET study (NCT05875974). This post-hoc analysis evaluated subgroups of participants with idiopathic hypersomnia stratified by patient-reported ideal nighttime sleep duration (with [>9 hours] and without [≤9 hours] long sleep need [LSN]), based on Idiopathic Hypersomnia Severity Scale (IHSS) Item 1. Methods DUET included screening, 8-day baseline (BL), 2−8-week LXB dose titration/optimization, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. Outcomes were Epworth Sleepiness Scale (ESS), IHSS, polysomnographic total sleep time (TST), and Patient Global Impression of Severity (PGI-S) and Change (PGI-C). Least squares mean (LSM) changes (BL-to-EOT) were BL-adjusted; P values are nominal. Treatment-emergent adverse events (TEAEs) were assessed by subgroup. Results Of 46 enrolled participants with idiopathic hypersomnia, 45 had BL IHSS data; 24 reported LSN (>9 hours) and 21 reported no LSN (≤9 hours). Most (LSN/without LSN) were female (100%/61.9%) and White (91.7%/76.2%), with mean±SD age 36.8±11.1/38.6±12.1 years; 20/24 and 19/21 completed the study. BL mean±SE (LSN/without LSN) ESS scores were 16.8±0.5/16.1±0.7; LSM changes (95% CI): LSN −9.5 (−11.5, −7.6; P< 0.0001; n=20), without LSN −7.4 (−9.4, −5.4; P< 0.0001; n=19). BL mean±SE (LSN/without LSN) IHSS total scores were 35.7±1.3/30.5±1.8; LSM changes (95% CI): LSN −18.3 (−22.4, −14.1; P< 0.0001; n=19), without LSN −12.5 (−16.9, −8.0; P< 0.0001; n=17). BL mean±SE (LSN/without LSN) IHSS long sleep/sleep inertia component scores were 12.5±0.6/9.2±0.6; LSM changes (95% CI): LSN −5.5 (−6.8, −4.1; P< 0.0001; n=19), without LSN −4.0 (−5.4, −2.5; P< 0.0001; n=17). BL mean±SE (LSN/without LSN) polysomnographic TSTs were 490.0±26.0/442.7± 24.7 minutes; LSM changes (95% CI): LSN −53.1 (−92.5, −13.7; P=0.0097; n=20), without LSN −59.4 (−99.8, −18.9; P=0.0052; n=19). On the PGI-C, most participants (LSN/without LSN) endorsed improved overall disease (100%/88.2%; n=19/n=17) at EOT. TEAEs were reported in 79.2% (LSN) and 66.7% (without LSN); most (LSN/without LSN) were mild (45.8%/42.9%) or moderate (33.3%/23.8%) in severity; 1 (without LSN) was serious (unrelated to study drug). Conclusion Participants with or without LSN (>9 hours or ≤9 hours, respectively) taking LXB showed improvements in multiple idiopathic hypersomnia symptoms and reduced TST. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974) was the first study to evaluate effectiveness/safety of low-sodium oxybate (LXB; Xywav®) >9 g/night (outside the recommended range: 6–9 g/night). This analysis evaluated changes in patient-reported hypersomnolence measures in participants with narcolepsy taking LXB >9 g/night compared with LXB 9 g/night. Methods DUET was a phase 4, prospective, open-label study with screening, 8-day LXB 9 g/night (9g-baseline), titration/optimization, stable-dose, and 8-day end-of-treatment (EOT) optimized LXB >9 g/night (up to 12g; >9g-EOT) periods. Patient-reported measures included Epworth Sleepiness Scale (ESS), electronic sleep diaries (completed daily during 9g-baseline and >9g-EOT; subjective total sleep time [TST], number of awakenings, sleep efficiency [TST divided by time in bed], sleep quality [5-point scale; “very good” to “very poor”], and how rested/refreshed the participant felt upon awakening [5-point scale; “very well” to “not at all”]), Karolinska Sleepiness Scale (KSS; administered 90 minutes post-polysomnography awakening at 9g-baseline and >9g-EOT), and Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10). LSM differences (95% CI) from 9g-baseline to >9g-EOT (nominal P-values) were 9g-baseline-adjusted. Results Forty-eight participants took LXB >9g (mean±SD age: 39.2±10.9 years; 62.5% female). Total stable-dose LXB (mean±SD) was 11.1±1.0 g/night (n=45). From 9g-baseline to >9g-EOT, ESS scores improved (LSM [95% CI]: –3.1 [–4.2, –1.9]; P< 0.0001; n=44), nocturnal TST increased (0.3h [0.1, 0.4]; P=0.0163; n=26), sleep efficiency increased (3.8% [1.7, 5.9]; P=0.0011; n=26), and number of awakenings remained stable (–0.2 [–0.7, 0.3]; P=0.3959; n=26). Percentage of participants rating sleep quality as “very good”/”good” increased from 26.9% (9g-baseline) to 61.5% (>9g-EOT), as did rested sleep (“very well”/”well”/”somewhat” rested) from 57.7% to 69.2%, respectively. From 9g-baseline to >9g-EOT, KSS scores decreased (–0.9 [–1.4, –0.4]; P=0.0004; n=39); FOSQ-10 scores also increased (1.3 [0.5, 2.0]; P=0.0014; n=40). Of 48 participants, 36 (75.0%) experienced ≥1 TEAE (mostly mild/moderate and 1 serious [syncope, unrelated to treatment]). No changes in respiratory polysomnography measures were observed. Conclusion Participants with narcolepsy who optimized to LXB >9 g/night, relative to 9 g/night, reported increased sleep quality and restfulness that paralleled improvements in daytime sleepiness and daytime functioning. TEAEs were consistent with those at lower dosages. Support (if any) Jazz Pharmaceuticals

Abstract Introduction People with idiopathic hypersomnia often experience sleep inertia, characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening. This post-hoc analysis of the DUET study (NCT05875974) evaluated objective and subjective sleep inertia in participants with idiopathic hypersomnia taking low-sodium oxybate (LXB; Xywav®) stratified by patient-reported ideal nighttime sleep duration (with [>9h] and without [≤9h] long sleep need [LSN]), based on Idiopathic Hypersomnia Severity Scale (IHSS) item 1. Methods DUET was a phase 4, prospective, open-label study of LXB with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness), administered BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before/after PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, in LSN subgroups, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 46 enrolled participants with idiopathic hypersomnia, 45 had BL IHSS data; 24 reported LSN and 21 reported no LSN. Most (with/without LSN) were female (100.0%/61.9%) and White (91.7%/76.2%); 20/24 and 19/21 completed the study. Based on PVT lapses, objective sleep inertia ±SE (with/without LSN) at BL was 17.0±4.2/4.2±2.8, and at EOT was 0.0±na/2.0±0.9 (BL-to-EOT changes [95% CI]: −17.0 [−25.5, −8.5] and −2.2 [−6.9, 2.5]). Based on KSS, subjective sleep inertia ±SE (with/without LSN) at BL was 6.5±0.3/5.1±0.5, and at EOT was 0.81±0.5/1.5±0.6 (BL-to-EOT changes [95% CI]: −5.7 [−6.7, −4.7] and −3.5 [−4.5, −2.6]). Sleep inertia dissipation time constants ±SE were 2.7±1.1h (PVT) and 13.9±3.8h (KSS). TEAEs were consistent with the known LXB safety profile. Conclusion Participants with idiopathic hypersomnia experienced subjective and objective sleep inertia at BL, with prolonged dissipation after awakening. Objective BL sleep inertia was particularly severe in participants with LSN (>9h). After LXB treatment, notable improvements in objective and subjective sleep inertia were observed for both subgroups. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Sleep inertia (characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening) is a core idiopathic hypersomnia symptom and may also be experienced by individuals with narcolepsy. Sleep inertia in individuals with narcolepsy is not well studied. This post-hoc analysis of the DUET study (NCT05875974) evaluated sleep inertia in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) subgroups of the DUET narcolepsy cohort. Methods DUET was a phase 4, prospective, open-label study with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness); both administered at BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before and after the PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, for NT1 and NT2, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 55 enrolled participants with narcolepsy, 26 and 29 had NT1 and NT2, respectively. Most (NT1/NT2) were female (73.1%/72.4%) and White (73.1%/86.2%); 16/26 and 18/29 completed the study. Based on PVT lapses, objective sleep inertia ±SE (NT1/NT2) at BL was 33.1±6.2/14.9±3.2, and at EOT was 8.3±1.7/3.2±1.1 (BL-to-EOT changes [95% CI]: −24.8 [−35.5, −14.1] and −11.8 [−17.4, −6.1]). Based on KSS ratings, subjective sleep inertia ±SE (NT1/NT2) at BL was 1.1±0.6/1.1±0.5, and at EOT was 0.8±0.5/1.3±0.5 (BL-to-EOT changes [95% CI]: −0.3 [−1.9, 1.2] and 0.2 [−1.3, 1.6]). Sleep inertia dissipation time constants ±SE were 1.6±0.3h (PVT) and 0.4±0.1h (KSS) for the overall cohort. TEAEs were consistent with the known LXB safety profile. Conclusion Participants with narcolepsy, especially NT1, demonstrated objective sleep inertia at BL. Participants with NT1 or NT2 showed substantial improvements in objective sleep inertia with LXB treatment. Support (if any) Jazz Pharmaceuticals

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

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<.0001, overall; NT1=−6.5 (1.4), P<.0001; NT2=−8.8 (1.3), P<.0001. Compared with BL, sleep architecture at EOT showed fewer deeper to lighter sleep stage shifts (LSM [SE]: −13.1 [2.9], P<.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<.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