Dai, Jing

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

Introduction: Excess sodium intake is strongly linked with hypertension and cardiovascular disease (CVD); people with narcolepsy (PwN) have increased CV risk. Hypothesis: Switching from high-sodium oxybate (SXB; Xyrem ® ; 6–9 g for ≥6 wks) to low-sodium oxybate (LXB; Xywav ® ; same regimen) reduces mean 24-hr ambulatory systolic blood pressure (ASBP) after ≈6 wks in PwN, regardless of antihypertensive (anti-HTN) use and site type. Methods: XYLO, an open-label, single-arm study (NCT05869773), assessed PwN aged 18−70 y with office SBPs of 130−155 mmHg. The primary and key secondary endpoints were changes from baseline (BL) to end-of treatment (EOT) in mean 24-hr ASBP and seated resting (“office”) SBP (OSBP), respectively; exploratory endpoints were diastolic BP (DBP) changes. Changes are baseline adjusted. Prespecified subgroup analyses explored BL anti-HTN use and participation site (ie, site-based [at study site] vs decentralized [at-home]). Results: In 43 PwN (mean age, 45 y; female, 65%; anti-HTN, 33%), mean±SD BL OSBP and DBP were 138.0±5.7 and 85.2±6.6 mmHg, respectively. Mean±SD total SXB vs LXB dosages were 8.0±1.1 vs 8.1±1.1 g/night, reflecting 1457±206 vs 118±16 mg sodium (difference: ≈1339 mg); median 24-hr urinary sodium was 4232 mg/d at BL and 2703 mg/d at EOT (median change: 1288 mg/d). Mean change in 24-hr ASBP (least squares mean [95% CI]) was −4.1 (−6.9, −1.4; 1-sided P =0.0019) mmHg (Fig 1) ; mean change in OSBP was −9.2 (−11.9, −6.5; 1-sided P <0.0001). Mean changes in 24-hr ambulatory and office DBP were −2.3 (−4.1, −0.5; 2-sided P =0.0118; nominal) and −3.8 (−6.0, −1.6; 2-sided P =0.0014; nominal) mmHg, respectively. In subgroups, mean change in 24-hr ASBP was −4.6 (−9.6, 0.3) mmHg with BL anti-HTN use and −3.9 (−7.3, −0.5) mmHg without BL anti-HTN use; changes in OSBP were −11.8 (−16.5, −7.1) and −7.9 (−11.1, −4.6) mmHg. Mean change in 24-hr ASBP was −3.6 (−8.0, 0.9) mmHg for site-based and −4.5 (−8.1, −1.0) mmHg for decentralized participation. Corresponding changes in OSBP were −9.0 (−13.3, −4.6; site-based) and −9.3 (−12.8, −5.8; decentralized) mmHg with a downward trend over 6 wks ( Fig 2 ). Treatment-emergent adverse events (all mild/moderate) occurred in 40% of PwN (N=67). Conclusions: Switching from SXB to LXB reduced daily medication-related sodium intake in PwN and was associated with clinically meaningful BP reductions overall and across subgroups, consistent with evidence on dietary and medication-related sodium effects.

BACKGROUND: People with narcolepsy are at increased risk for hypertension and cardiovascular disease; excessive sodium intake is linked to both. METHODS: We studied patients with narcolepsy and office systolic blood pressures (BPs) of 130 to 155 mm Hg taking twice-nightly high-sodium oxybate for ≥6 weeks who switched to low-sodium oxybate at the same dosage. The primary end point was the change from baseline in mean 24-hour ambulatory systolic BP at the end of treatment (≈6 weeks after switching). Secondary and exploratory end points included changes in diastolic BP, office BP, and 24-hour sodium excretion. RESULTS: Patients (n=43) had a mean age of 45 years, were 65% female, 33% on antihypertensives, with baseline mean (SD) office BP of 138.0/85.2 (5.7/6.6). Mean (SD) total high- and low-sodium oxybate dosages of 8.0 (1.1) and 8.1 (1.1) g/night, respectively, represented 1456.5 (206.2) and 117.8 (16.3) mg of sodium. The median 24-hour urinary sodium was 4278 mg/d at baseline and 2703 mg/d at the end of treatment (median change, 1288 mg/d). Mean (SE) 24-hour ambulatory systolic BPs at baseline and study end were 132.3 (1.8) and 128.2 (1.8) mm Hg (least-squares mean change, −4.1 [95% CI, −6.9 to −1.4] mm Hg; 1-sided P =0.0019). BP changes by narcolepsy subtype, sex, body mass index, baseline office BP, and baseline antihypertensive use were consistent with the overall effect size. CONCLUSIONS: People with narcolepsy switching from high- to low-sodium oxybate showed substantially reduced daily medication-related sodium intake and significant 24-hour BP reductions. These results demonstrate the importance of reducing pharmaceutical sodium content in this elevated cardiovascular risk patient population. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05869773.