Ruoff, Chad

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 Narcolepsy type 2 (NT2) is characterized by excessive daytime sleepiness, heterogeneous symptom severity, and typically normal endogenous orexin levels. The Vibrance-2 phase 2 study evaluated alixorexton, a selective orexin 2 receptor agonist, in patients with NT2. Methods Vibrance-2 was a placebo-controlled, dose-ranging phase 2 study. After a 2-week washout from current narcolepsy medications, adults with NT2 meeting ICSD-3-TR diagnostic criteria were randomized 1:1:1:1 to receive placebo or alixorexton once daily at doses of 10, 14, or 18mg for 8 weeks, followed by an optional 5-week open-label extension. Dual primary endpoints were the change from baseline to week 8 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT) and on the Epworth Sleepiness Scale (ESS). Safety evaluation included treatment-emergent adverse events (TEAEs). P-values were adjusted for multiplicity. Results Ninety-three patients were randomized to placebo (n=24) or alixorexton (10mg, n=23; 14mg, n=22; 18mg, n=24); 90 completed double-blind treatment. At baseline, patients had severe symptoms (MWT: 5.6 minutes; ESS: 17.4). The study met its dual primary endpoints. At week 8, MSL on MWT increased 9.3, 6.7, and 6.7 minutes at 10, 14, and 18mg, respectively, from baseline versus placebo, with statistically significant differences observed for the 14 and 18mg doses (adjusted p< 0.05). ESS improved by -2.1, -3.2, and -3.6 points from baseline versus placebo at week 8 for the 10, 14, and 18mg groups, respectively, with statistical significance observed for the 18mg dose (adjusted p< 0.05), where more than 70% of patients achieved normalization. TEAEs in 10% of all alixorexton-treated patients through week 8 were pollakiuria, insomnia, micturition urgency, dizziness, and headache. Most TEAEs were mild-to-moderate with no serious TEAEs. Conclusion Vibrance-2 was the first large clinical trial in patients with NT2 to demonstrate positive results with an orexin 2 receptor agonist. Alixorexton resulted in statistically significant and clinically meaningful improvements in wakefulness and daytime sleepiness at Week 8 and was generally well tolerated. These results support phase 3 clinical development of alixorexton as a treatment for NT2. Support (if any) Alkermes, Inc.

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 Once-nightly sodium oxybate (ON-SXB) is approved to treat cataplexy or excessive daytime sleepiness (EDS) in patients ≥7 years of age with narcolepsy. ON-SXB demonstrated significant improvements in both objective (Maintenance of Wakefulness Test) and subjective (Epworth Sleepiness Scale [ESS] score) measurements of sleepiness in the REST-ON trial and via the ESS in the real-world REFRESH study. Assessing ON-SXB ESS data from a specialty pharmacy and outside of clinical studies further informs the generalizability of effectiveness. Methods Demographic and clinical data were collected from Optum Frontier Therapies pharmacy for patients with ≥1 filled ON-SXB prescription, ≥1 ON-SXB-related clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). Participation in ESS assessment was voluntary. ESS scores were assessed for patients who switched from twice-nightly oxybate (TN-OXB) treatment (first ON-SXB prescription filled ≤30 days of last TN-OXB prescription [switch]) and those new to oxybate or with >30 days between TN-OXB and ON-SXB prescription fills (not-on-oxybate) who had ESS data at initial ON-SXB prescription and at each follow-up assessment. Results Of 452 identified patients, 215 had ≥1 follow-up ESS score (switch, n=82 [mean age, 38.4 years; female, 71%]; not-on-oxybate, n=133 [mean age, 40.0 years; female, 71%]). Of patients who had any prior oxybate use (switch, 100%; not-on-oxybate, 46%), the most common prior oxybate was mixed-salt oxybates (switch, 59%; not-on-oxybate, 70%). Stimulants/wake-promoting agents were taken by 51% of switch and 65% of not-on-oxybate patients. Baseline mean (SD) ESS scores were 11.3 (5.5) for switch and 12.5 (5.6) for not-on-oxybate patients; 23% of switch and 38% of not-on-oxybate patients experienced severe EDS. By the first follow-up (median [IQR], 49 [28-94] days), mean (SD) ESS scores were within the normal EDS range with ON-SXB for both subgroups (ie, ESS < 10; switch, 9.7 [5.5]; not-on-oxybate, 9.5 [5.2]); the majority reported normal levels of daytime sleepiness (switch, 56%; not-on-oxybate, 57%). Mean (SD) change in ESS score from baseline to follow-up was -1.6 [4.5] for switch and -3.1 [5.0] for not-on-oxybate groups. Conclusion Patients who initiated ON-SXB experienced improvements in daytime sleepiness regardless of prior TN-OXB use, and many achieved normal levels of daytime sleepiness in ≤2 months of starting ON-SXB. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Hypoglossal nerve stimulators (HGNS) are used in patients with moderate-to-severe obstructive sleep apnea (OSA) who are unable to tolerate or do not respond to continuous positive airway pressure (CPAP) therapy. However, a subgroup of patients fail to achieve resolution of OSA with HGNS alone. Previous studies have shown that lower BMI, lower nadir oxygenation, decreased sleep latency, and higher VOTE score on drug-induced sleep endoscopy (DISE) predict better treatment outcome. We hypothesize that baseline diagnostic polysomnography (PSG) may further predict which patients will achieve successful therapeutic outcome with HGNS therapy. Methods We conducted a retrospective analysis of all adult patients who underwent HGNS implantation at Mayo Clinic Arizona between 2019-2025 and had a pre-implantation diagnostic PSG available for review. Treatment success was defined by Sher Criteria: >50% reduction in post-treatment apnea hypopnea index (AHI) to a final AHI of < 20/hr. Responders met Sher criteria and non-responders did not meet Sher criteria. Demographics, sleep questionnaire results, PSG variables, and VOTE score on DISE were collected and analyzed using Spearman’s rank correlation of reduction in AHI. Results Twenty-three patients (11M/12F, median age: 69[IQR:64,75] years) met inclusion criteria. Median baseline AHI was 24[IQR:19,37]/hr. Median post-implant AHI was 8 [IQR:3, 14]/hr. Responders (n=15, 65%) and non-responders (n=8, 35%) demonstrated median post-implant AHI of 4.5[IQR:2.3,7.3]/hr and 15.7[IQR:12.3,28.5]/hr, respectively. Treatment response was associated with less time with SpO2 < 88% (T88%) (21min [IQR:3,64] vs. 73[IQR:36,105mins]; p=0.023) and higher central apnea index (CAI) (1[IQR:0.1,3] vs. 0[IQR:0,1], p=0.03) on pre-implantation PSG. Conclusion In this small cohort of OSA patients, less nocturnal hypoxemia as defined by T88% and higher baseline central apnea index were predictors of better treatment response to HGNS therapy as measured by Sher criteria. We hypothesize that greater nocturnal hypoxemia likely reflects more severe airway obstruction during sleep. Our analysis also showed that responders had higher baseline CAI than non-responders, however we believe this association is not clinically significant and likely driven by one outlier (CAI 13/hr). Further analysis in a larger HGNS cohort is needed to confirm these findings. Data enrichment efforts and more sophisticated analyses are underway. Support (if any)

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 Once-nightly sodium oxybate (ON-SXB; LUMRYZ™) is approved to treat excessive daytime sleepiness (EDS) or cataplexy in patients ≥7 years of age with narcolepsy. Findings from 2 studies have demonstrated improvements in objective and subjective EDS with ON-SXB in patients with narcolepsy type 1 (NT1) or 2 (NT2) (NCT02720744, NCT06792708). To evaluate the effect of ON-SXB on EDS in a larger, more diverse narcolepsy patient population, changes in Epworth Sleepiness Scale (ESS) score were analyzed using specialty pharmacy data. Methods Demographic/clinical data were collected from Optum Frontier Therapies pharmacy for adults with NT1 or NT2 with ≥1 filled ON-SXB prescription, ≥1 ON-SXB clinical assessment, and ≥1 follow-up ESS score (6/1/2023-9/30/2024). ESS total scores were assessed at baseline and at each follow-up assessment after ON-SXB initiation. ESS assessment participation was voluntary. Data were analyzed descriptively and stratified by narcolepsy subtype. Results Of 452 patients identified, 195 had ≥1 follow-up ESS score and reported narcolepsy type (NT1, n=123 [63%; mean age, 38.6 years; female, 69%]; NT2, n=72 [37%; mean age, 40.7 years; female, 74%]). More patients with NT1 vs NT2 (72% vs 58%) had any prior oxybate use. Baseline concomitant stimulant/wake-promoting agent use was 58% and 64% for NT1 and NT2, respectively. Mean (SD) ESS total scores at baseline were 12.1 (5.7) and 12.2 (5.3) for patients with NT1 and NT2, respectively; 31% of NT1 and 33% of NT2 had severe EDS. For both subtypes, mean (SD) ESS scores were within the normal EDS range (≤10) by the first follow-up (median time, 52 days; NT1, 10.0 [5.5]; NT2, 9.6 [4.8]). At first follow-up, more than half of patients in the NT1 (55%) and NT2 (54%) subgroups achieved normal levels (ESS total score ≤10) of sleepiness, while 20% of NT1 patients and 10% of NT2 patients had severe EDS. Mean (SD) change from baseline in ESS score was -2.1 (4.3) and -2.6 (5.3) in the NT1 and NT2 subgroups, respectively. Conclusion In this real-world dataset, both NT1 and NT2 patients quickly experienced clinically meaningful improvements in ESS score after initiating ON-SXB. These results support ON-SXB as an effective EDS treatment, regardless of narcolepsy subtype. Support (if any) Avadel 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