Citations

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 The relationship between sleep and brain metabolism remains unclear. This study aimed to examine whether overnight sleep features, using a home sleep apnea system based on peripheral arterial tonometry, are associated with regional FDG-PET changes in older adults. Methods We analyzed cognitively unimpaired adults (≥60 years) from the Mayo Clinic Study of Aging (MCSA) cohort who were not receiving sleep apnea treatment. Participants underwent overnight sleep assessment with the WatchPAT system, followed by FDG-PET imaging the next morning. FDG-PET data were co-registered to 3T MRI and automatically segmented into 122 anatomical regions. PET signal was referenced to the pons (SUVR). We computed voxel-weighted median FDG signal across 47 bilateral cortical and subcortical regions of interest (ROIs), excluding brainstem and cerebellum. Associations between sleep architecture and sleep apnea/hypoxemia burden and regional metabolism were assessed using partial Spearman’s rank correlation, adjusting for age. Results Thirty-seven participants were included (70.3% female; median [IQR] age: 72.0 [68.0–78.0] years). Wake after sleep onset (WASO) showed widespread negative associations with FDG uptake in cortical regions (p< 0.05), particularly the ventromedial/ventrolateral (rs=–0.47 to –0.33) prefrontal cortex, lateral temporal (rs=–0.38 to –0.33), and occipital (rs=–0.47 to –0.37) cortices. Total sleep time (TST) was positively associated with medial structures (p< 0.05), including the posterior cingulate (rs=0.39), retrosplenial cortex (rs=0.48), hippocampus/parahippocampal (rs=0.34 to 0.36), calcarine cortex (ρ=0.38), thalamus (rs=0.37), and caudate (rs=0.43). Hypoxic burden was positively associated with medial occipital regions (rs=0.35 to 0.39) and AHI-4% with cuneus (rs=0.33). Regional gray matter volume did not mediate these associations. WASO correlated with Insomnia Severity Index (rs=0.43, p=0.008) and self-reported refreshing sleep (rs=0.046). Conclusion Overnight sleep macrostructure features (WASO and TST) and hypoxic burden are significantly associated with brain metabolism, potentially underlying symptoms of sleep disturbance and cognitive aging. Support (if any) Mayo Clinic Alzheimer’s Disease Research Center Development Award (P30 AG062677), R01 AG056366, U01 AG006786, R01 AG056366, R01 AG034676, R37 AG011378, R01 AG041851, R01 NS097495, R01 AG068206, P30 AG062677, R01 HL065176. CLARA project work with funding from the European Union’s HORIZON EUROPE research and innovation programme (No 101136607).

Abstract Introduction Chronic and episodic headaches have a strong bidirectional relationship with insomnia and poor sleep outcomes. AM (morning) headaches are common among chronic pain populations, but additional research is needed to understand their pain experiences and potentially inform targeted interventions. Herein, we investigated whether presence of AM headaches is associated with differences in diary-based sleep parameters and pain ratings in women with pain and sleep complaints. We hypothesize individuals with AM headaches will have more sleep disturbances and fatigue as well as greater pain intensity and unpleasantness. Methods Women (N=293, Mage=39.59, SD 12.65, 65% with morning headaches) reporting insomnia and pain complaints (65% also reporting morning headaches) were recruited in mid-Missouri for an RCT (R01NR017168, ClinicalTrials.gov Identifier: NCT03744156). During baseline assessment, participants completed 2 weeks of daily electronic diaries and reported AM headache presence (Y/N). Independent samples t-tests (SPSS) evaluated differences in sleep parameters and pain ratings in those with and without AM headaches. Participants reporting diagnosed sleep apnea were excluded. Results Morning fatigue was higher among individuals with AM headaches (M=54.72+/-18.25) than those without (M=50.02+/-19.12), t(291)=-2.07, p=.04. Pain intensity was greater in the AM headache group in the morning (M=47.65+/-19.73 vs. M=42.52+/-21.91), t(291)=-2.04, p=.042, and evening, (M=49.62+/-19.10 vs. M=44.23+/-20.66), t(283)=-2.21, p=.028. Evening pain unpleasantness was also rated as higher among those with AM headaches (M=45.90+/-19.55) compared to those without (M=40.82+/-22.52), t(283)=-1.99, p=.048, but morning pain unpleasantness ratings only trended towards significance. Conclusion AM headaches can present as a chronic condition or as a symptom of other sleep disorders. Individuals with AM headaches had minimal sleep differences overall, but morning fatigue, pain intensity (AM and PM), and evening pain unpleasantness ratings were all significantly greater in those with AM headaches. Undiagnosed sleep disorders other than insomnia (i.e., obstructive sleep apnea) or other health concerns, like increased intracranial pressure, may have contributed to pain-related findings. Considering the high prevalence of COMISA in chronic pain populations, further investigation should examine its impact on sleep and headache severity. Support (if any) National Institute of Nursing Research (NR017168; Clinical trial: NCT03744156; PI: McCrae).

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 AD109, an investigational oral anti-apneic neuromuscular modulator, combines in one tablet the novel antimuscarinic, aroxybutynin (2.5 mg), with the selective norepinephrine reuptake inhibitor, atomoxetine (75 mg). AD109 significantly improved the apnea-hypopnea index and oxygenation vs placebo (PBO) in two phase 3 clinical trials in OSA. This exploratory analysis evaluated concomitant administration of AD109 with glucagon-like peptide-1 receptor agonists (GLP-1 RA) on weight change in OSA. Methods SynAIRgy (NCT05813275; N=646) and LunAIRo (NCT05811247; N=660) were randomized, double-blinded, PBO-controlled, parallel-arm phase 3 trials of AD109 vs PBO in adults with mild-to-severe OSA (AHI >5) who failed or refused positive airway pressure therapy. Participants must have had a body mass index (BMI) 18.5–40 kg/m2 for males / 18.5–42 kg/m2 for females. Participants receiving GLP-1 RA for diabetes were permitted. Body weight was assessed throughout the trials. Results One-hundred and six participants were enrolled in the phase 3 trials taking a GLP-1 RA for diabetes (PBO+GLP-1 RA: n=48; AD109+GLP-1 RA: n=58). In participants receiving a GLP-1 RA with baseline BMI < 30, AD109 reduced weight by 2.7% (vs PBO: -1.4%, P=0.08) and 0.5% (vs PBO: 2.3%, P=0.60) at Week 26 and Week 51, respectively. In participants receiving a GLP-1 RA with baseline BMI 30 to 34.9, AD109 reduced weight by 0.9% (vs PBO: 1.2%, P=0.84) and 2.5% (vs PBO: 3.3%, P=0.85) at Week 26 and Week 51, respectively. In participants receiving a GLP-1 RA with baseline BMI ≥35, AD109 reduced weight by 5.5% (vs PBO: 0.9%, P=0.02) and 11.5% (vs PBO: 3.8%, P=0.04) at Week 26 and Week 51, respectively. Participants not receiving GLP-1 RA (n=979) showed smaller weight reductions across BMI classes; in participants with BMI ≥35, AD109 reduced weight by 1.4% (vs PBO: 0.2%, P=0.002) and 2.8% (vs PBO: 1.4%, P=0.19) at Week 26 and Week 51, respectively. Conclusion In this exploratory analysis using pooled data from SynAIRgy and LunAIRo, results indicate that participants with a baseline BMI ≥35 receiving AD109+GLP-1 RA experienced progressively greater weight loss over time relative to GLP-1 RA alone. Future studies are needed to further evaluate concomitant administration of AD109+GLP-1 RA in OSA. Support (if any) These studies were supported by Apnimed, Inc.

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

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for the treatment of narcolepsy. Long-term efficacy and safety of AXS-12 in participants with narcolepsy with cataplexy (NT1) were previously reported from the Phase 3 ENCORE trial. To better understand the impact of AXS-12 on overall functional burden in NT1, we evaluated changes in cognition and functional outcomes during the ENCORE trial. Methods ENCORE included a 24-week open-label extension (OLE) period, followed by a 3-week double-blind randomized-withdrawal (DBRW) period. During the OLE, participants received AXS-12 (5 mg once-daily for 1 week, twice-daily for 23 weeks). Following this, participants were randomized 1:1 to continue twice-daily AXS-12 for 3 weeks or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. P-values reported are nominal. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In the OLE, participants treated with AXS-12 reported improvement in the NSAQ Ability to Concentrate item at 1 (54.8%) and 6 (58.5%) months. Participants reported improvement in concentration, assessed by PGI-C, at 1 (66.7%) and 6 (70.0%) months. Narcolepsy overall, assessed by the CGI-C, improved at 1 (90.3%) and 6 (90.2%) months; and improved at 1 (77.8%) and 6 (80.0%) months, assessed by the PGI-C. Functional impairment, assessed by the WPAI, was reduced from 53.0% at baseline to 34.0% at 1 month and 24.3% at 6 months. In the DBRW, a greater proportion of participants switched to placebo experienced worsening on the NSAQ Ability to Concentrate item (52.6% vs 14.3%; P=0.011), and PGI-C for ability to concentrate (57.9% vs 22.2%; P=0.029) at 3 weeks compared with those continuing AXS-12. A greater proportion switched to placebo also reported worsening of their narcolepsy overall (PGI-C) at 3 weeks compared with those continuing AXS-12 (52.6% vs 16.7%; P=0.024). Treatment with AXS-12 was generally well tolerated. Conclusion Long-term, open-label treatment with AXS-12 was associated with improvements in cognitive/functional domains and productivity. Randomized withdrawal to placebo led to worsening cognition and narcolepsy overall. These results further support the long-term therapeutic benefit of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics Inc.

Abstract Introduction Individuals with ostomies commonly report poor sleep quality years after ostomy surgery; however, little is known about the trajectory of insomnia and objective sleep characteristics in the early postoperative period. The purpose of this study was to describe the trajectory of insomnia and sleep characteristics in the first 3 months following ileostomy surgery. Methods We conducted a prospective, observational feasibility study of adults (18-65 years) undergoing ileostomy surgery. Sleep characteristics were obtained via Garmin smartwatches (vívosmart® 5) worn from 2 weeks to 3 months postoperatively. The Insomnia Severity Index (ISI) was used to elicit insomnia severity perioperatively and at postoperative months 1, 2, and 3. Descriptive and univariate statistics were used. Results We enrolled 22 participants [Mean age 41.55 years (SD 10.77), 10 female (45.5%), 19 White (86.4%), 9 colorectal cancer (40.9%), and 8 inflammatory bowel disease (36.3%)]. There was little change in insomnia severity from the perioperative period (mean = 9.95, SD 5.57) to 3 months after surgery (∆ = 0.76). At the time of ostomy surgery, most participants (n = 13, 59.1%) had insomnia (ISI≥8). Fifteen participants completed the postoperative surveys. Of those, 2 participants (13.3%) experienced resolution of insomnia symptoms, 3 participants (20%) continued to report no insomnia symptoms, 5 participants (33.3%) developed new insomnia symptoms, and 5 (33.3%) experienced persistent insomnia symptoms. There was little change in sleep duration (m = 462.10 min, SD = 79.07, ∆ = -24.1), deep sleep (m = 81.21 min, SD = 16.97, ∆ = -8.01), light sleep (m = 297.93 min, SD = 44.26, ∆ = -3.93), REM sleep (m = 82.82 min, SD = 44.50, ∆ = -12.02), wake after sleep onset (m = 51.87 min, SD = 29.93, ∆ = -3.05), or sleep score out of 100 (m = 59.15, SD = 11.83, ∆ = -1.74) from month 1 to month 3 after surgery. Conclusion Individuals undergoing ileostomy surgery experience symptoms of insomnia which often persist throughout the early postoperative period. Future research should explore the impact of insomnia on ostomy outcomes and should test interventions to treat insomnia in the early postoperative period. Support (if any) LabfrontXGarmin

Abstract Introduction The World Health Organization (WHO) has categorized pulmonary hypertension (PH) in five groups. Obstructive sleep apnea (OSA) is an independent cause of group 3 PH. The prevalence of OSA in PH patients is approximately 20% and untreated OSA may contribute to pulmonary vascular remodeling, exacerbating PH. Regular use of positive airway pressure (PAP) can improve pulmonary artery pressures. We hypothesized that untreated OSA is associated with mortality in all five groups of PH, and that mortality is reduced with PAP therapy. Methods We performed a retrospective chart review of the PH patient registry at Mayo Clinic Jacksonville, comprised of 696 patients classified per WHO classification of PH. Mortality in each WHO group of PH was abstracted as well as the presence of OSA as a comorbidity. Compliance with positive airway pressure therapy (PAP) was assessed across all patients with OSA. Results Patients in the registry were followed for a mean of 101.2 months. The mortality across all groups was 36.8%, ranging from 22.6% in group 4 to 64.3% in group 5. OSA was present in 46.9% patients, and it ranged from 33% in group 5 to 58% in group 2. Mortality did not vary significantly in the patients with OSA versus those without OSA (p=0.56). Of patients with OSA, 45.9% was deemed compliant with PAP therapy. Overall, the compliant patients had reduced mortality compared to the noncompliant ones (p=0.045), however this significance was due to pronounced effect in group 1 patients only. Conclusion Almost half of PH patients from our registry had OSA. Compliance with PAP therapy was associated with lesser mortality, primarily due to the effect seen in Group 1 PH patients. Support (if any)

Abstract Introduction Narcolepsy is a rare, chronic sleep disorder associated with decreased quality of life and multiple comorbid conditions, including sleep-related and psychiatric or mood disorders. This study used aggregate electronic health record (EHR) data to characterize the demographics and comorbidities of patients with narcolepsy. Methods An EHR-based search identified first-time Duke Health patients between January 1, 2012, and March 31, 2024. Included patients had ≥1 narcolepsy-specific ICD-9 (347.*) and ICD-10 (G47.4*) codes and ≥1 disease-supportive statement in clinical notes, identified using a natural language processing algorithm. A control cohort was propensity-matched for birth year, age at first institutional encounter, sex, race, number of diagnosis code instances, and mortality. Common comorbidities were compared and ranked between cohorts by odds ratio (OR). Statistical significance was determined using a chi-squared test; P values were corrected for multiple comparisons using Bonferroni correction. Results Within the EHR database of 2,617,188 patients, 1659 patients with a narcolepsy diagnosis were identified (mean age at first presentation, 32.4 years; white, 69%; female, 69%); the propensity-matched control cohort included 1659 patients (mean age at first presentation, 32.3 years; white, 69%; female, 69%). Comorbidities that occurred statistically significantly more frequently (all P< 0.0001) among the narcolepsy vs control cohort (OR [95% CI]) included sleep disorders: sleep-related movement disorders (26.26 [10.71-64.40]), hypersomnia (16.56 [12.54-21.87]), and circadian rhythm sleep disorders (15.43 [6.73-35.38]); psychiatric or mood disorders: posttraumatic stress disorder (3.08 [2.10-4.52]), attention deficit hyperactivity disorder (2.90 [2.28-3.68]), and depression (2.66 [2.27-3.11]); and pain disorders: trigeminal neuralgia (6.63 [2.80-15.70]), fibromyalgia (5.30 [3.58-7.85]), and chronic pain syndrome (3.37 [2.46-4.61]). Postural orthostatic tachycardia syndrome occurred statistically significantly more frequently (P< 0.0001) in the narcolepsy vs control cohort (7.24 [3.59-14.61]). Conclusion Consistent with prior EHR research, sleep, psychiatric, mood, and pain disorders were among the most frequently reported comorbidities of patients with narcolepsy. The results of this analysis of real-world demographic and clinical information of patients with narcolepsy may further inform clinicians of the most relevant concomitant disease states to consider when evaluating potential therapies. Support (if any) Avadel Pharmaceuticals