Citations

Abstract Introduction AXS-12 (reboxetine) is a highly selective norepinephrine reuptake inhibitor and cortical dopamine modulator under development for narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 significantly reduced weekly cataplexy attacks from baseline to Week 5 versus placebo in patients with narcolepsy. Here we report the Phase 3 ENCORE trial, assessing long-term efficacy and safety of AXS-12 in participants who completed SYMPHONY. 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, remaining participants were randomized 1:1 to continue twice-daily AXS-12 or switch to once-daily AXS-12 plus placebo for 1 week, then placebo twice-daily for 2 weeks. The primary endpoint was change in frequency of cataplexy attacks from randomization to DBRW Week 3. OLE efficacy outcomes included change in weekly frequency of cataplexy attacks, cataplexy response (≥50% reduction), and change in cataplexy-free days. Additional analyses are ongoing. Results ENCORE enrolled 68 participants; 42 completed the OLE and entered the DBRW (AXS-12, n=22; placebo, n=20). In SYMPHONY, baseline mean weekly frequency of cataplexy attacks was 31.5. At DBRW randomization, mean weekly frequency of cataplexy attacks was 4.2 (AXS-12) and 6.9 (placebo). Participants randomized to placebo experienced a mean increase of 10.29 weekly cataplexy attacks versus 1.32 for AXS-12, at end of DBRW (p=0.017). In the OLE, weekly frequency of cataplexy attacks decreased by 22.3 (71%) and 24.1 (77%) at 1 and 6 months, respectively. Cataplexy response was achieved by 72% and 82% at 1 and 6 months, respectively. Cataplexy-free days increased from 14.3% to 61% and 70% at 1 and 6 months, respectively. Common adverse events (AEs; ≥5%) during the OLE were nausea and tachycardia (both 5.9%); no new safety signals were detected. Discontinuations due to AEs occurred in 17.6% of participants in the OLE. Conclusion AXS-12 significantly reduced the frequency of cataplexy attacks during the DBRW. AXS-12 was well-tolerated and demonstrated maintenance of efficacy with long-term open-label use. These results align with SYMPHONY, supporting the positive therapeutic impact of AXS-12 for narcolepsy. Support (if any) Axsome Therapeutics, Inc.

Abstract Introduction The SleepImage is an HSAT device (sHSAT) that uses photoplethysmography and oxygen saturation data to generate an apnea hypopnea index (AHI). This sHSAT has been FDA cleared as a software-as-a-medical-device for use in children 2 years and older for diagnosing obstructive sleep apnea (OSA). To our knowledge this sHSAT has not been tested on children concurrent with the gold standard polysomnography (PSG). Methods This study evaluated 50 children 2-6 years of age with tonsillar hypertrophy and OSA symptoms with sHSAT during simultaneous in-lab PSG. Aims were to determine the technical feasibility of using sHSAT in this population and to compare sHSAT results to PSG. The primary endpoint was AHI by sHSAT compared to AHI by PSG and presence of OSA. Sensitivity analysis was performed for presence or absence of OSA diagnosis based on sHSAT versus PSG. Bland-Altman and concordance correlation calculations were used for comparisons. Results 50 patients, median age 4 (IQR 3-5), met criteria; 39 completed PSG and HSAT. The sensitivity with sHSAT for OSA prevalence based on proprietary categorization was 94.1%, specificity 22.7%, LR+ 1.22, and LR- 0.26, with PSG OSA prevalence of 43.6%. There was a 9% sHSAT total failure rate, and the device frequently fell off, resulting in TST difference of -226.9 ±182.8 min between sHSAT and PSG. PSG was trimmed to include only segments where HSAT was confirmed to be on before comparisons. Concordance correlation coefficient between sAHI and AHI-PSG was 0.52. The Bland-Altman analysis comparing sAHI and PSG AHI revealed a mean difference of 0.73 (95% confidence limits: -3.47 to 4.93). Considering only obstructive events, the Bland-Altman the sAHI vs the AHI-PSG shows a mean difference of 1.52 (95%CI -5.40 to 8.44). Conclusion This pilot study demonstrated challenges with feasibility in using the sHSAT in this age group given likelihood of technical difficulties leading to absent or truncated data. When compared with PSG, sHSAT demonstrated a high false-positive rate for diagnosis of OSA, particularly concerning if guiding surgical management. This topic is of considerable importance to the practice of pediatric sleep medicine; further investigation of technological advances in this area is imperative. Support (if any)

Abstract Introduction Despite AASM scoring guidelines encouraging classifying hypopneas as central or obstructive, classification is underutilized in practice. However, without that effort patients may receive an incorrect primary diagnosis and suboptimal treatment. The remedē® System Pivotal Trial studied transvenous phrenic nerve stimulation (TPNS) to treat adult patients with moderate to severe central sleep apnea (CSA). Entry criteria required apnea hypopnea index (AHI)≥20 with the central apnea index (CAI) greater than the obstructive apnea index and obstructive apneas< 20% of AHI but did not consider hypopnea differentiation. This analysis re-examined sleep studies from the trial to assess how hypopnea classification might lead to better patient selection for this therapy. Methods Hypopneas were classified as central versus obstructive by a sleep core laboratory following a modified version of AASM recommended criteria. The AHI composition was assessed at baseline and after 6 months of therapy. Results At baseline, 91% (138/151) of patients had ≥50% of events classified as central when accounting for hypopnea classification. If all hypopneas were assumed to be obstructive, only 63% (95/151) would have had ≥50% central events. Additionally, 95% (144/151) of patients had central AHI ≥15/hour, compared to 73% (110/151) with a central apnea index (CAI) ≥15/hour. The likelihood of achieving a ≥50% AHI reduction increased with the percentage of baseline events that were central: responder rates were 37.5% for patients with < 50% central events at baseline, incrementally increasing to 76.5% for those with ≥90% central events. At 6 months, the residual AHI predominantly consisted of obstructive events. Central events decreased by 89% with treatment, from a baseline median of 32/hour [1st and 3rd quartiles: 22, 50]. Obstructive apneas rose by 2/hour and obstructive hypopneas increased by 2/hour from a baseline median of 5 obstructive events/hour [2, 12]. Conclusion Distinguishing central from obstructive hypopneas is required to accurately determine if a patient has central sleep apnea/Cheyne Stokes respiration, and is crucial for epidemiologic studies, appropriate therapy selection, and managing patient expectations about treatment outcomes. This analysis suggests that accurate hypopnea classification may prevent disqualification of patients who could benefit from TPNS therapy, which effectively treats central sleep apnea syndrome. Support (if any) ZOLL Respicardia, Inc.

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

Abstract Introduction Narcolepsy is a chronic neurologic condition associated with severe symptom burden, impaired functioning and reduced quality of life. Patients commonly report comorbid mood disorders. AXS-12 (reboxetine) is a selective norepinephrine reuptake inhibitor and cortical dopamine modulator under investigation for the treatment of narcolepsy. In the Phase 3 SYMPHONY trial, AXS-12 met the primary endpoint, a statistically significant reduction in weekly cataplexy attacks from baseline to Week 5 versus placebo. Here, we report secondary endpoints assessing symptom severity, daily functioning, and mood. Methods SYMPHONY was a randomized, double-blind, placebo-controlled trial in patients with narcolepsy type 1 (NT1). Participants (15-75 years) were randomized 1:1 to AXS-12 or placebo for 5 weeks. Stable, concurrent modafinil/armodafinil use was allowed. Secondary endpoints included: the Clinical Global Impression of Severity (CGI-S) for narcolepsy, the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), and the EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire anxiety/depression domain. Results Ninety participants were enrolled. At baseline, mean (SD) CGI-S for narcolepsy score was 5.2 (1.0) in the AXS-12 arm and 4.9 (1.0) in the placebo arm. AXS-12 led to a significant reduction versus placebo in CGI-S for narcolepsy at Week 5 (LS mean difference [95% CI]=0.72 [0.29, 1.16]; p=0.001). At baseline, mean FOSQ-10 total score was 11.1 (3.1) in the AXS-12 arm and 11.6 (3.2) in the placebo arm. AXS-12 led to a statistically significant improvement from baseline to Week 5 in FOSQ-10 total scores compared to placebo (1.66 [0.51, 2.82], p=0.005). At baseline, 47.8% of participants in the AXS-12 arm and 45.5% in the placebo arm reported anxiety/depression (EQ-5D-5L). A numerically greater proportion of participants achieved improvements on this domain with AXS-12 (55.0%) versus placebo (31.6%) at Week 5 (p=0.146). Conclusion AXS-12 demonstrated significant reductions in clinical impressions of narcolepsy symptom severity. Functional impairment due to EDS was also significantly reduced, in-line with previously reported improvement in clinician-rated assessments. Anxiety and depression-related symptoms showed trends favoring AXS-12. Combined with prior findings on cataplexy and cognitive improvements, these results highlight the potential of AXS-12 as a therapeutic option addressing multiple symptoms of narcolepsy which affect QoL and functioning. Support (if any) Axsome Therapeutics, Inc.

Abstract Introduction Poor sleep quality is bidirectionally associated with cardiovascular and neurocognitive disorders. Preclinical data implicate nitric oxide (NO) in the onset, and maintenance, of sleep. Acute inorganic nitrate supplementation increases NO bioavailability via serial reduction for >12hrs. We tested if objective (Aim 1) or subjective (Aim 2) sleep quality was better following acute, pre-sleep nitrate supplementation relative to a placebo. Methods Seven non-shift working adults (4F/3M, 40±8yrs, 25.8±1.6kg/m2) with no history of sleep, cardiovascular, or neurocognitive disorders completed three overnight polysomnography (PSG) visits with time in bed standardized to 2200-0600hrs. Visit 1 was for acclimation and screening for sleep-disordered breathing. On Visits 2 and 3, participants consumed beetroot juice containing (6.45mmol) or devoid of (0mmol) inorganic nitrate at 2200 using a randomized, cross-over study design. PSG-derived outcomes included slow-wave (SWS) and rapid eye-movement (REM) sleep, sleep efficiency, and wake after sleep onset (WASO). Subjective sleep quality assessments were administered in-laboratory including a 0-10 scale, the Stanford Sleepiness Scale (SSS), and performance with mental arithmetic shortly after awakening. Results No participant demonstrated evidence for sleep-disordered breathing (apnea-hypopnea index = 1.7±0.9events/hr). Total sleep time (TST, 434±17 vs. 412±19min), sleep efficiency (89±3 vs. 85±4%), as well as SWS duration (75±10 vs. 66±9min) and percent of TST (17±2 vs. 16±2%) were higher after nitrate relative to the placebo (p< 0.05 for all). WASO (47±16 vs. 62±19min, p< 0.05) was lower after nitrate versus placebo and no differences were seen in REM sleep duration (131±23 vs. 117±12min, p=0.45) nor percent of TST (30±5 vs. 29±3%, p=0.80). Neither the 0-10 scale (6.7±0.5 vs. 6.8±0.6units, p=0.84), SSS (2.6±0.4 vs. 2.5±0.3units, p=0.68), or arithmetic performance (82±3 vs. 81±5% correct, p=0.85) differed post-nitrate compared to post-placebo. Conclusion These data suggest that acutely increasing nocturnal NO levels via pre-sleep inorganic nitrate supplementation improves objective indices of sleep quality in healthy adults. However, greater amounts of nitrate or prolonged supplementation (weeks) may be needed to improve perceived sleep quality. Support (if any) The National Institutes of Health (K12 AR084222 to JMB, R01s HL160619 and HL65176 to VKS), Sleep Research Society Foundation (CDA 038-JP-23 to JMB), and the American Heart Association (24POST1241616 to IMG).

Abstract Introduction Rapid eye movement (REM) sleep behavior disorder (RBD) is the single strongest predictor of Parkinson’s disease (PD) risk. Given neurotrauma and psychiatric morbidity, the aging post-9/11 Veteran cohort is a target population for understanding probable RBD frequency and neuroprotection opportunities. We previously reported over 50% of post-9/11 Veterans screened positive for probable RBD. We aimed to examine frequencies of prodromal PD markers and polysomnography (PSG)-confirmed RBD in post-9/11 Veterans. Methods Veterans with probable RBD based on the single-question RBD screen (n=12) were recruited from the Translational Research Center for Traumatic Brain Injury (TBI) and Stress Disorders (TRACTS) Houston cohort. Participants were assessed for subthreshold parkinsonism (Unified Parkinson’s Disease Rating Scale-III Motor score >3, excluding action tremor), olfactory loss (12-item Sniffin’ Sticks), TBI exposures, autonomic symptoms, orthostasis, excessive daytime sleepiness, post-traumatic stress disorder (PTSD), and psychiatric comorbidities. PSG studies were conducted per American Academy of Sleep Medicine guidelines. A board-certified sleep physician confirmed the presence of REM sleep without atonia. We compared the frequency of prodromal marker positivity between participants with and without subthreshold parkinsonism. Results All 12 participants were male (6 [50%] Black, 3 [25%] Hispanic) with a mean (SD) age of 44.4 ± 6.7 years. PSG data (n=10) revealed REM sleep without atonia in 5 (50%), moderate obstructive sleep apnea (OSA) in 2 (20%), and severe OSA in 2 (20%) participants. Five (41.6%) participants had mild motor dysfunction suggestive of subthreshold parkinsonism on the UPDRS-III (M±SD score of 8.6 ± 5.9), while 7 participants had normal or low UPDRS-III ratings (2.3 ± 1.3; p=0.02). Veterans with subthreshold parkinsonism had lower Sniffin’ Sticks scores than those without (M±SD 9.4 ± 2.07 vs. 11.29 ± 0.76; 95% CI: 0.01–3.76, p=0.049). Conclusion This pilot study suggests that motor and olfactory prodromal PD markers are frequent in post-9/11 Veterans with probable RBD. Larger prospective cohort studies are required to further quantify REM sleep without atonia and assess synuclein-specific biomarkers in this population. Support (if any) Center for Alzheimer’s and Neurodegenerative Diseases at Baylor College of Medicine [MJ]; VA CSR&D (#IK2CX002363-01A1) [MJ]; VA RR&D (B9268-X) [RJ]; NIH/NIA/NINDS (U19-AG071754 & R34-AG056639) [ES]; and AASM [ES].

Abstract Introduction Obstructive sleep apnea (OSA) has been linked to metabolic syndrome, heart failure, atrial fibrillation, and hypertension. Although ethnic differences related to OSA have been reported, no studies have evaluated the impact of OSA among Greek-Americans. Methods This prospective cross-sectional study, in partnership with the Greek-American community, employed a community-based participatory research framework. Individuals who were of Greek descent and ≥18 years of age were recruited. Anthropometric measurements, Mallampati score, BMI, and adiposity (DEXA scan) were determined. All subjects were administered the Epworth Sleepiness Scale (ESS) and underwent home sleep apnea test (WatchPAT ONE), using a desaturation threshold of 4% as diagnostic. Descriptive statistics were computed to describe the study population and data were analyzed using the student t-test and chi-squared test. Results A 76 Greeks, 34 males (44.8%) and 42 females (55.2%), were enrolled in this study with a mean ± SD age and BMI of 42.6±17.5 years (p< 0.01) and 27±6 kg/m2, respectively. A total of 22 (29%; 14 males and 8 females) individuals were diagnosed with OSA, of whom 13 (59.1%) had mild, 5 (22.7%) had moderate and 4 (18.2%) had severe OSA. Subjects with OSA were older (58.8±11.9 vs 36.0±15.1 years, p< 0.01), had higher BMI (32±7 vs 25±4 kg/m2, p< 0.01), larger neck circumference (40±4 vs 35±4 cm, p< 0.01) and higher waist-to-hip ratio (0.94±0.08 vs 0.84±0.07, p< 0.01). Body fat percentage was significantly higher among those with versus without OSA (38.8±9.6 vs 34.0±9.2%; p=0.04) while Mallampati and ESS scores were similar. Conclusion This is the first study to assess sleep metrics of Greek-Americans suffering from OSA. Characteristics of those with OSA are similar to other populations. However, the commonly used ESS screening appears to have limited application in this cohort of subjects. Greek-Americans with elevated body fat percentage when associated with concurrent OSA, may be at higher risk of developing cardiometabolic adverse events. Additional studies are required to further elucidate the effect of sleep physiology, cardiometabolic dysfunction and health outcomes. Support (if any) This work was supported by a grant from Sleep Number Corporation to Mayo Clinic, by WatchPATs provided by Zoll Itamar, and by the National Institutes of Health HL160619.

Abstract Introduction Cardiovascular disease (CVD) remains the leading cause of death in the United States. We previously showed a high prevalence of obstructive sleep apnea (OSA) among former National Football League (NFL) players. Further, we hypothesized that post-career OSA impacts CVD risk among retired professional athletes, even though these former NFL players are often near peak physical fitness for a significant portion of their lifespan. The Living Heart Foundation Heart-Obesity-Prevention-Education Group aimed to provide an in-depth health assessment for CVD risk factors among former NFL players to examine the role of OSA on blood pressure (BP) and echocardiographic measurements. Methods Forty-three former NFL players completed an at-home sleep study and outpatient health assessment to determine CVD risk including office BP and transthoracic echocardiogram (TTE) measurements. Seated BP readings were made in triplicate, TTE measurements, including ejection fraction, left atrial size, left ventricular size and thickness, and ascending aortic diameter, were obtained in 17 former NFL players without OSA (age: 46±10 years, BMI: 32±5 kg/m2, apnea-hypopnea index: 3±1 events/hour) and 26 with OSA (age: 51±9 years, BMI: 33±5 kg/m2, apnea-hypopnea index: 17±12 events/hour). Independent sample t-tests were utilized to determine differences in blood pressure and TTE measurements between OSA and non-OSA groups (α=0.05). Results Systolic BP was similar in non-OSA vs. OSA groups (131±12 vs. 135±16 mmHg, p=0.443), while diastolic BP was higher in former NFL players with OSA (78±8 vs. 86±9 mmHg, p=0.007). Ejection fraction, left atrial size, left ventricular size, and left ventricular thickness were similar between groups (p>0.05 for all). However, ascending aortic diameter was modestly larger in former NFL players with OSA (3.3±0.19 vs. 3.5±0.40 cm, p=0.048). Conclusion These findings suggest OSA may be a primary driver of increased BP and increased aortic diameter in former NFL players, and impact cardiac structural health, suggesting augmented CVD risk in former NFL players. Future work is warranted to investigate impact of race and player position on OSA-mediated CVD risk in retired NFL players. Support (if any) NFL Players Association, NIH T32-DK007013, and the American Heart Association (24POST1241616)

Abstract Introduction 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) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on daytime and nighttime symptoms, including excessive daytime sleepiness (EDS) and polysomnography in participants with idiopathic hypersomnia (IH) or narcolepsy. Data presented are from the IH cohort. Methods DUET included screening (with 2-week washout for oxybate users), 8-day baseline (BL), 2- to 8-week LXB titration, 2-week stable-dose, 8-day end-of-treatment (EOT), and 2-week safety follow-up periods. The primary endpoint was change in Epworth Sleepiness Scale (ESS) score from BL to EOT. Secondary endpoints for the IH cohort included change in Idiopathic Hypersomnia Severity Scale (IHSS) total score, Patient Global Impression of Change (PGIc)−overall IH disease, PGIc−sleep inertia, and Patient Global Impression of Severity (PGIs)−sleep inertia. Exploratory endpoints included IHSS component scores (daytime functioning, sleep inertia). Primary and key secondary (IHSS total score) endpoints were controlled for multiplicity with sequential testing; all other P-values are considered nominal. Results Forty-six people with IH enrolled and were dosed with LXB; 40 were completers. Enrolled participants were mostly female (80.4%) and White (84.8%), with a mean (SD) age of 38.1 (11.8) years. For completers, BL mean (SD) ESS score and IHSS total score were 16.5 (2.7) and 32.9 (7.1), respectively; least-squares mean (LSM) (SE) changes from BL to EOT were −8.4 (0.7), P<.0001 and −15.5 (1.5), P<.0001. BL mean (SD) IHSS component scores for daytime functioning and sleep inertia were 17.7 (4.2) and 10.7 (3.1), respectively; LSM (SE) changes from BL to EOT were −8.8 (1.0), P<.0001 and −4.8 (0.4), P<.0001. At EOT, most participants reported improvement (very much, much, minimally) on PGIc−overall IH disease (94.6%) and PGIc−sleep inertia (81.1%). At BL, 25.0% of participants reported sleep inertia severity as very mild/mild/not present on PGIs–sleep inertia vs 59.0% at EOT. Treatment-emergent adverse events were consistent with the known safety profile of LXB. Conclusion People with IH taking open-label LXB showed improvements in EDS and sleep inertia (decreased ESS and IHSS component scores) and reported reduced multi-symptom burden (decreased IHSS total scores and improved PGIc/PGIs ratings). Support (if any) Jazz Pharmaceuticals