Krahn, Lois E.

Abstract Introduction Extended-release once-nightly sodium oxybate (ON-SXB; FT218) is in development for adults with narcolepsy. In REST-ON, significant improvements on the Maintenance of Wakefulness test, Clinical Global Impression of Improvement rating, and number of weekly cataplexy episodes occurred with all analyzed ON-SXB doses vs placebo (week 3, 6-g dose; week 8, 7.5-g dose; week 13, 9-g dose; all P<0.001). ON-SXB was superior to placebo on Epworth Sleepiness Scale (ESS) score and sleep quality and refreshing nature of sleep using visual analog scales (VAS; all P<0.001). ON-SXB 4.5 g significantly reduced cataplexy episodes vs placebo at week 1 (P<0.05). Post hoc analyses investigated ON-SXB efficacy on ESS score, VAS sleep quality, and VAS refreshing nature of sleep at weeks 1 and 2. Methods Participants in the double-blind, phase 3 REST-ON (NCT02720744) trial were ≥16 years old, had narcolepsy type 1 or 2, and were randomized 1:1 to ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or placebo. Participants recorded ESS scores and VAS for sleep quality and refreshing nature of sleep (1-100; 1=poor quality/unrefreshing sleep; 100=good quality/refreshing sleep) using electronic diaries. P-values were calculated using a mixed-effects model for repeated measures in the modified intent-to-treat (mITT) population (ie, participants receiving ≥1 dose of study drug having ≥1 efficacy assessment at week 3). Results In the mITT population (n=190; ON-SXB, n=97; placebo, n=93), baseline ESS scores were 16.6 and 17.5 with ON-SXB and placebo, respectively. At week 2, ESS score was significantly improved with ON-SXB vs placebo (P<0.02) with numerical improvement seen at week 1. At baseline, sleep quality was 53.8 and 55.9 on VAS in the ON-SXB and placebo groups, respectively, and baseline refreshing nature of sleep was 46.5 and 49.9. At weeks 1 and 2, sleep quality (P<0.01; P<0.001) and refreshing nature of sleep (P<0.05; P=0.001) were significantly improved for ON-SXB vs placebo. Conclusion Improvement in daytime sleepiness, sleep quality, and refreshing nature of sleep occurred with ON-SXB beginning the first week of treatment. Some patients may experience early narcolepsy symptom relief with ON-SXB. Support (If Any) Avadel Pharmaceuticals

Abstract Introduction Immediate-release sodium oxybate (SXB) and mixed-salt oxybates require patients with narcolepsy to take a second nightly dose 2.5–4 h after the first. Extended-release, once-nightly SXB (ON-SXB; FT218) is an investigational treatment for adults with narcolepsy. Surveys evaluated patient and healthcare provider (HCP) perspectives on narcolepsy disease burden and satisfaction with current narcolepsy treatment options. Methods Individuals with narcolepsy and HCPs participated in 30-minute, web-based surveys. Participants were 1) adults with self-reported, physician-diagnosed narcolepsy for ≥1 year, and prior/current/no use immediate-release oxybates; and 2) board-certified/board-eligible HCPs (pulmonology, sleep medicine, neurology, psychiatry specialties); nurse practitioners; or physician assistants. Participants responded using 9-point scales; higher scores indicated greater severity/agreement/satisfaction/importance/preference. Results Mean patient participant (n=120) age was 40 years; most were white (81%), female (79%), and current/past users of twice-nightly SXB (n=86) or mixed-salt oxybates (n=56). Twenty-six were oxybate naive. Most HCPs (n=100; 68% male) had sleep medicine (37%) or neurology (30%) specialties; 91% and 83% had experience with twice-nightly SXB and mixed-salt oxybates, respectively. Patients and HCPs agreed that patients preferred narcolepsy treatments dosed fewer times (rated 6.7 and 7.7, respectively). Common symptoms patients experienced daily/almost daily at narcolepsy diagnosis were tiredness/fatigue (64%) and excessive daytime sleepiness (EDS; 68%). HCPs and patients expressed moderate-to-high satisfaction with mixed-salt oxybates (both 7.1) and twice-nightly SXB (6.8 and 6.6, respectively). Compared to HCPs, patients were less satisfied with modafinil (6.9 vs 4.5), armodafinil (6.9 vs 4.8), solriamfetol (6.8 vs 5.4), and pitolisant (6.6 vs 5.2). Twice-nightly SXB and mixed-salt oxybates received high ratings from patients and HCPs for reduction of cataplexy (patients: 7.3 and 7.4; HCPs, 6.7 and 6.8) and EDS (patients: both 7.0; HCPs, both 6.9). Lower satisfaction was reported for twice-nightly SXB and mixed-salt oxybates with dosing frequency (patients, 5.4 and 6.0; HCPs, 5.9 and 6.3) and medication taste (patients, 5.3 and 5.7; HCPs, 5.9 and 6.2). Conclusion While both individuals with narcolepsy and HCPs are relatively satisfied with current narcolepsy treatments, both groups are less satisfied with the dosing frequency of currently approved oxybate formulations. ON-SXB will be an additional treatment option that can address this unmet need. Support (If Any) Avadel Pharmaceuticals

Abstract Introduction Currently available immediate-release sodium oxybate (SXB) and mixed-salt oxybates are dosed twice nightly (second 2.5–4 hours after first). Extended-release, once-nightly SXB (ON-SXB; FT218) is in development. To characterize drivers of oxybate treatment attribute preferences, discrete choice experiments (DCEs) were conducted for both patients and healthcare providers (HCPs). Methods Thirty-minute web-based surveys were fielded to 1) adults with self-reported physician-diagnosed narcolepsy with/without prior/current use of oxybate, and 2) board-certified/board-eligible HCPs treating ≥5 narcolepsy patients in the last month. Choice sets of 2 hypothetical treatment profiles were generated combining attributes of twice-nightly SXB, mixed-salts oxybate, and ON-SXB. While viewing 12 choice sets, each participant indicated (1) their preferred product overall, (2) the product that would improve quality of life (QoL), and (3) the product that would result in less patient stress/anxiety. Results were analyzed using a mixed logit model. Results For patients (n=120) and HCPs (n=100), the most important attribute driving overall product choice was dosing frequency (relative attribute importance, 26.0 and 46.1, respectively), with once-nightly preferred over twice-nightly dosing (relative preference weight, ±25.6 and ±43.6); QoL (relative attribute importance, 28.7 and 41.7), with once-nightly preferred over twice-nightly dosing (relative preference weight, ±25.7 and ±38.5); and reducing patient anxiety/stress (relative attribute importance, 26.7 and 44.0), with once-nightly preferred over twice-nightly dosing (relative preference weight, ±23.9 and ±41.6). Other drivers of overall product choice were as follows: patients, clinical efficacy and sodium content (relative attribute importance, 23.5 and 20.8); HCPs, adverse reactions and sodium content (relative attribute importance, 19.7 and 18.6). Drivers of QoL preference were as follows: patients, clinical efficacy and sodium content (relative attribute importance, 28.3 and 20.9); HCPs, adverse reactions and clinical efficacy (relative attribute importance, 21.5 and 18.6). Drivers of reducing patient anxiety/stress were as follows: patients, clinical efficacy and sodium content (relative attribute importance, 17.4 and 17.3); HCPs, adverse reactions and sodium content (relative attribute importance, 18.2 and 14.2). Conclusion Dosing frequency was identified as the most important attribute driving preference for overall product choice, QoL, and reducing patient anxiety/stress for both patients and HCPs with once-nightly preferred over twice-nightly dosing. Support (If Any) Avadel Pharmaceuticals

Abstract Introduction Orexin deficiency in cerebrospinal fluid (CSF) was first reported in human narcolepsy in 2001, included in diagnostic criteria for narcolepsy in 2014, and made clinically available at the Mayo Clinic in 2019. The purpose of this publication is to report orexin test utilization and results, and other clinically relevant findings from patients evaluated at Mayo Clinic. Methods We retrospectively reviewed CSF orexin samples and clinical records from patients evaluated at Mayo Clinic from 2019 to 2021. Results A total of 98 internal samples (Rochester, n=56; Arizona, n=25, and Florida, n=17) from 95 patients (mean age 32.4 +/- 16.6 years with 20 %, 52 %, and 28 % of patients < 18, 18 – 40, and > 40 years, respectively, at time of CSF collection; 62 % female) have been submitted for CSF orexin measurement (mean CSF orexin 335.17 +/- 158.3 pg/ml; deficient < 110 pg/ml, n=11, 64 % <=40 years with mean age 32.9 +/- 17.0 years; intermediate 110 – 200 pg/ml, n=8, 100 % <= 40 years with mean age 21.1 +/- 12.8 years; normal > 200 pg/ml, n=79, 57 % <=40 years with mean age 33.5 +/- 16.7). No significant correlation was found between orexin levels, and time of collection (i.e., diurnal variation), gender, or age. Repeat testing was performed on three individuals (ages 10, 14, and 19 years) with a change in category of orexin level found in one patient from an intermediate to a normal level. Conclusion Orexin deficiency was found in 12 % of the patients (64 % of the deficient samples were found at ages <= 40 years). This result may reflect the fact that this test is frequently pursued in clinical patients presenting with inconclusive findings and/or comorbidities. Intermediate orexin levels found in 8 % of the samples (100 % <= 40 years). Although most of the patients tested were female (62.2%) and most were 40 years or younger (72%), no significant correlation was found between orexin levels, and time of collection (i.e., diurnal variation), gender, or age. Support (If Any) none

Abstract Introduction The ICSD-3 describes NREM-related parasomnias as abnormal sleep related complex movements where motor behavior occurs in the setting of absent or very minimal higher cognitive function. A population-based twin study reported that 3.9% of men and 3.1 % of women sleepwalk (SW) with 30% reported experiencing injury (Hublin 1997). Sleep related eating disorder (SRED) may be a variant of SW with a reported prevalence of 0.5-5 % (Michalska 2016). This study examined SW and SRED in a population-based sample permitting review of associated features, risk factors and outcomes. Methods The records-linkage system of the Rochester Epidemiology Project that includes all adults residing in Olmsted County MN was searched for documentation of patients seeking care for at least two episodes of sleepwalking and/or sleep eating. Records from 2007-2016 were included. Results 56 cases were identified with 50 (89 %) having SW and 16 (29%) SRED. The gender breakdown was 50% male and 50% female with the mean age at diagnosis of 40 (SD 13). Childhood parasomnia events were reported by 23/36 (62%) and a family history in 21/35 (64%). Data were unavailable for the others. The number of parasomnia incidents was ≥ 10 for 21 (37%). A variety of experiences were documented, including leaving the bedroom (39%), injury (25%), and exiting through a window/balcony (5%). Associated factors were sleep deprivation (52%), untreated obstructive sleep apnea (34%), antidepressant use (41%), zolpidem use (18%), circadian disruption (14%) and alcohol use (9%). Polysomnography was conducted for 41 (74%). Documented interventions were medication discontinuation (18%) and starting a benzodiazepine (16%). In 21%, no treatment was given. Conclusion This population-based study of adults with clinician diagnosed recurrent SW and SRED revealed equal rates in men and women. The majority of patients with SRED also had SW. 25% of cases were associated with injuries. Support Rochester Epidemiology Project supported by NIH R01 AG034676 and AG052425 and the Mayo Foundation.

Abstract Introduction Recent literature suggests that histamine may play an important role in narcolepsy. This post hoc analysis evaluates the efficacy of pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, in patients with high burden of the main narcolepsy symptoms. Methods Data were pooled from 2 randomized, placebo-controlled, 7- and 8-week studies of pitolisant (individually titrated; maximum dose, 35.6 mg/day) in adults with narcolepsy. Analyses included 3 independent patient subgroups: baseline score of >16 on the Epworth Sleepiness Scale (ESS), sleep latency of ≤8 minutes on the Maintenance of Wakefulness Test (MWT), and ≥15 cataplexy attacks per week. Results The analysis populations included 108 patients for the ESS (pitolisant, n=54; placebo, n=54), 105 for the MWT (pitolisant, n=59; placebo, n=46), and 31 for cataplexy (pitolisant, n=20; placebo, n=11). Mean change in ESS from baseline was significantly greater for pitolisant (-6.1) compared with placebo (-2.6; P=0.0002). A significantly greater percentage of pitolisant-treated patients were classified as treatment responders: for ESS score reduction ≥3, 68.5% in the pitolisant group versus 35.2% in the placebo group (P=0.0006); for final ESS score ≤10, 35.2% versus 9.3%, respectively (P=0.0026). Mean increase in sleep latency on the MWT was significantly greater for pitolisant (7.0 minutes) compared with placebo (3.4 minutes; P=0.0089). Decrease in mean weekly rate of cataplexy was significantly greater for pitolisant (baseline, 21.8; final, 3.9) compared with placebo (baseline, 20.9; final, 18.2); the rate ratio was 0.35 (95% CI, 0.26‒0.47; P<0.001). The adverse event profile in the analysis populations was consistent with the known safety profile for pitolisant; headache was the most common adverse event in pitolisant-treated patients (10.0%-20.4%). Conclusion In patients with severe symptom burden, pitolisant produced significantly greater improvements in excessive daytime sleepiness and cataplexy compared with placebo, highlighting the important role of histamine in narcolepsy. Support Bioprojet Pharma and Harmony Biosciences, LLC.