Sodium Oxybate Research Articles

0971 Case Report: Sleep-Related Painful Erections Treated with Sodium Oxybate

Abstract Introduction Sleep-related painful erection (SRPE) is a rare parasomnia characterized by painful penile erections during rapid eye movement sleep. Normal, painless erections continue to occur while awake. Approximately thirty cases have been reported in the literature. Multiple theories about potential pathophysiology have been proposed including neurologic dysfunction of the ischiocavernosus and bulbocavernosus, correlation with obstructive sleep apnea, and/or autonomic dysfunction. There is no known single effective treatment to date resulting in durable response despite multiple attempts at therapy. Report of case(s) A 39-year-old male presented with SRPE. This started in 2018 and occurred in the second half of the night every twenty minutes, contributing to discomfort and poor sleep quality. While awake, his erections were painless. He was prescribed baclofen at doses up to 30mg daily decreasing episode frequency to 1-6 times per night, but disabling somnolence precluded continuation. Pelvic physiotherapy was unhelpful while imipramine and clonazepam provided partial relief. Tadalafil was ineffective and cinitapride was not available in the United States. Oxycodone used for pain after a motor vehicle accident did effectively treat him for five hours per night, so morphine was trialed. This was effective for two weeks, but symptoms returned. In April 2022, he was begun on sodium oxybate. With an initial dose of 2.25 g twice nightly, symptoms were treated for four hours a night. After increasing to 2.75 g twice nightly, the SRPE was effectively treated. As of September 2022, he is taking sodium oxybate 3 g at bedtime, 3 g 3.5 hours later and the final 3 g at the 7th hour, promoting 9.5 hours of sleep without SRPE. Conclusion This 39-year-old male who presented with SRPE was trialed on multiple therapies without success, and ultimately successfully treated with an appropriate and titrated dose of sodium oxybate. This may represent a new treatment option, which we hypothesize may act by modulating GABA to result in relaxation of the bulbospongiosus and ischiocavernosus muscles. Further studies should include the study of both the efficacy of this drug for SRPE as well as potential mechanisms of action. Support (if any)

0985 Oxybate induced mania

Abstract Introduction Hypersomnia sleep disorders are characterized by overwhelming daytime sleepiness. Treatment options include sodium oxybate the sodium salt of γ-hydroxybutyric acid (GHB). Oxybate, an endogenous metabolite of GABA, acts through GABAB noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. < 1% may experience suicidal ideations or psychosis. Report of case(s) A 17-year-old female with obesity, spina bifida occulta follows with sleep for idiopathic hypersomnia with long sleep (TST 12.6 hours on polysomnography) and a delayed circadian rhythm. Her typical sleep zone is 11:00PM to 10:00AM, but she can easily sleep until 2:00PM. She started sodium oxybate to minimize her sleep burden and improve daytime wakefulness. She initially developed insomnia with concern for mania and migraines with photophobia and phonophobia. After 26 days, oxybate was discontinued. Her migraines persisted daily. Her sleep schedule and mood returned to baseline within 17 days thereafter. A 48-year-old female with anxiety/depression, PTSD has follows with sleep since age 42 for unspecified hypersomnia, either narcolepsy type 1 with long sleep versus idiopathic hypersomnia. Initial polysomnography/MSLT on fluoxetine revealed AHI 1.6, with a mean sleep latency of 6.4 minutes without SOREMPs. Her typical sleep zone was 8:00PM to 9:00AM. She was started on sodium oxybate for her cataplexy and daytime sleepiness. She had remarkable improvement in her symptoms after 4 days. After 35 days on 9 grams nightly she developed anxiety, extracorporeal sensations, and paranoia. The dose was decreased to 7.5 grams nightly. By 7 months of therapy her paranoia progressed to the point where she threatened her landlord and was facing legal consequences. Sodium oxybate was discontinued. At 53-years-old she was trial on mixed-salts oxybate. After three months of therapy, she became hypomanic with severe pressured speech despite a euthymic mood. She reported going without sleep entirely for 3-4 days at a time using this oxybate. Mixed-salts oxybate was discontinued and 36 days later with in addition to quetiapine, her hypomania was nearly resolved and she was able to get 8-9 hours of restful sleep. Conclusion Hypomania appears to be a rare but serious side effect of oxybate in long-sleepers. Discontinuing oxybate may not be sufficient therapy. Support (if any)

0596 Overlap of Psychiatric Disorders with Central Hypersomnia

Abstract Introduction In sleep clinics, hypersomnia is a frequently encountered condition. While narcolepsy and idiopathic hypersomnia are discrete diagnoses that typically do not have co-existing psychiatric co-morbidities, sleep practitioners often have to address mental illness and/or psychotropic medication needs in these patients with hypersomnia. The reasons for co-occurrence of idiopathic hypersomnia and narcolepsy with psychiatric disorders is not well understood. This study aimed to assess the degree of overlap between psychiatric diagnoses with central hypersomnias and the temporal relationship between the development of hypersomnia and psychiatric conditions. Methods Using the University of Utah EPIC database, patients with diagnoses of idiopathic hypersomnia or narcolepsy encountered over the last decade were identified. Out of the 307 available medical records, only those that met strict criteria for diagnosis of narcolepsy and idiopathic hypersomnia were included. Medical records were reviewed for the presence of psychiatric disorders and psychotropic medication use, and to assess the prevalence of mental illness with central hypersomnia. Results Out of 119 patients that met ICSD-2 criteria for central hypersomnia, 37 were diagnosed with narcolepsy type 1 (T1N), 59 with narcolepsy type 2 (T2N) and 23 with idiopathic hypersomnia (IH). There were 69/119 (58%) patients with central hypersomnia that had psychiatric comorbidities with 23/37 (62%) of T1N, 32/59 (54%) of T2N and 14/23 (60%) of IH experiencing psychiatric problems. Approximately 45% were prescribed antidepressants or a mood stabilizer either before, during or after diagnosis of a central hypersomnia. 46% of patients on stimulants alone vs. 23% of patients on sodium oxybate had a concurrent psychiatric diagnoses or psychotropic medication use. Conclusion Given the degree of overlap between psychiatric disorders and central hypersomnias, further research is necessary to understand whether this overlap is a result of common neurological substrates driving these disorders or whether the hypersomnia is from comorbid psychiatric disorder or psychotropic medication use. The highest prevalence of psychiatric illness was seen with T1N. Patients with hypersomnia on sodium oxybate had lower rates of psychiatric co-morbidities. Whether these findings point to more optimal diagnosis and treatment of underlying hypersomnia with reduced need for psychotropic medication needs to be understood. Support (if any) None

0601 An Atypical Cause of Hallucinations in Type 1 Narcolepsy

Abstract Introduction Narcolepsy is a disorder of hypersomnolence affecting between 1:5000-1:10,000 individuals. Type 1 Narcolepsy can be differentiated from Type 2 Narcolepsy by the presence of cataplexy. Visual hallucinations are reported in 50-80% of T1 Narcoleptics and ~25% of T2 Narcoleptics. This is thought to be a REM-related phenomenon occurring at transitions of sleep and wakefulness. Auditory hallucinations or paranoid delusions are more rare. We report a case of a 17 year old patient who experienced psychotic symptoms after trialing more than one class of stimulants. Methods This was primarily a retrospective case review. A subsequent literature search was performed reviewing similar reports of psychosis secondary to medications used to treat Narcolepsy. Results The patient is a 17 year old female who was 10 years old at the time of her diagnosis of Narcolepsy T1. At onset, the patient had reported cataplexy and visual hallucinations occurring at the time of sleep onset and wakening. After finding minimal help with stimulants, by age 15 she was maintained on sodium oxybate 6 grams per night for her cataplexy and started modafinil 200mg BID for wakefulness. She then reported new auditory hallucinations and hyperreligiosity and was admitted to inpatient psychiatry where both medications were discontinued. She was subsequently started on extended release methylphenidate and within 2 months had a recurrence of auditory hallucinations and hyperreligiosity resulting in two consecutive inpatient hospitalizations for psychosis. Conclusion Psychosis induced by medications for Narcolepsy has been reported in the literature where sodium oxybate and stimulants are the most common offending agents. Symptoms primarily related to modafinil or armodafinil are less frequently described. Most medications used to treat Narcolepsy may directly or indirectly act on dopamine pathways, which in theory have the propensity to lead to psychotic symptoms. Small studies of patients with Narcolepsy have reported psychosis in less than 1-2% of Modafinil users. Larger meta-analyses of patients with both Narcolepsy and Schizophrenia, have not found an increased likelihood for uncontrolled psychotic symptoms while on modafinil. Further case studies are needed to elucidate the relationship between stimulants and risk of psychosis in Narcolepsy patients. Support (if any)

0603 Characterization of Patients Who Had ≥5% Weight Loss With FT218 (Once-Nightly Sodium Oxybate): Post Hoc Analysis From REST-ON

Abstract Introduction Narcolepsy, particularly type 1 (NT1), is often comorbid with obesity. FT218 (LUMRYZ™) is an investigational once-nightly sodium oxybate (ON-SXB) formulation whose efficacy and safety were shown in the phase 3 REST-ON clinical trial (NCT02720744). Methods REST-ON was a 13-week, randomized (1:1), double-blind, placebo-controlled multicenter study in patients ≥16 years old with NT1/NT2. Stable concomitant stimulant use was permitted. A post hoc analysis of participants in the ON-SXB group experiencing ≥5% weight loss (weight-loss group) was conducted. Results In REST-ON (n=212), mean participant age was 31.2 years (range, 16–72), 67.9% were female, 75.5% were white, 76.4% had NT1, mean baseline BMI was 28.1 kg/m2 (range, 16.9–71.9), and 61.3% were taking stimulants. At week 13, 17.8% (19/107) of participants receiving ON-SXB experienced ≥5% weight loss vs 3.8% (4/105) of participants receiving placebo (P< 0.001). Compared to the REST-ON population, the weight-loss group had similar age and proportion of NT1 diagnosis, a smaller proportion was female, and a higher proportion was white and was taking stimulants. At baseline, mean BMI was 25.6 kg/m2 (range, 20.3–34.0) in the weight-loss group, 47.4% (9/19) were overweight (BMI 25.0–29.9 kg/m2) or obese (BMI >30 kg/m2); none were underweight (BMI < 18.5 kg/m2). At week 13, 31.6% (6/19) remained overweight or obese; none were underweight. Excessive daytime sleepiness was significantly improved from baseline to week 13 (ON-SXB 9 g) in the weight-loss group vs the ON-SXB group without weight loss (Maintenance of Wakefulness test, P< 0.05; Epworth Sleepiness Scale score, P< 0.001). Adverse events of nausea and vomiting were more frequent in the weight-loss group vs the ON-SXB group without weight loss; however, rate of discontinuations owing to AEs in the weight-loss group was approximately half that of the ON-SXB group without weight loss. Conclusion These data expand the body of knowledge regarding weight loss during treatment with sodium oxybate. Given the high proportion of comorbid obesity among people with narcolepsy, the additional benefit of potential weight loss with sodium oxybate may further inform treatment selection. Whereas ON-SXB was effective overall, further exploration of possible increased pharmacologic response in certain subgroups should be evaluated. Support (if any) Avadel Pharmaceuticals

0909 Pitolisant Pregnancy Registry: An Observational Study of the Safety of Pitolisant Exposure in Pregnant Women and Their Offspring

Abstract Introduction WAKIX (pitolisant) is a potent and highly selective histamine 3 receptor antagonist/inverse agonist approved for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy. The safety of pitolisant in pregnant women has not been established. Available case reports from clinical trials and postmarketing experience have not demonstrated a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The registry is a prospective, observational cohort study designed to evaluate the association between pitolisant exposure during pregnancy and subsequent maternal, fetal, and infant outcomes. Methods The primary study population consists of 3 cohorts: pregnant women with a diagnosis of narcolepsy who are exposed to pitolisant during pregnancy, pregnant women with narcolepsy who are unexposed to pitolisant but exposed to comparator products during pregnancy, and pregnant women with narcolepsy who are neither exposed to pitolisant nor comparator products. Comparator products include modafinil, armodafinil, sodium oxybate, oxybate mixed salts, solriamfetol, methylphenidate, and amphetamines. Outcomes of interest include major congenital malformation (primary outcome), minor congenital malformation, pre-eclampsia, eclampsia, spontaneous abortion, stillbirth, elective termination, small for gestational age, preterm birth, postnatal growth deficiency, and infant developmental deficiency. Data are collected from enrolled pregnant women and healthcare providers involved in their care or the care of their infants, if applicable. Only data that are routinely documented in patients' medical records during usual care are collected. Participation in the registry is voluntary and participants may withdraw their consent to participate at any time. The registry design follows current FDA guidance for designing and implementing pregnancy exposure registries. Results The registry was initiated in May 2021. Presently, data are insufficient to assess an association between pitolisant exposure and any endpoint of interest. Study completion is planned in 2030. Conclusion Healthcare providers are encouraged to discuss this voluntary pregnancy registry with their eligible patients and assist women who are interested in enrolling. The study is registered on Clinicaltrials.gov (ID# NCT05536011). Support (if any) This study is sponsored by Harmony Biosciences LLC.

1026 Severe Sleep Inertia Managed with Bupropion

Abstract Introduction Severe sleep inertia (SI) can often be managed with behavioral modifications and stimulants. This patient’s sleep inertia was resistant to such therapies but had remarkable improvement with Bupropion. Report of case(s) An 11-year-old male with a history of seizures presented with hypersomnolence, SI and difficulty arousing in the morning for 3 years. There was no reported cataplexy, with occasional hypnogogic hallucinations and sleep paralysis. Family denied witnessed apneas or snoring. He had previously undergone an adenotonsillectomy at 6 years of age for obstructive sleep apnea. When initially seen, he was not taking antiseizure medications, Epworth score was 14 and BMI was 30.5 kg/m2. Polysomnogram showed an AHI of 1.5 events/hour with REM latency of 179.5 minutes. Multiple sleep latency testing showed a mean sleep latency of 4 minutes, 7 seconds with 3 SOREM periods: consistent with narcolepsy. Melatonin and methylphenidate were initially prescribed, followed by dextroamphetamine-amphetamine, but were discontinued due to worsening hypersomnolence. Armodafinil improved his overall daytime sleepiness, however, severe SI persisted intermittently in the morning and with naps to the point of EMS being called on multiple occasions. EEG and brain-MRI were normal. For suspected cataplexy, venlafaxine was tried and not beneficial. Calcium-magnesium-potassium and sodium oxybate (XW) lead to no improvement in his SI. Therefore, Methylphenidate-20mg (MP) and then Armodafinil-50mg were added before bedtime, however, his SI persisted with frequently missed school. Bedtime Bupropion 150 mg was added with an immediate response. He has not missed school or daytime activities with Bupropion. Conclusion Sleep inertia is typically a characteristic of idiopathic hypersomnia rather than narcolepsy and is related to the abnormal transition of sleep to wakefulness resulting in reduced alertness, impaired performance, and desire to return to sleep. Such pronounced sleep inertia is atypical and caused significant quality of life impairment in our patient. Nighttime melatonin, XW, MP, and bupropion for SI has been described in the literature1. Our patient failed multiple treatments before bupropion which was immediately successful. Support (if any) 1. Treatment of severe morning sleep inertia with bedtime long-acting bupropion and/or long-acting methylphenidate in a series of 4 patients. Schenck, MD1 ; Golden, MD2 ; Millman, MD3

0969 Severe persistent specific sleep disorders in post-acute sequelae of SARS-CoV-2

Abstract Introduction Viral infections have long been associated with sleep disorders, especially hypersomnia following the acute phase The Covid-19 epidemic has resulted in a post-viral syndrome called post-acute sequelae of SARS-CoV-2 (PASC), or Long-Covid. Sleep has been reported to be severely disturbed during acute Covid-19 infection, and is a major feature of PASC. Much of the subjective data is based on questionnaires, with a paucity of objective sleep evaluations including polysomnography. We share our early experience with diagnosis and management of sleep disorders in PASC. Methods PASC patients are seen in a dedicated Long-Covid clinic at the Beth Israel Deaconess Medical Center for a comprehensive evaluation. The patients presented with new onset persistent sleep impairments shortly following acute COVID-19 infection, without pre-existing sleep impairments, in association with a clinical diagnosis of long covid. Sleep symptoms (excessive sleepiness, hypersomnia/long sleep, and insomnia) are identified and those who consider these a key symptom are referred to the Covid Sleep Clinic, for formal sleep evaluation by RJT. Diagnostic evaluations include polysomnography (extended for hypersomnia diagnosis), Multiple Sleep Latency Test for excessive daytime sleepiness, and home sleep apnea test for suspected sleep apnea. Sleep logs and sleep quality using a Ring oximeter-based SleepImage system complements evaluation of sleep-wake instability. Standard management is offered based on the ensuing diagnosis. Results Twenty-six patients (age range 22 to 58 years, 16 females) have been evaluated in this sleep pathology enriched pathway. Specific new sleep disorders diagnosis so far have included narcolepsy without cataplexy (3), hypersomnia with long sleep (3), hypersomnia without long sleep (3), rapid eye movement sleep disorder (2), persistent insomnia (3), a sleep-wake instability syndrome we call cyclical insomnia (2), and sleep apnea (7). Treatment has included CPAP, stimulants, modafinil, and sodium oxybate. Clinical responses to treatment have so far been as expected. One patient with cyclical insomnia has had a marked subjective and objective improvement with low dose (250 mg) sodium valproate. Conclusion PASC/Long-Covid can induce specific sleep syndromes. These include narcolepsy, hypersomnia, persistent insomnia, sleep-wake instability, and REM-behavior disorder. Support (if any)

0591 Effectiveness and Optimization of Lower-Sodium Oxybate in Participants With Narcolepsy Switching From Sodium Oxybate (SEGUE)

Abstract Introduction Lower-sodium oxybate (LXB, Xywav®) contains 92% less sodium than higher-sodium oxybate (SXB, Xyrem®) and is approved for treating cataplexy or excessive daytime sleepiness in patients with narcolepsy (≥7 years of age) and idiopathic hypersomnia in adults. The SEGUE study examines the safety, tolerability, effectiveness, and treatment optimization in participants with narcolepsy transitioning from SXB to LXB. Methods Eligible participants in this multicenter, open-label study were adults with narcolepsy type 1 or 2 who were on a stable dose (maximum 9 g/night; no single dose >6 g) and regimen (once, twice, or thrice nightly) of SXB. After 2 weeks on a stable SXB dose/regimen (baseline period), participants switched to the same dose/regimen of LXB (intervention period; 6 weeks). If needed, LXB dose/regimen was titrated to optimize efficacy/tolerability. Assessments included the Patient Global Impression of Change (PGIc), a forced preference questionnaire (FPQ), an ease of switching medication scale (EOSMS), and the Epworth Sleepiness Scale (ESS); all collected at end of treatment or early discontinuation. Results Of 60 participants who entered the intervention period, a majority were female (62%) and White (88%); mean (SD) age was 43.9 (15.33) years. Starting and ending (end of treatment or early discontinuation) median total nightly doses of LXB were 8.5 g and 9.0 g, respectively. In terms of regimen, most took LXB twice nightly (93% at both time points). Fifty-six participants completed the transition period; mean (SD) time to stable dose was 2.5 (4.82) days, and median (range) number of changes in dose/regimen was 0.0 (0, 1). At end of treatment or early discontinuation, most participants reported improvement (very much/much/minimal; 45%) or no change (48%) in narcolepsy symptoms on the PGIc, preferred LXB over SXB on the FPQ (79%), and reported the transition to LXB was easy, extremely easy, or not difficult at all on the EOSMS (93%). Mean (SD) change from baseline on the ESS (n=55) was −0.7 (2.31). Conclusion Most participants with narcolepsy switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment (ESS) was maintained after transition, and most preferred LXB over SXB. Support (if any) Jazz Pharmaceuticals.

0948 End-to-End utility of the Cardiopulmonary Coupling Sleep Spectrogram in Sleep Medicine

Abstract Introduction Technology has improved the diagnosis and therapeutic tracking of sleep disorders, but remains fragmented. For example, the laboratory polysomnogram and home sleep apnea test is disconnected from the data available from therapy devices. Remote patient monitoring has focused more on apnea metrics rather than sleep quality. There is some value to a device or system which can be used for diagnosis, risk stratification, and tracking of clinical outcomes across different sleep disorders. Methods A method which offers the potential of end-to-end utility in sleep medicine is the cardiopulmonary coupling (CPC) spectrogram. Originally an ECG-base device, the current form is that of a Ring oximeter (finger) with an integrated activity monitor. The oximeter data is processed via Bluetooth in a smartphone, and then transferred to a Cloud-based analysis (www.sleepimage.com). The CPC analysis integrates heart rate variability and ECG or photoplethysmography-derived respiration. Outputs include a Sleep Quality Index and percentage of stable sleep (high frequency coupling which covaries with delta power on the electroencephalogram and is associated with blood pressure dipping), unstable sleep (low frequency coupling), an apnea-hypopnea index, oxygen desaturation index, heart rate profile across the night (dipping or non-dipping heart rate), total sleep time and sleep efficiency. Data from two clinical systems were used: Empower Sleep (an Internet-based “digital sleep clinic”) and Sleep Continuum (a sleep tracking service offered by Neurocare, Inc, in the Boston area). Results Data from over 500 patients across a range of sleep disorders show end-to-end utility of the SleepImage system. These include diagnosis of sleep apnea including multi-night recording, sleep apnea phenotyping (high loop gain and sleep fragmentation), remote patient monitoring during CPAP or oral appliance use, supportive information for diagnosis of hypersomnia, tracking medication effects (sodium oxybate, sedative-hypnotics, acetazolamide), sleep-wake instability in mood disorders and Long-Covid, impaired sleep quality in chronic fatigue syndrome and restless legs syndrome, off-label therapies for central sleep apnea (oxygen, acetazolamide, buspirone), and sleep fragmentation in Long-Covid and parasomnia. Examples from each of these clinical use cases will be shown. Conclusion The CPC-based SleepImage Ring system can provide complete diagnostic, phenotyping, and tracking functions. Support (if any) The Institute for Personalized Sleep Health, BIDMC, Empower Sleep

0573 Application of AASM Clinical Significance Thresholds to Once-Nightly Sodium Oxybate for Improvement in Narcolepsy Symptoms

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; FT218), an investigational, extended-release treatment, was evaluated for the treatment of narcolepsy in adults in the phase 3 REST-ON clinical trial (NCT02720744). The 3 co-primary endpoints, mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement rating, and weekly number of cataplexy attacks (NCA), and the secondary endpoint of Epworth Sleepiness Scale (ESS) score were significant for ON-SXB vs placebo at weeks 3 (6-g dose), 8 (7.5-g dose), and 13 (9-g dose; all P< 0.001). These data were published after the cutoff for inclusion in the American Academy of Sleep Medicine (AASM) clinical practice guidelines for narcolepsy treatment; thus, REST-ON results were analyzed according to AASM clinical significance thresholds (CSTs). Methods Individuals with narcolepsy type 1/2 and age ≥16 years were randomized 1:1 to receive double-blind ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or matching placebo. For each dose (6 g, week 3; 7.5 g, week 8; and 9 g, week 13), least-squares mean (LSM) difference from placebo was calculated for change from baseline in mean sleep latency on the MWT, ESS score, and percentage reduction in NCA. As defined in the 2021 AASM guidelines, CSTs were the following changes vs placebo: MWT, ≥2-minute increase; ESS, ≥2-point decrease; and cataplexy, ≥25% decrease in NCA. Results 190 participants (ON-SXB, n=97; placebo, n=93) were in the modified intent-to-treat population. On the MWT, difference in LSM change from baseline was 5.0, 6.2, and 6.1 minutes for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM change from baseline ESS scores were −2.1, −3.2, and −3.9 for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM percentage reduction in NCA were 26.0%, 34.2%, and 36.1% for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Conclusion Clinically significant improvement in excessive daytime sleepiness and cataplexy per AASM-established criteria was met with ON-SXB 6, 7.5, and 9 g doses. If FDA approved, ON-SXB will provide a once-nightly treatment for improving EDS and cataplexy in adults with narcolepsy. Support (if any) Avadel Pharmaceuticals

0607 Improvement in Sleep Latency With FT218 (Once-Nightly Sodium Oxybate): Analysis From the Phase 3 REST-ON Clinical Trial

Abstract Introduction In the phase 3 REST-ON trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved vs placebo with investigational, extended-release once-nightly sodium oxybate (FT218 [ON-SXB]; P< 0.001). This post hoc analysis assessed response to treatment and improvement in excessive daytime sleepiness (EDS). Methods Participants (≥16 years) with narcolepsy type 1/2 were randomized 1:1 to double-blind ON-SXB or placebo. Doses were 4.5 g week 1, 6 g weeks 2‒3, 7.5 g weeks 4‒8, and 9 g weeks 9‒13. Mean sleep latency on the MWT was measured in 5 trials up to 30 minutes each at baseline and weeks 3, 8, and 13. Percentage of participants with improvement of ≥5, ≥10, ≥15, and ≥20 minutes from baseline and with mean sleep latency=30 minutes were assessed. Two-sided P values were calculated using Fisher exact test. Results The modified intent-to-treat population included 190 participants (ON-SXB, n=97; placebo, n=93). At baseline, mean (SD) sleep latency was as follows: ON-SXB, 5.0 (3.1) minutes; placebo, 4.7 (2.6) minutes. More participants receiving ON-SXB vs placebo had mean MWT=30 minutes at weeks 3 (6 g; 5.7% vs 0%; P< 0.05), 8 (7.5 g; 10.5% vs 1.3%; P< 0.05), and 13 (9 g; 13.2% vs 5.1%; P=0.14). A significantly greater percentage of participants receiving ON-SXB vs placebo had improved mean sleep latency ≥5 to ≥20 minutes over baseline at all doses (6 g: ≥5 min, 57.5% vs 25.0%; ≥10 min, 35.6% vs 9.1%; ≥15 min, 18.4% vs 3.4%; ≥20 min, 10.3% vs 1.1% [all P< 0.01]; 7.5g: ≥5 min, 63.2% vs 28.2%; ≥10 min, 43.4% vs 11.5%; ≥15 min, 31.6% vs 3.8%; ≥20 min, 15.8% vs 1.3% [all P< 0.001]; 9 g: ≥5 min, 66.2% vs 37.2% [P< 0.001]; ≥10 min, 50.0% vs 19.2% [P< 0.001]; ≥15 min, 32.4% vs 10.3% [P< 0.01]; ≥20 min, 17.6% vs 6.4% [P< 0.05]). Conclusion Clinically significant improvements in EDS occurred with 6-, 7.5-, and 9-g doses of ON-SXB. At the 2 highest doses, >10% of participants remained awake for the entire MWT. If ON-SXB is granted FDA approval, adults with narcolepsy will have a once-nightly treatment to improve EDS. Support (if any) Avadel Pharmaceuticals

0611 Treatment Satisfaction and Preferences in People With Narcolepsy Transitioning From Sodium Oxybate to Lower-Sodium Oxybate

Abstract Introduction Lower-sodium oxybate (LXB; Xywav®), which contains the same active moiety as higher-sodium oxybate (SXB; Xyrem®) but with 92% less sodium, is approved by the US Food and Drug Administration (FDA) for treating cataplexy or excessive daytime sleepiness in patients ≥7 years of age with narcolepsy. LXB is recognized as clinically superior to SXB in narcolepsy by the US FDA due to lower chronic sodium exposure; however, real-world data describing patient preferences and satisfaction are lacking. Methods Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR; NCT04803786) was a patient-centric, prospective, observational, noninterventional, virtual-format study of US adults with narcolepsy (type 1 or 2) transitioning from SXB to LXB within the previous/upcoming 7 days. Longitudinal data collected during transition and for 21 weeks thereafter included responses to the Ease of Switching Medications Scale (EOSMS), Forced Preference Questionnaire (FPQ), and Treatment Satisfaction Questionnaire for Medication-version II (TSQM-vII). Results The mean (standard deviation [SD]) age of the 85 participants (narcolepsy type 1, n=45; narcolepsy type 2, n=40) was 40.3 (13.0) years; most were female (73%) and White (87%). Mean (SD) time on current SXB regimen was 57.8 (52.1) months. Nearly all participants took SXB (82/85, 96%) twice nightly prior to transition and LXB (82/84, 98%) twice nightly after transition. Most participants (61/73, 84%) reported that switching from SXB to LXB was “extremely easy, not difficult at all” or “easy” on the EOSMS, and most (59/73, 81%) preferred LXB to SXB on the FPQ. Among participants who preferred LXB, lower sodium content (56/59, 95%) and fewer cardiovascular issues (27/59, 46%) were cited as the most common reasons. There were minimal mean (SD) changes in TSQM-vII scores for global satisfaction (1.1 [18.6]), satisfaction with effectiveness (1.0 [16.8]), side effects (4.1 [23.7]), or convenience (−3.9 [15.2]) after transitioning from SXB to LXB. Conclusion Overall, most participants indicated that switching from SXB to LXB was “easy” or “extremely easy.” Most participants preferred LXB to SXB, primarily because of its lower sodium content. Satisfaction with oxybate treatment was maintained following transition to LXB. Support (if any) Jazz Pharmaceuticals

0579 Long-Term Safety of Once-Nightly Oxybate for Narcolepsy: RESTORE Study Interim Analysis of Data

Abstract Introduction The pivotal phase 3 REST-ON trial (NCT02720744) evaluated the efficacy and safety of once-nightly sodium oxybate (ON-SXB; FT218), an investigational extended-release formulation for treatment of adults with narcolepsy. In REST-ON, ON-SXB met its 3 coprimary endpoints: improvement in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement rating (% much/very much improved), and number of weekly cataplexy attacks at all doses tested (P< 0.001 vs placebo). The safety profile of ON-SXB was consistent with that of immediate-release (IR) SXB. The ongoing RESTORE trial (NCT04451668) is an open-label/switch study evaluating the safety and tolerability of ON-SXB. Methods Participants aged ≥16 years with narcolepsy type 1 or 2 who completed the REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive are eligible for RESTORE. Initial doses were 4.5 g/night or equivalent/closest to the previous total IR oxybate dose/night for those switching; incremental adjustments (1.5 g/week; maximum dose, 9 g/night) were allowed. Safety data for participants receiving ≥1 dose of ON-SXB as of 01 July 2022 are reported here. Results This analysis includes interim data from 180 participants (REST-ON participants, n=15 [8.3%]; oxybate-naive, n=35 [19.4%]; switch, n=130 [72.2%]). Most participants are white (n=150 [83.3%]) and female (n=122 [67.8%]); mean age is 35 years [range, 16–84]). Most participants who reported an adverse event (AE; n=105 [58.3%]) had AEs that were mild (61.9%) or moderate (32.3%) in severity. Three participants had serious AEs (abscess, deep vein thrombosis, rib fracture and pneumothorax); all were deemed unrelated to ON-SXB and all 3 participants continued in the study. Adverse drug reactions (ADRs; ie, AEs related/possibly related to study drug) were reported by 76 (42.2%) participants with 6 (3.3%) participants discontinuing ON-SXB owing to ADRs. ADRs occurring in ≥3% of participants were nausea (11.7%), somnolence (6.7%), headache (5%), enuresis (5%), somnambulism (3.9%), dizziness (3.9%), tremor (3.9%), and vomiting (3.3%). Conclusion Interim data from the RESTORE study indicate that ON-SXB is generally well tolerated with a low rate of discontinuation owing to ADRs. If granted final FDA approval, ON-SXB will offer adults with narcolepsy a once-at-bedtime oxybate treatment option. Support (if any) Avadel Pharmaceuticals

Efficacy of Once-Nightly Sodium Oxybate (FT218) in Narcolepsy Type 1 and Type 2: Post Hoc Analysis From the Phase 3 REST-ON Trial.

Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2). Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5g, week 1; 6g, weeks 2-3; 7.5g, weeks 4-8; and 9g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups. The modified intent-to-treat population comprised 190 participants (NT1, n=145; NT2, n=45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, P<0.001) and NT2 (6 and 9g, P<0.05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, P<0.001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (P<0.001), nocturnal arousals (P<0.05), and ESS scores (P≤0.001) were reported for NT1 with directional improvements for NT2. Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

0584 Sodium Oxybate Treatment Patterns in Narcolepsy Patients: A Propensity Score–Matched Cohort Study Subanalysis

Abstract Introduction Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. Patients treated with available immediate-release oxybates are required to awaken for a second dose 2.5–4 hours after the bedtime dose to cover a full night of sleep. This study characterized SXB treatment patterns and discontinuation in narcolepsy patients. Methods Mayo Clinic patients from 1975–2020 were identified using an electronic health record–based search. Patients with ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (identified using a natural-language-processing [NLP] algorithm) were included. NLP was used to identify SXB non-use events with manual chart reviews performed to characterize reasons for discontinuation, switching, or missing the second dose and effects of missing the second dose. Results Of the patients with narcolepsy prescribed SXB (n=351; mean age at first diagnosis code observed at Mayo Clinic, 32 y [IQR: 23.2–46.1]; 65.5% female; 92.3% white), 113 (32.2%) had clinical notes indicating discontinuation of SXB, with 71 (20.2%) including reasons for discontinuation. The most common reasons for discontinuation (n≥5) included lack of efficacy (n=11), side effects (n=10), gastrointestinal side effects (n=10), neurological side effects (n=9), psychiatric side effects (n=8), lack of access (insurance/cost, n=10), and resolution/absence of cataplexy (n=5). Mentions of switching from SXB to other drugs (n=12 patients) included switching to stimulants (mixed amphetamine salts, n=3; dextroamphetamine, n=2; methylphenidate, n=1), sedative hypnotics (zolpidem, n=2), antidepressants (mirtazapine, n=1), and wake-promoting agents (solriamfetol, n=1). Of the 38 patients (10.8%) with mentions of missing the second nightly SXB dose, reasons were recorded for 24 (63.2%), including inability to wake up (n=14), forgetting the second dose (n=3), and having to wake up early the following day (n=3). Consequences of missing the second dose were recorded for a small subset (increased cataplexy, n=4; lower daytime alertness, n=3; awakens earlier, n=1; tiredness, n=1). Conclusion Limited data are available regarding real-world use of SXB. This novel study used a combination of NLP algorithm and manual chart review to identify difficulties patients have with the second, middle-of-the night immediate-release oxybate dose and patient-experienced consequences of not adhering to the prescribed dosing regimen. Support (if any) Avadel Pharmaceuticals

0598 Patient-Reported Sleep Quality in People With Narcolepsy Transitioning From Sodium Oxybate to Lower-Sodium Oxybate

Abstract Introduction Lower-sodium oxybate (LXB; Xywav®), which contains the same active moiety as higher-sodium oxybate (SXB; Xyrem®) but with 92% less sodium, is approved by the US Food and Drug Administration (FDA) for treating cataplexy or excessive daytime sleepiness in patients ≥7 years of age with narcolepsy. LXB is recognized as clinically superior to SXB in narcolepsy by the US FDA due to lower chronic sodium exposure. Real-world data related to sleep quality following transition from SXB to LXB are lacking. Methods Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR; NCT04803786) was a patient-centric, prospective, observational, noninterventional, virtual-format study of US adults with narcolepsy (type 1 or 2) transitioning from SXB to LXB within the previous/upcoming 7 days. Longitudinal data collected during transition and for 21 weeks thereafter were based on daily and weekly questionnaires and sleep diaries instructing participants to rate the quality of their sleep and how refreshed they felt upon waking, and to record their sleep latency, wake after sleep onset (WASO), time in bed (TIB), and total sleep time (TST). Results The mean (standard deviation [SD]) age of the 85 participants (narcolepsy type 1, n=45; narcolepsy type 2, n=40) was 40.3 (13.0) years; most were female (73%) and White (87%). Almost all participants took SXB (82/85, 96%) twice nightly prior to transition and LXB (82/84, 98%) twice nightly after transition. Most participants rated their sleep quality as “good” or “very good” at baseline (45/84, 54%) and end of study (38/71, 54%), while 24/84 (29%) and 30/71 (42%) reported feeling “well-rested” or “very well-rested” at baseline and end of study, respectively. At end of study, changes (n=71) in mean (SD) sleep latency, WASO, TIB, and TST were −10.5 (16.2), −14.8 (56.6), 7.6 (67.7), and 33.0 (93.8) minutes, respectively. Conclusion Although participant-reported sleep quality was generally unchanged during the study, a greater percentage of participants reported feeling refreshed at end of study (on LXB) than at baseline (on SXB); however, there was no non-transitioning arm for comparison. Small changes were noted at end of study in sleep parameters, including sleep latency, WASO, and TST. Support (if any) Jazz Pharmaceuticals

0612 Understanding Narcolepsy Treatments From the Patient’s Perspective: A Survey of People Living With Narcolepsy

Abstract Introduction Individuals with narcolepsy were surveyed to better understand desired treatment outcomes and how those outcomes map to commonly experienced symptoms, treatment awareness, and medication usage. Methods In February 2022, an email invitation to a 27-question online survey was sent to US members of MyNarcolepsyTeam, a social network of &amp;gt;9,800 members. Results In total, 110 members completed the survey. The most frequently mentioned desired treatment goals aligned with the most commonly reported symptoms: being able to stop sleeping during the day (77%); increased energy (62%); improved memory (36%); improved productivity (29%); improved sleep continuity (22%); and for patients with narcolepsy type 1, reducing cataplexy (28%). A common theme was desire for a medication that would treat the underlying cause and not just improve specific symptoms. In one patient’s own words: “I want to see treatments that target the root problem of poor nighttime sleep rather than just being a band-aid for [excessive daytime sleepiness] EDS, like stimulants are.” Only a small percentage of respondents (13%) were not currently taking any type of medication to address narcolepsy symptoms. 64% were currently taking ≥2 medications to address both the daytime and nighttime symptoms. Most commonly mentioned current treatments were dextroamphetamine-amphetamine (30%), modafinil (22%), melatonin (16%), armodafinil (15%), venlafaxine (14%), and oxybate (14%). Notably, 33% of patients taking sodium oxybate chose sleeping through the night as a desired outcome. Most common sources for learning about treatments were narcolepsy-specific websites (53%), MyNarcolepsyTeam specifically (45%), the patient’s doctor (42%), scientific articles (42%), and advocacy groups (37%). Conclusion Patients experience a wide range of both daytime and nighttime symptoms and seek relief from both sets of symptoms including EDS (93%), fatigue (79%), cognitive challenges (74%), as well as sleep disruptions (63%). As a result, the majority need multiple medications. Understanding the experiences and needs of people with narcolepsy provides significant opportunities for clinicians to support, educate, and treat their patients holistically. Additionally, content readily available on the internet, whether it is narcolepsy-specific content or social networks, helps patients proactively discuss options with their clinician. Support (if any) Avadel Pharmaceuticals

1017 Laughing in the Face of Laughter: Narcolepsy with severe cataplexy refractory to medication: A case report

Abstract Introduction Cataplexy, a transient muscle atonia, typically occurs in response to positive emotions such as laughter or mirth. Cataplexy occurs in association with hypocretin deficiency/narcolepsy type 1 (NT1) and involves descending REM sleep-motor inhibition pathways. 1. Here we present a case with late – onset NT1, refractory to medication. Report of case(s) A 65-year-old man with a normal BMI presented to the autonomic clinic for presumed syncope, facial and leg weakness, occurring up to 50 times daily, triggered by laughter and a stressful life event from 4 years prior. Tilt testing and brain magnetic resonance imaging, were unremarkable, while sleep–deprived electroencephalogram was concerning for cataplectic versus functional attacks. He underwent diagnostic polysomnography (PSG) that showed severe obstructive sleep apnea (OSA) and was treated with bilevel positive airway pressure (BPAP). A repeat PSG after his OSA was controlled on BPAP, followed by a multiple sleep latency test the next day, showed a mean sleep latency of 2.7, and sleep onset rapid eye movement in 3 of 5 naps; cerebrospinal fluid hypocretin was undetectable and DQB1*06:02 was positive. He denied sleep paralysis and sleepiness, and jovial by nature, he joked as a hobby, leading to cataplexy. Trials of sodium oxybate was ineffective causing vivid dreams and hallucinations. Venlafaxine was subsequently added, initially controlling his cataplexy, but lost efficacy, warranting a trial of duloxetine, also ineffective. He was then started on solriamfetol, which improved sleepiness. We attempted to enroll him in a clinical trial of Reboxetine, thereby discontinuing duloxetine; severe OSA disqualified him from the trial. Subsequently, status cataplecticus ensued, leading to abolished reflexes and multiple falls. Clomipramine 100mg and Modafinil 200mg was started, reportedly reducing the frequency of cataplexy to 12 episodes daily. Conclusion Our case is notable because of the challenges working through the differential of drop attacks, and his late onset of severe NT1. One suggestion is an associated functional component to the disease could be involved, and though the diagnosis is solid, an additional functional overlay, or his joking personality, render symptom control unusually difficult. This case illustrates complexities of some cases with late-onset NT1. Support (if any)

0575 Cataplexy Response With FT218 (Once-Nightly Sodium Oxybate): Post Hoc Responder Analysis From the Phase 3 Rest-ON Clinical Trial

Abstract Introduction In the phase 3 REST-ON trial (NCT02720744), participants with narcolepsy type 1 (NT1) treated with once-nightly sodium oxybate (ON-SXB; FT218), an investigational, extended-release formulation, had significant reductions in cataplexy episodes (ON-SXB vs placebo: 4.5 g, P&amp;lt; 0.05 [post hoc]; 6 , 7.5, and 9 g, all P&amp;lt; 0.001). This post hoc responder analysis further characterized improvements in mean weekly cataplexy episodes in trial participants. Methods In REST-ON, participants aged ≥16 years with NT1/NT2 were randomized 1:1 to double-blind ON-SXB or placebo for 13 weeks. Participants took 4.5 g (1 week), 6 g (2 weeks), 7.5 g (5 weeks), and 9 g (5 weeks). Participants with NT1 recorded number of cataplexy episodes per day (0, 1, 2, 3, 4, or ≥5) in a diary. Percentage of participants with ≥25%, ≥50%, ≥75%, and 100% reductions in weekly cataplexy episodes from baseline were compared (ON-SXB vs placebo; Fisher exact test). Results In the modified intent-to-treat population, 145 participants had NT1 (ON-SXB, n=73; placebo, n=72). Baseline mean (SD) number of weekly cataplexy episodes was 18.9 (8.7) for the ON-SXB group and 19.8 (8.9) for placebo. At week 1 (4.5 g), significantly more participants taking ON-SXB had ≥25% reduction in cataplexy (43.8% vs 26.4%; P&amp;lt; 0.05). Significantly more participants receiving ON-SXB had ≥25%, ≥50%, or ≥75% reduction in cataplexy vs placebo at weeks 3, 8, and 13 and complete resolution of cataplexy at weeks 8 and 13 (6-g dose: ≥25%, 68.5% vs 40.3% [P&amp;lt; 0.001]; ≥50%, 38.4% vs 20.8% [P&amp;lt; 0.05]; ≥75%, 23.3% vs 4.2% [P=0.001]; 100%, 2.7% vs 0 [P=NS]; 7.5-g dose: ≥25%, 67.1% vs 43.1%; ≥50%, 53.4% vs 25.0%; ≥75%, 32.9% vs 8.3% [all P&amp;lt; 0.001]; 100%, 6.8% vs 0 [P&amp;lt; 0.05]; 9-g dose: ≥25%, 58.9% vs 41.7% [P&amp;lt; 0.001]; ≥50%, 49.3% vs 26.4% [P&amp;lt; 0.001]; ≥75%, 32.9% vs 15.3% [P&amp;lt; 0.01]; 100%, 11.0% vs 2.8% [P&amp;lt; 0.05]). Conclusion In this post-hoc analysis, ON-SXB 4.5 g significantly reduced cataplexy by week 1. Additionally, ~10% of participants taking ON-SXB 7.5 and 9 g were free of cataplexy episodes. These data may be useful for clinicians when setting expectations of ON-SXB effectiveness for patients with cataplexy. Support (if any) Avadel Pharmaceuticals