Morse, Anne Marie

Abstract Introduction To further characterize the many struggles and unmet needs of people with narcolepsy (PWN), passive social listening was used to explore how PWN describe the condition using their own words. Methods MyNarcolepsyTeam is a social network where members can organically share their experiences living with narcolepsy with one another. Following an online survey, organic posts, comments, questions, and answers posted from January 2022 to present were analyzed. Results Of 110 survey respondents, 31% reported that the time from symptom onset to diagnosis was ≥10 years. Social listening highlighted both misdiagnoses (eg, depression) and “missed” diagnoses (eg, sleep apnea but not narcolepsy). Almost half (43%) of respondents reported pain as a comorbidity. Social listening revealed the burden of painful comorbidities (eg, fibromyalgia, migraines, neuropathy), which often lead to additional medications and further sleep disruption. While 90% of respondents reported excessive daytime sleepiness, 81% also reported sleep disturbances. Nighttime disruptions experienced by PWN included poor sleep quality, vivid dreams, frequent awakenings, sleep paralysis, and abnormal REM cycles. Structured routines helped improve sleep for some PWN. Additionally, 33% of respondents reporting cataplexy always experienced full body cataplexy; 21% always experienced localized cataplexy; 43% experienced a mix of both, with the remaining answering ‘not sure.’ Social listening highlighted the dangers of cataplexy, including falls/fractures. Organic conversations also brought to bear the full range of emotions that can trigger an attack – from laughter, to being startled, to feeling stressed. In total, 65% of respondents were taking ≥2 medications to treat daytime and/or nighttime narcolepsy symptoms. Organic conversations highlighted the challenges PWN experience managing complex treatment regimens in an attempt to cope with the full spectrum of narcolepsy symptoms. Conclusion Insight into how narcolepsy is experienced in patients’ own words and how patients try to mitigate their symptoms will help sleep specialists better understand the challenges and needs of PWN, which can lead to both faster diagnosis and more effective, individualized treatment. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Research was undertaken to better understand the path to a narcolepsy diagnosis, common symptoms, and the impact of narcolepsy on work, social interactions, and mental health. Methods In February 2022, an email invitation to an online, 27-question survey was sent to US members of MyNarcolepsyTeam, a social network of >9,800 members. Results In total, 110 members completed the survey. 38% of respondents started to experience symptoms before reaching 16 years of age. Most commonly experienced symptoms included excessive daytime sleepiness (EDS; 93%) and fatigue (84%). In total, 72% were also experiencing some form of sleep disturbance and 67% were already suffering from cognitive/memory challenges. 68% who were eventually diagnosed with narcolepsy type 1 (NT1) had cataplexy attacks. For 31%, getting to a narcolepsy diagnosis took ≥10 years. In fact, 64% were initially under- or misdiagnosed with something other than narcolepsy, including depression (73%), sleep apnea (36%), or attention-deficit/hyperactivity disorder (16%). 74% of patients with NT1 have continued to experience cataplexy, with 46% having some form of a cataplexy episode a few times per week. Cataplexy episodes were triggered by a wide range of emotional situations, including over-tiredness (70%), anger (48%), being startled (46%), laughter (46%), fear (44%), excitement (38%), or crying (33%). 76% of respondents indicated that the impact of narcolepsy on daily life is extremely or very severe. The far-reaching impact on quality of life was evident in that most respondents reported that narcolepsy interfered with work (82%), social life (86%), everyday chores (85%), and exercise (85%) and has limited career options (76%). The emotional toll of narcolepsy manifested in feeling isolated (83%), depressed (81%), anxious (80%), or embarrassed (75%). Conclusion Patients routinely experienced a misdiagnosis or a “missed” diagnosis based on common symptoms experienced. Being able to quickly identify narcolepsy as the root cause for symptoms of EDS, fatigue, and sleep disturbances can lead to getting the patient on the best treatment path as early as possible. Understanding the physical, emotional, and quality-of-life impact of narcolepsy can help clinicians provide a more holistic approach to treating their patients. Support (if any) Avadel Pharmaceuticals

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 >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

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea–hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Abstract Introduction Obstructive sleep apnea (OSA) is characterized by recurrent, partial or complete obstructive respiratory events accompanied by interruptions in sleep with frequent arousals, deoxygenation, and/or sleep disturbance. The present study profiled the largest array of plasma proteins, to date, to contribute to the identification of proteomic biomarkers associated with the presence and severity of OSA. Methods The SomaScan highly multiplexed aptamer assay was used to profile 5,000 proteins in 24–48-hour old EDTA plasma samples from the Stanford Technology Analytics and Genomics in Sleep (STAGES) study. The apnea-hypopnea index (AHI) was derived from overnight polysomnography and all participants provided a blood sample. OSA severity was classified as moderate-to-severe (AHI&gt;15) and controls/mild OSA (AHI&lt;15). Univariate linear regression analyses included log2-normalized relative protein expression as the dependent variable, AHI/OSA as the independent variable, and important covariates such as age, gender, BMI, BMI2, age x gender x BMI, sample storage time, and blood draw period. False discovery rate (FDR) to control for multiple testing was applied with an a-priori p-value of 0.05 for identifying significance. Results Univariate analyses identified 101 (65 upregulated, 36 downregulated) differentially expressed proteins (DEPs) between moderate-to-severe OSA and controls/mild OSA and 120 proteins (69 positive, 51 negative) associated with AHI as a continuous outcome with 70 proteins consistent in both models. Upregulated proteins involved pathways related to complement and coagulation cascades and metabolic processes and downregulated proteins involved pathways related to regulation of insulin-like growth factor, fibrin clot formation, and MAPK signaling. An OSA machine learning classifier (AHI&gt;15 vs AHI&lt;15) trained on relative protein expression performed robustly, achieving 72% accuracy in a validation dataset. Significant contributing features of the classifier included age, BMI, and 134 proteins, including 22 DEPs identified in univariate analyses for OSA categories. Conclusion The present study identified differential protein expression patters associated with OSA and AHI, thereby supporting the potential of proteomic biomarkers in OSA and providing new insight into the mechanisms underlying OSA. Support (If Any) This work was supported, in part, by the National Heart, lung, and Blood institute [T32HL110952] and the Klarman Family Foundation.

Abstract Introduction Periodic limb movements (PLMs) are episodes of involuntary, repetitive muscle movements that are highly associated with restless legs syndrome (RLS). Although PLMs and RLS are reportedly two separate phenomena, both are tightly correlated and may result from a similar pathology. The present study profiled plasma protein biomarkers of PLMs and RLS to contribute to the identification of mechanisms associated with each disorder/trait. Methods The SomaScan highly multiplexed aptamer assay was used to profile 5,000 proteins in 24–48-hour old EDTA plasma samples from the Stanford Technology Analytics and Genomics in Sleep (STAGES) study. PLMs per hour (PLMI) were derived from overnight polysomnography and RLS was classified based on affirmative responses to questions of the Alliance Sleep Questionnaire. Three linear regression models were conducted to examine significant protein markers of 1) PLMI in the sample as a whole; 2) PLMI controlling for the presence of RLS; and 3) RLS without PLMs (i.e.,PLMI&lt;5). All models included log2-normalized relative protein expression as the dependent variable and important covariates such as age, gender, BMI, sample storage time, and blood draw period. False discovery rate (FDR) to control for multiple testing was applied with an a-priori p-value of 0.05 for identifying significant associations. Results PLMI was significantly associated with 253 proteins (219 positive,34 negative). The inclusion of RLS in the model mitigated the significance of most proteins, and only 8 proteins remained significant. Negatively associated proteins (LEAP-1, Ferritin, SELH, Caspase-8) included functions related to iron storage, absorption, and delivery and negative regulation of inflammatory/immune responses. Positively associated proteins (SFRP4, RANTES, CathepsinA, DKK1) included proteins with functions related to immune response, inflammatory response, bone formation, and protein stability. RLS without PLMs was associated with 7 upregulated proteins (megalin, RUFY1, TADBP, ANGL7, LRTM2, SNAPN, STOM) with functions related to vitamin D metabolism, calcium and zinc binding, circadian rhythm regulation, and calcium-dependent neurotransmitter secretion. Conclusion These large proteomic analyses identified independent differential protein expressions for PLMs and RLS that suggest different pathophysiological contributions. Support (If Any) This work was supported, in part, by the National Heart, lung, and Blood institute [T32HL110952] and the Klarman Family Foundation.

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