Krahn, Lois E.

Abstract Introduction Patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) struggle to maintain wakefulness. Solriamfetol (Sunosi®) is a dopamine/norepinephrine reuptake inhibitor with agonistic properties at TAAR1 and serotonin 1A receptors; it is approved to treat EDS associated with narcolepsy (75–150 mg/day) or OSA (37.5–150 mg/day). This post-hoc analysis characterized the effects of solriamfetol on the propensity of participants with EDS associated with narcolepsy or OSA to maintain wakefulness. Methods The safety and efficacy of solriamfetol has been evaluated in participants with EDS and narcolepsy or OSA in the phase 3 trials, TONES 2 and TONES 3. Participants were randomized to placebo or solriamfetol (37.5 mg [OSA only], 75 mg, 150 mg, or 300 mg) once daily for 12 weeks. This post-hoc analysis evaluated the proportion of participants who achieved improvement from baseline on various 40-minute Maintenance of Wakefulness Test (MWT) thresholds (≥5, ≥10, ≥15, and ≥20 minutes) and mean sleep latencies ≥30 and ≥40 minutes at weeks 1, 4, and 12. Comparisons between solriamfetol and placebo were evaluated using Fisher’s exact test. Results A greater proportion of participants with narcolepsy achieved improvement from baseline of ≥15 and ≥20 minutes on the MWT with solriamfetol 150 mg (36% and 18%, respectively) and 300 mg (38% and 28%) compared with placebo (4% and 4%) at week 12 (P≤0.028); findings were similar at week 12 in participants with OSA with solriamfetol 75 mg (28% and 13%), 150 mg (37% and 25%), and 300 mg (44% and 28%) compared with placebo (8% and 3%; P≤0.034). A greater proportion of participants with narcolepsy achieved MWT sleep latency ≥30 minutes at week 12 with solriamfetol 150 mg (24%) and 300 mg (30%) compared with placebo (2%; P≤0.002); results were similar in participants with OSA for MWT sleep latency ≥30 minutes at week 12 with solriamfetol 75 mg (28%), 150 mg (34%), and 300 mg (44%) compared with placebo (11%; P≤0.012). Conclusion These findings suggest solriamfetol leads to substantial improvements on objective propensity to stay awake in a large proportion of patients with narcolepsy or OSA when compared with placebo. Support (if any) Axsome Therapeutics, Jazz Pharmaceuticals

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 Narcolepsy is a chronic sleep disorder with multiple comorbid conditions. Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. This study used aggregate electronic health record (EHR) data to characterize demographic characteristics and comorbidities of patients with narcolepsy treated with or without SXB. Methods An EHR-based search identified first-time Mayo Clinic patients between 1975–2020. Patients had ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (natural-language-processing algorithm). Patients with narcolepsy treated with SXB were age/sex matched with a cohort without SXB treatment. Common comorbidities were identified using ICD-9/-10 codes and compared between cohorts (odds ratio [OR]). Results Of 4387 patients identified, 8% received SXB treatment (n=351; mean [IQR] age at first diagnosis code observed at Mayo Clinic, 32 [23.2-46.1] y; 65.5% female; 92.3% white); 4036 patients had no SXB treatment (mean [IQR] age at first diagnosis code observed at Mayo Clinic, 44.8 [29.8-59.0] y; 58.0% female; 88.9% white). The 10 most commonly reported comorbidities (overall population) were insomnia (46.6%), fatigue (46.3%), depression (42.2%), hypertension (36.2%), hyperlipidemia (34.2%), obstructive sleep apnea (32.3%), diabetes mellitus (31.3%), arrhythmia (27.3%), idiopathic hypersomnia (IH; 26.8%), and coronary artery disease (17.6%). A cohort of 351 patients without SXB were age/sex matched to patients with SXB for comparison of comorbidities. In the unadjusted analysis, P values were significant for differences between cohorts (OR [95% CI] SXB vs no SXB) for fatigue (0.72 [0.54-0.97]; P< 0.05; adjusted P>0.9) and IH (0.60 [0.43-0.84]; P< 0.01; adjusted P=0.29). After P value adjustment (Bonferroni correction), there were no significant differences between these cohorts in ORs for any comorbidity. The matched cohorts, which were younger than the overall population, had numerically lower rates of these diagnoses vs the overall population, except fatigue and IH in patients without SXB and depression in patients with SXB. Conclusion Among age-/gender-matched cohorts of patients with/ without SXB, there were no significant differences in comorbidities. Prevalence of comorbid IH/narcolepsy diagnoses highlight the diagnostic challenge in differentiating IH from narcolepsy type 2. SXB is highly effective but used by < 1:10 patients with narcolepsy in the Mayo Clinic health system. 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

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

Abstract Introduction Placing a magnet over a Permanent Pacemaker (PPM) or Implanted Cardioverter-Defibrillator (ICD) may cause the device to pace asynchronously or inhibit tachyarrhythmia detection, respectively, potentially preventing delivery of electrical shocks. Manufacturers for masks used with positive airway pressure devices have started using magnets in place of more traditional headgear clips to connect the headgear to mask. Mask manufactures do not list presence of a PPM/ICD as a contraindication to use of a mask with magnet but do recommend keeping the mask some distance away from PPM/ICD. A published case series describes two patients with magnet response events captured during PPM/ICD interrogation that correlated with nightly use of CPAP. The authors were able to replicate the response by placing the mask with magnet directly over the patient’s pulse generate site. Although we advise all patients with implanted device to avoid use of masks with magnets, select patients refuse to stop using mask with magnets regardless of our policy. We, therefore, started offering these patients referral for PPM/ICD interrogation to evaluate for an interaction between mask with magnet and PPM/ICD as next best alternative. Methods We retrospectively reviewed all patients (n=10) referred for routine PPM/ICD interrogation to test whether the mask with magnet interacted with PPM/ICD when mask on face as during normal use (i.e., simulated normal use) or magnetic area of mask placed directly over the PPM/ICD (i.e., direct contact). Results Although no interaction was detected in any patient (n=10) with simulated normal use (0 %), one interaction was documented with direct contact (10 %). Conclusion Although simulated normal use of masks with magnets did not demonstrate any interactions, it is concerning that one patient (10 % of patients) demonstrated an interaction with direct contact of magnetic area of mask over the PPM/ICD. It is not uncommon for patients to remove a mask during the night while sleeping. This preliminary data along with the published case series calls for further research and increased awareness of this potential interaction for both sleep and cardiac health care providers. Support (If Any) None