Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on outcomes including polysomnography (PSG)-based sleep architecture in participants with idiopathic hypersomnia or narcolepsy. This abstract will include results from the idiopathic hypersomnia cohort. DUET included a screening period (2-week washout for current oxybate users), an 8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period (SDP), an 8-day end-of-treatment period (EOT), and a 2-week safety follow-up. Participants underwent nocturnal PSG using an ad libitum protocol at BL and EOT. PSGs were scheduled to allow a minimum of 10 hours in bed, unless the participant naturally awakened earlier; bedtime was determined by habitual bedtime. PSG recordings were centrally scored. Data were analyzed for participants in the idiopathic hypersomnia cohort completer set. P-values were uncontrolled for multiplicity and therefore considered nominal. Forty-six participants with idiopathic hypersomnia enrolled; 40 completed the study. Most were female (80%) and White (85%) with a mean±SD age of 38.1±11.8 years. Mean±SD total sleep time (TST) at BL and EOT was 467.5±111.9 and 413.4±97.9 minutes, respectively (LSM change [95% CI], –54.1 [–81.3, –26.9]; P=.0003). Mean±SD number of total shifts from deeper to lighter sleep stages at BL and EOT was 60.8±30.1 and 43.7±27.0, respectively (LSM [95% CI], –17.1 [–23.7, –10.5]; P<.0001). Mean±SD time spent in N1 at BL and EOT was 47.8±26.1 and 33.0±22.4 minutes (LSM [95% CI], –14.8 [–20.3, –9.3]; P<.0001), % of stage was 10.3% and 8.0% (P=.0017); in N2, 270.0±64.8 and 225.8±72.8 minutes (LSM [95% CI], –44.3 [–66.7, –21.9]; P=.0003), 58.5% and 54.2% (P=.0286); in N3, 51.9±35.3 and 92.5±53.5 minutes (LSM [95% CI], 40.6 [25.8, 55.4]; P<.0001), 11.2% and 22.8% (P<.0001); and in REM, 97.7±47.0 and 62.1±35.4 minutes (LSM [95% CI], –35.7 [–46.0, –25.3]; P<.0001), 20.0% and 15.0% (P<.0001). Participants with idiopathic hypersomnia treated with open-label LXB demonstrated reduced TST on ad libitum polysomnography compared with baseline, increases in N3 sleep, and changes in sleep architecture. Jazz Pharmaceuticals

Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on outcomes including sleep quality (using polysomnography [PSG] and self-reported questionnaires) in participants with idiopathic hypersomnia or narcolepsy. Data reported here are from the idiopathic hypersomnia cohort. DUET included a screening period (with 2-week washout for current oxybate users), an 8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period (SDP), an 8-day end-of-treatment (EOT) period, and a 2-week safety follow-up. Participants underwent nocturnal PSG (ad libitum protocol) at BL and EOT. The Karolinska Sleepiness Scale (KSS) was administered 90 minutes post-awakening from PSG to measure situational sleepiness (9-point scale; 1=“extremely alert” to 9=“extremely sleepy, can’t keep awake”). Participants completed an electronic sleep diary (eDiary) daily during the BL and EOT periods, including questions regarding nightly sleep patterns, total sleep time (TST), sleep quality (5-point scale; “very good” to “very poor”), and how rested/refreshed the participant felt upon awakening (5-point scale; “very well” to “not at all”). Completion of ≥5 eDiary days during the 8-day assessment before PSG visits was required for analysis. eDiary and KSS data were analyzed in the completer set (enrolled participants who were dosed with LXB and completed SDP and PSG at EOT). Forty-six participants with idiopathic hypersomnia enrolled (completer set, n=40). Most were female (37/46; 80%) and White (39/46; 85%); mean (SD) age was 38.1 (11.8) years. Mean (SD) self-reported nocturnal TST at BL (n=36) and EOT (n=30) was 8.6 (2.0) and 8.4 (2.7) hours, respectively. The percent of participants rating their sleep quality as “very good”/“good” increased from 19.4% (BL) to 56.7% (EOT). The percent of participants with rested sleep (“very well”/“well”/“somewhat” rested) increased from 22.2% (BL) to 73.3% (EOT). Likewise, mean (SD) rating of self-reported sleepiness decreased from 5.7 (2.0) at BL to 3.5 (2.0) at EOT. Following open-label LXB treatment, participants with idiopathic hypersomnia reported improvements in sleep quality and feeling more rested and less sleepy upon awakening. Jazz Pharmaceuticals

Abstract Introduction Prior studies report high incidences of psychiatric and/or neurologic comorbidities in patients with narcolepsy. Low-sodium oxybate (LXB; Xywav®) is an FDA-approved treatment for cataplexy or excessive daytime sleepiness in patients ≥7 years old with narcolepsy and for adults with idiopathic hypersomnia. This post hoc analysis of a phase 3 trial (NCT03030599) assessed LXB efficacy and safety in participants with narcolepsy with or without a medical history of psychiatric and/or neurologic comorbidities. Methods Participants were adults (18‒70 years) with narcolepsy with cataplexy. Participants optimized/titrated their LXB dose (up to 12 weeks) before a 2-week stable-dose period. During a 2-week double-blind randomized-withdrawal period, participants were either switched to placebo or continued LXB. Epworth Sleepiness Scale (ESS), average weekly number of cataplexy attacks, Patient Global Impression of Change (PGIc) scores, Patient Health Questionnaire-9 (PHQ-9) scores, and treatment-emergent adverse events (TEAEs) were evaluated in participants with and without psychiatric and/or neurologic comorbidities. Results Of 201 participants, 84 reported baseline comorbidities (most commonly depression, migraine headaches, anxiety, and headache [non-migraine]). Imbalances between subgroups were observed with regard to sex, race, ethnicity, and body mass index. Participants randomized to placebo in both subgroups showed worsening (increases) in ESS scores compared with participants who continued with LXB treatment (least squares mean differences, LXB vs placebo [95% CI], with comorbidities: −3.7 [−5.6, −1.9], P=0.0001; without comorbidities: −2.0 [−3.5, −0.6]; P=0.0050). Participants randomized to placebo in both subgroups had increased weekly cataplexy attacks compared with those continuing LXB (location shift, LXB vs placebo [95% CI], with comorbidities: −4.0 [−7.0, −1.1], P=0.0026; without comorbidities: −3.5 [−9.1, −1.1], P< 0.0001). Participants randomized to placebo in both subgroups showed worsening in PGIc scores compared with LXB (P< 0.0001, for both). Symptoms of depression, as measured by PHQ-9 scores, remained stable in both subgroups. TEAEs and serious TEAEs occurred in 69 (82.1%) and 1 (1.2%) participants with comorbidities, and 84 (71.8%) and 3 (2.6%) without comorbidities, respectively. Conclusion In this post hoc analysis of a phase 3 trial in patients with narcolepsy, the efficacy and safety of LXB in participants with psychiatric and/or neurologic comorbidities were similar to those in participants without such comorbidities. Support (if any) Jazz Pharmaceuticals

Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment) is a phase 4, prospective, multicenter, single-arm, multiple-cohort, open-label study (NCT05875974) evaluating the effectiveness of low-sodium oxybate (LXB, Xywav®) treatment on outcomes including sleep quality (using polysomnography [PSG] and self-reported questionnaires) in participants with narcolepsy or idiopathic hypersomnia. Data reported here are from the narcolepsy cohort. DUET included a screening period (with 2-week washout for current oxybate users), an 8-day baseline (BL) period, a 2- to 8-week LXB titration period, a 2-week stable-dose period (SDP), an 8-day end-of-treatment (EOT) period, and a 2-week safety follow-up. Participants underwent nocturnal PSG (ad libitum protocol) at BL and EOT. The Karolinska Sleepiness Scale (KSS) was administered 90 minutes post-awakening from PSG to measure situational sleepiness (9-point scale; 1=“extremely alert” to 9=“extremely sleepy, can’t keep awake”). Participants completed an electronic sleep diary (eDiary) daily during the BL and EOT periods, including questions regarding nightly sleep patterns, total sleep time (TST), sleep quality (5-point scale; “very good” to “very poor”), and how rested/refreshed the participant felt upon awakening (5-point scale; “very well” to “not at all”). Completion of ≥5 eDiary days during the 8-day assessment before PSG visits was required for analysis. eDiary and KSS data were analyzed in the completer set (enrolled participants who were dosed with LXB and completed SDP and PSG at EOT). Fifty-five participants with narcolepsy (type 1, n=26; type 2, n=29) enrolled (completer set, n=34). Most were female (40/55; 73%) and White (44/55; 80%); mean (SD) age was 33.4 (12.9) years. Mean (SD) self-reported nocturnal TST at BL (n=32) and EOT (n=20) was 8.1 (1.6) and 8.3 (0.9) hours, respectively. The percent of participants rating their sleep quality as “very good”/“good” increased from 15.6% (BL) to 70.0% (EOT). The percent of participants with rested sleep (“very well”/“well”/“somewhat” rested) increased from 46.9% (BL) to 90.0% (EOT). Likewise, mean (SD) rating of self-reported sleepiness decreased from 5.1 (2.0) at BL to 3.8 (1.9) at EOT. Following open-label LXB treatment, participants with narcolepsy reported improvements in sleep quality and feeling more rested and less sleepy upon awakening. Jazz Pharmaceuticals

To compare comorbid conditions between patients with idiopathic hypersomnia (IH) and matched non-IH controls.

Analyze response to low-sodium oxybate (LXB; Xywav®) by baseline sleep inertia in a phase 3 trial (NCT03533114) in participants with idiopathic hypersomnia.

Abstract Introduction Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration to treat excessive daytime sleepiness or cataplexy in patients ≥7 years of age with narcolepsy, and idiopathic hypersomnia in adults. LXB contains the same active moiety as high-sodium oxybates (sodium oxybate [SXB, Xyrem®] and fixed-dose SXB [Lumryz™]) but with 92% less sodium. Previous studies have reported increased cardiovascular (CV) and cardiometabolic (CM) comorbidities in people with narcolepsy. This post-hoc analysis of a phase 3 trial assessed LXB efficacy and safety in participants with narcolepsy with and without CV/CM comorbidities. Methods Participants 18–70 years of age with narcolepsy with cataplexy optimized/titrated their LXB dose (up to 12 weeks) before entering a 2-week stable-dose period (SDP) (NCT03030599). Following SDP, participants withdrew to placebo or continued LXB during a 2-week double-blind randomized-withdrawal period (DBRWP). Epworth Sleepiness Scale (ESS) scores, cataplexy (average N/week), Patient Global Impression of Change (PGIc) scores, and treatment-emergent adverse events (TEAEs) were assessed in participants with and without CV/CM comorbidities, per medical history. Results Of 201 participants, 69 reported CV/CM comorbidities at baseline (most commonly hypertension and obesity). Participants with and without CV/CM comorbidities, respectively, had mean (SD) BMI of 31.6 (6.4) and 27.2 (5.3); mean age was 43.4 (12.0) and 33.9 (11.0) years; 66.7% and 57.6% were female. Participants randomized to placebo in the DBRWP in both subgroups showed worsening (increases) in ESS scores compared with those randomized to LXB (least squares mean differences, LXB vs placebo [95% CI], with CV/CM comorbidities: −2.6 [−4.5, −0.70], P=0.0077; without CV/CM comorbidities: −2.7 [−4.2, −1.2], P=0.0004; subgroup interaction, P=0.95). Participants without CV/CM comorbidities randomized to placebo had increased cataplexy attacks compared with those taking LXB (median, placebo, 3.0; LXB, 0.0; P< 0.0001); those with CV/CM comorbidities had similar efficacy (placebo, 1.9; LXB, 0.0; P=0.0745). PGIc scores showed worsening in participants randomized to placebo vs LXB in both subgroups (P< 0.0001 for both). Serious TEAEs were reported by 3% of participants with CV/CM comorbidities and 2% of those without. Conclusion In this post-hoc analysis, the efficacy and safety of LXB were similar in participants with narcolepsy with and without CV/CM comorbidities. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Although the efficacy and safety of low-sodium oxybate (LXB, Xywav®) in the treatment of idiopathic hypersomnia and narcolepsy are well established, opportunities remain to better understand its impact on sleep architecture and other daytime/nighttime outcomes important to patients and clinicians. Jazz DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974) is a phase 4, prospective, multicenter, single-arm, open-label interventional study designed with novel methodology and expert input to evaluate the impact of LXB on excessive daytime sleepiness, polysomnographic (PSG) sleep parameters, and functional outcomes in adults with idiopathic hypersomnia or narcolepsy (type 1 or 2). Methods DUET includes a screening period (with a 2-week washout for participants taking oxybate at study entry), 1-week baseline period (off-treatment), 2- to 8-week titration period (for flexible LXB dosing adjustments based on participants’ needs), 2-week stable-dose period, 1- to 2-week end-of-treatment period (on LXB), and safety follow-up (after 2 weeks). To more comprehensively understand the impact of LXB on sleep architecture and other daytime/nighttime outcomes, novel design elements were integrated into the study. Input from an expert advisory board helped refine the study design and ensure that the most relevant elements for patients and clinicians were incorporated into the final DUET protocol. Responses from a premeeting survey of advisors focused on eligibility criteria, suitability of endpoints, newly created questionnaires, and analyses and were discussed during a 4-hour workshop with the study sponsor. Results Advisors were 6 clinicians with expertise in treating patients with idiopathic hypersomnia and narcolepsy and/or with expertise in PSG. Novel design aspects discussed and incorporated into the protocol included PSG conducted with ad libitum sleep duration, objective evaluation of sleep inertia using the Psychomotor Vigilance Test, a new questionnaire for capturing clinician-reported dosing to better understand dosing rationale, evaluation of motor activity during sleep (with PSG), and evaluation of dysautonomia using the Orthostatic Hypotension Questionnaire. Conclusion DUET is the first prospective evaluation of the impact of LXB on sleep architecture (PSG) in patients with idiopathic hypersomnia or narcolepsy. Results from these novel elements will provide patients and clinicians with additional information regarding the impact of LXB on nighttime/daytime symptomatology. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Low-sodium oxybate (LXB; Xywav®) is approved by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. To examine the long-term safety of LXB in this population, this post hoc analysis evaluated treatment-emergent adverse events (TEAEs) over time in a phase 3, double-blind, placebo-controlled, randomized withdrawal trial (NCT03533114), including its open-label extension period. Methods Participants were adults with idiopathic hypersomnia. TEAEs were analyzed across all study periods (open-label titration,10–14 weeks; stable-dose, 2 weeks; double-blind randomized withdrawal, 2 weeks; open-label extension, 24 weeks; safety follow-up, 2 weeks) in the analysis population (oxybate-naive participants who took ≥1 dose of study drug; N=148). Onset and duration of common TEAEs (≥5% of participants) were reported in the total population and by baseline medication group (treatment-naive, n=66; taking alerting agents [stimulants or wake-promoting agents], n=82). Duration was defined as the time from when a TEAE started until it was reported as ended. Results are presented using descriptive statistics. Results The majority of the most frequently reported TEAEs occurred within the first 5 weeks after study onset. In treatment-naive participants, the most common TEAEs (incidence; median duration) were nausea (n=13 [19.7%]; 7.5 days), headache (n=12 [18.2%]; 3.0 days), dizziness (n=11 [16.7%]; 4.0 days), anxiety (n=7 [10.6%]; 9.0 days), and decreased appetite (n=7 [10.6%]; 15.0 days). In participants taking alerting agents, the most common TEAEs were nausea (n=21 [25.6%]; 7.5 days), headache (n=15 [18.3%]; 2.0 days), vomiting (n=14 [17.1%]; 1.5 days), anxiety (n=10 [12.2%]; 28.0 days), insomnia (n=9 [11.0%]; 7.0 days), and tremor (n=9 [11.0%]; 11.0 days). Common TEAEs were of mild or moderate severity and infrequently led to study discontinuation (≤3.7% of participants each). Nine serious TEAEs occurred in 4/148 (2.7%) participants; none were considered related to study drug or led to study discontinuation. Conclusion In this study of LXB in participants with idiopathic hypersomnia, the common TEAEs (≥5% of participants) were consistent with the known safety profile of oxybate, peaked early (generally within 5 weeks), and were mild to moderate in severity, in both treatment-naive participants and participants taking alerting agents. Support (if any) Jazz Pharmaceuticals