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Introduction Obstructive sleep apnea (OSA) is a common disorder with often poorly tolerated treatment . While there is currently no approved pharmacotherapy for OSA, the combination of noradrenergic and antimuscarinic drugs, counteracting sleep-related upper airway muscle hypotonia, has recently shown encouraging results. AD109 is a combination of the norepinephrine reuptake inhibitor atomoxetine and the antimuscarinic aroxybutynin, the R-enantiomer of oxybutynin which recently showed efficacy over 1-night treatment in mild OSA patients. Safety and efficacy data over longer periods and in more severe OSA patients are needed. Methods Mariposa was a 25-center, randomized, controlled, parallel arms clinical trial designed to evaluate efficacy, safety, and tolerability vs placebo of 2 doses of AD109 (75/2.5mg and 75/5mg) and atomoxetine 75mg alone administered for 4 weeks in OSA patients with an apnea-hypopnea index (AHI4, 4% desaturation definition for hypopneas) between 10 and 45. The primary outcome was the change in AHI4, AD109 vs. placebo. Patient reported outcome questionnaires (PROMIS) were studied as exploratory outcomes. Results 211 patients (41% female) with median (IQR) age 55 (48-60) years and BMI 32.2 (28.0-35.2) kg/m2 were randomized. AHI4 was reduced from 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 75/2.5mg dose arm and from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the 75/5mg arm (both p< 0.0001 vs placebo). AHI4 was reduced from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (p< 0.01 vs placebo) and from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) on placebo. Overall, 44% had a reduction from baseline greater than 50% when treated with AD109. On AD109 75/2.5 dose, there was an improvement of PROMIS fatigue scores (p< 0.05 vs placebo and atomoxetine alone). Despite improving AHI4, atomoxetine alone reduced by 20+ minutes total sleep time vs placebo and AD109 (p< 0.05). There were no severe adverse events on AD109 with the most common side effects being dry mouth, insomnia, and nausea. Conclusion AD109 objectively and subjectively improved OSA severity in a group of patients with a wide range of AHI4 over 4 weeks of treatment. Results from the Mariposa trial are central for the design of phase 3 trials of AD109 in OSA. Support (if any) This study was supported by Apnimed.

Introduction FT218 (LUMRYZ™) is an investigational once-nightly sodium oxybate (ON-SXB) for treatment of adults with narcolepsy type 1 (NT1) or type 2 (NT2). The efficacy and safety of ON-SXB at doses 6, 7.5, and 9 g in patients with NT1/NT2 were confirmed in the phase 3 REST-ON clinical trial (NCT02720744). RESTORE is an ongoing, open-label extension/switch study to assess long-term safety and tolerability of ON-SXB (NCT04451668). Methods Individuals aged ≥16 years with NT1/NT2 are enrolled in Group A (participants who completed the REST-ON trial with no current oxybate use), Group B (participants who switched from twice-nightly immediate-release oxybates), or Group C (participants who are oxybate-naive). Initial ON-SXB dose is 4.5 g/night for Groups A/C and is the nearest equivalent or closest single dose to their previous nightly dose for Group B. Investigators may alter the nightly dose by 1.5 g/week (maximum, 9 g/night) based on effectiveness and tolerability. Results A total of 184 participants were enrolled (180, ≥1-dose) as of July 1, 2022. Most participants are white (n=150 [83.3%]) and female (n=122 [67.8%]), and mean age is 35 years. Most participants in Groups A/C (n=43/50 [86.0%]) increased from the 4.5-g initial dose and had 2–4 dose adjustments during initial titration (median [range], 3 [0–5]); 47% (17/36) are stable at 7.5 g. The most common initial doses in Group B were 7.5 g (50/130 [38.5%]) and 9 g (47/130 [36.2%]). Most in Group B reaching a stable dose maintained their initial dose (70/118 [59.3%]); 43 increased (36.4%) and 5 decreased (4.2%) their initial ON-SXB dose. In Group B, 49.1% (53/108) had no dose adjustments (median [range], 1 [0–5]) and 83.0% (n=39/47) who started at 9 g maintained this dose. Most common treatment-related adverse events (>3%; safety population [n=180]) are nausea (11.7%), somnolence (6.7%), headache (5.0%), enuresis (5.0), dizziness (3.9%), tremor (3.9%), somnambulism (3.9%), and vomiting (3.3%). Conclusion Most study participants had successful titration of ON-SXB to a therapeutic and tolerable dose within 1 month. If granted final approval by the US Food and Drug Administration, ON-SXB will offer a once-nightly treatment for adults with narcolepsy. Support (if any) Avadel Pharmaceuticals

Introduction Extended-release, once-nightly sodium oxybate (ON-SXB; FT218) is under FDA review for the treatment of adults with narcolepsy. RESTORE, an ongoing, open-label extension/switch study (NCT04451668), evaluates long-term ON-SXB safety and tolerability. This interim analysis assessed dosing titration, tolerability, and study continuation. Methods RESTORE enrolls adults with narcolepsy in 1 of 3 groups: those with prior REST-ON participation but no current oxybate use (Group A), those who switched from twice-nightly oxybates (Group B), and oxybate-naïve patients (Group C). No patients rolled directly from REST-ON to RESTORE. Initial dose for Groups A/C was 4.5 g/night. Group B switched to ON-SXB from stable doses of twice-nightly oxybate to the nearest equivalent single dose. Investigators could increase or decrease dose by 1.5-g increments weekly as needed. Descriptive statistics were used to analyze dose titration and discontinuations. Results At an interim data cutoff date of November 14, 2021, 99 participants were enrolled and had received ≥1 dose of ON-SXB (not currently taking oxybate, n=24; switch, n=75). For Groups A/C, 5 (21%) participants continued the 4.5-g dose, 8 (33%) increased to 6 g, 8 (33%) increased to 7.5 g, and 3 (13%) increased to 9 g by this data cutoff. Most Group B participants received initial ON-SXB doses of either 9 g (n=27) or 7.5 g (n=24). For Group B participants with >1 visit, 41 maintained their initial dose, 20 increased the dose, and 8 increased the dose but then later decreased it. All but 2 Group B participants with initial 9-g doses of ON-SXB maintained this dose. Twenty participants (20%) discontinued study treatment since the first patient enrolled in July 2020; the primary reason was withdrawal of consent (n=3; 3%). Two (2%) discontinued due to adverse reactions: vivid dreams/anxiety/lightheadedness and lack of efficacy (7.5 g); and difficulty breathing (6 g). Two discontinued due to taste/texture (2%); the remainder for miscellaneous reasons (eg, withdrew consent, could not adhere to schedule, left the country, caring for sick parent/child, wanted to get pregnant, using cannabis). Conclusion These interim data indicate that the majority of participants in all groups titrated to therapeutic and tolerable doses of ON-SXB. Support (If Any) Avadel Pharmaceuticals