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Study Objectives 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). Methods Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2–3; 7.5 g, weeks 4–8; and 9 g, 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. Results 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 Conclusions 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.

Sodium oxybate has been recognized as a gold standard for the treatment of disrupted nighttime sleep due to narcolepsy. Its short half-life and immediate-release formulation require patients to awaken 2.5-4 h after their bedtime dose to take a second dose. A novel extended-release, once-nightly sodium oxybate formulation (ON-SXB; FT218) is under US Food and Drug Administration review for the treatment of adults with narcolepsy.A phase III trial of ON-SXB in individuals with narcolepsy type 1 (NT1) or 2 (NT2) [the REST-ON trial; NCT02720744] has been conducted and the primary results reported elsewhere. Secondary objectives from REST-ON were to assess the efficacy of ON-SXB on disrupted nighttime sleep; the results of this analysis are reported here.In the double-blind, phase III REST-ON trial, patients aged ≥ 16 years were randomly assigned 1:1 to ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Secondary endpoints included polysomnographic measures of sleep stage shifts and nocturnal arousals and patient-reported assessments of sleep quality and refreshing nature of sleep at 6, 7.5, and 9 g; post hoc analyses included changes in time spent in each sleep stage, delta power, and assessments in stimulant-use subgroups for prespecified endpoints.In total, 190 participants (n = 97, ON-SXB; n = 93, placebo) were included in the efficacy analyses. All three ON-SXB doses demonstrated a clinically meaningful, statistically significant decrease vs placebo in the number of transitions to wake/N1 from N1, N2, and rapid eye movement (REM) stages (all doses p0.001) and the number of nocturnal arousals (p0.05 ON-SXB 6 g; p0.001 7.5 and 9 g). Sleep quality and refreshing nature of sleep were significantly improved with all three ON-SXB doses vs placebo (p0.001). Post hoc analyses revealed a significant reduction in time spent in N1 (p0.05 ON-SXB 6 g; p0.001 7.5 and 9 g) and REM (all p0.001) and increased time spent in N3 with ON-SXB vs placebo (all p0.001), with a significant increase in delta power (p0.01 ON-SXB 6 g; p0.05 7.5 g; p0.001 9 g) and increased REM latency (ON-SXB 7.5 g vs placebo; p0.05). Significant improvements in disrupted nighttime sleep were observed regardless of concomitant stimulant use.The clinically beneficial, single nighttime dose of ON-SXB significantly improved disrupted nighttime sleep in patients with narcolepsy.ClinicalTrials.gov NCT02720744.

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< 0.05 [post hoc]; 6 , 7.5, and 9 g, all P< 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< 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< 0.001]; ≥50%, 38.4% vs 20.8% [P< 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< 0.001]; 100%, 6.8% vs 0 [P< 0.05]; 9-g dose: ≥25%, 58.9% vs 41.7% [P< 0.001]; ≥50%, 49.3% vs 26.4% [P< 0.001]; ≥75%, 32.9% vs 15.3% [P< 0.01]; 100%, 11.0% vs 2.8% [P< 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

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

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

Introduction Sodium oxybate (SXB) is a standard-of-care treatment for adults with narcolepsy. Existing oxybate formulations are immediate release (IR), requiring patients to awaken for a second dose 2.5–4 hours after the first bedtime dose. Once-nightly SXB (ON-SXB; FT218), an investigational extended-release formulation, replaces this middle-of-the-night dosing with a once-at-bedtime regimen. RESTORE (NCT04451668) is an open-label/switch study evaluating the safety/tolerability of ON-SXB and patient preferences for ON-SXB or IR oxybate. Methods RESTORE includes participants aged ≥16 years with narcolepsy type 1 or 2 who completed the phase 3 REST-ON trial, were on stable-dose (≥1 month) IR oxybate, or were oxybate-naive. Initial doses for participants switching from IR oxybate are equivalent/closest to the previous total dose/night; incremental adjustments (1.5 g/week; maximum, 9 g/night) are allowed. A nocturnal adverse event (AE) questionnaire about switch participants’ IR oxybate experience in the previous 3 months was completed at baseline. Switch participants completed the preference questionnaire after 3 months of ON-SXB treatment. Results Data available from preference questionnaires (n=78) and nocturnal AE questionnaires (n=130) were analyzed at the interim data cutoff (01 July 2022). Most common AEs thus far were nausea, headache, and somnolence. The once-nightly dosing regimen was preferred by 93.6% (73/78) of participants. The second nightly IR oxybate dose was unintentionally missed in the previous 3 months by 65.4% (85/130) of switch participants; 80.2% (73/91) who intentionally and/or unintentionally missed the second dose felt worse the next day. Participants who took their second nightly IR oxybate dose >4 h after the first dose (51/130 [39.2%]) reported being somewhat, quite a bit, or extremely groggy/unsteady the next morning (26/51 [51.0%]). Inconvenience of the second dose was reported by 70.8%. Other issues related to the second dose were anxiety (29.2%) and the need to be woken by someone else (23.1%). In the past 3 months, 118 participants (90.8%) arose from bed after waking to take the second dose; 9 of these participants reported having fallen, with 5 reporting injuries. Conclusion These interim RESTORE data demonstrate patient preference for once-at-bedtime dosing of ON-SXB and indicate treatment burden associated with twice-nightly IR oxybate. Support (if any) Avadel Pharmaceuticals

What is this summary about? This is a plain language summary of an article originally published in the journal Sleep. Once-nightly sodium oxybate (ON-SXB for short; also known as FT218) is a potential treatment for excessive daytime sleepiness (EDS for short) and sudden muscle weakness known as cataplexy. The US Food and Drug Administration (FDA) is deciding whether to approve ON-SXB to be prescribed to adults with narcolepsy. The REST-ON clinical study looked at whether ON-SXB was better than a substitute that had no medicine in it (called a placebo) at treating narcolepsy symptoms. What were the results? The results of this study showed that people who took ON-SXB were able to stay awake longer during the day, felt less sleepy in the daytime, had less cataplexy, and were more improved overall than people who took placebo. Common side effects with ON-SXB were nausea, vomiting, dizziness, bedwetting, and headache. What do the results mean? If approved by the FDA, people with narcolepsy may have the option to choose a form of sodium oxybate that they only have to take once at bedtime. They could avoid taking a second middle-of-the-night dose. ClinicalTrials.gov NCT number: NCT02720744

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

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

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

Treatment for narcolepsy with sodium oxybate (SXB) has required twice-nightly dosing, at bedtime and 2.5-4 h later. This study evaluated the pharmacokinetics of FT218, an investigational, extended-release, once-nightly formulation of SXB (ON-SXB), vs twice-nightly SXB.In this phase 1, open-label study, healthy volunteers were randomized (1:1) to ON-SXB 6 g or twice-nightly SXB (two 3-g doses administered 4 h apart); minimum 3-day washout before crossover. Doses were administered 2 h post-evening meal. Blood samples for pharmacokinetic assessments were collected predose and up to 14 h after the first dose during each treatment period.Twenty-eight participants were enrolled (mean age, 39.6 years; 54% women; 93% white). Mean ± SEM area under the concentration-time curve for ON-SXB was 282.7 ± 30.2 μg·h/mL vs 273.3 ± 27.8 μg·h/mL for twice-nightly SXB. Geometric mean ratio (GMR; 90% CI) was 102.9 (98.0-108.0). Maximum γ-hydroxybutyrate (GHB) plasma concentration (CGHB exposure and C

Jordan Dubow,1 Alon Y Avidan,2 Bruce Corser,3 Amod Athavale,4 David Seiden,1 Clete Kushida5 1Avadel Pharmaceuticals, Chesterfield, MO, USA; 2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Sleep Management Institute, Cincinnati, OH, USA; 4Trinity Life Sciences, Waltham, MA, USA; 5Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford Sleep Medicine Center, Redwood City, CA, USACorrespondence: David Seiden, Tel +1 954 600-4625, Fax +1 636-449-1850, Email dseiden@avadel.comPurpose: Current US FDA-approved treatments for narcolepsy include sodium oxybate (SXB) and calcium, magnesium, potassium, and sodium oxybates (mixed-salt oxybates), which require 2 nightly doses, 1 at bedtime and another 2.5 to 4 hours later. Once-nightly SXB (ON-SXB; FT218) is under FDA review to treat adults with narcolepsy. This study quantitatively characterized attributes of SXB treatment preferred by individuals with narcolepsy via a discrete choice experiment (DCE) and evaluated preferences for the product profiles of once-nightly vs twice-nightly SXB treatment.Patients and Methods: Adults with self-reported physician-diagnosed narcolepsy for ≥ 1 year and current or prior twice-nightly SXB treatment were eligible for this 30-minute, web-based study capturing patient experiences and a DCE. Participants responded to a survey instrument using 9-point scales; higher scores indicated greater severity/preference/satisfaction. In the DCE, hundreds of profiles were generated, each combining attributes of twice-nightly SXB and ON-SXB based on clinical trial data. The DCE was analyzed using a hierarchical Bayesian model.Results: Seventy-five participants were surveyed (50 current and 25 past twice-nightly SXB users). Dosing frequency was the most important attribute of SXB treatment; once nightly was significantly preferred vs twice nightly. The most common reasons for overall product preference were lack of need to wake up in the middle of the night for a second dose (48%), fewer side effects (46%), and ease of administration (32%). Number of nightly doses was the most important driver of taking the medication exactly as directed and reduced anxiety/stress. Participants were significantly more likely to prefer the blinded product profile of once-nightly SXB over twice-nightly SXB (mean rating, 7.5 vs 4.3; P< 0.05).Conclusion: Among the choices presented, dosing frequency was the most important attribute for overall product choice, likelihood to take medication exactly as directed, and reducing anxiety/stress. The ON-SXB blinded profile was significantly preferred over twice-nightly SXB.Keywords: narcolepsy, patient preference, adherence, sodium oxybate, discrete choice experiment, once-nightly

Introduction Available, immediate-release oxybate products for narcolepsy require patients to awaken for a second dose 2.5-4 h after the first to cover a full night of sleep. The investigational, extended-release once-nightly sodium oxybate (ON-SXB; FT218) eliminates this middle-of-the-night dosing. This interim analysis from the ongoing RESTORE study (NCT04451668) assessed patient preferences for ON-SXB versus twice-nightly sodium oxybate (SXB) and experiences with the second nightly SXB dose in patients who switched from twice-nightly SXB to ON-SXB. Methods Participants enrolled in the open-label extension/switch study (RESTORE) were aged ≥16 y with a confirmed diagnosis of narcolepsy type 1 or 2 from the phase 3 REST-ON trial or receiving stable doses of twice-nightly SXB for ≥1 month. Initial ON-SXB doses for switch patients were equivalent/closest to their previous total nightly SXB dose. Patient preference questionnaires were completed by switch patients 3 months after switching and nocturnal adverse event (AE) questionnaires at baseline. Results At an interim data cutoff date of November 22, 2021, 46 participants completed patient preference questionnaires; 93.5% (43/46) preferred ON-SXB to twice-nightly SXB. Nocturnal AE questionnaires were completed by 76 switch participants. In the 3 months before switching to ON-SXB, 62% (47/76) had unintentionally missed their second twice-nightly SXB dose, with 86% experiencing worse narcolepsy symptoms the next day. Forty percent (30/76) reported taking their second twice-nightly SXB dose >4 h after the first dose, with 47% reporting being somewhat, quite a bit, or extremely groggy/unsteady the next morning. For 76% (58/76), taking a second nighttime dose was somewhat, quite a bit, or extremely inconvenient. Additionally, 91% (69/76) reported that they had arisen from bed after the second dose; of these, 5 reported associated falls, and 3 had injuries. Anxiety (25%) and the need for someone else to wake them (21%) were also reported. One participant reported that the medication was missing when they awoke for the second dose. Conclusion These interim data indicate that individuals with narcolepsy and prior experience taking SXB prefer ON-SXB to twice-nightly SXB. Treatment burden from the second nightly SXB dose may be alleviated with ON-SXB. Support (If Any) Avadel Pharmaceuticals

Introduction FT218 is an investigational, extended-release, once-nightly formulation of sodium oxybate (ON-SXB) for adults with narcolepsy. ON-SXB treatment achieved significant improvement vs placebo (6 g, 7.5 g, and 9 g, all P Methods Participants in REST-ON (aged ≥16 years with narcolepsy type 1 or 2) were randomized 1:1 to receive ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. MWT response was defined as ≥5-min increase from baseline in mean sleep latency, ESS response as a score ≤10, and cataplexy response as ≥50% reduction from baseline in mean NCA. Effect sizes were calculated using Cohen’s d; NNTs were the inverse of the absolute risk reduction. Results The modified intent-to-treat population included 190 participants (ON-SXB, n=97 [NT1, n=73]; placebo, n=93 [NT1, n= 72]). For MWT response, all ON-SXB doses (6 g at week 3, 7.5 g at week 8, and 9 g at week 13) had NNTs of 3 and effect sizes of 0.7–0.9. A dose-response effect was seen for ESS response with NNTs ranging from 3 to 6. Effect sizes were between –0.5 to –0.7 for the 3 doses (decreases signifying response). The NNT for cataplexy response was 6 for ON-SXB 6 g and 3 for ON-SXB 7.5 and 9 g; effect sizes were between –0.7 to –0.8. Conclusion NNT calculations show that 3–6 patients need to be treated with ON-SXB to achieve ≥5 minutes increased sleep latency on the MWT, ESS score ≤10, or a ≥50% reduction in cataplexy. Considering these post-hoc analyses may be useful to clinicians in discussing treatment expectations and provide support for the efficacy of ON-SXB for excessive daytime sleepiness and cataplexy in adults with narcolepsy.NNT calculations show that 3–6 patients need to be treated with ON-SXB to achieve ≥5 minutes increased sleep latency on the MWT, ESS score ≤10, or a ≥50% reduction in cataplexy. Considering these post-hoc analyses may be useful to clinicians in discussing treatment expectations and provide support for the efficacy of ON-SXB for excessive daytime sleepiness and cataplexy in adults with narcolepsy. Support (If Any) Avadel Pharmaceuticals

Introduction Once-nightly sodium oxybate (ON-SXB; FT218) was evaluated for treatment of narcolepsy in the phase 3 REST-ON trial (NCT02720744). Significant improvement was shown for the three coprimary endpoints mean sleep latency on the Maintenance of Wakefulness test (MWT), Clinical Global Impression of Improvement (CGI-I) rating, and weekly number of cataplexy attacks overall (all P Methods Participants aged ≥16 years were randomized 1:1 to receive ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Mixed-effects models for repeated measures were used to calculate P values for change from baseline vs placebo at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g) for secondary REST-ON endpoints of Epworth sleepiness scale (ESS) score, sleep shifts (ie, the number of shifts from stages N1, N2, N3 and rapid eye movement [REM] sleep to Wake and from N2, N3 and REM sleep to N1), nocturnal arousals (NA), and patient-reported sleep quality and refreshing nature of sleep (100-point visual analog scale). Results Of 190 participants, 145 had NT1 (ON-SXB, n=73; placebo, n=72) and 45 had NT2 (ON-SXB, n=24; placebo, n=21). Improvements with ON-SXB vs placebo were reported for shifts to a lighter stage of sleep (NT1: 6, 7.5, 9 g, all P Conclusion Results of these subgroup efficacy analyses are generally consistent with previously reported REST-ON endpoints and support ON-SXB treatment efficacy in adults with NT1 or NT2. Support (If Any) Avadel Pharmaceuticals

Study Objectives To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial. Methods Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness Test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments. Results In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n = 107) or placebo (n = 105). For the three coprimary endpoints and Epworth Sleepiness Scale, all three doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement versus placebo (all p < 0.001). For ON-SXB 9 g versus placebo, increase in mean sleep latency was 10.8 versus 4.7 min (Least squares mean difference, LSMD [95% CI], 6.13 [3.52 to 8.75]), 72.0% versus 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76 to 11.23]), change in mean weekly number of cataplexy attacks was –11.5 versus –4.9 (LSMD [95% CI], –6.65 [–9.32 to –3.98]), and change in Epworth Sleepiness Scale was –6.5 and –2.7 (LSMD [95% CI], –6.52 [–5.47 to –2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis. Conclusions ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose. Clinical Trial Registration ClinicalTrials.gov: NCT02720744, https://clinicaltrials.gov/ct2/show/NCT02720744.

Introduction: Levodopa remains the most effective treatment for the motor symptoms of Parkinson’s disease (PD). However, with chronic treatment, PD patients develop motor complications, whi...

Introduction Extended-release once-nightly sodium oxybate (ON-SXB; FT218) is in development for adults with narcolepsy. In REST-ON, significant improvements on the Maintenance of Wakefulness test, Clinical Global Impression of Improvement rating, and number of weekly cataplexy episodes occurred with all analyzed ON-SXB doses vs placebo (week 3, 6-g dose; week 8, 7.5-g dose; week 13, 9-g dose; all P Methods Participants in the double-blind, phase 3 REST-ON (NCT02720744) trial were ≥16 years old, had narcolepsy type 1 or 2, and were randomized 1:1 to ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or placebo. Participants recorded ESS scores and VAS for sleep quality and refreshing nature of sleep (1-100; 1=poor quality/unrefreshing sleep; 100=good quality/refreshing sleep) using electronic diaries. P-values were calculated using a mixed-effects model for repeated measures in the modified intent-to-treat (mITT) population (ie, participants receiving ≥1 dose of study drug having ≥1 efficacy assessment at week 3). Results In the mITT population (n=190; ON-SXB, n=97; placebo, n=93), baseline ESS scores were 16.6 and 17.5 with ON-SXB and placebo, respectively. At week 2, ESS score was significantly improved with ON-SXB vs placebo (P Conclusion Improvement in daytime sleepiness, sleep quality, and refreshing nature of sleep occurred with ON-SXB beginning the first week of treatment. Some patients may experience early narcolepsy symptom relief with ON-SXB. Support (If Any) Avadel Pharmaceuticals

Introduction In REST-ON, once-nightly sodium oxybate (ON-SXB; FT218) achieved significant improvement (P Methods Individuals aged ≥16 years were randomized 1:1 to receive ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Post-hoc sensitivity analyses were conducted with methods to handle missing data: completer population; placebo-based multiple imputation (MI) with missing not at random assumption; analysis of covariance (ANCOVA); and tipping point-based MI of worsening values until P>0.05. Results Completers (ON-SXB, n=69; placebo, n=79) showed significant improvement (P Conclusion These results support the robustness of the primary efficacy data for ON-SXB for narcolepsy treatment. Support (If Any) Avadel Pharmaceuticals

Introduction In the REST-ON trial (NCT02720744), once-nightly sodium oxybate (ON-SXB; FT218) was associated with significant improvement vs placebo for mean sleep latency on the Maintenance of Wakefulness test (MWT) and Clinical Global Impression of Improvement (CGI-I) rating in the overall population (both P Methods Participants (≥16 years of age) with narcolepsy type 1 or 2 were randomized 1:1 to ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Mixed-effects models for repeated measures calculated P values for change from baseline vs placebo at weeks 3 (6 g), 8 (7.5 g), and 13 (9 g) in ESS score, sleep shifts (ie, number of shifts from N1, N2, N3, and rapid eye movement [REM] sleep to Wake and from N2, N3, and REM sleep to N1), nocturnal arousals (NA), and patient-reported outcomes of sleep quality and refreshing nature of sleep on a 100-point visual analog scale. Results In the modified intent-to-treat population (n=190), 119 participants took concomitant stimulants (ON-SXB, n=66; placebo, n=53); 71 did not take stimulants (ON-SXB, n=31; placebo, n=40). Improvements with ON-SXB vs placebo were reported: ESS (stimulants: all doses, P≤0.01; no stimulants: 6 g, directional improvement; 7.5 g, P Conclusion Data from these post-hoc analyses were consistent with the previously reported results from REST-ON and support the efficacy of ON-SXB for EDS and DNS, as measured by objective and subjective endpoints whether or not stimulants were concurrently used. 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

Introduction Disturbed nocturnal sleep (DNS) is a common symptom in patients with narcolepsy, characterized by fragmented sleep, including frequent brief nightly awakenings. Sodium oxybate (SO) is an effective treatment for narcolepsy; however, currently available formulations must be taken twice nightly. FT218 is an investigational once-nightly controlled-release formulation of SO. Here, we evaluated the efficacy of FT218 on polysomnographic (PSG) measures of DNS and number of arousals (NAs) in patients with narcolepsy types 1 and 2. Methods This was a randomized, double-blind, placebo-controlled, multicenter study. Patients with narcolepsy aged ≥16 years were randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks. Secondary endpoints included PSG measurements of DNS (defined as shifts to wake/N1 from N1, N2, N3, and REM) and NAs (defined per AASM Scoring Manual guidelines [v2.6]). Results Patients receiving FT218 had significant improvements vs placebo in DNS; the LS mean difference between FT218 and placebo was −22.63 for 9.0 g (week 13), −17.70 for 7.5 g (week 8), and −11.00 for 6.0 g (week 3) (all P Conclusion FT218 at all evaluated doses showed significant reduction in DNS and number of NAs vs placebo for all doses of FT218 evaluated. FT218 was generally well tolerated; the most common adverse events were consistent with known SO side effects. FT218 could offer a new once-nightly treatment option for DNS in patients with narcolepsy as demonstrated by PSG measures. Support (if any) Avadel Pharmaceuticals.

Introduction Patients with narcolepsy are more likely to be obese compared with healthy controls. FT218 is an investigational once-nightly sodium oxybate formulation for the treatment of narcolepsy. Here, we report on changes in weight-related clinical values with FT218 treatment in patients with narcolepsy. Methods This was a randomized, double-blind, placebo-controlled multicenter study in patients with narcolepsy ≥16 years old. Patients were not excluded based on baseline weight or body mass index (BMI). Patients were randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Weight and BMI were measured at baseline and study end. LS mean difference in BMI between FT218 and placebo was analyzed using analysis of covariance. Results A total of 107 patients received FT218 and 105 patients received placebo. At baseline, mean (SD) weight was 81.2 (20.8) kg in the FT218 treatment group and 82.1 (22.5) kg in the placebo treatment group. At end of study (week 13), mean (SD) weight was 80.9 (21.9) kg in the FT218 treatment group and 82.25 (21.6) in the placebo treatment group. At week 13, mean (SD) change in weight from baseline was –1.29 (3.6) kg for FT218 and 0.19 (2.6) kg for placebo; 17.5% of patients receiving FT218 vs 3.8% of patients receiving placebo had ≥5% weight loss. At baseline, mean (SD) BMI was 28.1 (7.8) kg/m2 in the FT218 treatment group and 28.2 (6.6) kg/m2 in the placebo treatment group. At study end (week 13), LS mean (SE) change from baseline in BMI was ‒0.51 (0.13) kg/m2 for patients receiving FT218 and 0.08 (0.13) kg/m2 for patients receiving placebo (LS mean difference [95% CI], ‒0.59 [‒0.95 to ‒0.23]; P=0.001). FT218 was generally well tolerated. Conclusion Patients receiving FT218 experienced a significantly greater decrease in weight and BMI vs placebo. These results suggest that treatment with once-nightly FT218 may provide weight-related benefit for patients with narcolepsy and comorbid weight gain. Support (if any) Avadel Pharmaceuticals

Introduction FT218 is an investigational, once-nightly, controlled-release formulation of sodium oxybate for the treatment of narcolepsy. The purpose of this post hoc analysis of the REST-ON study was to evaluate the effect of FT218 on measures of excessive daytime sleepiness (EDS) in patients with narcolepsy subtypes 1 (NT1) and 2 (NT2). Methods This was a randomized, double-blind, placebo-controlled, multicenter study in patients with narcolepsy ≥16 years old. Patients were stratified by narcolepsy subtypes and randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Assessments of EDS included mean sleep latency (minutes) on maintenance of wakefulness test (MWT) and Clinical Global Impression-Improvement (CGI-I) in sleepiness. Results A total of 190 patients were included in the modified intent-to-treat population (NT1: FT218, n=72; placebo, n=73; NT2: FT218, n=21, placebo, n=24). Patients with NT1 or NT2 receiving FT218 had significant improvement in MWT. LS mean difference in mean sleep latency (minutes) vs placebo for NT1 was 5.97 for 9.0 g (week 13), 7.02 for 7.5 g (week 8), and 4.89 for 6.0 g (week 3; all P Conclusion FT218 had similar efficacy on EDS at evaluated doses in NT1 and NT2, with improvement in MWT and CGI-I greater than placebo. FT218 may provide effective treatment for EDS in patients with narcolepsy, with or without cataplexy. Support (if any) Avadel Pharmaceuticals.

Introduction Sodium oxybate (SO) is an effective treatment for patients with narcolepsy; however, currently available SO formulations require twice-nightly dosing. The purpose of this study was to evaluate efficacy and safety of FT218, an investigational once-nightly controlled-release SO formulation, for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy types 1 (NT1) and 2 (NT2). Methods This was a randomized, double-blind, placebo-controlled, multicenter study in patients with narcolepsy ≥16 years old. Patients were randomized 1:1 to receive FT218 or matching placebo: 4.5 g/night for 1 week, 6.0 g/night for 2 weeks, 7.5 g/night for 5 weeks, and 9.0 g/night for 5 weeks (maximum treatment duration, 13 weeks). Coprimary endpoints were mean sleep latency (minutes) on maintenance of wakefulness test (MWT), Clinical Global Impression-Improvement (CGI-I) of sleepiness, and weekly number of cataplexy attacks (NCAs; NT1 only). Results A total of 212 patients were randomized and received study treatment (FT218, n=107; placebo, n=105). FT218 showed significant (P Conclusion All evaluated doses of FT218 showed significant improvement vs placebo in mean sleep latency on MWT, CGI-I, and weekly NCAs. FT218 was generally well tolerated and the most common adverse events were consistent with known side effects of SO. Support (if any) Avadel Pharmaceuticals.

Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The approved formulation requires twice-nightly dosing: at bedtime and 2.5 - 4 hours later, which results in two distinct Cmax’s. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the pharmacokinetic-adverse event (AE) relationship for FT218, an investigational once-nightly sodium oxybate formulation. Methods Six single-dose, randomized, crossover studies that assessed the pharmacokinetics of FT218 at 4.5, 6, 7.5 and 9 g in healthy voluntters were used in this analysis. Lattice plots, “spaghetti” plots, and scatter plots of individual gamma hydroxybutyrate concentrations and indicators when AEs by system, organ, or class (SOC) were created to determine any PK-AE relationship. Results A total of 129 healthy volunteers received single doses of FT218 between 4.5 - 9 g. Most AEs, specifically for the neurological and gastrointestinal SOC, occurred close to Tmax, during the Cmax period, which for FT218 was around 1.5-2 hours after dosing. These AEs were known AEs associated with sodium oxbyate. There appeared to be no clear correlation between individual plasma GHB concentrations levels and AEs between subjects. Individual AEs were equally distributed above and below the mean population Cmax and AUCinf for the dataset. Conclusion In general, adverse events for FT218 occurred around Tmax. There was no clear population toxicokinetic range for when AEs occur with FT218, but mostly individual thresholds. Since it appears AEs are related to Cmax, and FT218 only has one Cmax compared to two with the currently available product, it is hypothesized that FT218 will have a favorable safety profile compared to twice-nightly dosing. Support This work was supported by Avadel Pharmaceuticals

Purpose FT218 is an investigational, once-nightly, modified-release formulation of sodium oxybate (SO). SO effectively treats excessive daytime sleepiness and cataplexy in patients with narcolepsy. Current approved SO formulations, at effective doses of 6, 7.5, and 9 g, require twice-nightly divided dosing, with the first dose taken at bedtime and the second 2.5–4 h later. The purpose of the following studies was to evaluate the pharmacokinetic properties, safety profile, and tolerability of FT218 in healthy adults. Methods Four crossover, single-dose studies were conducted. The first was a pilot study (n = 16) that compared 3 prototype formulations of FT218 4.5 g to twice-nightly SO 4.5 g (2 divided doses of 2.25 g); the second, a dose-proportionality study (n = 20) that evaluated FT218 4.5, 7.5, and 9 g; the third, a relative bioavailability study (n = 28) that compared FT218 6 g with twice-nightly SO 6 g (2 divided doses of 3 g); and the fourth, a food-effect study (n = 16) of FT218 6 g. Results In the pilot study, FT218 prototype 2 had a lower Cmax, lower plasma concentration 8 h after dosing (C8h), similar exposure (AUC), and comparable interperson variability to twice-nightly SO 4.5 g. Exploratory pharmacodynamic data indicated similar sleep quality and morning alertness between FT218 and twice-nightly SO. Prototype 2 was selected for further development. In the dose-proportionality study, FT218 had dose proportionality for Cmax and slightly more than dose proportionality for AUC. The relative bioavailability study confirmed that FT218 6 g had lower Cmax and C8h than twice-nightly SO 6 g but equivalent AUC and comparable variability. In the food-effect study, FT218 6 g had longer tmax (1 h later), lower Cmax (67%), and decreased AUC (86%) in fed versus fasted states. For all studies, adverse events with FT218 were mostly mild or moderate in severity, nonserious, and known to be associated with SO. Most common adverse events included somnolence, dizziness, and nausea. Safety profiles of FT218 and twice-nightly SO at 4.5 and 6 g were similar. Implications Once-nightly FT218 at 4.5 and 6 g had lower overall Cmax and C8h and similar exposure and variability compared with twice-nightly SO. FT218 was generally well tolerated and comparable to twice-nightly SO.

Objective: To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD). Methods: This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5–15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995. Results: All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis. Conclusions: After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED. Classification of evidence: This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.

Introduction OFF episodes negatively impact quality of life in patients with Parkinson's disease (PD). There remains a need for an acute, effective, noninvasive treatment. Background APL-130277 is a sublingually administered apomorphine oral strip. Methods The authors conducted a phase 2, open-label, proof-of-concept study. Patients presented to clinic in the morning in the practically defined OFF state and were dosed with APL-130277 10 mg. Assessments of OFF or ON state and MDS-UPDRS part III were conducted predose and at 15, 30, 45, 60, and 90 minutes. If a full ON was not achieved within 3 hours, the dose was increased in 5 mg increments until a full ON was achieved or to a maximum dose of 30 mg. Patients could be dosed up to two times a day over 3 days. Patients were pretreated with trimethobenzamide for 3 days, which was continued during the study. Results Of 19 patients, 15 (78.9%) achieved a full ON response. All 15 achieved a full ON response within 30 minutes and 6 of the 15 patients (40.0%) achieved a full ON response within 15 minutes. The mean (SD) duration of ON was 50 (19.4) minutes. Of the 15 patients, 9 (60.0%) remained fully ON for ≥90 minutes. There were no discontinuations as a result of an adverse event. The most common adverse events were dizziness (36.8%), somnolence (31.6%), and nausea (21.1%). Conclusion This was the first study of a new sublingual apomorphine formulation in PD patients. In this open-label study, APL-130277 appeared to provide a convenient, rapid, and reliable method for treating OFF episodes. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Background Continuous administration of levodopa‐carbidopa intestinal gel (carbidopa‐levodopa enteral suspension) through a percutaneous endoscopic gastrojejunostomy is a treatment option for advanced Parkinson disease (PD) patients with motor fluctuations resistant to standard oral medications. Safety data from 4 prospective studies were integrated to assess the safety of this therapy. Methods Safety data from 4 studies were summarized using 2 overlapping data sets, permitting the separation of procedure/device–associated (n = 395) from non‐procedure/device adverse events (n = 412). Results At the data cutoff, median exposure to levodopa‐carbidopa intestinal gel was 911 days (range, 1‐1980 days) with 963 total patient‐years of exposure. Procedure/device adverse events occurred in 300 patients (76%), and serious adverse events occurred in 68 (17%); most frequently reported procedure/device adverse events and serious adverse events were complications of device insertion (41% and 8%, respectively) and abdominal pain (36% and 4%, respectively). Non‐procedure/device adverse events occurred in 92% (379), with most frequently reported being insomnia (23%) and falls (23%); 42% (171) had non‐procedure/device serious adverse events, with most frequently reported being pneumonia (5%) and PD symptoms (2%). Adverse events led to discontinuation in 17% (72), most frequently because of complication of device insertion (2.4%). There were 34 treatment‐emergent deaths (8.3%) in the overlapping data sets, 2 of which (0.5%) were considered “possibly related” to the treatment system. Conclusion In the largest collection of levodopa‐carbidopa intestinal gel safety data from prospective clinical studies, procedure/device events were frequently reported and occasionally life threatening. Most non‐procedure/device events were typical for levodopa treatment and an elderly population. These factors combined with high treatment efficacy led to a relatively low discontinuation rate in advanced PD patients. © 2015 International Parkinson and Movement Disorder Society

Introduction Avadel Pharmaceuticals has developed FT218, a once nightly sodium oxybate (SO) formulation for the treatment of excessive daytime sleepiness (EDS) and cataplexy in narcoleptic patients. REST-ON, a pivotal efficacy/safety study is expected to be completed in the first half of 2020. Previous Phase 1 studies have demonstrated FT218 delivers a pharmacokinetic profile needed for once-nightly dosing. The purpose of this study is to evaluate long-term safety of FT218 in REST-ON completers and dosing strategy when switching from twice-nightly SO to FT218. Methods The study will enroll NT1/NT2 patients who completed REST-ON or patients switching from stable dose of twice-nightly SO to FT218. REST-ON completers will initiate FT218 at 4.5 g and increase by 1.5 g to the highest tolerated dose or the dose deemed effective (up to 9 g). Switch patients will initiate FT218 at the equivalent/closest dose to their current twice-nightly SO and titrate in accord with safety/efficacy. The study will enroll approximately 250 patients for a duration of two years. Results The primary endpoint for REST-ON completers will be safety and tolerability. Secondary endpoints for REST-ON completers will include changes in ESS, reported cataplexy and other REM associated phenomena as well as changes in clinician and patient global impression. For switch patients, endpoints will include percentage of subjects that stay on the same, higher or lower dose of FT218 compared to twice-nightly SO, as well as the percentage of subjects who report a preference for the once-nightly dosing regimen. Conclusion The results of this open label extension/switch study will further elucidate the potential benefits of once-nightly FT218 regarding long term safety/tolerability, nocturnal safety/tolerability and efficacy, and importantly provide dosing and preference data for patients switching from twice-nightly SO to once-nightly FT218. Support This work was supported by Avadel Pharmaceuticals.

Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The FDA approved formulation requires twice-nightly dosing; at bedtime and 2.5 - 4 hours later. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the relative bioavailability of investigational once-nightly sodium oxybate, FT218, 6 g, compared to commercially available twice-nightly sodium oxybate and the food effect of FT218. Methods Two crossover, single-dose pharmacokinetic studies were conducted in healthy volunteers. The first, a relative bioavailability study (n=28) was completed comparing FT218 6 g to twice-nightly sodium oxybate 6 g (in two divided doses of 3 g). The second, evaluated the food effect (n=16) of FT218 6g in the Fed vs. Fasted state. Results FT218 had a lower overall Cmax than twice-nightly sodium oxybate, while AUC was equivalent. C8h level and variability was comparable between FT218 and twice-nightly sodium oxybate. In the Fed, compared to the Fasted state, FT218 had a longer Tmax, lower Cmax and decreased AUC (Cmax 67%, AUC 86%, Tmax 1-hour slower than Fasted values). Adverse Events with FT218 were mostly mild or moderate in severity, non-serious and known AEs associated with sodium oxybate. The safety profiles of FT218 and twice-nightly sodium oxybate at 6 g appeared similar. Conclusion Once-nightly FT218 at 6 g demonstrated a lower overall Cmax and similar exposure to twice-nightly sodium oxybate, with similar C8h plasma levels and C8h variability. In the Fed state, AUC and Cmax of FT218 was lower than in the Fasted State. FT218 was generally safe and well tolerated and the safety profile appeared comparable to twice-nightly sodium oxybate. Support This work was supported by Avadel Pharmaceuticals.

Background: Previous studies have investigated associations between apolipoprotein E (APOE)-ɛ4 allele status and acetylcholinesterase inhibitor treatment response in patients with Alzheimer’s disease. The ability to draw definitive conclusions regarding the effect of APOE-ɛ4 genotype on treatment response has been hindered by inconsistent results among studies and methodological limitations that restrict interpretation of study findings. Objective: To determine whether APOE-ɛ4 carrier status influences the magnitude of change in 13-item Alzheimer’s Disease Assessment Scale−Cognitive Subscale (ADAS-cog) score associated with acetylcholinesterase inhibitor treatment (i.e., donepezil). Methods: Analyses were performed using pooled data from the donepezil and placebo treatment arms of three consecutive, similarly designed, 12-week, multi-national, randomized clinical studies that enrolled patients with mild-to-moderate Alzheimer’s disease. Correlations between APOE-ɛ4 carrier status and ADAS-cog scores were evaluated using analysis of covariance. Results: No appreciable interaction between donepezil response and APOE-ɛ4 carrier status or copy number was detected. Both carriers and non-carriers of APOE-ɛ4 who received donepezil experienced significant improvements from baseline in ADAS-cog score versus placebo (p < 0.05). Change from baseline to final observation in the donepezil treatment group was – 2.95 for APOE-ɛ4 carriers and – 4.09 for non-carriers (p = 0.23). In contrast, non-carriers of APOE-ɛ4 in the placebo treatment group exhibited a greater improvement from baseline versus carriers (–2.38 versus – 0.60, p = 0.05). Conclusion: Within this population, APOE genotype had no statistically significant effect on cognitive response to donepezil treatment; however, APOE-ɛ4 allele status was associated with a difference in the magnitude of the change in ADAS-cog of placebo-treated patients.

Background Levodopa-carbidopa intestinal gel (LCIG) provides continuous infusion and reduces “off” time in advanced Parkinson's disease (PD) patients with motor fluctuations despite optimized pharmacotherapy. Methods Clinical experience with 2 LCIG dosing paradigms from phase 3 studies was examined. In an open-label, 54-week study, LCIG was initiated as daytime monotherapy via nasojejunal (NJ) tube then switched to percutaneous endoscopic gastrojejunostomy (PEG-J) tube; adjunctive therapy was permitted 28 days postPEG-J. In a 12-week, double-blind, placebo-controlled, double-dummy trial, patients continued stable doses of existing anti-PD medications, but LCIG replaced daytime oral levodopa-carbidopa and was initiated directly via PEG-J. Results In the open-label study, 92% of 354 patients received monotherapy at post–PEG-J week 4; mean titration duration was 7.6 days; dosing remained stable post-titration (mean total daily dose [TDD] was 1572 mg at last visit). In the double-blind trial, 84% received polypharmacy; mean titration took 7.1 days for the LCIG arm (TDD post-titration: 1181 mg; n = 37). At post–PEG-J week 4, mean “off” time with LCIG was reduced by 3.9 h (open-label/monotherapy study) and 3.7 h (double-blind/polypharmacy trial). NJ treatment (open-label study only) required an additional procedure with related adverse events (AEs) and withdrawals. The most common AEs during PEG-J weeks 1–4 in the open-label/monotherapy and double-blind/polypharmacy trials, respectively, were complication of device insertion (35%, 57%) and abdominal pain (26%, 51%). Discontinuations due to nonprocedure/nondevice AEs were low (2.2%, 2.7%). Conclusion These results support the option of initiating LCIG with or without NJ and as either monotherapy or polypharmacy.

BACKGROUND Levodopa-carbidopa intestinal gel (LCIG) is delivered continuously via intrajejunal percutaneous gastrostomy tube. OBJECTIVE To examine long-term safety, efficacy and quality of life of LCIG in an open-label extension study. METHODS Patients received 52 weeks of open-label LCIG treatment following a 12-week double-blind, double-dummy trial in which they were randomized to either LCIG or immediate-release oral levodopa-carbidopa. Patient cohort designation was by receipt of LCIG in the preceding trial randomization (continuing-LCIG vs. LCIG-naive patients). RESULTS Sixty-two of 66 subjects in the double-blind proceeded to the open-label extension. Most subjects (95%) reported ≥1 adverse event (AE); only 3 subjects (4.8%) discontinued due to AEs. AE incidence declined gradually over 52 weeks. Serious AEs were reported by 23%. LCIG-naive patients (N = 29) showed a decrease in "Off" time and an increase in "On" time without troublesome dyskinesia (change from baseline to final visit in mean [SD] hours = -2.34 [2.78] P < 0.001 and 2.19 [3.70] P = 0.005, respectively), while continuing-LCIG patients (N = 33) showed sustained "Off" time duration and further improvement in "On" time without troublesome dyskinesia (-0.42 [2.67] P = 0.377 and 1.00 [2.58] P = 0.036, respectively). The majority of patients in both groups (LCIG-naive, continuing-LCIG, respectively) were rated 'Much Improved' or 'Very Much Improved' at final visit on the Clinical Global Impression-Improvement scale (69.0%, 69.7%). CONCLUSIONS Continuing-LCIG patients continued to derive benefit from LCIG while the magnitude of improvement among LCIG-naive patients was similar to that observed for patients on LCIG in the preceding double-blind study. The overall AE profile was consistent with previous phase 3 clinical trials involving the LCIG system.

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

OFF episodes negatively impact quality of life in patients with Parkinson's disease (PD). There remains a need for an acute, effective, noninvasive treatment.APL-130277 is a sublingually administered apomorphine oral strip.The authors conducted a phase 2, open-label, proof-of-concept study. Patients presented to clinic in the morning in the practically defined OFF state and were dosed with APL-130277 10 mg. Assessments of OFF or ON state and MDS-UPDRS part III were conducted predose and at 15, 30, 45, 60, and 90 minutes. If a full ON was not achieved within 3 hours, the dose was increased in 5 mg increments until a full ON was achieved or to a maximum dose of 30 mg. Patients could be dosed up to two times a day over 3 days. Patients were pretreated with trimethobenzamide for 3 days, which was continued during the study.Of 19 patients, 15 (78.9%) achieved a full ON response. All 15 achieved a full ON response within 30 minutes and 6 of the 15 patients (40.0%) achieved a full ON response within 15 minutes. The mean (SD) duration of ON was 50 (19.4) minutes. Of the 15 patients, 9 (60.0%) remained fully ON for ≥90 minutes. There were no discontinuations as a result of an adverse event. The most common adverse events were dizziness (36.8%), somnolence (31.6%), and nausea (21.1%).This was the first study of a new sublingual apomorphine formulation in PD patients. In this open-label study, APL-130277 appeared to provide a convenient, rapid, and reliable method for treating OFF episodes. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Hypertension is the single most important risk factor for all types of stroke: ischemic stroke, intracerebral hemorrhage, and aneurysmal subarachnoid hemorrhage. Epidemiologic studies over the past 30 years have demonstrated a dramatic reduction in the incidence and mortality of all stroke types with good control of hypertension, and it appears that all effective antihypertensive agents have similar efficacy in their ability to reduce stroke risk. In addition, it appears that acute treatment of hypertension in the setting of intracerebral hemorrhage and subarachnoid hemorrhage is beneficial, but it is still uncertain in the setting of ischemic stroke what level of blood pressure will result in the best possible outcome.

Background: Acute ischemia typically results in a flaccid paralysis. An immediate spastic hemiparesis following ischemia has rarely been reported. One case involved a left hemispheric transient ischemic attack and the other cases occurred after intracerebral hemorrhage. Case Report: A 46-year-old male developed an immediate spastic hemiplegia shortly after coil embolization of an unruptured anterior communicating artery aneurysm. A CT perfusion scan at the time of these symptoms demonstrated hypoperfusion in the right anterior cerebral artery (ACA) territory. The patient was emergently taken back to the angiography suite where he was found to have right A2 ACA occlusion. Following abciximab infusion, the artery recanalized and the patient’s symptoms resolved. Repeat CT perfusion demonstrated resolution of the perfusion deficit in the right ACA territory and the patient’s neurological exam remained normal. Conclusion: Acute ACA ischemia can present with spasticity in the hyperacute period instead of flaccid paralysis.

Botulinum toxin type B (BTX-B) has been approved by the Food and Drug Administration for the treatment of cervical dystonia. However, as with botulinum toxin type A (BTX-A) it has off-label uses, such as for hyperhidrosis, focal dystonias, spasticity, and facial wrinkles. BTX-B has also been shown to be a safe and effective alternative for patients who are resistant to BTX-A. The most commonly reported side effects include dry mouth and dysphagia. To date, there have been few reports of visual disturbances associated with BTX-B use. In this study, we report on three individual patients who received BTX-B and who subsequently developed parasympathetic dysfunction of the visual system after injections of BTX-B at remote sites.