Jennifer Gudeman

Data from the REST‐ON trial were not available before the 2021 American Academy of Sleep Medicine (AASM) clinical practice guideline update, which included a literature review through August 2020. This post hoc analysis from REST‐ON assessed participants who achieved clinically significant improvements on individual AASM clinical significance thresholds (CSTs). Composites of the coprimary endpoints and a secondary endpoint were also analysed. Participants with narcolepsy aged ≥ 16 years were randomised 1:1 to once‐nightly sodium oxybate (ON‐SXB) or placebo for 13 weeks. Coprimary endpoints were mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Improvement (CGI‐I) rating, and number of cataplexy episodes; secondary endpoints included the Epworth Sleepiness Scale (ESS) score. Outcomes with ON‐SXB treatment compared with baseline were assessed according to the CSTs, and for those who met CSTs, the proportions of participants who experienced clinically significant improvements on a composite of ≥ 2, ≥ 3, or 4 endpoints were calculated. For improvements from baseline with ON‐SXB at Week 13 (9‐g dose), mean sleep latency on the MWT increased 10.8 min (CST, ≥ 2‐min increase), 92.8% rated improvement on the CGI‐I (CST, ≥ 33% of participants reporting improvement), reduction in number of cataplexy episodes was 60.8% reduction (CST, ≥ 25% reduction), and reduction in ESS score was −6.5 (CST, ≥ 2‐point decrease). At Weeks 3, 8 and 13, significantly more participants treated with ON‐SXB versus placebo experienced clinical improvements on ≥ 2, ≥ 3, or 4 endpoints ( p ≤ 0.05). These data demonstrate the robust efficacy of ON‐SXB across multiple clinically important narcolepsy symptoms per established CSTs, further supporting the use of ON‐SXB in clinical practice. Trial Registration: This manuscript presents the results of a post hoc analysis from the REST‐ON clinical trial (NCT02720744).

Background Once-nightly sodium oxybate (LUMRYZ™; ON-SXB; FT218) significantly improved narcolepsy symptoms in the phase 3 REST-ON trial. The objective of this post hoc analysis was to investigate the early efficacy of ON-SXB at weeks 1 (4.5-g dose) and 2 (6-g dose). Methods In REST-ON, participants (≥ 16 years) with narcolepsy type 1 or 2 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. Protocol-prespecified efficacy assessments were conducted at weeks 3 (6-g dose), 8 (7.5-g dose), and 13 (9-g dose). A post hoc analysis was conducted to assess the early efficacy of ON-SXB, defined as efficacy at weeks 1 (4.5-g dose) and 2 (6-g dose) on Epworth Sleepiness Scale (ESS) score, visual analog scale (VAS) sleep quality, and VAS refreshing nature of sleep. Least squares mean differences (LSMD) in change from baseline to weeks 1 and 2, 95% confidence intervals (CIs), and P values were calculated using mixed-effects models for repeated measures. Results In the modified intent-to-treat population (n = 190; ON-SXB, n = 97; placebo, n = 93), baseline ESS scores were 16.6 and 17.5, sleep quality scores were 53.8 and 55.9, and refreshing nature of sleep scores were 46.5 and 49.9 with ON-SXB and placebo, respectively. At week 1 (4.5 g), numerical improvement in ESS score (LSMD [95% CI], − 0.7 [− 1.6 to 0.2]) and significant improvements in sleep quality (3.6 [1.1–6.1]; P < 0.01) and refreshing nature of sleep (3.2 [0.5–5.9]; P < 0.05) were observed with ON-SXB versus placebo. At week 2 (6 g), significant improvements with ON-SXB versus placebo were observed for ESS score (− 1.3 [− 2.4 to − 0.2]; P < 0.02), sleep quality (7.0 [3.8–10.1]; P < 0.001), and refreshing nature of sleep (5.8 [2.3–9.4]; P = 0.001). Conclusions ON-SXB improved daytime sleepiness, sleep quality, and refreshing nature of sleep, with observable benefits beginning in the first week of treatment. These data may help clinicians set expectations with patients. Clinical Trial ID NCT02720744.

Background Once-nightly sodium oxybate (ON-SXB; LUMRYZ™; FT218) treatment significantly improved the coprimary endpoints of mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Improvement (CGI-I) rating, and number of weekly cataplexy episodes versus placebo in a randomized, placebo-controlled trial (REST-ON). The objective of these post hoc sensitivity analyses was to evaluate the robustness of treatment with ON-SXB, while accounting for missing participant data. Number needed to treat (NNT) and effect size analyses were conducted to quantify the treatment benefits. Methods Participants ≥ 16 years of age with narcolepsy type 1 or 2 were randomized 1:1 to receive ON-SXB (4.5 g [week 1]; 6 g [weeks 2–3]; 7.5 g [weeks 4–8]; or 9 g [weeks 9–13]) or placebo. Sensitivity analyses included completer population, placebo-based multiple imputation (MI) with a missing-not-at-random assumption, analysis of covariance (ANCOVA), and tipping-point–based MI of worsening values until P > 0.05. Mean differences and P-values were calculated for the MWT and number of cataplexy episodes. For CGI-I, odds ratios and P-values were calculated for completers; mean differences (1–7 points; lower values indicate greater improvement) and P-values were calculated using ANCOVA. Effect sizes were calculated using Cohen’s d; NNTs were calculated as the inverse of the absolute risk reduction. Results In the completer population (ON-SXB, n = 69; placebo, n = 79), all ON-SXB doses demonstrated significant improvements versus placebo for all coprimary endpoints (P < 0.001). All ON-SXB doses demonstrated significant improvements (P < 0.001) versus placebo for all coprimary endpoints when missing values in both treatment arms were imputed from observed values in the placebo arm (i.e., missing data were replaced with placebo data) and when analyzed using ANCOVA. Tipping-point–based analysis on the change from baseline in mean sleep latency on the MWT demonstrated that implausible or nearly implausible baseline MWT assumptions were needed to render the differences between ON-SXB and placebo no longer statistically significant. All doses of ON-SXB had NNTs of three and effect sizes of 0.7–0.9 for MWT response. For the response in terms of number of cataplexy episodes, NNT was six for the 6 g dose and three for the 7.5 g and 9 g doses; the effect sizes were between −0.7 and −0.8. For the Epworth Sleepiness Scale (ESS) response, NNTs ranged from three to six, with a dose–response effect. Effect sizes were between −0.5 and −0.7 for all doses. Conclusions These post hoc results demonstrate the robustness of the REST-ON clinical trial efficacy data. Clinical Trial ID: NCT02720744.

Background Narcolepsy is a chronic, burdensome neurologic disorder that significantly impacts the daily life of people with narcolepsy (PWN). Real-world perspectives from PWN can help address their unique experiences and treatment needs. PWN were surveyed to examine the path to a narcolepsy diagnosis, the breadth of symptom burden experienced by PWN, and current trends in treatment. Methods A 15-min online survey was sent by email to 3959 US members of MyNarcolepsyTeam (February 2022). The survey was divided into three sections (screening [patient characteristics], diagnosis/symptoms, and patient quality of life) for a total of 27 questions. Results In total, 110 members completed the survey. Of these, most were female (84%) and nearly half (48%) were diagnosed with narcolepsy type 1 (with cataplexy). Approximately one-third (31%) of members reported receiving a definitive diagnosis ≥ 10 years after first speaking with a clinician; most were previously diagnosed with depression (73%). Excessive daytime sleepiness (EDS, 93%) and fatigue (84%) were the most frequently reported symptoms that prompted respondents to seek a diagnosis or feel that something was wrong. Additionally, EDS was reported as the most troubling symptom (92%). Respondents’ most desired treatment outcome was to stop sleeping during the day (77%). Most (76%) indicated an extremely or very severe impact on daily life. One in eight respondents were not taking any medication for their narcolepsy. Of those taking medication, 58% received polypharmacy to address narcolepsy symptoms. Conclusions These survey findings further characterize the diagnostic delay, symptom burden, and treatment needs of PWN. Understanding the breadth of impact of narcolepsy from the patients’ perspective could improve shared decision-making between PWN and their treating clinicians.

Background/Objectives: Narcolepsy is a chronic neurologic disorder associated with substantial challenges that affect the social, emotional, and financial quality-of-life domains. A social listening analysis and structured survey were conducted to better understand the candid perspective of people with narcolepsy (PWN) and their experience with twice-nightly sodium oxybate (SXB). Methods: To characterize conversations and experiences in narcolepsy communities where SXB was mentioned, a social media analysis was conducted from August 2011 to October 2022. A structured survey was administered to PWN taking oxybate therapy from October 2022 to November 2022. Results: From the social media analysis, the largest topic was related to “cataplexy”, with 537 posts/comments. The most frequent term was “xyrem”, with 22,200 mentions. Of the 87 survey respondents, 85 respondents had narcolepsy, 75.3% (64/85) reported missing their second dose of immediate-release SXB or mixed-salt oxybates, and 58.8% (50/85) of respondents reported that they took their second dose of oxybate > 4 h after the first dose. Respondents reported poor sleep quality as the greatest effect or issue experienced after missing their second oxybate dose. When respondents were asked whether they had ever been injured after waking to take their second oxybate dose, 31.8% (27/85) of respondents reported an injury. Conclusions: PWN taking twice-nightly oxybates often report inconsistent adherence to the prescribed dosing, which results in negative consequences in their lives. This research provided an anonymized forum for PWN to voice challenges with middle-of-the-night awakenings that they may be reluctant to explain to their clinician.