Cataplexy response with extended-release once-nightly sodium oxybate: Post hoc responder analyses from the phase 3 REST-ON clinical trial

Background Once-nightly sodium oxybate (ON-SXB), an extended-release oxybate formulation, yielded significant (P < 0.001 at 6 g, 7.5 g, and 9 g) reductions in cataplexy episodes in participants in the phase 3 REST-ON clinical trial (NCT02720744). This post hoc analysis from REST-ON further characterized changes in cataplexy episodes in participants with narcolepsy type 1 (NT1). Methods Participants with narcolepsy aged ≥16 years received ON-SXB (1 wk, 4.5 g; 2 wk, 6 g; 5 wk, 7.5 g; 5 wk, 9 g) or placebo. Percentages of participants with NT1 who had ≥25%, ≥50%, ≥75%, and 100% reductions from baseline in mean number of weekly cataplexy episodes were determined. Two-sided P values comparing ON-SXB vs placebo were calculated with Fisher exact test. Results Participants with NT1 (ON-SXB, n = 73; placebo, n = 72; modified intent-to-treat population) had a baseline mean number of weekly cataplexy episodes of 18.9 (ON-SXB) and 19.8 (placebo). Of participants receiving the highest doses of ON-SXB (7.5 and 9 g), approximately half had a 50% reduction, one-third had a 75% reduction, and one-tenth had a 100% reduction in their cataplexy episodes vs placebo. Significantly greater proportions of participants receiving ON-SXB vs placebo had respective reductions in weekly cataplexy episodes of ≥25% at weeks 1 (4.5 g; P < 0.05), 3 (6 g; P < 0.001), 8 (7.5 g; P < 0.001), and 13 (9 g; P = 0.001). Conclusions A significantly greater proportion of participants receiving ON-SXB vs placebo experienced reductions in weekly cataplexy episodes at all tested doses. Approximately 10% of participants taking the 2 highest ON-SXB doses had complete elimination of their cataplexy.


Introduction
Narcolepsy is a rare, chronic sleep disorder whose primary symptoms include excessive daytime sleepiness (EDS) and cataplexy [1][2][3].People who have narcolepsy with cataplexy (narcolepsy type 1; NT1) describe their cataplexy episodes as embarrassing or, at worse, emotionally oppressive and having a substantial impact on their lives [4].There are limited options available to treat cataplexy [5,6].Until recently, pitolisant and twice-nightly oxybate therapy (immediate-release [IR] sodium oxybate [SXB] and calcium/magnesium/potassium/sodium oxybates) were the only approved therapies for the treatment of EDS and cataplexy in adults with narcolepsy in the US [7][8][9]; IR SXB and pitolisant are approved in the EU [10,11].The IR oxybate formulations are administered twice nightly, with the first dose taken at bedtime and the second taken 2.5-4 hours later [8,9].Awakening during the night to take the second dose may compromise treatment adherence and lead to safety concerns [12][13][14].
The extended-release, once-nightly formulation of SXB (ON-SXB; FT218 [LUMRYZ™ (sodium oxybate) for extended-release oral suspension], Avadel Pharmaceuticals, Chesterfield, MO) received US Food and Drug Administration approval for the treatment of cataplexy or EDS in adults with narcolepsy in May 2023 [15,16].
In the pivotal phase 3 REST-ON clinical trial (NCT02720744) of individuals with narcolepsy, ON-SXB treatment resulted in statistically significant, clinically meaningful improvements vs placebo on all 3 coprimary endpoints: mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Improvement rating, and number of weekly cataplexy episodes at all doses analyzed (6 g [week 3], 7.5 g [week 8], and 9 g [week 13]; all P < 0.001) [17].A post hoc analysis revealed a significant reduction from baseline in the mean number of cataplexy episodes vs placebo starting at week 1 (ON-SXB 4.5 g; P < 0.05).This post hoc responder analysis further assessed reductions in weekly cataplexy episodes in participants with NT1.

Study design and participants
REST-ON study design and eligibility criteria were previously described [17].Briefly, REST-ON was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial with a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period.and had an Epworth Sleepiness Scale score >10.Participants with NT1 were required to self-report continuing cataplexy for the last 3 months, with a mean of ≥8 weekly cataplexy episodes during screening.
Individuals were randomly assigned 1:1 to receive ON-SXB (1 wk, 4.5 g; 2 wk, 6 g; 5 wk, 7.5 g; 5 wk, 9 g) or placebo.Randomization was stratified by narcolepsy type.Concomitant stable stimulant therapy was permitted.All anticataplectic drugs were discontinued before study entry with a 3-week washout period to account for rebound cataplexy.
The study protocol was approved by the site's institutional review board, and each participant (or legally authorized representative for those aged <18 years) provided written informed consent before participation.Study conduct adhered to the ethical principles of the Good Clinical Practice guidelines, the International Council for Harmonisation guidelines, and the Declaration of Helsinki, in addition to applicable national and local laws and regulatory requirements.

Cataplexy assessments
Participants with NT1 recorded the number of cataplexy episodes as 0, 1, 2, 3, 4, or ≥5 per day in an electronic daily diary.At least 3 entries per week were required for the average to be considered an observation.The mean number of weekly cataplexy episodes was calculated as the number of episodes divided by the number of days with available diary data of valid weeks within that period, then multiplied by 7.

Statistical analysis
Efficacy was assessed in the modified intent-to-treat (mITT) population (all randomized participants with ≥1 efficacy measurement after receiving the 6-g dose).Two-sided P values were calculated using Fisher exact test.A mixed-effects model for repeated measures was used to analyze percentage change from baseline in cataplexy frequency [17].

Participants
A total of 212 participants were enrolled in REST-ON and received medication (safety population); in the mITT population (n = 190), 145 participants had NT1 (ON-SXB, n = 73; placebo, n = 72).Baseline demographic and disease characteristics were well balanced between groups in the safety population (Table 1).

Discussion
In these post hoc responder analyses of the phase 3 REST-ON clinical trial, a significantly greater proportion of participants treated with ON-SXB (6, 7.5, and 9 g) experienced ≥25%, ≥50%, and ≥75% reductions in number of weekly cataplexy episodes vs placebo.At the 7.5-g (week 8) and 9-g (week 13) doses, a significantly greater percentage of participants receiving ON-SXB had complete resolution of cataplexy episodes vs placebo (both P < 0.05).All evaluated doses of ON-SXB reduced cataplexy ≥25% from baseline vs placebo, meeting the American Academy of Sleep Medicine (AASM) criteria for clinical significance [18].These findings support the primary data from REST-ON, showing statistically significant improvements in number of weekly cataplexy episodes with ON-SXB (P < 0.001 vs placebo) [17].
In the primary REST-ON analyses, comparable efficacy and safety profiles were observed for the 2 highest doses of ON-SXB (7.5 and 9 g) vs placebo, with numerically greater improvement with the 9-g dose (weeks 9-13) [17].Similar results were observed for the 7.5-and 9-g doses in this post hoc analysis: approximately 10% had complete elimination of cataplexy and approximately one-third and one-half had ≥75% and ≥50% reductions in weekly cataplexy episodes, respectively.REST-ON is the only controlled trial demonstrating efficacy with a 7.5-g dose of oxybate, thus providing evidence to assist clinicians in making dosing decisions for their patients.
REST-ON is also the first clinical trial to show significant reductions in the number of cataplexy episodes after 1 week of SXB treatment (4.5-g dose; P < 0.05 vs placebo) [17].Further clinically meaningful reductions in cataplexy episodes early in therapy were seen in this post hoc analysis, with 44% of participants experiencing ≥25% reductions at week 1.SXB treatment is typically initiated at 4.5 g/night and uptitrated in 1.5-g/night increments weekly until the optimal dose is obtained.These data suggest that patients receiving ON-SXB can expect to have reductions in cataplexy episodes early in titration.
Cataplexy is a burdensome symptom to patients [19], and there are limited approved treatment options [7][8][9][10][11].Although both SXB and pitolisant are strongly recommended by AASM for the treatment of cataplexy in adults, only SXB is strongly recommended by the European Academy of Neurology; pitolisant is weakly recommended because of moderate quality of evidence due to attrition bias and short trial durations [5,6].An additional treatment option, particularly one that offers clinically significant improvements in episode frequency earlier in treatment or complete elimination of cataplexy, would be beneficial for patients.
Other treatments evaluating cataplexy have varied in baseline levels of cataplexy.For immediate-release SXB, the first trial enrolled 136 participants with moderate to severe cataplexy with a median of 21 episodes per week [20], which is comparable to the REST-ON baseline value of 19-20 episodes [17].
There are limitations to consider, particularly the post hoc nature of this analysis.In REST-ON, daily episode frequency ≥5 was calculated as 5, which may lead to underreporting of events.The placebo group had an increasing reduction in the number of cataplexy episodes over the 13week trial, likely reflecting participants understanding that the dose in the active group would increase over time.Despite both these limitations, the observed differences from placebo with ON-SXB were statistically significant in this post hoc analysis, except for 100% reduction at week 3 with the 6-g dose.Additionally, the numbers of cataplexy episodes were not recorded as severe vs mild, or generalized vs local, similar to other prior trials.Therefore, it is not possible to determine if cataplexy severity decreased with ON-SXB treatment.As the impact to people with narcolepsy is greater if generalized, capturing these data in future studies of any cataplexy treatment is needed.Despite this, these findings demonstrate that treatment with ON-SXB significantly reduced the frequency of cataplexy episodes and led to the elimination of cataplexy episodes for some.

Conclusions
These post hoc analyses on cataplexy reduction corroborate the primary REST-ON results and provide unique insights into the efficacy of a once-at-bedtime dose of ON-SXB as a treatment for cataplexy.These data may provide a useful framework for clinicians when setting expectations of effectiveness for patients with NT1.
Richard Bogan reports a relationship with Suven Life Sciences Ltd that includes: funding grants.Richard Bogan reports a relationship with Balance that includes: funding grants.Richard Bogan reports a relationship with Vanda that includes: funding grants.

Table 1
Baseline characteristics of REST-ON participants with NT1 (safety population).
Richard Bogan reports a relationship with Merck & Co., Inc that includes: funding grants.Richard Bogan reports a relationship with Eisai that includes: funding grants and speaking and lecture fees.Richard Bogan reports a relationship with Philips that includes: funding grants.Richard Bogan reports a relationship with FRESCA Medical that includes: funding grants.Richard Bogan reports a relationship with LivaNova that includes: funding grants.Richard Bogan reports a relationship with Roche that includes: funding grants.Richard Bogan reports a relationship with Sommetrics that includes: funding grants.Richard Bogan reports a relationship with Harmony Biosciences that includes: speaking and lecture fees.Akinyemi O. Ajayi reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory.Bruce C. Corser reports a relationship with Jazz Pharmaceuticals that includes: speaking and lecture fees.Bruce C. Corser reports a relationship with Merck & Co., Inc that includes: speaking and lecture fees.Bruce C. Corser reports a relationship with Eisai that includes: speaking and lecture fees.Bruce C. Corser reports a relationship with Harmony Biosciences that includes: speaking and lecture fees.Bruce C. Corser reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees.Jennifer Gudeman reports a relationship with Avadel Pharmaceuticals that includes: employment.If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.