A post-hoc analysis of the pivotal phase 3 REST-ON trial has provided reassuring safety data for once-nightly sodium oxybate (ON-SXB; Lumryz; Avadel Pharmaceuticals) in narcolepsy patients, demonstrating that the treatment does not worsen sleep apnea parameters and maintains a favorable respiratory safety profile.
Respiratory Safety Profile Confirmed
The analysis, presented at the 2025 American Academy of Neurology Annual Meeting, examined 190 participants from the REST-ON trial who had narcolepsy with an apnea-hypopnea index (AHI) below 15. Led by Akinyemi O. Ajayi, MD, medical director at Florida Pediatric Research Institute, the study found that mean AHI values remained consistently low throughout the 13-week treatment period.
At baseline, mean AHI values were similar between the ON-SXB group (n=97) at 2.7 and placebo group (n=93) at 2.8. These values showed minimal change during treatment, with mean AHI reaching 0.1 in both groups at week 3, 0 in both groups at week 8, and 0 in the ON-SXB group versus 0.2 in the placebo group at week 13.
The least squares mean differences in AHI change from baseline between ON-SXB and placebo were -0.11 (P = .522) at week 3, -0.11 (P = .518) at week 8, and -0.12 (P = .515) at week 13, indicating no statistically significant worsening of sleep apnea parameters.
Minimal Respiratory Adverse Events
Respiratory-related adverse drug reactions were notably minimal throughout the study. Only 1 participant (0.9%) in the ON-SXB group and 1 participant (1.0%) in the placebo group experienced sleep apnea. Additionally, just 1 participant (0.9%) receiving ON-SXB reported snoring. All respiratory-related adverse events were classified as mild to moderate in severity.
Hallucination Reduction Benefits
A separate post-hoc analysis of the same trial examined the drug's effects on hypnagogic and hypnopompic hallucinations (HH) in 112 participants who experienced these symptoms at baseline. Led by Michael Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore, this analysis revealed significant improvements in hallucination frequency.
The baseline mean number of HH events per day was 0.60 (SD, 0.35) in the ON-SXB group and 0.66 (SD, 0.35) in the placebo group. Treatment with ON-SXB resulted in mean changes from baseline of -0.16 (95% CI, -0.21 to -0.11), -0.28 (95% CI, -0.37 to -0.19), and -0.29 (95% CI, -0.40 to -0.18) at weeks 3, 8, and 13, respectively (all P <.001).
Among the 12,455 HH events recorded, 62% were hypnagogic and 38% were hypnopompic. The most common hallucination types included feeling that shadows or objects are moving or distorting, feeling another presence in the room, and feeling about to be attacked.
Clinical Context and Approval History
The REST-ON trial was a double-blind, phase 3 study that led to ON-SXB's FDA approval in May 2023 for cataplexy or excessive daytime sleepiness in adults with narcolepsy. The study featured 222 patients with narcolepsy type 1 or 2, aged 16 years or older, who received dose escalation from 4.5 g to 9 g over 13 weeks.
The trial successfully met all three primary endpoints: change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression-Improvement, and weekly cataplexy attacks. Significant improvements in sleep latency were observed at week 3 for the 6-g dose group (8.1 vs 3.1 min; P <.001), at week 8 for the 7.5-g dose group (9.6 vs 3.3 min; P <.001), and at week 13 for the 9-g dose group compared with placebo (10.8 vs 4.7 min; P <.001).
In October 2024, the FDA expanded approval to include patients 7 years of age and older with narcolepsy, potentially reducing the burden on families and caregivers who previously had to wake pediatric patients for nighttime dosing with twice-nightly formulations.
