Post Hoc Analysis Shows Once-Nightly Sodium Oxybate Does Not Worsen Apnea-Hypopnea Index in Narcolepsy

In a post hoc analysis of the phase 3 REST-ON trial (NCT02720744), treatment with once-nightly sodium oxybate (ON-SXB; Lumryz; Avadel Pharmaceuticals) was not associated with worsening apnea-hypopnea index (AHI) among patients with narcolepsy and mild or no sleep apnea. The study also reported that patients who experienced respiratory-related adverse drug reactions (ADRs) were considered minimal and mild to moderate in severity.¹

The REST-ON trial was a double-blind, phase 3 study evaluating ON-SXB in individuals with narcolepsy and an AHI below 15. Participants aged 16 and older were randomized 1:1 to receive ON-SXB or placebo, with dose escalation from 4.5 g to 9 g over 13 weeks. Presented at the 2025 American Academy of Neurology (AAN) Annual Meeting, held April 5-9, in San Diego, California, researchers measured AHI at baseline and weeks 3, 8, and 13 via polysomnography, and ADRs were assessed.

At baseline, mean AHI values were similar between the ON-SXB (n = 97) and placebo (n = 93) groups, at 2.7 and 2.8, respectively. These values remained low throughout the study. At week 3, mean AHI was 0.1 in both groups; at week 8, it was 0 in both groups. At week 13, mean AHI was 0 in the ON-SXB group and 0.2 in the placebo group. 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.

Presented by lead author Akinyemi O. Ajayi, MD, FAAP, FCCP, D-ABSM, FAASM, medical director at Florida Pediatric Research Institute, the study reported that respiratory-related ADRs were minimal, with 1 participant (0.9%) in the ON-SXB group and 1 participant (1.0%) in the placebo group experiencing sleep apnea. Additionally, 1 participant (0.9%) receiving ON-SXB reported snoring. Overall, authors noted that the treatment was well tolerated, with minimal respiratory-related ADRs.

In May 2023, the FDA initially approved ON-SXB for cataplexy or excessive daytime sleepiness in adults with narcolepsy after Avadel submitted an amendment to the FDA’s request for final approval.² The initial approval was supported by data from the phase 3 REST-ON trial. Held under a special protocol assessment agreement with the FDA, the study featured 222 patients with narcolepsy type 1 or 2, all aged 16 years or older, who received uptitration doses of 4.5 g, 6 g, 7.5 g, and 9 g of ON-SXB or placebo over the course of a 3-week screening period, 13-week treatment period, and 1-week follow-up period.

The REST-ON trial met all 3 of its primary end points of change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression Improvement, and weekly cataplexy attacks in the 6-, 7.5-, and 9-g groups.³ The data from the trial showed a significantly greater increase in sleep latency with the treatment at week 3 for the 6-g dose group (8.1 vs 3.1 min, respectively; least-squares mean difference [LSMD], 4.98; 95% CI, 2.90-7.05; P <.001); at week 8 for the 7.5-g dose group (9.6 vs 3.3 min, respectively; LSMD, 6.21; 95% CI, 3.84-8.58; P <.001); and at week 13 for the 9-g dose group compared with placebo (10.8 vs 4.7 min, respectively; LSMD, 6.13; 95% CI, 3.52-8.75; P <.001).

In October 2024, the agency approved Avadel Pharamaceuticals' supplemental new drug application for ON-SXB for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. With this approval, ON-SXB could reduce the burden on families and caregivers of pediatric patients with narcolepsy who must wake up at night to administer a second dose.⁴

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REFERENCES
1. Ajayi AO, Bogan R, Corser BC, Abaluck B, Gudeman J. Effects of Once-nightly Sodium Oxybate on Apnea-hypopnea Index: Post Hoc Analysis from the Phase 3 REST -ON Clinical Trial. Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA.
2. Avadel Pharmaceuticals announces final FDA approval of Lumryz (sodium oxybate) for extended-release oral suspension as the first and only once-at-bedtime oxybate for cataplexy or excessive daytime sleepiness in adults with narcolepsy. News release. Avadel Pharmaceuticals. May 1, 2023. Accessed April 4, 2025. https://www.globenewswire.com/news-release/2023/05/01/2658536/0/en/Avadel-Pharmaceuticals-Announces-Final-FDA-Approval-of-LUMRYZ-sodium-oxybate-for-Extended-Release-Oral-Suspension-as-the-First-and-Only-Once-at-Bedtime-Oxybate-for-Cataplexy-or-Exc.html
3. Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvements of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. SLEEP. 2021; zsab200. doi:10.1093/sleep/zsab200
4. Avadel Pharmaceuticals Announces FDA Approval of LUMRYZ™ (sodium oxybate) Extended-Release Oral Suspension (CIII) for the Treatment of Cataplexy or Excessive Daytime Sleepiness in Patients 7 Years of Age and Older with Narcolepsy. News Release. Avadel Pharmaceuticals. Published October 17, 2024. Accessed April 4, 2025. https://investors.avadel.com/news-releases/news-release-details/avadel-pharmaceuticals-announces-fda-approval-lumryztm-sodium