Post-Hoc Analysis Gives Safety Insights on Switch From Twice-Nightly Oxybate to Once-Nightly Treatment

Sally Ibrahim, MD

A newly presented post-hoc analysis of the RESTORE trial (NCT04451668) further characterized the safety profile and adverse events (AEs) experienced by patients with narcolepsy who were on once-nightly sodium oxybate (ON-SXB; Lumyrz; Avadel Pharmaceuticals). Overall, the reported AEs were consistent with the known safety profile of oxybates, with only 4% of participants discontinuing treatment because of treatment-emergent AEs (TEAEs) during the stable dosing period.¹

RESTORE, an open-label switch study, included participants with narcolepsy type 1 or 2 who completed the phase 3 REST-ON study (NCT02720744), the supportive trial that led to the approval of Lumyrz in March 2023. In this latest safety analysis, investigators tested the safety profile of the therapy in 130 patients who switched from twice-nightly sodium oxybate (TN-OXB) to ON-SXB for a median duration of 502.5 (8-1169) days during the 3-year study. Of these, 115 continued into the stable dosing period and were included in the data collection.

Led by Sally Ibrahim, MD, a sleep specialist and clinical educator in the division of pediatric pulmonology at University Hospitals Cleveland Medical Center, nearly three-fourths (73.9%) of patients reported at least 1 TEAE with ON-SXB. Of these, the most common were COVID-19 (18.3%), nasopharyngitis (11.3%), nausea (10.4%), sinusitis (8.7%), and fall (8.7%). Other common TEAEs included headache (7.0%), enuresis (7.0%), cough (6.1%), upper respiratory tract infection (5.2%), urinary tract infection (5.2%), somnolence (4.3%), rash (3.5%), decreased appetite (3.5%), hypertension (3.5%), concussion (3.5%), and contusion (3.5%).

Avadel’s Lumyrz became the first and only FDA-approved once-nightly oxybate for the treatment of cataplexy or excessive daytime sleepiness in adults with narcolepsy in 2023. The medication’s label came with a boxed warning as a central nervous system depressant, and for its potential abuse and misuse. Patients may only receive the therapy through a restricted program under a Risk Evaluation and Mitigation Strategy called the Lumyrz REMS.

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In the latest analysis, 5 patients (4.3%) experienced at least 1 TEAE that led to ON-SXB discontinuation. These included upper abdominal pain, fatigue, fall, dizziness, paresthesia, irritability, nightmare, and hypertension, each with 1 case. In addition, there were 8 (7%) patients who reported at least 1 serious TEAE (events; n = 10), and of these, 2 were considered related to ON-SXB (gastroesophageal reflux disease and cataplexy).

Results from the original RESTORE study, published in Sleep Medicine: X in 2024, showed that 93.9% (92 of 98) of patients who completed the preference questionnaire preferred ON-SXB over TN-SXB. At baseline, 69.2% reported missing their second immediate-release (IR) oxybate dose at least once; in these cases, 80% felt worse the next day.²

Additional data from RESTORE showed that approximately 39% of patients reported taking a second nightly IR oxybate dose at least 4 hours after the first dose, 51% of whom felt somewhat to extremely groggy/unsteady the next morning. Most patients (92%) reported getting out of bed after their second oxybate dose. Of these, 9 (8%) reported falls and 5 (4%) reported injuries. Of the switch participants who completed the end-of-study questionnaire, 91.2% felt better able to follow the recommended ON-SXB dosing schedule.

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REFERENCES
1. Ibrahim S, Harsh J, Corser B, et al. LONG-TERM SAFETY AND TOLERABILITY OF ONCENIGHTLY SODIUM OXYBATE: A POST HOC ANALYSIS FROM RESTORE. Presented at: 2025 SLEEP Annual Meeting; June 8-11; Seattle, Washington. Abstract 0833.
2. Roy A, Stern T, Harsh J, et al. RESTORE: Once-nightly oxybate dosing preference and nocturnal experience with twice-nightly oxybates. Sleep Med X. 2024;8:100122. doi:10.1016/j.sleepx.2024.100122