Low-Sodium Oxybate Remains Efficacious Regardless of Baseline Sleep Inertia

Yves Dauvilliers, MD, PhD

Findings from a post-hoc analysis of a phase 3 trial (NCT03533114) revealed that patients with higher sleep inertia generally had greater baseline disease burden; however, treatment with low sodium oxybate (LXB; Xywav; Jazz Pharmaceuticals) remained efficacious regardless of inertia status.

Led by Yves Dauvilliers, MD, PhD, director, Sleep and Wake Disorders Center, Gui de Chauliac Hospital, the analysis featured patients who continued treatment with LXB into the open-label treatment titration and optimization period for 10-14 weeks. Following that, patients underwent a stable-dose period (SDP) of 2 weeks. Using the visual analog scale for sleep inertia (VAS-SI), participants rated their difficulty awakening during baseline, SDP, and the double-blind period on a 100-mm line with anchors at 0 (very easy) and 100 (very difficult).

Presented at the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, VAS-SI terciles comprised score segments of less than 44 (group A; n = 34), 44 to 70 (group B; n = 33), and greater than 70 (group C; n = 32). At baseline, those with the highest VAS-SI scores demonstrated numerically higher mean Epworth Sleepiness Scale (ESS; group A: 16.0 [SD, 3.1], B: 15.6 [SD, 2.6]; C: 17.1 [SD, 2.4]) and Idiopathic Hypersomnia Severity Scale (IHSS; A: 26.7 [SD, 7.7]; B: 34.5 [SD, 5.9]; C: 36.3 [SD, 5.5]) scores.

Low sodium oxybate was originally approved for the treatment of cataplexy or excessive daytime sleepiness in patients 7 year or older with narcolepsy in July 2020, and later received an expanded indication to treat idiopathic hypersomnia (IH) in August 2021, becoming the first FDA-approved therapy for IH. Also known as JZP-258, the phase 3 trial served as the basis for its approval.

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At the conclusion of the SDP, all groups, regardless of VAS-SI tercile, showed improvements in ESS (A = ­­–9.9 [SD, 5.1]; B = –9.8 [SD, 3.5]; C = –10.0 [SD, 5.1]) and IHSS (A = –14.1 [SD, 9.9]; B = –19.0 [SD, 9.0]; C = –18.1 [SD, 9.9]). Nearly all (99%) participants demonstrated improvement in the Patient Global Impression of Change (GCI) scale. At the SDP, investigators recorded decreases of 9.3 (SD, 11.9), 31.5 (SD, 14.8), and 42.8 (SD, 22.9), respectively, in VAS-SI scores for groups A, B, and C. Spearman correlation coefficients for VAS-SI and IHSS items assessing sleep inertia were moderate (≥3.0) to strong (≥0.6).

In addition to numerically higher ESS and IHSS, participants with the highest baseline sleep inertia were more frequently rated severely ill on GCI (A = 17.6%; B = 12.1%; C = 34.4%). Notably, baseline total sleep time trended higher with increasing VAS-IH scores.

In the original study, those who received JZP-258 reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. Furthermore, highly statistically significant worsening was observed for those who received placebo compared with JZP-258 for ESS (P <.0001), PGIC (P <.0001), and IHSS (P <.0001). The most common adverse reactions, occurring in at least 5% of adults were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.²

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REFERENCES
1. Dauvilliers Y, Chen A, Whalen M, Macfadden W, Thorpy M. Efficacy of lower-sodium oxybate by baseline sleep inertia in a phase 3 clinical study in patients with idiopathic hypersomnia. Presented at: 2023 SLEEP Annual Meeting; June 3-7; Indianapolis, Indiana. Abstract 0592
2. Jazz Pharmaceuticals Completes Submission of Supplemental New Drug Application for Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Idiopathic Hypersomnia. News release. February 16, 2021. Accessed June 4, 2023. prnewswire.com/news-releases/jazz-pharmaceuticals-completes-submission-of-supplemental-new-drug-application-for-xywav-calcium-magnesium-potassium-and-sodium-oxybates-oral-solution-for-idiopathic-hypersomnia-301228862.html