Adverse Events of Low-Sodium Oxybate in Idiopathic Hypersomnia Begin Early in Treatment Course

Richard Bogan, MD

Post-hoc data from a phase 3 trial (NCT03533114) and its open-label extension (OLE) showed that the safety profile of low-sodium oxybate (LXB; Xywav; Jazz Pharmaceuticals) was consistent in patients with idiopathic hypersomnia (IH), with treatment-emergent adverse events (TEAEs) typically occurring within the first 5 weeks after starting treatment. Overall, the safety profile of the therapy was similar in both treatment-naïve participants and those taking alerting agents.¹

The study, which served as the basis for low-sodium oxybate’s approval in IH in 2021, included an open-label titration period (10-14 weeks), stable-dose period (2 weeks), double-blind randomized withdrawal period (2 weeks), and OLE (24 weeks; safety follow-up, 2 weeks). Led by Richard Bogan, MD, medical director of SleepMed in South Carolina, 148 patients took at least 1 dose of the study drug, 66 of whom were treatment-naïve and 82 were on stimulants or wake-promoting agents. The analysis, showcased at the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, was presented using descriptive statistics.

In treatment-naïve participants, the most common TEAEs were nausea (19.7% [n =13]; 7.5 days), headache (18.2% [n = 12]; 3.0 days) and dizziness (16.7% [n = 11]; 4.0 days), anxiety (10.6% [n = 7]; 9.0 days), and decreased appetite (10.6% [n = 7]; 15.0 days). Among those taking alerting agents, the most common TEAEs were nausea (25.6% [n = 21]; 7.5 days), headache (18.3% [n = 15]; 2.0 days), vomiting (17.1% [n = 14]; 1.5 days), anxiety (12.2% [n = 10]; 28.0 days), insomnia (11.0% [n = 9]; 7.0 days), and tremor (11.0% [n = 9]; 11.0 days).

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As mentioned, the majority of the most frequently reported TEAEs occurred within the first 5 weeks after study onset, most of which were mild or moderate in severity. Between each group, less than 3.7% of participants discontinued the study because of TEAEs. Overall, serious TEAEs were observed in 2.7% (4 of 148) of participants, none of which were considered related to the study drug or led to study discontinuation.

Low-sodium oxybate, a combination agent of calcium, magnesium, potassium, and sodium oxybates, became the first approved therapy for IH in 2021, using results from the aforementioned phase 3 trial. The OLE population, which included 106 participants, showed a decrease in ESS scores (baseline: 16.3 [SD, 2.8]; 6-month OLE end: 5.3 [SD, 3.7]) and a trend towards decreased scores in Idiopathic Hypersomnia Severity Scale (IHSS) scores (study baseline: 32.6 [SD, 7.3]; OLE end: 14.8 [SD, 8.6]) with low-sodium oxybate.²

In the OLE, the proportion of patients reporting Patient Global Impression of Change ratings of “very much improved” increased from 36.7% at OLE week 2 to 53.8% at the OLE end. In addition, the incidence of newly reported TEAEs decreased over the duration of the OLE.

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REFERENCES
1. Bogan R, Whalen M, Bronson S, Fuller D, Macfadden W. Long-term Safety and Timing of Adverse Events with Low-Sodium Oxybate in a Phase 3 Idiopathic Hypersomnia Study. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX. 0639
2. Morse AM, Dauvilliers Y, Arnulf I, et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med. 2023;19(10):1811-1822. doi:10.5664/jcsm.10698