Low-Sodium Oxybate Remains Effective, Safe in Narcolepsy With Psychiatric and Neurologic Comorbidities

Craig Chepke, MD

Results from a post-hoc analysis of the pivotal phase 3 trial (NCT03030599) for which low-sodium oxybate (Xywav; Jazz Pharmaceuticals) was approved on showed that treatment with the medication resulted in similar effectiveness and safety among patients with narcolepsy with psychiatric and/or neurologic comorbidities. These results are significant considering narcolepsy has long been described to have high comorbidity for psychiatric disease, which is frequently quoted as the cause for delay in diagnosis.¹

The study featured 201 adults aged 18-70 years old with narcolepsy with cataplexy who underwent a 2-week dose optimization period, followed by a 2-week double-blind randomized-withdrawal period, where participants either switched to placebo or continued on low-sodium oxybate. Of these, 84 reported comorbidities at baseline, which mainly comprised of depression, migraine headaches, anxiety, and headache (non-migraine).

Presented at the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, those randomized to placebo in both subgroups showed worsening in Epworth Sleepiness Scale (ESS) scores compared with participants who continued with low-sodium oxybate treatment. Overall, the least square mean (LSM) difference in active vs placebo groups was –3.7 (95% CI, –5.6 to –1.9; P = .0001) for those with comorbidities and –2.0 (95% CI, –3.5 to –0.6; P = .0050) for those without comorbidities. Of note, there were imbalances between subgroups with regard to sex, race, ethnicity, and body mass index.

Led by Craig Chepke, MD, medical director at Excel Psychiatric Associates, treatment emergent adverse events (TEAEs) were observed in 82.1% (n = 69) of those with comorbidities and 71.8% (n = 84) for those without. Serious TEAEs were found in 1 participant (1.2%) with comorbidities and 3 (2.6%) without. In addition, symptoms of depression, as measured by PHQ-9 scores, remained stable in both subgroups.

In comparison with low-sodium oxybate, weekly cataplexy attacks remained higher among those on placebo, regardless of whether patients had comorbid psychiatric conditions. Investigators observed between-group differences of –4.0 (95% CI, –7.0 to –1.1; P = .0026) for those with comorbidities and –3.5 (95% CI, –9.1 to –1.1; P <.0001) for those without. In addition, those randomized to placebo in both subgroups showed worsening in Patient Global Impression of Change (PGIc) scores compared with low-sodium oxybate (P <.0001, for both).

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Low-sodium oxybate has been approved for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy since 2020. A year later, it had its label expanded to include the treatment of idiopathic hypersomnia, making it the first approved therapy for this condition. The medication consists of a combination of calcium, magnesium, potassium, and sodium oxybates.

In the original phase 3 trial for which the therapy was approved on, efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (n = 201). During the double-blind withdrawal period, participants randomized to placebo experienced 2.35 (IQR, 0.00-11.61) weekly cataplexy attacks compared with 0 (IQR, –0.49 to 1.75) in the low-sodium oxybate group. Additionally, significant increases in median ESS scores were observed in the placebo group (median, 2.0 [IQR, 0.0-5.0]) compared with those on active treatment (median, 0 [IQR, –1.0 to 1.0; P <.0001).²

Narcolepsy, a disabling neurodegenerative condition characterized by EDS, sleep fragmentation, sleep related hallucinations, sleep paralysis, and cataplexy, carries a high risk for development of social and occupational dysfunction. Deterioration in function may lead to the secondary development of psychiatric symptoms. Inversely, the development of psychiatric symptoms can lead to the deterioration in function and quality of life.³

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REFERENCES
1. Chepke C, Cutler A, Watson N, et al. Efficacy and safety of low-sodium oxybate in narcolepsy patients with/without psychiatric/neurologic comorbidities. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX. ABSTRACT 0633
2. Bogan RK, Thorpy MJ, Dauviliers Y, et al. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. 2021;44(3):zsaa206. doi:10.1093/sleep/zsaa206
3. Morse AM, Sanjeev K. Narcolepsy and Psychiatric Disorders: Comorbidities or Shared Pathophysiology? Med Sci (Basel). 2018;6(1):16. doi:10.3390/medsci6010016