Long-Term Treatment of Narcolepsy and Idiopathic Hypersomnia with Low-Sodium Oxybate

Abstract

Narcolepsy and idiopathic hypersomnia are chronic conditions that negatively affect alertness, mental and physical energy, functioning, and quality of life (QoL). Calcium, magnesium, potassium, and sodium oxybates (low-sodium oxybate; LXB) is an oxybate formulation with 92% less sodium than sodium oxybate (SXB; a treatment for narcolepsy) and the same active moiety. LXB is approved in the US for treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age or older with narcolepsy, and idiopathic hypersomnia in adults. In Phase 3 clinical trials, LXB exhibited a safety profile consistent with that of SXB in narcolepsy. Besides continued efficacy in treating symptoms, potential benefits of long-term LXB treatment include flexible optimization of dosing and regimen, improvement of QoL and functioning, weight loss, and (relative to SXB in narcolepsy) health benefits of reduced sodium content. Dosing of LXB is twice nightly (for narcolepsy) or once or twice nightly (for idiopathic hypersomnia) based on patient characteristics and response, and individualized titration can be leveraged over the long term as a patient’s life circumstances change. Patients with narcolepsy transitioning from SXB initiate LXB at the same dose, and most patients require no further changes to achieve similar efficacy and tolerability. Improvements in functioning and QoL with LXB treatment could have cascading positive effects in multiple domains, particularly in younger patients. In clinical trials, LXB was associated with weight loss in both narcolepsy (in which obesity is a well-established comorbidity) and idiopathic hypersomnia, only occasionally leading participants to be underweight. As both narcolepsy and idiopathic hypersomnia are associated with increased risk of cardiometabolic and cardiovascular comorbidities, limiting medication-related sodium intake with LXB may have significant health benefits, although this has not yet been verified prospectively due to the prolonged follow-up required. LXB is a promising long-term treatment for narcolepsy and idiopathic hypersomnia.

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Plain Language Summary

Narcolepsy and idiopathic hypersomnia are disorders that make people feel very sleepy. Low-sodium oxybate (LXB) is a medicine for these disorders. Doctors think LXB works on parts of the brain that keep people awake. LXB may quiet those brain parts down at night by reducing their electrical activity, which helps people sleep better. LXB wears off by the morning, so people can wake up normally and feel more alert the next day. LXB has less sodium (which is part of salt) than a medicine called sodium oxybate. Sodium oxybate has been used for narcolepsy for more than 20 years. LXB has several benefits. First, LXB may be healthier than medicines that contain a lot of sodium, such as a high-sodium oxybate. This is because sodium can increase blood pressure and risk of heart disease. Second, LXB can be taken twice each night for narcolepsy, or once or twice each night for idiopathic hypersomnia. This depends on a person’s lifestyle, how well the medicine is working, and side effects. Third, people taking LXB are more able to work and do other activities and have better quality of life. Finally, people taking LXB may lose weight. This can help overweight or obese people.

Keywords:

• cardiovascular
• dosing
• LXB
• hypersomnolence
• quality of life
• weight loss

Abbreviations

ADHD, attention deficit/hyperactivity disorder; AUC, area under the plasma concentration–time curve; BMI, body mass index; BOND, Burden of Narcolepsy Disease; CGIc, Clinical Global Impression of Change; CI, confidence interval; CV, cardiovascular; C_max, maximum plasma drug concentration; DNS, disrupted nighttime sleep; DBRWP, double-blind randomized withdrawal period; EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; FDA, Food and Drug Administration; FOSQ-10, Functional Outcomes of Sleep Questionnaire, short version; GABA_B, gamma-aminobutyric acid B; GHB, gamma-hydroxybutyrate; ICSD-3, International Classification of Sleep Disorders, 3rd Edition; IH, idiopathic hypersomnia; IHSS, Idiopathic Hypersomnia Severity Scale; IQR, interquartile range; LSM, least squares mean; LXB, low-sodium oxybate; MCS, Mental Component Summary; MSLT, Multiple Sleep Latency Test; NT1, narcolepsy type 1; NT2, narcolepsy type 2; OLE, open-label extension; OLOTTP, open-label optimized treatment and titration period; OLT, open-label titration and optimization period; PCS, Physical Component Summary; PD, pharmacodynamic; PGIc, Patient Global Impression of Change; PK, pharmacokinetic; PLMD, periodic limb movement disorder; QoL, quality of life; RBD, REM sleep behavior disorder; REM, rapid eye movement; REMS, Risk Evaluation and Mitigation Strategy; RLS, restless legs syndrome; SD, standard deviation; SDP, stable-dose period; SE, standard error; SF-36, 36-item Short-Form Survey; SOREMP, sleep onset rapid eye movement period; SXB, high-sodium oxybate; TEAE, treatment-emergent adverse event; T_max, time to C_max; VAS, visual analog scale; VAS-SI, visual analog scale for sleep inertia; WPAI:SHP, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem.

Acknowledgments

At the direction of the authors, Karyn Liu, PhD, and Michael J. Theisen, PhD, of Peloton Advantage, LLC, an OPEN Health company, provided medical writing and editorial support, which was funded by Jazz Pharmaceuticals.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Logan D. Schneider is a compensated member of advisory boards and speakers bureaus for Jazz Pharmaceuticals, Eisai, and Harmony Biosciences. Anne Marie Morse has received research/grant support and consultancy fees from Avadel, Geisinger Health Plan, ResMed Foundation, Harmony Biosciences, Jazz Pharmaceuticals, Takeda Pharmaceutical Co., Ltd, NLS Pharmaceuticals, Alkermes, UCB Pharmaceuticals, and NIH. She is also a paid expert consultant of Irish State Claims Agency; CEO of DAMM Good Sleep, LLC. Michael J. Strunc has participated in advisory boards for Jazz Pharmaceuticals. Joyce K. Lee-Iannotti has no conflicts of interest to disclose. Richard K. Bogan is a shareholder of Watermark Medical and Healthy Humming, LLC; serves on the board of directors for Watermark; is a medical consultant to Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, and Oventus; has conducted industry-funded research for Avadel, Axsome, Bresotec, Bayer, Idorsia, Suven, Jazz, Balance, NLS, Vanda, Merck, Eisai, Philips, Fresca, Takeda, LivaNova, Roche, Sanofi, Sommetrics, and Noctrix; and is on the speakers bureau for Jazz, Eisai, and Harmony.

Additional information

Funding

Support for the development of this article was funded by Jazz Pharmaceuticals.