The results of the open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study with low-sodium oxybate (LXB) by Morse et al1 is good news for patients with idiopathic hypersomnia (IH) and clinicians. It is the first-ever prospective, long-term drug study for IH. LXB is the only drug that has been approved for the treatment of IH by the Food and Drug Administration in the United States. A randomized study with sodium oxybate, which has been on the market for many years, has never been performed. The LXB studies will hopefully help to achieve worldwide approval for LXB, which will give IH patients access to a labeled drug. It certainly has been a long journey from the first description of IH by Bedrich Roth in 19562 to the approval of this promising and efficacious drug.
Over the years the classification of IH has undergone several changes. The present classifications by the third edition of the International Classification of Sleep Disorders (ICSD-3)3 and Diagnostic and Statistical Manual of Mental Disorders are still controversial.4 A part of the definitions is based on polysomnographic findings, mainly the Multiple Sleep Latency Test. The Multiple Sleep Latency Test discriminates narcolepsy type 2 from IH by the presence of 2 sleep-onset rapid eye movement periods. Repeated tests over time resulted in a change of diagnosis from narcolepsy type 2 to IH in about 26% of patients.5 The classifications are difficult and unprecise because the neurobiology of IH is not yet well understood, and a biomarker and valid diagnostic tools are still missing. In the present study participants were not only classified by ICSD-3, which was released in 2014, but also by ICSD-2, from 2005. Patients classified according to ICSD-2 probably did not have a new polysomnographic workup to exclude change of diagnosis.
The present study confirms the results of the initial 6-week, phase-3, placebo-controlled, double-blind, randomized withdrawal study.6 The outcome parameter Epworth Sleepiness Scale showed further improvements compared to the 6-week study and reached normal levels after week 2. In comparison to patients with narcolepsy type 1 and 2 transitioning from sodium oxybate to LXB in a 6-month open-label study,7 57% had normal Epworth Sleepiness Scale scores (< 10) under sodium oxybate and 75% at the end of LXB treatment, indicating a better efficacy of LXB on excessive daytime sleepiness.
The improvements of the results of the Idiopathic Hypersomnia Severity Scale (IHSS) and Patient Global Impression of Change remained stable throughout the study with a trend to further improvement. The mean values of the IHSS changed from severe to moderate. However, despite improvement of most typical IH symptoms in the IHSS, the items “do irrational things” and “problem for driving” did not decrease strongly compared to placebo. Although the item “time to feel functioning properly,” which indicates sleep inertia, was strongly reduced, the cognitive impairment “doing irrational things” during sleep inertia remained unaffected by LXB. The small reduction for “problem for driving” is difficult to interpret, because it does not relate to the time of day and of naps. However, it could indicate that the level of vigilance and alertness is not sufficiently restored by LXB throughout the day. These items might need further consideration in the process of improving IHSS, which otherwise covers the IH symptoms well.
Fast recovery after the double-blind, randomized withdrawal period within 2 weeks is good news for patients who need or want to stop their treatment for some time due to personal or medical reasons. The good safety profile, tolerance, and lack of abuse potential and withdrawal symptoms of LXB certainly will help to establish good long-term adherence.
The reduction of the IHSS score and the improvements of the Functional Outcomes of Sleep Questionnaire, short version and Work Productivity and Activity Impairment Questionnaire scores imply that treatment of IH patients can reduce long-term health costs and allow patients to lead lives with fewer challenges than before. The hurdle for future prescription of LXB for IH could become easier for patients and clinicians due to the long experience of sleep experts with sodium oxybate for the treatment of narcolepsy.
In this study 80% of participants were taking a stable dose of alerting medications. It will be of interest for future studies to investigate whether LXB alone will show the same improvements as a combination with alerting medications for IH patients with long and short sleep time. In both the 6-week and the open-label study only 19.8% of patients were classified as having IH with long sleep time. Apparently the 2 groups of IH patients did not have a different outcome. However, the classification was not established by long-term polysomnography or actimetry.
Despite the promising results of this long-term study, data about the natural course of IH are still missing and thus the concern of patients and clinicians about how long or when to taper or stop the medication will remain. Hopefully these insights will not last as long as the time between the first classification and the approval of the first medication for IH.
DISCLOSURE STATEMENT
This was not an industry-supported study. The authors report no conflicts of interest.
Citation: Mayer G, Rodenbeck A. Idiopathic hypersomnia: the long journey from classification to an efficacious drug. J Clin Sleep Med. 2023;19(10):1709–1710.
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