Advances in pharmaceutical treatment options for narcolepsy

ABSTRACT

Introduction: Narcolepsy is a syndrome characterized by excessive daytime sleepiness (EDS), cataplexy, and other abnormal manifestations of rapid eye movement sleep phenomena. Since hypocretin deficiency is presumed to be the main pathophysiology of narcoleptic symptoms, hypocretin replacement therapy would be promising; small molecule hypocretin receptor agonists and intranasal administration of hypocretin peptides are recognized as potential pharmaceutical treatments. Pitolisant, a histaminergic inverse agonist, recently became available in European countries for the treatment of EDS. Additionally, other emerging treatments such as immunotherapies, TRH analogs, and solriamfetol have been under investigation.

Areas covered: The pathophysiology of narcolepsy is summarized, along with the current and emerging pharmaceutical treatments for narcolepsy.

Expert opinion: Hypocretin replacement therapy might be the most straightforward and effective treatment to address both cataplexy and EDS. Although small molecule synthetic hypocretin receptor agonists and intranasal hypocretin administration have been developed, for hypocretin receptor agonists, only preliminary data are available, and the efficacy data for intranasal delivery in human subjects are also lacking. Recently, the U.S. FDA has accepted the New Drug Application of solriamfetol for excessive sleepiness. It is likely that other emerging treatments will also become available in the clinical setting in the future.

KEYWORDS:

• Cataplexy
• hypocretin
• narcolepsy type1
• narcolepsy type2
• orexin

Article highlights

• Narcolepsy is a syndrome characterized by excessive daytime sleepiness (EDS), cataplexy, and other rapid eye movement sleep phenomena caused by hypocretin deficiency due to the destruction of the hypocretin-producing neurons in the hypothalamus, presumably by autoimmune mechanisms.

• About 90% of narcolepsy subjects receive pharmacological treatments and a large majority of these narcoleptic subjects benefit from current treatments. There are three main approaches: stimulants for EDS, antidepressants for REM sleep-related symptoms, sodium oxybate for both symptoms. However, these are symptomatic treatments and no curative treatments currently exist.

• Although clinical data are still lacking, hypocretin replacement therapy such as small molecule synthetic hypocretin receptor agonists and intranasal hypocretin administration might be effective for both cataplexy and sleepiness.

• Immune-based treatments are presumed to play a pivotal role to prevent the autoimmune destruction especially if they are given at an early stage.

• Other emerging treatments (e.g., histaminergic compounds, TRH analogs, solriamfetol, GABA modulation, caffeine, paraxanthine, ONO-4127, R-baclofen, THN102, JZP-386, and TAAR1 agonists) are under investigation.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Declaration of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

This paper was not funded.