Recently Approved and Upcoming Treatments for Narcolepsy

Abstract

Narcolepsy is a chronic, disabling neurologic disorder characterised by excessive daytime sleepiness (EDS) and, in up to 60% of patients, cataplexy. Treatments for narcolepsy are aimed at improving wakefulness (e.g. modafinil, armodafinil, stimulants), reducing cataplexy attacks (e.g. sodium oxybate, venlafaxine), and treating the symptoms of disturbed nocturnal sleep, sleep paralysis and sleep-related hallucinations (e.g. sodium oxybate). In general, medications that increase the release, or inhibit the reuptake, of norepinephrine or dopamine have wake-promoting effects and are useful in managing EDS, whereas medications that inhibit serotonin or norepinephrine reuptake have anticataplectic effects. Modulation of γ-aminobutyric acid B (GABA B) receptors or histamine H 3 receptors (H3Rs) has effects on both EDS and cataplexy. Pitolisant, an H3R antagonist, and solriamfetol, a dopamine and norepinephrine reuptake inhibitor, are the most recently approved treatments for EDS associated with narcolepsy in the European Union (pitolisant) and the USA (pitolisant and solriamfetol). Several new agents are being developed and tested as potential treatments for EDS and cataplexy associated with narcolepsy; these agents include novel oxybate formulations (once-nightly [FT218]; low sodium [JZP-258]), a selective norepinephrine reuptake inhibitor (AXS-12), and a product combining modafinil and an astroglial connexin inhibitor (THN102). This review summarises the mechanisms of action, pharmacokinetics, efficacy, and safety/tolerability of recently approved and emerging treatments for narcolepsy. Key Points Excessive daytime sleepiness and cataplexy are common and disabling symptoms associated with narcolepsy. Emerging treatments, including two recently approved medications (pitolisant and solriamfetol) and several medications still in development (FT218, JZP-258, AXS-12, THN102, SUVN-G3031, TAK-925), provide new options for the treatment of narcolepsy.

A Randomized, Double‐Blind, Placebo‐ and Positive‐Controlled, 4‐Period Crossover Study of the Effects of Solriamfetol on QTcF Intervals in Healthy Participants

“…20 Pitolisant prolongs the QT interval, and it is recommended to avoid use in patients with known QT prolongation, in combination with other drugs known to prolong QT interval and in patients with a history of cardiac arrhythmias. 3 The PK profile of solriamfetol in this study is consistent with what has previously been reported in healthy adults. 5,6 Solriamfetol was rapidly absorbed, with a median t max of 2 and 3 hours following oral administration of 300-and 900-mg doses, respectively.…”

“…Solriamfetol is a dopamine and norepinephrine reuptake inhibitor 1 approved in the United States and European Union to improve wakefulness in adult patients with excessive daytime sleepiness (EDS) associated with narcolepsy (75-150 mg/day) or obstructive sleep apnea (OSA; 37.5-150 mg/day). [2][3][4] In vitro studies have shown that the action of solriamfetol differs from that of traditional stimulants (eg, amphetamines) and other reuptake inhibitors (eg, modafinil). 1 Solriamfetol exhibits dual activity at dopamine and norepinephrine transporters and lacks monoamine-releasing effects associated with amphetamines.…”

“…[7][8][9][10] Solriamfetol has low potential for drug-drug interactions, including a lack of interaction with oral hormonal contraceptives (a concern with some wake-promoting agents), and relatively low abuse potential (similar to or lower than that of phentermine). 2,3,11 In vitro and in vivo nonclinical safety pharmacology studies have indicated minimal effects of solriamfetol on assessments of cardiovascular function. Specifically, solriamfetol at concentrations up to 10 μM (approximately 2.2-and 2.6-fold the maximum plasma concentration [total and unbound] at the highest approved dose of 150 mg/day) did not reduce rapid potassium current in the human ether-a-go-go-related gene (hERG) assay, had no notable effects on cardiac contractility in isolated guinea pig atria, and had no relevant effects on electrophysiological parameters or early after-depolarizations in isolated rabbit Purkinje fibers.…”

Schisandrin B exerts hypnotic effects in PCPA‑treated rats by increasing hypothalamic 5‑HT and γ‑aminobutyric acid levels

“…Conversely, SchB administration increased the number of sleeping rats, reduced sleep latency and increased sleep duration in rats treated with PCPA, indicating that SchB may improve insomnia resulting from low 5-HT levels. 5-HT neurons affect the higher hypothalamic center through ascending projections, and 5-HT and its receptors in the hypothalamus are important components in the regulation of sleep and arousal (24,25). 5-HIAA is a metabolite of 5-HT.…”

<p>Pitolisant to Treat Excessive Daytime Sleepiness and Cataplexy in Adults with Narcolepsy: Rationale and Clinical Utility</p>

“…Solriamfetol, a novel dopamine and norepinephrine reuptake inhibitor, was recently approved by the United States Food and Drug Administration (FDA) as a first-line treatment for adult patients with EDS in the setting of narcolepsy. 32 The only drug approved by the FDA for the treatment of cataplexy is sodium oxybate whose mechanism is poorly understood but seems to be related to stimulation of GABA B receptors. It also improves EDS and can be considered a firstline therapy when cataplexy is coexistent and requires therapy.…”