How treatable is narcolepsy with current pharmacotherapy and what does the future hold?

1. Introduction

Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations and disturbed nocturnal sleep. It is a rare condition, with an estimated prevalence of 0.02–0.05% in the general population [1]. Disease onset occurs before the age of 18 in more than 50% of the patients, with long diagnostic delays, especially in children [2]. Narcolepsy can be comorbid with additional sleep disorders (obstructive sleep apnea, restless legs syndrome and REM behavior disorder), neuropsychiatric, metabolic and cardiovascular diseases [1].

The International Classification of Sleep Disorders (ICSD-3) recognizes two different phenotypes. In narcolepsy type 1 (NT1), EDS is associated with cataplexy and/or reduced levels of hypocretin in the cerebrospinal fluid (CSF). Narcolepsy type 2 (NT2) presents similar EDS and abnormal REM sleep manifestations on polysomnography (PSG), while cataplexy is absent and hypocretin levels in the CSF are normal or slightly reduced [1,3].

NT1 is presumed to have an autoimmune basis that induces loss of hypothalamic orexin neurons in genetically predisposed individuals [1,4,5]. NT2 may be caused by less extensive injury to those neurons, but data are quite limited, and its pathogenesis remains largely unclear [1].

2. Treatment of narcolepsy

2.1. Drugs currently used

Treatments currently used for narcolepsy are all based on control of symptoms. Four agents have been approved by the European Medicines Agency (EMA): sodium oxybate (SXB) for the treatment of narcolepsy with cataplexy, pitolisant for narcolepsy with or without cataplexy, modafinil [1,6,7] and solriamfetol [8] to treat EDS. The US. Food and Drug Administration (FDA) has approved seven drugs for the treatment of narcolepsy: methylphenidate and amphetamines for narcolepsy in general, SXB for EDS and cataplexy, while modafinil, armodafinil and solriamfetol for EDS only [1,6,7]; pitolisant, approved for EDS in 2019, has been recently authorized also for cataplexy [9]. Additionally, antidepressants such as venlafaxine are widely used off-label, mainly for cataplexy [1,6].

Modafinil may be considered the first-line therapy, although its effectiveness is limited to EDS. In the absence of direct comparisons, in 2018 a network meta-analysis was performed on 14 published randomized clinical trials (RCTs) involving pitolisant, modafinil and SXB. All treatments have shown similar effectiveness in reducing EDS, whereas only SXB and pitolisant were found to have comparable effectiveness on cataplexy [10].

SXB has been recently approved by EMA and FDA also in children with narcolepsy from the age of seven [7,11]. Pitolisant is currently used off-label in adolescents; however, results of a phase II RCT on pediatric patients (NCT02611687) are expected shortly.

Solriamfetol is a dopamine and norepinephrine reuptake inhibitor, approved by FDA and EMA in 2019 and 2020, respectively, for EDS. Despite its action on norepinephrine, it has not shown benefits on cataplexy. As it does not promote release of monoamines, contrary to traditional stimulants, solriamfetol has a low abuse potential (Table 1) [7,8,11,12].

Table 1. Drugs currently used for the treatment of narcolepsy

Drug	Daily dosage	Mechanism of action	Most common adverse reactions^a	Indication	Approval
Modafinil	100–400 mg	DA reuptake inhibitor DAT inhibitor	Headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, dyspepsia	EDS	FDA, EMA
Armodafinil	100–250 mg	DA reuptake inhibitor DAT inhibitor	Headache, nausea, dizziness, insomnia	EDS	FDA
Sodium oxybate	4.5–9 g	GABAB-receptor agonist	Nausea, dizziness, vomiting, somnolence, enuresis, tremor	EDS, cataplexy, fragmented sleep	FDA, EMA
Pitolisant	9–36 mg	H3-receptor antagonist/inverse agonist Increased H synthesis and release	Headache, insomnia, nausea	EDS, cataplexy	FDA, EMA
Solriamfetol	75–150 mg	DA and NE reuptake inhibitor DAT and NET inhibitor	Headache, nausea, decreased appetite, anxiety, insomnia	EDS	FDA, EMA
Methylphenidate	10–60 mg	DA reuptake inhibitor DAT inhibitor	Decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (in adults); abdominal pain upper (in children and adolescents)	Narcolepsy	FDA, EMA
Amphetamines	5–60 mg	DAT inhibitor DA reuptake inhibitor Increased DA release	Palpitations, tachycardia, blood pressure elevation, restlessness, dizziness, irritability, insomnia, dyskinesia, tremor, headache, anorexia, weight loss	Narcolepsy	FDA
Antidepressants Venlafaxine Fluoxetine Citalopram Clomipramine	37.5–300 mg 20–60 mg 10–75 mg 10–50 mg	5-HT and NE reuptake inhibitor 5-HT reuptake inhibitor 5-HT reuptake inhibitor 5-HT, DA and NE reuptake inhibitor	Nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, and libido decreased Abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, yawn Ejaculation disorder (primarily ejaculatory delay) Dry mouth, constipation, nausea, dyspepsia, anorexia, somnolence, tremor, dizziness, nervousness, myoclonus, changed libido, ejaculatory failure, impotence, micturition disorder, fatigue, sweating, increased appetite, weight gain, visual changes	Primarily for cataplexy	Off-label

^aFrom Food and Drug Administration prescribing information (incidence: ≥5% for modafinil, armodafinil, methylphenidate; ≥5% and at least twice the rate of placebo for sodium oxybate, pitolisant, venlafaxine, fluoxetine, citalopram; ≥ 5% and greater than placebo for solriamfetol). Abbreviations used: DA, dopamine; DAT, dopamine transporter; GABA, gamma-aminobutyric acid; H, histamine; NE, norepinephrine; NET, norepinephrine transporter; 5-HT, serotonin; EDS, excessive daytime sleepiness; FDA, US Food and Drug Administration; EMA, European Medicines Agency.

2.2. Drugs in development

Regarding emerging and future drugs for narcolepsy, specific treatments (including orexin-based and immune-based therapies) and new symptomatic agents (particularly two new oxybate formulations) are currently under development, promising innovative therapeutic options for narcolepsy.

Orexin-based treatments have a long way ahead to make it to clinical practice. Orexin peptides have had no success so far, due to their poor bioavailability across the blood-brain barrier. Intranasal orexin-A in patients with NT1, performed in two small trials, did not lead to significant improvements in wakefulness or cataplexy [6]. However, more promising results might come from non-peptide orexin-receptor agonists. TAK-925 and TAK-994 are hypocretin/orexin 2-receptor selective agonists for subcutaneous and oral use, respectively. These agents have shown to promote wakefulness and reduce cataplexy-like episodes in mice. Initial data suggest a good safety profile and wake-promoting effects for TAK-925, whereas an evaluation of TAK-994 tolerability and effectiveness is ongoing [6,11,12]. Given the growing evidence on the immune-mediated pathogenesis of this condition [1,5], several attempts with immune-based treatments have been made, including intravenous immunoglobulins, corticosteroids, plasmapheresis, alemtuzumab and rituximab. However, only limited and sometimes conflicting data, coming from single case reports or small case series, are currently available [6].

Two new oxybate formulations (FT218 and JZP-258) are next to complete the approval process in the US. FT218 is an extended-release SXB developed for once-nightly administration. Compared to the immediate-release form (administered twice per night), FT218 could significantly increase patient compliance with therapy [11,12]. JZP-258 is a lower-sodium oxybate (LXB), composed of a mixture of oxybate salts with 92% less sodium content. Effectiveness on EDS and cataplexy and tolerability of JZP-258 have been recently demonstrated, pointing to a safer alternative for patients with narcolepsy and comorbid cardiovascular and renal disorders. A New Drug Application was accepted by FDA for the treatment of narcolepsy with JPZ-258 in children over seven years old [11,12]. Few other symptomatic therapies are under development for the treatment of narcolepsy. SUVN-G3031 is a H₃-receptor inverse agonist under evaluation for the treatment of EDS [7,12]. Reboxetine (AXS-12) is a norepinephrine reuptake inhibitor which has shown effectiveness on EDS and cataplexy in a pilot study and is now under further investigation [11,12]. THN-102 is a combination of modafinil and flecainide with a hypothesized role in the modulation of astroglial connexins, which are thought to be involved in the regulation of sleep-wake rhythm; a phase II study has not established its superiority compared to modafinil alone [12]. Finally, clarithromycin is under investigation for the treatment of EDS in NT2 for its possible GABA-modulating properties [13] (Table 2).

Table 2. Drugs in development for the treatment of narcolepsy

Drug	Mechanism of action	Possible indication^a	Development phase (status)	NCT number
FT218	GABAB-receptor agonist	EDS, cataplexy, fragmented sleep	Phase III (recruiting)	NCT04451668
JZP-258	GABAB-receptor agonist	EDS, cataplexy, fragmented sleep	Phase III (completed)	NCT03030599
TAK-925	Hypocretin/orexin 2 receptor selective agonist	EDS, cataplexy, weight gain	Phase I (completed)	NCT03332784 NCT03748979
TAK-994	Hypocretin/orexin 2 receptor selective agonist	EDS, cataplexy, fragmented sleep	Phase II (recruiting)	NCT04096560
SUVN-G3031	H3-R inverse agonist	EDS, cataplexy	Phase II (recruiting)	NCT04072380
AXS-12	NE reuptake inhibitor 5-HT reuptake weak inhibitor	Primarily for cataplexy	Phase II (completed)	NCT03881852
THN-102	DA reuptake inhibitor DAT inhibitor Inhibitor of astroglial connexins	EDS	Phase II (completed)	NCT02821715
Clarithromycin	Negative allosteric modulator of GABAA receptor	EDS	Phase II (recruiting)	NCT04026958

^a(On the basis of mechanisms of action, preclinical studies and clinical trials). Abbreviations used: GABA, gamma-aminobutyric acid; H, histamine; NE, norepinephrine; 5-HT, serotonin; DA, dopamine; DAT, dopamine transporter; EDS, excessive daytime sleepiness; NCT, ClinicalTrials.gov identifier.

3. Expert opinion

Despite the progress in our understanding of mechanisms underlying this condition [1,4,5], there is currently no cure for narcolepsy [14]. Available drugs are all symptomatic therapies and cannot change the pathophysiologic course of the disease. More than 90% of patients with narcolepsy require a pharmacological treatment, usually needed lifelong.

Fortunately, drug research in narcolepsy is a strikingly active investigational area. Although the autoimmune nature of NT1 is still debated, there is growing evidence of a specific adaptive response against hypocretin/orexin neurons [1,5]. Available data support the hypothesis of T-cell mediated immune mechanisms [5], while the role of autoantibodies in NT1 remains uncertain [1,5,6]. This background has opened the way to immune-based therapies for the treatment of NT1 [1,6]. Immunomodulating agents used so far are mostly directed to the humoral immunity and, actually, the overall experience with immunotherapies in the last decade has generally led to disappointing results [6]. Some evidence of effectiveness was seen in a few cases with intravenous immunoglobulins administered very early after disease onset [6]. All these observations suggest a minor role of autoantibodies in the pathophysiology of NT1. In the light of recent data on T-cell immunity [5], we could probably expect better results with immunomodulators of T-cell response. Certainly, we need to better clarify NT1 pathophysiology to develop more tailored immune-therapies, which could reasonably work as disease-modifying treatments. For this purpose, further efforts are required to reduce the excessive delay in diagnosing narcolepsy [2], as it represents a necessary condition to change the natural history of the disease. Finally, potential serious adverse events related to immunosuppression must be carefully considered in the risk-benefit assessment, especially when good life standards may be obtained with safer symptomatic therapies, or possibly with orexin-based treatments in the future. With these caveats, large and standardized RCTs are still needed to evaluate the real effectiveness and safety of immunotherapies in NT1. Furthermore, orexin-based therapies are paving the way for replacement treatments in NT1. At the moment, obstacles in drug bioavailability give an advantage to the development of orexin-receptor agonists rather than orexin peptides, but gene therapy, stem cells and neuronal transplantation might become innovative strategies for replacement therapies in the future [6,12].

While we wait for technical progress to open new therapeutic horizons, we should make the best of the available treatments. Minimizing most relevant symptoms impacting on sleep and life quality still remains the priority. SXB and pitolisant should be considered as first options in subjects with both EDS and cataplexy, while other authorized agents are effective on sleepiness only. A recent survey shows that about half of the patients report residual EDS and cataplexy attacks even with pharmacologic treatments (57.1% and 46.4%, respectively), although most patients experience some (45.1%) or substantial (43.6%) improvement with drugs [2]. Dose escalation, in case of suboptimal response, is frequently the first step to achieve a better control on symptoms. In many patients, however, combined treatments acting on different neurotransmitter pathways may be needed to reach satisfactory results [7]. Ancillary symptoms and most common comorbidities (such as general fatigue, cognitive difficulties, other sleep disorders, weight gain, depression, anxiety, sexual dysfunctions) may also significantly affect living standards of patients [2]. Those features of narcolepsy are often undertreated and should be equally considered in the therapeutic choice. To give some examples: venlafaxine or reboxetine might be preferred in patients with NT1 and depressive disorders; pitolisant and SXB could be more appropriate in patients with sexual dysfunctions, which may be exacerbated by antidepressants; patients with body weight gain may benefit from treatment with SXB, and good results on weight control could be obtained with orexin agonists in the future [12,15]; LXB will be particularly useful in subjects with comorbid arterial hypertension, whereas extended-release SXB will increase patient adherence to treatment [11,12]. Abuse susceptibility should be carefully evaluated and clinicians should consider pitolisant or solriamfetol as an alternative to traditional stimulants because of their lower abuse potential [8,9].

Major problems with current treatments include adverse events (see Table 1), impact on lifestyle, poor effectiveness, insurance issues and costs [2]. Notwithstanding all therapeutic advances, non-pharmacological strategies, including lifestyle changes and psychological counseling, are still needed to offer patients with narcolepsy personalized and comprehensive care.

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

One reviewer was directly involved in the discovery, development and marketing of the anti-narcoleptic drug, pitolisant. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.