Narcolepsy: an interface among neurology, immunology, sleep, and genetics.

Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. The mechanism of narcolepsy type II is less understood. There is a delay of over ten years for the diagnosis of narcolepsy around the world. Patients with narcolepsy have many comorbidities with a negative impact on quality of life. The treatment of narcolepsy must contain an educational approach for the family, coworkers, and patients. Scheduled naps and sleep hygiene are essential to minimize the dose of medications. Much progress has been seen in the pharmacological treatment of narcolepsy with new stimulants, different presentations of oxybate, and recent studies with orexin agonists. Narcolepsy is a rare disease that needs to be more understood and highlighted to avoid delayed diagnosis and severe disabilities in patients.

A narcolepsia é um distúrbio primário do sistema nervoso central resultante das interações genéticas, ambientais e imunológicas definidas como sonolência diurna excessiva mais cataplexia, alucinações, paralisia do sono e fragmentação do sono. A fisiopatologia não é completamente conhecida, mas a interação entre predisposição genética, exposição ambiental e componente imunológico com consequente deficiência de hipocretina-1 é o modelo para explicar a narcolepsia tipo I. O mecanismo da narcolepsia tipo II é menos compreendido. Há um atraso de mais de dez anos para o diagnóstico da narcolepsia em todo o mundo. Pacientes com narcolepsia apresentam muitas comorbidades com impacto negativo na qualidade de vida. O tratamento da narcolepsia deve conter uma abordagem educativa para a família, colegas de trabalho e pacientes. Cochilos programados e higiene do sono são importantes para minimizar a dose dos medicamentos. Muito progresso foi observado no tratamento farmacológico da narcolepsia com novos estimulantes, diferentes apresentações de oxibato e estudos recentes com agonistas de orexina. A narcolepsia é uma doença rara que precisa ser mais compreendida e destacada para evitar atrasos no diagnóstico e incapacidades graves nos pacientes.

Quality of life in adolescents with narcolepsy type 1- a transversal study in a tertiary hospital.

PURPOSE: - Narcolepsy type 1 (NT1) is a rare chronic sleep disorder, usually arising by adolescence that negatively impacts quality of life. It is characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and sleep fragmentation. The goals of this work were to characterize NT1 adolescents regarding sleep characteristics, health-related quality of life (HRQoL) and future life perspectives and later to compare this group with a control group of healthy adolescents (HA). METHODS: - Transversal descriptive/analytical study including NT1 patients followed in a sleep center of a tertiary hospital and 23 HA. Data were collected through an online survey, fulfilled by the participants, including four sections: demographics; questionnaire evaluating sleep and EDS; questionnaire evaluating HRQoL; inquiry regarding future perspectives. An extra section for the NT1 group only, comprising questions about the characterization of narcolepsy, was included. RESULTS: 22 NT1 adolescents were included, with a median age of 15.0 years-old. Beyond EDS, all had presented cataplexy - 19 still reported it. Twenty patients took psychostimulants regularly for EDS, while 13 patients took venlafaxine or fluoxetine for cataplexy. Nineteen adolescents took regular naps and 19 maintained psychological appointments. Self-reported sleep quality was similar between groups (p = 0.112). EDS was identified in seven NT1 patients and none in the control group. HRQOL was significantly lower in NT1 patients only for the physical well-being domain (p = 0.001). Regarding future perspectives, results were similar, except for a lower probability of getting a driver's license in NT1 patients, despite no statistical significance (p = 0.104). DISCUSSION: Daytime sleepiness is difficult to control in NT1, despite specialized treatment. HRQoL was similar between groups in all domains except for the physical well-being. Despite good adherence to pharmacological and non-pharmacological treatments (namely psychological therapy) that account for these good results, the physical well-being domain is difficult to manage.

Once-nightly sodium oxybate (FT218) improved symptoms of disrupted nighttime sleep in people with narcolepsy: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a published article in the journal CNS Drugs. Narcolepsy is a rare sleep condition. Most people with narcolepsy experience disrupted nighttime sleep and have poor quality of sleep. Sometimes these symptoms are not easily diagnosed as a symptom of narcolepsy. Sodium oxybate is an approved treatment for narcolepsy. The only version of sodium oxybate that was available until 2023 required people to take their sodium oxybate at bedtime and then again in the middle of the night. The US Food and Drug Administration (FDA for short) has approved a once-nightly bedtime dose of sodium oxybate (ON-SXB for short, also known as FT218 or LUMRYZ™) to treat symptoms of narcolepsy in adults. These symptoms are daytime sleepiness and cataplexy, which is an episode of sudden muscle weakness. The once-nightly bedtime dose of ON-SXB removes the need for a middle-of-the-night dose of sodium oxybate. The REST-ON clinical study compared ON-SXB to a placebo (a substance that contains no medicine) to determine if it was better at treating symptoms of disrupted nighttime sleep associated with narcolepsy. This summary looks at whether; ON-SXB was better than placebo at treating symptoms of disrupted nighttime sleep. WHAT WERE THE RESULTS?: Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting. WHAT DO THE RESULTS MEAN?: A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.

Status Cataplecticus Induced by an Abrupt Duloxetine Withdrawal-A Case Report.

ABSTRACT: In persons with narcolepsy type 1, sudden withdrawal of antidepressants can cause status cataplecticus. We describe a 77-year-old female patient with long-standing history of narcolepsy type 1 complaining of recurrent short sudden episodes of whole-body paralysis, with preserved consciousness and memory. Episodes started an hour after her family invited her to celebrate Mother's Day. One week prior, patient had abruptly discontinued duloxetine. Cataplectic episodes resolved within 24 hours after resumption of duloxetine and treatment of hypokalemia. Status cataplecticus has been reported after withdrawal of venlafaxine, fluoxetine, and clomipramine. This is the first report of status cataplecticus due to duloxetine withdrawal. We review the pathophysiology of antidepressant withdrawal-induced status cataplecticus. In persons with narcolepsy type 1, physicians discontinuing any antidepressant should counsel on adverse effects of antidepressant withdrawal and reduce the dose in tapering manner.

The role of orexinergic system in the regulation of cataplexy.

Loss of orexin/hypocretin causes serious sleep disorder; narcolepsy. Cataplexy is the most striking symptom of narcolepsy, characterized by abrupt muscle paralysis induced by emotional stimuli, and has been considered pathological activation of REM sleep atonia system. Clinical treatments for cataplexy/narcolepsy and early pharmacological studies in narcoleptic dogs tell us about the involvement of monoaminergic and cholinergic systems in the control of cataplexy/narcolepsy. Muscle atonia may be induced by activation of REM sleep-atonia generating system in the brainstem. Emotional stimuli may be processed in the limbic systems including the amygdala, nucleus accumbens, and medial prefrontal cortex. It is now considered that orexin/hypocretin prevents cataplexy by modulating the activity of different points of cataplexy-inducing circuit, including monoaminergic/cholinergic systems, muscle atonia-generating systems, and emotion-related systems. This review will describe the recent advances in understanding the neural mechanisms controlling cataplexy, with a focus on the involvement of orexin/hypocretin system, and will discuss future experimental strategies that will lead to further understanding and treatment of this disease.

Pharmacological options for narcolepsy: are they the way forward?

INTRODUCTION: Narcolepsy is an under-recognized, rare neurologic disorder of hypersomnolence that is associated with increased mortality and medical and psychiatric co-morbidities. Narcolepsy exerts a substantial economic burden on patients and society. There is currently no cure, and life-long symptomatic therapy is needed. Available drugs do not modify the disease course. AREAS COVERED: This manuscript provides an overview of narcolepsy symptoms, diagnosis, pathophysiology, current pharmacotherapies, and emerging treatments. Gaps and unresolved issues in diagnosis and management of narcolepsy are discussed to answer whether pharmacological options are the way forward. EXPERT OPINION: Diagnostic criteria for narcolepsy (ICSD-3) need revision and greater clarity. Improved recognition of cataplexy and other symptoms through educational outreach, new biomarkers, improved test scoring through artificial intelligence algorithms, and use of machine learning may facilitate earlier diagnosis and treatment. Pharmacological options need improved symptomatic therapy in addition to targeted therapies that address the loss of hypocretin signaling. Optimal narcolepsy care also needs a better understanding of the pathophysiology, recognition of the different phenotypes in narcolepsy, identification of at-risk individuals and early recognition of symptoms, better diagnostic tools, and a database for research and disease monitoring of treatment, side-effects, and comorbidities.

[Multidrug resistant narcolepsy]. / Narcolepsia multirresistente.

INTRODUCTION: Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management. CASE REPORT: A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved. CONCLUSION: A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.

TITLE: Narcolepsia multirresistente.Introducción. La narcolepsia de tipo 1 es una enfermedad degenerativa focal del hipotálamo que afecta selectivamente a las neuronas productoras de orexina (hipocretina). Presenta múltiples manifestaciones clínicas, tanto en vigilia como en sueño. Con frecuencia, los síntomas son tan disruptivos que ocasionan enorme sufrimiento y deterioro de la calidad de vida de los pacientes. Aunque en ocasiones es suficiente con un abordaje no farmacológico, la gran mayoría de los enfermos necesita medicación para un adecuado control clínico. Caso clínico. Varón que a los 43 años comenzó a presentar de forma aguda excesiva somnolencia diurna y episodios de cataplejía. Tras un exhaustivo estudio se le diagnosticó narcolepsia de tipo 1. A lo largo de la evolución de la enfermedad se le prescribieron antidepresivos, neuroestimulantes y oxibato sódico, en monoterapia o en combinación. La respuesta al tratamiento farmacológico fue insuficiente y se acompañó de numerosos efectos secundarios. Tras la introducción de pitolisant se objetivó una franca mejoría de los síntomas, y se consiguió reducir la dosis de los otros fármacos y de sus efectos adversos. Conclusión. Son numerosas las medidas disponibles en la actualidad para abordar los síntomas cardinales de la enfermedad, aunque siguen existiendo casos resistentes al tratamiento antinarcoléptico. Los fármacos con mecanismos de acción sobre receptores del sistema histaminérgico pueden resultar de gran utilidad en estos casos.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1.

BACKGROUND: Narcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides. METHODS: We conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2-selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate. RESULTS: Of the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and -2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were -12.2 in the 30-mg group, -13.5 in the 90-mg group, -15.1 in the 180-mg group, and -2.1 in the placebo group (difference vs. placebo, -10.1 in the 30-mg group, -11.4 in the 90-mg group, and -13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy's law criteria occurred in 3 patients. CONCLUSIONS: In a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.).

The therapeutic potential of opioids in narcolepsy type 1: A systematic literature review and questionnaire study.

OBJECTIVE: Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. METHODS: We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. RESULTS: The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). CONCLUSIONS: Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.

Effects of sodium oxybate on hypocretin/orexin and locus coeruleus neurons.

Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXB's mechanism of action on narcolepsy.

Pitolisant: Pediatric First Approval.

Pitolisant (WAKIX®), a histamine H3 receptor antagonist/inverse agonist that has been developed by Bioprojet Pharma, is approved in the EU and USA and elsewhere for use in adults with narcolepsy with or without cataplexy. In February 2023, based on clinical data in patients aged 6 to < 18 years, pitolisant received its first approval in adolescents and children from the age of 6 years for the treatment of narcolepsy with or without cataplexy in the EU. This article summarizes the milestones in the development of pitolisant leading to this pediatric first approval for narcolepsy with or without cataplexy.

A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy.

BACKGROUND: Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and serotonin 5-HT1A receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy volunteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy and alertness in subjects with narcolepsy-cataplexy. METHODS: In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulotaront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment). RESULTS: Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group. CONCLUSIONS: Acute and sustained treatment with ulotaront reduced nighttime REM duration and daytime SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy. REGISTRATION: ClinicalTrials.gov identifier: NCT05015673.

Calcium, magnesium, potassium, and sodium oxybates oral solution for cataplexy or excessive daytime sleepiness associated with narcolepsy.

INTRODUCTION: Lower-sodium oxybate (LXB) is a novel formulation that is approved by the US Food and Drug Administration (FDA) to treat cataplexy and excessive daytime sleepiness (EDS) in adult patients and children ≥7 years with narcolepsy. LXB contains 92% less sodium than sodium oxybate (SXB), which adds 550-1640 mg of sodium/day at usual doses of 3-9 g/day. The FDA has declared LXB to be clinically superior to SXB due to greater safety by reducing the chronic sodium load. Narcolepsy patients have high comorbidities for hypertension and cardiovascular disease conditions, which can be adversely affected by high sodium intake. AREAS COVERED: This drug review discusses narcolepsy, current and upcoming pharmacotherapy, and LXB chemistry, pharmacodynamics, pharmacokinetics, and metabolism. Published results from LXB's phase 1 studies, a phase 3 study, and two post-marketing studies are reviewed. Databases searched included PubMed, Google Scholar, Lexi-Comp, Scopus, Science, and Ovid. EXPERT OPINION: LXB is efficacious in treating daytime sleepiness and cataplexy in adults and children ≥7 years with narcolepsy. Using LXB instead of SXB formulations may benefit narcolepsy patients with cardiovascular comorbidities and hypertension, but long-term studies are needed to prove it.

TAK-994, a Novel Orally Available Brain-Penetrant Orexin 2 Receptor-Selective Agonist, Suppresses Fragmentation of Wakefulness and Cataplexy-Like Episodes in Mouse Models of Narcolepsy.

Loss of orexin neurons is associated with narcolepsy type 1 (NT1), which is characterized by multiple symptoms including excessive daytime sleepiness and cataplexy. Orexin 2 receptor (OX2R) knockout (KO) mice, but not orexin 1 receptor (OX1R) KO mice, show narcolepsy-like phenotypes, thus OX2R agonists are potentially promising for treating NT1. In fact, in early proof-of-concept studies, intravenous infusion of danavorexton, an OX2R-selective agonist, significantly increased wakefulness in individuals with NT1. However, danavorexton has limited oral availability. Here, we report pharmacological characteristics of a novel OX2R agonist, TAK-994 [N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide sesquihydrate]. TAK-994 activated recombinant human OX2R (EC50 value of 19 nM) with > 700-fold selectivity against OX1R and activated OX2R-downstream signaling similar to those by orexin peptides in vitro. Oral administration of TAK-994 promoted wakefulness in normal mice but not in OX2R KO mice. TAK-994 also ameliorated narcolepsy-like symptoms in two mouse models of narcolepsy: orexin/ataxin-3 mice and orexin-tTA;TetO diphtheria toxin A mice. The wake-promoting effects of TAK-994 in orexin/ataxin-3 mice were maintained after chronic dosing for 14 days. These data suggest that overall in vitro and in vivo properties, except oral availability, are very similar between TAK-994 and danavorexton. Preclinical characteristics of TAK-994 shown here, together with upcoming clinical study results, can improve our understanding for orally available OX2R agonists as new therapeutic drugs for NT1 and other hypersomnia disorders. SIGNIFICANCE STATEMENT: Narcolepsy type 1 (NT1) is caused by a loss of orexin neurons, and thus an orexin 2 receptor (OX2R) agonist is considered to address the underlying pathophysiology of NT1. Oral administration of TAK-994, a novel OX2R agonist, promoted wakefulness in normal mice, but not in OX2R knockout mice, and ameliorated fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy. These findings indicate that TAK-994 is an orally available brain-penetrant OX2R-selective agonist with potential to improve narcolepsy-like symptoms.

Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy. METHODS: For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687. FINDINGS: Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group). INTERPRETATION: Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety. FUNDING: Bioprojet.

Long-Term Safety and Tolerability During a Clinical Trial and Open-Label Extension of Low-Sodium Oxybate in Participants with Narcolepsy with Cataplexy.

BACKGROUND: The safety and efficacy of low-sodium oxybate (LXB; Xywav®) were established in a randomized, double-blind, placebo-controlled, phase 3 withdrawal study in adults with narcolepsy with cataplexy; however, the longer-term safety profile has not yet been examined. The aim of the current analysis was to assess the time of onset and duration of common treatment-emergent adverse events (TEAEs) for LXB throughout the open-label optimized treatment and titration period (OLOTTP) and the stable dose period (SDP) portions of the main study, and the subsequent 24-week open-label extension (OLE). METHODS: In a double-blind, placebo-controlled, randomized withdrawal trial of LXB, TEAEs were evaluated during the 12-week OLOTTP, the 2-week SDP, and the subsequent 24-week OLE. Eligible participants were aged 18-70 years with a diagnosis of narcolepsy with cataplexy. At study entry, participants were taking sodium oxybate (SXB) alone, SXB with other anticataplectics, other anticataplectics alone, or were anticataplectic-treatment naive; other anticataplectics were tapered and discontinued during the OLOTTP. All participants initiated LXB during week 1 of the OLOTTP, and their dose was individually titrated based on safety and efficacy. Following the main study period, participants entered the OLE after rescreening (re-entry) after discontinuing LXB treatment or directly after completing the main study (rollover). TEAEs were assessed in the safety population as of database lock. TEAE duration was defined as time from TEAE start date to end date (or end of SDP or OLE, if end date was unrecorded). RESULTS: The safety population included 201 participants (SXB alone, n = 52; SXB with other anticataplectics, n = 23; other anticataplectics alone, n = 36; anticataplectic-treatment naive, n = 90). During the OLOTTP/SDP, headache was the most common LXB-emergent TEAE overall (71 events; n = 42 (21%); median (range) duration = 1 (1-147) day), followed by nausea (31 events; n = 26 (13%); median (range) duration = 9 (1-54) days) and dizziness (26 events; n = 21 (10%); median (range) duration = 7 (1-117) days). Among the 74 participants in the OLE, the most commonly reported TEAEs were headache (14 events; n = 7, 9%; peak incidence month 3 (n = 5/72); median (range) duration = 1 (1‒25) day), dizziness (8 events; n = 5, 7%; peak incidence month 1 (n = 3/74); median (range) duration = 26 (1‒181) days), and nasopharyngitis (6 events; n = 6, 8%; peak incidence month 6 (n = 2/69); median (range) duration = 9 (1‒24) days). Overall, study discontinuations attributed to TEAEs were 21/65 (32%) during the OLOTTP and SDP and 3/7 (43%) during the OLE. CONCLUSIONS: In this long-term analysis, the safety and tolerability profile of LXB was generally consistent with the known safety profile of SXB. During the OLOTTP and SDP, most TEAEs occurred early and were generally of short duration. TEAE prevalence decreased throughout the duration of the OLE; the most common TEAEs reported during the OLE were headache, dizziness, and nasopharyngitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03030599 (25 January 2017).

Low-sodium oxybate (LXB) is a medicine for narcolepsy. LXB treats daytime sleepiness and cataplexy (sudden muscle weakness). LXB is like sodium oxybate (SXB) but has 92% less sodium. This study looked at side effects in people taking LXB for many months. Three study periods were looked at in this report. In period 1, people could change their LXB dose for 12 weeks. This was to find their best dose. In period 2, people took that same best dose for 2 weeks. In period 3, some people kept taking LXB for 24 weeks. This was to study the longer-term effects. Everyone knew that they were taking LXB. During periods 1 and 2, the most common side effect was headache. Nausea and dizziness were also common. During period 3, headache was also the most common side effect. Dizziness and nasopharyngitis were also common. Nasopharyngitis is a cold in the nose and throat. In periods 1 and 2, most side effects happened early on. They also ended quickly. Fewer side effects happened in period 3. Among people leaving the study early, 32% left because of side effects during periods 1 and 2. During period 3, 43% left because of side effects. Overall, long-term side effects in people taking LXB were similar to those seen with SXB.

Real-world treatment of pediatric narcolepsy with pitolisant: A retrospective, multicenter study.

BACKGROUND: First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting. METHODS: This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected. RESULTS: 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%). CONCLUSION: First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated.

Evaluation of the efficacy of the hypocretin/orexin receptor agonists TAK-925 and ARN-776 in narcoleptic orexin/tTA; TetO-DTA mice.

The sleep disorder narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor-2 (HCRTR2) agonists in narcoleptic male orexin/tTA; TetO-DTA mice. TAK-925 (1-10 mg/kg, s.c.) and ARN-776 (1-10 mg/kg, i.p.) were injected 15 min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (Tsc ) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK-925 and ARN-776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK-925 and ARN-776 caused dose-related delays in NREM sleep onset. All doses of TAK-925 and all but the lowest dose of ARN-776 eliminated cataplexy during the first hour after treatment; the anti-cataplectic effect of TAK-925 persisted into the second hour for the highest dose. TAK-925 and ARN-776 also reduced the cumulative amount of cataplexy during the 6 h post-dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post-dosing. TAK-925 and ARN-776 also increased gross motor activity, running wheel activity, and Tsc , suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HCRTR2 agonists.

Diurnal changes in blood pressure and heart rate in children with narcolepsy with cataplexy.

The hypocretin neurons in the lateral hypothalamus are connected not only to brain alertness systems but also to brainstem nuclei that regulate blood pressure and heart rate. The premise is that regulation of blood pressure and heart rate is altered and affected by methylphenidate, a stimulant drug in children with narcolepsy with cataplexy. The changes in 24-hr ambulatory systolic and diastolic blood pressure and heart rate were compared among pre-treated narcolepsy with cataplexy patients (40 males, 10 females), with mean age 10.4 ± 3.5 years (M ±â€…SD, range 5-17 years) with values from 100 archival age-sex-body mass index matched controls. Patients had a lower diurnal systolic blood pressure (-6.5 mmHg; p = 0.000) but higher heart rate (+11.0 bpm; p = 0.000), particularly evident in the waketime, while diastolic blood pressure was comparable. With methylphenidate (18 mg sustained release at 08:00 hours), patients with narcolepsy with cataplexy had higher systolic blood pressure (+4.6 mmHg, p = 0.015), diastolic blood pressure (+3.3 mmHg, p = 0.005) and heart rate (+7.1 bpm, p = 0.028) during wake time, but nighttime cardiovascular values were unchanged from pre-treated values; amplitude variation in cardiovascular values was unchanged over 24 hr. In conclusion, children with narcolepsy with cataplexy had downregulation blood pressure profile but a higher heart rate, and lesser non-dipping profiles. Daytime methylphenidate treatment increases only waketime blood pressure and further elevated heart rate values.

[Real-life WAKE study in narcolepsy patients with cataplexy treated with pitolisant and unresponsive to previous treatments]. / Estudio WAKE de vida real en pacientes con narcolepsia con cataplejía tratados con pitolisant no respondedores a tratamientos previos.

INTRODUCTION: Type 1 narcolepsy is a disabling disease that requires continuous treatment, which is not always effective. Pitolisant is a new drug with a different mechanism of action that offers a new treatment option. The objective of the study was to analyse the effectiveness and safety of pitolisant in patients with type 1 narcolepsy that did not respond to or tolerate previous standard treatments. PATIENTS AND METHODS: Real-life multicentre descriptive observational study that included patients diagnosed with type 1 narcolepsy who did not respond to or tolerate previous treatments and started treatment with pitolisant. The study evaluated three different moments: the start of treatment, the stabilization of treatment with pitolisant and the three months after. RESULTS: In 32 patients included (mean age, 44 years; 37.5% women) the mean of the Epworth Sleepiness Scale was reduced from 17.1 to 13.5; 47.8% of the patients improved from their cataplexy; 65% of the patients improved their clinical global impression at the physician's and at the patient's discretion and the mean number of medications consumed was reduced from 2.0 to 1.4. The most frequent adverse effect was insomnia in 43.8% of patients. Of the 32 patients, 23 continued with the treatment during the 3-month follow-up period. CONCLUSIONS: In patients with type I narcolepsy who do not respond to or do not tolerate the available treatments, pitolisant can improve their clinical situation and reduce their medication consumption. Studies with a higher level of evidence are needed to confirm these results.

TITLE: Estudio WAKE de vida real en pacientes con narcolepsia con cataplejía tratados con pitolisant no respondedores a tratamientos previos.Introducción. La narcolepsia de tipo 1 es una enfermedad incapacitante que requiere tratamiento continuo, que no siempre es eficaz. El pitolisant es un nuevo fármaco con un mecanismo de acción diferente que ofrece una nueva opción de tratamiento. El objetivo del estudio fue analizar la efectividad y la seguridad del pitolisant en pacientes con narcolepsia de tipo 1 que no hubieran respondido o tolerado previamente los tratamientos habituales. Pacientes y métodos. Estudio observacional descriptivo multicéntrico de vida real que incluyó a pacientes diagnosticados de narcolepsia de tipo 1 no respondedores a tratamientos previos que iniciaron tratamiento con pitolisant. El estudio evaluó tres momentos: el inicio del tratamiento, la estabilización del tratamiento con pitolisant y los tres meses posteriores. Resultados. En 32 pacientes incluidos (media de edad, 44 años; 37,5% de mujeres), la media de la escala de somnolencia de Epworth se redujo de 17,1 a 13,5; un 47,8% de los pacientes mejoró subjetivamente de su cataplejía; un 65% de los pacientes mejoró su impresión clínica global a criterio médico y a criterio del paciente; y se redujo la media de medicamentos consumidos de 2,0 a 1,4. El efecto adverso más frecuente fue el insomnio, en un 43,8% de los pacientes. De los 32 pacientes, 23 mantuvieron el tratamiento durante los tres meses de seguimiento. Conclusiones. En pacientes con narcolepsia de tipo 1 que no responden a o no toleran los tratamientos disponibles, el pitolisant puede mejorar su situación clínica y reducir su consumo de medicamentos. Son necesarios estudios de mayor nivel de evidencia para confirmar estos resultados.