Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial

Szakács, Zsolt; Dauvilliers, Yves; Mikhaylov, V. I.; Повереннова, И. Е.; Krylov, Sergei; Janković, Srdja; Šonka, Karel; Lehert, Philippe; Lecomte, Isabelle; Lecomte, Jeanne‐Marie; Schwartz, Jean‐Charles; Полуэктов, М Г; Yakupov, E. Z.; Калинкин, А. Л.; Aksu, Murat; Yılmaz, Hikmet; Benbir, Gülçin; Wołyńczyk-Gmaj, Dorota; Jernajczyk, W.; Staykov, Ivan; Tavarari, Arben N

doi:10.1016/s1474-4422(16)30333-7

Cited by 310 publications

(125 citation statements)

References 21 publications

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“…The pitolisant development program in narcolepsy was characterized by eight Phase II/III studies (P07-03 and P09-15, respectively, Harmony I and Harmony Ibis were pivotal studies). In addition, two studies, P11-05 (Harmony CTP)43 and P09-10 (Harmony III), were supportive for the evaluation by EMA 44. Key characteristics of the study designs and a summary of the main results are reported in Table 1.…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 94%

“…P11-05 (Harmony CTP) was a supportive double-blind, randomized, parallel-group study on pitolisant versus placebo in narcoleptic patients (n=105, age range 18–66, mean age 34 years for the pitolisant group and 39 years for the placebo group) 43. The patients included showed a high frequency of cataplexy attacks and an ESS score of 12 or more at baseline.…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

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Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Romigi

Vitrani

Giudice

et al. 2018

DDDT

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Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and rapid eye movement sleep dysregulation, manifesting as cataplexy and sleep paralysis, as well as hypnagogic and hypnopompic hallucinations. Disease onset may occur at any age, although adolescents and young adults are mainly affected. Currently, the diagnosis delay ranges from 8 to 10 years and drug therapy may only attenuate symptoms. Pitolisant is a first-in-class new drug currently authorized by the European Medicines Agency to treat narcolepsy with or without cataplexy in adults and with an expanded evaluation for the treatment of neurologic diseases such as Parkinson’s disease and epilepsy. This article reviews the pharmacokinetic and pharmacodynamic profile of pitolisant, highlighting its effectiveness and safety in patients with narcolepsy. We performed a systematic review of the literature using PubMed, Embase, and Google Scholar. We report on the efficacy and safety data of pitolisant in narcoleptic patients regarding cataplexy episodes and subjective and objective daytime sleepiness. The development program of pitolisant was characterized by eight Phase II/III studies. One proof-of-concept study followed by two pivotal studies, three randomized controlled trials, and two open studies were evaluated. Our review confirmed the effectiveness of pitolisant in treating major clinically relevant narcolepsy symptoms, including cataplexy, as compared to placebo. In addition, pitolisant revealed a safe profile when compared with placebo and active comparators. Headache, insomnia, and nausea were the prominent side effects. Further long-term randomized controlled trials comparing the efficacy of pitolisant with active comparators (ie, modafinil and sodium oxybate) may clarify its real place in therapy and its possible use as a first-line agent on the basis of its safety and tolerability.

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Section: Pitolisant: Design and Developmentmentioning

confidence: 94%

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Romigi

Vitrani

Giudice

et al. 2018

DDDT

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“…Recent placebo-controlled studies have confirmed a modest positive effect on cataplexy symptoms with improved wakefulness in people with narcolepsy 31. The agent is taken once daily in a dose range 9–36 mg.…”

Section: Treatmentmentioning

confidence: 99%

Cataplexy

Reading

2018

Pract Neurol

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Remarkably and almost invariably, the clinical phenomenon of cataplexy results from the loss of around 40 000 hypocretin-containing neurones in the lateral hypothalamus in the context of narcolepsy type 1. Cataplexy reflects the dysregulation of rapid-eye-movement (REM) sleep, such that REM-sleep atonia intrudes inappropriately into wakefulness as brief episodes of either focal or total paralysis of voluntary muscle. The semiology of cataplexy differs between adults and children. A defining and enigmatic aspect is that certain emotional stimuli usually trigger the episodes. Cataplexy can be the most disabling symptom of the narcolepsy syndrome, severely limiting normal activities of daily living. Antidepressant drug therapy at relatively low doses is the traditional treatment; these most likely work through inhibiting REM sleep, predominantly by increasing brain monoamine concentrations. Sodium oxybate is probably the most effective drug for severe cataplexy, taken before overnight sleep and once through the night; its precise mechanism of action remains obscure. Pitolisant is a new agent for treating the excessive daytime sleepiness of narcolepsy that also helps cataplexy control by increasing histamine concentrations in the hypothalamus. Further understanding of the neurobiology of cataplexy and how it relates to hypocretin deficiency should improve our understanding of the brain’s emotional processing and provide insights into REM sleep and its control.

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“…7 The fact that reported mean sleep latencies in the cohort of Szakacs et al (4.2-4.7 minutes) were somewhat higher than reported in other cohorts including ours (2.6-2.9 minutes), leaves some uncertainty about patient inclusion. 2,8 Even if there remain this and other minor methodological concerns, this study is important and deserves attention by clinicians, politicians, and scientists, and here is why:…”

mentioning

confidence: 99%

“…1 Now, some of the same authors performed another well-designed randomized, double-blind, placebo-controlled trial in 105 narcolepsy patients and found that pitolisant also reduces the average number of cataplexy attacks per week. 2 Although it remains speculative how histaminergic neurotransmission modulates the expression of cataplexy, these results are interesting as they provide further clues that the histamine system may play an important role in narcolepsy. 3 The main limitation of the study is the fact that the diagnosis of narcolepsy was based on criteria which lack specificity.…”

mentioning

confidence: 99%

Wide implications of a trial on pitolisant for cataplexy

Baumann

2017

The Lancet Neurology

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Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial

Cited by 310 publications

References 21 publications

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Cataplexy

Wide implications of a trial on pitolisant for cataplexy

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