Elsevier

Sleep Medicine

Volume 33, May 2017, Pages 125-129
Sleep Medicine

Original Article
The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use

https://doi.org/10.1016/j.sleep.2017.01.002Get rights and content

Highlights

  • A marketing authorization was issued in the European Union (EU) for pitolisant for the treatment of narcolepsy.

  • Pitolisant is a first-in-class drug acting on histamine H3 receptors.

  • This article summarizes the scientific review leading to approval of pitolisant in the EU.

Abstract

On 31 March 2016, the European Commission issued a decision for a marketing authorisation valid throughout the European Union (EU) for pitolisant (Wakix) for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant is an antagonist/inverse agonist of the human histamine H3 receptor. The dose should be selected using an up-titration scheme depending on individual patient response and tolerance and should not exceed 36 mg/day.

The main evidence of efficacy of pitolisant was based on two Phase III clinical trials. The improvement on excessive daytime sleepiness was shown against placebo in the Harmony I study (−3.33 points; 95% confidence interval (CI) [−5.83; −0.83]; p = 0.024) and in Harmony CTP (−3.41 points; 95% CI [−4.95; −1.87]; p < 0.0001). The daily cataplexy rate in Harmony I improved against placebo with a rate ratio (rR) of 0.38 whilst in the Harmony CTP the ratio of improvement on weekly cataplexy rate against placebo was 0.512. The most commonly reported adverse reactions were headache, insomnia and nausea. This article summarizes the scientific review leading to approval of pitolisant in the EU. The assessment report and product information are available on the European Medicines Agency website (http://www.ema.europa.eu).

Introduction

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness (EDS) and cataplexy. A deficit of hypocretin (orexin), a wake-stimulating peptide produced by the hypothalamus, is hypothesized to be the key underlying mechanism [1]. It is a chronic and often extremely incapacitating disease with negative impact on the quality of life of affected patients. The current therapeutic options are limited and rely on relief of symptoms. Pitolisant is a first-in-class drug acting on histamine H3 receptors. As pitolisant's mechanism of action is different from the currently available treatments, it can offer an alternative option for the patients and physicians.

In 2014, the European Medicines Agency (EMA) received an initial marketing authorisation application for pitolisant. The scientific review was conducted by the EMA's Committee for Medicinal Products for Human Use (CHMP). Based on this review, a marketing authorisation was issued in the European Union (EU) for pitolisant for the treatment of narcolepsy with or without cataplexy in adults. The detailed scientific assessment report and product information [including the summary of product characteristics (SmPC)] for this product are available on the EMA website (http://www.ema.europa.eu).

Section snippets

Mode of action

Pitolisant is a histamine H3 receptor (H3R) antagonist/inverse agonist. It triggers a long-lasting activation of histaminergic neurons in the brain, a neuronal system involved in the maintenance of wakefulness, attention and cognition. Pitolisant crosses the blood–brain barrier and elicits histamine release in the whole central nervous system accompanied by release of other wake-promoting neurotransmitters (dopamine, noradrenaline and acetylcholine) in cerebral cortex, presumably via an

Non-clinical aspects

Safety pharmacology studies showed that pitolisant has the ability to prolong the QT interval in humans. In vitro, it blocked hERG currents with an IC50 of 1.3 μM and affected action potential parameters in rabbit Purkinje fibres at concentrations higher than 1 μM. In vivo, slight QTc prolongation was observed in telemetered dogs.

Pitolisant is extensively metabolized, including an active first-pass metabolism by CYP3A4 in gut, and is widely distributed in tissues. Pitolisant crosses the

Clinical pharmacology

Pitolisant's absorption is rapid with Cmax typically achieved between two and four hours after dosing. Exposure to pitolisant showed moderate to high interindividual variability and increased more than proportionally with a dose up to 216 mg after once-daily dosing. Drug exposure increased in patients with renal and hepatic impairment as well as in the elderly.

The metabolism pathways of pitolisant in humans are not fully characterized. The major hydroxylated metabolite is formed by CYP3A4 and

Clinical efficacy

The narcolepsy development program included eight phase II/III studies of which two (P07-03 [Harmony I] and P09-15 [Harmony Ibis]) were considered pivotal. Two further studies, P11-05 (Harmony CTP) and P09-10 (Harmony III), were considered supportive for the evaluation. The patients were aged 18–75 years and were predominantly Caucasian. The analysis of baseline characteristics did not show clinically relevant differences between treatment groups.

The pivotal studies were double-blind,

Clinical safety

Pitolisant is the first inverse agonist/antagonist H3R to be introduced in clinics, thus its safety profile could not be directly compared with drugs from a similar pharmacologic class. Clinical safety assessment was based on the data generated from narcolepsy studies as well as additional supportive data from clinical trials in other indications (EDS associated with Parkinson disease, EDS secondary to obstructive sleep apnoea, epilepsy, schizophrenia, dementia and attention deficit

Benefit-risk assessment

Efficacy of pitolisant has been demonstrated on both major clinical symptoms of narcolepsy; excessive daytime sleepiness and cataplexy. Although the results of the two pivotal trials were not consistent on the ESS improvement and cataplexy rates, data obtained from the supportive studies provided additional evidence for the efficacy of pitolisant. The minimal difference of 3 points on final ESS score between pitolisant and placebo groups pre-defined in clinical trials and exceeded in the

Disclaimer

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of the EMA or one of its Committees or Working Parties.

References (9)

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