PARIS, January 25, 2017 /PRNewswire/ --

The Lancet Neurology today published the results from a Phase III controlled trial of pitolisant in severely affected narcoleptic patients with cataplexy.

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Narcolepsy is a rare but debilitating disease the main symptoms are Excessive Daytime Sleepiness (EDS) and cataplexy, a sudden loss of muscular tonus triggered by emotions. Whereas several psychostimulants are available to promote wakefulness, safe and effective therapeutic options against cataplexy are limited.

The trial showed that pitolisant, the first drug promoting histamine neurotransmissions in brain, and previously shown to be active against EDS, was also able to significantly reduce cataplexy when given once-a-day for two months in severely affected patients.

Cataplexy attacks (on which psychostimulants like amphetamines or modafinil are not significantly active) were reduced, by up to 75% (50% compared to placebo), even in severely affected patients experiencing nearly 10 attacks per week on average.

The number of patients with very high cataplexy level at the end of treatment (more than 15 attacks per week) were also more than 3 times less frequent with pitolisant than placebo.

In addition to cataplexy, EDS was significantly improved when evaluated using either a subjective test (Epworth) or an objective laboratory test (MWT, Maintenance of Wakefulness Test, which measures the delay after which patients fall asleep under a dim light). This wake-promoting effect confirms previous trials with pitolisant.

Treatment with Wakix® also improved other symptoms of the disease such as hallucinations and enhanced patients' assessment of their quality of life (the "suffering" criterion).

Wakix® tolerance was good with no serious adverse events . Side effects were generally mild (except one episode of severe nausea) and reversible, the most frequent ones being headaches, nausea and anxiety.

Importantly, there was no withdrawal symptoms after abrupt treatment cessation, which is consistent with preclinical or clinical data pointing out to the lack of drug abuse liability of this novel class of anti-narcoleptic agents.

All together these data suggest that pitolisant may represent a first-line treatment of narcolepsy, for which well-tolerated and effective therapeutic options are limited.

About the Phase III Study HARMONY CTP 

HARMONY CTP was a Phase III ,multi-center, prospective, double blind, randomized, and placebo-controlled study .It was conducted in 16 centers in 8 countries and a total of 105 narcoleptic patients were randomized to treatment with Wakix® (n=54 ) or placebo (n=51).

At baseline, the enrolled patients had a high frequency of cataplexy (7-9 attacks per week), a high level of diurnal somnolence (Epworth score about 17, high propensity to fall asleep e.g. in the MSLT, multiple sleep latency test, and MWT) and a high fraction of them displayed associated symptoms like hallucinations (64%).

After one week wash-out and 2 weeks screening, patients received pitolisant for a period of one month orally with individual dose titration (from 5 mg to 40 mg)

The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat.

The frequency of cataplexy attacks per week decreased from 9.15 to 2.27 with pitolisant and from 7.31 to 4.52 with placebo (P<0.0001).

About Narcolepsy 

Narcolepsy is a rare neurological disorder affecting one out of 2500 people in Europe (it is therefore considered as an "orphan disease") characterized by marked daytime sleepiness with impaired ability to sustain attention and sudden urges to sleep.

In addition, a large fraction of patients suffer from cataplexy attacks (sudden and temporary loss of muscle tone possibly leading to dangerous falls), the most distinctive and disabling symptom of the disease.

The most common form of narcolepsy is caused by the destruction, often in childhood, of a group of hypothalamic neurons that secrete small awakening peptides called hypocretin or orexins. This neurotransmitter plays a major role in the maintenance of wakefulness during the day, mainly via activation of wake-promoting histaminergic neurons.

In narcolepsy, their absence is partly compensated by an increase in the number of histamine neurons but this is not sufficient to maintain wakefulness to an adequate level and prevent the occurrence of dangerous cataplectic attacks.

To date, approved treatments were psychostimulants (amphetamines, modafinil) to treat excessive daytime sleepiness (EDS) and sodium oxybate to alleviate cataplexy and decrease EDS. These treatments activate catecholamine or GABA pathways but a need was persisting for drugs with improved safety, efficacy and convenient regimen.

About Wakix 

Pitolisant (Wakix®) is a first-in-class treatment for sleep-wake disorders developed by Bioprojet, a European pharmaceutical company established in 1982.It is a highly-selective histamine H3 receptor inverse agonist/antagonist that is indicated in adults for the treatment of narcolepsy with and without cataplexy.

By acting on presynaptic histamine H3 receptors, Wakix® enhances histamine release in the brain, leading to increased wakefulness and alertness.

By increasing the activity of histaminergic neurons and histamine release, Wakix indirectly acts upon other neurotransmitter systems, increasing acetylcholine, norepinephrine and dopamine release in the brain.

The medicine is available for in the form of 4.5mg or 18mg film coated tablets. (Each tablet contains 5mg or 20 mg of pitolisant hydrochloride)

On 19th November 2015, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended Wakix® for EU-wide marketing authorization for treatment of narcolepsy in adults with or without cataplexy.

In addition Wakix had already received an orphan drug designation from the Committee for Orphan Medicinal Products (COMP) on 10th July 2007 which was renewed 18th February 2016.

The Lancet publication of the results of the Harmony CTP study can be found at

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30333-7/fulltext

SOURCE Bioprojet Pharma