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New Agent Identified for Cataplexy in Narcolepsy


Experts reported that pitolisant, the first drug in a class to target histamine, reduced cataplexy in patients with narcolepsy.

A randomized, double-blinded trial showed that pitolisant, a drug that targets a specific histamine receptor, works to reduce cataplexy, a vexing symptom of narcolepsy that throws people into a REM sleep-like state of paralyzing spells triggered by strong emotions.

“If these data are confirmed in long-term studies, this drug could be useful for narcolepsy patients with or without cataplexy and those with less severe sleep disturbances,” said Jean-Charles Schwartz, PhD, the lead author of the study published January 24 in the online edition of the Lancet Neurology.

Pitolisant targets the histamine H3 receptor, and is the first in a new class of drugs for narcolepsy, Dr. Schwartz noted. Pitolisant is a histamine H3 receptor inverse agonist. Blocking the receptor with pitolisant activates histamine release in the brain and increases wakefulness and reduces cataplexy events, he explained.

Many of the therapies approved by the US Food and Drug Administration (FDA) for sleepiness associated with this disorder alter dopamine transmission. Medicines that work on serotonin and norepinephrine are also used off-label for narcolepsy. But these drugs do not work well for treating cataplexy, Dr. Schwartz noted. The only FDA drug available for cataplexy is sodium oxybate (Xyrem), a short-acting liquid drug that must be swallowed twice during the night.

Dr. Schwartz and Jeanne Marie Lecomte, PhD, started a biotechnology company, Bioprojet Pharma, and are now preparing an application to seek FDA approval of pitolisant.


Dr. Schwartz became interested in studying histamine in the 1970s. By 1975, his lab discovered histamine's role as a neurotransmitter. Eight years later, Dr. Schwartz identified the H3 receptor. He went on to describe its critical role in the sleep-wake cycle, and designed a drug that singularly targets these receptors. He believed – and then proved – that blocking these receptors would work as a treatment for narcolepsy. The studies led to pitolisant's approval in Europe in 2015.

Histamine is released from a group of only 2,000 neurons, specifically in the tuberomammillary nucleus of the hypothalamus that innervates the brainstem and up into the basal forebrain, Dr. Schwartz explained.

Cataplexy, an autoimmune disease, leads to the near death of hypocretin (also known as orexin) neurons, which are located in a nearby hypothalamic pathway that stabilizes the activity of wake-promoting monoaminergic systems, like histamine.


For the Lancet Neurology study, researchers randomized 106 narcolepsy patients with cataplexy to receive pitolisant or a placebo. The phase 3 study, known as HARMONY-CTP, was conducted at 16 centers in eight countries, and was led by Dr. Schwartz's biotech company.

To be eligible for the study, patients had to have at least three cataplexy attacks a week. Many had more than 10 weekly episodes, which is considered severe.

Most of the patients stopped taking anti-cataplexy medication before the study but were allowed to add it to their regimen if they felt they needed it; this was the case in 7 percent who received pitolisant and 16 percent who received placebo.

In the first three weeks, participants received flexible doses at 5, 10, and 20 mg; then, for the next four weeks they received a stable dose of the medicine of up to 40 mg, depending on the response and side effects identified during the first four weeks. (Most patients ended up on the highest dose.) The treatment lasted up to two months, at which time the research team compared the number of cataplexy spells at baseline and every week until the drug was stopped.

The drug, given in one oral dose in the morning, has a 10-hour half-life, which means it does not alter the nighttime sleep schedule.

The researchers reported a significant reduction in the occurrence of attacks: 75 percent in the medicated group compared with 30 percent in those who had received a daily placebo (p<0.0001). The weekly rate of cataplectic attacks fell — from seven to nine per week at baseline — to two per week among patients taking pitolisant and five per week among on a placebo. The benefit was seen in all dosing groups, Dr. Schwartz added.

Among secondary endpoints, scores on the Epworth Sleepiness Scale (ESS), a 24-point assessment tool that measures daytime sleepiness, fell 5.4 points in those taking pitolisant compared to 1.9 points for those on a placebo. (Higher scores indicated more sleepiness; the baseline in the study was around 17 points.) The ESS scores correlated with the drop in the number of cataplectic attacks per week. Patients also reported more wakefulness and a greater global impression of change. The frequency of dream-like hallucinations also dropped in the medication group. Side effects of the drug were mild, including headache (most commonly), followed by irritability and anxiety.

The maximum benefit was reached at five weeks, Dr. Schwartz said.


“The H3 receptor has always been an attractive target,” said Emmanuel Mignot, MD, PhD, professor of psychiatry and behavioral sciences at Stanford University and director of the Stanford Center for Sleep Sciences and Medicine, who discovered the role of orexin in narcolepsy. “I have always been interested in the way this drug works.”

Most of the drugs for narcolepsy used today modulate dopamine, he pointed out. “This is the first drug that blocks the H3 receptor. It is an important discovery.”

Dr. Mignot noted that his colleagues in France have started to prescribe the drug and say that it's been helpful.

Logan D. Schneider, MD, a clinical instructor in sleep medicine at the Stanford Sleep Center and chair of the AAN Sleep Medicine Section, added: “This drug offers an alternative therapy, and it's a great story. Dr. Schwartz discovered the H3 receptor and now he has created a drug that binds to it and treats a very disabling problem.”

Dr. Schneider said he'd like to see longer-term studies conducted, however, because of the signal showing that the drug reached its maximum effect at five weeks. “We have to be cautious. This drug may lose its efficacy over time,” he said, adding: “It may be possible that the histamine H3 system becomes overstimulated and it might downregulate the system.”



DR. EMMANUEL MIGNOT noted that most of the drugs for narcolepsy used today modulate dopamine. “This is the first drug that blocks the H3 receptor. It is an important discovery.”


DR. LOGAN D. SCHNEIDER said hed like to see longer-term studies conducted, because of the signal showing that the drug reached its maximum effect at five weeks. “We have to be cautious. This drug may lose its efficacy over time. It may be possible that the histamine H3 system becomes overstimulated and it might downregulate the system.”


• Szakacs Z, Dauvilliers Y, Mikhaylov V, et al; for the HARMONY-CTP Study Group. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: A randomized, double-blind, placebo-controlled trial Lancet Neurol 2017; Epub 2017 Jan 24.
    • Dauvilliers Y, Bassetti C, Lammers GJ, Schwartz JC. Pitolisant versus placebo or modafinil in patients with narcolepsy: A double-blind, randomized trial Lancet Neurol 2013;12(11):1068–1075.