ARTICLE IN BRIEF
Investigators reported that pitolisant, which has a novel mechanism, was effective for treating excessive daytime sleepiness compared with placebo, and was well tolerated compared with modafinil.
In the nearly 15 years since the approval of modafinil (Provigil) by the US Food and Drug Administration (FDA) in 1999, there have been no genuinely new therapeutic options for the treatment of narcolepsy or excessive daytime sleepiness (EDS). The FDA approved armodafinil (Nuvigil) in 2007, but it belongs to the same class and has the same mechanism of action as modafinil.
Now, an entirely new class of drugs has been identified that appears to also be effective in the treatment of narcolepsy, which is caused by loss of hypothalamic hypocretin (orexin) neurons. Pitolisant, an inverse agonist of the histamine H3 receptor, presents another potential treatment, sleep experts not involved with the study said.
In the November edition of Lancet Neurology, the HARMONY I study group reported that in a double-blind trial, pitolisant was superior to placebo for at least two months. Although it was not found to be significantly more effective for EDS than modafinil, it appeared to be better tolerated, the investigators — led by Yves Dauvilliers, MD, division head of Sleep Medicine at the University Hospital of Montpellier, France — wrote.
THE THERAPEUTIC MECHANISM
The mechanism behind pitolisant hinges around its role in inhibiting histamine receptors. Histamine, acting via H1 and/or H3 receptors, plays a pivotal role in the regulation of sleep-wakefulness. Histamine or H1 receptor agonists induce wakefulness, whereas H1 receptor antagonists promote sleep. When H3 receptors are activated, they reduce histamine release and promote sleep. Conversely, inhibiting H3 receptors promotes wakefulness.
“Tuberomammillary histaminergic neurons, which are crucial for maintenance of wakefulness, seem largely, if not completely, preserved in narcolepsy, and seem to be essential in the waking action of hypocretins,” the study authors wrote.
The researchers wanted to determine whether the hypocretin deficit could be circumvented by activating these neurons. Previous research in hypocretin-knockout mice had shown that pitolisant activates histamine release in the brain, increases wakefulness, and decreases narcolepsy episodes, and, in a small single-blinded trial, decreased EDS in narcoleptic patients, they explained.
“This is very exciting,” said Mark Mahowald, MD, professor of neurology at the University of Minnesota Medical School and former director of the Minnesota Regional Sleep Disorders Centers, who was not involved with the current study. “The authors have identified a drug that works through a mechanism completely different from all existing medications used to treat narcolepsy or other causes of excessive daytime sleepiness. It's nice to see a drug coming out that is not a ‘me-too’ drug.”
The multicenter trial involved 95 patients at 32 European centers, randomized on a 1:1:1 basis to placebo, modafinil, or pitolisant. Treatment lasted eight weeks: with three weeks of flexible dosing, followed by five weeks of stable dosing. During the first week of treatment, all patients received a low dose (10 mg of pitolisant or 100 mg of modafinil or placebo), followed by a medium dose (20 mg of pitolisant or 200 mg of modafinil or placebo) for the second week. On day 14, investigators were free to randomize their patients to individual doses based on their own assessments, with pitolisant dosing of 10 mg, 20 mg, or 40 mg, and placebo/modafinil dosing of 100 mg, 200 mg, or 400 mg.
The investigators found that pitolisant was superior to placebo on the commonly used Epworth Sleepiness Scale (difference –3.0, 95% CI –5.6 to –0.4; p=0.024), the study's primary endpoint. But on several measures of excessive sleepiness, there were not statistically significant differences between modafinil and pitolisant (difference 0.12, 95% CI –2.5 to 2.7; p=0.250).
The study employed additional measures of excessive sleepiness, including the Maintenance of Wakefulness Test (MWT), the Sustained Attention to Response Test (SART), and the subjective physician-reported Clinical Global Impression of Change (CGI-C) and Clinical Global Impression of Severity (CGI-S) as secondary endpoints. MWT values increased from baseline in the pitolisant group, while they declined in the placebo group. The modafinil group also experienced an improvement in MWT values, but there was no statistically significant difference between modafinil and pitolisant in the level of MWT improvement. SART scoring was similar: patients improved with both modafinil and pitolisant, with no statistically significant difference between the two, and did not improve with placebo.
Both modafinil and pitolisant were well tolerated, with the most common side effects being insomnia and abdominal discomfort. Six treatment-related adverse events occurred during the treatment period, one in the pitolisant group (abdominal pain) and five in the modafinil group — abdominal pain, abnormal behavior, amphetamine-like withdrawal symptoms, lymphadenopathy, and an inner ear disorder.
“This is a very well done paper,” said Michael Silber, MD, professor of neurology at the Mayo Clinic College of Medicine and co-director of the Center for Sleep Medicine at the Mayo Clinic in Rochester, MN. Dr. Silber praised the authors for the use of multiple endpoints. “It appears that pitolisant is about as effective as modafinil, and certainly no less.”
The management of narcolepsy and excessive daytime sleepiness poses a challenge for sleep specialists, said Dr. Silber. “Some patients respond very nicely to modafinil or a variant, and do fine with minimal side effects. But if they don't respond, we have to go to the amphetamines, which are very effective at controlling sleepiness, but have serious side effects such as racing heart, tremor, and loss of weight. There is a subset of patients that it seems we can do very little with, and a new class of drugs would be very welcome.”
That said, Dr. Silber cautioned that pitolisant is not likely to be a miracle new stimulant that will prove dramatically effective in everyone with narcolepsy. “Modafinil is a very useful stimulant, but relatively weak for patients with severe narcolepsy, and pitolisant seems to be similarly potent.”
It may be possible to combine modafinil with pitolisant or other agents in some challenging situations, suggested Alon Avidan, MD, MPH, professor of neurology and director of the Sleep Disorders Center at the University of California, Los Angeles David Geffen School of Medicine. “It may help to potentiate wakefulness by combining medications that work on different sites of action in the brain.”
Experts all agreed that the small size of the study clearly calls for a larger trial — a conclusion that was echoed by the study authors. “The treatment group was only 33 patients, which is somewhat limited,” Dr. Avidan noted.
Dr. Mahowald praised the authors as “really good, responsible, experienced ethical researchers.” But the large number of centers involved, he said, might lead to variations. “There were 95 patients from 32 sleep disorders centers, or about three per center. Right away that creates some logistical problems. Even though everybody's supposed to do things the same way, when you have 30-plus sleep centers recruiting, there will be some variation. This will obviously need to be replicated in a larger population.”
While pitolisant isn't about to get approved anywhere based on this study alone, it's an exciting finding, Dr. Silber said. “We still need major phase 3 trials, including a large US trial, but as an early trial in Europe, this is a very promising study.”