Pitolisant works on histamine to boost alertness and combat sleep disorders.

Pitolisant, a drug for patients with hypersomnia caused by sleep disorders like narcolepsy, is offering new hope to patients and families, including those with the genetic disorder Prader-Willi syndrome.

Traditional stimulant medications like methyphenidate, the mainstay treatment for hypersomnia, work on dopamine neurotransmitters in the brain. In contrast, pitolisant targets the brain’s histamine transmitters.

“Patients with Prader-Willi syndrome can struggle with hypersomnia despite getting sufficient sleep and having treatment for other sleep disorders like obstructive sleep apnea.”

“Patients with Prader-Willi syndrome can struggle with hypersomnia despite getting sufficient sleep and having treatment for other sleep disorders like obstructive sleep apnea,” said Althea R. Shelton, M.D., an associate professor of neurology at Vanderbilt.

Shelton served as a site investigator for a recent phase 2 proof-of-concept clinical trial of pitolisant. Encouraging results from that randomized, double-blinded, placebo-controlled phase 2 trial were reported at the Associated Professional Sleep Societies international SLEEP conference in 2023.

Prader-Willi: Life Interrupted

Shelton has treated sleep disorders in patients with Prader-Willi syndrome for more than 12 years. The genetic disorder affects several organ systems in the body and is one of the known genetic causes of morbid obesity. It is present in approximately one in 20,000 individuals.

People with Prader-Willi syndrome have appetite dysregulation and thus never feel satiated; they are always hungry. They also experience issues with body temperature regulation and excessive daytime sleepiness.

“These school-aged children and adolescents struggle to pay attention, learn and have enough energy for an after-school activity,” Shelton said.

Used Abroad

Since 2016, pitolisant has been available in Europe for treatment of narcolepsy. Although not all people with Prader-Will syndrome meet all the criteria for narcolepsy, they typically usually appear narcoleptic, Shelton explained.

In the United States, some parents of children with Prader-Willi syndrome who have found private-pay physicians to prescribe pitolisant were able to obtain it from overseas suppliers. That is an expensive proposition, Shelton explained.

“The majority of families who need the treatment don’t have the means to do that,” she said.

Posts on a website for caregivers of people with Prader-Will syndrome report good results with the drug compared to results obtained with older treatments in use in the U.S., she said.

Alertness with Fewer Side Effects

Clinicians in the U.S. have long used drugs such as methylphenidate (Ritalin) to help children with Prader-Willi syndrome stay awake, Shelton said. These drugs primarily target dopamine neurotransmitters.

“But common side effects with those drugs, such as anxiety and agitation, can be amplified in patients with Prader-Willi syndrome when using traditional stimulant medications,” she said. “Also, people with Prader-Will syndrome have compulsive tendencies like skin picking, and those medicines make the patients focus in on those behaviors and pick even more.”

Clinically Meaningful Improvement Seen

In the phase 2 study, children and adults with Prader-Willi syndrome and excessive daytime sleepiness were randomized to receive high-dose pitolisant, low-dose pitolisant, or placebo. A total of 65 people between the ages 6 to 65 years were enrolled across multiple sites.

The trial, sponsored by the manufacturer, Harmony Biosciences, employed the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). On this scale, a score above 10 suggests excessive daytime sleepiness, with scores above 16 indicating extreme excessive daytime sleepiness.

The trial found clinically meaningful change was experienced across all age groups. The measure was defined as an improvement of 2 or more points on the ESS-CHAD scale. The investigators noted additions of 3.7 to 5.5 points in both the high- and the low-dose treatment arms.

To satisfy the FDA’s requirement for further data, a phase 3 trial is planned, Shelton said.

Certain Neurotransmitters Affect Alertness

For some time, researchers have been studying the many brain neurotransmitters that play a role in alertness.

“These neurotransmitters work in a beautifully timed dance to help keep us alert, and any one of them that is not functioning can cause a person to experience excessive daytime sleepiness,” Shelton said.

“It would be great if we could measure the levels of these alerting neurotransmitters and replace any that are deficient, but we don’t have that ability.”

Brain Histamines

Histamine-3 resides in the brain, and it is the form affected by pitolisant, which can cross the blood-brain barrier, she explained.

Brain histamines levels are high during periods of alertness and low during sleep. Brain histamine promotes alertness and as Shelton notes, “antihistamines make you sleepy.”

Pitolisant is the first drug in its class that targets brain histamine.

Cost Is High

Pitolisant comes in two different strengths, 4.45 mg and 17 mg, and they can be costly. Patients use the drug on a long-term, ongoing basis.

“Right now, insurers are only approving pitolisant for patients who meet the criteria for narcolepsy and another sleep disorder called idiopathic hypersomnia,” Shelton said.

Companies also want to see that the patient has failed one or two more common, less costly narcolepsy medications before approving pitolisant, she added.

“What would be great would be the FDA approving pitolisant for Prader-Willi syndrome,” Shelton said. “Then it wouldn’t matter about patients meeting strict criteria for narcolepsy, this would be available for our patients.”

About the Expert

Althea R. Shelton, M.D.

Althea R. Shelton, M.D., is an associate professor of neurology at Vanderbilt University Medical Center specializing in pediatric sleep medicine. Her research and clinical work focuses on sleep problems in children with neurodevelopmental disorders, such as nocturnal seizures and restless legs.