New call-to-action
New call-to-action
New call-to-action

Pitolisant for Excessive Daytime Sleepiness in PWS [2020 CONFERENCE VIDEO]

In this video, Albena Patroneva from Harmony Biosciences discusses a clinical trial of pitolisant (approved for narcolepsy in adults) in patients with PWS.

In this 30‑minute video, Albena Patroneva from Harmony Biosciences explains what pitolisant is and how it works, and describes Harmony's Phase 2 clinical trial of pitolisant in patients with PWS. The session includes Q&A from participants in the 2020 FPWR Virtual Conference.

Click below to watch the video. If you're short on time, scroll down for timestamps to find the portions you're most interested in.


Presentation Summary With Timestamps

0:50 Albena Patroneva presents

Pitolisant and Its Relationship to Prader‑Willi Syndrome

  • Overview of the topics to be covered: what pitolisant is and how it works, how histamine works in the brain, why studying pitolisant in patients with PWS makes sense for Harmony Biosciences.
  • Harmony Biosciences was founded in October 2017, started a PK program shortly after with a smaller PWS population of children, and a year later they met with FPWR key members.
  • At the beginning of 2019, they made the decision to do a formal development program with the FDA, and attended the FPWR annual meeting in New Orleans, while also presenting the concept of a potential Phase 2 trial in the PWS population.
  • At the same time, there was a Phase 1 PK trial in children with PWS that was completed and which gave way to an open‑label long‑term safety study.

5:15 What Is Pitolisant and How Does It Work?

  • Pitolisant is a new mechanism of action (MOA), targeting histamine‑3 (H3)and being a histamine receptor antagonist. It works by increasing histamine signaling in the synaptic gap in the brain.
  • Histamine is a major wake‑promoting neurotransmitter, which helps to stabilize states of sleep and wakefulness.
  • Pitolisant is a drug discovered in France, and the scientific director has been closely involved in the discovery of the mechanism of histamine‑3 receptors.
  • It has been used in the treatment of narcolepsy in adults since it was approved in the EU in March 2016.
  • In August 2019, it was approved in the US as a treatment for excessive daytime sleepiness in adult patients with narcolepsy, with or without cataplexy.
  • It’s not a scheduled drug, making it the first wake drug agent that is not scheduled by the DEA.
  • It comes in an oral tablet form, and the therapeutic dose range approved for narcolepsy is from 17.8 to 35.6 mg.
  • The most common side effects were headaches, insomnia, nausea, and anxiety.

10:11 On Histamine

  • Histamine is produced in our bodies and it mediates many different functions, and it depends on the type of histamine receptors that it binds to. There are three main types of histamine receptors that have been discovered.
  • H1 receptors are located in the skin, mucous membranes, and blood vessels throughout the body.
    • When excess histamine binds to these receptors, there is an allergic reaction as a result (e.g. a rash, swelling, itching).
    • Antihistamines block these reactions by preventing histamine from binding to H1 receptors.
  • H2 receptors are located mainly in the stomach/GI tract. 
    • They are responsible for acid production for digestion.
    • Anti‑ulcer medications or histamine‑2 blockers keep histamine from binding to H2 receptors to decrease acid production.
  • H3 receptors were recently discovered and are located mainly in the central nervous system (CNS)
    • They mediate the level of histamine release in the brain, a major wake‑promoting neurotransmitter.
    • The interaction between histamine and H3 receptors controls histamine signaling in the brain. Histamine works closely with orexin, another neurotransmitter that can be the lead cause of narcolepsy in certain cases. 

12:44 The Role of Histamine in the CNS

  • H3 receptors have different functions based on their location within the brain.
  • The sleep‑wake switch is located in the hypothalamus, where the change from sleep promotion to histamine’s effect of wake promotion along with sleep inhibition occurs.
  • Other functions of histamine are attention, vigilance, cognition; emotional control and behavioral processing, consolidation of memory, and there is some evidence as well that it controls hunger and satiety. 

15:00 The Role of Histamine in Wakefulness

  • Histamine is produced in the hypothalamus, and it’s a key brain metabolite that helps stabilize states of sleep and wakefulness.
    • It activates wake‑promoting brain regions.
    • It inhibits sleep‑promoting (both REM and non‑REM) brain regions 
    • It activates the cerebral cortex.
  • Decreased levels of histamine and hypocretin result in sleep‑wake state instability and decreased activation of the cerebral cortex (which mediates attention and alertness)

16:40 PWS as a Disorder of Hypothalamic Dysfunction

  • Hypothalamic dysfunction in PWS can result in:
    • Excessive daytime sleepiness (EDS)
    • Disrupted night sleep
    • Impaired attention
    • Dysregulation of hunger/satiety, which leads to hyperphagia
    • Sleep‑wake state instability
    • Dysregulation of growth hormone release, endocrine function, metabolism, and body temperature.
  • The cause of EDS in PWS is multifactorial:
    • Sleep‑wake state instability (little histamine produced)
    • Obstructive sleep apnea (OSA)
    • Central hyperventilation
    • Narcolepsy

19:05 Why Study Pitolisant in Patients with PWS

  • PWS is a disorder of hypothalamic dysfunction
    • There have been found abnormalities in the hypothalamus in patients with PWS
    • Growth hormone deficiency, hypogonadism, hyperphagia, and sleep abnormalities are some of the common features of patients with PWS and come as a result of this dysfunction. 
  • The hypothalamus regulates sleep‑wake state stability via hypocretin and histamine. 
  • Pitolisant increases histamine levels in the brain and has demonstrated significant improvement in daytime wakefulness in patients with narcolepsy.
  • Preliminary evidence from both animal and human studies has suggested that there is a potential benefit of pitolisant in attention, vigilance, and cognitive function.
  • Further studies are needed in patients with PWS.

20:33 Phase 2 Clinical Trial of Pitolisant in Patients with PWS

  • A randomized, double‑blind, placebo‑controlled, parallel‑group, study followed by a long‑term, open‑label extension.
  • This study is planning an enrollment of approximately 60 patients from ages 6 to 65; the duration of the treatment is 11 weeks: a 3‑week titration period followed by an 8‑week stable dosing period. An open‑label extension is planned to run throughout the development of the program.
  • There are three treatment groups based on age (children, adolescents and adults) with either a low or high dosage of the drug, along with the placebo.

22:16 Study Objectives

  • Primary Objective: To evaluate the safety and efficacy of pitolisant compared to placebo in treating EDS in patients with PWS ages 6 to 65 years old.
  • Key Secondary Objectives: Caregiver‑rated impressions of severity of EDS; Clinician‑rated impressions of severity of overall clinical status in patients with PWS ages 6 to 65 years old.
  • Other Secondary Objectives: To evaluate the impact of pitolisant on behavioral symptoms, cognitive function, and overall caregiver burden; to assess the effectiveness of pitolisant during long‑term treatment in patients with PWS ages 6 to 65.
  • Exploratory Objectives: The impact of pitolisant on the ESS‑CHAD as rated by caregivers; the impact of pitolisant on other measures of sleep as assessed by actigraphy; the impact of pitolisant on hyperphagia and ghrelin levels.

24:00 Q & A

  • There are certain specific criteria that will allow some patients with PWS to participate in the clinical trial, as well as some criteria that will exclude them from participating in the trial.
  • There are ten participating sites in various locations around the US, and they will all be ready to receive participation for the clinical trial by January 2021.

Learn more about this and other PWS Clinical Trials.

New call-to-action

Topics: Research

Susan Hedstrom


Susan Hedstrom is the Executive Director for the Foundation for Prader-Willi Research. Passionate about finding treatments for PWS, Susan joined FPWR in 2009 shortly after her son, Jayden, was diagnosed with Prader-Willi Syndrome. Rather than accepting PWS as it has been defined, Susan has chosen to work with a team of pro-active and tireless individuals to accelerate PWS research in order to change the future of PWS. Inspired by her first FPWR conference and the team of researchers that were working to find answers for the syndrome, she joined the FPWR team in 2010 and led the development of the One SMALL Step walk program. Under Susan’s leadership, over $15 million has been raised for PWS related research.