Prader-Willi Syndrome (PWS)


Prader-Willi syndrome (PWS) is a rare neurobehavioral disorder caused by nonexistent expression of imprinted genes in the paternally derived region of chromosome 15q11.2-q13. Features of PWS include infantile lethargy and hypotonia, short stature, hypogonadism, hyperphagia and obesity, developmental delay, facial abnormalities, and intellectual disability.1

Current pharmacological therapy in PWS includes the use of recombinant growth hormone (rGH), for which positive clinical results have been reported, including improvements of growth, motor, and mental development. Several therapeutic strategies are currently in development that aim to prevent hyperphagia and obesity and control behavioral problems in patients with PWS.2,3

Vagus Nerve Stimulation

It is common to observe temper outbursts in individuals with PWS. These outbursts occur from childhood through adulthood, with a significant impact on quality of life in both patients and caregivers.3 

Vagus nerve stimulation (VNS) is a nonpharmacological therapy approved for managing epilepsy and depression in which a device is used to stimulate the vagus nerve with electrical impulses.4 VNS has also been studied as a potential treatment for multiple sclerosis and Alzheimer’s disease.4,5 The vagus nerve is involved in satiety signals that travel from the gastrointestinal system to the brain, and a pilot study in 3 patients with PWS revealed the potential impact of this therapeutic approach on behavior improvement.5

Read more about PWS prognosis

Diazoxide Choline Controlled Release

Diazoxide is an activator of the adenosine triphosphate-sensitive potassium (KATP) channel that crosses the blood-brain barrier. The activation of the KATP channel in certain neurons in the hypothalamus leads to decreased levels of neuropeptide Y (NPY) and agouti-related protein (AgRP), which are endogenous appetite-stimulating neuropeptides. Through this mechanism, diazoxide is expected to help reduce hyperphagia, hyperinsulinemia, and excess body fat.6

Diazoxide choline controlled release (DCCR) is an investigational therapy developed by Soleno Therapeutics as a tablet formulation that is orally administered once per day. Five phase 1 clinical studies involving healthy volunteers, three phase 2 clinical trials (one involving patients with PWS), and one phase 3 clinical trial have been completed with DCCR.7,8 Results from the open-label extension study C602 (NCT03714373) reported improvements in hyperphagia and behavioral problems.7,9

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RGH-706 is an investigational therapy in development by Gedeon Richter Plc for managing weight in PWS. This is an oral melanin-concentrating hormone receptor 1 (MCHR1) antagonist that is currently under evaluation in a phase 2 clinical trial (NCT05322096) to determine the efficacy, safety, and tolerability in patients with PWS.10 The binding of MCH to receptors in the brain reinforces the desire to eat. RGH-706 is designed to block this effect and decrease appetite.11


Wakix® (pitolisant) is a histamine H3 receptor antagonist/inverse agonist developed by Harmony Biosciences and approved for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. Wakix stimulates the release of histamine in the central nervous system and dopamine, norepinephrine, and acetylcholine in the cerebral cortex. Histamine has effects on sleep maintenance, neuroendocrine function, feeding and appetite, and cognition; therefore, Wakix is regarded as a potential therapy for managing EDS in patients with PWS.12

Safety and efficacy data from a phase 2 proof-of-concept study evaluating Wakix in patients with PWS have recently been reported. Wakix demonstrated clinically meaningful results in all age groups in both the high- and low-dose treatment arms, with no serious adverse events reported. A phase 3 clinical trial is expected to start in 2023.13

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ACP-101 (intranasal carbetocin) is an investigational therapy developed by Acadia Pharmaceuticals for the treatment of hyperphagia in PWS. Carbetocin is an oxytocin analogue with improved duration of action and increased specificity for oxytocin receptors. ACP-101 is presented as an intranasal formulation to allow the direct delivery of the treatment into the brain, thereby reducing the potential development of side effects.14,15

A phase 3 multicenter, randomized, double-blind, 8-week placebo-controlled study with ACP-101 has been completed to evaluate 2 doses of the experimental treatment (3.2 mg and 9.6 mg) vs a placebo, administered 3 times per day. The treatment was safe and well-tolerated, and the results reported that the 3.2-mg dose had a statistically significant effect.14

Read more about PWS clinical features


NNZ-2591 is being developed by Neuren Pharmaceuticals for the treatment of PWS. NNZ-2591 was preclinically evaluated in the Magel2-null mouse model that mimics the behavior and metabolic profile of PWS in humans. Results showed normalized fat mass, insulin levels, and circulating insulin-like growth factor 1 (IGF-1).16

A phase 2 clinical trial is ongoing to evaluate the safety, tolerability, and pharmacokinetics of NNZ-2591 in children and adolescents with PWS (NCT05879614).17 Treatment with the experimental therapy will occur for 13 weeks, and NNZ-2591 will be administered as an oral liquid.18


ARD-101 is an experimental drug developed by Aardvark Therapeutics for the management of hyperphagia and aggressive food-seeking behaviors that is currently under phase 2 clinical testing in PWS patients.19,20 This drug is designed to activate the secretion of several gut peptide hormones, including glucagon-like peptides-1 and -2 (GLP-1, GLP-2), and cholecystokinin (CCK). Gut CCK release from the gut enteroendocrine I-cells in PWS patients is compromised, leaving patients with a constant sense of hunger.20 

The ongoing phase 2 clinical trial has enrolled 12 patients for evaluating the safety and efficacy of the oral intake of ARD-101, and based on recently reported promising results, additional participants are being recruited for the study.20

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Tesomet is an investigational fixed-dose combination therapy, consisting of tesofensine and metoprolol, in development by Saniona.21 Tesofensine is a triple monoamine reuptake inhibitor, and metoprolol is a beta-1 selective blocker. This specific combination acts by blocking the reabsorption of serotonin, noradrenaline, and dopamine in the brain. These blockages increase the levels of the neurotransmitters in the brain, leading to a reduction of appetite and food cravings, while increasing metabolic fat burn.21

A phase 2 clinical trial of tesofensine/metoprolol in PWS (NCT03149445) reported that patients treated with the experimental drug achieved significant weight loss.1 Both safety and efficacy of Tesomet have been investigated in another phase 2 clinical trial (NCT03845075) which reported a significant weight reduction in patients with hypothalamic obesity following treatment with the experimental drug. Tesomet also showed a good tolerability profile.22 A subsequent phase 2b clinical trial aimed at studying Tesomet efficacy in hyperphagia in PWS has been launched but also voluntarily paused due to funding constraints (NCT05198362).23


RAD011 is a pharmaceutical-grade synthetic cannabidiol oral solution with an Orphan Drug and Fast Track Designation granted by the FDA. RAD011 has been studied in over 150 patients for multiple indications, with potential use in endocrine and metabolic orphan diseases,24 as the endocannabinoid system plays a role in the regulation of appetite, body weight and metabolism.1

RAD011 is being developed by Radius Health, and a pivotal study for evaluating the experimental drug use in the treatment of hyperphagia in PWS was launched. The SCOUT (Synthetic Cannabidiol Oral Solution) phase 2/3 clinical trial (NCT05098509) aimed to evaluate both safety and tolerability of RAD011 in PWS; however, it was voluntarily terminated by the sponsor.24,25


  1. Tan Q, Orsso CE, Deehan EC, et al. Current and emerging therapies for managing hyperphagia and obesity in Prader-Willi syndrome: a narrative review. Obes Rev. 2020;21(5):e12992. doi:10.1111/obr.12992
  2. Harris RM, Stafford DEJ. Prader-Willi syndrome: endocrine updates and new medical therapies. Curr Opin Endocrinol Diabetes Obes. 2020;27(1):56-62. doi:10.1097/MED.0000000000000517
  3. Manning KE, Beresford-Webb JA, Aman LCS, et al. Transcutaneous vagus nerve stimulation (t-VNS): a novel effective treatment for temper outbursts in adults with Prader-Willi syndrome indicated by results from a non-blind study. PLoS One. 2019;14(12):e0223750. doi:10.1371/journal.pone.0223750
  4. Bohonowych J. Will vagus nerve stimulation effectively treat behavior in PWS? Foundation for Prader-Willi Research. March 22, 2017. Accessed July 25, 2023.
  5. Manning KE, McAllister CJ, Ring HA, et al. Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation. J Intellect Disabil Res. 2016;60(2):149-155. doi:10.1111/jir.12203
  6. Miller JL, Gevers E, Bridges N, et al; DESTINY PWS Investigators. Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2023;108(7):1676-1685. doi:10.1210/clinem/dgad014
  7. Soleno Therapeutics announces positive data showing continued significant improvements in symptoms of PWS following one year treatment with DCCR. News release. Soleno Therapeutics; September 8, 2021.
  8. A study of diazoxide choline in patients with Prader-Willi syndrome. February 22, 2018. Updated June 8, 2022. Accessed July 25, 2023.
  9. Soleno Therapeutics announces presentation of long-term hyperphagia and behavioral data in patients receiving DCCR for treatment of Prader-Willi syndrome. News release. Soleno Therapeutics; May 2, 2022.
  10. Study to evaluate efficacy, safety, and tolerability of RGH-706 in Prader-Willi syndrome. April 11, 2022. Updated June 26, 2023. Accessed July 25, 2023.
  11. RGH-706 as a potential therapeutic for PWS. Foundation for Prader-Willi Research. Accessed July 25, 2023.
  12. Pennington S, Stutzman D, Sannar E. Pitolisant in an adolescent with Prader-Willi syndrome. J Pediatr Pharmacol Ther. 2021;26(4):405-410. doi:10.5863/1551-6776-26.4.405
  13. Harmony Biosciences announces positive phase 2 signal detection study evaluating pitolisant for excessive daytime sleepiness in Prader-Willi syndrome at Sleep 2023. News release. Harmony Biosciences; June 6, 2023.
  14. Acadia Pharmaceuticals announces phase 3 development candidate ACP-101 (intranasal carbetocin) for Prader-Willi syndrome. News release. Acadia Pharmaceuticals; June 13, 2023.
  15. Phase 3 study of intranasal carbetocin (LV-101) in patients with Prader-Willi syndrome (CARE-PWS). August 28, 2018. Updated July 26, 2022. Accessed July 25, 2023.
  16. NNZ-2591: Prader-Willi syndrome. Neuren Pharmaceuticals. Accessed July 25, 2023.
  17. An open-label study of oral NNZ-2591 in Prader-Willi syndrome (PWS-001) (PWS-001). Updated May 30, 2023. Accessed July 25, 2023.
  18. Neuren opens first site in US for Prader-Willi syndrome phase 2 trial. News release. Neuren Pharmaceuticals; June 28, 2023.
  19. A Study of Oral ARD-101 in Patients With Prader-Willi Syndrome. Accessed August 07, 2023.
  20. Aardvark Therapeutics announces receipt of FDA Rare Pediatric Disease designation for Prader-Willi syndrome and expands the ongoing phase 2 clinical trial. News release. August 03, 2023.
  21. Tesomet. Saniona. Accessed August 17, 2023.
  22. Huynh K, Klose M, Krogsgaard K et al. Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity. Eur J Endocrinol. 2022;186(6):687-700. Doi:10.1530/EJE-21-0972
  23. Study of Tesomet with open-label extension in subjects with Prader-Willi syndrome (PWS). Accessed August 17, 2023.
  24. Radius Announces First Patient Randomized in the RAD011 Pivotal Trial for Prader-Willi Syndrome. News release. GlobeNewswire: July 7, 2022.
  25. A Phase 2/3 Study of RAD011 (Cannabidiol Oral Solution) for the Treatment of Patients With Prader-Willi Syndrome (SCOUT-015). Accessed August 16, 2023.

Reviewed by Hasan Avcu, MD, on 7/27/2023.