Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a complex genetic disorder that affects multiple body systems. In infancy, this condition is characterized by hypotonia, feeding difficulties, poor growth, and delayed development. In childhood, affected children have an insatiable appetite, which results in hyperphagia and obesity. Type 2 diabetes can also develop in some patients with PWS, particularly those who are obese.1

Current pharmacologic treatment for PWS includes the use of recombinant growth hormone (rGH), which has shown positive clinical results, such as improvements in growth, motor, and mental development. To prevent obesity and behavioral issues in patients with PWS, several therapeutic approaches are currently being developed.2,3 


The nonpharmacological therapy known as vagus nerve stimulation (VNS) uses electrical impulses to stimulate the vagus nerve to treat depression and epilepsy.4

VNS modifies nerve activity to stimulate the parts of the brain responsible for regulating emotions and behavior. Transcutaneous VNS (tVNS) involves an external device worn in the left ear and an electrode stimulating the auricular branch of the vagus nerve. This has replaced the previous method, which involved surgically implanting a device that would send regular short electrical pulses through the vagus nerve in the neck.5

The phase 3 clinical trial VNS4PWS aims to assess the efficacy of a VNS device in reducing disruptive behaviors and irrational outbursts in patients with PWS. Eligible participants will wear a tVNS device for 4 hours each day, and their caregiver will answer a brief daily survey of 1 to 3 questions to collect information on the frequency and intensity of the day’s outbursts. The 9-month research only calls for 2 in-person visits. Participants in the trial must be a patient with PWS aged 10 to 40 years, have a history of disruptive behaviors during the last 6 months, and be taking stable medications for the last 90 days. Trial participants will have the option to enroll in an extension study so they can continue using the device.6 

Read more about PWS prognosis


KITE-PWS (NCT05322096) is an ongoing phase 2 trial of RGH-706 for participants with PWS aged 17 years and above. The study is sponsored by Gedeon Richter, a Hungarian company.7

It is a randomized, multicenter, double-blind, placebo-controlled trial evaluating the safety, efficacy, and tolerability of RGH-706 in patients with PWS.8 

The KITE-PWS trial seeks to assess the impact of RGH-706, an investigational therapy, on hyperphagia in adults with PWS. RGH-706 inhibits a hormone in the hypothalamus whose signaling encourages food-seeking behaviors. It is proposed that by inhibiting this receptor, hyperphagia is reduced because people with PWS have an imbalance between the controls of melanin-concentrating hormone and orexigenic signaling.7 

The KITE-PWS trial aims to determine whether RGH-706 effectively inhibits this receptor and reduces hyperphagia.7 The study is estimated to be completed in April 2024.8

Read more about PWS pathophysiology

Study C602

The blood-brain barrier-crossing adenosine triphosphate-sensitive potassium (KATP) channel is activated by diazoxide. Endogenous neuropeptides that stimulate appetite, neuropeptide Y (NPY) and agouti-related protein (AgRP), are decreased when the KATP channel in certain hypothalamic neurons is activated. Diazoxide has the potential to decrease hyperphagia and excessive body fat via this mechanism.9

Study C602 (NCT03714373) is assessing the safety and efficacy of daily diazoxide choline extended-release tablets in around 105 patients with PWS, all of whom had previously participated in the placebo-controlled DESTINY PWS phase 3 trial (NCT03440814) and are currently being administered the treatment. Study C602 is an open-label extension study of diazoxide choline controlled release (DCCR) in patients with PWS followed by a double-blind, placebo-controlled, randomized withdrawal period.10 The study is expected to be completed in August 2023.11

Read more about PWS therapies


The lead product of Aardvark, ARD-101, is a first-in-class oral composition that has demonstrated encouraging results in clinical studies and pre-clinical investigations for lowering hunger cravings and aiding in weight loss. ARD-101 has a very low systemic exposure and is largely gut-restricted.12  

It is hypothesized that ARD-101 exerts its systemic effects via triggering the release of a number of gut peptide hormones, including cholecystokinin (CCK) and the glucagon-like peptides-1 and -2 (GLP-1, GLP-2). Gut CCK is regarded as a “satiety signal” that regulates appetite by acting on the gut-brain axis. PWS individuals have a normal CCK receptor, but because their gut enteroendocrine I-cells are unable to release CCK in response to consuming food, they experience acute hunger all the time. Phase I trials on healthy human volunteers showed the product to be safe and tolerable.12 

A Phase 2, open-label trial (NCT05153434) will inquire into ARD-101’s impact on PWS patients. Twelve people between the ages of 17 and 65 are needed for this study. For 28 days, participants will be given increasing oral dosages of ARD-101 twice daily. The trial will have screening phase (up to 28 days), treatment phase (28 days), and follow-up phase (end-of-study visit within 14 days of last ARD-101). Once the process for obtaining informed permission has been completed, the screening procedures will begin. Subjects will be enrolled to receive ARD-101 in an outpatient setting when the screening processes are finished and their eligibility has been verified. They will also be given instructions on how often to attend the clinical facility for safety and efficacy evaluations.13,14 The study is expected to be completed on March 1, 2024.13,14


Tesomet is an experimental fixed-dose combination treatment that combines the beta-1 selective blocker metoprolol with the triple monoamine reuptake inhibitor tesofensine. 

This particular combination works by preventing the brain’s reabsorption of serotonin, noradrenaline, and dopamine. These blockages raise neurotransmitter levels in the brain, which decrease appetite and food cravings, while boosting metabolic fat burning.15,16

In a randomized, double-blind, placebo-controlled first Phase 2 trial, Saniona previously assessed Tesomet in adults and adolescents with PWS. Tesomet treatment for adult patients led to a statistically significant decrease in hyperphagia and a loss in body weight. In open-label extensions of the research, adolescent patients showed dose-dependent decreases in hyperphagia and body weight. Tesomet was given orphan drug designation in PWS from the FDA.15,16 

A safety and efficacy Tesomet study (NCT05198362) with Open-label Extension (OLE) period was started in January 2022 for PWS subjects. However, this trial was suspended in April 2022 and withdrawn in December 2022 due to financial considerations by Saniona. It was not withdrawn over safety concerns. No subjects were randomized to treatment, so no study was done nor were results found about safety or efficacy.17 

Read more about PWS experimental therapies


The synthetic cannabidiol oral solution RAD011, developed by Radius Health, is an experimental drug, produced using conventional pharmaceutical manufacturing techniques. With over 150 individuals evaluated across several indications, RAD011 has the potential to treat a variety of endocrine and metabolic orphan illnesses. The FDA has already given RAD011 Orphan Drug and Fast Track Designation.18 

The Phase 2/3 study (NCT05098509), SCOUT (Synthetic Cannabidiol Oral Solution), was established in late 2021 to assess safety and tolerability in PWS. However, the study was voluntarily terminated in December 2022 by Radius for reasons other than safety.19 


  1. Prader-Willi syndrome. MedlinePlus. Updated May 13, 2022. Accessed July 31, 2023. 
  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 31, 2023.
  5. Vagus nerve stimulation for behaviour in PWS. Prader-Willi Syndrome Association New Zealand. September 30, 2022. Accessed July 31, 2023.
  6. VNS4PWS. Foundation for Prader-Willi Research. Accessed July 31, 2023.
  7. Hedstrom S. What can I expect if I participate in the KITE-PWS clinical trial? Foundation for Prader-Willi Research. June 14, 2023. Accessed July 31, 2023.
  8. Study to evaluate efficacy, safety, and tolerability of RGH-706 in Prader-Willi syndrome. April 11, 2022. Updated June 26, 2023. Accessed July 31, 2023.
  9. 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
  10. Shapiro L. New phase of DCCR trial may support regulatory approval request. Prader-Willi Syndrome News. October 14, 2022. Accessed July 31, 2023.
  11. Open-label extension study of DCCR in PWS followed by double-blind, placebo-controlled, randomized withdrawal period. October 22, 2018. Updated June 28, 2023. Accessed July 31, 2023.
  12. Aardvark Therapeutics Announces Receipt of FDA Rare Pediatric Disease Designation for Prader-Willi Syndrome and Expands the Ongoing Phase 2 Clinical Trial. News release. PR Newswire; August 03, 2023.
  13. A Study of Oral ARD-101 in Patients With Prader-Willi Syndrome. December 10, 2021. Updated August 14, 2023. Accessed August 19, 2023.
  14. ARD-101 as a Potential Treatment for PWS. Foundation for Prader-Willi Research. January 12, 2022. Accessed August 19, 2023.
  15. Tesomet. Saniona. Accessed August 19, 2023.
  16. Hedstrom S. Saniona Initiates Phase 2b Clinical Trial of Tesomet for PWS. Foundation for Prader-Willi Research. January 7, 2022. Accessed August 19, 2023.
  17. Study of Tesomet With Open-label Extension in Subjects With Prader-Willi Syndrome (PWS). January 20, 2022. December 13, 2022. Accessed August 19, 2023.
  18. Hedstrom S. Radius Health Announces Pivotal Study for Prader-Willi Syndrome. Foundation for Prader-Willi Research. July 22, 2021. Accessed August 19, 2023.
  19. A Phase 2/3 Study of RAD011 (Cannabidiol Oral Solution) for the Treatment of Patients With Prader-Willi Syndrome (SCOUT-015). October 28, 2021. December 7, 2022. Accessed August 19, 2023.

Reviewed by Kyle Habet, MD, on 7/31/2023.