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Mahmoud, R.; Kimonis, V.; Butler, M.G. Clinical Trials in Prader–Willi Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/42410 (accessed on 08 December 2025).
Mahmoud R, Kimonis V, Butler MG. Clinical Trials in Prader–Willi Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/42410. Accessed December 08, 2025.
Mahmoud, Ranim, Virginia Kimonis, Merlin G. Butler. "Clinical Trials in Prader–Willi Syndrome" Encyclopedia, https://encyclopedia.pub/entry/42410 (accessed December 08, 2025).
Mahmoud, R., Kimonis, V., & Butler, M.G. (2023, March 22). Clinical Trials in Prader–Willi Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/42410
Mahmoud, Ranim, et al. "Clinical Trials in Prader–Willi Syndrome." Encyclopedia. Web. 22 March, 2023.
Clinical Trials in Prader–Willi Syndrome
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24032150

Prader–Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. Individuals with the different PWS molecular classes present with varying clinical findings. 

Prader–Willi syndrome obesity hyperphagia

1. Introduction

Prader–Willi syndrome (PWS) is a rare, genetic, neurodevelopmental disorder caused by errors in a complex genomic mechanism, referred to as genomic imprinting, comprised of three PWS molecular genetic classes. PWS is characterized by severe hypotonia with a poor suck and feeding difficulties causing failure to thrive during infancy, hypogenitalism/hypogonadism in both sexes, motor and cognitive delays, low muscle tone, slow metabolism, behavior disturbances, and endocrine findings involving growth and other hormone deficiencies with short stature, infertility, and small hands and feet (e.g., [1][2][3][4][5][6]). Mild cognitive impairment and behavior problems, including self-injury, anxiety, compulsions, and outbursts, can occur in childhood along with food seeking and hyperphagia, leading to morbid obesity and a shortened life expectancy if not controlled (e.g., [7]). PWS is considered the most commonly known cause of life-threatening obesity in humans, affecting approximately 400,000 people worldwide and one in every 20,000 live births [8]. Occurrences of this rare disorder are sporadic, but the cause is due to errors in the genomic imprinting of the chromosome 15q11-q13 region in humans. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. The remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15 or have chromosome 15 translocations or inversions (e.g., [4]). Individuals with the different PWS molecular classes present with varying clinical findings. Those with the typical 15q11-q13 deletion, specifically the larger 15q11-q13 type I deletion, have a more severe phenotype with self-injuries, compulsions, and lower cognition than those with the typical, smaller 15q11-q13 Type II deletion or maternal disomy 15 (e.g., [9][10][11]).
If not externally controlled, significant hyperphagia leads to morbid obesity in PWS and contributes to diabetes, cardiovascular or orthopedic problems, and even death [12]. The most common cause of death in PWS is respiratory failure followed by cardiac failure, gastrointestinal failure, and infection [7][13]. According to a 2014 survey of parents and caregivers of PWS patients, reducing hunger and improving food-related behaviors were the most important unmet needs in PWS. These needs could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for the treatment of hyperphagia in PWS.

2. Beloranib Clinical Trial in Prader–Willi Syndrome

Beloranib treatment was undertaken in a large cohort of individuals with genetic confirmation of PWS in a clinical trial sponsored by Zafgen, Inc. (Boston, MA, USA). The goal was to investigate the efficacy of beloranib treatment for hyperphagia and obesity, as well as to determine its safety with tolerability over 26 weeks of treatment in both PWS adolescent and adult participants. The study was stimulated by early reported data indicating a clinically significant and sustained weight loss with decreased hunger in obese subjects using beloranib [14]. Beloranib inhibits methionine aminopeptidase 2 (MetAP2) by removing methionine residue from proteins, impacting fat metabolism. Inhibitors of MetAP2 were found to reduce food intake, body weight, fat content and adipocyte size in animal models [14]. Hence, a Phase Three, randomized, placebo-controlled, double-blind trial was conducted in 15 states in the United States between 2014 and 2015. Those with genetically confirmed PWS were enrolled between the ages of 12 to 65 years. Participants had an elevated body mass index (BMI) (ages 12 to 17 years: BMI ≥ 95th percentile for age and sex; ages 18 to 65 years: BMI 27–60 kg/m2), with a total score ≥ 13 on the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), and a stable weight for at least three months, but otherwise demonstrated health-related findings, such as blood pressure readings, within the normal range. Those with type II diabetes were accepted, if stable. Growth hormone treatment was allowed if a stable dose was prescribed for at least three months before entry into the trial. Participants living in a group home for less than 50% of the time were excluded. All participants were randomized via computer access using a centralized interactive system with a 1:1:2:2 ratio of lower dose placebo: higher dose placebo: lower dose beloranib (1.8 mg): higher dose beloranib (2.4 mg) per participant.
Following a two-week single-blind placebo lead-in, participants were randomized to study treatment with doses selected based on previous experience, with the study drug administered twice weekly. The study included an optional twenty-six-week, open-label extension trial in which all participants received four weeks of 1.8 mg beloranib, followed by 2.4 mg beloranib use for 22 weeks. The prespecified co-primary endpoints were a change in hyperphagia-related behaviors, captured via a questionnaire form, and a percent change in body weight from baseline to week 26. The HQ-CT form consisted of nine question items with responses ranging from 0 to 4 units each, with a possible total score range of 0 to 36 designed to measure symptoms of food-related preoccupations and behaviors. The form was completed by the caregiver for each participant. It was estimated that a sample size of 20 participants per group would provide 94% power to detect the between-group difference in each of the co-primary endpoints. Out of 126 screened individuals, 108 participants were randomized and 107 received the study drug. Demographic and baseline characteristics were well-matched across the treatment groups for age, sex, growth hormone use, weight, BMI, fat mass, and genetic subtype. The participants were primarily Caucasian. A significant reduction in fat mass was found in both the low- and high-dosage beloranib-treated groups when compared with the placebo, with participants having a weight loss greater than or equal to 5%. A change in HQ-CT individual question scores indicating improvement were found for eight out of the nine measures in the beloranib-treated participants. The questionnaire measures were classified as: upset when denied food, bargain to get more food, forage through trash for food, up at night to seek food, persistent asking for food, time spent talking about food, distress when stopped from asking about food, and interferes with activities. Unfortunately, the randomized, double-blind portion of the trial was stopped early due to venous thromboembolic events, including two participant deaths in the beloranib-treated group.

3. Oxytocin Clinical Trials in PWS

Oxytocin is a neuropeptide hormone which plays an important role in social interactions, social skills, food intake, anxiety, energy expenditure, maternal behaviors, and body weight regulation [15][16]. All of these parameters are severely affected in patients with Prader–Willi syndrome (PWS). They have a decreased number of oxytocin-producing neurons in the hypothalamic periventricular nuclei and a small number of observed periventricular nuclei [17]. The deficiency of these neurons could be related to PWS patients’ poor social judgement and their inability to control their emotions. Two mouse models deficient for PWS genes, including necdin and Magel2, also showed decreased oxytocin levels [18]. Additionally, postnatal treatment with oxytocin has been reported to normalize suckling and feeding behavior in the Magel2-knockout mouse [19]. Approximately one half of the surviving mice showed an improvement in social recognition skills, which would suggest that oxytocin could be helpful in managing behavioral problems in PWS [20].
To date, there have been seven clinical trials on the use of oxytocin in PWS. The first study was a double-blind, randomized, placebo-controlled trial undertaken by Tauber et al. [21] in 2011. Twenty-four patients were included, with a median age of 28.5 years, and grouped based on gender and intelligence quotient (IQ). Every patient received a single dose (24 IU) of either oxytocin or a placebo. The behavior of the patients was assessed three times: the first at two days before drug administration, the second at one half-day after administration (early effects), and for the last time at two days after drug administration (late effects). A behavior grid was developed to assess ten social and emotional behaviors. There was also as a separate set of four questions relating to eating behavior. There was no difference between the two groups before intranasal administration, but a significant increase in trust in others, less sadness tendencies, and disruptive behavior were observed in the two days after intranasal drug administration. While no statistical difference was observed in the eating behavior scores between both groups, there was improvement in social skills in the oxytocin-treated group. The limitations of this study were the use of only one dose of oxytocin and a placebo with the effect of treatment appearing only in the behavior grid.
The second study was a double-blind, randomized, controlled trial with intranasal use of oxytocin in patients with PWS to examine its effect on physical, behavioral, and cognitive function. Thirty patients with PWS were included in this study, and two different doses of oxytocin were used according to the age of patients: a 24 IU dosage for patients aged 16 years and more, and an 18 IU dosage for patients aged between 12 and 15 years. The dose was increased to 40 IU for patients older than 16 years and 32 IU for patients between 12 and 15 years. The oxytocin and placebo were given for eight weeks; this was followed by a two-week washout period. The Developmental Behavior Checklist (DBC), the Yale–Brown Obsessive Compulsive Scale (Y-BOCS), the Dykens Hyperphagia Questionnaire, the Reading the Mind in the Eyes Test (RMET), and the Epworth Sleepiness Scale (ESS) were used to assess behavioral and related problems. No improvement was found in any of the behavioral problems or in hyperphagia in response to the oxytocin treatment [22].
The third trial was applied only to children with PWS [23]. The randomized, double-blind, placebo-controlled, cross-over study was conducted on 25 children with the aim of investigating the effect of oxytocin on social and eating behavior in PWS. Children received either oxytocin or a placebo for four weeks. They then crossed over to the alternative treatment for another four weeks. The Dykens Hyperphagia Questionnaire was used to evaluate changes in eating behavior and hyperphagia and the Oxytocin Study Questionnaire, designed by PWS experts, was used for the evaluation of social behavior. When the participants were divided into two groups, <11 years and >11 years, there was no significant effect between either oxytocin or the placebo in the whole group. The younger children showed beneficial effects of oxytocin on social behavior and hyperphagia. Less anger and sadness and an improvement in social behavior were noted during oxytocin treatment when compared with the placebo, as was documented by the participants’ parents. The lack of response in the older group could be related to the small number of older children, a miscalculation of the oxytocin dose, the wrong administration of oxytocin, or that the behavior of older children may be more fixed in their personality and may need a longer duration of treatment to generate a significant effect [23].
The fourth study was a double-blinded, placebo-controlled, crossover trial performed on 24 children with PWS, reported by Miller et al. [24] in 2017. The participants received 16 IU of intranasal oxytocin or placebo for five days, followed by a four-week washout period, and finally an adjustment to the alternative treatment for another five days. The Aberrant Behavior Checklist, Social Responsiveness Scale (SRS-P), Repetitive Behavior Scale- Revised (RBS-R), Hyperphagia Questionnaire, and the Clinical Global Impression (CGI) scale were used to evaluate hyperphagia and other behaviors. The authors reported that the use of oxytocin in children over five days was safe, and a significant improvement was noted in anxiety and self-injurious behavior when compared to the placebo [24].
The fifth study was performed to examine the safety and efficacy of a single dose of oxytocin in infants less than six months of age with PWS. Oxytocin was well-tolerated in infants, with no side effects noted during the seven days of treatment. The effects of oxytocin on oral feeding and social skills in human infants were first reported in this study. Sucking and swallowing were also evaluated before and after oxytocin administration by using the Neonatal Oral–Motor Assessment Scale (NOMAS), video fluoroscopy of swallowing, and the Clinical Global Impression (CGI) scale. The authors reported positive treatment effects on social and feeding behaviors [25].

4. Setmelanotide Clinical Trial in PWS

A clinical trial on 40 participants diagnosed with PWS was sponsored by Rhythm Pharmaceuticals (Boston, MA, USA) to treat hyperphagia and obesity. The preliminary results were reported in abstract format at the 2017 PWSA Scientific Conference (Orlando, FL, USA) and are available online [26][27][28]. Studies on Setmelanotide, a melanocortin (MC)-4 receptor agonist that impacts satiety and feeding centers to decrease eating, were undertaken with a once-per-day administration via subcutaneous injection in those with PWS. The proof-of-concept trial included 40 participants diagnosed with PWS (19 males and 21 females) with a mean age of 26.4 years, with an age range of 16 to 25 years; a mean body mass index (BMI) of 39.4 kg/m2, with a BMI range of 26.1 to 74.1; and a mean Dykens Hyperphagia Questionnaire (HQ) score of 23.9, with a range of 12 to 45.
The results of this phase-two study using the MC-4 receptor (MC4R) agonist (Setmelanotide) were obtained in a four-week trial at five centers in the U.S.A. A primary study was randomized as a double-blind comparison of a placebo to three daily doses of Setmelanotide (0.5, 1.5, and 2.5 mg) preceded by a two-week, single-blind placebo run-in time interval. A percent bodyweight change was the primary endpoint, with secondary endpoints including HQ scores; dual-energy x-ray absorptiometry (DEXA) measures of body composition for fat, muscle, and bone; metabolic and laboratory parameters; and safety with tolerability assessments. The mean weight changes at four weeks showed no difference when comparing the Setmelanotide versus the placebo. The mean hyperphagia questionnaire scores demonstrated a small, not-statistically-significant reduction from baseline at the two highest Setmelanotide doses. No changes were observed in the DEXA measurements or laboratory findings. Adverse events included occasional, mild-to-moderate injection-site reactions reported in approximately two-thirds of the participants for both active and placebo administration. Skin and nevi darkening was noted, along with intermittent, spontaneous penile erections. There were no serious adverse events, but one patient discontinued the trial due to injection site reactions. Although the results in PWS were not promising, later studies in other rare, monogenic obesity disorders, such as those with POMC gene mutations or Bardet–Biedel syndrome—a ciliary protein group of genetic disorders—have met with success using this MC4R agonist [29].

5. Diazoxide Choline Controlled-Release Clinical Trial in PWS

Diazoxide choline, a new chemical entity, is a benzothiadiazine that acts by stimulating an ion flux through ATP-sensitive K+ channels (KATP). It is the choline salt of diazoxide, and is currently used to treat infants, children, and adults with hyperinsulinemia hypoglycemia. Diazoxide choline controlled-release (DCCR) is diazoxide choline formulated as an oral, once-a-day, extended-release tablet.
The hyperphagia signal in PWS likely occurs due to the dysregulation of neuropeptide Y/Agouti Related Protein/Gamma-aminobutyric Acid (NAG) neurons, which are regulated by leptin via reduction in their excitability [30]. This dysregulation results in marked elevations in the synthesis and secretion of NPY, the most potent endogenous neuropeptide. Leptin’s activation of adenosine triphosphate (ATP)-sensitive potassium channels (KATP) via phosphoinositide-3-kinase (PI3-K) [31][32][33] serves to hyperpolarize the resting membrane potential, which results in a limitation in the release of NPY by these neurons. Depolarizing the resting membrane potential of neurons in the arcuate nucleus (including the NAG neurons) via perfusion with potassium chloride results in the doubling of the NPY release rate, which returns to normal following perfusion [34]. There is strong evidence that the activation of NAG neurons results in insulin resistance and impaired glucose tolerance [35]. Inhibiting these neurons by agonizing the KATP channel has the potential to improve insulin sensitivity and improve glucose tolerance. Agonizing the KATP channel in NAG neurons using diazoxide choline is expected to result in reduced NPY secretion. Diazoxide readily crosses the blood–brain barrier [36], and diazoxide choline can be orally administered and can effectively agonize the KATP channels in the hypothalamic NAG neurons. Therefore, agonizing the KATP channel in these neurons amplifies the regulatory effects of leptin, reducing the secretion of NPY and likely AgRP and GABA, blunting hyperphagia and impacting obesity.
This preliminary trial consisted of a single-center, Phase II clinical study including a 1ten-week open-label treatment period followed by a four-week double-blind, placebo-controlled, randomized-withdrawal treatment period conducted at the University of California, Irvine. Patients were initiated on a once-daily oral diazoxide choline controlled-release (DCCR) dose of approximately 1.5 mg/kg (maximum starting dose of 145 mg) and titrated every two weeks to approximately 2.4 mg/kg, 3.3 mg/kg, 4.2 mg/kg, and 5.1 mg/kg (or to a maximum dose of 507.5 mg, whichever was less) at the discretion of the investigator. Any patient who showed any increase in resting energy expenditure and/or any reduction in hyperphagia from baseline through week six or week eight was designated a responder and was eligible to be randomized in the double-blind treatment period. During the double-blind treatment period, all individuals designated as responders were to be randomized in a 1:1 ratio to either continue active treatment at the dose they were treated at during week eight or to the placebo equivalent of that dose for an additional four weeks. Non-responder patients continued open-label treatment for an additional four weeks. Screening began in June 2014, and the last subject’s visit took place in April 2015. The trial was registered on www.clinicaltrials.gov, identifier NCT02034071. Hyperphagia was measured in the study using a nine-question Modified Dykens Hyperphagia questionnaire, posed to the parent or caregiver, which utilized a two-week recall period. Changes in body fat and lean body mass were measured using dual-energy x-ray absorptiometry (DEXA) at baseline and at the end of the open-label treatment period. Behavioral assessments were also conducted using a questionnaire to assess the presence or absence of 23 PWS-associated behaviors (grouped into four categories) at baseline and at the end of the open-label treatment period. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured by indirect calorimetry.

6. Livoletide Clinical Trial in PWS

Livoletide is an unacylated or inactive ghrelin analogue which works by decreasing the amount of active ghrelin in the brain. Ghrelin is a neuropeptide, produced by the stomach, which directly stimulates eating behavior in the hypothalamus in humans and is reportedly elevated in PWS (e.g., [37]). The ZEPHYR study sponsored by Millendo (Ann Arbor, MI, USA) was a randomized, double-blind, placebo-controlled, pivotal Phase 2b/3 study [38]. The therapy showed promising results in the phase 2a trial, in which daily Livoletide treatment or a placebo were administered via subcutaneous injection for 12 weeks. The Phase 2b study included 158 patients with PWS who were randomized to either (60 µg/kg or 120 µg/kg) receive the Livoletide dosage or the placebo. Livoletide was well-tolerated during this time, and the most-reported side effect was an injection site reaction of mild severity. However, no significant change was found in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) scores, which measured hunger and food-related behaviors, when compared with placebo. Hence, Livoletide also did not significantly improve hyperphagia and food-related behaviors and had no effect on fat mass, body weight, or waist circumference via DEXA data. As this drug was rigorously studied and the results were negative, it has been suggested that ghrelin may not be a driving force for the hyperphagia observed in PWS patients via this therapeutic route. However, this study may stimulate other gene–protein interactions or pathway analysis to study therapeutic options for treating hyperphagia and obesity in PWS. The company announced that it would discontinue this therapeutic development as a potential treatment model for PWS.

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Subjects: Pathology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ranim Mahmoud
, Virginia Kimonis , Merlin G. Butler
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Update Date: 23 Mar 2023
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