Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

Liraglutide for Weight Management in Children and Adolescents With Prader-Willi Syndrome and Obesity.

CONTEXT: Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. OBJECTIVE: To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS. METHODS: This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage <2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety. RESULTS: Change in BMI SDS from baseline to weeks 16 and 52 was not significantly different between treatments in adolescents (estimated treatment difference: -0.07 at week 16 and -0.14 at week 52) and children (-0.06 and -0.07, respectively). Changes in other weight-related parameters between treatments were not significant. At week 52, hyperphagia total and drive scores were lower in adolescents treated with liraglutide vs no treatment. The most common adverse events with liraglutide were gastrointestinal disorders. CONCLUSION: Although the coprimary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population.

Central adrenal insufficiency screening with morning plasma cortisol and ACTH levels in Prader-Willi syndrome.

OBJECTIVES: Prader-Willi syndrome (PWS) is a complex genetic disorder with severe hypotonia, failure to thrive, childhood obesity, hypogonadism/hypogenitalism and learning/behavioral problems with endocrine-related growth and other hormone deficiencies. The prevalence of central adrenal insufficiency (CAI) using dynamic testing ranges from rare to 60%. We compared routine morning plasma cortisol (MPC) and ACTH levels in large cohorts of PWS and control children to address CAI. METHODS: Retrospective analysis of MPC and ACTH levels was undertaken in 128 PWS growth hormone (GH)-treated children under medical care before considering dynamic testing for CAI and 128 non-syndromic control children with short stature evaluated for GH deficiency. RESULTS: The average MPC level in PWS was 9.7 ± 3.7 µg/dL with no difference in age, gender or PWS genetic subtype and 13.4 ± 5.7 µg/dL in the control group. MPC levels were significantly lower (p < 0.05) in PWS but in the normal range. The morning plasma ACTH level in the PWS group was 22.1 ± 8.0 pg/mL with one individual having an initial low plasma ACTH level (8 pg/mL), but normal upon repeat. CONCLUSIONS: MPC levels in PWS are normal and comparable with control children, without evidence or increased risk of CAI. Lower but normal MPC levels were seen in PWS and suggestive of reduced local regeneration of cortisol from cortisone in adipose tissue by the GH-IGF-I system. Hence, MPC measures alone or in combination with ACTH should be considered for initial screening for CAI in PWS but prior to dynamic testing.

Outcomes in children treated with growth hormone for Prader-Willi syndrome: data from the ANSWER Program® and NordiNet® International Outcome Study.

BACKGROUND: Growth hormone (GH) deficiency is common in patients with Prader-Willi syndrome (PWS) and leads to short adult stature. The current study assessed clinical outcomes based on real-world observational data in pediatric patients with PWS who were treated with GH. METHODS: Data from patients previously naïve to treatment with GH who began therapy with somatropin were collected from 2006 to 2016 in the observational American Norditropin® Studies: Web-Enabled Research (ANSWER) Program® and NordiNet® International Outcome Study. Variables affecting change from baseline in height standard deviation scores (HSDS; n = 129) and body mass index standard deviation scores (BMI SDS; n = 98) were determined. RESULTS: Patients included in both HSDS and BMI SDS analyses were treated with a mean GH dose of 0.03 mg/kg/d (SD, 0.01 mg/kg/d). Results from the HSDS analysis revealed that baseline age and years on treatment had a significant impact on the change in HSDS. In the BMI SDS analysis, longer GH treatment time led to a greater change in BMI SDS from baseline, and patients with a higher BMI at the start of treatment had a greater decrease in BMI over time. CONCLUSIONS: GH is effective in the management of children with PWS. Earlier treatment resulted in a greater gain in height, and a longer treatment period resulted in better outcomes for both height and BMI. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov ( NCT01009905 ) on November 9, 2009.

Cycloid Psychosis Comorbid with Prader-Willi Syndrome: A Case Series.

Psychosis is a relatively common psychiatric phenomenon seen in patients with Prader-Willi Syndrome (PWS). However, the presentation is atypical and difficult to classify within currently defined affective or psychotic disorders. This distinct presentation may be better understood as a phenomenon called "cycloid psychosis," described as an episodic psychosis with rapid full recovery between episodes. This study retrospectively analyzed the cases of 12 patients with genetically confirmed PWS who presented to an ambulatory psychiatric center for a change in behavior consistent with psychosis. Each case was then assessed for symptoms of cycloid psychosis, bipolar disorder, depression with psychotic features, schizophrenia, and schizoaffective disorder. Out of the 12 patients, 11 (91.7%) met the currently described diagnostic criteria for cycloid psychosis. Of the 12 patients, 7 (58.3%) also met the diagnostic criteria for bipolar disorder, and 1 (8.3%) also met the diagnostic criteria for schizoaffective disorder. None of the patients met the criteria for schizophrenia or depression with psychotic features. The findings in this study suggest that cycloid psychosis and bipolar disorder may both be comorbid with PWS. Psychiatric comorbidities in patients with PWS are atypical and clinicians should be aware of conditions such as cycloid psychosis when managing this vulnerable population.

Guanfacine Extended Release for the Reduction of Aggression, Attention-Deficit/Hyperactivity Disorder Symptoms, and Self-Injurious Behavior in Prader-Willi Syndrome-A Retrospective Cohort Study.

Objective: To examine the role of Guanfacine Extended Release (GXR) in the management of behavioral disturbances in patients with Prader-Willi Syndrome (PWS). Methods: Twenty from a total of 27 individuals with genetically confirmed PWS, 6-26 years of age, with the following symptoms were identified: significant aggression/agitation, skin picking, and/or symptoms of attention-deficit/hyperactivity disorder (ADHD). Response to GXR for the above noted symptoms was categorized as improved, worsened, or unchanged, while assessing for side effects and tolerability. Results: Eleven of the 20 individuals reported skin-picking, 17 reported aggression/agitation, and 16 reported symptoms of ADHD. Nine (81.8%), 14 (82.3%), and 15 (93.7%) individuals showed an improvement in skin-picking, aggression/agitation, and ADHD, respectively, while on GXR treatment. Two patients with prior complaints of psychotic symptoms did not respond to GXR. Of note, no abnormal weight gain or significant adverse reaction was observed in this group, while on GXR. Conclusions: In this study, GXR demonstrated improvement in symptoms of skin picking, aggression/agitation, and ADHD in patients with PWS. GXR was not effective in reducing psychosis or agitation related to psychotic symptoms. Future studies are warranted to further establish the utility of GXR in PWS patients.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS: Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS: Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION: I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

An open-label pilot study of N-acetylcysteine for skin-picking in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by an abnormality on the long arm of chromosome 15 (q11-q13) that results in a host of behavioral characteristics including excessive interest in food, skin picking, difficulty with a change in routine, and obsessive and compulsive behaviors. Skin-picking can result in serious and potentially life-threatening infections. Recent evidence suggests that the excitatory neurotransmitter glutamate is dysregulated in obsessive-compulsive behaviors, and modulation of the glutaminergic pathway may decrease compulsive behaviors, such as recurrent hair pulling or skin-picking behaviors. N-acetylcysteine (NAC), a derivative of the amino acid cysteine, is thought to act either via modulation of NMDA glutamate receptors or by increasing glutathione in pilot studies. Thirty-five individuals with confirmed PWS (ages 5-39 years, 23 females/12 males) and skin-picking behavior for more than 1 year were treated with N-acetylcysteine (Pharma-NAC®) at a dose of 450-1,200 mg/day. Skin-picking symptoms and open lesions were assessed after 12 weeks of treatment by counting and measuring lesions before and after the medication. All 35 individuals had improvement in skin-picking behaviors. Ten (29%) individuals (six males and four females) did not have complete resolution of skin-picking behavior, but had significant reduction in the number of active lesions. Longer-term, placebo-controlled trials are needed to further assess the potential benefit of this treatment.

Prader-Willi syndrome: A primer for clinicians.

The advent of sensitive genetic testing modalities for the diagnosis of Prader-Willi syndrome has helped to define not only the phenotypic features of the syndrome associated with the various genotypes but also to anticipate clinical and psychological problems that occur at each stage during the life span. With advances in hormone replacement therapy, particularly growth hormone children born in circumstances where therapy is available are expected to have an improved quality of life as compared to those born prior to growth hormone.This manuscript was prepared as a primer for clinicians-to serve as a resource for those of you who care for children and adults with Prader-Willi syndrome on a daily basis in your practices. Appropriate and anticipatory interventions can make a difference.

Psychiatric adverse effects of rimonobant in adults with Prader Willi syndrome.

BACKGROUND: Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS. METHOD: This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP-3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant. RESULTS: Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment. CONCLUSION: Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition.

Gastric rupture and necrosis in Prader-Willi syndrome.

Hyperphagia and obesity are common features in individuals with Prader-Willi syndrome (PWS). Demographic and cause-of-death data from individuals with PWS were obtained through a national support organization. Four reports of unexpected mortality due to gastric rupture and necrosis were found in 152 reported deaths, accounting for 3% of the causes of mortality. Four additional individuals were suspected to have gastric rupture. Vomiting and abdominal pain, although rare in PWS, were frequent findings in this cohort. The physician should consider an emergent evaluation for gastric rupture and necrosis in individuals with PWS who present with vomiting and abdominal pain.

Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment.

Short stature is characteristic of children with Prader-Willi syndrome (PWS). While previous studies have demonstrated acceleration of linear height velocity with growth hormone (GH) treatment, the long-term benefit on final adult height (AH) has not been reported. The objective of this study was to compare AH attained in PWS subjects with and without GH treatment. We reviewed the records of 21 children (aged 8.3 +/- 2.7 years) with PWS and confirmed GH deficiency that attained AH after receiving human GH treatment (0.25 +/- 0.06 mg/kg/week) for a period of 7.9 +/- 1.7 years. A group of 39 non-GH-treated adults with matched initial height standard deviation score (SDS) at age 6.8 +/- 1.3 years was used as control. In the GH-treated group the mean initial height and AH-SDS was -1.9 +/- 1.7 and -0.3 +/- 1.2 respectively (P < 0.0001), whereas the mean initial and AH-SDS in the control group was -1.9 +/- 1.3 and -3.1 +/- 1 respectively (P < 0.0001). Scoliosis was seen in 43% and 39% in the GH-treated and control group respectively. Premature adrenarche (PA) was noticed in 57% of GH-treated group. Six subjects in the control group but none of the GH-treated subjects developed type 2 diabetes mellitus. Our data show that administration of GH to children with PWS restores linear growth and final AH without significant adverse effects other than PA. Further studies will be necessary to determine related morbidity and mortality in individuals with PWS that reached final AH with or without GH treatment.

Deaths due to choking in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common known syndromic cause of life-threatening obesity, yet few studies have examined the causes of death in PWS. The objective of this study was to examine the contribution of choking leading to mortality in PWS. In 1999, a brief survey was made available from the Prader-Willi Syndrome Association (USA) bereavement program, which documented demographic data and causes of death. Families were subsequently offered the opportunity to fill out a detailed questionnaire and additional forms to release medical records. Demographic information was available on 178 deceased individuals with PWS, and cause of death available on 152 individuals. Fifty-four families completed questionnaires. Of the deceased individuals with completed questionnaires, 34% reported a history of choking. Choking was listed by familial report as the cause of death in 12 (7.9%) of 152 subjects with an average age of 24 years (range 3-52 years; median 22.5 years) at death from choking. Only two of these individuals were less than 8 years of age. The data suggest that risks associated with choking are different in the PWS population compared with others. Potential causes of increased choking in PWS include poor oral/motor coordination, poor gag reflex, hypotonia, hyperphagia, decreased mastication, and voracious feeding habits. We recommend implementation of preventive measures and education for families and group home care providers for all individuals with PWS including the Heimlich maneuver, supervised meals, better food preparation, and diet modification to avoid high-risk choking items.