Faculty Bibliography

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.

INTRODUCTION/BACKGROUND: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. MATERIALS AND METHODS/METHODS:In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, Phase 3 trial, 127 participants with PWS age ≥4 years with hyperphagia were randomized 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. The primary endpoint was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other endpoints included Global Impression Scores, and changes in body composition, behaviors, and hormones. RESULTS:DCCR did not significantly improve hyperphagia (HQ-CT Least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145], p=0.198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896], p=0.012). Two of three secondary endpoints were improved (Clinical Global Impression of Improvement [CGI-I], p=0.029; fat mass, p=0.023). In an analysis of results generated Pre-COVID, the primary (HQ-CT, p=0.037) and secondary endpoints were all improved (CGI-I p=0.015, Caregiver Global Impression of Change p=0.031, fat mass p=0.003). 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 (NS). DISCUSSION/CONCLUSIONS: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.

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.

CONTEXT/BACKGROUND: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. DESIGN/METHODS:A 52-week, placebo-controlled trial with a 16-week double-blinded period. SETTING/METHODS:Multicenter study. PATIENTS/METHODS: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. INTERVENTIONS/METHODS: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. MAIN OUTCOMES MEASURES/METHODS:The co-primary endpoints were change in body mass index standard deviation score (BMI 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. CONCLUSIONS:Although the co-primary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population.

Objectives Prader-Willi syndrome (PWS), a rare genetic neurobehavioral-metabolic disease, is characterized by hyperphagia, endocrinopathies, abnormal weight gain, hypotonia, and behavioral problems. There are no currently approved pharmacological treatments for hyperphagia in PWS. The objective was to evaluate long-term safety and efficacy of DCCR in 125 participants with PWS who took part in multi-center studies conducted at 29 sites in the US and the UK: a 13-week Phase 3 double-blind, placebo-controlled study (DESTINY PWS) and its long-term, open-label extension study (through 52 weeks). Methods Enrolled participants had genetically confirmed PWS, had hyperphagia and were >=4 years old. The target DCCR dose for this study was >=3.3 mg/kg with an optimal dose of 4.2 mg/kg with 103 participants receiving DCCR for 52 weeks. Results There was a statistically significant decrease in hyperphagia as measured by the Hyperphagia Questionnaire-Clinical Trials total score change from baseline at Week 52 of DCCR (LS mean - 9.9 + 0.77, p<0.0001). There were significant improvements in all domains of the Prader-Willi Syndrome Profile questionnaire at 52 weeks (aggression, anxiety, compulsivity, depression, disordered thinking and rigidity; all p<0.0001). There was a significant increase in lean body mass from baseline at Week 52 (p<0.0001) and an improvement of the ratio of lean body mass to fat mass (p=0.0005). There were significant improvements in metabolic and hormonal markers: leptin, adiponectin (p=<0.0001), and fasting insulin (p=0.0004) at Week 52. Insulin resistance as measured by HOMA-IR was significantly improved at Week 52 (p=0.0033). Scores on the Clinical Global Impression of Severity showed significantly reduced disease severity with similar results obtained from the Caregiver Global Impression of Severity. DCCR was generally well tolerated. The most common treatment-emergent adverse events were those expected for the immediate release form of diazoxide and similar to those seen in prior studies of DCCR and included hypertrichosis, peripheral edema and hyperglycemia. Conclusions In participants with PWS, DCCR resulted in sustained and significant improvements in hyperphagia, characteristic behavioral problems, disease severity, as well as improved body composition and metabolic/hormonal markers. These represent meaningful changes in PWS, where no therapeutic options are available to address these unmet needs

BACKGROUND: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: 8.0 pg/mL with one individual having an initial low plasma ACTH level (8 pg/mL), but normal upon repeat. CONCLUSIONS:

Objectives The objective of this analysis was to evaluate the therapeutic response of participants with Prader-Willi syndrome to DCCR (Diazoxide Choline) Extended-Release Tablet prior to the onset of the COVID-19 pandemic. The COVID-19 pandemic caused significant disruptions in the lives of participants and their caregivers making it more difficult to control access to food and manage behavioral issues, with increased caregiver stress. We hypothesized the pandemic affected trial efficacy results. Prader-Willi syndrome (PWS), a rare genetic neurobehavioral-metabolic disease, is characterized by hyperphagia, accumulation of excess fat, hypotonia, and behavioral/psychological complications. There are no approved treatments for hyperphagia in PWS. Methods In this 13-week, international, randomized, double-blind, placebo-controlled, Phase 3 clinical trial, 127 participants with genetically confirmed PWS ages 4 and older with hyperphagia were randomized 2:1 to DCCR or placebo at 29 sites in the US and UK. The primary endpoint was hyperphagia change from baseline using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Secondary endpoints included clinical and caregiver global impression scores and changes in body fat mass. Exploratory endpoints included changes in behavioral assessments and cardiometabolic markers. This analysis focused on data generated in the period ending March 1, 2020, before any significant effects of the pandemic. Results DCCR significantly improved hyperphagia (LSmean difference -3.13+/-1.481, p=0.0369) and all of the secondary endpoints (Clinical Global Impression of Improvement, p=0.0145; Caregiver Global Impression of Change, p=0.0314; fat mass, LSmean difference -1.51+/-0.51 kg, p=0.0040) and other important endpoints including anxiety (p=0.0182), compulsivity (p=0.0075), communication disturbance (p=0.0025) and social relating (p=0.0078), leptin (p<0.0001), acylated ghrelin (p=0.0089), and insulin (p=0.0449), and adiponectin (p<0.0001). In the DCCR arm, 79.8% of participants experienced a treatment emergent adverse event compared to 73.8% in the Placebo arm. In general, DCCR was well tolerated. Conclusions In this analysis, DCCR significantly improved a range of behaviors, body composition, and cardiometabolic endpoints and with overall improvements recognized by caregivers and clinicians. DCCR may contribute to improved outcomes and quality of life of patients with PWS

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/BACKGROUND:This study was registered with ClinicalTrials.gov ( NCT01009905 ) on November 9, 2009.

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.