IntroductionPrader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS.MethodThis was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period.ResultsFive female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide.ConclusionDCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.

Introduction 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 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 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.

To evaluate the potential role of ATP-sensitive potassium (K ATP ) channel activation in the treatment of hyperphagic obesity, a PubMed search was conducted focused on the expression of genes encoding the K ATP channel, the response to activating the K ATP channel in tissues regulating appetite and the establishment and maintenance of obesity, the evaluation of K ATP activators in obese hyperphagic animal models, and clinical studies on syndromic obesity. K ATP channel activation is mechanistically involved in the regulation of appetite in the arcuate nucleus; the regulation of hyperinsulinemia, glycemic control, appetite and satiety in the dorsal motor nucleus of vagus; insulin secretion by β-cells; and the synthesis and β-oxidation of fatty acids in adipocytes. K ATP channel activators have been evaluated in hyperphagic obese animal models and were shown to reduce hyperphagia, induce fat loss and weight loss in older animals, reduce the accumulation of excess body fat in growing animals, reduce circulating and hepatic lipids, and improve glycemic control. Recent experience with a K ATP channel activator in Prader-Willi syndrome is consistent with the therapeutic responses observed in animal models. K ATP channel activation, given the breadth of impact and animal model and clinical results, is a viable target in hyperphagic obesity.Genes 2020, 11, 450 2 of 16 pharmacological activators of the channel in obese hyperphagic animal models, and clinical studies of K ATP channel activators in obese hyperphagic syndromes. Search terms used included K ATP , SUR1, SUR2b, Kir6.1, Kir6.2, ABCC8, ABCC9, KCNJ8, KCNJ11, agonist, hypothalamus, motor neuron of vagus, adipocyte, β-cell, hyperphagia, appetite, neuropeptide, obesity, obese, animal model, leptin, insulin, α-MSH, insulin-resistance, and hyperinsulinemia. Terms were combined to generate searches which identified tissues in which the genes encoding the K ATP channel might be expressed that have a known role in appetite and obesity, hormones with known roles in appetite and the K ATP channel, and obese or hyperphagic obese animal models in which a K ATP channel agonist might have been evaluated. Prior to conducting the searches, the authors already possessed extensive knowledge of the K ATP channel and its role in the regulation of appetite, having studied the channel for more than 15 years. The searches were conducted to supplement that understanding, rather than as the sole source of information summarized in this publication.Genes 2020, 11, 450 3 of 16 NPY injected into the brain either in the ventricles or in different hypothalamic nuclei induces a robust feeding response, even in sated animals [11]. NPY achieves this effect by reducing the latency to eat, delaying satiety and thereby augmenting meal size and meal duration [11]. NPY also causes treated animals to be more motivated to obtain food [11]. Specifically activating neurons pharmacologically with AgRP induces a robust hyperphagic response in rodents with a distinct temporal dynamic from that of NPY [7], NP...

A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS). Of these 154 PWS individuals, 87 (56.5%) showed the typical 15q11-q13 deletion subtypes, 62 (40.3%) showed non-deletion maternal disomy 15 and five individuals (3.2%) had separate unexpected microarray findings. For example, one PWS male had Klinefelter syndrome with segmental isodisomy identified in both chromosomes 15 and X. Thirty-five (40.2%) of 87 individuals showed typical larger 15q11-q13 Type I deletion and 52 individuals (59.8%) showed typical smaller Type II deletion. Twenty-four (38.7%) of 62 PWS individuals showed microarray patterns indicating either maternal heterodisomy 15 subclass or a rare non-deletion (epimutation) imprinting center defect. Segmental isodisomy 15 was seen in 34 PWS subjects (54.8%) with 15q26.3, 15q14 and 15q26.1 bands most commonly involved and total isodisomy 15 seen in four individuals (6.5%). In summary, we report on PWS participants consecutively enrolled internationally in a single clinical trial with high-resolution chromosome microarray analysis to determine and describe an unbiased estimate of the frequencies and types of genetic defects and address potential at-risk genetic disorders in those with maternal disomy 15 subclasses in the largest PWS cohort studied to date.

Background: Prader-Willi syndrome (PWS) is a rare, complex, multisystem disorder caused by the loss of multiple paternally expressed genes on chromosome 15q11-13 and is present in 1/15,000-30,000 individuals. Characteristics of PWS include low muscle mass and hypotonia, accumulation of excess body fat, short stature, hyperphagia, behavioral problems, cognitive disabilities, developmental delays, and hypogonadism. In these patients, serum creatinine (SCr)-based methods to calculate estimated glomerular filtration rate (eGFR) can lead to inaccurate results. eGFR is reported to be negatively correlated to muscle mass and PWS-associated low lean body mass may contribute to low SCr levels. Therefore, eGFR calculations may not accurately reflect PWS patient’s renal function. A more accurate, non-invasive, inexpensive means to monitor renal function for this patient population is desirable. Objective: To assess methods of estimating renal function in pediatric PWS patients and summarize the relationship between eGFR and patient-specific factors. Methods: The pre-treatment data of patients ≥4 years old with genetically confirmed PWS participating in an investigational study of DCCR (diazoxide choline) were evaluated. Lean body mass was measured using dual X-ray absorptiometry. Lean body mass and age were correlated to eGFR/creatinine clearance (CrCl) values calculated using four different equations: Bedside Schwartz (BS), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), and Cockcroft-Gault (C-G). Results: Of the 124 patients enrolled in the study, 99 were <18 years old and 103 were taking growth hormone (GH). Mean SCr was below normal range at 0.52 mg/dL, with only two subjects (1.6%) having SCr in the normal range (0.84 to 1.21 mg/dL). eGFR calculated using BS was 120±22 mL/min/1.73m2; CKD-EPI 154±23 mL/min/1.73m2; MDRD 211±77 mL/min/1.73m2; and CrCl by C-G 191±80 mL/min. Among the three eGFR equations, CKD-EPI presented with the most reasonable eGFR values <200 mL/min/1.73m2. When stratified by different age groups, SCr increased with age while eGFR decreased (and surprisingly CrCl by C-G increased). When correlating the eGFR values to various parameters, lean mass and age showed significant negative correlations with eGFR for BS, CKD-EPI, and MDRD. In contrast, for C-G there were significant positive correlations between CrCl and both lean mass and age. Conclusion: In PWS, the combination of low SCr and excess accumulation of body fat results in eGFR values that likely overestimate actual renal function in PWS patients. The inconsistent trends in correlation values between eGFR or CrCl by C-G and both lean mass and age indicate current SCr-based methods to estimate renal function in PWS may be inadequate. The use of CKD-EPI or other non-SCr-based methods to monitor renal function should be considered in PWS.