Background Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental condition, characterized by hyperphagia, obesity, hormone deficiencies and behavioral/psychological manifestations. DCCR is under investigation as a treatment for hyperphagia in PWS through its actions on hypothalamic circuits involved in appetite regulation including NPY neurons and central inhibition of DMV neurons to improve insulin sensitivity. In addition to these effects, DCCR acts on pancreatic beta cells, to reduce glucose stimulated insulin secretion, which might have additional effects to reduce fat deposition in adipocytes, serum leptin concentrations and insulin resistance. Objectives and methods This analysis characterized changes in hormonal and cardiometabolic parameters in patients with PWS receiving oral daily DCCR. 125 participants with genetically-confirmed PWS ≥4 years old with hyperphagia were treated with DCCR 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 (analysis at 52 weeks). The target DCCR dose for these studies was ≥3.3 mg/kg with an optimal dose of 4.2 - 5.8 mg/kg. Overall, 103 patients received DCCR (100-525 mg/day) for 52 weeks. For all parameters, the baseline measurement was defined as (immediately prior to) start of DCCR treatment. Results Serum leptin, insulin, and HOMA-IR were significantly reduced following 52 weeks of DCCR administration. Results are expressed as Least square (LS) mean change from baseline [Standard Error (SE)]. There were significant decreases in: Leptin (ng/mL) = -11.08[1.26], p<0.001; Insulin (μIU/mL) = -2.5[0.69], p<0.001; and HOMA-IR = -0.5 [0.17], p=0.003. Serum adiponectin (µg/mL) was significantly increased: 1.82[0.41], p < 0.001. Fat mass measured by DXA was stable at 52 weeks. Conclusions The reductions in fasting leptin, insulin and HOMA-IR, and the increase in adiponectin with prolonged DCCR treatment in the absence of reductions in total body fat are consistent with improved insulin sensitivity that may also reflect improvement in leptin sensitivity and healthier body fat distribution, such as reduced visceral adiposity. This could result from both direct pancreatic and hypothalamus-to-periphery actions of DCCR. It remains to be determined if such beneficial metabolic changes also result in reduced systemic inflammation and cardiovascular health. DCCR administration was associated with significant reductions in leptin, insulin, and HOMA-IR, increases in adiponectin and stabilization of body fat. These and other changes in cardiometabolic parameters suggest that DCCR may have long term health benefit in patients with PWS. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.

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.