A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome

Abstract

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.

MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity

“…Moreover, GLWL-01, a ghrelin O-acyltransferase inhibitor, showed no significant effect on hyperphagia after 4 weeks of double-blind treatment (NCT03274856). Other therapies are being tested in PWS, such as K+-ATP channel agonists (diazoxide choline controlled released), showing a decrease in hyperphagia score in patients with the highest scores at baseline (79). Glucagon-like peptide 1 (GLP-1) receptor agonists, such as liraglutide and exenatide, have been tried out in non-randomized studies or reported in clinical cases (80,81,82).…”

Obesity management in Prader–Willi syndrome: current perspectives

“…A Phase 2 study (PC025 pilot study) with diazoxide choline controlled-release (DCCR) tablet has been completed in children with PWS, obtaining a reduction of appetite, improvement in cardiovascular risk factors, insulin sensitivity, and a reduction in waist circumference (suggestive of a loss of visceral fat). 109 In this context, a multicenter Phase 3 clinical trial ( ClinicalTrials.gov : NCT03440814) with DCCR for the treatment of PWS was initiated in May 2018.…”

Current and emerging therapies for managing hyperphagia and obesity in Prader‐Willi syndrome: A narrative review

“…In this pilot trial, participants (aged 11‐21 years) received a 10‐week open‐label, dose‐escalation treatment with DCCR, which was followed by a 4‐week double‐blind, placebo‐controlled treatment period. In a dose‐dependent manner, treatment with DCCR was shown to significantly improve hyperphagia (n = 11, P = .006), lower the number of aggressive behaviours (n = 10, P = .01), reduce body fat mass (n = 11, P = .02), and increase lean body mass (n = 11, P = .003), with a corresponding decrease in waist circumference . Adverse events, including peripheral oedema and transient increases in glucose, were reported.…”

“…Diazoxide is a K + ‐ATP channel agonist approved for the treatment of hyperinsulinemia hypoglycaemia and acute hypertension. Diazoxide may exert therapeutic effects on PWS through the down‐regulation of insulin secretion from pancreatic β‐cells, the modulation of hypothalamic neuropeptide Y concentrations, the increase of excitability of the GABAnergic neuron, and/or the activation of K ATP channels in adipocytes . The effect of chronic diazoxide treatment on fat mass and metabolism was recently examined in mice with high‐fat diet‐induced obesity and inactivation of Magel2 , a gene also inactivated in PWS .…”

“…Very recently, a new once‐a‐day formulation of diazoxide, diazoxide choline controlled release (DCCR), was evaluated in children and adults with PWS and overweight/obesity in a phase 2 study . In this pilot trial, participants (aged 11‐21 years) received a 10‐week open‐label, dose‐escalation treatment with DCCR, which was followed by a 4‐week double‐blind, placebo‐controlled treatment period.…”