Diazoxide choline extended-release tablet safe, effective in Prader-Willi syndrome

Treatment with diazoxide choline extended-release tablet (DCCR) demonstrates good tolerability and delivers significant improvements in people with Prader-Willi syndrome, a rare, complex genetic neurobehavioral/metabolic disorder, results from an open-label study have shown.

In addition, DCCR provides potentially beneficial changes in body composition, including the prevention of body fat accumulation and an increase in lean body mass.

“Administration of DCCR may result in reduced disease severity and improved quality of life for these patients and a reduced burden of care for their families, thereby benefitting people with PWS and their families with a favourable risk benefit profile,” said the researchers.

A total of 125 participants with PWS, aged ≥4 years, who were enrolled in the DESTINY PWS phase III study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension were included in this analysis.

The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score was the primary endpoint, while secondary endpoints included body composition, behavioural assessments, hormonal measures, and safety. [Obesity 2024;32:252-261]

DCCR administration significantly improved HQ-CT (mean ‒9.9; p<0.0001) as well as those with more severe baseline hyperphagia (HQ-CT >22). Behavioural improvements in aggression, anxiety, and compulsivity (p<0.0001 for all) were observed.

Use of DCCR also resulted in reduced leptin, insulin, and insulin resistance as well as in a significant increase in adiponectin (p<0.004). In addition, lean body mass increased (p<0.0001), while disease severity subsided as assessed by clinician and caregiver (p<0.0001 for both).

Treatment-emergent adverse events (TEAEs) reported were hypertrichosis, peripheral oedema, and hyperglycaemia. Treatment discontinuation due to AEs were rare (7.2 percent).

"Although some of these improvements might conceivably be due to the participant being enrolled in a research study, we know the effects of DCCR administration on hyperphagia develop gradually over time,” the researchers said.

This benefit was “less consistent with the effect of trial participation that typically results in apparent rapid response and may reflect a combination of direct effects of [DCCR] in the hypothalamus and indirect effects mediated by reduced central insulin and leptin resistance.” [Genes (Basel) 2020;11:450]

On the other hand, the decreases observed in concentrations of leptin and insulin and the improvement seen in the Homeostatic Model Assessment for Insulin Resistance supported the proposed mode of action of DCCR in PWS. [Genes (Basel) 2020;11:450]

“The impact of DCCR on insulin is a direct effect of the drug at the level of the β cell, whereas the impact on leptin secretion by adipocytes is probably due both to a direct effect of the drug on adipocytes and an indirect effect through reductions in insulin, resulting in substantial reductions in circulating leptin levels when expressed on a per-kilogram of body fat basis,” the researchers said.

Leptin decrease at 52 weeks occurred without a change in body fat, potentially suggesting an improvement in leptin resistance. Furthermore, adiponectin concentration increase with DCCR in PWS patients could lead to reduced systemic inflammation and improved insulin sensitivity and cardiovascular health. [World J Diabetes 2014;5:328-341; Int J Obes Relat Metab Disord 1999;23:645-649]

“DCCR administration, resulting in further increases in adiponectin, may reinforce these benefits,” the researchers said.

“This was an open-label study, which is uncontrolled and subject to bias and other factors that may limit the applicability of the conclusions,” they noted.