DCCR is a once daily tablet formulation of the choline salt of diazoxide, a KATP channel agonist. DCCR is being developed for the treatment of hyperphagia in Prader-Willi syndrome (PWS), the most common genetic cause of life-threatening obesity. In a phase 2 study, DCCR treatment resulted in significant reductions of hyperphagia and aggressive behaviors. Diazoxide increases glucose by decreasing beta-cell insulin secretion in hyperinsulinemic conditions. However, other effects have been documented in animal models and clinical studies to counterbalance insulin suppressive effects. For example, central KATP channel agonization leads to partial suppression of hepatic gluconeogenesis and peripheral agonization causes marked and progressive improvements in insulin sensitivity. Since PWS patients are hypoinsulinemic and insulin sensitive, it is presumed that changes in appetite and behavior are due to central effects of the drug. In PWS and VHTG patients, DCCR treatment resulted in a transient rise in fasting glucose, post-prandial glucose and HbA1c, with regression towards baseline with longer term treatment. In PWS, fasting glucose returned to baseline by Day 97 or 126, depending on titration schedule, target dose, and patient population. Fasting glucose regressed more rapidly than OGTT glucose or HbA1c. Clinical Study PC025 evaluated 13 PWS subjects. In subjects completing the study, change from baseline in fasting glucose at Day 69 was +7.9 mg/dl (+9.4%) and then regressed to baseline by the end of treatment (+0.4 mg/dl, +0.5%) on Day 98 in those who continued DCCR treatment. In a limited number of PWS patients treated with DCCR for 6 months, HbA1c dropped incrementally toward baseline values. Follow-up of PWS at the end of treatment confirmed that when elevated, fasting and OGTT glucose returned to Baseline values within 4 weeks. In patients with VHTG treated with DCCR, fasting glucose had increased on Day 84 by 13 mg/dl (+12.2%) compared to an increase of 3.9(3.7%) in the placebo arm. By Day 126, change from Baseline in the DCCR arm was comparable to the Placebo arm (0.9 mg/dl, 0.9%, vs 0.8 mg/dl, 0.8%). In the DCCR arm, HbA1c rose by 0.18% by Day 84, but returned to baseline (+0.09%) by Day 126. Diazoxide has historically been used to increase glucose levels in hyperinsulinemic patients, and increased glucose levels in PWS have been seen with short-term treatment. However, counterbalancing effects of KATP channel agonization appear to cause normalization of glucose levels with longer-term use in the patients studied.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology