ESPE Abstracts

Background: Congenital hyperinsulinism (CHI) is a chronic and complex rare endocrinopathy with dysregulated insulin secretion causing severe and recurrent hypoglycemia resulting in adverse neurologic and developmental sequelae in children. Current treatment options are limited and often inadequate to treat CHI. Dasiglucagon (DASI), a glucagon analog administered by subcutaneous continuous infusion, has demonstrated reduction in glucose infusion rate (GIR) in Part 1 of a randomized placebo-controlled trial over a 48-hour period in neonates and infants with CHI.

Study Design: We report efficacy and safety of DASI in Part 2 of this phase 2/3 trial in children with CHI aged ≥7 days to <1 year requiring intravenous glucose infusion rates (GIR) > 10 mg/kg/min. Following completion of Part 1 of the study, all participants continued open label DASI for an additional 21 days (Part 2). Outcomes included the ability to reduce intravenous glucose infusion, total daily carbohydrates and hypoglycaemia frequency (<70 and <54 mg/dL by self-monitored blood glucose (SMBG) and continuous glucose monitoring (CGM). Safety markers included hyperglycaemia (SMBG >180 mg/dL), tolerability and adverse events (AE).

Study Results: All 12 children (age 0.5-10.7 months, mean 2.4) enrolled in Part 1 continued into Part 2. Baseline GIR for 12 hours prior to study initiation was 15.7 ± 4.5 mg/kg/min (mean ± SD). In Part 1, DASI resulted in a significant reduction in GIR (treatment difference: -5.2 [-8.3;-2.1] mg/kg/min, P=0.0037) vs placebo (55% decrease). In Part 2, DASI enabled reduction or discontinuation of intravenous glucose infusion in 10 out of 12 children. Seven of them, who did not require pancreatectomy, were completely weaned-off. CGM measures of hypoglycaemia trended lower with a reduction in median time <70 mg/dL from 7.0% to 5.2% (week 1 to 3) and <54 mg/dl, 1.9% to 0.88% (week 1 to 3). There was no increase in hyperglycaemia. DASI was well tolerated with skin rashes and gastrointestinal disturbance reported commonly as AE but not requiring discontinuation of treatment. No serious AE were reported.

Conclusions: The use of continuous subcutaneous infusion of dasiglucagon in a 21-day open-label trial in infants with CHI suggests that dasiglucagon may reduce intravenous glucose requirements, time in hypoglycaemia and enabled discontinuation of intravenous glucose in most infants, thus obviating the need for subtotal pancreatectomy for glycaemic stability. In combination with results from Part 1, these data support the efficacy and safety of DASI as a potential novel treatment for CHI.