Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children

Context: Congenital hyperinsulinism (CHI) is characterised by dysregulated insulin secretion causing hypoglycaemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI.Objective: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycaemia as add-on to standard of care (SoC).Methods: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 mu g/hour) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycaemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycaemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2-4.Results: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n=16) or SoC (n=16). The rate of SMPG-detected hypoglycaemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2-4 (event rate ratio: 0.85 [0.54; 1.36], p=0.5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycaemia (<3.9 mmol/L) vs. SoC alone during Weeks 2-4 (post-hoc analysis; event rate ratio: 0.57 [0.39; 0.83], p=0.0029). Dasiglucagon enabled reductions (of 37-61%) in all other measures of hypoglycaemia assessed by CGM vs. SoC alone including extent and %-time in hypoglycaemia (post-hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only.Conclusion: Clinically meaningful reductions in all CGM-recorded measures of hypoglycaemia support using dasiglucagon as a potential treatment for CHI.