medwireNews: Preliminary trial findings published in the Journal of Clinical Endocrinology & Metabolism point to the possible use of a glucagon analogue for the treatment of congenital hyperinsulinism (CHI) in children.
The open-label, phase 3 study demonstrated an improvement in all measures of continuous glucose monitoring (CGM)-detected hypoglycaemia with a dasiglucagon dose of 10–70 µg/hour via a subcutaneous infusion pump alongside standard care versus standard care alone.
The trial recruited children aged between 3 months and 12 years with a bodyweight of at least 4 kg. The participants were experiencing three or more episodes of hypoglycaemia per week as determined by a self-measured plasma glucose (SMPG) value of below 3.9 mmol/L (70.2 mg/dL).
The children had either undergone a 95% or greater pancreatectomy or received nonsurgical treatment for CHI. They did not require exogenous insulin and did not receive glucagon during the study, explain Indraneel Banerjee, from the Royal Manchester Children’s Hospital in the UK, and co-authors.
Results were reported for part 1 of the study, in which 16 patients were randomly assigned to receive dasiglucagon for 4 weeks while continuing their usual care of gastric carbohydrates delivered by nasogastric or gastrostomy tube, diazoxide or a somatostatin analogue.
Although these patients experienced a significant decrease in the weekly rate of any SMPG-detected hypoglycaemic episodes (<3.9 mmol/L; <70.2 mg/dL) between weeks 2 and 4 of treatment, this did not significantly differ from the decrease detected in 16 patients who continued to receive standard of care treatment alone. Nor was there a significant difference detected in the rate of clinically significant SMPG-detected hypoglycaemic episodes (<3.0 mmol/L; <54 mg/dL).
However, post-hoc CGM analysis showed a 43% greater decrease in the rate of any hypoglycaemic events between weeks 2 and 4 compared with standard of care alone (12.0 vs 6.0 fewer events/week) and a “similar magnitude” in the decrease of clinically significant hypoglycaemic events (5.4 vs 4.2 fewer events/week and 44% reduction), Banerjee et al say.
The team also reports that dasiglucagon achieved “consistent reductions” compared with standard care in CGM-measured nocturnal hypoglycaemic events and extent of hypoglycaemia.
The authors say that there was a “large variation” in the study group with regard to total gastric carbohydrate delivered but note that the average total weekly intake fell significantly from baseline by an average of 146.56 g among the dasiglucagon-treated patients, whereas the control group experienced an average 160.44 g increase.
The average dasiglucagon dose was 30.1 µg/h during the first 4 weeks of treatment, rising to 34.3 µg/h in part 2 of the study, when all 32 patients were given the glucagon analogue for weeks 4–8; just eight patients were titrated up to the maximum dose.
“There was no impact of age, body weight, or severity of CHI […] on dasiglucagon dose”, the investigators remark.
Dasiglucagon was associated with more treatment-emergent adverse events (AEs) in the first month of treatment than standard care (87.5 vs 50.0%), most commonly manifesting as mild gastrointestinal disorders, infections, and skin or subcutaneous tissue disorders. None of the six serious AEs reported in four children were considered to be related to dasiglucagon.
Banerjee and co-authors say that it is “noteworthy that 31 of 32 patients who completed the trial continued dasiglucagon treatment in a long-term extension trial following investigator confirmation of a continued positive benefit-risk balance.”
They conclude: “Pending the results of this extension trial, dasiglucagon may therefore represent an attractive new therapeutic option for the prevention and treatment of hypoglycemia in CHI.
“Should this be realized, dasiglucagon treatment could have the potential to reduce the detrimental effects of hypoglycemia on childhood neurodevelopment and to delay and ultimately avoid pancreatectomy and related exocrine and endocrine complications.”
By Lynda Williams
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