ESPE Abstracts

Introduction: Congenital hyperinsulinism (CHI) is a rare disease affecting 1 in 25,000 to 50,000 newborns that requires emergent treatment of recurrent hypoglycemia to prevent neurological sequelae. There is a high unmet need for novel treatments due to the limited effectiveness and adverse effects associated with the current standard of care medications, namely diazoxide and somatostatin analogues.

Methods: Efpegerglucagon (HM15136) is a novel long-acting glucagon analogue conjugated with a human IgG Fc fragment to provide a longer half-life than traditional glucagon. Currently, an open-label phase 2 trial is ongoing to assess the therapeutic potential of efpegerglucagon in CHI patients aged two years and older who experience recurrent hypoglycemia events (> 3 episodes/week) while on standard of care treatment (ACHIEVE, NCT No. 04732416, EUCT No. 2024-515290-98-00). In this study, eight patients receive weekly doses of subcutaneous efpegerglucagon for eight weeks at each of the two dosing levels (0.04 mg/kg for Cohort 1 and 0.06 mg/kg for Cohort 2), and reductions in the weekly number of hypoglycemia events are measured.

Results: After the sixth subject in Cohort 1 completed treatment for eight weeks, a data review meeting was held to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of efpegerglucagon. Efpegerglucagon was safe and well tolerated, with no significant changes in vital signs, physical examinations, safety laboratory tests, or electrocardiograms. The most common adverse event was gastrointestinal disorders such as upper abdominal pain and diarrhea. Most of the adverse events were mild and moderate in severity. There were no adverse events leading to discontinuation of study treatment, adverse events of special interest, or death. The mean number of weekly hypoglycemia events (blood glucose < 70 mg/dL) as measured by 7-point self-monitored blood glucose was 3.8 (± 2.3, standard deviation) during Week 8 compared to 13.0 (± 7.8) at baseline, which represents approximately 70% reduction in the number of weekly hypoglycemia events. The mean glycated hemoglobin (HbA1c) was 4.7% at baseline and increased to 5.6% by Week 8. The mean elimination half-life at Week 8 was 146 hours, which supports the weekly dosing interval.

Conclusion: After eight weeks of treatment with efpegerglucagon, patients with CHI demonstrated clinically significant reductions in hypoglycemia events. These findings, combined with favorable safety and tolerability profiles, strongly suggest its therapeutic potential as a safe and effective therapy for CHI patients.