Endocrine Abstracts

JOINT734

Introduction: Congenital hyperinsulinism (CHI) is a rare disease affecting 1 in 25,000 to 50,000 newborns, characterized by severe hypoglycemia that can lead to neurological damage or death. Current treatments, which include dietary management, medications, and surgical interventions, are often limited by suboptimal efficacy and significant side effects, highlighting the urgent need for novel therapeutic approaches.

Methods: Efpegerglucagon (HM15136), a long-acting glucagon analogue, is being evaluated in a Phase 2 open-label, multicenter trial across five countries (ACHIEVE, NCT No. 04732416, EUCT No. 2024-515290-98-00). The study targets CHI patients aged two years and older with recurrent hypoglycemia (>3 episodes/week) despite standard care. The trial includes two dosing cohorts: Cohort 1 (0.04 mg/kg) and Cohort 2 (0.06 mg/kg). Each cohort consists of 8 subjects receiving weekly subcutaneous injections over an 8-week period. Enrollment for Cohort 1 (n=8, median age: 16 years, equal male-to-female ratio) has been completed, and Cohort 2 is currently ongoing.

Results: The most frequent adverse events were gastrointestinal (e.g., upper abdominal pain, diarrhea, vomiting, nausea) and metabolic(e.g., hyperglycemia, decreased appetite) in nature. These events were predominantly mild or moderate, with no treatment discontinuation, adverse events of special interest, or deaths reported. Efficacy analysis based on the data from eight patients in Cohort 1 showed significant reductions in level 1 or level 2 hypoglycemia events (blood glucose<70 mg/dl [<3.9 mmol/l]). After 8 weeks of treatment, the mean weekly level 1 or level 2 hypoglycemia events measured by 7-point self-monitored blood glucose (SMBG) decreased from 10.1 (±8.5, standard deviation) at baseline to 2.8 (±2.3), representing a 72.3% reduction. Home monitoring SMBG data also reflected a significant decline in weekly level 1 or level 2 hypoglycemia events decreasing from 16.0 (±19.4) at baseline to 3.6 (±6.5) at Week 8, indicating a 77.5% reduction. Notable improvements were demonstrated, including reductions in the weekly number and rate of level 2 hypoglycemia events (blood glucose<54 mg/dl [<3.0 mmol/l]) at Week 8, as measured by 7-point SMBG, and improvements in nutritional parameters such as total carbohydrate intake during treatment compared to baseline.

Conclusion: Efpegerglucagon demonstrated a favorable safety profile and clinically meaningful efficacy. After eight weeks of treatment, CHI patients experienced significant reductions in hypoglycemia events. These findings emphasize its therapeutic potential as a safe and effective treatment for CHI and support the continued enrollment of Cohort 2.