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Updated: Jun 16, 2025
Hyperinsulinemic-Euglycemic Clamp in the Conscious Rat
Published on: February 7, 2011
Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug), an insulin receptor antibody, for congenital
Huseyin Demirbilek1, Maria Melikyan2, Violeta Iotova3
1Hacettepe University Faculty of Medicine, Department of Pediatrics, Ankara, Turkey.
Insights
Ersodetug significantly reduced hypoglycemia events and time in children with congenital hyperinsulinism (cHI). This novel insulin receptor (INSR) antibody therapy showed promising safety and efficacy in a Phase 2b study.
Area of Science:
- Endocrinology
- Pediatric Rare Diseases
- Pharmacology
Background:
- Congenital hyperinsulinism (cHI) is a rare pediatric condition causing severe hypoglycemia due to dysregulated insulin secretion.
- Persistent hypoglycemia in cHI can lead to lifelong neurological damage.
- Current standard-of-care therapies often fall short in managing cHI-related hypoglycemia.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and glycemic efficacy of ersodetug in pediatric patients with cHI.
- To assess ersodetug as a novel therapy targeting the insulin receptor (INSR) for hypoglycemia in cHI.
Main Methods:
- A global, open-label, Phase 2b study enrolled 23 pediatric patients with cHI.
- Participants received add-on ersodetug (3-9 mg/kg IV bi-weekly) for 8 weeks.
- The study assessed hypoglycemia metrics via self-monitored blood glucose and continuous glucose monitoring.
Main Results:
- Ersodetug demonstrated dose-proportional pharmacokinetics with no serious adverse events or withdrawals.
- Hypoglycemia events decreased by a median of 59% and time in hypoglycemia by 54% across all doses (p < 0.001).
- Higher doses (6-9 mg/kg) showed significant improvements (48%-84% for events, 61%-65% for time) with near-universal patient response.
Conclusions:
- Ersodetug was well-tolerated and significantly improved hypoglycemia in cHI patients.
- This novel INSR-targeted therapy holds potential for treating all forms of cHI, as monotherapy or in combination.
Background:
Congenital hyperinsulinism (cHI) is a rare, primarily pediatric disease characterized by dysregulated insulin secretion resulting in severe, persistent hypoglycemia, frequently leading to lifelong neurologic impairments. The safety, pharmacokinetics, and glycemic efficacy of ersodetug, a fully human monoclonal antibody that allosterically and reversibly binds the insulin receptor (INSR) and reduces excess insulin action, are being evaluated for the treatment of cHI-related hypoglycemia.
Methods:
A global, open-label, phase 2b study (ClinicalTrials.gov: NCT04538989) was conducted in 23 patients with cHI with persistent hypoglycemia on standard-of-care (SOC) therapies. Eligible participants (age ≥2 years) received add-on ersodetug at dose levels between 3 and 9 mg/kg intravenously (i.v.) bi-weekly for 8 weeks in 4 sequential dose cohorts.
Findings:
Enrolled participants (average age = 6.7 years) on SOC (87% medications; 17% previous pancreatectomy) experienced 13 events/week and 23% time in hypoglycemia at baseline. Ersodetug resulted in predictable, dose-proportional pharmacokinetics. No deaths, adverse drug reactions, study withdrawals, or dose-limiting toxicities occurred. Hypoglycemia (<70 mg/dL) events (self-monitored blood glucose) and time (continuous glucose monitoring) improved from baseline by medians of 59% (p < 0.001) and 54% (p < 0.001), respectively, across pooled dose levels and by 48%-84% (events) and 61%-65% (time) at doses of 6 or 9 mg/kg (p < 0.05) with a nearly universal individual patient response rate. Additional hypoglycemia metrics, including overnight hypoglycemia, similarly improved.
Conclusion:
Ersodetug was generally well tolerated and significantly improved hypoglycemia in participants with cHI. Ersodetug represents a novel INSR-targeted mechanism of action with the potential to be an effective therapy for all forms of cHI, alone or in combination with other therapies.
Funding:
Rezolute, Inc. (Redwood City, CA), provided funds.
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