Ersodetug Shows Target Engagement but Misses Primary Endpoints in Phase 3 cHI Study

Ersodetug (RZ358) was associated with target engagement, pharmacologic activity, and consistent trends toward hypoglycemia reduction across multiple endpoints in patients with congenital hyperinsulinism (cHI), according to findings from the global, multicenter, double-blind, placebo-controlled phase 3 SunRIZE study.

Although the trial did not meet its primary or key secondary glycemic endpoints, investigators presenting at the Endocrine Society (ENDO) Annual Meeting 2026 suggested that behavioral differences between treatment groups may have influenced patient-monitored glucose endpoints while emphasizing evidence of target engagement and pharmacologic activity.

Congenital hyperinsulinism is a rare, monogenic disorder characterized by dysregulated insulin secretion from pancreatic beta cells, resulting in persistent hypoglycemia. Without timely treatment, prolonged glucose deprivation can lead to permanent brain injury, intellectual disability, and seizures, with the risk estimated at 25% to 50% in affected infants.

“The main challenge with congenital hyperinsulinism is that there is no effective and safe medication that's appropriate for all patient groups to date,” Huseyin Demirbilek, MD, professor at Hacettepe University and pediatric endocrinologist, told HCPLive. “The only FDA-approved medication is diazoxide, which more than 50% of individuals with congenital hyperinsulinism do not respond to. For the remaining patients, we do use some off-label medications, but they have limited efficacy and side effects.”

Ersodetug is a fully human monoclonal antibody designed to allosterically and reversibly bind the insulin receptor, reducing the effects of excess circulating insulin. Unlike existing therapies that primarily suppress insulin secretion, ersodetug targets insulin action at the receptor. Investigators reported that target drug concentrations and pharmacologic activity were achieved across all age groups studied.

The SunRIZE trial included 63 participants who were > 3 months of age with inadequately controlled hypoglycemia, defined as ≥3 self-monitored events/week (SMBG) and ≥8% time in hypoglycemia by CGM, despite standard-of-care. , They were randomized to receive ersodetug 5 mg/kg (n = 18), ersodetug 10 mg/kg (n = 20), or placebo (n = 17) every 2 to 4 weeks for 24 weeks.

At the 10 mg/kg dose, ersodetug was associated with an approximate 25% reduction in time spent in hypoglycemia compared with an approximate 5% increase in the placebo group, although the difference was not statistically significant. Investigators also observed concordant reductions in self-monitored hypoglycemic events and CGM-measured hypoglycemia that were consistent with drug concentrations and insulin biomarker changes. A statistically significant improvement compared with placebo was observed at Week 16 by CGM (P <.05).

“This drug was binding to the receptor and was decreasing insulin binding, so receptor-mediated insulin clearance decreases, and so blood insulin levels increase. And clinically we do see improvement in blood glucose levels and a reduction in hypoglycemia in substantial amounts, so this is the clinical evidence for efficacy of the medication.”

According to the investigators, ersodetug was generally well tolerated. In total, 4 participants discontinued treatment because of adverse events, including 3 allergic reactions and 1 case of hypertrichosis. Mild hypertrichosis was reported in 36% of erodotug-treated participants.

Investigators noted that high participation and retention in the ongoing open-label extension (n = 59) may provide additional insight into the long-term clinical benefit of the therapy.

Editor’s Note: Demirbilek has declared relevant disclosures with Rezolute, Inc.

References

1. Demirbilek, H, Dastamani A, Vu D, et al. Ersodetug (RZ358) in Congenital Hyperinsulinism: Top-Line Results from a Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study (sunRIZE) Poster presented at: Endocrine Annual Meeting; June 12-17, 2026; Chicago, Ill.

2. Demirbilek H, Melikyan M, Iotova V, et al. Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug), an insulin receptor antibody, for congenital hyperinsulinism. Med. Published online March 18, 2025:100611. doi:https://doi.org/10.1016/j.medj.2025.100611

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