Hüseyin Demirbilek is a pediatric endocrinologist at Hacettepe University Faculty of Medicine in Ankara, Turkey.

Huseyin Demirbilek, MD

Ersodetug (RZ358) demonstrated 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 trial presented at the Endocrine Society (ENDO) Annual Meeting 2026.

Although the study did not meet its primary or key secondary glycemic endpoints, investigators highlighted evidence of biologic activity and suggested behavioral differences between treatment groups may have influenced patient-monitored glucose outcomes, potentially obscuring treatment effects.

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

The SunRIZE trial enrolled 63 participants older than 3 months with inadequately controlled hypoglycemia despite standard of care. Eligibility required at least 3 self-monitored blood glucose (SMBG) hypoglycemic events per week and ≥8% time in hypoglycemia on continuous glucose monitoring (CGM).

Participants were randomized to 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, though the difference was not statistically significant. Investigators also observed concordant reductions in SMBG-measured hypoglycemic events and CGM-derived measures, alongside biomarker evidence of insulin receptor engagement.

A statistically significant improvement versus placebo was observed at Week 16 on CGM measures (P < .05).

Despite the missed primary endpoint, investigators noted that multiple measures consistently favored ersodetug and aligned with its proposed mechanism of action as an insulin receptor–targeting monoclonal antibody.

Investigators suggested the trial results may have been influenced by behavioral changes in caregiver-managed disease monitoring, a known challenge in congenital hyperinsulinism studies where families frequently intervene to prevent hypoglycemia.

"Statistical significance is not same with the clinical meaningful. We saw about a 45% reduction in the number of hypoglycemia events, and normally 25% reduction is clinically meaningful. We also saw a 32% difference between placebo and the study treatment group in continuous glucose monitoring. The statistics were not significant, but it was a clinically important correction," Hüseyin Demirbilek, MD, professor at Hacettepe University and pediatric endocrinologist, told 

He added that feeding behaviors and glucose monitoring patterns can shift during long-term trials, particularly in pediatric populations where caregivers actively respond to low glucose readings, potentially reducing differences between treatment arms.

Ersodetug was generally well tolerated. Four participants discontinued treatment due to adverse events, including three allergic reactions and one case of hypertrichosis. Mild hypertrichosis occurred in 36% of ersodetug-treated participants and was the most common treatment-related adverse event.

"When you compare benefits and risks, hypertrichosis is mild. It is not life-threatening; it's just a cosmetic side effect," Demirbilek said.

Investigators noted that 59 participants continue in the ongoing open-label extension study, which may provide additional insight into the durability of response and long-term safety of ersodetug in congenital hyperinsulinism.

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

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.

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. 

. Published online March 18, 2025:100611. doi:

https://doi.org/10.1016/j.medj.2025.100611

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Ersodetug Shows Hypoglycemia Reduction Trends, Target Engagement in Phase 3 cHI Trial

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 (

“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.

Ersodetug showed target engagement and hypoglycemia reduction trends in phase 3 cHI study but missed primary endpoints in SunRIZE trial.

Huseyin Demirbilek, MD

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