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

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.

Study Design

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.

Efficacy Results

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.

Interpreting the Primary Endpoint Miss

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 HCPLive.

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.

Safety and Tolerability

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.

Open-Label Extension

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.

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