ESPE Abstracts

Background: Congenital hyperinsulinism (cHI) is characterized by recurrent, persistent hypoglycemia due to dysregulated insulin secretion from dysfunctional pancreatic beta cells. Hypoglycemia in combination with hypoketonemia can cause irreparable brain damage including lifelong neurologic impairments, seizures, and death. Avoidance of life-threatening hypoglycemia around-the-clock via vigilant glucose monitoring and frequent interventions, places immense psychosocial burden on cHI patients and caregivers, particularly during the overnight period. RZ358 is a fully human monoclonal IgG2 antibody that allosterically and reversibly binds the insulin receptor, thereby mitigating hypoglycemia mediated by hyperinsulinism.

Objectives: While results of overall hypoglycemia by self-monitored blood glucose (SMBG) and continuous glucose monitor (CGM) from the RIZE study have been previously reported, this analysis highlights the impact of RZ358 therapy on CGM-based overnight (12-8am) glycemic endpoints, including average time below range (<70 mg/dL [<3.9mmol]), Cumulative Normoglycemia Exposure (Average 8h Overnight Glucose Area Under the Curve (AUC) at Area>70 mg/dL) and Cumulative Hypoglycemia Exposure (Average 8h Overnight Glucose Area Over the Curve (AOC) at Area <70 mg/dL).

Methods: RIZE, a global, multi-center, open-label, repeat-dose Phase 2b study enrolled 23 participants with cHI (57% M; aged 2-22 years [70% 2-6 years old]) who had uncontrolled hypoglycemia on standard of care. Participants were organized into four sequential ascending dose cohorts of 3-9 mg/kg (n = 3-8/cohort) and were dosed with the study drug, RZ358, biweekly for eight weeks while remaining on SOC (e.g. diazoxide, somatostatin). Dexcom G6® was used to measure glucose and Wilcoxon rank sign test (SAS 9.3®) was used to evaluate median glycemic endpoints, comparing baseline screening to end of treatment (EOT) evaluable periods.

Results: In a dose-dependent manner, across all dose levels, baseline overnight hypoglycemia time (13.6% time [65 min]) improved by a median of 52% (P = 0.001). Similar improvements were also observed across all dosing cohorts with a median increase of 48% (P <0.001) in cumulative 8h overnight normoglycemia exposure and a reduction in median 8h overnight cumulative exposure to hypoglycemia by 52% (P = 0.03). Average overnight glucose shifted slightly from baseline median of 99 mg/dL to 113 mg/dL (P <0.001) at EOT.

Discussion: RZ358 led to a substantial reduction in overnight hypoglycemia in patients with cHI in the RIZE study. Minimizing hypoglycemia during the vulnerable overnight period not only offers safety for the child but also promotes undisturbed sleep for the entire family. These and previously reported results suggest that RZ358 has the potential to be a safe and effective therapy to treat all forms of cHI. A Phase 3 study is ongoing.