ESPE Abstracts (2022) 95 FC3.2

ESPE2022 Free Communications Early Life and Multisystem Endocrinology (6 abstracts)

Results from a Global, Multi-Center, Phase 2b Study (RIZE) in Congenital Hyperinsulinism: Characterization of a High Unmet Treatment Need and Glycemic Response to RZ358

Huseyin Demirbilek 1 , Maria Melikyan 2 , Sonya Galcheva 3,4 , Antonia Dastamani 5 , Paul Thornton 6 , Diva De Leon 7 , Julie Raskin 8 , Brian Roberts 9 , Davelyn Hood 9 , Erin O'Boyle 9 & Henrik Christesen 10


1Department of Paediatric Endocrinology, Hacettepe University Faculty of Medicine, Ankara, Turkey; 2National Medical Research Center of Endocrinology, Department of Pediatrics, Moscow, Russian Federation; 3Department of Pediatrics, Varna Medical University, Varna, Bulgaria; 4University Hospital “St. Marina”, Varna, Bulgaria; 5Endocrinology Department, Great Ormond Street Hospital for Children, London, United Kingdom; 6Department of Endocrinology, Cook Children's Hospital, Fort Worth, USA; 7Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA; 8Congenital Hyperinsulinism International, Glen Ridge, USA; 9Rezolute, Inc., Redwood City, USA; 10Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark

Background: Congenital Hyperinsulinism (CHI) is the most frequent cause of severe, persistent hypoglycemia in children. Persistent hypoglycemia places patients at risk for adverse clinical outcomes, and current guidelines recommend maintaining plasma glucose >3.9mmol/l. CHI patients often have substantial, residual hypoglycemia and fail to meet treatment goals with currently available standard of care (SOC) therapies. In this study, we aimed to characterize the demographics, disease history, and glycemic control by CGM and blood glucometer (BGM) before and after intervention with RZ358 (negative allosteric modulator of the insulin receptor) in CHI patients on SOC.

Methods: RZ358-606 (RIZE) was an open-label study (30-minute RZ358 IV infusion given biweekly for 8 weeks) conducted in CHI patients (4 sequential dose cohorts, 3-9mg/kg, 3-8 patients each) ages 2-45 years. Patients’ history and extent of hypoglycemia on SOC by CGM [DexcomG6] and BGM were obtained.

Results: 23 patients (13M/10F; mean age 6.7y [2-22y]; 48% kATP mutations) were enrolled, of whom 16 (70%) had seizure history with five (22%) reporting seizures within past 12 months. Fourteen (61%) reported hospitalizations within past year due to CHI-related complications. At baseline, hypoglycemia (<3.9mmol/l) was present 23% [6-86%] of time by CGM with 16 [5-78] events/week by BGM on one or more SOC therapies (35% diazoxide, 56% somatostatin analogs,17% enteral feeds). RZ358 resulted in >50% improvement (P≤0.01) in hypoglycemia time and events across pooled doses, and up to ~75% improvement in hypoglycemia (P≤0.05) at the top doses. Patient response rates at clinically relevant hypoglycemia correction thresholds are shown in Table 1.

Table 1. Response Rates to RZ358 at Clinically Relevant Hypoglycemia Correction Thresholds
Hypoglycemia Correction Threshold 3mg/kg (n=4) 6mg/kg (n=8) 9mg/kg (n=7) Titrate 3-9mg/kg (n=3) RZ358 Pooled (n=22)
Responders N(%)
Severe (<2.8mmol/l) 3(75%) 7(88%) 7(100%) 2(67%) 19(86%)
Overall (<3.9mmol/l) 3(75%) 7(88%) 7(100%) 3(100%) 20(91%)
Severe (<2.8mmol/l) 3(75%) 6(75%) 7(100%) 2(67%) 18(82%)
Overall (<3.9mmol/l) 1(25%) 7(88%) 7(100%) 1(33%) 16(73%)
Severe (<2.8mmol/l) 1(25%) 5(63%) 6(86%) 2(67%) 14(64%)
Overall (<3.9mmol/l) 1(25%) 3(38%) 5(71%) 1(33%) 10(45%)

Conclusion: Additional therapeutic interventions demonstrating clinically-meaningful hypoglycemia correction beyond what is currently available could be expected to translate to better clinical outcomes. RZ358 was generally safe, well-tolerated and demonstrated clinically-relevant dose-response improvement in glycemic measures, particularly at planned phase 3 dose levels (6, 9mg/kg).

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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