Efficacy and Safety Evaluation of Ersodetug in Tumor-Associated Hyperinsulinism with Inadequately Controlled Hypoglycemia: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the **glycemic efficacy**, safety, and tolerability of ersodetug as an add-on to standard of care therapy in patients with inadequately controlled hypoglycemia due to tumor-associated hyperinsulinism. This condition, characterized by excessive insulin production from islet-cell (insulinomas/proinsulinomas) and non-islet cell tumor hyperinsulinism (NICT), can lead to severe hypoglycemia, posing significant clinical challenges. The study aims to determine whether ersodetug can effectively manage blood glucose levels, thereby improving patient outcomes and reducing the risk of hypoglycemic episodes.

The clinical trial involves a total of **36 participants** diagnosed with **tumor-associated hyperinsulinism**, specifically due to islet-cell (insulinomas/proinsulinomas) and non-islet cell tumor hyperinsulinism (NICT). The study population includes both male and female participants aged 18 years and older. Participants were selected based on their clinical diagnosis of neuroendocrine tumors (NET) with biochemical evidence of hyperinsulinism, confirmed via laboratory assessment, and who have not achieved adequate control of hypoglycemia with standard care therapies. The trial population includes individuals who have been hospitalized for uncontrolled hypoglycemia requiring intravenous glucose infusion or parenteral nutrition for at least three days. Participants are required to have an estimated minimum life expectancy of three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Lifestyle considerations such as diet and physical activity are not specified, but participants must not be pregnant or breastfeeding and must agree to use effective contraceptive measures during the study and for at least three months after the last dose of the study drug. The trial includes a vulnerable population, ensuring that all eligibility criteria are evaluated by a multidisciplinary team led by the principal investigator, including an oncologist, to confirm the appropriateness of each participant for the clinical trial.

The clinical trial is a **Phase 3, randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of ersodetug in patients with inadequately controlled hypoglycemia due to **tumor-associated hyperinsulinism**. The trial aims to assess the glycemic efficacy, safety, and tolerability of ersodetug as an add-on to standard of care therapy. The study will involve participants with a clinical diagnosis of islet-cell (insulinomas/proinsulinomas) and non-islet cell tumor hyperinsulinism who have not achieved adequate control of hypoglycemia with usual therapies. The trial is expected to commence recruitment on September 8, 2025, and conclude by September 9, 2030.

Participants will be randomly assigned to receive either the investigational product, ersodetug, or a placebo, both administered as a **solution for infusion**. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess overall outcomes. The primary endpoint is the percent change from baseline in the average weekly count of Level 2 and Level 3 hypoglycemia events during the treatment period. Secondary endpoints include changes in hypoglycemia event counts and glucose infusion rates.

The expected duration of participant involvement is up to 39 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must be at least 18 years old, provide informed consent, and meet specific inclusion criteria, such as experiencing frequent hypoglycemia events and having a minimum life expectancy of three months. Exclusion criteria are not specified in the provided data. The study will ensure that all participants are evaluated by a multidisciplinary team, including an oncologist, to confirm their suitability for the trial.

The clinical trial involves the administration of **RZ358**, an **anti-(insulin receptor) human monoclonal antibody**, as the experimental medication. This biological product is formulated as a **solution for infusion** and is provided by Rezolute, Inc. The administration route is via **intravenous infusion**. The dosing regimen is based on body weight, with a maximum daily dose of 9 mg/kg and a total maximum dose of 1476 mg/kg over a treatment period of up to 39 weeks. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind study. The placebo is a sterile solution for parenteral administration, packaged in an ISO 2R, type I clear glass vial with a fluoropolymer-faced, grey chlorobutyl rubber stopper, and an aluminum seal with a plastic flip-off cap. The buffered vehicle of the placebo contains 10mM L-histidine, 10mM L-methionine, 270mM sorbitol, and 0.01% polysorbate 20, with a pH of 5.8. The placebo is designed to match the experimental medication in appearance and administration method to maintain blinding.

The efficacy of the investigational product, **ersodetug**, in the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the percent change from baseline in the average weekly count of aggregate Level 2 and adjudicated Level 3 hypoglycemia events during the entire pivotal treatment period. Additionally, the number of participants with a clinically meaningful reduction (≥50%) in glucose infusion rate from baseline will be evaluated. Long-term glycemic efficacy will also be assessed by monitoring changes in background standard of care (SOC) medications for hypoglycemia, including the occurrence of overall use, de-escalation, and escalation of the SOC regimen.

Secondary endpoints will focus on changes from baseline in the average weekly count of aggregate Level 2 and Level 3 hypoglycemia events, as well as the percent change from baseline in the average daily percent time with Level 2 hypoglycemia by continuous glucose monitoring (CGM) during Weeks 1-8 of the pivotal treatment period. Other secondary measures include the percent change from baseline in the average weekly count of overall hypoglycemia events and changes in the average daily intravenous glucose/dextrose infusion rate. The time to complete weaning off intravenous glucose administration after initiating ersodetug will also be recorded.