A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ersodetug in Patients With Inadequately Controlled Hypoglycemia Due to Tumor-Associated Hyperinsulinism (tHI)

The objectives of this study are to evaluate the glycemic efficacy, safety, and tolerability of ersodetug for treatment of hypoglycemia in patients with Tumor-Associated Hyperinsulinism (tHI).

More details:

This study will include participants who are suffering from low blood sugar (hypoglycemia) related symptoms due to over-production (too much) of hormones (e.g. insulin or similar substances) by certain tumors that cannot be treated satisfactorily with available treatment. The study is divided into 3 periods: Screening (up to 4 weeks), Treatment (8 weeks) and either Follow-up (4 weeks) or optional Open Label Extension (OLE) phase (up to 3 years). Overall, the study will enroll about 48 participants. Participants will be assigned to the appropriate treatment group depending on the type of tumor and whether they are hospitalized or not. For those not hospitalized, participants will be assigned in random order to either receive ersodetug or placebo (substance that looks like the study drug but does not contain active study drug) for the 8-week treatment period. All patients will receive ersodetug in the optional OLE period. The study will be comprised of the following treatment groups: * Not hospitalized (referred to as ambulatory) insulin secreting tumor participants who receive usual treatment/standard of care therapies (SOC) and 9 mg/kg of ersodetug * Ambulatory insulin secreting tumor participants who receive SOC and placebo * Hospitalized (receiving IV dextrose or TPN ≥3 days) insulin or IGF secreting tumor participants who receive SOC and 9 mg/kg of ersodetug * Ambulatory IGF secreting tumor participants who receive SOC and 9 mg/kg of ersodetug Participants should continue to use pre-existing anti-hypoglycemic medications and anti-tumor therapies throughout the study.

Overview

Ersodetug (RZ358) is a fully human IgG2 monoclonal antibody in late-stage development for the treatment of hypoglycemia caused by hyperinsulinism, including congenital hyperinsulinism (cHI) and tumor-associated hyperinsulinism (tumorHI). A global, randomized, double-blind, placebo-controlled Phase 3 study in cHI (sunRIZE; RZ358-301) completed enrollment in 2025, with topline results expected in late 2025. A separate Phase 3 program in tumorHI has FDA IND clearance. Orphan Drug Designation (US/EU), US Pediatric Rare Disease Designation, and EMA PRIME designation have been reported. (ir.rezolutebio.com)

Mechanism of action

Ersodetug binds allosterically and reversibly to the insulin receptor (INSR) and acts as a negative allosteric modulator, reducing excessive insulin signaling to correct hypoglycemia. Preclinical and early clinical work with this antibody class shows selective attenuation of insulin action without complete blockade, consistent with the intended “insulin counter-regulatory” effect. The mechanism may also mitigate hypoglycemia driven by IGF‑2 in tumorHI. (pubmed.ncbi.nlm.nih.gov)

Efficacy

• Phase 2b (RIZE; open‑label, multicenter; NCT04538989): 23 participants with cHI (≥2 years) inadequately controlled on standard of care received ersodetug 3–9 mg/kg IV every 2 weeks for 8 weeks. Across pooled doses, median weekly hypoglycemia events (<70 mg/dL; SMBG) decreased 59% (p<0.001) and percent time in hypoglycemia (CGM) decreased 54% (p<0.001). At 6–9 mg/kg, event reductions were 48–84% and time-in-hypoglycemia reductions 61–65%, with a near-universal individual responder rate. Overnight hypoglycemia improved similarly. (pubmed.ncbi.nlm.nih.gov)

• Expanded access (tumorHI; case series, NANETS 2024): In five adults with refractory hypoglycemia from insulin‑secreting/metabolically active tumors, ersodetug (typically 6–9 mg/kg IV every 1–2 weeks) enabled discontinuation of parenteral dextrose in four patients and a 50% reduction in one; three achieved complete resolution of hypoglycemia within two weeks. (endocrine-abstracts.org)

• Ongoing Phase 3 (sunRIZE): Parallel‑arm, placebo‑controlled trial in patients 3 months–45 years with cHI. Doses: 5 or 10 mg/kg (loading every 2 weeks, then every 4 weeks during a 6‑month pivotal period). Primary endpoint: change from baseline in average weekly hypoglycemia events; key secondary: percent time in hypoglycemia. (ir.rezolutebio.com)

Safety

• Phase 2b (RIZE): No deaths, adverse drug reactions, study withdrawals, or dose‑limiting toxicities were reported over 8 weeks; pharmacokinetics were predictable and dose‑proportional. (pubmed.ncbi.nlm.nih.gov)

• Healthy volunteer Phase 1 with the same antibody class (XOMA 358/X358): single ascending doses up to 9 mg/kg IV were well tolerated, with no serious adverse events; expected pharmacodynamic effects included transient insulin resistance markers (e.g., higher postprandial glucose), supporting target engagement. (academic.oup.com)

• Regulatory updates: In September 2024, FDA lifted partial clinical holds on ersodetug in cHI, allowing US participation (including infants ≥3 months) at all doses in the ongoing global Phase 3 study; the agency concluded rodent liver signals were likely strain‑specific and not relevant to humans. (globenewswire.com)

Further reading

• Phase 2b trial report in cHI (peer‑reviewed): Global, multi‑center, repeat‑dose study of ersodetug. Med (Cell Press), 2025. (pubmed.ncbi.nlm.nih.gov)
• Mechanism/first‑in‑human (class): Attenuation of insulin action by an allosteric insulin receptor antibody in healthy volunteers. JCEM, 2017. (academic.oup.com)
• Foundational mechanism: Inhibition of insulin receptor function by a human, allosteric monoclonal antibody. mAbs, 2014. (tandfonline.com)
• TumorHI expanded access case series (conference abstract). NANETS 2024. (endocrine-abstracts.org)
• NEJM correspondence: Anti–Insulin Receptor Antibody for Malignant Insulinoma and Refractory Hypoglycemia (clinical experience with the class). NEJM, 2023. (nejm.org)
• Phase 3 cHI study design update and timelines (company): ENDO 2025 late‑breaking abstract announcement; FDA IND clearance for tumorHI Phase 3; FDA hold removal. (ir.rezolutebio.com)

Notes - As of October 7, 2025, Phase 3 efficacy results for cHI had not yet been published; topline data were expected in late 2025 per company statements. (ir.rezolutebio.com)

Last updated: Oct 2025

Double-Blind Arm: (Ambulatory ICT and Ambulatory NICT participants)

Inclusion Criteria:

* The eligibility criteria of all participants must be evaluated by a multidisciplinary team led by the PI which must include an oncologist

* Male or female participants of ≥18 years of age who provide written informed consent

* Participants with a clinical diagnosis and laboratory confirmation of ICT or NICT, with associated hypoglycemia that is considered refractory to surgery and to usual SOC anti-hypoglycemia therapies, per investigator judgement.

* Experiencing an average of ≥ 3 hypoglycemia events per week that meet Level 2 criteria and/or Level 3 criteria during the two weeks before randomization

Exclusion Criteria:

* Participants who have not previously received tumor-directed therapy (including at least one course/trial of systemic tumor-directed therapy, as appropriate) but are considered appropriate for tumor-directed therapies by the investigator and/or a multi-disciplinary oncology care team.

* Initiation of, or changes to tumor directed therapies within 8 weeks prior to initiation of study drug, or expected initiation or significant changes to these therapies over the course of the pivotal treatment period

* Initiation of, or significant changes to, SOC medical (e.g. diazoxide, SSAs, continuous glucagon, mTOR-Inhibitors, etc.) or supplemental enteral treatments (e.g. continuous tube feeds) used for the chronic management of hypoglycemia within 4 weeks of screening (per investigator's discretion), or expected changes to SOC medical therapies over the course of the pivotal treatment period.

* Any out-of-range laboratory value at screening (other than glucose) that is assessed as clinically significant by the investigator.

Open-Label Arm: (Hospitalized ICT and NICT participants)

Inclusion Criteria:

* The eligibility criteria of all participants must be evaluated by a multidisciplinary team led by the PI which must include an oncologist

* Male or female participants of ≥18 years of age who provide written informed consent.

* Clinical diagnosis of neuroendocrine tumor (NET) (ICT or NICT) with biochemical evidence of tHI confirmed via laboratory assessment who have failed to achieve adequate control of hypoglycemia with usual SOC anti-hypoglycemic therapies, per investigator judgement.

* Requiring IV glucose infusion and/or parenteral nutrition for ≥3 days for management of uncontrolled hypoglycemia

Exclusion Criteria:

* Evidence of active infection including human immunodeficiency virus, hepatitis B, or hepatitis C (excluding immunization patterns).

* Any out-of-range laboratory value at screening (other than glucose) that is assessed as clinically significant by the investigator.

* Any organ condition, concomitant disease (e.g., psychiatric illness, severe alcoholism, or drug abuse, cardiac, hepatic, or kidney disease), or other abnormality that itself, or the treatment of which in the opinion of the investigator and/or Sponsor's Medical Monitor would pose an unacceptable risk to the participant in the study.