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 monoclonal antibody in late-stage development for hypoglycemia caused by hyperinsulinism. It is being studied primarily in congenital hyperinsulinism (cHI) and is also advancing toward Phase 3 in tumor-associated hyperinsulinism. As of September 2025, a global, randomized, placebo-controlled Phase 3 study in cHI (sunRIZE) has completed enrollment (n=62), with topline results anticipated in December 2025. The FDA lifted prior partial clinical holds in September 2024, enabling U.S. enrollment; the program has since received FDA Breakthrough Therapy Designation (January 2025) and EMA PRIME eligibility (October 2023). (ir.rezolutebio.com)

Mechanism of action

• Target: Insulin receptor (INSR) on liver, adipose, and muscle.
• Modality: Negative allosteric modulator (IgG2 mAb) that binds a site distinct from insulin’s orthosteric site, reducing insulin’s binding affinity and signaling efficacy, thereby attenuating pathologic insulin action while avoiding direct competition at the ligand-binding site. Preclinical work (XMetD) demonstrated nanomolar INSR binding, ~3-fold reciprocal affinity shifts with insulin, and inhibition of INSR autophosphorylation/Akt signaling; in vivo, it reversed insulin-induced hypoglycemia in mice. A first‑in‑human study with the related antibody (XOMA 358) in healthy volunteers confirmed dose-dependent, reversible induction of insulin resistance with a ~21‑day half‑life. (pmc.ncbi.nlm.nih.gov, pubmed.ncbi.nlm.nih.gov)

Note: Because INSR over-activation can also be driven by IGF‑2 in some tumors, the downstream INSR mechanism is being explored in tumor hyperinsulinism as well. (pmc.ncbi.nlm.nih.gov)

Clinical development

• Congenital hyperinsulinism
• Phase 2b (RIZE; NCT04538989): open-label, 23 participants aged ≥2 years with persistent hypoglycemia despite standard care; biweekly IV dosing for 8 weeks across 3–9 mg/kg cohorts. (pubmed.ncbi.nlm.nih.gov)

• Phase 3 (sunRIZE; RZ358-301): multicenter, double-blind, randomized, placebo-controlled, parallel-arm study evaluating 5 or 10 mg/kg using a biweekly loading then every-4-week maintenance schedule over 6 months; includes infants ≥3 months. Enrollment completed in May 2025; topline readout expected December 2025. (ir.rezolutebio.com)

• Tumor hyperinsulinism

• FDA cleared an IND in August 2024 for a Phase 3 registrational study; Orphan Drug Designation granted December 2024. A NEJM case report described clinical improvement with ersodetug under emergency/expanded access in malignant insulinoma. (ir.rezolutebio.com, pmc.ncbi.nlm.nih.gov)

Efficacy

• Phase 2b (RIZE; cHI)
• Primary/Key outcomes: change from baseline in hypoglycemia events (self-monitored capillary glucose) and percent time in hypoglycemia by CGM over 8 weeks.
• Results (peer‑reviewed): Across pooled doses, median hypoglycemia events and time in hypoglycemia improved by 59% and 54%, respectively (both p<0.001). At 6–9 mg/kg, improvements were 48%–84% (events) and 61%–65% (time), with a near‑universal individual response; overnight metrics also improved. (pubmed.ncbi.nlm.nih.gov)
• Initial conference/company disclosures similarly reported ~75% reductions at the anticipated therapeutic doses and ≥50% improvement in 100% of patients in the high‑dose cohort. (Peer‑reviewed data above should be considered primary.) (ir.rezolutebio.com)

No Phase 3 efficacy results have been released yet (as of September 2025). (ir.rezolutebio.com)

Safety

• Phase 2b (RIZE; cHI): Ersodetug was generally well tolerated; no deaths, adverse drug reactions, study withdrawals, dose‑limiting toxicities, or clinically significant hyperglycemia were reported over 8 weeks of biweekly IV dosing. Pharmacokinetics were predictable and dose‑proportional. (pubmed.ncbi.nlm.nih.gov)
• Phase 1 (healthy volunteers, allosteric anti‑INSR antibody XOMA 358): Single IV doses up to 9 mg/kg were well tolerated with no serious adverse events; pharmacology consistent with reversible attenuation of insulin action. (pubmed.ncbi.nlm.nih.gov)
• Phase 3 safety: As of interim updates, the infant open‑label arm achieved target exposures with Data Monitoring Committee support to include infants in the blinded portion; full safety results pending. (ir.rezolutebio.com)

Regulatory designations and status

• FDA Breakthrough Therapy Designation (cHI): January 7, 2025. (ir.rezolutebio.com)
• EMA PRIME eligibility (cHI): October 17, 2023. (ir.rezolutebio.com)
• Orphan Drug Designation: U.S. and EU for cHI (prior), and U.S. for tumor hyperinsulinism (December 3, 2024). (ir.rezolutebio.com)

Further reading

• Demirbilek H, et al. Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug) in congenital hyperinsulinism (peer‑reviewed). Med (Cell Press). 2025. (pubmed.ncbi.nlm.nih.gov)
• Johnson KW, et al. Attenuation of insulin action by an allosteric insulin receptor antibody in healthy volunteers (first‑in‑human). J Clin Endocrinol Metab. 2017. (academic.oup.com)
• Corbin JA, et al. Inhibition of insulin receptor function by a human, allosteric monoclonal antibody (preclinical mechanism). mAbs. 2014. (pmc.ncbi.nlm.nih.gov)
• Osataphan S, et al. Anti–Insulin Receptor Antibody for Malignant Insulinoma and Refractory Hypoglycemia (case report). N Engl J Med. 2023. (pmc.ncbi.nlm.nih.gov)
• sunRIZE Phase 3 status and design updates (company communications). (ir.rezolutebio.com)

Note: No Phase 3 efficacy/safety outcomes have been disclosed yet; the next planned update is topline data from the sunRIZE study, anticipated December 2025. (ir.rezolutebio.com)

Last updated: Sep 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.