FDA Streamlines Pathway for Ersodetug in Tumor Hyperinsulinism

In a significant development for the rare disease community, Rezolute has announced a streamlined clinical pathway for its lead therapeutic candidate, ersodetug (RZ358) in the treatment of hypoglycemia associated with tumor hyperinsulinism (HI). The announcement, following alignment with the US FDA, allows for a significantly condensed phase 3 trial design, potentially accelerating the drug's path to market and providing a much-needed treatment option for patients.¹

The revised plan for the upLIFT study (NCT06881992), a phase 3 registrational trial, will now be a single-arm, open-label trial with as few as 16 patients. This marks a notable departure from the previously planned double-blind, randomized, placebo-controlled design. The decision was based on a combination of factors, including real-world evidence of ersodetug's benefit from the company's Expanded Access Program and the drug's mechanistic plausibility. According to the company, the FDA acknowledged the favorable outcomes observed in over 10 patients treated under this program, which was a key factor in their decision to simplify the trial design. The company also stated that the pivotal sunRIZE trial in congenital HI (NCT04841961), which is on track to report topline results in December 2025, would serve as confirmatory clinical evidence for the tumor HI indication.

“This revised and simplified plan for the upLIFT study and approval pathway marks an important development for us as well as the community of healthcare providers, patients, and families living with serious hypoglycemia caused by tumor HI. By focusing on an open-label study in upLIFT, while building upon the robust clinical foundation established in the congenital HI indication, we are expediting development with the goal of making this therapy available as efficiently as possible,” said Brian Roberts, MD, chief medical officer at Rezolute, in a press release.

Tumor HI is a rare condition that leads to severe hypoglycemia, a result of the overactivation of the insulin receptor. This can be caused by 2 distinct types of tumors: islet cell tumors (ICTs), such as insulinomas, which overproduce insulin, and nonislet cell tumors (NICTs), which produce insulin-like paraneoplastic substances such as IGF-2. These substances bind to and activate the insulin receptor, leading to excessive glucose uptake and profound hypoglycemia. The high morbidity and mortality rates associated with tumor HI highlight the significant unmet need for effective therapeutic interventions.

Ersodetug is a fully human monoclonal antibody that functions by binding allosterically to the insulin receptor. By doing so, it decreases the receptor's overactivation by insulin and related substances. This unique mechanism of action, which acts downstream from the pancreas, gives ersodetug the potential to be universally effective in treating hypoglycemia across various congenital and acquired forms of HI. The drug's broad applicability is a key factor in its potential to address multiple facets of this complex disease.

The primary end point of the upLIFT study is the number of patients with a clinically meaningful reduction (≥50%) in glucose infusion rate from baseline.² Secondary end points include change in average daily intravenous (IV) glucose/dextrose infusion rate, change in average daily amount of total IV glucose during the pivotal treatment period, and •time to complete stopping of IV glucose after the first ersodetug dose.

REFERENCES:

1. Rezolute Announces Alignment with FDA on Streamlined Design for Ongoing Phase 3 Trial of Ersodetug in Tumor Hyperinsulinism. News release. Rezolute Inc. September 2, 2025. Accessed September 5, 2025. https://tinyurl.com/458fzzfr

2. A Phase 3 Study of Ersodetug in Patients With Tumor-Associated Hyperinsulinism (tHI). ClinicalTrials.gov. Updated August 15, 2025. Accessed September 5, 2025. https://clinicaltrials.gov/study/NCT06881992