Rezolute Raises $130 Million on Heels of Positive Phase 2 Study of RZ358 in Patients with Congenital Hyperinsulinism

Rezolute, a company focused on therapies for devastating metabolic diseases, reported positive results from its Phase 2b RIZE study of RZ358 in patients with congenital hyperinsulinism and priced an underwritten registered direct offering to raise $130 million to fund the experimental compound’s continued development, other pipeline development, working capital, and general corporate purposes.

Photo: Brian Roberts, an endocrinologist and senior vice president of Clinical Development for Rezolute

The results were presented in a late-breaking oral presentation at the Pediatric Endocrine Society 2022 Annual Meeting. The study exceeded expectations for correction of hypoglycemia, including a highly significant reduction of approximately 75 percent in hypoglycemia events by blood glucometer (BGM) as well as time in hypoglycemia by continuous glucose monitoring (CGM).

“Patients with congenital hyperinsulinism often have continued hypoglycemia in spite of available therapies, as has been clearly demonstrated in the RIZE study,” said Paul Thornton, a pediatric endocrinologist at Cook Children’s Hospital. “The magnitude of improvement in hypoglycemia in this study demonstrates the potential for RZ358 to become a much-needed therapy for treating congenital hyperinsulinism.”

Congenital hyperinsulinism (HI) is the most common cause of recurrent and persistent hypoglycemia in children. It typically presents early in life, with about 60 percent of infants with congenital HI experiencing hypoglycemia within the first month of life. These episodes can result in significant brain injury and death if not recognized and managed appropriately. Recurrent hypoglycemia can lead to progressive and irreversible damage over time, including serious and devastating brain injury, seizures, neuro-developmental problems, feeding difficulties, and significant impact on patient and family quality of life. The two commonly used long-term medications, diazoxide and somatostatin analogs, are not Food and Drug Administration approved for all forms of this condition and often are ineffective or have intolerable side effects. In cases of congenital HI that are unresponsive to medical management, surgical removal of the pancreas may be required. In those with diffuse congenital HI where the whole pancreas is affected, a near-total pancreatectomy can be undertaken, although about half of these children will continue to have hypoglycemia and require medical treatment for congenital HI.

RZ358 is a human monoclonal antibody that binds to a unique allosteric site on insulin receptors in the liver, fat, and muscle. The antibody counteracts the effects of elevated insulin in the body by modifying insulin’s binding, signaling, and activity to maintain glucose levels in a normal range. Rezolute believes that RZ358 is ideally suited as a potential therapy for congenital hyperinsulinism (HI) and other conditions characterized by excessive insulin levels. As RZ358 acts downstream from the beta cells, it has the potential to be universally effective at treating congenital HI, regardless of the causative genetic defect. RZ358 received Orphan Drug designation in the United States and European Union as well as Pediatric Rare Disease Designation in the United States.

The RIZE study enrolled a diverse group of congenital HI patients with an average age of 6.5 years, including 16 patients between the ages of 2 and 6 years old, and with substantial continued hypoglycemia despite being on currently available therapies. During a robust screening and baseline run-in period on stable standard of care, the average RIZE study patient was hypoglycemic for 23 percent of their overall monitored time on a CGM, corroborated by having an average of 16 hypoglycemia events per week by point-of-care blood glucometer. There was also a significant amount of severe hypoglycemia at baseline (defined by glucose values below 50 mg/dL). RZ358 was administered via a thirty-minute intravenous infusion every other week for an 8-week treatment period in four sequential cohorts ranging from 3 to 9 mg/kg.

RZ358 led to a better than 50 percent reduction from baseline in overall (<70 mg/dL) and severe (<50 mg/dL) hypoglycemia events (by BGM) and time in hypoglycemia (by CGM) in the pooled group of patients across all doses. A larger magnitude of improvement of about 75 percent was seen at the anticipated therapeutic doses of 6 mg/kg and 9 mg/kg.

The blood concentrations of RZ358 were highly predictable and dose-proportional, with no apparent impact from factors relevant to this patient population, such as age distribution, food aversions, or gastrointestinal absorption and tolerability. A clear dose and exposure response was observed with RZ358.

A safety review committee comprised of three expert investigators in congenital HI met over the course of the study to review and confirm safety prior to dose escalation. RZ358 was generally safe and well-tolerated across the studied dose and age range. There were no adverse drug reactions, study discontinuations, or occurrences of clinically significant hyperglycemia. The observed blood levels of RZ358 were well below levels that were safely tested in long term toxicology studies in non-human primates.

There was a high patient response rate to RZ358, as shown by the percentage of patients who achieved improvements in hypoglycemia across different clinically relevant thresholds. Notably, at the top dose, all patients achieved at least a 50 percent improvement, and all but one patient achieved at least a 75 percent improvement, indicating that the substantial reductions in hypoglycemia observed on average were nearly universally experienced by the wide variety of congenital HI patients across the study.

“These data show a very pronounced effect of RZ358 in improving hypoglycemia, across a broad range of patient characteristics, thereby demonstrating the potential for RZ358 to be a safe and effective therapy for all forms of congenital HI,” said Brian Roberts, an endocrinologist and senior vice president of Clinical Development for Rezolute. “We are extremely pleased by the results, which we believe enable the continued advancement of RZ358 into a phase 3 registrational program.”

Author: Rare Daily Staff