India Pharma Outlook Team | Wednesday, 04 May 2022
Rezolute, Inc., a clinical-stage biopharmaceutical company, announced positive results from its phase 2b RIZE study of RZ358 in patients with congenital hyperinsulinism (HI), which were unveiled in a late-breaking oral presentation at the Paediatric Endocrine Society 2022 Annual Meeting. The study exceeded expectations for correction of hypoglycaemia, including a highly significant reduction of ~75% in hypoglycaemia events by blood glucometer (BGM) as well as time in hypoglycaemia by continuous glucose monitoring (CGM).
“Patients with congenital hyperinsulinism often have continued hypoglycaemia in spite of available therapies, as has been clearly demonstrated in the RIZE study,” said Dr. Paul Thornton, a Paediatric Endocrinologist at Cook Children’s Hospital. Dr Thornton continued, “The magnitude of improvement in hypoglycaemia in this study demonstrates the potential for RZ358 to become a much-needed therapy for treating congenital hyperinsulinism.” 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 hypoglycaemia 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% of their overall monitored time on a CGM, corroborated by having an average of 16 hypoglycaemia events per week by point-of-care blood glucometer.
There was also a significant amount of severe hypoglycaemia 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% reduction from baseline in overall (<70 mg/dL) and severe (<50 mg/dL) hypoglycaemia events (by BGM) and time in hypoglycaemia (by CGM) in the pooled group of patients across all doses.A larger magnitude of improvement of ~75% 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 hyperglycaemia. 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 hypoglycaemia across different clinically relevant thresholds. Notably, at the top dose, all patients achieved at least a 50% improvement, and all but one patient achieved at least a 75% improvement, indicating that the substantial reductions in hypoglycaemia 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 hypoglycaemia, 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 Dr. Brian Roberts, an Endocrinologist and senior vice president of
clinical development for Rezolute. Dr. Roberts continued, “We are extremely pleased by the results, which we believe enable the continued advancement of RZ358 into a phase 3 registrational programme. We’re also extremely thankful for the contributions of the RIZE Investigators and their study staff, patient advocacy organizations, and particularly the participating patients and families, and we are looking forward to further advancing our combined efforts to find better therapies for congenital hyperinsulinism.” Julie Raskin, founding member and executive director of Congenital Hyperinsulinism International, added, “I am happy to learn of the encouraging topline data from the RZ358 Phase 2b study.
The current treatment options for many children and adults with congenital HI are very limited and suboptimal, and many with the condition don’t have any treatment option approved for their condition. Babies born with HI typically face long hospital stays and once home, their parents face a dauntingly complicated care regime. The constant activities of feeding and monitoring blood sugar crowd out the typical experiences babies and their families should have, and this pattern can go on for years.
The threat of hypoglycemia and the ensuing damage that can occur from it often rules the lives of families who have a child with HI. Novel treatments that keep hypoglycemia at bay are urgently needed. RZ358 gives the HI community hope for a better future.” RIZE is a phase 2b, multicenter, open label, repeat-dose study, designed to assess the safety and tolerability, pharmacokinetics, and glycemic efficacy of RZ358 administered bi-monthly for 8 weeks in patients with congenital hyperinsulinism whose hypoglycaemia was not adequately controlled on standard of care therapies. A total of 23 patients participated in the study in four sequential dosing cohorts ranging from 3 mg/kg to 9 mg/kg.
The effects of RZ358 on hypoglycaemia were assessed by continuous glucose monitor (hypoglycemia time) and glucometer self-monitored blood glucose (hypoglycemia events). 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, signalling, 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 Paediatric Rare Disease Designation in the US. Congenital HI is the most common cause of recurrent and persistent hypoglycaemia in children.
It typically presents early in life, with about 60% of infants with congenital HI experiencing hypoglycaemia within the first month of life. These episodes can result in significant brain injury and death if not recognized and managed appropriately. Additionally, recurrent, or cumulative, hypoglycaemia 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 most commonly used long-term medications, diazoxide and somatostatin analogs, are not Food and Drug Administration (FDA) 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 hypoglycaemia and require medical treatment for congenital HI. Rezolute strives to disrupt current treatment paradigms by developing transformative therapies for devastating rare and chronic metabolic diseases.
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