An investigational glucagon-like peptide-1 (GLP-1) antagonist, exendin-(9-39), prevents fasting and protein-induced hypoglycemia among children with congenital hyperinsulinism, new data suggest.
Results from the open-label crossover phase 2 trial were recently published online in Diabetes Care by Darko Stefanovski, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, and colleagues.
A rare disorder, occurring in 1 in 20,000 to 1 in 50,000 US live births, congenital hyperinsulinism is caused by several different genetic mutations.
"Babies are diagnosed shortly after birth because they have severe hypoglycemia and require high glucose infusion rates to maintain normal glucose levels," senior author Diva D. De León, MD, told Medscape Medical News.
Without treatment these children will develop severe brain damage.
"These kids are exposed to hypoglycemia at a period when the brain is growing and developing at such a rapid rate, so about 50% have developmental delays. Even today with all we know, that's the frequency," said De León, chief of the Division of Endocrinology and Diabetes and director of the Congenital Hyperinsulinism Center at Children's Hospital of Philadelphia (CHOP).
"A Very High Unmet Need" for the Most Severe Hyperinsulinism Types
The most common and severe form of congenital hyperinsulinism is due to inactivating mutations of two genes that encode subunits of the beta-cell KATP channel, leading to dysregulated insulin secretion.
One drug, diazoxide, is a KATP channel agonist that suppresses insulin release in some types of hyperinsulinism but not in the majority of patients who have those two particular KATP channel mutations.
However, about half of those who don't respond to diazoxide have focal disease affecting a small part of the pancreas, and surgical removal of that area is typically curative.
The remainder of patients, with diffuse hyperinsulinism, "are the most severe and most difficult group to treat." Somatostatin analogs are sometimes used as second-line therapy but their effectiveness is limited and they have significant side effects, particularly in newborns, De León said.
"So very frequently what we end up having to do for these children is to remove 98% of their pancreas, a near-total pancreatectomy, because that's the only way of controlling the hypoglycemia sufficiently so these babies can be discharged home. Even then, about half continue to have hypoglycemia," she noted, adding that diabetes and pancreatic insufficiency then typically develop after about a decade.
"So, we're basically trading one disease that is very difficult to manage for another disease that is easier to manage but has long-term consequences. It's really a very high unmet need for more effective treatments," she noted.
Phase 3 Trials on Horizon
Exendin-(9-39) is a modified form of the GLP-1 receptor agonist exendin-4, better known as exenatide (Byetta), a widely used drug for lowering blood glucose in type 2 diabetes. Truncating the protein by removing the first nine amino acids turns it into an antagonist with the opposite effect, that is, it reduces insulin secretion and increases blood glucose, De León explained.
Exendin-(9-39) has been granted an orphan drug designation by the European Medicines Agency for the treatment of congenital hyperinsulinism and by the US Food and Drug Administration for the treatment of hyperinsulinemic hypoglycemia (which includes congenital hyperinsulinism). It has also been granted a rare pediatric disease designation by FDA.
The form of exendin 0-39 used in the current phase 2 trial was intravenously administered. The compound has now been acquired by Eiger BioPharmaceuticals with plans for a phase 3 trial that will use a subcutaneous exenatide-(9-39) formulation for at-home injection, similar to the way exenatide is now used for type 2 diabetes, De León said.
And patients may not have to take it for life. "We would predict based on the few cases that have been managed without pancreatectomy that we can typically withdraw therapy around puberty...Later in life they may just be able to follow a diet. Right now, because we're doing a near-total pancreatectomy we're guaranteeing that they're going to need treatment for life. The ultimate goal is to have a way of treating these children without pancreatectomy," De León said.
Exendin-(9-39) Prevented Hypoglycemia in Small Study
The current study involved 16 children (6 girls, 10 boys), aged 10 months through 15 years with persistent hypoglycemia due to congenital hyperinsulinism. There were four parts to the study: parts 1 and 2 investigated the effect on fasting glucose of three different dosing regimens of exendin-(9-39) delivered by infusion (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) compared with vehicle.
In parts 3 and 4, a subset of eight subjects (three girls, five boys) received either vehicle or 0.6 mg/kg exendin-(9-39) during a mixed-meal tolerance test and an oral protein tolerance test. The KATP channel mutation form of hyperinsulinism is characterized by both fasting- and protein-induced hypoglycemia, De León noted.
During fasting and with adjustment for order of administration, the area under the curve of fasting plasma glucose was significantly higher in treatment group 2 compared with vehicle (P = .037). As a result, fasting hypoglycemia was reduced by 76% in group 2 (P = .009) and by 84% in group 3 (P = .014).
Plasma insulin was significantly decreased in group 3 versus vehicle (P = .009) and C-peptide was significantly decreased for group 2 (P = .01) and group 3 (P < .001) compared with vehicle.
During the mixed-meal test, plasma glucose was significantly elevated with exendin-(9-39) compared with vehicle, by 28% (P ≤ .001). With the protein test, plasma glucose was also significantly greater with exendin-(9-39) compared with vehicle (P = .010).
Plasma insulin levels didn't change during the mixed-meal test (P = .827) but nearly doubled with exendin-(9-39) during the protein challenge test (P = .004). C-peptide didn't significantly change (P = .059).
"When the KATP channel is missing due to this mutation there's a switch in the fuel-sensing mechanism of the beta cells where they are not responsive to glucose. So they don't turn off when glucose is low and they don't increase insulin secretion in response to more glucose. But they have this response to amino acids, which is not normal. The beta cells secrete more insulin in response to amino acids," De León explained.
Exendin-(9-39) treatment significantly reduced the likelihood of hypoglycemia in response to the protein challenge (P = .007), an 82% reduction compared with vehicle (odds ratio, 0.177).
There were no serious adverse events during the study. One patient had emesis during the exendin-(9-39) infusion but didn't require intervention or study withdrawal.
This study was funded by the National Institutes of Health and the Clifford and Katherine Goldsmith Foundation. The project described was supported by the National Center for Research Resources. Stefanovski has reported no relevant financial relationships. De León holds patents in the United States and Europe for the use of exendin-(9-39) for treating hyperinsulinism and postprandial hypoglycemia. She has donated all financial proceeds from the patents to The Children's Hospital of Philadelphia. She has also served as a consultant for Zealand Pharma, Crinetics Pharmaceuticals, Hanmi Pharmaceutical, Heptares Therapeutics, Poxel Pharma, Ultragenyx, and Eiger BioPharmaceuticals. She has received research funding unrelated to this project from Tiburio Therapeutics, Crinetics Pharmaceuticals, and Twist Bioscience. She owns stock options in Merck.
Diabetes Care. Published online April 13, 2022. Full text
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.
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Cite this: Early Promise for New Agent in Congenital Hyperinsulinism in Kids - Medscape - Apr 21, 2022.