ESPE2021 ePoster Category 2 Diabetes and insulin (72 abstracts)
Oral administration of CRN04777, a nonpeptide selective SST5 receptor agonist, suppresses insulin secretion and rescues hypoglycemia in neonatal rat models of congenital hyperinsulinism
Melissa Fowler , Jian Zhao , Emmanuel Sturchler , Jon Athanacio , Taylor Kredel , Agnes Antwan , Claudia Yan , Christine Staley , Jenny Chen , Ana Karin Kusnetzow , R. Scott Struthers , Yun Fei Zhu , Stephen Betz & Stacy Markison
Crinetics Pharmaceuticals, San Diego, USA
CRN04777 is an orally administered nonpeptide that is a potent and selective agonist of somatostatin 5 (SST5) receptors and is currently under development for the treatment of congenital hyperinsulinism (HI), the most common cause of persistent hypoglycemia in newborns and infants. Congenital HI arises from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet beta cells. This excess insulin can result in profound hypoglycemia which can lead to neurological impairment, coma, and even death if not treated promptly. The neuropeptide somatostatin is an important modulator of hormonal signaling in the pancreas, and SST5 activation has been shown to suppress insulin and raise blood glucose, thus providing a potential treatment mechanism for patients with congenital HI. We characterized the ability of CRN04777 to raise blood glucose and lower plasma insulin in preclinical models using neonatal (PND7-11) rats. Oral administration of CRN04777 in neonatal rats suppressed insulin secretion and dose-dependently increased blood glucose levels for up to 6 hours after a single dose. Furthermore, the CRN04777 mediated increase in blood glucose was sustained over 5 days of repeated oral administration. The most common mutations underlying congenital HI are found in the genes encoding the ATP-sensitive potassium (KATP) channel, which controls the membrane potential of pancreatic beta cell, and children with KATP-dependent HI are typically unresponsive to diazoxide, the only FDA-approved drug for HI. Sulfonylurea drugs, such as glyburide, close KATP channels and can be used to induce a hyperinsulinemic hypoglycemic state in rats that mimics some of the characteristics of KATP-HI. As expected, a single administration of glyburide in neonatal rats induced a pronounced increase in plasma insulin levels, with a concomitant decrease in blood glucose that persisted for several hours. Oral administration of CRN04777 rescued the glyburide-induced hyperinsulinemic hypoglycemia, lowering insulin levels and restoring blood glucose levels to >60 mg/dl. These findings provide evidence that CRN04777 is an efficacious nonpeptide SST5 agonist that suppresses insulin and increases blood glucose in neonatal rats. In addition, oral administration of CRN04777 rescued hypoglycemia in a neonatal rat model of congenital HI, demonstrating its potential as an oral therapeutic for children with congenital HI.
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