MON-477 Octreotide and ONO-ST-468, a Novel and Potent Somatostatin Receptor Type-2 (SST2) Agonist, Suppress GH Hypersecretion in the Monkey

Abstract

Purpose: The verification of efficacy of new drug candidates in primate models may address the translational gap between non-clinical and clinical studies and support the prediction of efficacy in humans. Given this, and to support the evaluation of novel SST2 agonists, a GHRH/arginine-induced GH hypersecretion model was established in the monkey. This model was used to evaluate the effect of both octreotide and ONO-ST-468, a novel and potent selective SST2 agonist. Methods: Male cynomolgus monkeys (3-6 years old) were anesthetized with ketamine and maintained with constant infusion of propofol. Octreotide (0.23, 0.47 or 0.70 μg/0.88mL/kg/h), ONO-ST-468 (0.35 or 1.05 μg/1.1mL/kg/h) and saline were continuously administrated by intravenous (i.v.) infusion 2 hours before and after GH hypersecretion (n=7-9 in each group). GH hypersecretion was induced by i.v. bolus administration of GHRH (“time zero”), followed immediately by a 30 minutes i.v. infusion of arginine. Blood samples were collected for 2 hours after GHRH/arginine treatment and the plasma GH level was measured by ELISA. Inhibitory rates of GH hypersecretion were calculated by the area under the curve (AUC0-2h). Results: As a result of examinations for several experimental conditions, excessive GH secretion was induced by i.v. bolus administration of GHRH (30 μg/0.5mL/kg) and the i.v. infusion of arginine (5 g/17.9mL/kg/h). GH AUC0-2h was approximately 72 ng·h/mL in the vehicle group. Octreotide inhibited GHRH/arginine-induced GH hypersecretion in a dose dependent manner. The inhibitory rates (AUC0-2h) by octreotide were 18% (low dose), 59% (medium dose) and 83% (high dose), respectively. The plasma concentration of octreotide in high dose group was 1.76 ng/mL at 2 hours after GHRH/arginine treatment, being similar to effective plasma concentration of octreotide in acromegaly patient (approximately 1 ng/mL). ONO-ST-468 also inhibited GHRH/arginine-induced GH hypersecretion in a dose dependent manner. The inhibitory rates (AUC0-2h) by ONO-ST-468 were 70% (low dose) and 94% (high dose), respectively, demonstrating that the maximum inhibitory effect of ONO-ST-468 was similar to that of octreotide and has the potential to suppress GH hypersecretion in acromegaly patients. Conclusion: Octreotide and ONO-ST-468, a novel small molecule SST2 agonist, suppressed excessive GH secretion in a newly established GHRH/arginine-induced GH hypersecretion model in the monkey.