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.

Current and Emerging Medical Therapies in Pituitary Tumors

“…A phase II study showed, in 20 untreated acromegalic patients, that somatoprim (dose from 100 to 1800 µg) led to a similar inhibition of GH secretion as compared to octreotide (300 µg) [178]. Finally, ONO-5788 and ONO-ST-468 represent two new orally available SST2 agonists that have shown promising in vitro and in vivo results [65,179,180]. Antisense oligonucleotides that target GHR mRNA (ATL1103 and ISIS 766720, respectively) are currently under phase I/II trials [173].…”

Clinical Management of Acromegaly: Therapeutic Frontiers and New Perspectives for Somatostatin Receptor Ligands (SRLs)

“…The former demonstrated in studies in vivo on rats to significantly reduce basal and GHRH-stimulated GH [51]; phase 1 trials assessing pharmacokinetics of ONO-5788 on healthy volunteers have ended (ClinicalTrials.gov Identifier: NCT03849872 and NCT03571594), although data are still not available. ONO-ST-468 demonstrated to successfully suppress excessive GH secretion in a GHRH/arginine-induced GH hypersecretion model in the monkey [52], but no studies on humans are registered to date [53].…”

The Future of Somatostatin Receptor Ligands in Acromegaly

“…Another SST2 selective agonist, ONO-ST-468, was evaluated in comparison with octreotide in 1 study with male cynomolgus monkeys, showing similar GH suppression ( 101 ). No trials in human subjects exist to date.…”