MON-464 Non-Clinical Profiling of ONO-5788, a Novel Oral Small Molecule Somatostatin Receptor Type-2 (SST2) Agonist, to Support Studies in Humans

Abstract

Somatostatin analogues (SSAs) are indicated for use in acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP NETs). However, SSAs are administered as injections which can be a challenge for patients and healthcare providers. ONO-5788 is a novel low molecular weight orally administered molecule with potent and selective agonistic effects at the human SST2 subtype. ONO-5788 could offer the advantages of a more convenient route of administration for patients with acromegaly and other indications and also a preferential safety profile compared to injections. In order to support clinical evaluation of ONO-5788, a series of non-clinical experiments were undertaken. Findings: In vitro, ONO-5788 and its active metabolite, ONO-ST1-641, has a greater agonistic effect on human SST2 compared to other somatostatin receptor subtypes, with EC50 values of 0.11 and 0.016 nmol/L, respectively. There is no difference in mean EC50 values between human SST2 and rat SST2. ONO-5788 and ONO-ST1-641 significantly inhibits growth hormone-releasing hormone (GHRH)-induced GH secretion from primary cultured rat pituitary cells. In vivo studies in rats confirmed that a single oral dose of ONO-5788 resulted in systemic exposure of ONO-5788 and ONO-ST1-641 that increased in a dose dependent manner. Orally administrated ONO-5788 significantly inhibited both GHRH-induced GH secretion and basal GH secretion at all the doses tested (≥0.1 and ≥0.03 mg/kg, respectively). ONO-5788 and ONO-ST1-641 administrated intravenously significantly inhibited GHRH-induced GH secretion with effect on maximum inhibition of GH secretion similar to octreotide (ONO-5788 98.0%, ONO-ST1-641 98.6%, octreotide 98.7%, respectively). Plasma concentrations of ONO-5788 and ONO-ST1-641 required to supress serum GH level to a clinically meaningful degree in acromegaly patients were estimated to be 21.3 and 1.29 ng/mL. In experiments evaluating the effects on insulin and glucagon secretion in anaesthetised rats, ONO-5788, ONO-ST1-641, octreotide and pasireotide significantly inhibited glucagon secretion, but ONO-5788 and ONO-ST1-641 had no significant impact on insulin secretion at doses up to 10-fold higher than the dose required for either of these compounds to almost maximally inhibit GH secretion. In contrast, pasireotide and octreotide showed a significant inhibition of insulin secretion at equivalent doses of both ONO-5788 and ONO-ST1-641. A standard battery of preclinical safety and toxicology studies provided adequate evidence of safety to support commencement of a Phase I study in healthy volunteers to measure the safety, pharmacokinetics, and pharmacodynamics of ONO-5788. Conclusion: Orally administered ONO-5788 demonstrates potency as a SST2 agonist and has the potential to be a new treatment option for patients with acromegaly and NET.