SAT-430 A Phase 1 Study in Healthy Volunteers to Assess the Safety, Tolerability, and Pharmacokinetics of ONO-5788: A Novel Oral Small Molecule Somatostatin Receptor Type-2 Agonist

ONO-5788 is a novel low molecular weight orally administered molecule with potent and selective agonistic effects at the human SST2 receptor 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. Methods: This First in Human study includes a double-blind, randomized, placebo-controlled, single ascending dose (SAD) part (including an assessment of food effect) in healthy adult male and female volunteers, 18-55 years of age. 34 males and 14 females were enrolled. Subjects were randomised to ONO-5788 or placebo (6:2 ratio) in each cohort with escalating doses of ONO-5788 (0.4, 1.6, 5, 20, 50 or 120mg) assessed. The first 2 dose levels were dosed as an oral liquid solution, the 4 remaining dose levels were dosed as oral API in capsule. Findings: Preliminary blinded data suggested no significant safety issues during administration of single doses of ONO-5788. A low incidence of mild to moderate gastrointestinal adverse events was observed at the higher doses (loose stools n=4; abdominal cramping n=3; abdominal discomfort, abdominal tenderness, discolouration of stools, pale stools, dyspepsia, nausea, all n=2). There were no safety findings for safety labs, ECGs or vital signs and no SAEs were reported. A transient increase in serum glucose was noted at 6 hours post-dose (3 hours post-meal) which followed a dose-response pattern when comparing mean glucose values across all 6 cohorts; all subjects were asymptomatic and no intervention was required. Pharmacokinetics of ONO-5788 and its active metabolite (ONO-ST1-641) were well characterized at the doses tested. Parent drug concentrations were notably higher than the active metabolite (approximately 40-fold greater). A 300-fold dose range was explored (0.4mg to 120mg) but, using arithmetic mean Cmax, AUClast and AUCinf values, ONO-5788 exposure was approximately 59-90 times higher at the highest dose compared to the lowest and ONO-ST1-641 exposure was 139-193 times higher at the highest dose. There were less than dose-proportional increases in exposure observed with both ONO-5788 and ONO-ST1-641 at doses above 20mg. Lower exposure was observed with food at the 20mg dose. The mean half-life of ONO-5788 ranged between 6.4-22 hours and for ONO-ST1-641 between 62-110 hours. Conclusion: ONO-5788 was found to be well tolerated in this SAD study at all doses tested. The pharmacokinetic profiles of ONO-5788 and its active metabolite were well characterised with a half-life suggesting the potential for once-daily dosing. Safety, tolerability, pharmacokinetics and pharmacodynamics will continue to be assessed in healthy volunteers with multiple dosing, dosing of a cohort of elderly subjects and a proof-of-principle study to further characterize ONO-5788 prior to studies in patients.