Oral SSTR5 Antagonist SCO-240 for Growth Hormone Stimulation: A Phase I Single-Dose Study in Healthy Individuals.

Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1-5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO-240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single-center, double-blind, placebo-controlled, phase I study included healthy Japanese and White individuals. The effects of ascending single oral doses of SCO-240 were evaluated in healthy individuals. The main outcome measures were safety, tolerability, pharmacokinetics, and pharmacodynamics (gallbladder contractions and levels of serum insulin and plasma glucagon-like peptide-1 (GLP-1)). The levels of pituitary hormones were evaluated in our exploratory analysis. The results indicated that SCO-240 was safe and well-tolerated at all tested doses. Oral SCO-240 was readily absorbed, with its systemic exposure increasing in a dose-dependent manner. The median time to maximum concentration and mean terminal half-life of SCO-240 were 3-4 and 10.2-12.6 hours, respectively, in the ascending dose section. No clinically meaningful changes in SCO-240 pharmacokinetic profiles were observed between fed and fasted or between Japanese and White individuals. No increase in gallbladder contractions or levels of insulin and GLP-1 were detected. SCO-240 induced robust growth hormone (GH) secretion without altering the levels of other pituitary hormones. In conclusion, the study is the first to demonstrate that SSTR5 antagonism stimulates GH secretion in humans. SCO-240 was safe and well-tolerated and exhibited once-daily oral dosing potential. The robust effects of SCO-240 on GH secretion suggest that it may be a treatment option for GH-related disorders.

An Exploratory Randomized Trial of SCO-792, an Enteropeptidase Inhibitor, in Patients With Type 2 Diabetes and Albuminuria.

Introduction: Elevated plasma amino acid levels overload kidney function by increasing glomerular filtration rate (GFR). Inhibiting gut amino acid intake may have therapeutic benefits for patients with kidney dysfunction. For a prospective phase 2a trial, we carried out an exploratory evaluation of the safety and efficacy of SCO-792, an enteropeptidase inhibitor that blocks gut amino acid intake, in patients with type 2 diabetes mellitus (T2DM) and albuminuria. Methods: Seventy-two patients with T2DM, a urine albumin-to-creatinine ratio (UACR) of 200-5000 mg/g, and an estimated GFR >30 ml/min per 1.73 m2 were included. Patients were randomly assigned (1:2:2) to the following groups and received treatment for 12 weeks: placebo (n = 15), SCO-792 500 mg once daily (SCO-792 QD; n = 29), or SCO-792 500 mg 3 times daily (SCO-792 3 times a day (TID); n = 28) by following a double-blind approach. We evaluated UACR changes from the baseline along with safety as the primary end points and other parameters as secondary or exploratory end points. Results: SCO-792 was safe and well tolerated up to 1500 mg/day for 12 weeks. UACR changes from baseline were -14% (P = 0.4407), -27% (P = 0.0271), and -28% (P = 0.0211) in placebo, SCO-792 QD, and SCO-792 TID, respectively, whereas UACR changes in SCO-792 groups were not statistically significant compared with placebo. The hemoglobin A1c (HbA1c) levels from baseline, an exploratory end point, decreased in the SCO-792 TID group. Conclusion: SCO-792 was safe and well tolerated for 12 weeks and may be associated with decreased UACR in patients with T2DM and albuminuria. Further clinical studies are essential to confirm our findings.

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans.

SCO-267 is a full agonist of the free fatty acid receptor 1 (GPR40), which regulates the secretion of islet and gut hormones. In this phase 1 study, we aimed to evaluate the clinical profile of single and multiple once-daily oral administration of SCO-267 in healthy adults and patients with diabetes. Plasma SCO-267 concentration was seen to increase in a dose-dependent manner after administration, and its plasma exposure was maintained for 24 h. Repeated dose did not alter the pharmacokinetic profile of SCO-267 in healthy adults. SCO-267 was generally safe and well tolerated at all evaluated single and multiple doses. Single and repeated doses of SCO-267 stimulated the secretion of insulin, glucagon, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and peptide YY in healthy adults. Furthermore, a single dose of SCO-267 stimulated the secretion of these hormones, decreased fasting hyperglycemia, and improved glycemic control during an oral glucose tolerance test in patients with diabetes, without inducing hypoglycemia. This study is the first to demonstrate the clinical effects of a GPR40 full agonist. SCO-267 is safe and well tolerated and exhibits once-daily oral dosing potential. Its robust therapeutic effects on hormonal secretion and glycemic control make SCO-267 an attractive drug candidate for the treatment of diabetes.