No abstract

Activation of GPR40 (G-protein coupled receptor 40) in pancreatic β-cells may improve glycaemic control in type 2 diabetes (T2D) patients through enhancement of glucose-stimulated insulin secretion (GSIS). Here we present phase I an open label, dose-escalation study with single oral administration of GPR40 agonist - CPL207280 in healthy subjects in fasting conditions. The study was performed in conventional 3+3 design, where MTD (maximum tolerated dose) is to be determined. Caucasian male and female subjects (24 volunteers) were enrolled in 8 cohorts (n=3 per). Subjects received CPL207280 in doses ranging from 5 to 480 mg. Safety assessment included adverse events (AE) reporting, clinical laboratory tests, glucose, insulin, proinsulin, c-peptide and glucagon level monitoring, vital signs, physical examination, electrocardiography (ECG). Blood samples for pharmacokinetic (PK) analysis were collected up to 48 hours after administration. CPL207280 concentrations in human plasma were evaluated by HPLC/MS/MS. Pharmacokinetic parameters were calculated using a non-compartmental modelling approach. Administration of CPL207280 was safe and well tolerated with no serious AE. All adverse events were classified as not related to the study product. Despite administration up to 480 mg of CPL207280, no dose limiting toxicity (DLT) was observed, therefore no MTD was determined. The CPL207280 exposure increased in a dose-dependent manner. The CPL207280 mean maximum plasma concentration (Cmax) values ranged from 19 to 516 ng/mL for cohort 1 and 8, respectively, and were observed at 1-3 hours after administration. The area under the curve of plasma concentration vs. time (AUC0-24h) ranged from 516 to 4603 ng/mL*h, for cohort 1 and 8, respectively. CPL207280 administration in all doses was safe and well tolerated. No adverse events were related to the study product. Pharmacokinetics of CPL207280 supports once daily dosing regimen. The results justify further clinical development. Disclosure K. Bazydlo-guzenda: Employee; Self; Celon Pharma SA. A. Gierczak-pachulska: Employee; Self; Celon Pharma SA. K. Jarus-dziedzic: Other Relationship; Self; Celon Pharma SA. P. Rudzki: Employee; Self; Celon Pharma SA. M. Wieczorek: Other Relationship; Self; Celon Pharma SA. Funding National Centre for Research and Development (POIR.01.01.01-00-0334/17)

GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

G protein-coupled receptor 40 (GPR40) is a free fatty acid receptor mainly expressed in pancreatic βcells activated by medium-and long-chain fatty acids and regulating insulin secretion via an increase in cytosolic free calcium ([Ca 2+ ] i ). Activation of GPR40 in pancreatic β-cells may improve glycemic control in type 2 diabetes through enhancement of glucose-stimulated insulin secretion. However, the most clinically advanced GPR40 agonist -TAK-875 (fasiglifam)was withdrawn from phase III due to its hepatotoxicity resulting from the inhibition of pivotal bile acid transporters. Here, we present a new, potent CPL207280 agonist and compare it with fasiglifam in numerous in vitro and in vivo studies. CPL207280 showed greater potency than fasiglifam in a Ca 2+ influx assay with a hGPR40 protein (EC 50 =80 vs. 270 nM, respectively). At the 10 µM concentration, it showed 3.9 times greater enhancement of GSIS in mouse MIN6 pancreatic β cells. In Wistar Han rats and C57BL6 mice challenged with glucose, CPL207280 stimulated 2.5-times greater insulin secretion without causing hypoglycemia at 10 mg/kg compared with fasiglifam. In three diabetic rat models, CPL207280 improved glucose tolerance and increased insulin area under the curve by 212%, 142%, and 347%, respectively. Evaluation of potential off-target activity (Safety47™) and selectivity of CPL207280 (at 10 μM) did not show any significant off-target activity. We conclude that CPL207280 is a potent enhancer of glucose-stimulated insulin secretion in animal disease models with no risk of hypoglycemia at therapeutic doses. Therefore, we propose the CPL207280 compound as a compelling candidate for type 2 diabetes treatment.