761-P: Safety and Pharmacokinetic Study of GPR40 Agonist (CPL207280) after a Single Dose in Healthy Subjects

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)

First‐in‐human study of CPL207280, a novel G‐protein‐coupled receptor 40/free fatty acid receptor 1 agonist, in healthy volunteers after single and multiple administration

“…The median T max ranged from 1 to 3 h after administration 16 and did not seem to be dose‐dependent (Table S3). A single outlier for the dose 240 mg was observed with a T max of 16 h. C max and AUC 0–24h increased in each consecutive cohort.…”

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

“…Combination of TGR5 agonist, DPP4 inhibitor, and SSTR5 antagonist showed a robust suppression in both oGTT and ipGTT in GIP-deficient mice. These effects were mediated by GLP-1 as blocking GLP-1 receptor abolished the efficacies (Briere et al, 2018). In line with this finding, Jespen et al showed glucose-stimulated GLP-1 secretion was enhanced in mice deficient in SSTR5 or treated with SSTR5 antagonist (Jepsen et al, 2021), and SSTR5 antagonist and DPP4 inhibitor synergistically increased GLP-1 and improved oral glucose tolerance in mice (Liu et al, 2018;Jepsen et al, 2021).…”

“…Phase I trial of CPL207280 was safe and well tolerated with no serious AEs in healthy participants. No dose limiting toxicity was observed at up to 480 mg (Bazydlo-Guzenda et al, 2021c). CPL207280 is now under development in phase II trial for T2D (ClinicalTrials identifier NCT05248776, 2022).…”

“…Many targets have been reported to affect incretin secretagogue in the gut (reviewed in Gimeno et al, 2020). Briere et al compared induction of different mechanisms on circulating levels of active GLP-1 in mice, ranging from 5 to 30 pM, and the magnitude of induction was ranked from high to low as GPR40 agonist, TGR5 agonist, DPP4 inhibitor, somatostatin receptor 5 (SSTR5) antagonist (Briere et al, 2018). When combined together, these mechanisms formed a multiplicative synergy to increase active GLP-1 to unprecedented 300-400 pM, comparable to the concentrations of subcutaneously administered exenatide at 3 nmol/kg, and reached maximal efficacy in intraperitoneal glucose tolerance test (ipGTT) in wild type mice.…”

“…The C max of oral Semaglutide at 20 mg (once daily) and subcutaneous Semaglutide at 1 mg (once weekly) is over 30 nM in humans (Kapitza et al, 2015;Granhall et al, 2019). In comparison, the highest GLP-1 levels induced by combination treatment were 300-400 pM (Briere et al, 2018). Fourth, there is no concern of drug-drug interaction (DDI) in the liver when the gut-restricted GPR40 agonist is combined with other mechanisms.…”