2333-PUB: CPL207-280, a Potent and Safe GPR40 Agonist for the treatment of Type 2 Diabetes

Abstract

Targeting GPR40 receptor has been proposed as novel modality for patients with insufficient blood sugar control or in tolerating popular drugs. It belongs to G-protein coupled receptors family and is highly expressed in pancreatic β-cells where it mediates free fatty acid-induced insulin secretion. Although several synthetic GPR40 agonists have been generated none of them found use in the clinic predominantly due to safety issues. Therefore, the greatest interest in the field has been focused on safety and favorable pharmacokinetics. In previous study we showed a new, effective GPR40 agonist, which displayed promising safety profile in vitro. Here we show the safety, biological and pharmacological effects of CPL207-280 in rats and non-human primate (NHP) T2D models. Pharmacokinetic studies in rats and NHP showed very high bioavailability (F) (80% and 87% in rats and monkeys, respectively) of the compound CPL207-280 and favorable half-time (t1/2kel): 4,75 h in rats and 3,95 h in monkeys which can protect against compound accumulation (especially in the liver) during long term administration. CPL207-280 increased insulin secretion and showed dose-dependent improvement (at a dose range of 3-100 mg/kg) in GTT test in ZDSD rats and at a dose 15 mg/kg in diabetic NHP study. During toxicology study the maximum tolerated dose (MTD) for CPL207-280 was found at a dose of 1000 mg/kg and 500 mg/kg in rats and monkeys, respectively. In the 14-days (dose range finding) DRF study the (no observable adverse effect level) NOAEL was found at the level of 300 mg/kg and 100 mg/kg in rats and monkeys, respectively. Additionally, during a 28-days study in diabetic NHP at dose 15 mg/kg administrated p.o., no significant side effects were observed and all haematology and biochemical parameters including: total bile acids (TBA), total bilirubin (TB), ALT, AST, GGT were not changed compared to control group. This clearly demonstrates that CPL207-280 has a great potential to become a safe and effective candidate for treatment of T2D. Disclosure K. Bazydlo-Guzenda: Employee; Self; Celon Pharma S.A. P. Buda: Employee; Self; Celon Pharma S.A. I. Kozlowska: Employee; Self; Celon Pharma S.A. M. Mach: Employee; Self; Celon Pharma S.A. M. Teska-Kaminska: Employee; Self; Celon Pharma S.A. F. Stelmach: Employee; Self; Celon Pharma S.A. M. Wasinska-Kalwa: Employee; Self; Celon Pharma S.A. K. Galazka: Employee; Self; Celon Pharma S.A. K.K. Dubiel: Employee; Self; Celon Pharma S.A. J.S. Pieczykolan: Employee; Self; Celon Pharma S.A. M. Wieczorek: Other Relationship; Self; Celon Pharma S.A. Funding National Centre for Research and Development