124-LB: Development of IDG-16177, a Selective and Safe GPR40 Agonist for the Treatment of Type 2 Diabetes

Abstract

GPR40 has been considered a potential therapeutic target for type 2 diabetes because activation of GPR40 stimulates insulin secretion when glucose levels increased. Fasiglifam, a GPR40 agonist, was withdrawn from clinical development in Phase III due to DILI. Therefore, we evaluated the safety profiles of IDG-16177, a novel GPR40 agonist. The potential for IDG-16177 to have off-target effects was assessed in a panel of 173 binding assays. 10 μM IDG-16177 demonstrated activity (>50% inhibition) against DP, EP2, EP3 and EP4 with 81, 83, 57 and 67 % inhibition, respectively. In a functional assay against the same targets, IDG-16177 was inactive in agonist and antagonist mode except for DP with 62.2% activity inhibition at a concentration of 10 μM. IDG-16177 and fasiglifam showed the similar level of hepatotoxic response in HμRELToxTM assay. Formation of reactive metabolite and covalent binding to proteins was evaluated in human hepatocytes. IDG-16177 shows lower covalent binding burden at expected human efficacious dose (0.3~1 mg) than fasiglifam. Transporter inhibitory potential of IDG-16177 was assessed in hepatic transporter-expressing membrane vesicles. IDG-16177 and fasiglifam showed the similar inhibition level of BSEP, MRP2, MRP3, and MRP4. But clinically predicted plasma concentration of IDG-16177 is lower than that of fasiglifam, so the safety margin of IDG-16177 is wider than that of fasiglifam. A core battery of safety pharmacology was evaluated and IDG-16177 did not induce adverse effect in all studies. A 4-week toxicity study was conducted in rats and monkeys, and the liver was determined as the target organ in monkeys. The NOAEL was over 60-fold than in vivo efficacy dose. IDG-16177 was not genotoxic in Ames test, in vitro and in vivo micronucleus test. And no phototoxicity was observed in in vitro 3T3 NRU study. These results shows that the potential for IDG-16177, a safe and effective GPR40 agonist, to treat patients with type 2 diabetes. Disclosure J. Yoon: None. J. Kim: None. K. An: None. C. Hong: None. H. Kwak: None. I. Je: None. H. Song: None. H. Song: None. J. Kim: None. S. Lee: None. C. Shin: None. Y. Jun: None. D. Hong: None. D. Lee: None. E. Jang: None.