YH25724, a novel long-acting GLP-1/FGF21 dual agonist

YH25724, a novel long-acting GLP-1/FGF21 dual agonist provides potent and sustained glycaemic control, body weight loss and lipid profile improvement in animal models

H.N. Hong, J.H. Kim, H.H. Choi, D. Kim, S. Lim, M. Seo, M.K. Ju, J.Y. Park, B.H. Choi, J.G. Kim, S.Y. Nam;

Yuhan Corporation, Seoul, Republic of Korea.

Background and aims:

Targeting multiple metabolic pathways provides better therapeutic potential compared to molecules targeting a single pathway, because metabolic disorders are triggered by various complicated factors. Glucagon-like peptide-1 (GLP-1) receptor agonists have been developed and approved for the treatment of type 2 diabetes given their benefit from the glucose-dependent insulinotropic effects of GLP-1. Fibroblast growth factor 21 (FGF21) is a promising drug candidate for the treatment of metabolic diseases, which enhances insulin sensitivity. Thus, a complementary and synergistic therapeutic potential may be anticipated with a dual agonist capable of delivering both GLP-1 and FGF21 agonism. However, dual agonist should be rationally designed to provide balanced activity and to reduce the GLP-1 related side-effects. YH25724 is a novel long-acting dual agonist, which is an immunoglobulin Fc-fused protein comprising GLP-1 variant and FGF21 variant. Here we report the characterization of a novel long-acting GLP-1/FGF21 dual agonist, YH25724.

Materials and methods:

In vitro activation of GLP-1 receptor was measured by cAMP formation in CHO cells stably expressing the human GLP-1 receptor. In vitro activation of the FGF receptor and βKlotho complex was measured by ERK phosphorylation in HEK293 cells stably expressing human βKlotho. Pharmacokinetic characterization of YH25724 was performed in mice and monkeys. Pharmacodynamic effects of YH25724 were investigated in db/db mice and low-dose streptozotocintreated mice fed with high-fat diet (HFD/STZ) by measuring blood glucose levels and body weight change. The effects on body weight loss and lipid profiles by YH25724 were investigated in diet-induced obese (DIO) mice. Immunogenicity of YH25724 was assessed using ex vivo T cell activation assays.

Results:

YH25724 exhibited balanced in vitro activity for GLP-1 and FGF21. GLP-1 activity of YH25724 was deliberately attenuated in order to reduce side effects, while FGF21 activity was maintained to exert beneficial metabolic outcomes. Based on PK data in mice and monkeys, YH25724 has an optimal PK profile for once-weekly dosing in human. After single subcutaneous injection in db/db mice and HFD/STZ mice, YH25724 elicited rapid, potent, sustained and dose-dependent glucoselowering and profound weight loss compared to either single agonism (GLP-1 or FGF21 agonist) or dulaglutide. Following repeat dosing in DIO mice, YH25724 produced a synergistic effect with more potent and sustained body weight loss compared to dulaglutide or single agonism. In the adipose tissue of DIO mice, YH25724 induced UCP-1 and PGC1α expression, indicating that these effects may be due to increased energy expenditure. YH25724 treatment also improved serum lipid profiles with reduction of hepatic triglyceride contents.  Furthermore, ex vivo T cell activation assay results indicate that YH25724 has a low potential risk for clinical immunogenicity.

Conclusion:

Given these findings, YH25724, a novel long-acting, well-balanced GLP-1/FGF21 dual agonist, has a complementary and synergistic mechanism of insulin secretion and insulin sensitivity, which is well translated into a potent and sustained glycemic control with the additional benefits of body weight loss and lipid profile improvement, indicating that YH25724 may be the ideal therapeutic for the treatment of type 2 diabetes

YH25724, a novel long-acting GLP-1/FGF21 dual agonist lowers both non-alcoholic fatty liver disease activity score and fibrosis stage in a diet-induced obese mouse model of biopsy-confirmed non-alcoholic steatohepatitis

Background and aims

It has been proposed that an ideal drug candidate for nonalcoholic steatohepatitis (NASH) should reduce hepatic inflammation and liver cell injury, correct the underlying insulin resistance and have anti-fibrotic effects. Glucagon-like peptide-1 (GLP-1) is known to suppress lipogenesis and reduce fat accumulation and pro-inflammatory responses in liver. Fibroblast growth factor 21 (FGF21) is a metabolic regulator, which can improve insulin sensitivity and lipid metabolism in addition to having anti-fibrotic effect. Thus, addressing both GLP-1 and FGF21 may be an effective therapeutic strategy for NASH due to their complementary mechanisms of action. YH25724 is a novel long-acting dual agonist, which is an immunoglobulin Fc-fused protein comprising an GLP-1 variant and an FGF21 variant. We evaluated the therapeutic potential of the YH25724 in a diet-induced obese mouse model of biopsy-confirmed NASH.

Methods

YH25724 was administered by subcutaneous injection every other day for 8 weeks (3 or 10 nmol/kg) in a diet induced NASH model (fed the AMLN diet (Research Diets, USA) with 40% energy from fat, 20% fructose and 2% cholesterol for 33 weeks, n = 12/group). Body weight, plasma liver enzymes, triglyceride (TG) and total cholesterol (TC) in plasma and liver were measured, and treatment effects on NAFLD activity score (NAS) and fibrosis staging were performed comparing liver pre-biopsies and terminal liver samples from all animals. Finally, hepatic gene expression was analyzed by RNA sequencing to elucidate the molecular mechanisms affected by treatment.

Results

YH25724 reduced body weight (16% at 3 nmol/kg, 26% at 10 nmol/kg), relative liver weight (47% at 3 nmol/kg, 58% at 10 nmol/kg), and liver enzymes (up to 88% in ALT, 63% in AST). YH25724 also decreased plasma TG and TC levels (approximately 30%) and hepatic TG and TC content (up to 77% and 93%, respectively). YH25724 significantly reduced total NAS score (from 6.2 to 1.4 at 3 nmol/kg, from 5.9 to 0.8 at 10 nmol/kg). The reduction in NAS was brought about by reductions in steatosis, inflammation and ballooning. Also, YH25724 10 nmol/kg significantly reduced liver fibrosis stage when compared to baseline. Consistent with these improvements, YH25724 changed the expression of specific genes known to be related with NASH.

Conclusions

YH25724 showed anti-steatotic, anti-inflammatory and anti-fibrotic effect in a diet-induced obese mouse model of biopsy-confirmed NASH, indicating a role for GLP-1/FGF21 dual agonism for the treatment of NASH.