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Lipolytic, Energy Expenditure, and Insulinotropic Effects of HM12525A: A Novel Long-Acting GLP-1/Glucagon Dual Agonist SY Jung 1,, YJ Park 1, JK Kim 1,

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Presentation on theme: "Lipolytic, Energy Expenditure, and Insulinotropic Effects of HM12525A: A Novel Long-Acting GLP-1/Glucagon Dual Agonist SY Jung 1,, YJ Park 1, JK Kim 1,"— Presentation transcript:

1 Lipolytic, Energy Expenditure, and Insulinotropic Effects of HM12525A: A Novel Long-Acting GLP-1/Glucagon Dual Agonist SY Jung 1,, YJ Park 1, JK Kim 1, JS Lee 1, YM Lee 1, YH Kim 1, JH Kang 1, M Trautmann 2, M Hompesch 2, SC Kwon 1 1 Hanmi Pharm. Co., Ltd., Seoul, South Korea, 2 Profil Institute, Chula Vista, CA, USA Test materials Relative activity (cAMP assay) GLP : Glucagon % of GLP-1% of Glucagon GLP Glucagon HM12525A30371 : 1 BACKGROUND Potential beneficial effects of GLP-1/Glucagon dual agonist  Energy expenditure  & Lipolysis   Insulin secretion  & Food intake  GLP-1/Glucagon dual agonist Liver TG ↓ Ketogenesis ↑ FGF21 ↑ Brain Food intake ↓ Fat Cells Lipolysis ↑ Lipogenesis ↓ Energy Expenditure ↑ Pancreas Insulin secretion ↑ Stomach Gastric emptying ↓ HM12525A is a long acting GLP-1/Glucagon dual agonist with balanced dual agonism at GLP-1 and Glucagon receptors METHODS P866 a) Energy expenditure b) Locomotor activity  HM12525A increased energy expenditure without locomotor activity change. Figure 4. Energy expenditure in DIO mice (n=10, 4 weeks) Figure 3. Body weight loss in DIO mice (n=6, 2 weeks) Improved BWL by Increase of Energy Expenditure -1% -10% -17% -31% a) Body weight lossb) Cumulative food intake  HM12525A showed more potent weight loss even with less food intake inhibition compared with liraglutide. -51% -36% RESULTS Figure 1. HbA1c and body weight reduction in db/db mice (n=7, 4 weeks) a) HbA1c b) Body weight gain  HM12525A decreased HbA1c as well as body weight gain in db/db mice. ** p<0.01, *** p<0.001 vs vehicle Improved Glycemic Control by GLP-1R Activation AIMS 1.To assess glycemic control of HM12525A 2.To assess body weight and fat mass changes by HM12525A 3.To assess liver function improvement by HM12525A  Db/db mice (n=7) were treated (s.c) with HM12525A once a week, or liraglutide once daily, for 4 weeks respectively. Blood glucose levels were measured using a glucometer.  For ipGTT, overnight fasted C57BL/6J mice were administrated with either HM12525A or liraglutide (i.v.), and the 2 g/kg of glucose was subsequently administrated (i.p.). Blood glucose and the serum insulin level was determined at 0, 30, 60, 120 min using commercially available kit.  26 weeks HFD induced C57BL/6J mice (n=6) were treated (s.c) with HM12525A once a week, or with liraglutide once daily for 2 weeks respectively. The body weight and food intake was monitored daily.  Energy Expenditure as well as home-cage activity were assessed by using a combined indirect calorimetry system for 1 week after the first administration in DIO mice. O2 consumption and CO2 production were measured every 10 min for a total of 7 days to determine the respiratory quotient and energy expenditure. Home-cage locomotor activity was determined using a multidimensional infrared light beam system..  To differentiate into adipocytes, confluent 3T3-L1 cells (day 1) were incubated with 0.5 mM IBMX, 0.5 μM dexamathasone, and 1 μg/ml insulin added to DMEM/10% FBS for 2 days. On day 3, the medium was changed to DMEM/FBS 10% with 1 μg/ml insulin, which was repeated every 2 days. The cells were fully differentiated into adipocytes after 10 to 14 days incubation of differentiation medium. HM12525A was co-incubated in the presence or absence of GCGR antagonist from day 3 to the end of experiment. On day 14, to evaluate the effects of HM12525A on lipid droplet formation, Oil-Red O staining was conducted. Briefly, the cells were fixed with 4% paraformaldehyde for 30 min, followed by incubation of Oil-Red O solution for 1 hr. After washing, Oil-Red O stained lipid droplet was determined using optical microscope European Association for the Study of Diabetes 50 th Annual Meeting; Vienna, Austria; September 15-19, 2014 For any questions, please contact Hanmi Pharm. Co., Ltd., Phone: ; Hanmi Hanmi Pharm. Co., Ltd. CONCLUSIONS REFERENCES  HM12525A showed glucose lowering efficacy in normal and db/db mice by balanced activity on both GLP-1 and glucagon receptors.  Potent body weight loss was driven by fat mass reduction and the lean/muscle mass did not changed, because of increased energy expenditure.  HM12525A showed therapeutic potential in NASH animal model 1. Diabetes (2009) 58 : 2258 ~ Nat. Rev Endocrinol. (2014) 10 : 24 ~ Diabetes (2013) 62 : 1131 ~1138 Figure 10. Clinical development milestone HM12525A NDA submission First In Human (SAD + MAD) T2DM 2019 Obesity 2020 P3 P2 P3 P1 P2 2% 4% Immunogenic threshold Figure 9. Ex vivo T cell activation of HM12525A  Both non-conjugated active moiety and HM12525A showed negligible T cell activation, which is below the immunogenic threshold among 50 healthy human donors. Figure 8. Liver function improvement in MCD-diet db/db mice (12 days) 2014 Immunogenic Potential Improved Liver Function in NASH Animal Model Body weight (MCD + db/db mice, n=7) Liver weight (MCD + db/db mice, n=7) *** **p<0.01, ***p<0.001 vs vehicle by Anova test ** SREPB-1c mRNA level (MCD + db/db mice, n=3-6)  HM12525A showed reduction of liver weight and SREPB-1c mRNA level in MCD- diet db/db mice which indicates NASH could be improved by HM12525A Figure 2. ipGTT in normal mice (n=7) a) ipGTT b) AUC ipGTT **p<0.01, ***p<0.001 vs vehicle by Anova test  HM12525A improved glucose tolerance dose-dependently in normal mice. Figure 6. Body composition change in normal and DIO mice (n=10, 4 weeks) Lipid and Fat Mass Reduction by Lipolytic Activity Body weight -23 % *** Body fat mass % *** *** ; P<0.001, vs DIO vehicle Body muscle mass Lean body mass Not significant  No lean mass and body muscle reduction was observed by HM12525A treatment Figure 7. Reduction of lipid droplet formation in 3T3-L1 adipocytes *Glucagon antagonist : (des His 1, Glu 9 ) GCG (1-29) + Glucagon antagonist * Vehicle HM12525A, 100 nM Vehicle Epinephrine 1000 nM HM12525A 100 nM  HM12525A reduced lipid droplet formation in 3T3-L1 adipocytes via glucagon action. Figure 5. Changes in energy expenditure mediator expression by HM12525A in white adipocytes (3T3-L1 cells) 3T3-L1 (White adipocyte) 6h ~9 day UCP-1 mRNA 3T3-L1 differentiation  HM12525A increased the expression of UCP-1 in white adipocytes, suggesting browning of WAT by HM12525A. UCP1 mRNA in 3T3-L1 cells (Mouse adipocyte, Q-PCR) *** SAD : Q MAD : Q 22.4% (+9.3 g) 13.9% (+5.7 g) 1.0% (+0.4 g) 14.5% (+5.7 g)


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