Hanmi Pharmaceutical Co., Ltd. · KRX:128940
Hanmi Pharmaceutical — European Association for the Study of Diabetes (EASD) 57th Annual Meeting 2021
27 slides from Hanmi Pharmaceutical's conference presentation, Sep 27, 2021
Slide 1: Multi-target engagement effect of a novel long-acting Glucagon/GIP/GLP-1 triple agonist (HM15211) in animal model of NASH
Abstract #191 Multi-target engagement effect of a novel long-acting Glucagon/GIP/GLP-1 triple agonist (HM15211) in animal model of NASH Jae Hyuk Choi, Jong Suk Lee, Jung Kuk Kim, Hyunjoo Kwon, Eun Jin Park, Jong soo Lee, Dae Jin Kim, Younghoon Kim, In Young Choi Hanmi Pharm. Co., Ltd., Seoul, Republ
Slide 2: Presenter Disclosure
Presenter Disclosure Employee of Hanmi Pharm. Co., Ltd. European Association for the Study of Diabetes (EASD) 57th Annual Meeting (Virtual), 27 Sep. - 01 Oct. 2021
Slide 3: NASH progression
NASH progression Normal NAFL NASH Cirrhosis Steatosis Inflammation Fibrosis Metabolic stress Circulating - Obesity monocyte - Dyslipidemia - Insulin resistance, T2DM M2 TGF-β MФ Kupffer cell Tissue adherent macrophage Smad signaling Quiescent Fat accumulation HSC Activated HSC in Hepatocyte Hepatocy
Slide 4: NASH progression
NASH progression Normal NAFL NASH Cirrhosis Steatosis Inflammation Fibrosis Metabolic stress Circulating - Obesity monocyte - Dyslipidemia - Insulin resistance, T2DM M2 TGF-β MФ Kupffer cell Tissue adherent macrophage Smad signaling Quiescent Fat accumulation HSC Activated HSC in Hepatocyte Hepatocy
Slide 5: NASH progression
NASH progression Targeting multiple aspects of this disease should be required for efficient management of NASH and fibrosis Normal NAFL NASH Cirrhosis Steatosis Inflammation Fibrosis Metabolic stress Circulating - Obesity monocyte - Dyslipidemia - Insulin resistance, T2DM M2 TGF-β MФ Kupffer cell T
Slide 6: Biologic effects of incretins in NASH an fibrosis
Biologic effects of incretins in NASH an fibrosis GLP-1 GIP Insulin resistance improvement Glycemic control Weight loss by appetite regulation Anti-inflammation May be indirect benefits NASH resolution Fibrosis improvement (?) European Association for the Study of Diabetes (EASD) 57th An
Slide 7: Biologic effects of incretins in NASH an fibrosis
Biologic effects of incretins in NASH an fibrosis GLP-1 GIP Glucagon Insulin resistance improvement Glucose production Glycemic control Weight loss by energy expenditure Weight loss by appetite regulation [Liver targeting] Anti-inflammation Favorable lipid metabolism reprograming Bil
Slide 8: Biologic effects of incretins in NASH an fibrosis
Biologic effects of incretins in NASH an fibrosis GLP-1 GIP Glucagon Insulin resistance improvement Glucose production Glycemic control Weight loss by energy expenditure Weight loss by appetite regulation [Liver targeting] Anti-inflammation Favorable lipid metabolism reprograming Bil
Slide 9: Biologic effects of incretins in NASH an fibrosis
Biologic effects of incretins in NASH an fibrosis GLP-1 GIP Glucagon Insulin resistance improvement Glucose production Glycemic control Weight loss by energy expenditure Weight loss by appetite regulation [Liver targeting] Anti-inflammation Favorable lipid metabolism reprograming Bil
Slide 10: Biologic effects of incretins in NASH an fibrosis
Biologic effects of incretins in NASH an fibrosis GLP-1 GIP Glucagon Insulin resistance improvement Glucose production Glycemic control Weight loss by energy expenditure Weight loss by appetite regulation [Liver targeting] Anti-inflammation Favorable lipid metabolism reprograming Bil
Slide 11: What is long-acting Glucagon/GIP/GLP-1 triple co-agonist?
What is long-acting Glucagon/GIP/GLP-1 triple co-agonist? Hanmi’s Glucagon/GIP/GLP-1 triple co-agonist (HM15211) is GCG/GIP/GLP-1 conjugated with a human IgG Fc fragment via flexible linker triple co-agonist Flexible PEG Linker [General profile] • Single drug moiety with triple activity • Extended h
Slide 12: Tissue distribution & hepatic lipid metabolism (vs. GLP-1RA)
Tissue distribution & hepatic lipid metabolism (vs. GLP-1RA) 1) Tissue distribution over time 1) Liver targeting 80 4 hr 48 hr 168 hr L iv e r 2) Increase β-oxidation T /S * r a t io o f H M 1 5 2 1 1 (% ) 60 H e ra t Lung L a rg e I. 3) More liver fat reduction vs. GLP-1RA 40 S p le e n P a n c re
Slide 13: Liver fat reduction in MCD-diet mice [Lean NASH model]
Liver fat reduction in MCD-diet mice [Lean NASH model] Experimental scheme MCD-diet* for 10 weeks *Methionine-choline deficient Drug treatment MCD mice for 4 weeks (C57BL/6 strain, n=7/group) Liver fat by MRI/MRS MRI MRI Normal, Veh, week 4 MCD, Veh, week 4 BW change at EOT Liver TG B W c h a n g e
Slide 14: Hypothesis & study methods
Hypothesis & study methods HM15211, long-acting Glucagon/GIP/GLP-1 triple agonist, might have therapeutic potential for NASH and fibrosis • The efficacy in NASH and fibrosis was evaluated in various rodent disease models Species / Strain Induction method Expected disease status Abstract # 1. Diet-in
Slide 15: Hypothesis & study methods
Hypothesis & study methods HM15211, long-acting Glucagon/GIP/GLP-1 triple agonist, might have therapeutic potential for NASH and fibrosis • The efficacy in NASH and fibrosis was evaluated in various rodent disease models Species / Strain Induction method Expected disease status Abstract # 1. Diet-in
Slide 16: Change of NASH prognosis markers in AMLN-diet mice [Study #1]
Change of NASH prognosis markers in AMLN-diet mice [Study #1] Experimental scheme [Group assignment] Normal, Vehicle AMLN-diet* for 49 weeks AMLN, Vehicle *40% kcal from fat Drug treatment AMLN, OCA 30 mg/kg, QD AMLN mice† 22% fructose, 2% cholesterol for 12 weeks (C57BL/6 strain, n=7/group) AMLN, H
Slide 17: Change of NASH prognosis markers in AMLN-diet mice [Study #1]
Change of NASH prognosis markers in AMLN-diet mice [Study #1] Experimental scheme AMLN-diet* for 49 weeks *40% kcal from fat Drug treatment AMLN mice† 22% fructose, 2% cholesterol for 12 weeks (C57BL/6 strain, n=7/group) †Except for baseline biopsy, same disease model w/ Gubra’s NASH mice Hepatic TG
Slide 18: Change of NAFLD activity score in AMLN-diet mice [Study #1]
Change of NAFLD activity score in AMLN-diet mice [Study #1] Experimental scheme AMLN-diet* for 49 weeks *40% kcal from fat Drug treatment AMLN mice† 22% fructose, 2% cholesterol for 12 weeks (C57BL/6 strain, n=7/group) †Except for baseline biopsy, same disease model w/ Gubra’s NASH mice H&E staining
Slide 19: Change of NAFLD activity score in AMLN-diet mice [Study #1]
Change of NAFLD activity score in AMLN-diet mice [Study #1] Experimental scheme AMLN-diet* for 49 weeks *40% kcal from fat Drug treatment AMLN mice† 22% fructose, 2% cholesterol for 12 weeks Definition of NASH resolution (C57BL/6 strain, n=7/group) - Inflammation score: 0 or 1 †Except for baseline b
Slide 20: Change of NAFLD activity score in AMLN-diet mice [Study #2]
Change of NAFLD activity score in AMLN-diet mice [Study #2] [Group assignment] Experimental scheme Normal, Vehicle AMLN, Vehicle AMLN-diet* for 37 weeks AMLN, Acylated GLP-1 20.5 nmol/kg, Q2D (2.4 mg/wk in human) *40% kcal from fat Drug treatment AMLN, Acylated GLP-1/GIP 109.5 nmol/kg, Q2D (15 mg/wk
Slide 21: Change of NAFLD activity score in AMLN-diet mice [Study #2]
Change of NAFLD activity score in AMLN-diet mice [Study #2] Experimental scheme AMLN-diet* for 37 weeks *40% kcal from fat Drug treatment AMLN mice 22% fructose, 2% cholesterol for 12 weeks (C57BL/6 strain, n=7/group) H&E staining (representative image) NAFLD activity score (NAS) Normal, Vehicle AML
Slide 22: Change of NAFLD activity score in AMLN-diet mice [Study #2]
Change of NAFLD activity score in AMLN-diet mice [Study #2] Experimental scheme AMLN-diet* for 37 weeks *40% kcal from fat Drug treatment AMLN mice 22% fructose, 2% cholesterol for 12 weeks Definition of NASH resolution (C57BL/6 strain, n=7/group) - Inflammation score: 0 or 1 - Ballooning score: 0 H
Slide 23: Change of NAFLD activity score in AMLN-diet mice [Study #2]
Change of NAFLD activity score in AMLN-diet mice [Study #2] Experimental scheme AMLN-diet* for 37 weeks *40% kcal from fat Drug treatment AMLN mice 22% fructose, 2% cholesterol for 12 weeks Definition of NASH resolution (C57BL/6 strain, n=7/group) - Inflammation score: 0 or 1 - Ballooning score: 0 H
Slide 24: Proposed mechanism for anti-inflammatory effects of HM15211
Proposed mechanism for anti-inflammatory effects of HM15211 Circulating monocyte Blood vessel Kupffer cell CCL-2 1) Migration Liver Tissue adherent 2) Differentiation macrophage 3) Activation M1 polarized macrophage Pro-inflammatory cytokines “Tissue inflammation” European Association for the Study
Slide 25: Proposed mechanism for anti-inflammatory effects of HM15211
Proposed mechanism for anti-inflammatory effects of HM15211 THP-1 monocyte migration 200 □ Vehicle ( % v s . v e h ic le c o n t r o l) ■ CCL-2 50 ng/mL M o n o c y te m ig r a t io n Blood vessel ■ CCL-2 50 ng/mL + HM15211 1 μM Circulating monocyte 150 * ■ CCL-2 50 ng/mL + HM15211 10 μM *** Kupffer
Slide 26: Proposed mechanism for anti-inflammatory effects of HM15211
Proposed mechanism for anti-inflammatory effects of HM15211 Pro-inflammatory cytokine expression & secretion by THP-1 macrophage TNF-α IL-1β IL-12p40 [mRNA expression] Circulating monocyte Blood vessel 20 4000 5 R e la t iv e e x p r e s s io n R e la t iv e e x p r e s s io n R e la t iv e e x p r
Slide 27: Summary & Conclusions
Summary & Conclusions • HM15211 is Glucagon/GIP/GLP-1 triple agonist with unique activity features designed to treat NASH and fibrosis by targeting multiple aspects of this disease • Previous studies demonstrated that HM15211 showed greater liver fat reduction than GLP-1RA via hepatic lipid metaboli