Hanmi Pharmaceutical Co., Ltd. · KRX:128940
Hanmi Pharmaceutical — European Association for the Study of Diabetes (EASD) 54th Annual Meeting 2018
23 slides from Hanmi Pharmaceutical's conference presentation, October 2018
Slide 1: Therapeutic effect of a novel long-acting GLP-1/GIP/Glucagon triple agonist (HM15211) in NASH and fibrosis animal models
Therapeutic effect of a novel long-acting GLP-1/GIP/Glucagon triple agonist (HM15211) in NASH and fibrosis animal models Jung Kuk Kim, Jong Suk Lee, Eunjin Park, Dae Jin Kim, Young Hoon Kim, and In Young Choi Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea
Slide 2: Presenter Disclosure
Presenter Disclosure Employee of Hanmi Pharm. Co., Ltd. European Association for the Study of Diabetes (EASD) 54th Annual Meeting, Berlin, Germany; 1-5 Oct., 2018
Slide 3: NASH progression
NASH progression Normal NAFL NASH Cirrhosis Hepatocyte lipotoxicity Inflammation Fibrosis • Obesity; • Lipid peroxidation ↑ • Inflammatory tissue injury Dyslipidemia; • Oxidative stress ↑ • HSC activation Insulin resistance and T2DM • Fibrogenic component ↑ Liver cell Liver fat accumulation apop
Slide 4: NASH progression and potential drug candidates
NASH progression and potential drug candidates Normal NAFL NASH Cirrhosis Hepatocyte lipotoxicity Inflammation Fibrosis • Obesity; • Lipid peroxidation ↑ • Inflammatory tissue injury Dyslipidemia; • Oxidative stress ↑ • HSC activation Insulin resistance and T2DM • Fibrogenic component ↑ Liver cell
Slide 5: What is long-acting GLP-1/GIP/Glucagon triple agonist?
What is long-acting GLP-1/GIP/Glucagon triple agonist? GLP-1/GIP/GCG Hanmi’s GLP-1/GIP/GCG triple co-agonist is conjugated triple co-agonist with a human IgG Fc fragment via flexible linker Flexible PEG Linker [General profile] • Extended half-life (t1/2 = 42.7 ~ 55 hrs in mice; 82.8 ~ 85.7 hrs in r
Slide 6: Efficient weight loss by HM15211 and related MoA
Efficient weight loss by HM15211 and related MoA White adipose tissue browning Vehicle Liraglutide HM15211 Weight change in pair-fed controlled DIO mice PGC-1α 10 100μm B o d y w e ig h t c h a n g e 0 ( % vs. day 0) -5.0 % UCP-1 -1 0 ** -18.6 % -5.8 % -21.8 % n.s. ††† -2 0 White Beige *** adipocy
Slide 7: Efficient hepatic fat reduction by HM15211 and related MoA
Efficient hepatic fat reduction by HM15211 and related MoA 1) Liver preferential distribution HM15211 3000 4 hr 48 hr 168 hr 3) Enhanced hepatic fat reduction in DIO mice ( n g /m L fo r S e r u m , n g /g f o r T is s u e ) S e ru m L iv e r Vehicle Liraglutide HM15211 H M 15211 Conc. H e a rt 250
Slide 8: Hypothesis: Weekly triple agonist (Glucagon)
Hypothesis Weekly triple agonist Browning of WAT Glucagon : Energy expenditure ↑ Liver targeting : Lipolysis ↑ & lipogenesis ↓ Appetite ↓ GLP-1 Inflammation ↓ • Body weight ↓ • Fat mass, blood lipid ↓ • Liver fat ↓ HM15211 [Ph1, US] NASH improvement: Steatosis ↓, Inflammation ↓ • Expected fo
Slide 9: Hypothesis: Weekly triple agonist (Glucagon, GIP)
Hypothesis Weekly triple agonist Browning of WAT Glucagon : Energy expenditure ↑ Liver targeting : Lipolysis ↑ & lipogenesis ↓ Appetite ↓ Inflammation ↓ GLP-1 GIP Inflammation ↓ • Body weight ↓ • Liver inflammation ↓ • Fat mass, blood lipid ↓ • Liver fat ↓ HM15211 [Ph1, US] NASH improvemen
Slide 10: Hypothesis: Weekly triple agonist (GLP-1, GIP, Glucagon)
Hypothesis Weekly triple agonist Browning of WAT Glucagon : Energy expenditure ↑ Liver targeting : Lipolysis ↑ & lipogenesis ↓ BG increasing risk ↑ Appetite ↓ Inflammation ↓ GLP-1 GIP Inflammation ↓ INS secretion ↑ INS secretion ↑ • Body weight ↓ • Liver inflammation ↓ • Fat mass, blood
Slide 11: Objective & study strategies
Objective & study strategies HM15211, long-acting GLP-1/GIP/Glucagon triple agonist, might have therapeutic potential in NASHand fibrosis as well as obesity • The efficacy was evaluated in rodent disease models Induction periods Disease status AMLN-diet 28 weeks Obese; Fatty liver C57BL/6 mice (8 we
Slide 12: Change of weight and steatosis score in AMLN-diet mice
Change of weight and steatosis score in AMLN-diet mice Experimental scheme Model induction Drug treatment Analysis AMLN-diet Body weight 28 weeks 4 weeks Hepatic TG C57BL/6 mice Steatosis score (8 weeks old) Weight change (AMLN mice, n=7) 0 ††† B o d y w e ig h t c h a n g e -1 0 (% vs. D0) -2 0 -3
Slide 13: Change of weight and steatosis score in AMLN-diet mice
Change of weight and steatosis score in AMLN-diet mice Experimental scheme Model induction Drug treatment Analysis AMLN-diet Body weight 28 weeks 4 weeks Hepatic TG C57BL/6 mice Steatosis score (8 weeks old) Weight change (AMLN mice, n=7) Steatosis score (AMLN mice, n=7) H&E staining (AMLN mice, rep
Slide 14: Change of hepatic fat content in MCD-diet mice
Change of hepatic fat content in MCD-diet mice Experimental scheme Model induction Drug treatment Analysis MCD-diet Hepatic TG, TBARS 6 weeks 4 weeks Blood liver function marker C57BL/6 mice (8 weeks old) Marker expression (qPCR, IHC) NAS MRI MRI MRI Hepatic TG (MCD mice, n=7) Real-time liver MRI (M
Slide 15: Change of NASH prognosis markers in MCD-diet mice
Change of NASH prognosis markers in MCD-diet mice Hepatic TBARS1) Blood ALT and bilirubin level (MCD mice, n=7) (MCD mice, n=7) B lo o d t o t a l b ilir u b in ( m g /d L ) (n m o l/m g liv e r ) †† 1200 30 1 .5 ††† B lo o d A L T ( IU /L ) 1000 25 20 800 1 .0 600 1) 15 H e p a t ic T B A R S * 10
Slide 16: Change of hepatic marker expression in MCD-diet mice
Change of hepatic marker expression in MCD-diet mice F4/80 staining (MCD mice, representative image) Inflammation & HSC activation marker Normal, vehicle MCD, vehicle gene expression (MCD mice, n=7, qPCR) 5 R e la t iv e e x p r e s s io n 4 ( F o ld in c r e a s e ) 3 100μm 2 1 0 TNF-α Normal, Vehi
Slide 17: Change of hepatic marker expression in MCD-diet mice
Change of hepatic marker expression in MCD-diet mice F4/80 staining (MCD mice, representative image) Inflammation & HSC activation marker Normal, vehicle MCD, vehicle gene expression (MCD mice, n=7, qPCR) 5 R e la t iv e e x p r e s s io n 4 ( F o ld in c r e a s e ) 3 100μm 2 * *** *** 1 0 TNF-α TG
Slide 18: Change of NAFLD activity score in MCD-diet mice
Change of NAFLD activity score in MCD-diet mice Experimental scheme Model induction Drug treatment Expected disease status MCD-diet Liver fat ↑ 6 weeks 4 weeks Study #1 Inflammation onset C57BL/6 mice (8 weeks old) NAFLD activity score (MCD mice, n=7) Study #1 4 Steatosis N A F L D a c t iv ity s c
Slide 19: Change of NAFLD activity score in MCD-diet mice
Change of NAFLD activity score in MCD-diet mice Experimental scheme Model induction Drug treatment Expected disease status MCD-diet Liver fat ↑ 6 weeks 4 weeks Study #1 Inflammation onset C57BL/6 mice (8 weeks old) Inflammatory liver damage ↑ 10 weeks 5 weeks Study #2 liver fat ↓, ballooning ↑ NAF
Slide 20: Change of NAFLD activity score in MCD-diet mice
Change of NAFLD activity score in MCD-diet mice Experimental scheme Model induction Drug treatment Expected disease status MCD-diet Liver fat ↑ 6 weeks 4 weeks Study #1 Inflammation onset C57BL/6 mice (8 weeks old) Inflammatory liver damage ↑ 10 weeks 5 weeks Study #2 liver fat ↓, ballooning ↑ NAF
Slide 21: Hepatic collagen and fibrosis score
Change of hepatic collagen and fibrosis score in MCD-diet mice Experimental scheme Model induction Drug treatment Analysis MCD-diet 6 weeks 4 weeks Study #1 C57BL/6 mice Marker expression (qPCR) (8 weeks old) 10 weeks 5 weeks Study #2 Hydroxyproline Sirius red staining 12 weeks 4 weeks Study #3 Hepa
Slide 22: Change of hepatic fibrosis marker expression in MCD-diet mice
Change of hepatic fibrosis marker expression in MCD-diet mice Experimental scheme Model induction Drug treatment Analysis MCD-diet 6 weeks 4 weeks Study #1 C57BL/6 mice Marker expression (qPCR) (8 weeks old) 10 weeks 5 weeks Study #2 Hydroxyproline Sirius red staining 12 weeks 4 weeks Study #3 Hepat
Slide 23: Summary & Conclusion
Summary & Conclusion • Considering the progression of NAFLD from simple steatosis to NASH and fibrosis, recent drug candidates may have limited efficacy because they mainly target one step of disease progression • In addition to efficient weight loss (energy expenditure ↑), the long-acting GLP-1/GIP