Hanmi Pharmaceutical Co., Ltd. · KRX:128940
Hanmi Pharmaceutical — European Association for the Study of Diabetes (EASD) 53rd Annual Meeting 2017
25 slides from Hanmi Pharmaceutical's conference presentation, September 2017
Slide 1: Potent body weight loss and efficacy in a NASH animal model by HM15211
Potent body weight loss, and therapeutic efficacy in a NASH animal model by a novel long-acting GLP-1/GIP/Glucagon tri-agonist (HM15211) In Young Choi, Jong Suk Lee, Jung Kuk Kim, Young Jin Park, Sang Hyun Lee, Young Hoon Kim, Sun Jin Kim, Se Chang Kwon Hanmi Pharm. Co., Ltd., Seoul, Republic of Kor
Slide 2: Presenter Disclosure
Presenter Disclosure An employee of Hanmi Pharm. Co., Ltd. European Association for the Study of Diabetes (EASD) 53rd Annual Meeting, Lisbon, Portugal; 11-15 Sep., 2017
Slide 3: General properties of incretins single- and co-agonist
General properties of incretins single- and co-agonist Single agonist Dual agonist Triple agonist GLP-1RA GLP-1/GCG GLP-1/GIP GLP-1/GIP/GCG Body weight ~ Lipid profile ~ NASH ~ Blood glucose ~ Suitable for Improved BWL efficacy Enhanced glycemic Target indications depend on glycemic control control
Slide 4: HM15211, a novel long-acting GLP-1/GIP/Glucagon tri-agonist
HM15211, a novel long-acting GLP-1/GIP/Glucagon tri-agonist GLP-1/GIP/GCG Hanmi’s GLP-1/GIP/GCG triple agonist is conjugated with a triple agonist human IgG Fc fragment via flexible linker Flexible PEG Linker [General profiles] • High glucagon activity, suitable for liver preferential distribution a
Slide 5: Time-dependent tissue distribution of HM15211
Time-dependent tissue distribution of HM15211 Tissue distribution in SD rats (n=3/group, single administration) ( n g /m L f o r S e r u m , n g / g f o r T is s u e ) 3000 4 hr 48 hr 168 hr 336 hr S e ru m L iv e r H M 15211 Conc. H e a rt 2000 Lung L a rg e I. S p le e n P a n c re a s 1000 A d ip
Slide 6: Objective
Objective HM15211, long-acting GLP-1/GIP/Glucagon tri-agonist, might have therapeutic potential in NASH and obesity • To assess the a. Efficacy and related MoAs in NASH animal models b. Efficacy and related MoAs in obesity animal models European Association for the Study of Diabetes (EASD) 53rd Annu
Slide 7: Efficacy and related MoAs in NASH animal models
Efficacy and related MoAs in NASH animal models European Association for the Study of Diabetes (EASD) 53rd Annual Meeting, Lisbon, Portugal; 11-15 Sep., 2017
Slide 8: Change in hepatic lipid metabolic gene expression
Change in hepatic lipid metabolic gene expression Lipid metabolism gene expression in DIO mice (n=7/group, 4 wks treatment, qPCR) V e h ic le L ir a g lu tid e 5 0 n m o l/k g , B ID (3 m g /d a y in h u m a n ) De novo lipogenesis H M 1 5 2 1 1 1 .4 4 n m o l/k g , Q 2 D (2 m g /w k in h u m a n )
Slide 9: Change in blood lipid profile
Change in blood lipid profile Serum lipid profiles in DIO mice (n=7/group, 4 wks treatment) Triacylglycerol (TG) Free fatty acid (FFA) Cholesterol (CHO) 80 1 .5 500 ††† S e r u m F F A ( m E q /d L ) S e r u m C H O ( m g /d L ) S e r u m T G ( m g /d L ) 1 .2 400 60 † ††† 0 .9 300 40 *** 0 .6 200 *
Slide 10: Change in NASH prognosis markers
Change in NASH prognosis markers Experimental scheme Drug treatment Week 0 6 10 Hepatic TG, TBARS C57BL/6 mice NASH markers MCD diet Hepatic lipid metabolism & liver function markers in MCD diet mice (n=7/group, 4 wks treatment) 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 ) ††
Slide 11: Change in hepatic inflammatory markers and NAS
Change in hepatic inflammatory markers and NAS Inflammation & HSC activation marker gene expression H&E staining in MCD diet mice (representative image, 4 wks treatment) in MCD diet mice (n=7/group, 4 wks treatment, qPCR) Normal, vehicle MCD, vehicle 5 R e la t iv e e x p r e s s io n 4 ( F o ld in
Slide 12: Change in hepatic fibrosis marker
Change in hepatic fibrosis marker Fibrosis marker gene expression in MCD diet mice Sirus red staining in MCD diet mice (n=7/group, 4 wks treatment, qPCR) (representative image, 4 wks treatment) Normal, vehicle MCD, vehicle 8 †† R e la t iv e e x p r e s s io n ( F o ld in c r e a s e ) 6 †† 4 2 ** *
Slide 13: Proposed MoAs of HM15211 for NASH treatment
Proposed MoAs of HM15211 for NASH treatment HM15211 Liver preferential distribution Progression of NASH HSC activation, followed by Kupffer cell activation increased fibrogenic properties Fibrosis ROS Fatty acid Inflammation Dyslipidemia pool ↑ Oxidative stress Excess dietary lipid Macrophage infi
Slide 14: Efficacy and related MoAs in obesity animal models
Efficacy and related MoAs in obesity animal models European Association for the Study of Diabetes (EASD) 53rd Annual Meeting, Lisbon, Portugal; 11-15 Sep., 2017
Slide 15: Body weight change in obese animal models
Body weight change in obese animal models DIO mice (n=7/group, 2 wks treatment) DIO rats (n=6/group, 4 wks treatment) 20 +18.6 % 0 +0.5 % B o d y w e ig h t c h a n g e B o d y w e ig h t c h a n g e *** 10 ( % vs. day 0) -9.7 % ( % vs. day 0) -1 0 0 *** -0.9 % ††† *** -2 0 -18.9 % ††† -1 0 *** ***
Slide 16: Anorexia-independent body weight change, and underlying MoAs
Anorexia-independent body weight change, and underlying MoAs Vehicle Liraglutide HM15211 Body weight change in pair-fed controlled DIO mice H&E (n=6/group, 4 wks treatment) 100μm 10 PGC-1α B o d y w e ig h t c h a n g e 0 ( % vs. day 0) -5.0 % -1 0 -5.8 % -21.8 % UCP-1 -18.6 % n.s. ††† -2 0 -3 0 -35
Slide 17: Summary & Conclusion
Summary & Conclusion • HM15211 is a novel long-acting triple agonist possessing high GCG and balanced GLP-1 and GIP activity • High GCG activity makes HM15211 be preferentially distributed to liver In NASH animal models • HM15211 favorably reprograms hepatic lipid metabolic gene expression • HM15211
Slide 18: Back-up
Back-up Hanmi Pharm. Co., Ltd.
Slide 19: Unmet needs in obesity, and rationale of triple agonist development
Unmet needs in obesity, and rationale of triple agonist development Insufficient weight loss by current anti-obesity Therapeutic benefits of GCG in obesity and related disorders medication could be appeared under tight glycemic control by balanced GLP-1/GIP action M ean w e ig h t lo s s Energy
Slide 20: Improved lipid profile by new-born GIP action of HM15211
Improved lipid profile by new-born GIP action of HM15211 LPL expression in WAT & serum cholesterol (n=5/group, normal mice, day 1 result after single administration) Proposed GIP role of HM15211 in lipid profile improvement 2 .0 qPCR 120 ††† HM15211 S e r u m C H O ( m g /d L ) R e la t iv e e x p
Slide 21: No hyperglycemic risk of HM15211 by harmonized GLP-1 & GIP action
No hyperglycemic risk of HM15211 by harmonized GLP-1 & GIP action AUCipGTT in normal mice (n=5, single administration) Antagonist only HM15211 + Antagonist HM15211 only 800 +GLP-1 *** ** & GIP ( m g /d L * h r , m e a n ± S E M ) antagonist +GLP-1 Which is more active ### 600 antagonist in glycemic
Slide 22: PK profiles of HM15211
PK profiles of HM15211 PK in ICR mice PK in SD rats (n=3/time point, single administration) (n=3/group, single administration) 10000 S e r u m c o n c . (n g /m L ) S e r u m c o n c . (n g /m L ) 10000 1000 1000 100 t1/2 = 82.9 hr 100 t1/2 = 85.7 hr t1/2 = 55.0 hr t1/2 = 42.7 hr 10 10 HM15211 5 nmo
Slide 23: Change in energy expenditure and respiratory exchange ratio
Change in energy expenditure and respiratory exchange ratio Experimental scheme Vehicle Liraglutide 50 nmol/kg, BID DIO mice HM15211 2.87 nmol/kg, Q2D Week 0 1 2~4 D6 D8 Indirect calorimetry Lipid profile, IHC, marker expression Energy expenditure in DIO mice RER [Respiratory Exchange Ratio] in DIO
Slide 24: Liver steatosis resolution in obese animal model
Liver steatosis resolution in obese animal model Vehicle Liraglutide HM15211 Hepatic TG in DIO mice (n=7/group, 4 wks treatment) H&E 250 H e p a t ic T G ( m g /g ) 200 100μm 150 100 *** Oil-red O *** 50 0 V e h ic le L ir a g lu tid e 5 0 n m o l/k g , B ID (3 m g /d a y in h u m a n ) H M 1 5 2 1
Slide 25: Hepatic inflammatory marker expression in liver tissue
Hepatic inflammatory marker expression in liver tissue H&E staining in MCD diet mice F4/80 staining in MCD diet mice (representative image, 4 wks treatment) (representative image, 4 wks treatment) Normal, vehicle MCD, vehicle Normal, vehicle MCD, vehicle 100μm 100μm MCD, Liraglutide MCD, HM15211 MCD