Young-Mi Lee1, TaeHun Song1, ChangKi Lim1, DaeJin Kim1, YeJin Yun1, KyungJin Choi1, Michael Trautmann2, SeChang Kwon1

1Hanmi Pharm. Co., Ltd., Seoul, South Korea, 2Profil Institute, Chula Vista, CA, USA

American Diabetes Association’s (ADA) 76th Scientific Sessions, New Orleans, Louisiana, USA; June 10 - 14, 2016

METHODS

• To evaluate the pharmacokinetic and excretion

profiles of differently radiolabeled Efpeglenatide in-

vivo.

STUDY OBJECTIVEFigure 1. Pharmacokinetic profiles following IV and SC

administration at a dose of 24 nmol/kg in rats (n=3)

(a) IV administration

(b) SC administration

Table 1. Pharmacokinetic parameters following IV and SC

administration at a dose of 24 nmol/kg in rats (n=3)

Figure 2. Summary of excretion in rats (n=3)

(a) [125I-CA-Ex4] Efpeglenatide, IV (b) [125I-CA-Ex4] Efpeglenatide, SC

(c) [125I-IgG4 Fc] Efpeglenatide, IV (d) [125I-IgG4 Fc] Efpeglenatide, SC

(e) [14C-PEG] Efpeglenatide, IV (f) [14C-PEG] Efpeglenatide, SC

Figure 3. Excretion of radioactivity in excreta and cage

wash (24 nmol/kg, n=3)

(a) IV administration

(b) SC administration

• When differently labeled on three comprising moieties,

the absorption and elimination profiles were well

characterized and comparable indicating that the

compound is stable in the body.

• Fragments of Efpeglenatide were cleared from the

system via urine and the urinary excretion was the

major route of elimination.

• In conclusion, this study demonstrated that

Efpeglenatide has favorable pharmacokinetic

properties with a high bioavailability and a long half-life

ensuring the prolonged PD effect and a satisfactory

elimination profile.

CONCLUSION

REFERENCES1. David Parkes et al. Drug Development Research, 2001, 53:260-267

2. L.L. Nielsen and A.D. Baron. Current Opinion in Investigational Drugs, 2003, 4:401-405

ABSTRACTEfpeglenatide is composed of CA-Exendin-4 chemically conjugated to

recombinant human immunoglobulin G4 Fc fragment through a non-

peptidyl linker. Efpeglenatide has an extended pharmacokinetic (PK)

profile with prolonged pharmacodynamic (PD) action through its

unique LAPSCOVERY conjugation and through CA Exendin-4’s

hypothesized super-agonistic pharmacologic properties on the GLP-1

receptor. The absorption and the excretion profiles of Efpeglenatide

were evaluated in a rat model following intravenous (IV) or

subcutaneous (SC) administration of radiolabeled Efpeglenatide at the

dose of 24 nmoles/kg. Efpeglenatide was labeled on three different

positions: [125I]-radiolabeling on CA-Exendin-4 and IgG4 Fc fragment,

and [14C]-radiolabeling on the non-peptide linker PEG. The level of

radioactivity in serum and excreta was determined based on liquid

scintillation counting or gamma counting methods. The bioavailability

(BA) was in the range from 81 to 88% and long terminal elimination

half-lives (47-56h) were the most pronounced PK characteristics of

radiolabeled Efpeglenatide. Following both IV and SC administration

of Efpeglenatide labeled as [125I-CA-Exendin-4] and as [125I-IgG4 Fc],

the excretion profiles were qualitatively similar with a fast initial

elimination up to 7 to 9 days and a subsequent slower process until

the end of study. The major route of elimination was via the kidneys

(78-84%) with a total recovery of radioactivity at Day 21 of 96-99%.

The amount of dose eliminated via feces after [14C]-Efpeglenatide

administration was slightly higher than [125I]-Efpeglenatide (18% vs. 7-

10%). In conclusion, radioactivity of [125I]-and [14C]-Efpeglenatide

exhibited similar absorption profiles with BA (81-88%) and showed

long terminal half-lives, and the urinary excretion was the major route

of elimination.

• Efpeglenatide is a long-acting glucagon-like peptide-1 receptor

agonist under development for the treatment of type 2 diabetes.

• Efpeglenatide is the site-specific conjugated form of CA Exendin-4

and the constant region of human immunoglobulin G4 fragment linked

via a non-peptidyl 3.4 kDa PEG linker which is based on a novel

strategy LAPSCOVERY.

BACKGROUND

Ag

lyc

os

yla

ted

Fc

Ag

lyc

os

yla

ted

Fc

Key features

• Decrease food intake and increase glucose-

dependent insulin secretion

• The long half-life and slow absorption lead

to low peak-trough ratio

• Potent HbA1c reduction & body weight loss

• Excellent Gastrointestinal Tolerability

• Flexible Dosing Strategy (Weekly to Monthly)

125I

125I

14C

• MaterialsThree differently labeled Efpeglenatide molecules were used in this study.

The labeled sites were as following:

[125I]-radiolabeling on CA-Exendin-4

[125I]-radiolabeling on immunoglobulin G4 (IgG4) Fc fragment

[14C]-radiolabeling on the non-peptide linker PEG

• Study DesignFor PK study, rats were assigned to total of 6 groups (n=3). Each two

groups received [125I-CA-Ex4], [125I-IgG4 Fc] and [14C-PEG] Efpeglenatide

via IV or SC administration. For excretion balance study, rats were

assigned to total of 6 groups (n=3). Each two groups received [125I-CA-

Ex4], [125I-IgG4 Fc] and [14C-PEG] Efpeglenatide via IV or SC

administration.

• DosingEfpeglenatide was intravenously (IV) and subcutaneously (SC)

administered at the dose level of 24 nmoles/kg. The radioactivity doses of

[125I]-labeled Efpeglenatide were approximately 200 kBq/kg; the

radioactivity dose of [14C]- labeled Efpeglenatide was 263 kBq/kg.

• Sample collection• Serial blood samples of about 0.5 mL were collected from each animal at

0.5, 1, 3, 6, 12, 24 and 24 hr intervals up to 504 hr post dose for [125I]-

and [14C]- labeled Efpeglenatide.

• Urine and feces samples were collected from each animal with 24 hr

intervals up to 504 hours post dose for [125I]-labeled Efpeglenatide and

up to 648 hour post dose for [14C]-labeled Efpeglenatide.

• Carcass samples were collected at 504 hour for [125I]-labeled

Efpeglenatide and at 648 hour for [14C]-labeled Efpeglenatide.

• Quantification of Efpeglenatide[125I]-radioactivity in samples was measured by gamma counting and

[14C]-radioactivity was measured by Liquid Scintillation Counting (LSC)

using Packard analyzers. The data were presented as mean ± standard

deviation (SD).

The slow absorption with long half-life (47.1-55.8 hr) and high BA

(81-88%) of [125I]- and [14C]-labeled Efpeglenatide after SC

administration

The pharmacokinetic profiles of the three differently labeled

Efpeglenatide were similar.

“ High bioavailability, a long half-life and high

stability in the system were observed ”

RESULTS

“Fragments of Efpeglenatide were mainly

excreted in urine”

Fragments of the [125I-CA-Ex4] Efpeglenatide and [125I-IgG4 Fc]

Efpeglenatide were mainly excreted by urine (83-91%) and the

range of total recovery of radioactive doses was 96-99%.

In terms of fragments of [14C-PEG] Efpeglenatide, the amounts of

radioactivity excreted were 61-65% in urine and 22% in feces. The

total recovery was 91-93% of the administered doses.

Radiolabeled

EfpeglenatideRoutes

AUCinf

(hr*nmoleq/L)

C0 or Cmax

(nmoleq/L)

Tmax

(hr)

t½

(hr)

BA

(%)

[125I-CA-Ex4]

IV

15900 1190 452 39.9 - 49.1 4.1 -

[125I-IgG4 Fc] 16700 1100 559 17.8 - 47.7 7.3 -

[14C-PEG] 15900 733 562 38.9 - 58.2 1.7 -

[125I-CA-Ex4]

SC

12800 565 101 6.7 48.0 0.0 47.1 1.8 81

[125I-IgG4 Fc] 14300 1140 116 11.7 40.0 13.9 53.3 4.2 86

[14C-PEG] 14000 1320 99.2 0.8 56.0 13.9 55.8 3.6 88

p> 0.05; in AUC and Cmax of Radiolabeled Efpe. analyzed by one-way ANOVA, Mean SD

Excretion profile of Efpeglenatide

Pharmacokinetic profile of Efpeglenatide

Analysis of Absorption and Excretion Route of Efpeglenatide Using Radiolabeled [125I-CA-Ex4] Efpeglenatide, [125I-IgG4 Fc] Efpeglenatide and [14C-PEG] Efpeglenatide

1061-P

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0 .0 1

0 .1

1

1 0

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T im e ( h r )

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on

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(n

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l eq

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[1 2 5

I -C A - E x 4 ] E f p e g le n a t id e

[1 2 5

I - Ig G 4 F c ] E f p e g le n a t id e

[1 4

C - P E G ] E f p e g le n a t id e

0 7 2 1 4 4 2 1 6 2 8 8 3 6 0 4 3 2 5 0 4

0 .0 1

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1

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T im e ( h r )

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m c

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[1 2 5

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[1 2 5

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[1 4

C - P E G ] E f p e g le n a t id e

0 7 2 1 4 4 2 1 6 2 8 8 3 6 0 4 3 2 5 0 4

0

2 0

4 0

6 0

8 0

1 0 0

T im e ( h r )

Cu

mu

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ve

% R

ec

ov

ery

[1 2 5

I -C A - E x 4 ] E f p e g le n a t id e

[1 2 5

I - Ig G 4 F c ] E f p e g le n a t id e

[1 4

C - P E G ] E f p e g le n a t id e

0 7 2 1 4 4 2 1 6 2 8 8 3 6 0 4 3 2 5 0 4

0

2 0

4 0

6 0

8 0

1 0 0

T im e ( h r )

Cu

mu

lati

ve

% R

ec

ov

ery

[1 2 5

I -C A - E x 4 ] E f p e g le n a t id e

[1 2 5

I - Ig 4 F c ] E f p e g le n a t id e

[1 4

C - P E G ] E f p e g le n a t id e

U r in e

F e c e s

C a g e w a s h

C a r c a s s

8 4 %

7 %

7 %U r in e

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1 1 %

9 %

U r in e

F e c e s

C a g e w a s h

C a r c a s s

7 8 %

1 0 %

6 %

U r in e

F e c e s

C a g e w a s h

C a r c a s s

8 0 %

8 %

6 %

U r in e

F e c e s

C a g e w a s h

6 5 %

2 2 %

7 %

C a r c a s s

U r in e

F e c e s

C a g e w a s h

6 1 % 2 2 %

7 %C a r c a s s

c A M P in R IN m 5 F

0 .0 0 1 0 .0 1 0 .1 1 1 0 1 0 0 1 0 0 0

0

1 0

2 0

3 0

4 0

5 0C A E x e n d in -4

E x e n d in -4

C o n c e n tra t io n (n M )

Co

nc

. o

f c

AM

P (

nM

)

0 7 1 4 2 1 2 8

-2 0

-1 0

0

1 0

T im e (d a y )

Bo

dy

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igh

t C

ha

ng

e

(% v

s.

Da

y 0

)

4

6

8

1 0

1 2

1 4

V e h ic le

L ira g lu t id e 3 0 n m o l/k g , B ID (= 1 .8 m g /w k in h u m a n )

D u la g lu t id e 0 .9 8 n m o l/k g , Q 2 D (= 1 .5 m g /w k in h u m a n )

E fp e g le n a tid e 2 .8 9 n m o l/k g , Q 2 D (= 4 m g /w k in h u m a n )

Hb

A1

c (

%)

Underlying Superagonistic Mechanisms of Efpeglenatide in Glycaemic Control and Weight Loss PotencyIY Choi1, SH Park1, M Trautmann2, MJ Moon1, JY Kim1, YM Lee1, M Hompesch2, SC Kwon1

1Hanmi Pharm. Co., Ltd, Seoul, South Korea, 2Profil Institute, Chula Vista, CA, USA

ABSTRACTEfpeglenatide is a long-acting GLP-1 receptor (GLP-1R) agonist developedfor the treatment of type 2 diabetes. It consists of an exendin-4 analog andhuman Fc fragment conjugated via non-peptidyl linker. As previouslyreported, efpeglenatide possesses a superagonistic property that activatesthe GLP-1R without triggering immediate receptor internalization andsubsequent degradation. Through controlled in vitro and in vivo studies weinvestigated if additional evidence of superagonism and additional beneficialeffects on pancreatic β-cells exist. The attenuation of GLP-1 signaling is dueto internalization of GLP-1R, therefore the β-arrestin-2 recruitment andreceptor internalization by efpeglenatide were assessed in GLP-1Roverexpressing cells. In addition to 3 to 5 fold less β-arrestin-2 recruitment,significantly more GLP-1Rs remained on the cell surface (68%) after 1 hrtreatment of 100 nM efpeglenatide when compared with dulaglutide andliraglutide (31% and 26%). Subsequently, efpeglenatide led to 30% greatermaximum cAMP accumulation overtime and less desensitization of cAMPsignaling, compared with dulaglutide. We also assessed the β-cell protectiveeffects of efpeglenatide. Efpeglenatide restored insulin secretion andimproved the cell survival (data not shown) in INS-1E cells in the presence ofhigh glucose. After 12 weeks of treatment, efpeglenatide protected from β-cell degeneration and showed glycemic improvement in 12 weeks old db/dbmice. The above benefits were translated into more potent glucose loweringwith greater weight loss in db/db mice and DIO mice. Efpeglenatidedemonstrated superior HbA1c reduction (-3.8% vs. liraglutide -2.6% anddulaglutide -2.8%) as well as superior weight loss (efpeglenatide -20.9% vs.liraglutide -18.6% and dulaglutide -7.1%) after 4 weeks of treatment. Theseresults suggest that the superagonism of efpeglenatide enhances GLP-1receptor signaling and consequently leads to superior efficacy.

RESULTS

• Efpeglenatide possesses superagonistic properties compared with

other long-acting GLP-1RAs which are derived from a fast receptor

dissociation of CA Exendin-4.

• Efpeglenatide leads to significantly less GLP-1R internalization and

consequently can continuous signaling in contrast to liraglutide and

dulaglutide in human GLP-1R transformed cells.

• The superagonistic property of efpeglenatide was translated into

more potent glucose lowering with greater weight loss in db/db

mice and DIO mice.

• GLP-1RAs restore β-cell functions in INS-1E cells under high

glucose conditions. Efpeglenatide showed significantly higher

restoration compared with other GLP-1RAs.

• These results suggest that the superagonism of efpeglenatide

enhances GLP-1 receptor signaling and consequently leads to

superior efficacy.

METHODS

CONCLUSIONS

REFERENCES• Zaccardi F. et al., Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor

Agonist Treatments: A Systematic Review and Network Meta-analysis. Ann Intern Med

2016;164:102-113

• Schrage R. et al., Superagonism at G protein-coupled receptors and beyond. Br J Pharmacol

2015

• Roed SN. et al., Real-time trafficking and signaling of the glucagon-like peptide-1 receptor.

Mol Cell Endocrinol 2014;382:938-949.

• Smith NJ. et al., When simple agonism is not enough: emerging modalities of GPCR

ligands.Mol Cell Endocrinol2011;331:241-247.

• Jorgensen R. et al., Characterization of glucagon-like peptide-1 receptor beta-arrestin 2

interaction:a high-affinity receptor phenotype. Mol Endocrinol2005;19:812-823.

BACKGROUND

Fast dissociating kinetics for GLP-1 receptor may lead tosuperior efficacy via less receptor internalization andsubsequent desensitization.

Superagonistic Mechanism of Efpeglenatide

CA-Exendin-4N-terminally modified exendin-4 analogue

Fast dissociation Compared to other GLP-1RAs

In vitro properties of efpeglenatide vs. other GLP-1RAs

• Intracellular cyclic AMP and insulin released to the assay medium were measured,following 1hr treatment with GLP-1RAs in a rat insulinoma cell, RINm5F or GLP-1R overexpressed CHO cells. Intracellular cAMP was measured using the Catch-Point Fluorescent Assay Kit (Molecular Devices) .

• In vitro insulin secretion was measured in RIN-m5F cells, Cells were starved inassay buffer (0.5% FBS, no glucose in RPMI 1640 medium) for 4 h and followedby treatment with 16.8 mM glucose and various concentrations of GLP-1RAs inassay buffer for 1 h. The insulin levels in conditioned assay buffer were measuredusing Ultrasensitive Rat Insulin ELISA Kit (Mercodia AB, Uppsala,Sweden).

• The receptor kinetics were measured by a SPR (Surface Plasmon Resonance)assay using immobilized extracellular domain of the human GLP-1 receptor whichis fused to the GST (glutathione S transferase). The hGLP-1R/GST wasexpressed in transformed CHO cells and purified by GST affinity chromatography.

• Recruitment of β-arrestin-2 was investigated using the PathHunter eXpress GLP-1R CHO-K1 β-arrestin GPCR Assay (DiscoveRx). Briefly, hGLP-1R-β-arrestin-2/CHO-K1 cells were stimulated with 1-1,000 nM of GLP-1RAs for 90 min.Recruited β-arrestin-2 was detected according to the manufacturer's instructions.

• Internalization of GLP-1 receptor was assessed in hGLP-1R/U2OS cells using thePathHunter™ eXpress Kit (DiscoveRx Corporation. Ltd., UK). Surface GLP-1receptors were measured in hGLP-1R/CHO cells after pretreatment with 10 nM or100 nM GLP-1RAs at 37°C for 60 min. Surface-bound ligands were removed byacidic wash using PBS (pH 3.0) and the remaining surface receptors weredetected by binding of 100 pM125I-GLP-1 at 4°C for 4 h.

• To investigate restorative effects against glucotoxicity, INS-1E cells were culturedat 5.5mM or 30mM glucose for 72h and subsequently exposure to KRB buffercontaining 16.8mM glucose in the presence of different concentration of GLP1Ragonists for 2 hours. cAMP accumulation and insulin secretion were determinedusing a cAMP Fluorescent Assay kit and insulin EIA kit.

• In vivo efficacy between efpeglenatide and other GLP-1RAs was compared bysubcutaneous administration in a human PK mimic dosing interval, Change ofblood glucose was monitored during 4 weeks and HbA1c was determined at theend point in db/db mice. Efficacy in body weight loss and food intake inhibitionwas compared in DIO mice for 4 weeks.

• The pancreatic β cell preservative effect was investigated in 12 week old db/dbmice by subcutaneous administration of efpeglenatide in a human PK mimicdosing interval (Q2D) for 12 weeks. IPGTT and β cell mass was determined at theend point.

Figure 2. Receptor kinetics for GLP-1 receptor

Efeglenatide showed fast dissociation rate for GLP-1R compared to other

GLP-1RAs

Figure 3. GLP-1 receptor internalization by GLP-1RAs

(c) Cell surface receptorsin hGLP-1R/CHO cells

(a) β-arrestin-2 recruitment in hGLP-1R+β-arrestin-2/CHO-K1 cells

(b) Receptor internalizationin hGLP-1R/U2OS cells

Efpeglenatide induces less GLP-1R internalization compared to other

long-acting GLP-1R agonists

Benefits of GLP-1RAs on β-cells experiencing glucotoxicity

1068-P

kd (1/s, X10-3)

Liraglutide 2.8 ± 0.2

Dulaglutide 3.5 ±0.01

Efpeglenatide 10.1 ± 0.1

******

0

5 0

1 0 0

T im e (s e c )

Re

so

rn

an

ce

Un

it (

RU

)

0

1 0 0

2 0 0

3 0 0

T im e (s e c )

Re

so

rn

an

ce

Un

it (

RU

)

Dulaglutide Efpeglenatide

400 nM

200 nM

100 nM

50 nM

25 nM

Liraglutide

400 nM

200 nM

100 nM

50 nM

25 nM

0

2 0 0

4 0 0

6 0 0

T im e (s e c )

Re

so

rn

an

ce

Un

it (

RU

)

200 nM

100 nM

50 nM

25 nM

12.5 nM

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0

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1 5 0 0

2 0 0 0

Inte

rn

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ze

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LP

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(%

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Su

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r

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N o t r e a t

L ira g lu tid e

D u la g lu tid e

E fp e g le n a tid e

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6 0 0 0

8 0 0 0

-a

rre

stin

-2

re

cru

itm

en

t

(%

of i

nit

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**p<0.01, ***p<0.001, 2-way ANOVA test

Figure 5. Restoration of β-cell functions after glycotoxic stress†

GLP-1RAs restored cAMP accumulation and insulin release after glucotoxic

stress in the rat pancreatic β-cell line. Especially, efpeglenatide showed

significantly higher restoration compared with other GLP-1RAs.

1 n M 1 0 n M 1 0 0 n M 1 0 0 0 n M

0

2 0 0 0

4 0 0 0

6 0 0 0

8 0 0 0

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* * *

* * *

* * ** * *

* * *

* * * * * *

E fp e g le n a tid e

N o t r e a t

L ira g lu tid e

D u la g lu tid e

Efpeglenatide protected against β-cell degeneration in late T2DM stage of

db/db mice with glycemic improvement

Figure 6. Benefits of efpeglenatide on β-cells in a late T2DM

model mice

(a) β-cell mass preservation(db/db mice, n=7, for 12 to 24 weeks)

2 .0

2 .5

3 .0

3 .5

4 .0

V e h ic le , 2 4 w e e k s o ld

E fp e g le n a t id e 0 .3 6 n m o l /k g /Q 2 D ( = 0 .5 m g /w e e k in h u m a n )

-c

ell

ma

ss

(m

g)

V e h ic le , 1 2 w e e k s o ld

2.3

+0.5

*

β-cell mass depend on age

in db/db mice

(b) ipGTT at the end of the treatment (db/db mice, n=7,12 to 24 weeks)

† Pretreatment w/ 30 mM glucose for 72 hr.One way anova

** p<0.01, *** p<0.001 vs high glucose-basal

# p<0.05, ## p<0.01 vs efpeglenatide

(a) cAMP accumulation after

hyperglycemic stressin INS-1E cell

(b) Insulin secretion after

hyperglycemic stressin INS-1E cell

Ag

lyco

syla

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Ag

lyco

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Fc

+

From Bacterial

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Ag

lyco

syla

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Ag

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Site specific

Conjugation & Purification

Langlenatide(LAPS-Exendin-4; HM11260C) Efpeglenatide(LAPSCA Exendin-4)

CA Exendin-4 possesses superagonistic property derived from fast

dissociation for GLP-1 receptor.

(b) Insulin release vs. exendin-4in RINm5F cells

Figure 1. In vitro activity of CA Exendin-4

Figure 4. Glucose lowering and body weight loss efficacy in a human

weekly mimic condition in diabetic and obese animal models

Efpeglenatide showed superior glycemic control and weight loss compared

to other long-acting GLP-1RAs.

5.9

(a) HbA1c(db/db mice, n=6, 4 wks)

(b) Body weight loss (DIO mice, n=6, 4 wks)

B W (% )

0 2 4 6 8

-1 5

-1 0

-5

0

5

V e h ic le

L ira g lu t id e 5 0 n m o l/k g , B ID (= 3 .0 m g /d a y in h u m a n )

D u la g lu t id e 0 .9 8 n m o l/k g , Q 2 D (= 1 .5 m g /w k in h u m a n )

T im e (d a y )

Bo

dy

We

igh

t C

ha

ng

e

(%

vs

. D

ay

0)

E fp e g le n a tid e 4 .3 5 n m o l/k g , Q 2 D (= 6 m g /w k in h u m a n )

-7.1%

-18.6%

-20.9%

+3.4%

** P<0.01, *** P<0.001 One-way ANOVA with Dunnett’s

multiple comparisons test vs. Vehicle

***

**

***

12

8.6 8.9

6.6

In vivo efficacy of efpeglenatide vs. other GLP-1RAs

Faster kd

GLP-1R

Continuous activation

by less desensitization

Superagonistic activity

0

1 0

2 0

3 0

4 0

5 0

8 0

1 0 0

1 2 0

Co

nc

. o

f c

AM

P

(% o

f lo

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#

##

***

*****

0

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1 5 0

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(% o

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***

*** ***

#

##

American Diabetes Association’s (ADA) 76th Scientific Sessions, New Orleans, Louisiana, USA; June 10-14, 2016

FURTHER INFORMATION[Acknowledgments] This study was supported by a grant of the Korea Drug Development Fund

R&D Project.(KDDF-201204-03)

+2.0

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

AU

C0

-2h

r(m

g/d

L*h

r)

***

HbA1c : 9.9 %11.3 %

*p<0.05, ***p<0.001 vs. vehicle by One-way ANOVA

(a) cAMP accumulation vs. exendin-4in RINm5F cells

-4 -2 0 2 4

-4 0

-3 0

-2 0

-1 0

0

E x e n d in -4

C A -E x e n d in -4

lo g p e p tid e c o n c e n tra tio n (n M )

% C

ha

ng

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f p

las

ma

glu

co

se

0 .0 0 0 1 0 .0 1 1 1 0 0 1 0 0 0 0

1 0 0

1 5 0

2 0 0

C A e x e n d in -4

E x e n d in -4

C o n c e n tra t io n (n M )

Ins

uli

n c

on

c.

(%

of c

on

tro

l)

***

***

***

***

***

***

-4 -2 0 2 4

-4 0

-3 0

-2 0

-1 0

0

E x e n d in -4

C A -E x e n d in -4

lo g p e p tid e c o n c e n tra tio n (n M )

% C

ha

ng

e o

f p

las

ma

glu

co

se

0

1 0

2 0

3 0

4 0

5 0

8 0

1 0 0

1 2 0

Co

nc

. o

f c

AM

P

(% o

f lo

w g

luc

os

e-b

as

al)

L o w g lu c o s e (5 .5 m M )

H ig h g lu c o s e (3 0 m M )

L ira g lu tid e 1 0 0 n M

D u la g lu tid e 1 0 0 n M

E fe p g le n a tid e 1 0 0 n M