PS069-792 LAPS CA-Exendin-4 (efpeglenatide) Enhances ...HM11260C).pdf · LAPS CA-Exendin-4 (efpeglenatide) Enhances Insulin Secretion and Beta Cell Responsiveness in Subjects with

LAPS CA-Exendin-4 (efpeglenatide) Enhances Insulin Secretion and Beta Cell

Responsiveness in Subjects with Type 2 Diabetes

Background and Aims LAPS Exendin-4 (HM11260C) is a glucagon like

peptide -1 (GLP-1) receptor agonist being developed for the treatment of

type 2 diabetes mellitus (T2DM). In this phase 1B study the effects of

different HM11260C regimens on insulin secretion rate (ISR), β-cell

responsiveness, and gastric emptying (GE) compared to placebo and to

liraglutide were investigated.

Materials and Methods Subjects with T2DM received 6 mg HM11260C

weekly (cohort A; age: 52.8 years, HbA1c: 8.4, n=13), 16 mg HM11260C

monthly (cohort B; age: 50.1 yr, HbA1c: 8.1, n=13), 1.8 mg liraglutide

daily (cohort C; age: 54.9 yr, HbA1c: 8.02 n=13), or placebo (age: 54.1

yr, HbA1c: 8.6, n=8). Subjects in cohorts A and C were evaluated at

baseline and steady state, and cohort B was evaluated at trough

(day[d]82) and peak(d89) drug concentration. Islet β-cell function was

assessed during a graded IV glucose infusion (GGI); infusion steps: 2, 4,

6, 8, 12 mg/kg/min of 20% IV glucose for 30 min each. Insulin C-peptide

levels, and plasma glucose response to each GGI step were measured.

ISR were determined using a population based C-peptide de-convolution

model. AUC(insulin) and AUC(C-peptide) as measures of ISR were

determined for each treatment. β-cell responsiveness was assessed as

the ratio of ISR/ blood glucose (BG) over the duration of the GGI, and

the slope of the ISR/BG was compared between the treatments. The rate

of GE was determined for 1g of liquid acetaminophen following a mixed

meal and a mixed meal tolerance test (MMTT) was performed. For GE,

non-inferiority to liraglutide was tested using a margin of 0.8 for the least

squares (LS) mean ratio.

Results Insulin secretion for all active treatments was increased

compared to placebo and for HM11260C 6 mg and 16 mg was greater

than for liraglutide (point estimates LS mean ratio: 1.765 mU/L, 90% CI:

1.331, 2.342 mU/L, one-sided p=0.0008, and LS mean ratio: 1.440 mU/L,

90% CI: 1.080, 1.920 mU/L, one-sided p=0.0196). Comparisons of the

relationship between ISR and plasma glucose using mixed effects

modelling showed an improvement in beta cell responsiveness relative to

placebo/baseline which was not different among treatments. In the

monthly treatment group, there was a diminution of effect at PK trough

(d82). For postprandial glucose following the MMTT the LS means of the

Cmax, AUC0-180, and AUC0-360 parameters were significantly (two-

sided p < 0.05) reduced in subjects who received either 6 mg HM11260C

or 16 mg HM11260C when compared to placebo. Cohort A demonstrated

less inhibition of GE and was non-inferior (lower CI limit >0.8) to

liraglutide in terms of acetaminophen Cmax, AUC0-120minand AUC0-

180min. While for Cohort B the effect on gastric emptying appeared to be

similar or even less when compared to liraglutide, formal non-inferiority

could not be established for all parameters. GE was delayed in cohorts A

and B compared to placebo.

CONCLUSIONS

STUDY DESIGN

Contact Information: Jahoon Kang, Executive Director, Hanmi Pharma., Co., Ltd

e-mail: [email protected]

Phone: +82-2-410-9041

PS069-792

51st European Association for the Study of Diabetes (EASD) Annual Meeting, Stockholm, Sweden; September 14 – 18, 2015

This study was sponsored by Hanmi Pharmaceuticals

ABSTRACT

REFERENCES

Elaine Watkins1, Jahoon Kang2, Michael Trautmann1, Soomin Choi2, Oakpil Han2, Marcus Hompesch1 1Profil Institute for Clinical Research, Inc., Chula Vista, CA, USA. 2Hanmi Pharmaceuticals, Seoul, Republic of Korea.

Conclusions HM11260C improved measures of β-cell function

significantly compared to placebo, and for the weekly treatment

regimen (cohort A), significantly compared to liraglutide. The results

of this trial suggest that HM11260C is a safe and efficacious GLP-1

receptor agonist and that with regard to gastric emptying it inhibited

less or similarly compared to other known GLP-1 receptor agonists.

• LAPS-Exendin-4 (HM11260C) is a novel long-

acting form of CA Exendin-4 (an Exendin-4

analog) that has decreased renal and slow

vascular endothelial clearance.

• LAPS-Exendin-4 is a conjugate of exendin-4

linked to a non-glycosylated Fc molecule

• Super-agonist activity at the GLP-1 receptor

(Kang J et al. 2013)

BACKGROUND

• Flexible regimen from weekly to monthly

• Low Immunogenicity

• GLP-1 receptor agonists such as liraglutide improve aspects

of β-cell function including glucose-stimulated insulin

secretion and responsiveness to glucose

RESULTS Study Population: Demography

BMI Body Mass Index

Mean + SD

Cohort A Cohort B Cohort C

HM11260C

6 mg/wk Placebo

Hm11260C

16 mg/mo Placebo

Liraglutide

1.8 mg/d

N 13 4 13 4 13

Age (y) 53+6 51+5 50+12 56+5 55+10

M:F 9:4 3:1 6:7 2:2 7:6

BMI (kg/m2)

34.3+4.3 30.3+4.0 31.6+6.0 28.9+3.1 29.4+5.1

HbA1c (%)

8.4+1.1 9.3+0.5 8.1+1.1 7.9+1.2 8.0+ 0.7

Mixed meal tolerance test - Compared to placebo, the least square (LS)

means for glucose Cmax, AUC0-180, and AUC0-360 were significantly (two-sided

p < 0.05) reduced in subjects who received either 6 mg HM11260C or 16 mg

HM11260C at the peak drug concentration (Figure 1a). Similar results were

observed at the trough drug concentration for 16 mg HM11260C with the

exception of Cmax which was reduced. Postprandial glucose concentration

was higher with 16 mg HM11260C a trough drug concentration compared to

peak. Serum insulin concentrations increased in cohorts A and B (Figure

1b). In contrast, postprandial serum insulin concentrations were reduced

relative to placebo with liraglutide.

Plasma glucagon concentrations were reduced by HM11260C and

liraglutide.

Figure 1a and 1b. Mean glucose and insulin responses the MMTT

Graded glucose infusion (GGI) - Insulin secretion for all treatments

was increased significantly compared to placebo over the range of

blood glucose concentrations.

During GGI the areas under the curve (AUC)-insulin (Figure 2) and

AUC-C-peptide (Figure 3) were larger (p<0.05) in cohort A compared

to cohort C.

Comparisons of the relationship between ISR and plasma glucose

using mixed effects modeling showed a significant treatment effect

relative to placebo/baseline (p<0.0001) which was not different among

the treatments (Figure 4).

In the monthly HM11260C treatment group, there was a significant

diminution of effect on ISR at PK trough.

Figure 2. Mean insulin concentrations during GGI

Figure 3. Mean ISR by C-peptide deconvolution

• HM11260C improved measures of β-cell function significantly

compared to placebo.

• For the weekly treatment regimen of HM11260C (cohort A) β-cell

function was significantly improved compared to QD liraglutide.

• Kang J, Choi S, Choi IY, Kwon S C, Trautmann M, Hompesch M, et al.

Activation of GLP-1 Receptor by CA Exendin-4 (exendin-4 analog)

with fast dissociation rate constant. Diabetes 2013; 62, Suppl 1

• Hovorka R, Koukkou E, Southerden D, Powrie JK, Young MA.

Measuring pre-hepatic insulin secretion using a population model of

C-peptide kinetics: accuracy and required sampling schedule.

Diabetologia 1998;41:548-54

Safety and tolerability - HM11260C was generally well tolerated.

The most common adverse effects considered to be related to the

study drugs were transient and intermittent gastrointestinal,

i.e. diarrhea, nausea and vomiting.

Figure 4. Relationship between plasma glucose and pre-hepatic

insulin secretion rates by treatment and occasion.

Gastric emptying - Cohort A demonstrated less inhibition of GE and was

non-inferior (lower confidence interval limit >0.8) to liraglutide in terms of

acetaminophen Cmax, AUC0-120min and AUC0-180min.

While for Cohort B the effect on gastric emptying appeared to be similar or

even less when compared to liraglutide, formal non-inferiority could not be

established for all parameters.

GE was delayed in cohorts A and B compared to placebo.

• Table 3. Percent of Patients Achieving HbA1c Targets

• Efpeglenatide demonstrated dose-dependent Glucose-Lowering

effects

3 mg dose fairly similar to the reference Liraglutide

4 mg dose perhaps better than Liraglutide to be further tested

• Body Weight loss with Efpeglenatide 3 and 4 mg was fairly

similar to the reference Liraglutide group

• Nausea and Vomiting AEs were consistent with GLP-1 receptor

agonists class and rapidly subsided after the initial 2 weeks

• GI AE profiles can be improved by applying titration approach

based on simulation data

• Heart rate increases seemed less than the reference Liraglutide

• No neutralizing antibodies were detected with Efpeglenatide

n (%)

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=33

HM

3 mg

N=36

HM

4 mg

N=36

liraglutide

1.8mg/day

N=36

Any AEs 23 (62%) 19 (51%) 26 (70%) 24 (73%) 24 (67%) 24 (67%) 29 (81%)

GI Disorders

Nausea

Vomiting

Diarrhea

11 (30%)

6 (16%)

0 (0%)

2 (5%)

8 (22%)

4 (11%)

0 (0%)

5 (14%)

6 (16%)

3 (8%)

1 (3%)

1 (3%)

12 (36%)

9 (27%)

4 (12%)

3 (9%)

15 (42%)

8 (22%)

4 (11%)

4 (11%)

19 (53%)

12 (33%)

8 (22%)

2 (6%)

16 (44%)

12 (33%)

4 (11%)

5 (14%)

Injection Site Reaction 6 (16%) 5 (14%) 9 (24%) 8 (24%) 8 (22%) 1 (3%) 13 (36%)

Skin and Subcutaneous 4 (11%) 1 (3%) 1 (3%) 0 (0%) 1 (3%) 3 (8%) 3 (8%)

Treatment-Emergent

Anti-Drug Antibody1 0 (0%) 0 (0%) 5 (14%) 2 (6%) 4 (11%) 4 (11%) 15 (8%)

Serious AE (SAEs) 0 (0%) 0 (0%) 0 (0%) 1 (3%) 2 (6%) 0 (0%) 0 (0%)

Any TEAE Leading to

Discontinuation

Total

Nausea

Vomit

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

1 (3%)

0 (0%)

1 (3%)

3 (8%)

1 (3%)

1 (3%)

1 (3%)

1 (3%)

1 (3%)

4 (11%)

2 (6%)

2 (6%)

Heart Rate Change,

BPM2

0.7

(10.49)

0.3

(7.39)

-0.5

(7.02)

1.8

(8.40)

3.9

(9.08)

3.0

(10.14)

5.6

(8.50)

6 .0

6 .5

7 .0

7 .5

8 .0

8 .5

9 .0

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 (w e e k )

Me

an

Hb

A1

co

ve

r ti

me

(%

)

7 .6

7 .2

6 .8

6 .66 .46 .3

1 3

L ira 1 .8 m g /d a y4 m g /w e e k3 m g /w e e k

2 m g /w e e k1 m g /w e e k0 .3 m g /w e e kP la c e b o

Once Weekly HM11260C (efpeglenatide) Significantly Improves Glycemic Control and Reduced Body Weight in Patients with Type 2 Diabetes: A Phase II Dose Finding Study

Kun-Ho Yoon1, JH Kang2, OP Han2, KH Gee2, IY Choi2, SC Kwon2, M Trautmann3, M Hompesch3

1Catholic University of Korea, Seoul, South Korea, 2Hanmi Pharm. Co., Ltd., Seoul, South Korea, 3Profil Institute, Chula Vista, CA, USA

Background and aims: HM11260C (HM) is a novel long acting GLP-1R

agonist with a T1/2 of ~ 158 hrs resulting in a flat PK profile. This 12-week,

randomized, placebo (PBO) controlled, double-blind parallel group study

with an open label active control liraglutide (LIRA) arm, was designed to

investigate the dose ranging efficacy, safety, and tolerability of once weekly

(QW) doses of HM in subjects with Type 2 Diabetes (T2DM).

Materials and methods: Stratified by metformin use 254 patients (mean

age 55.3 yrs, BMI 31.76 kg/m2, diabetes duration 73.08 months) were

randomized to one of five HM QW doses, PBO or to LIRA QD up-titrated to

1.8 mg. All HM doses were not titrated.

Results: HM 0.3 to 4 mg produced dose-dependent reduction in HbA1c,

fasting plasma glucose, and 7-point daily glucose. In addition, HM 4 mg

reached statistical significance in demonstration for non-inferiority to LIRA

by mean % change of HbA1c from baseline (Difference= -0.23, 95.1% CI=[-

0.56, 0.10]). Attainment of target HbA1c ≤ 7% with HM was 83.3% (3 mg,

p<0.0001) and 80.6% (4 mg, p<0.0001) vs 30.3% (PBO), and 61.1% (LIRA).

The reduction in body weight with HM 3 mg (2.732 kg) and 4 mg (3.309 kg)

was significantly greater than that with PBO (1.290 kg, p<0.049, both). The

most frequent AEs were gastrointestinal side effects of mild or moderate

severity: nausea and vomit that subsided over time.

Conclusion: In summary, all doses of HM demonstrated clinically

meaningful improvements in blood glucose and body weight, with higher

doses being more effective. Safety profiles were comparable to LIRA. The

current results warrant further studies to assess the long-term efficacy and

safety of HM11260C in T2DM.

• Figure 1. Study Design

Placebo (n= 37)

Total patient numbers = 254

Ra

nd

om

iza

tio

n

HM 0.3 mg (n= 37)

HM 1 mg (n= 37)

HM 2 mg (n= 35)

Follow

up HM 3 mg (n= 36)

HM 4 mg (n= 36)

Liraglutide 0.6 1.2 1.8 mg (n= 36)

6 weeks

12 weeks Treatment

(HM: without titration)

T2DM

Drug Naïve

or

on Stable

Metformin

SUMMARY & CONCLUSIONS • Figure 2. Disposition

Screened

N=593

Randomised

N=254

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=35

HM

3 mg

N=36

HM

4 mg

N=36

Lira

1.8 mg

N=36

Placebo

N=33

HM

0.3 mg

N=33

HM

1 mg

N=34

HM

2 mg

N=27

HM

3 mg

N=29

HM

4 mg

N=27

Lira

1.8 mg

N=28 Discontinued

N=4

Discontinued

N=3

Discontinued

N=8

Discontinued

N=7

Discontinued

N=9

Discontinued

N=8

Discontinued

N=4

Completed 12-Week Trial and the 6-Week Follow-up, N=211

• Table 1. Baseline Characteristics

BACKGROUND

STUDY DESIGN • Figure 3. HbA1c Values from Baseline to Week 13

FAS (Full analysis set); Data are Means (SE)

• Figure 4. 7-Point Glucose Profile (SMBG)

SMBG is self-monitoring blood glucose; FAS; Data are Means (SD);

*p-value<0.05 compared with Placebo

FAS using Cochran-Mantel-Haenszel test with LOCF; *p-value<0.05 compared with Placebo

• Table 5. Mean Body Weight Change at Week 13

FAS; *p-value<0.05; difference with Placebo; Data are LS Means (SE) from MMRM

• Table 6. Adverse Events

• Figure 5. Nausea/Vomiting Simulation

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=35

HM

3 mg

N=36

HM

4 mg

N=36

liraglutide

1.8mg/day

N=36

Age: years (SD) 55 (9) 56 (11) 55 (9) 56 (10) 54 (10) 56 (10) 54 (11)

Sex: F/M (%) 57/43 35/65 49/51 46/55 36/64 50/50 56/44

White/Black/Asian/Other (%) 89/5/5/0 84/8/5/3 78/16/5/0 85/12/3/0 78/14/8/0 92/6/3/0 83/14/0/3

Time since initial diagnosis

of T2DM: months (SD) 6 (5) 7 (6) 5 (3) 6 (5) 6 (5) 6 (6) 7 (5)

Metformin use: n (%) 33 (89) 34 (92) 32 (87) 29 (88) 33 (92) 32 (89) 32 (89)

Weight: kg (SD) 86 (18) 95 (20) 90 (18) 90 (17) 94 (19) 87 (18) 90 (16)

BMI: kg/m2 (SD) 31 (5) 32 (5) 32 (5) 32 (4) 32 (5) 31 (6) 32 (4)

FPG: mg/dL (SD) 163 (35) 163 (39) 152 (30) 152 (39) 164 (32) 165 (48) 156 (36)

HbA1c: % (SD) 8.0 (0.8) 7.9 (0.7) 7.8 (0.6) 7.7 (0.7) 7.8 (0.9) 8.0 (0.8) 8.0 (0.8)

Safety set; N: number of patients contributing to analysis

1The overall incidence of treatment-induced ADAs (titer increased by at least 2) and treatment-boosted

ADAs (titer of pre-existing ADA level was boosted by at least 2) 2Mean (SD)



Phone: +82-2-410-9041

This study is supported by a grant of the Korean Health

Technology R&D Project, Ministry of Health & Welfare, Republic

of Korea (KDDF-201204-03)

PS069-793

51st European Association for the Study of Diabetes (EASD) Annual Meeting, Stockholm, Sweden; September 14 – 18, 2015

ABSTRACT

• Overview of HM11260C (Efpeglenatide)

A modified Exendin4 (CA-EXD4) has been

conjugated to a human IgG4 Fc using a PEG

linker which leads to slow elimination, thereby

resulting in a decreased dosing schedule.

• Study Objectives

a. Primary objective

- To assess and compare the efficacy of five doses of HM11260C

(once weekly subcutaneous injections) over the 12 weeks from

baseline in comparison with placebo (once weekly subcutaneous

injections) on glycaemic control, as assessed by HbA1c in

subjects with T2DM

b. Secondary objectives

- To assess the effect on safety, tolerability, immunogenicity,

diabetes-related parameters (FPG and 7-point glucose profile)

and body weight change.

- To explore the relationship between PK and PD measurements

RESULTS

Key inclusion criteria

• T2DM age 18-75 yrs

• Drug Naïve or

Metformin ≥ 1500 mg

• HbA1c ≥ 7.0%, ≤ 10%

• BMI < 40 kg/m2

Key exclusion criteria

• Diagnosis of T1DM

• Pregnant or nursing women

• Uncontrolled diabetes: FPG > 240

mg/dL (13.3 mmol/L)

• Significant change in body weight

(at least ± 10%)

a. Total N=254

b. Discontinued: Withdrawal by subject, Adverse effect, Lost to follow-up, protocol deviation,

Noncompliance, etc.

Safety set; N: Based on the randomized patients

REFERENCES • Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties,

functions, and clinical implications. Am J Med 124 (Suppl.);S3–S18, 2011

• HM11260C, a New Generation Long Acting GLP-1R Agonist with a unique

Pharmacokinetic Profile Improves Glucose Control and GI tolerability; a Phase

IIa Clinical Trial in Type 2 Diabetes Mellitus (HM-EXC-202), 59-LB, 73rd ADA,

2013

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=33

HM

3 mg

N=36

HM

4 mg

N=36

liraglutide

1.8mg/day

N=36

% of subjects with

HbA1c ≤ 7.0% 27.0 35.1 75.7* 72.7* 83.3* 80.6* 61.1*

% of subjects with

HbA1c ≤ 6.5% 5.4 21.6* 37.8* 57.6* 55.6* 55.6* 50.0*

Be fo

re B

rea k fa

s t

Aft

e r B

rea k fa

s t

Be fo

re L

u n c h

Aft

e r L u n c h

Be fo

re D

inn e r

Aft

e r D

inn e r

At b

e d t ime

4

6

8

1 0

1 2

1 6

-1 .3 6 *-2 .9 0 * -1 .7 9 *

Me

an

Blo

od

Glu

co

se

(m

mo

l/L

)

-2 .1 2 *

-0 .9 1 *

-1 .8 9 *

-1 .8 4 *

Be fo

re B

rea k fa

s t

Aft

e r B

rea k fa

s t

Be fo

re L

u n c h

Aft

e r L u n c h

Be fo

re D

inn e r

Aft

e r D

inn e r

At b

e d t ime

4

6

8

1 0

1 2

1 6

-1 .7 1 *-3 .0 6 *

-2 .3 6 *

-1 .4 0 *-2 .2 4 *

Me

an

Blo

od

Glu

co

se

(m

mo

l/L

)

-2 .3 5 *-2 .0 2 *

HM 3 mg HM 4 mg

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=33

HM

3 mg

N=36

HM

4 mg

N=36

liraglutide

1.8mg/day

N=36

Body weight change, kg -1.29

(0.511)

-1.21

(0.526)

-2.01

(0.508)

-1.52

(0.553)

-2.73*

(0.550)

-3.31*

(0.543)

-3.21

(0.558)

Body weight change, % -1.18

(0.570)

-1.10

(0.588)

-2.28

(0.568)

-1.61

(0.618)

-2.66

(0.615)

-3.47*

(0.608)

-3.54

(0.623)

• Table 2. Mean HbA1c Change at Week 13

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=33

HM

3 mg

N=36

HM

4 mg

N=36

liraglutide

1.8mg/day

N=36

HbA1c change, %

[95.1% CI]†

-0.40

(0.111)

-0.56*

(0.114)

-0.95*

(0.111)

-1.19*

(0.121)

-1.41*

(0.119)

-1.61*

(0.118)

[-0.56, 0.10]†

-1.38*

(0.120)

FAS; *p-value<0.05; difference with Placebo; Data are LS Means (SE) from MMRM †Non-inferiority in HbA1c reduction was concluded if the upper limit of the two-sided 95.1% confidence

interval (CI) for the difference in HbA1c at Visit 7 (Visit 7/Week 13) was smaller than 0.3.

Incidence of Nausea/Vomiting for 4 mg QW in

T2DM Patients at 24 by titration schedule (%)

Weekly titration schedule

(Simulated data)

FAS; Data are LS Means (SE) from MMRM; *p-value<0.05 compared with Placebo

Placebo

N=37

HM

0.3 mg

N=37

HM

1 mg

N=37

HM

2 mg

N=33

HM

3 mg

N=36

HM

4 mg

N=36

liraglutide

1.8mg/day

N=36

Fasting plasma

glucose change,

mmol/L

-0.49

(0.283)

-0.48

(0.295)

-1.31*

(0.282)

-1.27

(0.307)

-2.19*

(0.305)

-2.44*

(0.303)

-1.46

(0.306)

• Table 4. Mean Fasting Plasma Glucose at Week 13

Without titration schedule

(Observed data)

Days since first dosing

Cumulative distribution of

time to first ‘Nausea/Vomiting’

Cum

ula

tive p

roport

ion w

ith e

vent

1-2-4 2-2-4 2-2-2-2-4 None

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Incidence of Nausea/Vomiting for 4 mg QW in T2DM Patients at Week 24

Weekly Titration Schedule

Incid

en

ce

of N

au

se

a/V

om

itin

g a

t W

ee

k 2

4 (

%)

Baseline Week 13

Placebo HM 3 mg

Baseline Week 13

Placebo HM 4 mg

Significant Effects of HM11260C (efpeglenatide) on Body Weight over 20 weeks in Obese Subjects without Diabetes: a Randomized, Double-blind, Placebo Controlled study

ABSTRACT Background and aims: HM11260C (HM) is a novel long acting GLP-1R

agonist with a T1/2 of ~ 158 hrs resulting in a flat PK profile. This 20-week,

randomized, double-blind, placebo (PBO) controlled, parallel group study

was designed to evaluate the efficacy, safety, and tolerability of once a

week (QW) or every other week (Q2W) doses of HM in obese subjects

without diabetes.

Materials and methods: 297 subjects (mean age 43.4 yrs and BMI 35.5

kg/m2) were randomized to one of four HM doses (4 mg QW, 6 mg QW, 6

mg Q2W, or 8 mg Q2W) or to PBO. HM was administered subcutaneously

for 20 weeks. The diet and exercise regimens remained unchanged during

the study.

Results: The body weight loss with HM 4mg QW, 6 mg QW, 6 mg Q2W

and 8 mg Q2W was 6.2 kg, 7.8 kg, 7.0 kg and 7.1 kg (LS Mean, p<0.0001

all HM treatment groups), whereas body weight gain was observed with

PBO (0.8 kg). More subjects in the HM treatment groups achieved

significant body weight loss ≥5% or ≥10%, and the mean reductions in BMI

from baseline were greater, compared with PBO. Changes from baseline in

waist circumference were -6.00 cm, -9.45 cm, -7.11 cm, -8.00 cm and -

0.21 cm (LS Mean) with HM 4mg QW, 6 mg QW, 6 mg Q2W, 8 mg Q2W

and PBO. The most frequent adverse events were gastrointestinal events

which were observed relatively frequently and increased injection site

reactions which were less common.

Conclusion: All doses of HM meaningfully reduced body weight and were

well tolerated. These results warrant further studies to assess titration

schemes as well as the long-term efficacy and safety of HM in obesity.

STUDY DESIGN

RESULTS

SUMMARY

BACKGROUND

• Figure 1. Disposition

• Table 1. Baseline Characteristics

Mean (SD)

Placebo

N=60

HM

4 mg QW

N=59

HM

6 mg QW

N=59

HM

6 mg Q2W

N=59

HM

8 mg Q2W

N=58

Age: years 43.7 (11.8) 42.9 (12.1) 43.0 (13.0) 43.3 (12.5) 43.9 (9.2)

Sex: F/M (%) 73.3/26.7 69.5/30.5 78.0/22.0 72.9/27.1 87.9/12.1

Race (%)

White/Black/

Asian/Other

65.0/26.7/

5.0/3.4

69.5/20.3/

6.8/3.4

62.7/18.6/

13.6/5.1

76.3/13.6/

8.5/1.7

67.2/22.4/

8.6/1.7

Weight: kg 97.5 (12.1) 100.8 (19.3) 101.7 (19.4) 99.5 (18.4) 95.6 (13.3)

BMI: kg/m2 34.9 (3.2) 35.2 (4.5) 36.3 (4.4) 35.6 (4.8) 35.2 (3.9)

Waist

Circumference: cm 109.3 (10.7) 109.8 (12.2) 111.9 (13.3) 109.6 (11.8) 108.9 (10.9)

Waist/Hip

Circumference 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1) 0.9 (0.1)

• Figure 2. Body Weight Change over 20 weeks

• Figure 3. BMI Change at Week 21

CONCLUSION

• All doses of efpeglenatide meaningfully reduced body weight and

exceeded regulatory requirements for anti-obesity drugs. These

results warrant further studies to assess titration schemes as well as

the long-term efficacy and safety of efpeglenatide in obese

population.

OBJECTIVES

Ran

do

miz

ati

on

HM 4 mg QW (N=59)

HM 6 mg QW (N=59)

Follow-up HM 6 mg Q2W (N=59)

HM 8 mg Q2W (N=60)

Placebo (N=60)

6 weeks

2 weeks Titration + 18 weeks Treatment

Obese subjects

without diabetes

Total patient numbers = 297

20w

eeks

• Table 5. Immunogenicity

N (%)

Placebo

N=60

HM

4 mg QW

N=59

HM

6 mg QW

N=59

HM

6 mg Q2W

N=59

HM

8 mg Q2W

N=58

ADAs at any time a 0 12 (20.3) 12 (20.3) 14 (23.7) 18 (31.0)

Total treatment-

emergent ADAs

(Treatment-induced

and -boosted) b

0 10 (16.9) 10 (16.9) 12 (20.3) 15 (25.9)

Neutralizing ADAs 0 0 0 0 0

PS050-643

Screened

N=509

Randomised

N=297

HM

4 mg QW

N=59

Discontinued

N=13

Completed 20-Week Trial and the 6-Week Follow-up, N=207

Placebo

N=60

HM

6 mg QW

N=59

HM

6 mg Q2W

N=59

HM

8 mg Q2W

N=60

HM

4 mg QW

N=42

Placebo

N=47

HM

6 mg QW

N=41

HM

6 mg Q2W

N=39

HM

8 mg Q2W

N=38

Discontinued

N=17

Discontinued

N=18

Discontinued

N=20

Discontinued

N=22b

a. Discontinued: Withdrawal by subject, Adverse effect, Lost to follow-up, Protocol deviation, Other

b. Two subjects in 8mg Q2W group are excluded from Safety set as they had not received any IP.

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0

-1 0

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

W e e k

Ch

an

ge

in

Bo

dy

We

igh

t

fro

m B

as

eli

ne

(K

g)

P la c e b o4 m g Q W

6 m g Q W

6 m g Q 2 W

8 m g Q 2 W

- 6 .4

- 6 .6

- 7 .1

- 7 .3


a. The number of subjects who were positive for anti-drug antibody at any time

b. The treatment-induced ADAs (titer increased by at least 2) and treatment-boosted ADAs (titer of

pre-existing ADA level was boosted by at least 2)

REFERENCES

• WHO Fact Sheets, “Obesity and Overweight,” (2013).

• Kang J, Choi S, Kwon SC, et al. (2013) HM11260C, a new

generation long acting GLP-1R agonist with a unique

pharmacokinetic profile improves glucose control and GI tolerability;

a phase IIa clinical trial in type 2 diabetes mellitus. Abstract

presented at the 73rd Scientific Session of the American Diabetes

Association, San Diego, CA, USA.

FAS (full analysis set); Data are LS Means (SE) from MMRM (a mixed-effects repeated

measures model, using an unstructured covariance matrix; change from baseline as the

outcome variable; baseline as a covariate; treatment group, visit and their interaction as

factors.)

Safety set; Data are n (%); TEAE, Treatment-Emergent Adverse Event

Key inclusion criteria

• Aged ≥ 18 and < 65 years

• BMI 30 kg/m2 or 27 kg/m2, with treated

or untreated co-morbidity(ies)

• Stable body weight (less than 5% change)

for at least 3 months

Key exclusion criteria

• BMI 42 kg/m2

• Diabetes mellitus (type 1, 2, or other)

• HbA1c 6.5%

• Pregnant or nursing women


RE Pratley1, JH Kang2, PK Kim2, EH Kwak2, OP Han2, KH Gee2, IY Choi2, SC Kwon2, M Trautmann3, M Hompesch3 1Florida Hospital Translational Research Institute, Orlando, FL, USA, 2Hanmi Pharm. Co., Ltd., Seoul, South Korea, 3Profil Institute, Chula Vista, CA, USA

• The abstract included the results of an interim analysis available at the

time of submission. Since then, the final analysis has been completed

and is reported in the poster.

• Obesity is highly associated with a majority of metabolic diseases (WHO

Obesity and Overweight Fact sheet; updated March 2013).

• Few effective drugs are currently available for the treatment of obesity;

better therapeutic options that are safe and well tolerated and that can

lower the risks associated with obesity are needed.

• 8 weeks of treatment with HM11260C (LAPSCA-Exendin-4, efpeglenatide),

a GLP-1 agonist, resulted in marked weight loss compared with placebo

(Kang et al., 2013). The purpose of this study is to determine the optimal

dose and regimen of efpeglenatide, when administered subcutaneously

weekly or biweekly to reduce weight in obese subjects without diabetes.

• Primary objective

To assess the effect of efpeglenatide on body weight over the 20 weeks

from baseline in obese subjects

• Secondary objectives

To assess the safety, tolerability, and immunogenicity of efpeglenatide

over the 20 weeks from baseline in obese subjects

***p-value <0.0001, **p-value <0.01 compared with Placebo; FAS

• Statistically significant body weight reduction was observed over 20

weeks with once a week (QW) and every other week (Q2W)

treatment of efpeglenatide in all groups.

• Statistically significant increases in heart rate were observed, however,

they were within the expected range for GLP-1 receptor agonists.

Blood pressure decreased within the expected range for GLP-1

receptor agonists, but was only significant at the 6 mg QW dose.

• Most of nausea and vomiting occurred with the first few injections and

subsided over the time.

• Overall treatment emergent anti-efpeglenatide antibodies were

detected in 20.0% (47 out of 235 efpeglenatide-treated subjects).

None of patients with positive drug antibodies showed neutralizing

antibody against efpeglenatide.

AUTHOR DISCLOSURE

Richard E. Pratley, MD

• Research Support: Merck, Novo Nordisk, Takeda, Sanofi, Lilly

• Consultant: GSK, Merck, Novo Nordisk, Takeda, Sanofi, Astra

Zeneca, Hanmi, Janssen, Boehringer-Ingleheim



Phone: +82-2-410-9041 51st European Association for the Study of Diabetes (EASD) Annual Meeting, Stockholm, Sweden; September 14 – 18, 2015

• Figure 4. Waist Circumference Change at Week 21

-1 0

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

Ch

an

ge

in

Wa

ist

Cir

cu

mfe

re

nc

e

fro

m B

as

eli

ne

(c

m)

- 0 .9

- 5 .2

- 6 .7

- 6 .2

- 8 .3

**

*****

***

B a s e l in e (c m ) 1 0 9 .3 1 0 9 .8 1 1 1 .9 1 0 9 .6 1 0 8 .9

P la c e b o 4 m g Q W 6 m g Q W 6 m g Q 2 W 8 m g Q 2 W

***p-value <0.0001 compared with Placebo; FAS; Data are LS Means (SE) from MMRM

• Table 2. Subjects Who Lost at Least 5% and 10%

Body Weight at Week 21

Placebo

N=60

HM

4 mg QW

N=59

HM

6 mg QW

N=59

HM

6 mg Q2W

N=59

HM

8 mg Q2W

N=58

Body weight

change, % a 0.1 (0.6) -6.7 (0.6)*** -7.3 (0.6)*** -6.7 (0.6)*** -7.4 (0.6)***

Subjects with

BW loss ≥ 5% b 2 (3.3) 32 (54.2)*** 33 (55.9)*** 31 (52.5)*** 35 (60.3)***

Subjects with

BW loss ≥ 10% b 1 (1.7) 12 (20.3)** 16 (27.1)*** 12 (20.3)** 13 (22.4)**

***p-value <0.0001, **p-value <0.01 compared with Placebo; FAS; and

Data are LS Means (SE) from MMRM

• Table 4. Adverse Events

Placebo

N=60

HM

4 mg QW

N=59

HM

6 mg QW

N=59

HM

6 mg Q2W

N=59

HM

8 mg Q2W

N=58

Any TEAEs 48 (80.0) 51 (86.4) 54 (91.5) 51 (86.4) 51 (87.9)

GI Disorders 28 (46.7) 43 (72.9) 49 (83.1) 38 (64.4) 44 (75.9)

Nausea 11 (18.3) 32 (54.2) 35 (59.3) 28 (47.5) 36 (62.1)

Vomiting 4 (6.7) 13 (22.0) 13 (22.0) 10 (16.9) 19 (32.8)

Injection Site

Reaction 13 ( 21.7) 11 (18.6) 7 (11.9) 5 (8.5) 8 (13.8)

Serious TEAE

(SAEs) 0 (0) 1 (1.7) 3 (5.1) 0 (0) 2 (3.4)

Any TEAE

Leading to

Discontinuation

4 (6.7) 3 (5.1) 11 (18.6) 7 (11.9) 10 (17.2)

• Table 3. Heart Rate and Blood Pressure Change at Week 21

Placebo

N=60

HM

4 mg QW

N=59

HM

6 mg QW

N=59

HM

6 mg Q2W

N=59

HM

8 mg Q2W

N=58

Heart Rate (BPM)

Baseline a 67.8 (9.3) 67.2 (9.1) 69.2 (8.5) 69.1 (8.1) 68.9 (11.1)

Change b 0.5 (1.1) 4.7 (1.1)** 6.2 (1.1)** 5.2 (1.1)** 3.6 (1.1)*

SBP (mmHg)

Baseline a 124.2 (12.8) 120.5 (10.4) 119.8 (9.3) 121.4 (10.8) 121.8 (10.8)

Change b -0.1 (1.3) -3.5 (1.4) -6.1 (1.4)** -0.3 (1.4) -3.0 (1.4)

DBP (mmHg)

Baseline a 78.7 (8.2) 77.0 (8.0) 76.1 (7.4) 77.7 (7.5) 78.8 (7.1)

Change b 0.1 (0.9) -0.1 (0.9) -1.3 (0.9) 1.8 (0.9) -0.3 (0.9)

a. Data are LS Means (SE) from MMRM.

b. Data are n (%) from LOCF.

-4 .0

-3 .5

-3 .0

-2 .5

-2 .0

-1 .5

-1 .0

-0 .5

0 .0

0 .5

1 .0

Ch

an

ge

in

BM

I fr

om

Ba

se

lin

e

0 .0

- 2 .4

- 2 .6

- 2 .3- 2 .6

******

******

B a s e l in e 3 4 .9 3 5 .2 3 6 .3 3 5 .6 3 5 .2

P la c e b o 4 m g Q W 6 m g Q W 6 m g Q 2 W 8 m g Q 2 W

a. Data are Means (SD).

b. Data are LS Means (SE) from MMRM.

**p-value <0.01, *p-value <0.049 compared with Placebo; Safety set

788-P

1 0 n M 1 0 0 n M

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

Inte

rn

ali

ze

d G

LP

-1 r

ec

ep

tor

(% o

f in

itia

l)

E x e n a tid e

C A E x e n d in -4

N o t re a t

Superagonistic mechanism of increased glucodynamic and weight loss effects of LAPSCA-Exendin-4 (efpeglenatide)

IY Choi1, SH Park1, M Trautmann2, SY Hwang1, JY Kim1, SM Bae1, YM Lee1, JH Kang1, SC Kwon1 1Hanmi Pharm. Co., Ltd, Seoul, South Korea, 2Profil Institute, Chula Vista, CA, USA

RESULTS

• Following conjugation to Fc the fast receptor dissociation kinetics of

CA-Exendin-4 were maintained in efpeglenatide. (kd 4.2x10-3s-1 vs.

1.0x10-3 s-1 for efpeglenatide).

• Efpeglenatide lead to significantly less GLP-1R internalization than

liraglutide and dulaglutide in human GLP-1R transformed cells. This

translated into more potent glucose lowering in db/db mice and

greater body weight loss in DIO mice in comparison to liraglutide

and dulaglutide.

• Efpeglenatide maintained potent glucose lowering efficacy in db/db

mice even at conditions mimicking human dosing.

• CA-Exendin-4 even after conjugation to the human Fc-fragment

seems to achieve more pronounced GLP-1R activation due to

reduced receptor internalization and consequently leads to more

potent effects. These findings may explain the observed efficacy of

efpeglenatide in clinical trials relative to liraglutide.

Less GLP-1R desensitization by efpeglenatide

CONCLUSIONS

REFERENCES • Alan J. Garber et al., Diabetes Care 2011, 34(S2): S279-284

• Briones M, Bajaj M er al., Expert Opin Pharmacother 2006, 7(8): 1055-1064.

• Monika Malm-Erjefält et al., Drug Metabolism and Disposition 2010, 38(11): 1944-1953.

• Scott E. et al., Endocrinol 2011, 152(8): 3103-3112.

• Young Min Cho et al., Pharmacology and Therapeutics 2012, 135: 247-278.

BACKGROUND

Fast dissociating kinetics on the hGLP-1 receptor may lead to superior efficacy via less receptor internalization and subsequent desensitization.

Hypothesis: Superagonistic activation of GLP-1R by efpeglenatide

Exendin-4 CA-Exendin-4

5 fold faster dissociation

(nM)

200

100

50

25

12.5

6.25

Continuous activation

CA-Exendin-4Exendin-4

Receptor

Internalization /

desensitization

Receptor

internalization

/desensitization

More continuous

signaling due to

reduced internalization

Slow dissociation

(kd: 1.1x10-3 s-1) (kd: 6.0 x 10-3 s-1)

CA-Exendin-4

Exendin-4

Superior glycodynamic effect of CA-Exendin-4

(nM)

200

100

50

25

12.5

6.25

Figure 1. GLP-1R internalization by CA-Exendin-4 and Exendin-4

(a) Receptor internalization in hGLP-1R/U2OS cells

(b) Cell surface receptors in hGLP-1R/CHO cells

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

0 .5 n M @ 6 0 m (4 /1 3 & 4 /1 4 )

Su

rfa

ce

GL

P-1

re

ce

pto

r

(%

of i

nit

ial) 0 .5 n M C A -E x e n d in -4

N o t r e a t

0 .5 n M E x e n d in -4

***

***

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

E x d -4 v s . C A -E x d -4

Su

rfa

ce

GL

P-1

re

ce

pto

r

(% o

f in

itia

l) C A -E x e n d in -4 (1 0 n M )

N o tre a tm e n t

E x e n d in -4 (1 0 n M )

*** P<0.001, Paired t-test

CA-Exendin-4 induced less receptor internalization and more cell surface receptors

compared to exendin-4

*** ***

E x d -4 v s C A E x d -4

0 1 2

0

5

1 0

1 5V e h ic l e

E x e n d in - 4 1 n m o l /k g

C A -E x e n d in - 4 1 n m o l/k g

T im e (h r )

Blo

od

Glu

co

se

(m

mo

l/L

)

T ra n s fo rm o f A U C

0 .0 1 1 1 0 0

1 0 0

2 0 0

3 0 0

4 0 0

E x d - 4

C A E x d -4

D o s e (n m o l/k g )

IpG

TT

glu

co

se

AU

C (

hr*

mg

/dL

)

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

*** P<0.001, 2-way ANOVA test

Figure 2. Comparison of in vitro and in vivo potencies

(b) Insulin release in RINm5F cells

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

)

-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

(c) Glucose lowering in C57BL6 mice, 1 nmol/kg, n=5

(a) cAMP accumulation in RINm5F cells

CA-Exendin-4 showed more potent in vitro and in vivo potency compared to exendin-4

Table 1. Dissociation kinetics for GLP-1 receptor

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

(a) Receptor internalization in hGLP-1R/U2OS cells

(b) Cell surface receptors in hGLP-1R/CHO cells

Efpeglenatide induced less receptor internalization and retained more cell surface

receptors compared to liraglutide and dulaglutide.

ED50

0.13 nmol/kg

ED50

0.65 nmol/kg

>5 fold

(d) Dose dependencyin ipGTT C57BL6 mice, n=5

-4 -2 0 2 4

-4 0

-3 0

-2 0

-1 0

0

E x e n d in -4



% C

ha

ng

e o

f p

las

ma

glu

co

se

E x d -4 v s C A E x d -4

0 1 2

0

5

1 0

1 5V e h ic l e

E x e n d in - 4 1 n m o l /k g

C A -E x e n d in - 4 1 n m o l/k g

T im e (h r )

Blo

od

Glu

co

se

(m

mo

l/L

)

Figure 7. Development plan of QUANTUM project

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

Project.(KDDF-201204-03)

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 )In

su

lin

co

nc

. (%

of

co

ntr

ol)

-4 -2 0 2 4

-4 0

-3 0

-2 0

-1 0

0

E x e n d in -4



% C

ha

ng

e o

f p

las

ma

glu

co

se

kd (1/s, X10-3)

Liraglutide 2.8 ± 0.2

Dulaglutide 3.5 ±0.01

Efpeglenatide 10.1 ± 0.1

*** ***

Faster kd Slower kd

1 0 n M 1 0 0 n M

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

1 0 , 1 0 0 n M _ G L P -1 R A s @ 1 h

Su

rfa

ce

GL

P-1

re

ce

pto

r

(% o

f in

itia

l)

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

***

***

1 0 n M 1 0 0 n M

0

3 0 0

6 0 0

9 0 0

1 2 0 0

1 5 0 0

Inte

rna

liz

ed

GL

P-1

re

ce

pto

r

(% o

f in

itia

l) L ira g lu tid e

D u la g lu tid e


N o t r e a t

***

***

GLP-1R 0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

E x d -4 v s . C A -E x d -4

Su

rfa

ce

GL

P-1

re

ce

pto

r

(% o

f in

itia

l) C A -E x e n d in -4

N o tre a tm e n t

E x e n d in -4

METHODS • The receptor kinetics were measured by a SPR (Surface Plasmon Resonance) assay using immobilized extracellular domain of the human GLP-1 receptor which is fused to the GST (glutathione S transferase).

• 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 overexpressing CHO cells.

• Acute glucose lowering efficacy was investigated by intraperitonial glucose tolerance test following a single dose of various concentrations of exendin-4 analogs in normal C57BL/6 mice.

• Internalization of GLP-1 receptor was assessed in hGLP-1R/U2OS cells using the PathHunter™ eXpress Kit (DiscoveRx Corporation. Ltd., UK). Surface GLP-1 receptors were measured in hGLP-1R/CHO cells after pretreatment with 10 nM or 100 nM GLP-1RAs at 37°C for 5 min to 60 min. The remaining surface receptors were detected by binding of 100 pM125I-GLP-1 at 4°C for 4 h.

• In vitro activity after chronic treatment of GLP-1RAs was determined by measuring intracellular cyclic AMP in GLP-1R/CHO and insulin release in RINm5F cells. The cells were pre-treated with 10 nM of GLP-1RAs for 4 to 24 hours and followed by cAMP or insulinotropic induction by re-challenge with 0-5,000 nM of GLP-1RAs.

• In vivo efficacy between efpeglenatide and other GLP-1RAs was compared by subcutaneous administration in human PK fluctuation mimic condition, Change of blood glucose was monitored during 4 weeks and HbA1c was determined at the end point in db/db mice. Efficacy in body weight lowering and food intake inhibition was compared in DIO mice for 4 weeks.

European Association for the Study of Diabetes (EASD) 51st Annual Meeting, Stockholm, Sweden, 14-18 September 2015

AIMS

• To explore the mechanism of increased glucose lowering and weight loss by efpeglenatide

• To compare the glucose lowering and weight loss with the other GLP-1R agonists in extended dosing intervals

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

1 0 0 0

3 0 0 0

5 0 0 0

7 0 0 0

L ira v s . D U v s . H M 1 1 2 6 0 C (5 /2 1 _ R u n # 2 )_ D a ta 사 용

-a

rre

sti

n-2

re

cru

itm

en

t

(% o

f in

itia

l)

L ira g lu tid e

D u la g lu tid e

N o t r e a t


1 0 n M 1 0 0 n M1 n M 1 0 n M 1 0 0 n M 1 0 0 0 n M

1 0 0 0

3 0 0 0

5 0 0 0

7 0 0 0

L ira v s . D U v s . H M 1 1 2 6 0 C (5 /2 1 _ R u n # 2 )_ D a ta 사 용

-a

rre

sti

n-2

re

cru

itm

en

t

(% o

f in

itia

l)

L ira g lu tid e

D u la g lu tid e

N o tre a tm e n t


***

***

Figure 4. Comparison of DPP-IV susceptibility in long-term digestion

0 2 4 4 8 7 2 9 6 1 2 0

0

2 0

4 0

6 0

8 0

1 0 0

1 2 0

D P P -IV in c u b a tio n t im e (h r )

h G L P -1

L i r a g lu t id e

E x e n d in - 4

Re

lati

ve

cA

MP

ac

tiv

ity

(%v

s.

w/o

DP

P-4

)

C A -E x e n d in - 4

E f p e g le n a t id e

Hydrophobic

1. Exendin-4

8Ala 8Gly substitution

: Reducing affinity to substrate

binding pocket

2. Efpeglenatide

N-terminal modification

: Further reducing affinity

to binding pocket

P1 P2

Binding pocket of DPP-4

H G E G T FN’- H G E G T F

Susceptibility of efpeglenatide to DPP-IV

Figure 6. Glucose lowering by human monthly fluctuation mimic

condition in db/db mice (n=6, 4 weeks)

Efpeglenatide showed superior glucose lowering efficacy in monthly regimen

compared to liraglutide daily.

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 3 0 n m o l/k g , B ID (= 1 .8 m g /d a y in h u m a n )

E fp e g le n a tid e 5 .0 7 n m o l/k g , Q W (= 8 m g /m o n th in h u m a n )

T im e (d a y )

Bo

dy

We

igh

t C

ha

ng

e

(% v

s.

Da

y 0

)

E fp e g le n a tid e 7 .6 0 n m o l/k g , Q W (= 1 2 m g /m o n th in h u m a n )

0 7 1 4 2 1 2 8

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

V e h ic le

T im e (d a y )

Blo

od

Glu

co

se

(m

g/d

L)

L ira 3 0 n m o l/k g , B ID

5 .0 7 , Q W

7 .6 0 , Q W

A1c : 7.1%

A1c : 5.9%

A1c : 8.8%

A1c : 6.1%

5.9

Figure 5. Glucose lowering and body weight loss efficacy at human drug fluctuation

mimicking condition in diabetic and obese animal models

(a) Blood glucose lowering (db/db mice, =6, 4 wks)

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

Efpeglenatide showed superior glycemic control and weight loss compared to other

long-acting GLP-1RAs.

B W (% )

0 2 4 6 8

-1 5

-1 0

-5

0

5

V e h ic le


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 )

A c y la te d G L P -1 9 .4 9 n m o l/k g , Q 2 D (= 1 m g /h e a d in h u m a n )

L A P SC A -E x e n d in -4 1 .4 5 n m o l/k g , Q 2 D (= 2 m g /h e a d 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 )

T im e (d a y )

Bo

dy

We

igh

t C

ha

ng

e

(% v

s.

Da

y 0

)

L A P SC A -E x end in -4 4 .3 5 n m o l/k g , Q 2 D (= 6 m g /h e a d in h u m a n )

B lo o d g lu c o s e

0 7 1 4 2 1 2 8

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

V e h ic le

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

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

L A P SC A -E x e n d in -4 2 .8 9 n m o l/k g , Q 2 D (= 4 m g /h e a d in h u m a n )

T im e (d a y )

Blo

od

Glu

co

se

(m

g/d

L)

A1c 7.1% A1c 7.1%

A1c 5.9%

A1c 9.6%

In vivo efficacy of efpeglenatide depend on regimens

B W (% )

0 2 4 6 8

-1 5

-1 0

-5

0

5

V e h ic le


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

(% v

s.

Da

y 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%

-22.2%

+3.4%

B W (% )

0 7 1 4 2 1 2 8

-2 0

-1 0

0

1 0

V e h ic le

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

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

T im e (d a y )

Bo

dy

We

igh

t C

ha

ng

e

(% v

s.

Da

y 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 /h e a d in h u m a n )

Time (day)

Efpeglenatide is almost not susceptible from enzymatic degradation by DPP-IV

compared to liraglutide.

PS069-792 LAPS CA-Exendin-4 (efpeglenatide) Enhances ...HM11260C).pdf · LAPS CA-Exendin-4 (efpeglenatide) Enhances Insulin Secretion and Beta Cell Responsiveness in Subjects with

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