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The ultra-long acting LAPSGLP/GCG dual agonist, HM12525A, demonstrated safety and prolonged pharmacokinetics in healthy volunteers: a phase 1 first-in-human study
Jahoon Kang1, Ji-Hye Kim1, Jiyoung Yi1, OakPil Han1, Youngmin Kim1, Eunhye Baek1, Sung Yeob Jung1, Se Chang Kwon1, Michael E. Trautmann2, Marcus Hompesch2
1Hanmi Pharmaceutical Co., Ltd. Seoul, Republic of Korea,2Profil™ Institute for Clinical Research, Inc., Chula Vista, CA, USA
ABSTRACT
51st European Association for the Study of Diabetes (EASD), Stockholm, Sweden; September 14 - 18, 2015
PS-069-791
REFERENCES • Estall, J. L. and Drucker, D. J. (2006). Glucagon and glucagon-like peptide receptors
as drug targets. Curr Pharm Des 12, 1731-50.
• Lorenz M, Evers A, Wagner M. Recent progress and future options in the development
of GLP-1 receptor agonists for the treatment of diabesity. Bioorg Med Chem Lett
2013;23(14):4011-8.
Contact Information: Jahoon Kang, Executive Director, Hanmi Pharma., Co., Ltd
e-mail: [email protected]
Phone: +82-2-410-9041
RESULTS
Table 1. Baseline Characteristics
• HM12525A is a novel ultra-long-acting
dual agonist which consists of a
chemically synthesized GLP-1/GCG
peptide, conjugated with a human IgG
Fc fragment via a flexible PEG linker
• HM12525A exhibits a well balanced
agonism at the GLP-1 receptor and
the glucagon receptor (1:1 ratio)
Overview of HM12525A
Study Objectives
• Primary objective
- To evaluate safety and tolerability of HM12525A in healthy
volunteers after single administration of HM12525A
• Secondary objectives
- To assess pharmacokinetics(PK) profile of HM12525A
- To assess effects of HM12525A on glucose metabolic profiles
BACKGROUND Potential beneficial effects of GLP-1/GCG dual agonist
• Decrease food intake and increase glucose-dependent insulin
secretion through GLP-1 activity
• Energy expenditure and lipolysis increased by GCG activity
STUDY DESIGN Figure 1. Study Design
Figure 2. Serum PK exposure of HM12525 (linear scale)
N (%) Placebo HM12525A (nmol/kg)
(N=10) 0.25
(N=6) 0.5
(N=6) 1.0
(N=6) 2.0
(N=6) 4.0
(N=6)
ADA at any time1)
0 (0) 1 (16.7) 1 (16.7) 2 (33.3) 3 (50.0) 0 (0)
Emerging ADAs
during study2) 0 (0) 0 (0) 1 (16.7) 1 (16.7) 2 (33.3) 0 (0)
Neutralizing ADAs 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
Injection site
reaction 0 (0) 0 (0) 0 (0) 1 (16.7)* 0 (0) 0 (0)
Injection site reaction
within ADA-positive
subjects 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
1) The number of subjects who were positive for anti-drug antibody at any time
2) The overall incidence of treatment-induced ADAs and treatment-boosted ADAs (4-fold or greaterincrease in titer from baseline measurement)
3) * Mild injection site erythema (diameter: 50 mm) was reported on Day 2 .
Figure 4. Incidence of gastrointestinal events
- Note: GI events include nausea, vomit, diarrhea, and appetite decrease.
Figure 3. 24hr ambulatory monitoring: systolic/diastolic
blood pressure and heart rate at peak PK concentration
• The confirmed long half life after a single dose supports the
potential use of HM12525A for weekly or longer injection intervals.
• Heart rate elevation was observed with increasing dose levels,
while no clinically relevant changes in BPs during 24hr ABP
monitoring at peak concentration were observed.
• As expected, GI disorders—known to be related to the mode of
action of GLP-1 and GCG—were the major AEs, and no clinically
meaningful changes in laboratory parameters were observed.
• Low incidence of treatment emergent antibodies and no
neutralizing antibodies were observed.
• Further clinical trials will investigate the efficacy and the safety in
the disease population.
CONCLUSIONS
Placebo HM12525A (nmol/kg) 0.25
(N=6) 0.5
(N=6) 1.0
(N=6) 2.0
(N=6) 4.0
(N=6) (N=10)
Age: years (SD) 49.2 (10.7) 52.3 (11.9) 51.3 (4.9) 41.3 (9.8) 40.7 (11.6) 54.3 (6.2)
Sex: F/M (%) 50/50 17/83 33/67 0/100 17/83 50/50
Race (%)
White 10 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0) 6 (100.0)
Weight: kg (SD) 86.8 (14.0) 102.1 (7.5) 95.9 (10.7) 103.1 (9.5) 95.5 (11.6) 83.3 (18.8)
BMI: kg/m2 (SD)
28.5 (4.3) 31.8 (2.2) 30.0 (2.5) 31.9 (1.3) 29.2 (3.3) 27.9 (3.4)
HM12525A (nmol/kg)
0.25 (N=6)
0.5 (N=6)
1.0 (N=6)
2.0 (N=6)
4.0 (N=6)
Cmax (pmol/L) 1,004 (24.0) 1,213 (36.7) 4,236 (34.9) 7,750 (26.6) 14,190 (22.8)
Tmax (hr) 104.8 (27.5) 128.2 (39.1) 75.4 (76.6) 89.0 (55.5) 103.8 (101.1)
T1/2 (hr) 172.5 (38.6) N/C* 130.6 (12.4) 136.9 (17.1) 176.3 (14.4)
AUC0-inf (hr*nmol/L) 386.6 (22.6) N/C* 1,350 (27.8) 2,608 (13.7) 6,040 (20.6)
1) Presented data are geometric means with geometric CV (%).
2) * Not calculated: analysis is unavailable to be performed.
Screening
4 weeks
Ra
nd
om
iza
tio
n
HM12525A 0.25 nmol/kg or Placebo
HM12525A 0.5 nmol/kg or Placebo
HM12525A 1.0 nmol/kg or Placebo
HM12525A 2.0 nmol/kg or Placebo
HM12525A 4.0 nmol/kg or Placebo
4 weeks
4 weeks treatment period
HM12525A : Placebo = 3:1 (Total N = 40)
Follow up
N (%) [#AEs] Placebo HM12525A (nmol/kg)
(N=10) 0.25
(N=6) 0.5
(N=6) 1.0
(N=6) 2.0
(N=6) 4.0
(N=6)
Any AESIs 2 (33.3) [2] 0 (0) [0] 0 (0) [0] 2 (33.3) [4] 4 (66.7) [12] 6 (100.0) [16]
Nausea 0 (0) [0] 0 (0) [0] 0 (0) [0] 1 (16.7) [1] 4 (66.7) [7] 5 (83.3) [6] Mild 0 (0) [0] 0 (0) [0] 0 (0) [0] 1 (16.7) [1] 3 (50.0) [5] 3 (50.0) [3]
Moderate 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 2 (33.3) [2] 3 (50.0) [3] Severe 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0]
Vomit 1 (16.7) [1] 0 (0) [0] 0 (0) [0] 1 (16.7) [1] 4 (66.7) [4] 3 (50.0) [5] Mild 1 (16.7) [1] 0 (0) [0] 0 (0) [0] 1 (16.7) [1] 2 (33.3) [2] 1 (16.7) [2]
Moderate 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 2 (33.3) [2] 3 (50.0) [3] Severe 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0]
Diarrhea 1 (16.7) [1] 0 (0) [0] 0 (0) [0] 0 (0) [0] 1 (16.7) [1] 1 (16.7) [1] Mild 1 (16.7) [1] 0 (0) [0] 0 (0) [0] 0 (0) [0] 1 (16.7) [1] 1 (16.7) [1]
Moderate 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] Severe 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0]
Appetite loss 0 (0) [0] 0 (0) [0] 0 (0) [0] 2 (33.3) [2] 0 (0) [0] 4 (66.7) [4] Mild 0 (0) [0] 0 (0) [0] 0 (0) [0] 2 (33.3) [2] 0 (0) [0] 0 (0) [0]
Moderate 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 4 (66.7) [4] Severe 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0] 0 (0) [0]
Table 2. Summary of gastrointestinal events General safety summary
Table 3. Summary of immunogenicity
Tmax= 75~128 hr
T1/2= 131~176 hr
• Most of GI events were mild and moderate, and observed at high dose
levels(HM12525A 1.0, 2.0, and 4.0 nmol/kg).
• No major changes in systolic and diastolic blood pressure at Tmax.
• Overall elevation in the mean heart rate with high dose exposure
(HM12525A 2.0 and 4.0 nmol/kg) compared to placebo 5.8 and 8.1 bpm,
respectively (LS-means).
• Treatment-induced and treatment-boosted anti-drug-antibodies (ADA) were
detected in 4 subjects out of 7 subjects with ADA-positive results.
• No neutralizing antibodies were observed
• No obvious ADA induced-interference with PK profiles
• Total 99 TEAEs occurred; 84 were related to HM12525A, while no SAE
was observed.
• The majority of TEAEs were GI disorders; 34% of TEAEs were nausea,
vomit, diarrhea, and appetite loss.
• No elevations of liver/pancreas enzymes (lipase, amylase > 3x ULN or
bilirubin >2x ULN) were seen, except in one subject on placebo.
• No major safety observations in any other laboratory values.
• No subject discontinuation occurred.
1) Presented data are mean plot of each treatment groups and placebo.
2) * ABPM was assessed on Day 4 in subjects treated with HM12525A 0.25, 0.5 and 1.0 nmol/kg,and on Day 5 in those treated with HM12525A 2.0 and 4.0 nmol/kg.
Day -1 Day 4/5*
Day -1 Day 4/5*
Day -1 Day 4/5* Background and aims Glucagon-like peptide-1 (GLP-1)
/glucagon (GCG) dual agonists may have potential to treat
obesity and diabetes by activating both GLP-1 and GCG
receptors. The once-weekly LAPSGLP/GCG dual agonist,
HM12525A, is site-specifically conjugated by LAPSCOVERY
technology for sustained duration of activity. By combining the
synergetic GLP-1/GCG effects with this long-acting platform,
HM12525A may improve patient compliance and thereby
treatment outcomes further. This First-in-Human, Phase I,
randomized, double-blind, placebo-controlled single
ascending dose study evaluated the safety, tolerability, PK
and PD of HM12525A in healthy volunteers.
Materials and methods Forty subjects (age: 48.3±10.4
years; male: 70%; BMI: 29.7±3.3kg/m2) were randomly
assigned to 5 cohorts (0.25, 0.5, 1.0, 2.0, and 4.0 nmol/kg),
and received a single subcutaneous injection of either
HM12525A or placebo (ratio, 3:1). The total duration of the
study was 56 days, including follow up.
Results HM12525A demonstrated prolonged PK profiles.
The observed Cmax in each cohort ranged from 0.759 to 18.5
nmol/L at 113.1±55.3 hr post-dose. AUC0-last (120 to 6560
hr·nmol/L) and T1/2 (112.5 to 276.2 hr) was also observed.
Among the 5 cohorts, the maximum tolerated single dose was
determined at a dose level of 2.0 nmol/kg. Overall, none of
the subjects exhibited any clinically significant alterations in
vital signs, laboratory values, and 24hr ambulatory ECG.
During 24hr ambulatory blood pressure (24hr ABP)
assessments, no significant change in heart rate (HR) was
observed up to 1.0 nmol/kg dose. At 2.0 and 4.0 nmol/kg
doses, mean HR was elevated by 5.77±2.30 and 8.06±2.56
(p-value: 0.017 and 0.004) compared to placebo, while mean
systolic and diastolic BPs showed no significant changes.
Anti-drug antibodies were detected in 7 subjects; 3 subjects
already had ADA at baseline, while the other 4 were newly
detected during the study. None of these 7 subjects had
neutralizing antibodies. The most frequent treatment
emergent adverse events (TEAEs) were gastrointestinal
disorders, such as nausea and vomiting. No serious TEAEs
were occurred.
Conclusion In summary, this single ascending dose study
demonstrated that HM12525A had a prolonged PK profile and
was well tolerated, confirming the potential for once-weekly
injections. Further investigation in T2DM patients will explore
the synergistic potential of this LAPSGLP/GCG dual agonist to
provide for a beneficial and effective therapeutic regimen.
790-P
Potent weight loss mechanism and improvement of NASH by the long-acting GLP-1/Glucagon receptor dual agonist HM12525A
SY Jung1, JS Lee1, JY Kim1, SH Kim1, YM Lee1, YH Kim1, JH Kang1, M Trautmann2, M Hompesch2, SC Kwon1 1Hanmi Pharm. Co., Ltd., Seoul, South Korea, 2Profil Institute, Chula Vista, CA, USA
RESULTS
BACKGROUND
METHODS
European Association for the Study of Diabetes (EASD) 51st Annual Meeting, Stockholm, Sweden, 14-18 September 2015
AIMS
Dual agonists activating the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCG-R) may represent a new therapeutic approach for obesity with the potential for enhanced weight loss beyond those of GLP-1R agonists. Oxyntomodulin, a human gut hormone with agonism to the GLP-1R and the GCG-R, causes a significant reduction in weight by regulating both, appetite and energy expenditure, however its clinical application is limited due to a short half-life. HM12525A is a long-acting GLP-1/glucagon receptor dual agonist for once-weekly administration. It consists of a GLP-1/ glucagon receptor dual agonist conjugated via non-peptidyl linker to a non-glycosylated human Fc fragment. The aim of this development was to achieve increased body weight loss (BWL) compared to GLP-1R agonists while extending the half-life.
• To investigate the mechanism for potent anti-obesity efficacy by HM12525A • To investigate the effect on nonalcoholic steatohepatitis (NASH) by
HM12525A
Potent BWL mechanism by HM12525A vs. GLP-1RAs • Decrease food intake by GLP-1 activity • Increase of EE and lipolysis by glucagon activity
Anti-Obesity efficacy beyond GLP-1RAs
Brain
Appetite ↓
Muscle
Pancreas
Insulin secretion ↑
EE ↑
HM12525A GLP-1/Glucagon dual agonist
Fat mass ↓ EE ↑ (Browning ↑)
Adipose tissue
• Animal study DIO rats were treated (s.c) with HM12525A Q3D and liraglutide BID for 3 weeks, respectively. Pair-fed controls were given a daily food allotment equal to that consumed by a drug-treated group. The body weight and food intake was monitored daily. DIO mice were treated (s.c) with HM12525A QW and liraglutide QD for 4 weeks. The body weight, fat mass, and lean mass were measured.
Figure 1. Body weight loss in DIO rats (n=7, 3wks) (a) Body weight change (b) Cumulative Food Intake
0 3 6 9 1 2 1 5 1 8 2 1-4 0
-3 0
-2 0
-1 0
0
1 0
T im e (d a y s )
' B
W (
% v
s.
Ve
hic
le)
V e h ic le
H M 1 2 5 2 5 A 3 .3 n m o l/k g
L ira g lu tid e 2 5 n m o l/k g B ID
H M 1 2 5 2 5 A 2 .2 n m o l/k g
H M 1 2 5 2 5 A p a ir fe d
L ira g lu tid e p a ir fe d
0 3 6 9 1 2 1 5 1 8 2 1-4 0
-3 0
-2 0
-1 0
0
1 0
T im e (d a y s )
' B
W (
%v
s.
Ve
hic
le)
V e h ic le
L ira g lu t id e 2 5 n m o l/k g B ID (3 m g /d a y in h u m a n )
P a ir - fe d _ L ira g lu t id e 2 5 n m o l/k g
0 3 6 9 1 2 1 5 1 8 2 1-4 0
-3 0
-2 0
-1 0
0
1 0
T im e (d a y s )
' B
W (
%v
s.
Ve
hic
le)
H M 1 2 5 2 5 A 3 .3 n m o l/k g Q 3 D (6 m g /w k in h u m a n )
H M 1 2 5 2 5 A 2 .2 n m o l/k g Q 3 D (4 m g /w k in h u m a n )
P a ir - fe d _ H M 1 2 5 2 5 A 3 .3 n m o l/k g
Drug class (Compound) Animal Dose (nmol/kg)
Body weight (% vs. Vehicle)
Food intake (% vs. vehicle)
GLP-1RA (Liraglutide) 25, BID -15 % -23 % Pair-fed -12 %
Dual agonist (HM12525A) 2.2, Q3D -17% -19 % 3.3, Q3D -32% -37 % Pair-fed -16 %
¾HM12525A showed superior body weight loss compared with Liraglutide ¾Potent BWL effect of HM12525A is twice than pair-fed groups indicating increase of EE
ns
***
ns, p>0.05, ***p < 0.001 by T-test
0 3 6 9 1 2 1 5 1 8 2 10
1 0 0
2 0 0
3 0 0
4 0 0
T im e (d a y s )
Cu
mu
lati
ve
fo
od
in
tak
e(g
)
V e h ic le
H M 1 2 5 2 5 A 3 .3 n m o l/k g
L ira g lu tid e 2 5 n m o l/k g B ID
H M 1 2 5 2 5 A 2 .2 n m o l/k g
Figure 2. In vitro increase of EE specific marker gene expression
-32%
-15%
(a) 3T3-L1 adipocytes (b) C2C12 myocytes
P G C 1 a N R F 1 U C P 10 .0
0 .5
1 .0
1 .5
2 .0
2 .5
mR
NA
(Ex
pre
ss
ion
le
ve
l v
s.
co
ntr
ol)
** ** * **
** ** *
*
*
P G C 1 a N R F 1 U C P 20 .0
0 .5
1 .0
1 .5
2 .0
2 .5
mR
NA
(Ex
pre
ss
ion
le
ve
l v
s.
co
ntr
ol)
* *
* ** **
**
**
**
*
*p<0.05, **p<0.01 vs. control by ANOVA test
¾HM12525A induces the expression of PGC1α, NRF-1, and UCP as an action of glucagon in adipocytes and myocytes indicating the increase of EE
P GC 1 a
N R F 1
U C P 1
0 .0
0 .5
1 .0
1 .5
2 .0 C o n tro l
H M 1 2 5 2 5 A 1 0 PM
H M 1 2 5 2 5 A 1 PM
G lu c a g o n 0 .3 PMm
RN
A(E
xp
res
sio
n l
ev
el
vs
. c
on
tro
l)
L ir a g lu t id e 1 0 PM
P GC 1 a
N R F 1
U C P 1
0 .0
0 .5
1 .0
1 .5
2 .0 C o n tro l
H M 1 2 5 2 5 A 1 0 PM
H M 1 2 5 2 5 A 1 PM
G lu c a g o n 0 .3 PM
mR
NA
(Ex
pre
ss
ion
le
ve
l v
s.
co
ntr
ol)
L ir a g lu t id e 1 0 PM
†Abbreviation UCP : Uncoupling protein, PGC1a : PPARg coactivator 1a, NRF-1 : Nuclear respiratory factor 1
Figure 3. In vitro induction of mitochondria biogenesis
HM12525A (10 μM)
Control
Glucagon (0.3 μM)
(a) Mitochondria staining Myocytes Adipocytes
(b) Relative intensity
Ad ip o c yte s M yo c yte s0 .0
0 .5
1 .0
1 .5
2 .0
Rel
ativ
e in
tens
ity(g
ree
n s
ign
al/c
ell)
* * *
P GC 1 a
N R F 1
U C P 1
0 .0
0 .5
1 .0
1 .5
2 .0 C o n tro l
H M 1 2 5 2 5 A 1 0 PM
G lu c a g o n 0 .3 PM
mR
NA
(Ex
pre
ss
ion
le
ve
l v
s.
co
ntr
ol)
*p<0.05 vs. control by ANOVA test
¾HM12525A increased the mitochondrial biogenesis in both adipocytes and myocytes
¾HM12525A reduced BW and fat mass without a change in lean body mass supporting that increasing EE may be the driving force for the potent BWL.
Figure 4. Body composition change in DIO mice (n=10, 4 wks)
0
2 0
4 0
6 0
Bo
dy
we
igh
t (g
)
-23 %
0
1 0
2 0
3 0
Fa
t m
as
s (
g)
0
2 0
4 0
6 0
Bo
dy
le
an
(g
)
(a) Body weight (b) Body fat mass (c) Lean body mass
ns p>0.05, *** p<0.001 vs. vehicle by ANOVA test
*** -49 % ***
ns
Anti-NASH efficacy beyond GLP-1RA
METHODS • Animal study
ALIOS- and MCD-diet C57BL/6 mice were treated (s.c) with liraglutide BID and HM12525A (Q2D) for 4 weeks, respectively. After 4 weeks treatment, the hepatic TG level and liver histology by H&E staining were evaluated. In addition, TNF-D (as a inflammation marker) and collagen-1 mRNA (as a fibrosis marker) level were determined by quantitative PCR analysis from liver extracted after treatment for 4 weeks.
“NASH is high prevalence disease without approved medical therapy”
Drug class Body Wight
b-oxidation (CPT-1)
TG Level
Early stage Late stage NAFLD activity score
Inflammation (TNF-α)
Fibrosis (Collagen-1)
Steatosis /Inflammation/ Ballooning
GLP-1RA
Dual agonist
RESULTS
*p<0.05, **p<0.01, *** p<0.001 vs. Normal+ALIOS by ANOVA test †p<0.05, ††p<0.01 by T-test
(a) Hepatic TG level
H e p a t ic T G le v e l
0
5 0
1 0 0
1 5 0
H M 1 2 5 2 5 A 0 .7 n m o l/k g Q 2 D (1 m g /w k in h u m a n )
H M 1 2 5 2 5 A 1 .4 n m o l/k g Q 2 D (2 m g /w k in h u m a n )
He
pa
tic
TG
le
ve
l (m
g/g
)
**
H e p a t ic T G le v e l
0
5 0
1 0 0
1 5 0
N o r m a l (C h o w )
N o r m a l + A L IO S
L ir a 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 )
He
pa
tic
TG
le
ve
l (m
g/g
)
**
(b) Collagen-1 mRNA (C) Steatosis score
0
2
4
6
8
A L IO S d ie t
H M 1 2 5 2 5 A 0 .7 n m o l/k g /Q 2 D
H M 1 2 5 2 5 A 1 .4 n m o l/k g /Q 2 D
L ira g lu tid e 3 0 n m o l/k g /B ID
Ste
ato
sis
sc
ore
gra
de
of f
ind
ing
(0
-1
0)
ALIO
S
*** ***
***
††
0
1
2
3
4
5
o b /o b + A L IO S
H M 1 2 5 2 5 A , 0 .7 n m o l/k g , Q 2 D
H M 1 2 5 2 5 A , 1 .4 n m o l/k g , Q 2 D
L ir a g lu t id e , 5 0 n m o l/k g , B ID
Co
lla
ge
n-1
mR
NA
(fo
ld v
s c
on
tro
l)
* ***
†
ALIO
S
0
2 0
4 0
6 0
8 01 5 0
2 0 0
2 5 0
A L IO S + v e h ic le
H M 1 2 5 2 5 A 0 .7 n m o l/k g /Q 2 D
H M 1 2 5 2 5 A 1 .4 n m o l/k g /Q 2 D
L ira g lu tid e 5 0 n m o l/k g B ID
He
pa
tic
TG
(m
g/g
)
***
***
***
†
ALIO
S
ALIOS or chow diet for 16 wks.
C57BL/6 1. Food Source: High fat, 55% fructose and 45% sucrose (added in water, wt/vol) 2. Expected NASH stage: Steatosis
¾ HM12525A significantly reduces hepatic TG, collagen-1and steatosis score indicating therapeutic potential for liver disease.
Figure 5. Therapeutic potential in ALIOS diet mice (n=7, 4 weeks)
• In DIO rats, HM12525A showed superior body weight loss compared with liraglutide and the potent BWL effect of HM12525A is twice than pair-fed groups indicating increase of EE
• HM12525A induces the expression of EE specific marker gene (i.e. PGC1α, NRF-1, and UCP) and mitochondria biogenesis as an action of glucagon in adipocytes and myocytes
• HM12525A reduced BW and fat mass without a change in lean body mass supporting that increasing EE may be the driving force for the potent BWL
• In NASH animal models, HM12525A reduces hepatic TG, inflammation, fibrosis marker, and histological scores
• Our results suggest that the novel GLP-1/glucagon dual agonist HM12525A may have clinical potential for the treatment of obesity and obesity-related liver disease.
¾HM12525A reduced TNF-D (pro-inflammation cytokine), collagen-1 mRNA (pro-fibrogenic marker), and NAFLD activity score more than liraglutide
Figure 6. Therapeutic potential in MCD mice (n=7, 4 weeks)
CONCLUSIONS
REFERENCES
Figure 7. Clinical development milestone
• JA Parker et al. (2013). International Journal of Obesity: 1-8.
• Patel V et al. (2013) Can J Physiol Pharmacol. 91(12):1009-15.
• Jornayvaz FR et al. (2010) Essays Biochem. 47:69-84.
1. High sucrose (40%) , fat (10%), methionine (-), and choline (-) 2. Expected NASH stage: steatosis Æ InflammationÆ fibrosis MCD or chow
diet for 4 wks.
B W C (g ) v s p re d o s e
-1 0
-5
0
5
1 0
o b /o b ( L F D )
C o n t r o l (o b /o b + H T F )
L A P S G L P /G C G 0 .7 n m o l/k g /Q 2 D (= 0 .9 5 m g in h u m a n )L A P S G L P /G C G 1 .4 n m o l/k g /Q 2 D (= 1 .9 m g in h u m a n , F IH )
L ir a g lu t id e 3 0 n m o l/k g /B ID (1 .8 m g in h u m a n , N A S H )
Bo
dy
we
igh
t ch
ang
e (g
)v
s p
red
ose
L A P S C A - E x e n d in -4 0 .7 n m o l/k g /Q 2 D (= 1 .0 m g in h u m a n )L A P S C A -E x e n d in -4 1 .4 n m o l/k g /Q 2 D (= 2 .0 m g in h u m a n , D ia b e te s )L A P S C A -E x e n d in -4 2 .9 n m o l/k g /Q 2 D (= 4 .0 m g in h u m a n , O b e s it y )
B W C (g ) v s p re d o s e
-1 0
-5
0
5
1 0
N o r m a l (C h o w )
V e h ic le ( M C D )
L A P S G L P /G C G 0 .7 n m o l/k g /Q 2 D (= 0 .9 5 m g in h u m a n )L A P S G L P /G C G 1 .4 n m o l/k g /Q 2 D (= 1 .9 m g in h u m a n , F IH )L A P SC A -E x e n d in -4 0 .7 n m o l/k g /Q 2 D (= 1 .0 m g in h u m a n )L A P SC A -E x e n d in - 4 1 .4 n m o l/k g /Q 2 D ( = 2 .0 m g in h u m a n , D ia b e t e s )L A P SC A -E x e n d in -4 2 .9 n m o l/k g , Q 2 D (= 4 .0 m g in h u m a n , O b e s ity )
L ir a g lu t id e 3 0 n m o l/k g /B ID (= 1 .8 m g in h u m a n , D ia b e t e s )
L ir a g lu t id e 5 0 n m o l /k g /B ID (= 3 .0 m g in h u m a n , O b e s ity )
Bo
dy
we
igh
t ch
ang
e (g
)v
s p
red
ose
B W C (g ) v s p re d o s e
-1 0
-5
0
5
1 0
o b /o b ( L F D )
C o n t r o l (o b /o b + H T F )
H M 1 2 5 2 5 A 0 .7 n m o l/k g /Q 2 D (0 .9 5 m g in h u m a n )
H M 1 2 5 2 5 A 1 .4 n m o l/k g /Q 2 D (1 .9 m g in h u m a n )
Bo
dy
we
igh
t c
ha
ng
e (
g)
vs
pre
do
se
• Gene expression in adipocytes and myocytes 3T3-L1 adipocytes and C2C12 myocytes were differentiated for 2 and 3 days, respectively. Cells were treated with glucagon, HM12525A or liraglutide for 24 hours. PGC1α, NRF1, and UCP gene expression were evaluated by quantitative real-time PCR analysis.
• Confocal microscopic analysis for mitochondria biogenesis 3T3-L1 adipocytes and C2C12 myocytes were differentiated for 2 and 3 days, respectively. Cells were treated with glucagon or HM12525A for 48 hours. Cells were stained with Mitotracker (Invitrogen) and Hoechst (Molecular Probes). The cell images were obtained by confocal microscopy (Carl Zeiss).
(d) Liver histology (H&E staining) Normal Chow Vehicle (MCD) Liraglutide 50 nmol/kg, BID HM12525A 1.4 nmol/kg, Q2D
Healthy liver Steatosis Inflammation Fibrosis Cirrhosis
Fat accumulation
Early stage Late stage
Progression of NASH
(a) TNF-D mRNA (b) Collagen-1 mRNA (c) NAFLD activity score
0
5
1 0
N o rm a l (C h o w )
N o rm a l + M C D
L ira g lu tid e , 3 0 n m o l/k g , B ID
H M 1 2 5 2 5 A , 0 .7 n m o l/k g , Q 2 D
H M 1 2 5 2 5 A , 1 .4 n m o l/k g , Q 2 D
TN
F- D
mR
NA
(fo
ld v
s c
on
tro
l)
0 .0
0 .5
1 .0
1 .5
2 .0
2 .5
N o r m a l (C h o w )
N o r m a l + M C D
H M 1 2 5 2 5 A , 0 .7 n m o l/k g , Q 2 D
H M 1 2 5 2 5 A , 1 .4 n m o l/k g , Q 2 D
L ir a g lu t id e , 3 0 n m o l/k g , B ID
Co
lla
ge
n-1
mR
NA
(fo
ld v
s c
on
tro
l)
0
2
4
6
N o rm a l (C h o w )
N o rm a l + M C D
H M 1 2 5 2 5 A 0 .7 n m o l/k g /Q 2 D
H M 1 2 5 2 5 A 1 .4 n m o l/k g /Q 2 D
L ira g lu tid e 3 0 n m o l/k g /B ID
NA
S (
0~
10
po
int)
*** ***
***
**
***
** ***
***
†††
†††
**p <0.01, ***p<0.001 vs. Vehicle (MCD) by ANOVA test †††p<0.001 by T-test
HM12525A 2015 2016 2017 2018 2019 2020 BLA submission
Healthy Obese (SAD) Obese T2DM (MAD)
T2DM 2019
Obesity 2020 P3 P2
P3 P2
P1
