Lobeglitazone,
A Novel PPAR-γ agonist with balanced efficacy and safety
Kim, Sin Gon. MD, PhD.Professor,Division of Endocrinology and MetabolismDepartment of Internal Medicine, Korea University College of Medicine.
2013 International Conference on Diabetes and Metabolism
This symposium is sponsored by Chong Kun Dang Pharmaceutical Corp.I have received lecture and consultation fees from Chong Kun Dang.
Disclosure of Financial Relationships
Pros• Good glucose lowering• Durability (ADOPT)• Insulin sensitizing
effects (especially in MS, NAFLD, PCOS etc)
• Prevention of new-onset diabetes (DREAM, ACT-NOW)
• Less hypoglycemia• Few GI troubles• Outcome data
(PROactive)
Cons• Adverse effects
(edema, weight gain,CHF, fracture or rare macular edema etc)
• Possible safety issues(risk of MI? – Rosi orbladder cancer? - Pio)
Pros & Cons of PPAR-γ agonist
So, there is a need to develop PPAR-γ agonist with balanced efficacy and safety
1994 1997 1999 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Rosi, lipid profiles Rosi, lipid profiles
Dr. NissenDr. Nissen
Rosi (5)Rosi (5)
Pio (7)Pio (7)
PIO, bladder cancerPIO, bladder cancer
FDA, Black box
warning
FDA, Black box
warning
ADOPTADOPT BARI-2DBARI-2D
Rosi , CV safety
= no evidence
Rosi , CV safety
= no evidence
Tro out d/t
hepatotoxicity
Tro out d/t
hepatotoxicity
Rosi,
- REMS in USA
- Europe out
Rosi,
- REMS in USA
- Europe out
META analysis
(5,8)
META analysis
(5,8)RECORDRECORD
Dr. NissenDr. NissenDREAMDREAM
Rosi, Peak sale ($3.3 billion)
FDA, All diabetes
drug CV safety
FDA, All diabetes
drug CV safety
Discovery& Preclinical study Discovery& Preclinical study
2000.6-2004.6
Phase IPhase I Phase IIPhase II Phase IIIPhase III
CKD 5012004.11-2007.1 2007.3-2008.10 2009.11-2011.04
Lobeglitazone
Insulin Sensitizers : Several Issues
Discovery & Preclinical study Discovery & Preclinical study
2000.06 - 2004.06
Phase IPhase I
Phase IIPhase II
Phase IIIPhase III
2004.11 - 2007.01
2007.03 - 2008.10
2009.11 - 2011.04
EfficacyEfficacy
ADMEADME SafetySafety
• PPAR activity• In vitro & vivo efficacy• Potent efficacy
• In vitro screening•Metabolites• CYP 450• DDI
• Repeated dose toxicity• Geno toxicity• Reproductive toxicity• Carcinogenic toxicity
CV Safety / (Bladder) Cancer / Liver Toxicity / Bone loss
Developmental Strategy
Lobeglitazone (Duvie)
• PPAR-γ agonism4. MOA4. MOA
1. Structure1. Structure
N
N
OH3CO
NO
S
HNO O
H2SO4
3. Features3. Features • Insulin sensitizer• Favorable lipid profiles & Improves Metabolic Syndrome• Better safety (No bladder cancer in animal study)
2. Nomenclature2. Nomenclature • Durable (for a long time ) + Vie (a life), in French• A better life or longer life
C24H24N4O5S H2SO4 : MW = 578.62
DNA microarray analysis
72373 68
158
26
Glucose and lipid metabolismGlucose and lipid metabolism
Rosi Pio
Lobe
311 28
Gene Expression
In vitro study – PPARγ agonism
PPARγ
1000
nM
1000
nM
1000
nM
3.0
2.5
2.0
1.0
1.5
0.5
0
DM
SO
1 nM
10 n
M
100
nM
DM
SO
1 nM
10 n
M
100
nM
DM
SO
1 nM
10 n
M
100
nM
PioglitazoneLobeglitazone
Rosiglitazone
Dose(mg/kg/
d)
B.W (g)
Glucose(mg/dl)
Insulin(ng/ml)
TG(mg/dl)
NEFA(μEq/L)
Control - 359.8 ± 4.8 402.1 ± 15.4 16.6 ± 1.4 625.0 ± 46.0 685.7 ± 80.9
Lobeglitazone
0.03 491.4 ± 10.2*** 115.4 ± 8.1*** 27.0 ± 5.7 526.8 ± 50.5 206.1 ± 44.1***
0.1 530.9 ± 10.7*** 108.1 ± 5.4*** 10.2 ± 0.3* 282.0 ± 18.3*** 50.1 ± 4.0***
0.3 513.1 ± 11.2*** 105.6 ± 4.4*** 8.6 ± 1.1** 145.2 ± 9.8*** 15.7 ± 3.1***
Pioglitazone
10 522.0 ± 8.6*** 99.5 ± 1.7*** 10.0 ± 1.0* 213.8 ± 22.0*** 62.9 ± 12.6***
30 512.4 ± 11.7*** 103.4 ± 2.6*** 7.0 ± 0.6*** 159.3 ± 10.5*** 23.9 ± 3.3***
p.o., 28 days / Mean± SD. *<0.05, **<0.01, ***<0.001TG : triglyceride. NEFA : non-esterified fatty acid.
In vivo study – ZDF rats
1 Insulin Sensitizers and CV safety
2 Insulin Sensitizers and (Bladder) cancer
3 Insulin Sensitizers and Liver toxicity
4 Insulin Sensitizers and Bone loss
Safety – Toxicology data
Effect of Lobeglitazone on Plasma volume
Group Dose(mg/kg)
B.W.(g)
Heart Wt. Plasma Volume
g/kg Inc.% ml/kg Inc.%
Vehicle - 299 ± 26 2.91 ± 0.07 - 50.0 ± 3.5 -
Lobeglitazone
1 294 ± 13 2.91 ± 0.11 - 54.4 ± 5.0 8.8
3 292 ± 16 2.93 ± 0.14 0.7 58.0 ± 8.7 16.0
10 308 ± 26 2.95 ± 0.11 1.4 63.3 ± 3.8* 26.6
Pioglitazone10 301 ± 11 2.86 ± 0.20 -1.7 56.5 ± 3.0* 13.0
30 311 ± 26 2.90 ± 0.17 -0.3 57.5 ± 3.4* 15.0
p.o., qdx5/week, 4 weeksSD rat
Insulin Sensitizers & CV safety
1
2
Carcinogenic studies
Bladder tumor studies
Rodents [Mice & Rats]
Rodents [Rats]
Insulin Sensitizers & (Bladder) Cancer
Carcinogenicity in Mice
CompoundsDose
(mg/kg)LOAEL
(mg/kg)Neoplastic lesions AUC
(㎍.h/ml)Exposure
ratio
Lobeglitazone 0.2, 1.0, 6.0 > 6.0 - > 18 > 26
Rosiglitazone 0.4, 1.5, 6.0 > 6.0 - > 26 > 8.7
Pioglitazone 3, 10, 30, 100 30Pheochromocytoma
Leiomyosarcoma180 14
Troglitazone 50, 400, 800 400Hemagiosarcoma
Hepatocelluar carcinoma- 2
Muraglitazar 1, 5, 20 20 Adenoma 304 62
Insulin Sensitizers & (Bladder) Cancer – (1)
Uninary bladder tumors with pioglitazone [Male rats]
Urinary Bladder LesionIncidence by dose (mg/kg/day)
Vehicle Placebo 1 4 8 16 63
Males
Carcinoma, transitional cell 0 0 0 2 3 5 4
Transitional tumor, benign 0 0 0 0 4 2 2
Transitional hyperplasia 4 3 1 4 12 12 8
…… increased incidence of urinary bladder tumor ≥ 4 mg/kg/day (40 mg/human).
From pioglitazone NDA files
Insulin Sensitizers & (Bladder) Cancer – (2)
Uninary bladder hyperplasia with Lobeglitazone
Sex Male Female
Dose (mg/kg/day) Vehicle 0.03 0.12 1.0/0.24 Vehicle 0.03 0.06 0.12
Carcinoma,Transitional cell
- - - - - - - -
Transitional tumor, benign
- - - - - - - -
Urinary Bladder
Transitional cell hyperplasia
0 1 3 1 0 1 2 7
A 2-year carcionogenicity study in Rats
Insulin Sensitizers & (Bladder) Cancer – (3)
Scheme of 1o metabolic pathways involved in TGZ metabolism
Liver toxic metabolite
Drug metabolism and disposition. 2004;32:639-646.
Insulin Sensitizers & Liver toxicity – (1)
Lobeglitazone Rosiglitazone Troglitazone
Clinical dose (mg) 0.5 8 600
Liver : plasma ratio (rat) 0.85 0.5 15
Biliary recirculation No No Yes
Quinone metabolites No No Yes
In vitro liver toxicity (IC50) 57.6 uM 190 uM 37.5 uM
Half-life in humans (h) 9.5 (M), 15 ( F) 4 16-34
Cmax (liver) 0.085 μM 0.85 μM 95 μM
In vitro liver toxicity : Cmax 676 223 0.39
Insulin Sensitizers & Liver toxicity – (2)
Insulin Sensitizers & Bone Loss
Oil red O staining
MSC, male wistar rat (6 wks)
Rosiglitazone
Pioglitazone
Lobeglitazone
0.0
0.2
0.4
0.6
0.8
1.0
1.2
con 5nM 50nM 500nM 5uM 50uM
Rosiglitazone
Pioglitazone
Lobeglitazone
ALP activity
Relative Increase
A 52-week oral capsule toxicity study in monkeys
- No increased toxicity compared to pioglitazone
Lobeglitazone
An Evaluation of Glycemic Effects of LobeglitazoneMonotherapy in Patients With Type 2 Diabetes Mellitus
Monotherapy
Phase III clinical trial
Study Design - Monotherapy
� Objective: To assess the efficacy and safety of Lobeglitazone 0.5mg in T2DM
� Patients: 173 patient (Type 2 DM for a duration of at least 3 months)
� Dose: Lobeglitazone 0.5mg vs matching placebo (a 2:1 ratio)
� Treatment period: 24 weeks (extension to 52 weeks)
� Primary endpoint: HbA1c change from baseline
� Study sites: 5 sites in Korea
Visit 2 Visit 4 Visit 5 Visit 7
Randomization
Week-10 ~ -6
Week-2
Day0
Week4
Week10
Week24
Visit 3Visit 1
Run-in period(2 weeks)
Treatment period (24 Weeks)
Screening period(4 Weeks)
Visit 6
Week16
Placebo
Lobeglitazone 0.5 mgPlacebo(single blind)
Efficacy - HbA1c (Monotherapy)
Difference at 24 weeks
-0.2
0.0
0.2
0.1
-0.4
-0.6
-0.7
-0.1
-0.3
-0.5
0.09
-0.57
Mea
n ch
ange
from
bas
elin
e (%
)
0.66 % DifferenceP < 0.0001
Study week
7.8
8
8.2
7.6
7.2
7
7.4
HbA1c
(%
)
0 4 10 16 24
7.958.05 8.03
7.968.04
7.757.71 7.49
7.267.18
*
Placebo (N=43) Lobeglitazone 0.5 mg (N=87)
: P < 0.05 vs Baseline*
Lobeglitazone 0.5 mg (N=87)Placebo (N=43)
� A significant reduction in HbA1c was observed with lobeglitazone versus placebo
� The HbA1c target of <7% was achieved significantly more often in the lobeglitazonegroup compared to the placebo group
Efficacy – Response rate (Monotherapy)
A1c target achievement rate (%) <7.0 %
40
60
50
10
0
30
20
11.63%
51.72%
P < 0.0001
Lobeglitazone 0.5 mg (N=87)Placebo (N=43)
Effects on various gluco-metabolic andlipid parameters of lobeglitazone
Lobeglitazone (n=110) Placebo (n=58)
HOMA-IR 3.51 ± 1.86 2.80 ± 1.58c 4.30 ± 3.82 4.70 ± 5.25 0.002
HOMA- β 44.42 ± 23.02 54.93 ± 34.16c 44.48 ± 26.65 45.05 ± 35.89 0.0277
Total cholesterol
(mg/dL)178.70 ± 32.08 184.70 ± 34.48a 188.26 ± 37.66 193.10 ± 42.63 0.7191
Triglyceride (mg/dL) 137.51 ± 74.72 118.45 ± 56.24b 177.14 ± 119.34 193.28 ± 160.61 0.0006
HDL cholesterol
(mg/dL)48.69 ± 12.78 52.99 ± 13.62c 46.33 ± 13.56 47.09 ± 11.57 0.0038
LDL cholesterol
(mg/dL)109.00 ± 32.25 109.95 ± 32.89 114.76 ± 34.01 112.12 ± 29.83 0.6358
Small dense LDL (%) 8.10 ± 6.70 6.40 ± 6.55a 9.51 ± 6.81 10.13 ± 7.49 0.0033
Free Fatty acid (uEq/L) 622.28 ± 214.18 561.89 ±236.24a 699.57 ± 262.28 698.57 ± 253.69 0.0047
Apolipoprotein B
(mg/dL)80.15 ± 19.64 76.01 ± 18.73b 85.93 ± 21.85 86.43 ± 20.19 0.0046
� Lobeglitazone 0.5 mg significantly lowered the proportion of subjects with metabolic syndrome
Metabolic syndrome (Monotherapy)
-10
-6
0
-4
-16
-8
-12
0
-14 %
Abso
lute
diff
eren
ce in
pro
port
ion
of M
S (%
)
50
60
30
10
0
40
20
60.34
pro
port
ion
of s
ubje
cts
with
met
abolic
syn
dro
me
(%)
P = 0.0223
14%▼P = 0.0039
70
60.3455.45
41.82
-14
-2
0 week 24 week 0 week 24 week
Lobeglitazone 0.5 mgPlacebo
Lobeglitazone 0.5 mgPioglitazone 15 mg
Hypoglycemia & Weight (Monotherapy)
� Hypoglycemia was not observed in both treated groups
� More weight gain was observed in the lobeglitazone group than in the placebo group, about 1kg over 24 weeks
: P < 0.05 vs Baseline*
Placebo (N=58)
50
70
30
10
0
40
20
65.93
Wei
ght
(kg
)
80
66.55 67.38
0 week 24 week 0 week 24 week
*
60
*65.37
P < 0.0001
Hypoglycemia
PlaceboN (%)
0 (0%)
LobeglitazoneN (%)
0 (0%)
< Incidence rate of hypoglycemia >
Lobeglitazone 0.5 mg (N=112)
Adverse events summaryPlacebo N (%)
Lobeglitazone 0.5 mgN (%)
P value
Number of patients 58 112 -
Number of patients experienced an AE 30 (51.72) 55 (49.11) 0.7463
Number of patients experienced a SAE - 4 (3.57) 0.3005
Summary of AE (Monotherapy)
Number of patients experienced an ADR 3 (5.17) 10 (8.93) 0.5461
• Serious AEs in the lobeglitazone 0.5 mg group included lung cancer, traumatic cerebral
hemorrhage, cerebrovascular accident (underlying atrial fibrillation), and right scrotal
laceration and hemorrhoidectomy. These serious AEs were not considered by the
investigators to be related to the study medication.
• In addition, heart failure, ischemic heart disease, renal insufficiency, or bone
fracture was not observed in either group.
� Effectively controlled blood glucose(Significantly reduced HbA1c)
� Increased target HbA1C achievement rates
� Improved insulin resistance and beta-cell function
� Improved lipid profile(Significantly reduced triglyceride, small dense LDL-C and increased HDL-C)
� Lowered the proportion of subjects with metabolic syndrome
Summary (Monotherapy)
� Lobeglitazone 0.5 mg
� The safety profile was comparable between the two groups and lobeglitazone was well tolerated
Efficacy and Safety of Lobeglitazone Versus Pioglitazone
When Added to Metformin
Combination therapy
Phase III clinical trial
� Objective: To assess the efficacy and safety of Lobeglitazone 0.5 mg compared with Pioglitazone 15 mg as an add-on therapy in patients with T2DM
� Patients : 253 patient (Inadequate glycemic control while taking metformin alone (HbA1c 7~10%))
� Dose: Lobeglitazone 0.5mg vs Pioglitazone 15 mg
� Treatment period: 24 weeks (extension to 52 weeks)
� Primary endpoint: HbA1c change from baseline
� Study sites: 18 sites in Korea
Study design - Combination therapy
Visit 2 Visit 4 Visit 5 Visit 6Week
-15 ~ -7Week
-3Day1
Week4
Week12
Week24
Visit 3Visit 1
Run-in period(2주)
Treatment period(24주)
Screening
Metformin Placebo+ Metformin
Lobeglitazone 0.5 mg QD + Pioglitazone 15 mg placebo
Pioglitazone 15 mg QD + Lobeglitazone 0.5 mg placebo
Stabilization period(8주)
Randomization
Efficacy - HbA1c (Combination therapy)
� Lobeglitazone 0.5mg showed non-inferiority in HbA1c reduction compared to pioglitazone 15mg
7.80
8.00
7.60
7.20
7.00
7.40HbA1c
(%
)
0 4 12 24 week
7.93
7.79
7.40
7.17
7.92
7.74
7.31
7.100 week 24 week
7.60
7.80
7.20
6.80
6.60
7.40
7.00
7.93
8.00
7.92
7.17 7.10
0.82 %Difference
0.76 %Difference
**
: P < 0.05 vs Baseline*
Pioglitazone 15mg (N=103) Lobeglitazone 0.5mg (N=97)Lobeglitazone 0.5 mg (N=97)Pioglitazone 15mg (N=103)
Difference at 24 weeksStudy week
Mea
n ch
ange
from
bas
elin
e (%
)
� Proportion of patients achieving HbA1c < 7 % in the lobeglitazone group was comparable to the pioglitazone group
Response rate (Combination therapy)
Proportion of patients achieving HbA1c < 7 %
48.0
52.0
50.0
44.0
36.0
42.0
38.0
49.5151.55
NS
46.0
40.0
Pioglitazone 15 mg (N=103) Lobeglitazone 0.5 mg (N=97)
Insulin resistance and ß cell function(Combination therapy)� Both pioglitazone 15mg and lobeglitazone 0.5mg significantly improved insulin
resistance and β cell function
-0.40
0
-0.20
-1.20
-1.60
-0.60
-1.00
-1.34-1.49
Mea
n ch
ange
from
bas
elin
e
-0.80
6.00
9.00
7.00
2.00
0
5.00
3.00
7.70M
ean
chan
ge
from
bas
elin
e
4.00
0.015
0.003
0
0.012
0.006
0.013 0.013
Mea
n ch
ange
from
bas
elin
e
0.009
HOMA-β QUICKI
**
*HOMA-IR
NS
36.43%▼3.93%▲
-1.40 1.00
8.00
34.18%▼
6.82
16.67%▲15.21%▲
NS
*
*
NS
*
3.97%▲
: P < 0.05 vs Baseline*
Lobeglitazone 0.5 mg (N=97)Pioglitazone 15 mg (N=103)
Lipid profile - TG, FFA (Combination therapy)
� Both pioglitazone 15mg and lobeglitazone 0.5mg significantly improved triglyceride and free fatty acid levels
-40
-20
0
-10
-70
-90
-30
-50-59.70
Mea
n ch
ange
from
bas
elin
e (m
g/d
L)
-20.0
-10.0
0
-5.0
-30.0
-40.0
-45.0
-15.0
-25.0
-35.0
-17.48-14.7
Mea
n ch
ange
from
bas
elin
e (m
g/d
L)
*
NS
free fatty acid
11.09%▼10.38%▼
9.20%▼
12.45%▼
NS
Triglyceride
-60
-80
*
: P < 0.05 vs Baseline*
-84.60
*
Lobeglitazone 0.5 mg (N=97)Pioglitazone 15 mg (N=103)
Lipid profile-HDL-C, small dense LDL-C (Combination therapy)� Both Pioglitazone 15mg and Lobeglitazone 0.5mg significantly improved HDL-C
and small dense LDL-C levels.
-0.8
-0.4
0
-0.2
-1.2
-1.4
-0.6
-1.0
-1.25M
ean
chan
ge
from
bas
elin
e (m
g/d
L)
*
5
7
3
1
0
4
2
Mea
n ch
ange
from
bas
elin
e (m
g/d
L)
HDL-C
13.15%▲29.48%▼
*
10.07%▲
small dense LDL-C
16.38%▼
6 6.38
4.98
*NS
-0.78
NS
: P < 0.05 vs Baseline*
Lobeglitazone 0.5 mg (N=97)Pioglitazone 15 mg (N=103)
Subgroup Analysis – BMI (Combination Therapy)
-0.40
-0.20
-0.30
-0.70
-0.80
-0.50
-0.60
-0.85HbA1c
(%
) ch
ange
from
bas
elin
e -0.10
0
-0.93
-0.61-0.54
*
*
: P < 0.05 vs Baseline*
-0.90
-1.00
*
*< BMI 25 kg/m2 ≥ BMI 25 kg/m2
Lobeglitazone 0.5 mg (N=97)Pioglitazone 15 mg (N=103)
NS NS
-0.40
-0.20
-0.80
-0.60
-0.88
HbA1c
(%
) ch
ange
from
bas
elin
e
0
NS
-1.02
-0.60-0.53
*
*
: P < 0.05 vs Baseline*
-1.00
-1.20
NS
*
*
Male > 90 or Female > 80Male < 90 or Female < 80
Lobeglitazone 0.5 mg (N=97)Pioglitazone 15 mg (N=103)
Subgroup Analysis – Waist Circumference (Combination Therapy)
Hypoglycemia & Weight (Combination therapy)
� The incidence of hypoglycemia and weight gain were not different between the two groups
50
70
30
10
0
40
20
66.11
1.3%▲
Wei
ght
(kg
)
80
67.14 67.28 68.31
0 week 24 week 0 week 24 week
2.50
3.00
1.50
0.50
0
2.00
1.00
2.40
Hyp
ogly
cem
ia e
vent
(%)
NS
*
0.78
60
1.1%▲
NS
*
: P < 0.05 vs Baseline*
Lobeglitazone 0.5 mg (N=97)Pioglitazone 15 mg (N=103)
Adverse events summaryLobeglitazone 0.5 mg
N (%)Pioglitazone 15 mg
N (%)P value
Number of patients 128 125 -
Number of patients experiencing an AE 66 (51.56) 64 (51.20) 0.9540
Number of patients experiencing an SAE 7 (5.47) 6 (4.80) 0.8096
Summary of AE (Combination therapy)
Number of patients experiencing an ADR 8 (6.25) 6 (4.80) 0.6140
Summary (Combination therapy)
� A1c reduction
� Achievement rate in HbA1c goal
� Improvement in insulin resistance, β cell function, and lipid profiles
� Lobeglitazone 0.5mg was not inferior to pioglitazone 15mg regarding,
� The safety profile was comparable between the two groups and lobeglitazone was well tolerated
Conclusion
� Lobeglitazone 0.5 mg showed improvements in glucose and lipids endpoints with a favorable safety profile. The results support lobeglitazone as a promising option for treating type 2 diabetes, especially in patients with metabolic syndrome
Thank you for
Your Attention !