victoza cs pi fda v6 draft
TRANSCRIPT
Microsoft Word - Victoza CS PI FDA v6 draftPage 1
: C LiraglutideC Victoza®
MTC2(Multiple Endocrine Neoplasia syndrome type 2, MEN 2)calcitonin
calcitonin
C
calcitonin
1 2 metformin sulphonylurea
metformin sulphonylurea metformin sulphonylurea
metformin thiazolidinedione metformin
sulphonylurea metformin thiazolidinedione 1.1 C Victoza®
Victoza®
Victoza®
Victoza®
Victoza®
Victoza® insulin Victoza® 1
(prandial insulin) Victoza®
2 Victoza®
Victoza® 0.6 mg 0.6 mg
0.6 mg
1.2 mg 1.2 mg 1.8 mg Victoza®(
sulphonylureas) [(5.3)(6)] Victoza® insulin Victoza® insulin
Victoza®
3 0.6 mg
Victoza®
Victoza® 3
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0.6 mg, 1.2 mg, 1.8 mg (6 mg/mL, 3 mL)
4 (1) (medullary thyroid carcinoma, MTC) 2
(Multiple Endocrine Neoplasia syndrome type 2, MEN 2) (2) Victoza® 5 5.1 C Liraglutide
C (/)[(13.1)] C
8 liraglutide
liraglutide C
Victoza® C (medullary thyroid carcinoma, MTC) [ (4)] Victoza® 6 C 2
(1.3 vs.1.0 / 1000 ) MTC calcitonin >1000 ng/L
calcitonin
Victoza®6 5 calcitonin
Victoza® Victoza® calcitonin Calcitonin MTC Victoza®
calcitonin (lower limit of quantification, LLOQ) 0.7 ng/L 5.0 ng/L 8.4 ng/L 26 52 Victoza®
calcitonin
calcitonin (~ 1.0 ng/L) LLOQ 0.1 ng/L
calcitonin
Victoza® 1.8 mg/day calcitonin 5-6
Victoza® 1.8 mg/day 1.9% calcitonin
Victoza® 0.6 1.2mg 0.8-1.1% calcitonin 12 Victoza® 1.8 mg/day 1.3% calcitonin (
) Victoza® 1.2mg
0.6%, 0% 1.0%Victoza®
calcitonin MTC calcitonin >50 ng/L Victoza® calcitonin <50 ng/L calcitonin >50 ng/L Victoza®
calcitonin >50 ng/L Victoza® 10.7 ng/L 12 30.7 ng/L 6 53.5 ng/L Victoza® 2.5 calcitonin 22.3 ng/L calcitonin glimepiride
19.3 ng/L 65 44.8 ng/L 104 38.1 ng/L
calcitonin <20 ng/L calcitonin >20 ng/L Victoza® 0.7%
0.3% 0.5% 1.8 mg/day Victoza®
1.1% MTC (
) calcitonin MTC
calcitonin
calcitonin 5.2 Victoza®
Victoza®(
) Victoza®
Victoza® Victoza®
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Victoza®Victoza® 13 (glimepiride) 1 (2.7 vs.0.5 /1000 ) Victoza® 13 9 4
Victoza®
5.3 Victoza®(sulphonylurea) insulin
sulphonylurea() insulin
[ (6.1)] 5.4 Victoza® Victoza®
[ (6.2)]
[ (6.1)]
( Victoza®)
Victoza®[(8.6)] 5.5 () Victoza®
Victoza® GLP-1 (receptor agonist) GLP-1
Victoza® Victoza®
5.6 (macrovascular outcomes) Victoza® 6 6.1
8 Victoza®[(14)] 52 Victoza® 1.2 mg, Victoza® 1.8 mg
glimepiride 8 mg
26 metformin Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, glimepiride 4 mg
26 glimepiride Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, rosiglitazone 4 mg
26 metformin + glimepiride Victoza® 1.8 mg,
insulin glargine
26 metformin + rosiglitazone Victoza® 1.2 mg,
Victoza® 1.8 mg
26 metformin and/or sulphonylurea Victoza® 1.8 mg exenatide 10 mcg
26 metformin Victoza® 1.2 mg,
Victoza® 1.8 mg sitagliptin 100 mg
26 insulin detemir Victoza® 1.8 mg + metformin
Draft from FDA v6; revised 04/2013
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(2.8% vs. 0%)(1.5% vs.0.1%)
2-3 1, 2, 3 4 26 Victoza®( ) 26 Victoza® 41%
17% Victoza®
26
13% Victoza® 2% 2
26 Victoza® exenatide metformin / sulphonylurea
Victoza® exenatide ( 3) 26 Victoza® 1.2 mg, Victoza® 1.8 mg sitagliptin 100 mg
metforminVictoza® sitagliptin ( 4) 26 12 (run-in period) Victoza® 1.8 mg + metformin 167 ( 17%)76 (
46%) 15 ( 9%)
26 insulin detemir Victoza® 1.8 mg + metformin 26 ≥5% Victoza® 1.8 mg + metformin + insulin detemir (11.7%) Victoza® 1.8 mg metformin (6.9%) 1 Victoza® ≥ 5%52
Victoza® N=497
Glimepiride N=248
(%) (%) 28.4 8.5 17.1 8.9 10.9 3.6 9.9 4.8 9.1 9.3
2 Victoza® ≥ 5%Victoza®
26 Metformin
Victoza® + Metformin
N=724
+ Metformin
N=121
Glimepiride + Metformin
N=242 (%) (%) (%) 15.2 4.1 3.3 10.9 4.1 3.7 9.0 6.6 9.5 6.5 0.8 0.4
Glimepiride
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N=695
+ Glimepiride
N=114
Rosiglitazone + Glimepiride
N=231 (%) (%) (%) 7.5 1.8 2.6 7.2 1.8 2.2 5.3 0.9 1.7 5.2 0.9 2.6
Metformin + Glimepiride
Glargine + Metformin + Glimepiride
N=232 (%) (%) (%) 13.9 3.5 1.3 10.0 5.3 1.3 9.6 7.9 5.6 6.5 0.9 1.7 6.5 3.5 0.4
Metformin + Rosiglitazone
N=175
(%) (%) 34.6 8.6 14.1 6.3 12.4 2.9 8.2 4.6 5.1 1.1 3 26 Exenatide Victoza®≥ 5% Victoza® 1.8 mg +
metformin / sulphonylurea N= 235
Exenatide 10 mcg + metformin / sulphonylurea
N= 232 (%) (%) 25.5 28.0 12.3 12.1 8.9 10.3 8.9 4.7 6.0 9.9 5.1 2.6 4 26 Sitagliptin Victoza® ≥ 5% All Victoza®
+ metformin N = 439
N= 219
(%) (%) 23.9 4.6 10.3 10.0 9.3 4.6 8.7 4.1 Victoza®
liraglutide 26 50-70%Victoza®
Draft from FDA v6; revised 04/2013
Page 6
) liraglutide
Victoza® 52 6.9%
glucagon-like peptide-1 (GLP-1) liraglutide Victoza®
26 4.8%
GLP-1 GLP-1
52 2.3%Victoza® liraglutide (in vitro ) 26 1.0% Victoza® liraglutide
Victoza® liraglutide 40%
Victoza® 36%, 34% 35% Victoza®
Victoza® 11% Victoza®
7%, 7% 5% Victoza®
Victoza®
43%, 18% 19%
HbA1c Victoza®
3 liraglutide Victoza® HbA1c Victoza®(e.g. , )
Victoza® 0.8% 0.4% Victoza®
liraglutide liraglutide
26 2%Victoza®
() 0.2% Victoza® Victoza®Victoza® 7 1
(1.5 vs.0.5 / 1000 ) <1 cm
calcitonin
26 11 Victoza®(2.3
/ 1000 ) exenatide 2 11 Victoza®
metformin sulphonylurea sulphonylurea metformin( 65 94 mg/dL) Victoza® (
insulin Victoza®
insulin 26 Victoza sitagliptin
<56 mg/dL ( 5%) 5 52 26 (%)(/) Victoza®
Victoza® (N = 497) Glimepiride (N = 248) None 0 0 - 9.7 (0.24) 25.0 (1.66) - 1.2 (0.03) 2.4 (0.04) - Metformin Victoza® + Metformin
(N = 724) Glimepiride +
Metformin (N = 242) + Metformin
(N = 121) 0.1 (0.001) 0 0 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Victoza® + Metformin
Insulin detemir + Victoza® + Metformin (N = 163)
Continued Victoza® + Metformin alone
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(N = 695) Rosiglitazone +
Glimepiride (N = 231) + Glimepiride
(N = 114) 0.1 (0.003) 0 0 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) 0.9 (0.05) 0.9 (0.02) 0 Metformin + Rosiglitazone
Victoza® + Metformin + Rosiglitazone
(N = 355) None
+ Metformin + Rosiglitazone
(N = 175) 0 - 0 7.9 (0.49) - 4.6 (0.15) 0.6 (0.01) - 1.1 (0.03) Metformin + Glimepiride
Victoza® + Metformin + Glimepiride
+ Metformin + Glimepiride (N = 114)
2.2 (0.06) 0 0 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) 0 1.7 (0.04) 0 * 25
(
)( 1000 ) Victoza® 10.9% 6.3%
7.2%[(6.1)]
1 Victoza® (4 1 1 )
() 26 4.0%Victoza®( ) 2.1% 3.5%
Victoza® Victoza® 2 3 [(5.6)] 6.2
[(5.4)(17.3)]
Victoza®
8 8.1 C Victoza® Victoza®
-(AUC)
(maximum recommended human dose, MRHD1.8 mg/day) 0.8 liraglutide
Draft from FDA v6; revised 04/2013
Page 8
( AUC )Liraglutide 0.1 0.25 1.0 mg/kg/day liraglutide 17
MRHD 0.8 3 11 ( AUC ) 1.0 mg/kg/day
)Liraglutide
(concurrent and historical controls) 0.01 mg/kg/day ()≥ 0.01 mg/kg/day () 0.025 mg/kg/day (
) ≥ 0.025 mg/kg/day () 0.05 mg/kg/day ()/
() 0.1 0.25 1.0 mg/kg/day liraglutide MRHD (1.8 mg/day) 0.8 3 11 ( AUC
) liraglutide
1 mg/kg/day liraglutide
liraglutide
8.3 Victoza®
liraglutide
Victoza®liraglutide 50% 8.4 Victoza®Victoza® 8.5 Victoza® 65 797 (20%) 75 113
(2.8%)
(sensitivity) 8.6 Victoza®
[(5.4) (6.2)] Victoza®[ (12.3)] 8.7
Victoza®[(12.3)] 8.8 (gastroparesis) Victoza® 10 Victoza®
11 Victoza® liraglutide GLP-1 GLP-1 (agonist)
Saccharomyces cerevisiae DNA liraglutide 34 lysine
arginine GLP-1 97%Liraglutide 26 lysine
Draft from FDA v6; revised 04/2013
Page 9
glutamic acid C-16 ()Liraglutide C172H265N43O51
3751.2 Daltons 1
1 liraglutide Victoza® 1mL Victoza® 6mg liraglutide
3mL Victoza® 18mg liraglutide()1.42 mg disodium phosphate dihydrate14 mg propylene glycol5.5 mg phenol; hydrochloric acid; sodium hydroxide 12 12.1 Liraglutide Glucagon-Like Peptide-1 (GLP-1)(agonist)
GLP-1(7-37) 97% GLP-1(7-37) GLP-1
20% GLP-1(7-37)liraglutide beta GLP-1 G (Gs)
(adenylyl cyclase)liraglutide
(cAMP)Liraglutide
dipeptidyl peptidase IV (DPP-IV) neutral endopeptidase (NEP)
GLP-1(7-37) 1.5-2 GLP-1liraglutide
13 Liraglutide
DPP-IV NEP 12.2 Victoza® Victoza®
[(12.3)] Victoza® 0.61.2 1.8 mg
5 1.2 mg Victoza®
AUC0-300min 35% 1.8 mg Victoza® 38% 10 2 7.5 mcg/kg (~0.7 mg) Victoza®
(ISR)ISR ( 2)
Draft from FDA v6; revised 04/2013
Page 10
Victoza®7.5 mcg/kg (~0.7 mg) Victoza® 7.5 mcg/kg (~ 0.7 mg) Victoza® Victoza® (QTc) QTc Victoza®Victoza® 1.8 mg
QTc 12.3 –liraglutide 8-12 0.6 mg
(Cmax) liraglutide (AUC) 35 ng/mL 960 ngmh/mL
liraglutide Cmax AUC 0.6 mg-1.8 mg 1.8 mg Victoza®24
liraglutide 128 ng/mL AUC0-∞
AUC0-∞ 22% liraglutide
liraglutide 55% – 0.6 mg Victoza® 13 L Victoza®
0.07 L/kgLiraglutide (>98%) - [3H]-liraglutide 24
liraglutideLiraglutide
liraglutide ( 6% 5%)
6-8 liraglutide 1.2 L/h
13 Victoza® - (64 83 ) 18 80
Victoza®[ (8.5)] - 34%
- /
Victoza® – Victoza® baseline liraglutide 1.2 mg 1.8 mg
Victoza® 40 – 160 kg >160 kg
Draft from FDA v6; revised 04/2013
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- Victoza®[ (8.4)] - Victoza®
(creatinine 50-80 mL/min)(creatinine <30 mL/min)
liraglutide AUC 35%, 19%, 29% 30%[ (8.6)] - liraglutide
(Child Pugh score 5-6)(Child Pugh score >9)
liraglutide AUC 11%, 14% 42%[ (8.7)] (in vitro) Victoza® cytochrome P450 (CYP) (in vivo) Victoza®1.8 mg/day
0.6mg 1.8 mg/day Victoza® Cmax(8-12 h)
Cmax Digoxin Victoza® 7 digoxin 1 mg Victoza®
digoxin AUC 16%Cmax 31%Digoxin (Tmax) 1 1.5 Lisinopril Victoza® 5 lisinopril 20 mg
Victoza® lisinopril AUC 15%Cmax 27% Victoza® lisinopril Tmax
6 8 Atorvastatin Victoza® 5 40 mg atorvastatin Victoza® atorvastatin (AUC)atorvastatin Cmax 38% Tmax 1 3 Acetaminophen Victoza® 8 1000mg acetaminophenVictoza®
acetaminophen (AUC)acetaminophen Cmax 31% Tmax
15 Griseofulvin Victoza® 500 mg griseofulvin Victoza®Victoza®
griseofulvin (AUC)Griseofulvin Cmax 37% Tmax Oral Contraceptives Victoza® 7 oral contraceptives 0.03 mg ethinylestradiol 0.15 mg levonorgestrelVictoza®
ethinyloestradiol levonorgestrel Cmax12% 13%Victoza® ethinyloestradiol
(AUC)Victoza® levonorgestrel AUC0-∞ 18%Victoza®
ethinyloestradiol levonorgestrel Tmax 1.5 Insulin Detemir 2 insulin detemir 0.5 Unit/kg () Victoza® 1.8 mg (steady state) Victoza® insulin detemir 13 13.1 104 CD-1 0.03, 0.2, 1.0 3.0 mg/kg/day liraglutide MRHD (1.8 mg/day) 0.2-, 2-, 10- 45- ( AUC ) 1.0 3.0 mg/kg/day C
13% 19% 6% 20% 0.03 0.2
Draft from FDA v6; revised 04/2013
Page 12
mg/kg/day C 3.0 mg/kg/day 3%
(treatment-related) C C 3 mg/kg/day
(fibrosarcomas)Liraglutide
(6 mg/mL) 3 mg/kg/day liraglutide 10 104 Sprague Dawley 0.075, 0.25, 0.75 mg/kg/day liraglutide MRHD (1.8 mg/day)
0.5-, 2-, 8-( AUC ) 0.25 0.75 mg/kg/day
C 0 (), 0.075, 0.25 0.75 mg/kg/day 12%, 16%, 42% 46% liraglutide
10%, 27%, 33% 56% C liraglutide
0.25 0.75 mg/kg/day 0 (), 0.075, 0.25 0.75 mg/kg/day
2%, 8%, 6% 14% 0%, 0%, 4% 6% C
C [ (5.1)] Liraglutide Ames test
liraglutide in vivo micronucleus test 0.1, 0.25 1.0 mg/kg/day liraglutide 4
2 17 1.0 mg/kg/day
MRHD (1.8 mg/day) 11 ( AUC )
1.0 mg/kg/day 1.0 mg/kg/day 14. 6090 2 8 3 5 (
insulin glargine) 52 26
26 Victoza® exenatide Victoza®
sitagliptin Victoza®+metformin+insulin detemir Victoza®+metformin
Victoza® insulin detemir 2
7
2/3 8 6090
272(4%) 8 18-80 54%
82%6% 5 10%(N=630) Victoza®(HbA1c)(FPG) Victoza® 0.6 mg/day 1.2 mg 1.8 mg
0.6 mg 1.2 mg 1.8 mgVictoza® 0.6 mg
[(2)] 14.1 Metformin 26 1091 metformin Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, glimepiride 4 mg( ) (run-in period)
3 metformin 3 6
metformin 2000 mg/day metformin metformin Victoza® 1.2 mg 1.8 mg HbA1c
metformin glimepiride 4 mg ( 6)Victoza® 1.8 mg + metformin 5.4%Victoza® 1.2 mg + metformin 3.3% + metformin 23.8%glimepiride + metformin 3.7%
6 26 Victoza® + metformin a
Victoza® 1.8 mg +
Page 13
(N) 242 240 121 242 HbA1c (%) () 8.4 8.3 8.4 8.4
()b -1.0 -1.0 +0.1 -1.0 + metformin
() b
-1.1** -1.1**
95% (-1.3, -0.9) (-1.3, -0.9) glimepiride + metformin
() b
0.0 0.0
95% (-0.2, 0.2) (-0.2, 0.2) A1c <7%(%) 42 35 11 36
(mg/dL) () 181 179 182 180 () b -30 -30 +7 -24 + metformin
() b
-38** -37**
95% (-48, -27) (-47, -26) glimepiride + metformin
() b
-7 -6
(kg) ()
() b -2.8 -2.6 -1.5 +1.0 + metformin () b
-1.3* -1.1*
95% (-2.2, -0.4) (-2.0, -0.2) glimepiride + metformin
() b
-3.8** -3.5**
95% (-4.5, -3.0) (-4.3, -2.8) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value †glimepiride *p-value <0.05 **p-value <0.0001
Victoza® Sitagliptin Metformin 26 665 metformin ≥1500 mg
Victoza® 1.2 mg Victoza® 1.8 mg sitagliptin 100 mg
metformin (primary endpoint) 26 HbA1c sitagliptin 100 mg Victoza® 1.2 mg Victoza® 1.8 mg HbA1c( 7)
Victoza® 1.2 mg 3.1% Victoza® 1.8 mg 0.5%
sitagliptin 100 mg 4.1% 94kg Victoza® 1.2 mg 2.7 kg Victoza® 1.8 mg 3.3 kg sitagliptin 100 mg 0.8kg 7 26 Victoza® Sitagliptin ( metformin)a
Victoza® 1.8 mg + Metformin
Victoza® 1.2 mg + Metformin
Sitagliptin 100 mg + Metformin
Page 14
8.4 8.4 8.5 ()b -1.5 -1.2 -0.9 sitagliptin () b -0.6** -0.3** 95% (-0.8, -0.4) (-0.5, -0.2) A1c <7%(%) 56 44 22 (mg/dL) () 179 182 180 () b -39 -34 -15 sitagliptin () b -24** -19** 95% (-31, -16) (-26, -12)
a(Intent-to-treat population) bLeast squares mean adjusted for baseline value **p-value <0.0001
3 26 HbA1c 26 (Last Observation Carried Forward (LOCF, intent-to-treat)) Metformin Insulin 26 988 metformin (≥1500 mg/day) (HbA1c 7-10%) metformin (≥1500 mg/day) sulphonylurea
(HbA1c 7-8.5%) metformin sulphonylurea sulphonylurea
12 (run-in period) Victoza® 1.8 mg
498 (50%) Victoza® 1.8 mg metformin HbA1c <7%
167 (17%)[ (6.1)] 323 ( 33%)HbA1c ≥7% 26
insulin detemir (N=162) Victoza® 1.8 mg metformin (N=161)Insulin detemir 10 units/day 26 39 units/day 26
Victoza® 1.8 mg
metformin 11.2% insulin detemir 1.2% insulin detemir Victoza® 1.8 mg + metformin HbA1c FPG
Victoza® 1.8 mg + metformin ( 8) 96 kg insulin detemir 0.3 kg Victoza® 1.8 mg +
Draft from FDA v6; revised 04/2013
Page 15
metformin 1.1 kg 8 26 12 Metformin and Victoza® HbA1c < 7%
insulin detemir Victoza® + metformin Victoza® + metformin a
Insulin detemir +
Victoza® + Metformin
Victoza® + Metformin
(N) 162 157 HbA1c (%) () (week 0) 7.6 7.6 ()b -0.5 0 Victoza® + metformin
(LS ) b - 0.5**
95% (-0.7, -0.4) A1c <7%(%) 43 17 (mg/dL) () (week 0) 166 159 () b -39 -9 Victoza® + metformin
(LS ) b -31**
**p-value <0.0001
Sulphonylurea 26 1041 glimepiride Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, rosiglitazone 4 mg ( ) 4
(run-in period) 2 glimepiride 2
glimepiride 4 mg/day
glimepiride 4mg/day 3 mg/day 2mg/day ( ) glimepiride glimepiride Victoza® 1.2 mg 1.8 mg HbA1c
( 9)Victoza® 1.8 mg glimepiride 3.0%Victoza® 1.2 mg glimepiride 3.5% glimepiride 17.5%rosiglitazone + glimepiride 6.9% 9 26 Victoza® + sulphonylurea a
Victoza® 1.8 mg + Glimepiride
Victoza® 1.2 mg+ Glimepiride
Rosiglitazone 4mg† + Glimepiride
(N) 234 228 114 231 HbA1c (%) () 8.5 8.5 8.4 8.4 ()b -1.1 -1.1 +0.2 -0.4 + glimepiride
() b - 1.4** -1.3**
95% (-1.6, -1.1) (-1.5, -1.1) A1c <7%(%) 42 35 7 22
(mg/dL) () 174 177 171 179 () b -29 -28 +18 -16 + glimepiride
() b -47** -46**
95% (-58, -35) (-58, -35)
(kg) () 83.0 80.0 81.9 80.6 () b -0.2 +0.3 -0.1 +2.1
Draft from FDA v6; revised 04/2013
Page 16
95% (-0.9, 0.6) (-0.4, 1.2) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value †rosiglitazone **p-value <0.0001
Metformin + Sulphonylurea 26 581 metformin+glimepiride Victoza® 1.8 mg, insulin glargine6 3 metformin+glimepiride
3 metformin glimepiride 2000 mg/day 4 mg/day Victoza® 1.8 mg 2 Victoza® metformin
glimepiride insulin glargine insulin glargine 8
8 insulin glargine
12 18 20% insulin glargine
≤100 mg/dL insulin glargine
glimepiride+metformin+glimepiride+metformin+ Victoza® HbA1c
( 10)Victoza® 1.8 mg+ metformin+glimepiriden 0.9%insulin glargine+metformin+glimepiride 0.4%+metformin+glimepiride 11.3%
10 26 Victoza® + metformin + sulphonylurea a
Victoza® 1.8 mg + Metformin +
insulin glargine † +Metformin +
Glimepiride (N) 230 114 232 HbA1c (%) () 8.3 8.3 8.1 ()b -1.3 -0.2 -1.1 + metformin+ glimepiride
() b -1.1**
95% (-1.3, -0.9) A1c <7%(%) 53 15 46
(mg/dL) () 165 170 164 () b -28 +10 -32 + metformin +glimepiride
() b -38**
95% (-46, -30)
(kg) () 85.8 85.4 85.2 () b -1.8 -0.4 1.6 + metformin + glimepiride
() b -1.4*
95% (-2.1, -0.7) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value †insulin glargine : 80% *p-value <0.05 **p-value <0.0001
Victoza® Exenatide ( Metformin / Sulphonylurea ) 26 464 metformin sulphonylurea
Metformin + Sulphonylurea Victoza® 1.8 mg exenatide 10 mcg exenatide 5 mcg 4 10 mcg
Draft from FDA v6; revised 04/2013
Page 17
exenatide Victoza®1.8 mg HbA1c FPG ( 11)
Victoza® 0.4%exenatide 0% 3 kg 11 26 Victoza® Exenatide ( metformin / sulphonylurea )a
Victoza® 1.8 mg
Exenatide 10 mcg
+ Metformin / sulphonylurea
(N) 233 231 HbA1c (%) () 8.2 8.1 ()b -1.1 -0.8 exenatide () b -0.3** 95% (-0.5, -0.2) A1c <7%(%) 54 43 (mg/dL) () 176 171 () b -29 -11 exenatide () b -18** 95% (-25,- 12)
a(Intent-to-treat population) bLeast squares mean adjusted for baseline value **p-value <0.0001
Metformin Thiazolidinedione 26 533 rosiglitazone (8 mg) metformin (2000 mg)
Victoza® 1.2 mg, Victoza® 1.8 mg 9 ( 6 ) rosiglitazone 4mg 2 8 mg/daymetformin 500mg 500mg 2000 mg/day rosiglitazone (8 mg/day) metformin (2000 mg/day) 6
+ metformin+ rosiglitazone Victoza®+ metformin+ rosiglitazone HbA1c
( 12)Victoza® 1.8 mg+ metformin+ rosiglitazone 1.7%Victoza® 1.2 mg+ metformin+ rosiglitazone 1.7%+ metformin+ rosiglitazone 16.4% 12 26 Victoza® + metformin+thiazolidinedione a
Victoza® 1.8 mg + Metformin + Rosiglitazone
Victoza® 1.2 mg + Metformin + Rosiglitazone
+ Metformin +Rosiglitazone
(N) 178 177 175 HbA1c (%) () 8.6 8.5 8.4 ()b -1.5 -1.5 -0.5 + metformin+ rosiglitazone () b
-0.9** -0.9**
95% (-1.1, -0.8) (-1.1, -0.8) A1c <7%(%) 54 57 28
(mg/dL) () 185 181 179 () b -44 -40 -8 + metformin + rosiglitazone () b
-36** -32**
95% (-44, -27) (-41, -23)
(kg) () 94.9 95.3 98.5 () b -2.0 -1.0 +0.6 + metformin + rosiglitazone -2.6** -1.6**
Draft from FDA v6; revised 04/2013
Page 18
() b 95% (-3.4, -1.8) (-2.4, -1.0) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value **p-value <0.0001
16 / 16.1 Victoza® 12 3
0.6mg1.2mg 1.8mg (6 mg/mL, 3 mL) Victoza®Victoza® 16.2 Victoza® 2°C 8°C (36ºF 46ºF)( 13)
Victoza® Victoza® Victoza®(15°C 30°C; 59°F 86°F)
(2°C 8°C; 36°F 46°F) 30 Victoza®
Victoza®
13 Victoza®
2°C8°C (36°F46°F)
15°C 30°C (59°F 86°F)
2°C8°C (36°F46°F)
30
17 17.1 C liraglutide C
(
17.3
() Victoza®
[(5.5)] 17.5 Victoza® Victoza®
17.6 Victoza®
A1c/
Victoza® Victoza®
Victoza®
Page 19
Victoza®
30.6 mgVictoza®
Victoza®[ (2)] 17.7 A1c
A1c ™ Victoza® NovoFine® NovoTwist® Novo Nordisk A/S, Denmark © 2013 Novo Nordisk A/S Novo Nordisk A/S Hallas Allé, DK-4400, Kalundborg, Denmark () Novo Allé, DK-2880 Bagsværd, Denmark () Brennum Park DK-3400 Hillerød, Denmark () 216 7 1 02-2377-2566 02-2377-0111 www.novonordisk.com.tw
Draft from FDA v6; revised 04/2013
Page 20
0.6 mg1.2 mg1.8 mg Victoza®32G()8 mm
()NovoFine® NovoTwist®
Victoza® ()
Victoza® 1. Victoza® 2. Victoza®
liraglutide
1.2 mg
–
liraglutide liraglutide – 0.6 mg1.2 mg 1.8 mg
Page 21
: C LiraglutideC Victoza®
MTC2(Multiple Endocrine Neoplasia syndrome type 2, MEN 2)calcitonin
calcitonin
C
calcitonin
1 2 metformin sulphonylurea
metformin sulphonylurea metformin sulphonylurea
metformin thiazolidinedione metformin
sulphonylurea metformin thiazolidinedione 1.1 C Victoza®
Victoza®
Victoza®
Victoza®
Victoza®
Victoza® insulin Victoza® 1
(prandial insulin) Victoza®
2 Victoza®
Victoza® 0.6 mg 0.6 mg
0.6 mg
1.2 mg 1.2 mg 1.8 mg Victoza®(
sulphonylureas) [(5.3)(6)] Victoza® insulin Victoza® insulin
Victoza®
3 0.6 mg
Victoza®
Victoza® 3
Page 2
0.6 mg, 1.2 mg, 1.8 mg (6 mg/mL, 3 mL)
4 (1) (medullary thyroid carcinoma, MTC) 2
(Multiple Endocrine Neoplasia syndrome type 2, MEN 2) (2) Victoza® 5 5.1 C Liraglutide
C (/)[(13.1)] C
8 liraglutide
liraglutide C
Victoza® C (medullary thyroid carcinoma, MTC) [ (4)] Victoza® 6 C 2
(1.3 vs.1.0 / 1000 ) MTC calcitonin >1000 ng/L
calcitonin
Victoza®6 5 calcitonin
Victoza® Victoza® calcitonin Calcitonin MTC Victoza®
calcitonin (lower limit of quantification, LLOQ) 0.7 ng/L 5.0 ng/L 8.4 ng/L 26 52 Victoza®
calcitonin
calcitonin (~ 1.0 ng/L) LLOQ 0.1 ng/L
calcitonin
Victoza® 1.8 mg/day calcitonin 5-6
Victoza® 1.8 mg/day 1.9% calcitonin
Victoza® 0.6 1.2mg 0.8-1.1% calcitonin 12 Victoza® 1.8 mg/day 1.3% calcitonin (
) Victoza® 1.2mg
0.6%, 0% 1.0%Victoza®
calcitonin MTC calcitonin >50 ng/L Victoza® calcitonin <50 ng/L calcitonin >50 ng/L Victoza®
calcitonin >50 ng/L Victoza® 10.7 ng/L 12 30.7 ng/L 6 53.5 ng/L Victoza® 2.5 calcitonin 22.3 ng/L calcitonin glimepiride
19.3 ng/L 65 44.8 ng/L 104 38.1 ng/L
calcitonin <20 ng/L calcitonin >20 ng/L Victoza® 0.7%
0.3% 0.5% 1.8 mg/day Victoza®
1.1% MTC (
) calcitonin MTC
calcitonin
calcitonin 5.2 Victoza®
Victoza®(
) Victoza®
Victoza® Victoza®
Page 3
Victoza®Victoza® 13 (glimepiride) 1 (2.7 vs.0.5 /1000 ) Victoza® 13 9 4
Victoza®
5.3 Victoza®(sulphonylurea) insulin
sulphonylurea() insulin
[ (6.1)] 5.4 Victoza® Victoza®
[ (6.2)]
[ (6.1)]
( Victoza®)
Victoza®[(8.6)] 5.5 () Victoza®
Victoza® GLP-1 (receptor agonist) GLP-1
Victoza® Victoza®
5.6 (macrovascular outcomes) Victoza® 6 6.1
8 Victoza®[(14)] 52 Victoza® 1.2 mg, Victoza® 1.8 mg
glimepiride 8 mg
26 metformin Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, glimepiride 4 mg
26 glimepiride Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, rosiglitazone 4 mg
26 metformin + glimepiride Victoza® 1.8 mg,
insulin glargine
26 metformin + rosiglitazone Victoza® 1.2 mg,
Victoza® 1.8 mg
26 metformin and/or sulphonylurea Victoza® 1.8 mg exenatide 10 mcg
26 metformin Victoza® 1.2 mg,
Victoza® 1.8 mg sitagliptin 100 mg
26 insulin detemir Victoza® 1.8 mg + metformin
Draft from FDA v6; revised 04/2013
Page 4
(2.8% vs. 0%)(1.5% vs.0.1%)
2-3 1, 2, 3 4 26 Victoza®( ) 26 Victoza® 41%
17% Victoza®
26
13% Victoza® 2% 2
26 Victoza® exenatide metformin / sulphonylurea
Victoza® exenatide ( 3) 26 Victoza® 1.2 mg, Victoza® 1.8 mg sitagliptin 100 mg
metforminVictoza® sitagliptin ( 4) 26 12 (run-in period) Victoza® 1.8 mg + metformin 167 ( 17%)76 (
46%) 15 ( 9%)
26 insulin detemir Victoza® 1.8 mg + metformin 26 ≥5% Victoza® 1.8 mg + metformin + insulin detemir (11.7%) Victoza® 1.8 mg metformin (6.9%) 1 Victoza® ≥ 5%52
Victoza® N=497
Glimepiride N=248
(%) (%) 28.4 8.5 17.1 8.9 10.9 3.6 9.9 4.8 9.1 9.3
2 Victoza® ≥ 5%Victoza®
26 Metformin
Victoza® + Metformin
N=724
+ Metformin
N=121
Glimepiride + Metformin
N=242 (%) (%) (%) 15.2 4.1 3.3 10.9 4.1 3.7 9.0 6.6 9.5 6.5 0.8 0.4
Glimepiride
Page 5
N=695
+ Glimepiride
N=114
Rosiglitazone + Glimepiride
N=231 (%) (%) (%) 7.5 1.8 2.6 7.2 1.8 2.2 5.3 0.9 1.7 5.2 0.9 2.6
Metformin + Glimepiride
Glargine + Metformin + Glimepiride
N=232 (%) (%) (%) 13.9 3.5 1.3 10.0 5.3 1.3 9.6 7.9 5.6 6.5 0.9 1.7 6.5 3.5 0.4
Metformin + Rosiglitazone
N=175
(%) (%) 34.6 8.6 14.1 6.3 12.4 2.9 8.2 4.6 5.1 1.1 3 26 Exenatide Victoza®≥ 5% Victoza® 1.8 mg +
metformin / sulphonylurea N= 235
Exenatide 10 mcg + metformin / sulphonylurea
N= 232 (%) (%) 25.5 28.0 12.3 12.1 8.9 10.3 8.9 4.7 6.0 9.9 5.1 2.6 4 26 Sitagliptin Victoza® ≥ 5% All Victoza®
+ metformin N = 439
N= 219
(%) (%) 23.9 4.6 10.3 10.0 9.3 4.6 8.7 4.1 Victoza®
liraglutide 26 50-70%Victoza®
Draft from FDA v6; revised 04/2013
Page 6
) liraglutide
Victoza® 52 6.9%
glucagon-like peptide-1 (GLP-1) liraglutide Victoza®
26 4.8%
GLP-1 GLP-1
52 2.3%Victoza® liraglutide (in vitro ) 26 1.0% Victoza® liraglutide
Victoza® liraglutide 40%
Victoza® 36%, 34% 35% Victoza®
Victoza® 11% Victoza®
7%, 7% 5% Victoza®
Victoza®
43%, 18% 19%
HbA1c Victoza®
3 liraglutide Victoza® HbA1c Victoza®(e.g. , )
Victoza® 0.8% 0.4% Victoza®
liraglutide liraglutide
26 2%Victoza®
() 0.2% Victoza® Victoza®Victoza® 7 1
(1.5 vs.0.5 / 1000 ) <1 cm
calcitonin
26 11 Victoza®(2.3
/ 1000 ) exenatide 2 11 Victoza®
metformin sulphonylurea sulphonylurea metformin( 65 94 mg/dL) Victoza® (
insulin Victoza®
insulin 26 Victoza sitagliptin
<56 mg/dL ( 5%) 5 52 26 (%)(/) Victoza®
Victoza® (N = 497) Glimepiride (N = 248) None 0 0 - 9.7 (0.24) 25.0 (1.66) - 1.2 (0.03) 2.4 (0.04) - Metformin Victoza® + Metformin
(N = 724) Glimepiride +
Metformin (N = 242) + Metformin
(N = 121) 0.1 (0.001) 0 0 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Victoza® + Metformin
Insulin detemir + Victoza® + Metformin (N = 163)
Continued Victoza® + Metformin alone
Page 7
(N = 695) Rosiglitazone +
Glimepiride (N = 231) + Glimepiride
(N = 114) 0.1 (0.003) 0 0 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) 0.9 (0.05) 0.9 (0.02) 0 Metformin + Rosiglitazone
Victoza® + Metformin + Rosiglitazone
(N = 355) None
+ Metformin + Rosiglitazone
(N = 175) 0 - 0 7.9 (0.49) - 4.6 (0.15) 0.6 (0.01) - 1.1 (0.03) Metformin + Glimepiride
Victoza® + Metformin + Glimepiride
+ Metformin + Glimepiride (N = 114)
2.2 (0.06) 0 0 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) 0 1.7 (0.04) 0 * 25
(
)( 1000 ) Victoza® 10.9% 6.3%
7.2%[(6.1)]
1 Victoza® (4 1 1 )
() 26 4.0%Victoza®( ) 2.1% 3.5%
Victoza® Victoza® 2 3 [(5.6)] 6.2
[(5.4)(17.3)]
Victoza®
8 8.1 C Victoza® Victoza®
-(AUC)
(maximum recommended human dose, MRHD1.8 mg/day) 0.8 liraglutide
Draft from FDA v6; revised 04/2013
Page 8
( AUC )Liraglutide 0.1 0.25 1.0 mg/kg/day liraglutide 17
MRHD 0.8 3 11 ( AUC ) 1.0 mg/kg/day
)Liraglutide
(concurrent and historical controls) 0.01 mg/kg/day ()≥ 0.01 mg/kg/day () 0.025 mg/kg/day (
) ≥ 0.025 mg/kg/day () 0.05 mg/kg/day ()/
() 0.1 0.25 1.0 mg/kg/day liraglutide MRHD (1.8 mg/day) 0.8 3 11 ( AUC
) liraglutide
1 mg/kg/day liraglutide
liraglutide
8.3 Victoza®
liraglutide
Victoza®liraglutide 50% 8.4 Victoza®Victoza® 8.5 Victoza® 65 797 (20%) 75 113
(2.8%)
(sensitivity) 8.6 Victoza®
[(5.4) (6.2)] Victoza®[ (12.3)] 8.7
Victoza®[(12.3)] 8.8 (gastroparesis) Victoza® 10 Victoza®
11 Victoza® liraglutide GLP-1 GLP-1 (agonist)
Saccharomyces cerevisiae DNA liraglutide 34 lysine
arginine GLP-1 97%Liraglutide 26 lysine
Draft from FDA v6; revised 04/2013
Page 9
glutamic acid C-16 ()Liraglutide C172H265N43O51
3751.2 Daltons 1
1 liraglutide Victoza® 1mL Victoza® 6mg liraglutide
3mL Victoza® 18mg liraglutide()1.42 mg disodium phosphate dihydrate14 mg propylene glycol5.5 mg phenol; hydrochloric acid; sodium hydroxide 12 12.1 Liraglutide Glucagon-Like Peptide-1 (GLP-1)(agonist)
GLP-1(7-37) 97% GLP-1(7-37) GLP-1
20% GLP-1(7-37)liraglutide beta GLP-1 G (Gs)
(adenylyl cyclase)liraglutide
(cAMP)Liraglutide
dipeptidyl peptidase IV (DPP-IV) neutral endopeptidase (NEP)
GLP-1(7-37) 1.5-2 GLP-1liraglutide
13 Liraglutide
DPP-IV NEP 12.2 Victoza® Victoza®
[(12.3)] Victoza® 0.61.2 1.8 mg
5 1.2 mg Victoza®
AUC0-300min 35% 1.8 mg Victoza® 38% 10 2 7.5 mcg/kg (~0.7 mg) Victoza®
(ISR)ISR ( 2)
Draft from FDA v6; revised 04/2013
Page 10
Victoza®7.5 mcg/kg (~0.7 mg) Victoza® 7.5 mcg/kg (~ 0.7 mg) Victoza® Victoza® (QTc) QTc Victoza®Victoza® 1.8 mg
QTc 12.3 –liraglutide 8-12 0.6 mg
(Cmax) liraglutide (AUC) 35 ng/mL 960 ngmh/mL
liraglutide Cmax AUC 0.6 mg-1.8 mg 1.8 mg Victoza®24
liraglutide 128 ng/mL AUC0-∞
AUC0-∞ 22% liraglutide
liraglutide 55% – 0.6 mg Victoza® 13 L Victoza®
0.07 L/kgLiraglutide (>98%) - [3H]-liraglutide 24
liraglutideLiraglutide
liraglutide ( 6% 5%)
6-8 liraglutide 1.2 L/h
13 Victoza® - (64 83 ) 18 80
Victoza®[ (8.5)] - 34%
- /
Victoza® – Victoza® baseline liraglutide 1.2 mg 1.8 mg
Victoza® 40 – 160 kg >160 kg
Draft from FDA v6; revised 04/2013
Page 11
- Victoza®[ (8.4)] - Victoza®
(creatinine 50-80 mL/min)(creatinine <30 mL/min)
liraglutide AUC 35%, 19%, 29% 30%[ (8.6)] - liraglutide
(Child Pugh score 5-6)(Child Pugh score >9)
liraglutide AUC 11%, 14% 42%[ (8.7)] (in vitro) Victoza® cytochrome P450 (CYP) (in vivo) Victoza®1.8 mg/day
0.6mg 1.8 mg/day Victoza® Cmax(8-12 h)
Cmax Digoxin Victoza® 7 digoxin 1 mg Victoza®
digoxin AUC 16%Cmax 31%Digoxin (Tmax) 1 1.5 Lisinopril Victoza® 5 lisinopril 20 mg
Victoza® lisinopril AUC 15%Cmax 27% Victoza® lisinopril Tmax
6 8 Atorvastatin Victoza® 5 40 mg atorvastatin Victoza® atorvastatin (AUC)atorvastatin Cmax 38% Tmax 1 3 Acetaminophen Victoza® 8 1000mg acetaminophenVictoza®
acetaminophen (AUC)acetaminophen Cmax 31% Tmax
15 Griseofulvin Victoza® 500 mg griseofulvin Victoza®Victoza®
griseofulvin (AUC)Griseofulvin Cmax 37% Tmax Oral Contraceptives Victoza® 7 oral contraceptives 0.03 mg ethinylestradiol 0.15 mg levonorgestrelVictoza®
ethinyloestradiol levonorgestrel Cmax12% 13%Victoza® ethinyloestradiol
(AUC)Victoza® levonorgestrel AUC0-∞ 18%Victoza®
ethinyloestradiol levonorgestrel Tmax 1.5 Insulin Detemir 2 insulin detemir 0.5 Unit/kg () Victoza® 1.8 mg (steady state) Victoza® insulin detemir 13 13.1 104 CD-1 0.03, 0.2, 1.0 3.0 mg/kg/day liraglutide MRHD (1.8 mg/day) 0.2-, 2-, 10- 45- ( AUC ) 1.0 3.0 mg/kg/day C
13% 19% 6% 20% 0.03 0.2
Draft from FDA v6; revised 04/2013
Page 12
mg/kg/day C 3.0 mg/kg/day 3%
(treatment-related) C C 3 mg/kg/day
(fibrosarcomas)Liraglutide
(6 mg/mL) 3 mg/kg/day liraglutide 10 104 Sprague Dawley 0.075, 0.25, 0.75 mg/kg/day liraglutide MRHD (1.8 mg/day)
0.5-, 2-, 8-( AUC ) 0.25 0.75 mg/kg/day
C 0 (), 0.075, 0.25 0.75 mg/kg/day 12%, 16%, 42% 46% liraglutide
10%, 27%, 33% 56% C liraglutide
0.25 0.75 mg/kg/day 0 (), 0.075, 0.25 0.75 mg/kg/day
2%, 8%, 6% 14% 0%, 0%, 4% 6% C
C [ (5.1)] Liraglutide Ames test
liraglutide in vivo micronucleus test 0.1, 0.25 1.0 mg/kg/day liraglutide 4
2 17 1.0 mg/kg/day
MRHD (1.8 mg/day) 11 ( AUC )
1.0 mg/kg/day 1.0 mg/kg/day 14. 6090 2 8 3 5 (
insulin glargine) 52 26
26 Victoza® exenatide Victoza®
sitagliptin Victoza®+metformin+insulin detemir Victoza®+metformin
Victoza® insulin detemir 2
7
2/3 8 6090
272(4%) 8 18-80 54%
82%6% 5 10%(N=630) Victoza®(HbA1c)(FPG) Victoza® 0.6 mg/day 1.2 mg 1.8 mg
0.6 mg 1.2 mg 1.8 mgVictoza® 0.6 mg
[(2)] 14.1 Metformin 26 1091 metformin Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, glimepiride 4 mg( ) (run-in period)
3 metformin 3 6
metformin 2000 mg/day metformin metformin Victoza® 1.2 mg 1.8 mg HbA1c
metformin glimepiride 4 mg ( 6)Victoza® 1.8 mg + metformin 5.4%Victoza® 1.2 mg + metformin 3.3% + metformin 23.8%glimepiride + metformin 3.7%
6 26 Victoza® + metformin a
Victoza® 1.8 mg +
Page 13
(N) 242 240 121 242 HbA1c (%) () 8.4 8.3 8.4 8.4
()b -1.0 -1.0 +0.1 -1.0 + metformin
() b
-1.1** -1.1**
95% (-1.3, -0.9) (-1.3, -0.9) glimepiride + metformin
() b
0.0 0.0
95% (-0.2, 0.2) (-0.2, 0.2) A1c <7%(%) 42 35 11 36
(mg/dL) () 181 179 182 180 () b -30 -30 +7 -24 + metformin
() b
-38** -37**
95% (-48, -27) (-47, -26) glimepiride + metformin
() b
-7 -6
(kg) ()
() b -2.8 -2.6 -1.5 +1.0 + metformin () b
-1.3* -1.1*
95% (-2.2, -0.4) (-2.0, -0.2) glimepiride + metformin
() b
-3.8** -3.5**
95% (-4.5, -3.0) (-4.3, -2.8) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value †glimepiride *p-value <0.05 **p-value <0.0001
Victoza® Sitagliptin Metformin 26 665 metformin ≥1500 mg
Victoza® 1.2 mg Victoza® 1.8 mg sitagliptin 100 mg
metformin (primary endpoint) 26 HbA1c sitagliptin 100 mg Victoza® 1.2 mg Victoza® 1.8 mg HbA1c( 7)
Victoza® 1.2 mg 3.1% Victoza® 1.8 mg 0.5%
sitagliptin 100 mg 4.1% 94kg Victoza® 1.2 mg 2.7 kg Victoza® 1.8 mg 3.3 kg sitagliptin 100 mg 0.8kg 7 26 Victoza® Sitagliptin ( metformin)a
Victoza® 1.8 mg + Metformin
Victoza® 1.2 mg + Metformin
Sitagliptin 100 mg + Metformin
Page 14
8.4 8.4 8.5 ()b -1.5 -1.2 -0.9 sitagliptin () b -0.6** -0.3** 95% (-0.8, -0.4) (-0.5, -0.2) A1c <7%(%) 56 44 22 (mg/dL) () 179 182 180 () b -39 -34 -15 sitagliptin () b -24** -19** 95% (-31, -16) (-26, -12)
a(Intent-to-treat population) bLeast squares mean adjusted for baseline value **p-value <0.0001
3 26 HbA1c 26 (Last Observation Carried Forward (LOCF, intent-to-treat)) Metformin Insulin 26 988 metformin (≥1500 mg/day) (HbA1c 7-10%) metformin (≥1500 mg/day) sulphonylurea
(HbA1c 7-8.5%) metformin sulphonylurea sulphonylurea
12 (run-in period) Victoza® 1.8 mg
498 (50%) Victoza® 1.8 mg metformin HbA1c <7%
167 (17%)[ (6.1)] 323 ( 33%)HbA1c ≥7% 26
insulin detemir (N=162) Victoza® 1.8 mg metformin (N=161)Insulin detemir 10 units/day 26 39 units/day 26
Victoza® 1.8 mg
metformin 11.2% insulin detemir 1.2% insulin detemir Victoza® 1.8 mg + metformin HbA1c FPG
Victoza® 1.8 mg + metformin ( 8) 96 kg insulin detemir 0.3 kg Victoza® 1.8 mg +
Draft from FDA v6; revised 04/2013
Page 15
metformin 1.1 kg 8 26 12 Metformin and Victoza® HbA1c < 7%
insulin detemir Victoza® + metformin Victoza® + metformin a
Insulin detemir +
Victoza® + Metformin
Victoza® + Metformin
(N) 162 157 HbA1c (%) () (week 0) 7.6 7.6 ()b -0.5 0 Victoza® + metformin
(LS ) b - 0.5**
95% (-0.7, -0.4) A1c <7%(%) 43 17 (mg/dL) () (week 0) 166 159 () b -39 -9 Victoza® + metformin
(LS ) b -31**
**p-value <0.0001
Sulphonylurea 26 1041 glimepiride Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, rosiglitazone 4 mg ( ) 4
(run-in period) 2 glimepiride 2
glimepiride 4 mg/day
glimepiride 4mg/day 3 mg/day 2mg/day ( ) glimepiride glimepiride Victoza® 1.2 mg 1.8 mg HbA1c
( 9)Victoza® 1.8 mg glimepiride 3.0%Victoza® 1.2 mg glimepiride 3.5% glimepiride 17.5%rosiglitazone + glimepiride 6.9% 9 26 Victoza® + sulphonylurea a
Victoza® 1.8 mg + Glimepiride
Victoza® 1.2 mg+ Glimepiride
Rosiglitazone 4mg† + Glimepiride
(N) 234 228 114 231 HbA1c (%) () 8.5 8.5 8.4 8.4 ()b -1.1 -1.1 +0.2 -0.4 + glimepiride
() b - 1.4** -1.3**
95% (-1.6, -1.1) (-1.5, -1.1) A1c <7%(%) 42 35 7 22
(mg/dL) () 174 177 171 179 () b -29 -28 +18 -16 + glimepiride
() b -47** -46**
95% (-58, -35) (-58, -35)
(kg) () 83.0 80.0 81.9 80.6 () b -0.2 +0.3 -0.1 +2.1
Draft from FDA v6; revised 04/2013
Page 16
95% (-0.9, 0.6) (-0.4, 1.2) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value †rosiglitazone **p-value <0.0001
Metformin + Sulphonylurea 26 581 metformin+glimepiride Victoza® 1.8 mg, insulin glargine6 3 metformin+glimepiride
3 metformin glimepiride 2000 mg/day 4 mg/day Victoza® 1.8 mg 2 Victoza® metformin
glimepiride insulin glargine insulin glargine 8
8 insulin glargine
12 18 20% insulin glargine
≤100 mg/dL insulin glargine
glimepiride+metformin+glimepiride+metformin+ Victoza® HbA1c
( 10)Victoza® 1.8 mg+ metformin+glimepiriden 0.9%insulin glargine+metformin+glimepiride 0.4%+metformin+glimepiride 11.3%
10 26 Victoza® + metformin + sulphonylurea a
Victoza® 1.8 mg + Metformin +
insulin glargine † +Metformin +
Glimepiride (N) 230 114 232 HbA1c (%) () 8.3 8.3 8.1 ()b -1.3 -0.2 -1.1 + metformin+ glimepiride
() b -1.1**
95% (-1.3, -0.9) A1c <7%(%) 53 15 46
(mg/dL) () 165 170 164 () b -28 +10 -32 + metformin +glimepiride
() b -38**
95% (-46, -30)
(kg) () 85.8 85.4 85.2 () b -1.8 -0.4 1.6 + metformin + glimepiride
() b -1.4*
95% (-2.1, -0.7) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value †insulin glargine : 80% *p-value <0.05 **p-value <0.0001
Victoza® Exenatide ( Metformin / Sulphonylurea ) 26 464 metformin sulphonylurea
Metformin + Sulphonylurea Victoza® 1.8 mg exenatide 10 mcg exenatide 5 mcg 4 10 mcg
Draft from FDA v6; revised 04/2013
Page 17
exenatide Victoza®1.8 mg HbA1c FPG ( 11)
Victoza® 0.4%exenatide 0% 3 kg 11 26 Victoza® Exenatide ( metformin / sulphonylurea )a
Victoza® 1.8 mg
Exenatide 10 mcg
+ Metformin / sulphonylurea
(N) 233 231 HbA1c (%) () 8.2 8.1 ()b -1.1 -0.8 exenatide () b -0.3** 95% (-0.5, -0.2) A1c <7%(%) 54 43 (mg/dL) () 176 171 () b -29 -11 exenatide () b -18** 95% (-25,- 12)
a(Intent-to-treat population) bLeast squares mean adjusted for baseline value **p-value <0.0001
Metformin Thiazolidinedione 26 533 rosiglitazone (8 mg) metformin (2000 mg)
Victoza® 1.2 mg, Victoza® 1.8 mg 9 ( 6 ) rosiglitazone 4mg 2 8 mg/daymetformin 500mg 500mg 2000 mg/day rosiglitazone (8 mg/day) metformin (2000 mg/day) 6
+ metformin+ rosiglitazone Victoza®+ metformin+ rosiglitazone HbA1c
( 12)Victoza® 1.8 mg+ metformin+ rosiglitazone 1.7%Victoza® 1.2 mg+ metformin+ rosiglitazone 1.7%+ metformin+ rosiglitazone 16.4% 12 26 Victoza® + metformin+thiazolidinedione a
Victoza® 1.8 mg + Metformin + Rosiglitazone
Victoza® 1.2 mg + Metformin + Rosiglitazone
+ Metformin +Rosiglitazone
(N) 178 177 175 HbA1c (%) () 8.6 8.5 8.4 ()b -1.5 -1.5 -0.5 + metformin+ rosiglitazone () b
-0.9** -0.9**
95% (-1.1, -0.8) (-1.1, -0.8) A1c <7%(%) 54 57 28
(mg/dL) () 185 181 179 () b -44 -40 -8 + metformin + rosiglitazone () b
-36** -32**
95% (-44, -27) (-41, -23)
(kg) () 94.9 95.3 98.5 () b -2.0 -1.0 +0.6 + metformin + rosiglitazone -2.6** -1.6**
Draft from FDA v6; revised 04/2013
Page 18
() b 95% (-3.4, -1.8) (-2.4, -1.0) a(Intent-to-treat population) bLeast squares mean adjusted for baseline value **p-value <0.0001
16 / 16.1 Victoza® 12 3
0.6mg1.2mg 1.8mg (6 mg/mL, 3 mL) Victoza®Victoza® 16.2 Victoza® 2°C 8°C (36ºF 46ºF)( 13)
Victoza® Victoza® Victoza®(15°C 30°C; 59°F 86°F)
(2°C 8°C; 36°F 46°F) 30 Victoza®
Victoza®
13 Victoza®
2°C8°C (36°F46°F)
15°C 30°C (59°F 86°F)
2°C8°C (36°F46°F)
30
17 17.1 C liraglutide C
(
17.3
() Victoza®
[(5.5)] 17.5 Victoza® Victoza®
17.6 Victoza®
A1c/
Victoza® Victoza®
Victoza®
Page 19
Victoza®
30.6 mgVictoza®
Victoza®[ (2)] 17.7 A1c
A1c ™ Victoza® NovoFine® NovoTwist® Novo Nordisk A/S, Denmark © 2013 Novo Nordisk A/S Novo Nordisk A/S Hallas Allé, DK-4400, Kalundborg, Denmark () Novo Allé, DK-2880 Bagsværd, Denmark () Brennum Park DK-3400 Hillerød, Denmark () 216 7 1 02-2377-2566 02-2377-0111 www.novonordisk.com.tw
Draft from FDA v6; revised 04/2013
Page 20
0.6 mg1.2 mg1.8 mg Victoza®32G()8 mm
()NovoFine® NovoTwist®
Victoza® ()
Victoza® 1. Victoza® 2. Victoza®
liraglutide
1.2 mg
–
liraglutide liraglutide – 0.6 mg1.2 mg 1.8 mg
Page 21