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1.2. 0 75 mg 1 5 mg 75 0 75 mg 1 ly ll 97 2 1 FDA
3. 5 2 5 3 5 4 70 6 1 2
4. t_ 4 5 5 INR GBCS t S 4 R 5 5 S R AUC _ R C S C
5. IF IF IF A4 9 IF IF 2 IF IF
6. 4 IF IF IF
7. 2 0 75 mg GBDP 52 280 8 2 9 SU GBDY 26 181 47 26 0 GBDQ 52 SU 131 44 33 6 61 2 3 3 w GY 65 4 6 2 TZD 66 4 6 1 71 7 9 9 SU 2
8. 6 8 2 V 3 V 1 5 B MAO B PB
9. 9 KLH IgM IgG 1 C SD 20 0 5 mg kg 2 52 C AUC 5 mg kg 95 0 5 mg kg 5 mg kg
10. 11 15 12 13 Company Core Data Sheet CCDS
11. 52 LOCF p 0 004 PR QTc QTcF 52 LOCF QTc QTcF 52 LOCF LOCF 2 9 8 280 2 9 4 137 2 9 2 70
12. 10 11 12 13 1 3 72
13. NOEL 0 05 mg kg rasH2 rasH2 CByB6F1 Tg HRAS 2Jic 25 0 0 3 1 3 mg kg 2 26 AUC 0 3 1 3 mg kg 1 76 4 76 7 56 C 0 3 mg kg C 0 3 mg kg NOEL 3 mg kg 2 90 3 4 5
14. 2 0 75 mg 1 gt 1 13 gt 2 I GBCB GBCL I GBCZ GBDP GBDY GBDQ 1 GBDP 2 0 75 mg 48 4 5
15. 1 1 26 26 PR p lt 0 001 26 26 0 47 181 47 8 86 180
16. p lt 0 001 95 1 57 1 79 1 35 p lt 0 001 0 75 mg 95 0 10 0 27 0 07 95 0 4 0 75 mg PPS MMRM FAS LOCF ANCOVA HbAlc 4
17. 21 4 0 7 0 mg 400 mg am ama ana 7 0 mg 1 54 7 0 mg 4 0 mg 4 0 mg 3 55 4 0 mg 1
18. http kanja ds pharmajp products www illyanswersjp 3 5 URL RMP http www pmda_ gojjp safety info services drugs items information rmp 0001 html 6 0 75 mg 0 5 mL 2 93 J ABS PC CO 2014 9 18 10
19. 0 75 mg 1 51 2 5 1 GBDP 2 0 75 mg 1 7 1 26 Visit 2 1 2 7 7 1 7
20. 95 0 54 0 67 0 41 p lt 0 001 95 0 4 0 75 mg 95 0 0 75 mg p lt 0 001 HbAlc 8 26 p lt 0 001 a 1 2 5 26 HbAlc FAS 26 26 Mean SD LS Mean SE LS Mean SE Sim 8 06 0 82 6 58 0 05 7 99 0
21. ESRD AUC 28 C 23 p lt 0 031 ESRD AUC 90 1 20 1 06 1 35 1 28 1 13 1 44 1 14 1 00 1 29 1 12 0 995 1 26 C 90 1 13 0 963 1 31 1 23 1 05 1 43 1 20 1 02 1 40 1 11 0 950 1 30 E 1 5 mg ngrhr mL ng hr mL ng mL hr hr L hr L 25 24 29 12 02 96 05 84 4 169 24 23 9 0 0 0 em G 0 11 18 15 47 3
22. 2 3 GLP 1 4 3 4
23. 52 SU 33 6 44 131 3 3 2 61 a GI 6 2 4 65 TZD 6 1 4 66 9 9 7 71 SU 6 9 9 131 1 4 1 71 4 2 3 9 394 SU 1 a GI 1 TZD 3 4 9 GLP 1 3 TZD 1 2 GLP 1 2
24. GBDP gt 2 280 0 75 mg 1 52 HbAlc 4 52 p lt 0 001 GBDQ gt SUY TZD o GF 9 2 394 0 75 mg 1 52 HbAlc 14 52 LOCF p lt 0 001 a b
25. 0 7 2 280 4 3 2 GLP 1 2 1 2 29 52 66 1 185 280 68 6 94 137 75 7 53 70 56 5 35 62
26. 0 75 mg SU c GI ov TZD 5 2 GBDY 37 38 3 GBDQ gt SU TZD a GI 2 52 SU TZD o GI 2 394 1 Visit 1 2
27. G GLP 1 B cAMP NH2 NH2 GLP 1 ON HOOC COOH lgG4 Fc 43 sl GLUT2 Caz ATP ADP GL1 4 mC cAMP 1 uy gt eo oe
28. 3 RE TT PR ti 1 2 a 2 NT II Company Core Data Sheet CCDS 78 4
29. p lt 0 001 8 8 16 181 26 7 48 180 p lt 0 001 181 176 4 1 2 1 2 SU 2 0 75 mg 1
30. 1 9 13 14 23 42 52 917 272 29 7 57 6 2 56 6 1 53 5 8 77 78 5 IT 1 1 0 75 mg 2 TRULICITY ATEOS 3 True Simplicity 2 1 JAN 2 Dulaglutide Genetical Recombination JAN dulaglutide INN 3 tide 3
31. z 7 I 3 MM 3 3 3 3 26 LOCF mg dL 00 ne Poriod Bascline se Baseline se Beseline oC Endpoint COCP Endpoint LOCF Endpoint OCF Pula 0 Liregiutde mg dL 2 2 2 2 2 2 2 2 2 52 LOCF ng dL 26 0 02 0 14 kg 0 36 0 20 kg 0 63 0 29 kg
32. 2 2 2 26 2 1 2 26 LOCF 7 7 3 1 53 VI 1 1 2 3 RIA 3 1 2 1 GBCB gt 2 32 1 8 0 3 1 0 3 0 6 0 mg
33. 6000 5000 4000 3000 2000 1000 0 1 2 3 4 5 7T 3910 111213 1415 16 17 18 19 20 21 22 23 24 GBDP GBDY GBDQ 2 GBCB GBCL I GBCZ 2 GBDP GBDY GBDQ 0 75 mg m GBDP 0 75 mg 1 SU II GBDY 0 75 mg 1
34. 6 GLP 1 6 7 9 WL 1 3 1
35. 3 2 0 75 mg GBDP 340 3 0 9 SU GBDY 176 1 0 6 GBDQ 394 9 2 3 2 a 1 1 V 2 In vitro hERG ether a go go
36. 7 1 I 0 75 mg 1 1 2 GLP 1 10 0 75 mg 1
37. 8 g AUC 9 53 NOAEL mg kg 34 9 149 7 2 SD Sprague Dawley NZW NOAEL 4 1 SD 60 0 0 05 0 5 1 5 5 mg kg 2 104 AUC 0 05 0 5 1 5 5 mg kg 0 829 12 2 32 5 95 0 20 93 0 05 mg kg 0 5 mg kg C C 0 5 mg kg C 1 5 mg kg 5 mg kg C
38. FDA 1 1 0 75 mg 71 21 1 0 75 mg 27 1 0 75 mg 149 2
39. 3 GLP 1 GIP SPA GLP 1 4 20 0 45 nM Ki GIP K gt 697 nM gt 1360 nM GLP 1 K nM EE BSSESESSS2 GPP GLP 1 7 36 NH 50 K gt n x y 50 K y x Ki
40. 6 Visit 1 1 5 7 Visit 1 24 2 1 1 1 1 0 25 0 5 0 75 mg 2 4 12 12 4 4 na 0 25mg LY2189265 8 9 10 11 12 16 Visit 1 6 1 1 1 LY2189265 a TZD 8 TZD 12
41. 52 0 17 0 18 kg 0 13 0 26 kg 1 03 0 37 kg gt 26 56 1 157 280 55 5 76 137 55 7 39 70 20 4 57 280 27 7 38 137 8 6 6 70 p 0 023 5
42. 0 75 mg 2015 7 3 22700AMX00701000 11 2015 8 31 12 13 14 8 15 107 18 3 6 28 8 1 14 16 oro 0 75mg 1244229010101 2499416G1029 622442201 17 94 XI 1 1 Glaesner W et al Diabetes Metab Res Rev 26 287 296 2010 HMN30205 2 in vitro LY2189265 3 Terauchi et al Endocrine Journal 61 10 949 959 2014 HMN30397 4 2 GBDP 5 2
43. Day 1 Day 24 Day 36 AUC _ C 90 0 80 1 25 Day 24 Day 36 t Day 3 1 0 3 0 mg C 36 50 t Day 1 2 1 0 3 0 mg Day 3 3 4 1 0 mg p 0 003 3 0 mg p 0 031 7 4
44. HbA1c 7 0 6 5 FAS 26 LOCF HbA1c 7 0 3 71 3 51 1 127 178 91 178 52 45 8 24 0 82 179 43 179 26 34 3 1 9 mg dL 37 8 1 9 mg dL 8 26 LOCF 8 7 2
45. QTc SU SU TZD c GI a Oa
46. mg kg hERG In 0 51 1 52 5 1 DL HEK293 15 2 ng mL 3 5 6 cell 0 1 10 gt 1mg kg dP dt dP dt 6 10 mg kg QTc 2 4 0 1 3 gt 1 mg kg QTc 9 10 3 2 13 0 0 41 27 1 63 8 15 QTc 6 2 9 0 0 41 79 1 63 8 15 QTc 0 8 15 mg kg 6
47. 4 DPP 4 GLP 1 GLP 1 IgG4 Fc Fc IgG4 Fc B GLP 1 cAMP GLP 1 0 75 mg 2014 9 EU 2014
48. 0 75 mg SU TZD c GTF 9 II GBDQ HbA1c 14 52 LOCF GBDP GBDY GBDQ 0 75 mg 2 0 75 mg a b c ov d LOCF gt 1 gt WL
49. 7 t 87 6 t 48 0 3 mg 6 0 mg 2 C AUC 1 68 90 1 58 1 79 1 59 90 1 40 1 81 2 0 3 1 0 3 0 6 0 mg 2 AUC AUC CL F V F WW nghr mL nghr mb 2 mL a hr ee 23 6 29 1 48 72 31 3 56 7 47 3 24 96 749 213 56 7 9 37 39 77 89 0 ge9 eeo a 9 9 43 5 17 0 35 3 48 96 70 9 102 17 0 14 9 a 20 4 17 3 21 7 24 72 65 8 84 7 17 3 23 8 oo en WS Go 24 96 65 8 213 40 4 22 8 CL F V F a b c 1
50. BMI Part 1 Part 2 a ON B 12 5 3 2 a gt m aa BI ey 1 2 ie GBCH 2 GBDM
51. 9 0 7 2 280 0 7 1 137 4 3 2 GLP 1 2 1 2 2 0 75 mg 1 SU TZD 4 2
52. IF 3 IF IF 2013 PDF IF IF IF MR IF IF IF
53. Recommendation 9 7 8 2 V 3 8 8 2 10
54. 65 2 0 5 0 75 1 5 mg 1 6 GBCT 6 GBCB GBCL GBCZ GBCD GBCJ GBCK 65 2 2 0 75 mg 1 GBDP SU GBDY 26 HbAlc 65 65 83
55. IF IF IF 2013 IF 2013 IF PDF IF IF 2013 25 10 IF 2013
56. 26 7 2 200 Baselina 180 160 140 0 75mg mg dL 120 100 0 1 2 3 4 5 6 7 Days 1 2 3 4 5 6 7 N 22 21 18 11 9 11 18 N 84 71 64 63 55 63 84 0 75mg 1 MMRM 0 75nw 26 LOCF 7 26 LOCF 7 7
57. 300 nM D exendin 4 9 39 GLP 1 VT 45 46 3 6 B n 4 0 EN 16 8 mM 1E B mM ns imiM Geose th Fold Insulin Secretion mean SEM Insulin Concentration ngfml mean SEM 0 0 asal 3n 30 mM Basal3nM 3 nn 3 nl 1 3 1 1 0 3 100 00 BPR 1 LY2189265 nM LY2189265 LY2189265 n 3 6 D n 3 6 GLP 1 2 mM glucose 0puhd ere
58. I FDA Pregnancy Category C 2015 3 An Australian categorisation of risk of drug 2015 5 use in pregnancy FDA Pregnancy Category C Animal reproduction studies have shown an adverse effect on the fetus there are no AWC studies in humans AND the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks OR animal studies have not been conducted and there are no AWC in humans 98 2 SPC 8 4 Pediatric Use 2015 3 Safety and effectiveness of TIRULICITY have not been established in pediatric patients TRU LICITY is not recommended for use in pediatric patients younger than 18 years SPC Paediatric population 2014 12 The safety and efficacy of dulaglutide in children aged less than 18 years have not yet
59. 1 1 5 mg 13 3 0 75 mg 1 2 8 2 14 1 2 3
60. Visit 1 3 2 8 14 Visit 1 4 9 2 2 26 30 4 SU LYJ18B2GBTSU SU 9 Wasit 2 3 LY2189265 TV LV Last Visit Visit 11 Visit 10 30 gt 0 75 mg 1
61. B B MAO MAO 8 2 75 76
62. 22 international normalized ratio INR NR_ INR AUC AUCj 2 INR VL 1 5 8 1 917 272 29 7 57 6 2 56 6 1 53 5 8 2 GBDP GBDY GBDQ 0 75 mg 1
63. 3 72 1 3 72 14 15 DPP 4 GLP 1 1 6 7 8 9 7 2 3 1 2
64. Vo GLP 1 exendin 4 9 39 16 8mM 2 8mM exendin 4 9 39 A B exendin 4 9 39 C
65. GBDM 2 12 Day 1 Day 8 15 22 29 1 5 mg AUC Day 3 Day 17 31 15 C Day 3 Day 17 12 t 0 75 mg 1 6
66. 1 2 GBCI 2 Day 1 1 5 mg Day 3 1 2 2 2 21 10 1 10 2 10 180 2 1 2 AUC 7 92 2 44 49 50 Healthy subjects Patients with T2DM First Phase En Phase Firms FPh ECmii
67. GBDP J 1 32 GBDY gt SU 2 SU a 2 361 1 Visit 1 6 2 2 SU Visit 1 8 a 2 5 5 mg b 60 80 mg c 2 3 mg d 750
68. http www info pmda go jp e IF e IF IF 2008 4 IF IF 2013 2 IF IF
69. 4 1 2 lt 8C 2 14 30C 1 2 GBCN 85 1 5 mg 3 V
70. 1 2 gt 52 HbA1c 14 52 LOCF p lt 0 001 t 52 LOCF HbAlc 1 69 0 13 TZD 1 57 0 11 LOCF 52 HbA1c FAS HbA1c HbA1c HbA1c 7 0 6 5 52 LOCF HbA1c 7 0 SU 48 9 64 131 73 8 45 61 a GI
71. GLP 1 7 DPP 4 GLP 1
72. pH 3 2 1 0 75 mg 1 0 5 mL 0 75 mg 2 0 75 mg 1 0 5 mL D 80 3 4 5 J 2 gt 8C 0 75 mg 24 A hl rk 25 60 RH
73. 8 7 p lt 0 05 p 0 022 p 0 005 LOCF Tirne Period Baseline BEndpoint LOCP Baseline Endpoint LOCF 250 Glagine Duls 0 75 mg dL 2 2 2 2 2 2 26 LOCF ng dL 35 36
74. New York Heart Association IV 7 Visit 1 Visit 1 3 2 8 1 9 14 Visit 1 4 10 23 24 2 2 8 26 26 30 5 0 75 mg
75. GBCB GBCL 2 1 0 msg II GBCZ 0 75 mg 2 3 3 1 GBCB gt 3 3 1 I GBCL gt 18 3 QT QTc GBCC gt QT 3 18 65 147 83 64 6
76. 5 mg kg 1 5 mg kg 0 5 mg kg NOAEL 1 5 mg kg ZDF 2 91 92 1 C 20 0 8 15 mg kg 1 1 2 52 C 8 15 mg kg C
77. GBDP SU GBDY BMI 0 75 mg m SU GBDY 0 75 mg 65 a 30 GBDY 0 75 mg N 181 N 180 0 07 30 0 02 0 19 30 0 03 65 0 14 30 0 04 0 41 30 0 11 30 GBDY 0 75 msg
78. SU Visrt 1 24 GLP 1 DPP 4 Visit 1 24 Visit 1 12 2 2 Visit 1 4 3 4 Visit 1 24 5
79. 2 2 3 m ADA 1 4 13 910 1 0 05 0 5 1 5 5 mg kg 2 104 0 5 mg kg AUC 12 2 C C rasH2 0 3 1 3 mg kg 2 26 3 mg kg AUC 7 56 2 4 2
80. 0 75 mg 1 8 GBCQ 19 1 2 1 1 28 2 Day 19 1 5 mg 0 25 mg 0 035 mg 21 7 AUC AUC _ C
81. 0 41 mg kg AUC 21 2 0 2 0 49 1 63 mg kg 3 1 Biel F1 2 1 63 mg kg AUC 26 8 F1 1 F1 0 5 2 7 mg kg 7 3 1 Biel 7 mg kg AUC
82. N 181 N 180 Negative Binomial Mean SE Negative Binomial Mean SE 7 0 06 30 0 02 0 16 30 0 04 7 0 96 0 2 30 003 99 031 30 0 06 81 0 75 mg 0 75 mg 2 0 GBDP 52 3 2 7 9 a N 280 N 269 nh nh 185 66 1 109 43 21 12 EE 1 76 271 49 13 6 8 6 2279 17 2 3 OO 123 7 0 0 0 5 932 7 2 0 0O Ll 090 2 gt 2 _ WM I I 42 4 0 0 0O 6 2 tt 1j 1 44 4 0 0 0O
83. 6 3 1 6 Pr emcg 2 2 a 1 GBDT II 2 BC 1 2 BDP mm 2 GBDY 2 GBDQ EC 2 Wo 1 0 GBCM ke ee 65 2 GBCT EE JIL GBDO ArTe BMI GBCN Part 1 GBCO Part 2 mee kmO 19 eoN mA GBCS
84. 63 ee E 0 90 90 90 1 mg 1 1000 ne 3 mg 1 1 5 mg 1 1 06 0 95 0 50 0 91 1 24 0 81 1 12 1 00 0 00 1 05 1 02 1 00 0 89 1 24 0 86 1 21 1 00 1 00 1 19 1 32 1 00 100 mg 20 19 1 11 1 28 1 20 1 45 0 00 3 00 10 mg S 1000 mg 5 lt 40 mg 0 99 0 78 4 02 0 96 1 01 0 74 0 83 3 00 5 00 0 99 0 86 5 50 0 96 1 02 0 82 0 90 4 00 8 00 1 12 0 88 0 02 1 02 1 22 0 80 0 98 0 05 1 03 1 15 0 99 0 02 1 05 1 26 0 89 1 10 1 03 1 02 0 96 0 78 0 50 0 25 mg ES 28 L le a OH 0 89 1 04 0 71 0 98 0 00 0 50 R 0 79 0 30 49 ne 227 ppsogg moag
85. 1 3 3 V 5 1 2 3 4 5
86. 4 6 18 394 1 2 SU 1 w GI 2 5 3 1 SU 1 a GI 1 a GI 1 a GI 1 TZD 2 LOCF
87. GLP 1 C 0 5 ng mL 24 C 20 ug C 4 HbA1c 3 lt 4
88. 4 Visit 1 3 New York Heart Association IV 5 Visit 1 Visit 1 3 2 6 Visit 1 6 3 7 14 Visit 1 4 8 Visit 1 20 pg mL 9 2
89. HbA1c 52 70 mg dL NN HeAtcm 0 66 169 O13 61 1 52 2 52 52 0 10 0 24 kg w 1 24 0 42 kg 0 87 0 40 kg 1 02 0 35 kg 0 04 0 26 kg 6 2 GBDQ 3 1 1
90. p lt 0 001 52 14 26 38 52 7 26 LOCF 7 7 2 26 LOCF p lt 0 05 52
91. GBCP 27 1 40 mg 2 Day 1 1 5 mg Day 3 t 40 mg t 2 5 hydroxyatorvastatin C 70 AUC 21 hydroxyatorvastatin t 17 41 30 2 AUC 30
92. p lt 0 05 SU 2 1 52 LOCF le 52 LOCF p lt 0 05 a GI SU PR p lt 0 05 TZD QT p lt 0 05 1 SU 4 SU 3 c GI 1 ke LOCF
93. 1 4 7 10 13 16 19 F1 1 63 mg kg 21 AUC 3 12 1 63 mg kg 22 7 29 26 8 1 63 mg kg Biel 2 NOAEL mg kg 0 2 a 0 49 1 63 0 49 1 63 69 0 0 5 2 7 gt 0 5 mg kg SD 7 91 7 mg kg 25 3 7 mg kg 0 0 5 2 mg kg 7 mg kg
94. 2 7 7 7 7 LOCF e 274 ey 26 1 84 220 2 71 3 64 4 63 180 5 55 6 63 7 84 140 100
95. 43 2 16 37 0 25 mg 47 2 17 36 0 5 mg 48 6 18 37 0 75 mg 42 9 15 35 5 4 2 37 0 25 mg 8 3 3 36 0 5 mg 24 3 9 37 0 75 mg 14 3 5 35 5 0 5 mg 16 2 6 37 5 4 2 37 0 75 mg 5 7 2 35 12 0 5 mg 1 0 7
96. 6 2015 9 3 HH 2J 87 2499 IF 2013 GLP 1 5 TRULICITYJATEOS 0 75 mg 1 0 5 mL 0 75 mg JAN Dulaglutide Genetical Recombination JAN 6 2015 7 3 ah 2015 8 31 a 2015 9 16 TEL 0120 034 389 h
97. 2 0 75 mg 52 SU w GI v TZD 6 2 GBDQ 4 6 1 2 VI 1 GLP 1 glucagon like peptide 1 DPP 4 dipeptidyl peptidase 4 2 1 GLP 1 IgG4 Fc DPP 4
98. Child Puah B 6 Child Pugh C 3 1 5 mg AUC C AUC _ C AUC _ 67 C 70 AUC 90 0 774 0 649 0 922 0 669 0 556 0 805 0 791 0 632 0 989 C 90 0 791 0 654 0 957 0 703 0 582 0 849 0 761 0 597 0 971 t 58
99. GBDY 6 2 GBDQ 7 2 1 9 BR 9 SGi 10 SGi 11 1 2 12 2 13 2 14 15 16 17 18
100. 93 3 93 4 93 em ee ee 93 UE 93 0 94 8 94 9 94 10 94 11 44 94 12 94 13 W ErirEicictctctcitctct 94 14 94 15 i 94 0 i 94 17 94 Ni 95 1 I 95 2 kk 96 Si 97 1 97 2 98 1 D2 1 GLP 1 CHO
101. 150 mg kg 40 50 60 p 0 05 Student t SGI 7 yo 6 SGi 1 PBS 1 2 10 25 mg kg 20 40 3 0 1 mg kg 1 5 7 4 8 10 1 10 0 10 mg kg
102. p lt 0 001 HbAlc 25 26 95 0 20 0 39 0 01 p 0 040 HbAlc 4 52 p lt 0 001 52 HbA1c FAS 52 52 1 p Mean SD LS Mean SE LS Mean SE 8 18 0 81 6 58 0 12 _ ee 8 15 077 6 74 0 06 N 280 N 261 1 39 0 06 lt 0 001 8 08 0 88 6 94 0 08 N 136 N 123 1 19 0 08 lt 0 001 N Mean SD LS Mean SE a b p MMRM
103. 19 20 21 22 Narwal R et al Clin Pharmacokinet 49 10 693 702 2010 HMN30392 23 24 25 26 27 Keech A et al Lancet 366 9500 1849 1861 2005 HMN30393 28 Noel RA et al Diabetes Care 32 5 834 838 2009 HMN18830 29 Girman CJ et al Diabetes Obes Metab 12 9 766 771 2010 HMN19010 30 Urushihara H et al PLoS One 7 12 e53224 2012 31 2 209 211 2001 HMN17507 32 11 12 2014 2015 HMN30394 33 GLP 1 DPP 4 34 9 2 176 179 1990 HMN04294 35
104. 2013 4 i SU 0 020 1 SS 3 kh 2 3 oo A NM kkk 1 2 RC OO KG DR CAS KKKK Nu i LI nr d RSS i 7 ui ui ee i uu uuu A V 9 1 4 9 2 SS eA 9 3 11 VI
105. 74 7 1 2 DPP 4 SGLT2 GLP 1
106. 1 1 4 8 70 110 mg dL gt 26 lt gt 26 HbA1c HbAlc 7 0 6 5 8 2 gt gt 1 361 FAS 181 180 33 34 lt gt 26 HbA1c 26 HbA1c
107. Met GBDR I GBCJ 2 2 2 24 RN Met Met Met SU TZD
108. HGEGTFTSDV SSYLEEQAAK E FIAWLVKGG GGGGGSGGGG SGGGGSAESK YGPPCPPCPA PEAAGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTIKP REEQFNSTYR VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKIISKAKG QPREPQVYTL PPSQEEMTIKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD GSFFLYSRLT_VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG 4 CsHo4N4O0 s Sja 2 63 000 Da 5 1 lt 31 1 48 275 IgG4 Fc 2 16 30 57 63 64 Gly Glu Gly Pro Ala Ala 275 2 63 000 Dulaglutide is a recombinant fusion glycoprotein containing modified human glucag
109. 0 75 mg GBDC 52 270 30 11 1 GBDB 78 272 154 56 6 GBDD 293 258 88 4 DPP 4 SU c GI 77 6 V 3 a b wv lt d
110. 2 1 6 GBCZ GBDP GBDY GBDQ
111. 3 72 AA B 100 100 g g FE 80 8 8 40 Time week Time week 3 4 4 3 0 75 mg 1 5 A 6 B 14 15 DPP 4 GLP 1
112. 200 W hr m 24 72 2 8 C 72 72 24 72 2 8 C 72 72 2 3 1 2 4 TV 1 1 0 75 mg 0 1 0 5 mL 0 75 mg 2 pH pH
113. 3 Terauchi et al Endocrine Journal 61 10 949 959 2014 2 m GBDP gt 2 26 26 2 487 1 2 2 TZD 8
114. 5 SU 12 2 16 131 10 7 14 131 9 2 12 131 6 9 9 131 5 3 7 131 6 6 4 61 a GI 12 3 8 65 6 2 4 65 TZD 7 6 5 66 7 0 5 71 5 6 4 71 SU 1 TZD 1 1 52 SU 1 52
115. 149 2 3 11 12 13 1 2
116. 2 GBDP 0 75 mg 1 7 1 9 73 gt 3 72 3 72 1 1 3 72 1 gt
117. 2 GBDP GBDY GBDQ 917 272 29 7 79 m GBDP GBDY GBDQ MedDRA ver1 7 0 n 575 n 342 n 91 7 MedDRA 7 0 n 575 n 342 n 91 7 7 iey iey zey 0 80 5
118. 24 3 68 280 28 5 39 137 21 4 15 70 16 1 10 62 5 6 1 17 280 7 3 10 137 5 8 8 137 5 1 7 137 3597 1 1 1 1
119. 5 4 15 280 7 3 10 137 5 8 8 137 5 1 7 137 1 2 1 p 0 007
120. 1 0 6 0 mg 7 2 0 3 6 0 mg GLP 1 0 75 mg 1 GBCL gt 7 2 1 0 1 5 mg 1 5 20 75 2 20 18 2
121. 0 0 41 1 63 8 15 3 mg kg a SD 20 SD 20 SD 7 25 NZW9 20 0 1 63 489 16 3 gt 1 63 mg kg 3 gt 4 89 mg kg 4 16 3 mg kg 2 AUC 24 7 60 7 264 NOAEL mg kg 16 3 0 1 63 4 89 16 3 gt 1 63 mg kg 3 mg kg 2 4
122. 13 14 V 1 S 2 gt 0709 1 22 7 9 2 II GBCZ I GBDP 2 GBDQ 2 GBDY
123. c v d LOCF 5 6 2 24 0 75 mg 1 GBDP 1 5 4 5 108 5 AUC 1 45 1 3
124. EE EE LL 35 OA LT315536 H 1H r OT 2 1 1 i LEI 1 Eg 3 5 F a 2 8 LY2189265 OAM D E Visit 15 Visit 14 30 gt 0 75 mg 1 1 0 3 mg 2 0 6 mg 0 9 mg 1 1 26 1 26 0 75 mg 26 1 lt gt 52
125. GBCO 5 40 mg 23 1 5 mg 1 4 1 1 AUC AUC Cp AUC AUC C Day 1 10 t Day 1 Day 3 24 t 1 p lt 0 001 0 75 mg 1 3 GBCO 20
126. 0 5 mL 1 5 mg 1 0 5 mL 0 75 mg 1 0 5 mL 1 5 mg 2 0 75 mg 1 1 5 mg 1 1 5 mg 1 1 1 ml Tk CC EU Trulicity 1 5 mL 0 75 mg 1 5 mL 1 5 mg 1 5 mL 0 75 mg 1 5 mL 1 5 mg 2
127. 0 75 mg 1 6 1 GBCB GBCL II GBCZ 8 1065 152 1 2 BMI 2 1 1 2 2 65
128. C C 8 15 mg kg PanIN PanIN pancreatic intraepithelial neoplasia X 1 075 mg 2 24 3 2 8 C 4 1 2 WL 14
129. 5C 6 5 a a 1 1 40C 20 C 120 lx hr 200 W hr mz 1 eat i 30C 0 75 mg 14 60 RH 4 65 RH 2 8 C 23 4 10 11 12
130. 30 1 0 mg 22 3 0 mg 8 1 4 1000 mg Day 1 Day 3 24 t Day 36 2 Day 3 1000 mg Day 1 t 1 0 3 0 mg 1 2 C 36 50 AUC 12 Day 24 Day 36 AUC C 0 75 mg 1 60 2
131. GBCB gt 2 0 3 1 0 3 0 6 0 mg 30 75 2 40 27 13 4 1 10 8 2 0 3 1 0 3 0 6 0 mg 15 Day 1 1 3 8 40 gt 40
132. 0 4 52 HbA1c 1 39 0 06 1 19 0 08 0 20 95 0 39 0 01 70 mg dL 52 8 280 2 9 4 137 2 9 of fat 4 2 GBDP 2 GBDY 2 361 181 180 0 75 mg 1 1 1 26 26
133. 1 2 3 4 69 1 2 3 4 5 2 9 GLP 1
134. V 5 32 L 0 75 mg 1 7 2 3 1 2 3 4 5 1 gt 2 CYP450 3 4 67 5
135. 1 3 0 mg 1 0 mg p lt 0 05 2 0 3 6 0 mg gt VIL gt Day 3 Day 8 1 0 mg p lt 0 05 Day 3 Day 8 p lt 0 05
136. 1 5 65 2 6 GBCB GBCL GBCZ GBCD GBCJ GBCK 65 2 65 2 0 5 0 75 1 5 mg 1 6 _ 1 6 A EA ee N mg ng hr mL 7 L hr L A mm lel 9 1eaesl 5 41 44 48 0 95 5 EE 42 37 12 0 72 0 113 134 42 21 17 4630 37 7 71 7 IT gt 32 30 24 0 72 5 107 189 32 19 17 22 23 24 0 95 8 Ro lo 8 29 30 240 72 0 98 1 147 29 24 19 CL F V F R a b c N 7 d N 9 man 1 cy 1D 8 Cu hi
137. Oo WW 44 GLP 1 Mo GLP 1 HEK 293 GLP 1 cAMP GLP 1 GLP 1 EC 12 6 2 5 pM LY307161 2 p lt 0 0001 Student LY307161 GLP 1 7 37 OH 60 GLP 1 7 37 OH 50 EC pM n a GLP 1 7 37 OH 8 b 2
138. nH lt 65 wr yr 5 WT 5 WT Tt 65 65 6 CL F 1 5 mg 1 AUC 0 75 mg 1 3 GBCM CrCL gt 80 mL min 16 50 lt CrCL lt 80 mL min 8 30 lt CrCL lt 50 mL min 8 CrCL lt 30 mL min 8 ESRD 3 8 1 5 mg t t
139. 147 4 0 7 0 mg QT QTc 90 10 msec QT QTc 0 75 mg 1 4 5 1 I GBCZ gt 2 2 145 1
140. 2 3 0 75 mg 1 3 4 1 2 8 C 4 2 14 30 15 16 86 1 C 1 0 75 mg 12 rasH2
141. 6 3 1 0 mg 2 28 6 1 5 mg 3 42 9 6 1 0 mg 2 28 6 1 5 mg 2 28 6 1 0 mg 1 5 mg 1 0 mg 1 5 mg p 0 050 p 0 032 2
142. Plc Dula 7 m _ HLiraglutide 6 5 Dula 0 75 6 0 U 4 8 14 20 2 8 2 Endpaint Plc Dula 5 d 3 ai GO 5 am Dula0 75 250 250 279 275 271 270 257 251 2 Liragutide 135 13G 134 132 129 12 125 123 136 52 LOCF HbA1c HbA1c 7 0 6 5 26 LOCF HbA1c 7 0 6 5 p lt 0 001 26 LOCF 52 LOCF HbA1c 7 0 6 5 LOCF HbA1c 7 0 6 5 FAS 26
143. 0 962 0 858 1 08 45 3 1 5 mg AUC 90 0 973 0 941 1 01 0 989 0 956 1 02 0 75 mg 1 2 24 0 75 mg 1 CL F 0 0875 L h N 23 2 24 0 75 mg 1 1 V F 11 9 L 22 0 1 mg
144. B ATP ATP Ca Ca GLP 1 B GLP 1 cAMP Ca 2 1 GLP 1 GLP 1 o GLP 1 GIP
145. 0 25 mg 0 035 mg 3 0 75 mg 1 100 mg CoadmnisteredLiuq FR Rato and S90 C Recommendaton Lisinngpl No dnse ajustrent Cmanr Metoprolal LC In dose adjustnent Cm FT Rn No dose sjustrnent Eimear Miprelneshronmih ALC EL No dose ajushrient Elhimiestradiol AUC No dose a WlEsTadi Do dose adjushrmier Cmean toryastatn LC i No dose adjustrent Emmak fnrmmin AUC ho dose adjustrent Cmian a ietaminogphen AUC lo dose ajustrent Cman arfari 10 ho dnse sjustrent mma R warf ann No dose sjustrent iman FIF rm LC No dose ajustrent Cmean nh 1 1 5 2 Ratin Relatiwe to RETETETC 1 5 mg 1 0 3 0 mg AUC C_
146. 2 SC mg kg CByB6F1 Tg HRAS 2Jic 10 Fischer344 10 SD 10 SD 0 16 29 mg kg 25 1 63 4 89 mg kg 15 0 16 29 mg kg 10 3 6 3 0 8 15 mg kg 6 0 41 1 63 mg kg 4 0 8 15 mg kg 2 SD Sprague Dawley NOAEL 88 2 4 9 2 5 10 2 13 27 2 6 53 1 2 4 9 2 13 27 1 2 9 79 2 100 20 0 NOAEL 100 mg kg 1 gt 10 mg kg 10 100 0 NOAEL 20 mg kg 2 gt 2 mg kg
147. 52 C C C Zucker 3 ZDF 0 mg kg 27 0 5 1 5 5 mg kg 20 0 0 5 1 5 5 mg kg 2 13 AUC 0 5 1 5 5 mg kg 4 33 13 4 48 6 0 5 mg kg 4 4 12 HbA1c 5 mg kg
148. 1 0 1 5 mg 1 5 gt VIL gt 1 0 mg 1 5 mg p lt 0 05 5 HbA1c 1 0 mg 1 5 mg p lt 0 05 2 1 0 1 5 mg 1 5 0 75 mg 1 7 2 1
149. 50 mg kg 30 150 mg kg 30 20 10 0 50 mg kg 10 20 30 150 mg kg 40 50 60 8 24 3 30 nmol kg p lt 0 05 Student t Vehicl 18 6 70 cl LY2189265 dl 0 3 nmol kg n 4 LY2189265 60 TTT 1 nmol kg n 3 LY2189265 50 EE 3 mokg cn 7 LY2189265 A 30 nmolkg n 4 LY2189265 Plasma Insulin ng ml mean SEM Baseline 50 mg kg min 150 mg kg min Glucose Infusion Rate 20 10 0 50 mg kg 10 20 30
150. w GI v Met a 2 GBDC 2 2 2 2 GBDA GBDD IL III 2 Stage 1 Met GBCF II III Stage 2 Met Stage 1 2 1 GBCZ 2 145 0 25 0 5 0 75 mg 1 12 12 HbA1c 0 75 mg 1 35 0 09
151. 10 20 25 mg kg 30 40 C 0 1 mg kg 7 p lt 0 0001 A C 1 5 7 p lt 0 05 1 324 7 ng mL 7 B 47 48 7 A B 2500 100 no ay1 E a Day5 t Day7 a lt 100 1500 gt _ 1000 Pl 6 A lt Ek a 10 ry yu 1 8 0 1 10 0 10 20 30 40 Day 1 Day 5 Da
152. 2 1 2 1 1 MK 52 LOCF p lt 0 05 52 LOCF p lt 0 05
153. 1 2 3 7 CO 68 J 7 1 2 1 Io 3 1 2
154. 26 13 t 2 0 3 0 75 mg 1 9 GBDW 2 29 1 Day 1 1 5 mg 1 100 mg 1 1 18 Day 5 1 12 2 1 5 mg 2 1 AUC _ 2 AUC 7 4 C 23 1 1
155. ta 43 1 43 2 I 43 54 1 lk 54 2 65 3 I 67 A EOE Et 67 RR SS 67 Cc Cc 68 7 uur 68 8 68 69 1 Ek 69 2 69 3 69 4 69 5 i 69 6 71 0 75 88 No 77 9 83 10 84 Ro 85 12 85 1 1 PR 85 14 85 KR KITI 86 16 I 86 un 87 1 RNN 87 2 88 X 93 RF 93 2
156. 1 6 Day 38 6 C 2 Day 38 2 114 mg dL 176 mg dL 3 GBDC 2 267 0 75 mg 1 26 1 71 pmol L 127 AUC ueageno swre 0 3 6 89 pmol hr L 52 AUC oagon0 3hrs 9 1
157. GBCR 21 Day 1 0 5 mg 12 2 Day 2 17 0 25 mg 1 1 Day 8 1 15 2 1 5 mg AUC t C 1 Day 10 2 Day 17 22 17 C 4 4 24 0 75 mg 1 7
158. 2 52 30 4 SU TZD o GI 0 75 mg SU 075mq 0 75 mg p GI 0 75 mg TZD D 75 mg N _I _ a _ ww PJ 4 8 14 38 Vistt 1 2 J 4 5 6 10 11 Visit 14 Visit 13 30 gt 0 75 mg 1 SU TZD o GI lt gt 52 gt gt HbA1c
159. 0 18 0 09 0 75 mg p lt 0 001 t 0 75 mg 1 3 Terauchi et al Endocrine Journal 61 10 949 959 2014 GBDP 2 487 280 70 137 0 75 mg 1 0 9 mg 1 1 26 26 HbAlc 1 43 0 05 0 14 0 10 1 57 95 1 79 1 35 HbA1c 0 10 95 0 27 0 07 95
160. 2 ta 0 5 GLP 1 DPP 4 100 mg 1 5 mg AUC _ 38 C 27 t 24 0 75 mg 1 AUC C
161. 63 2 IF IF 10 9 3 IF 10 20 9 IF 2008 IF 2008 IF PDF e IF e IF e IF
162. 7 52 LOCF 7 7 2 p lt 0 05 LOCF 52 LOCF SU 0 10 0 24 kg 0 87 0 40 kg a GI 1 24 0 42 kg TZD 1 02 0 35 kg 0 04 0 26 kg o GI p lt 0 05 TZD p 0 005 LOCF
163. LOCF 7 7 2 52 LOCF 7 p 0 033 2 p 0 036 p 0 011 2 p 0 004 52 LOCF 27 Time red oP Boling tne arene Bdpoint LOCF Bndpoint ULDC ts Endpoint LOCPI Pulm 0 5 Liraglubda mgydLi
164. 0 41 1 63 mg kg 4 2 4 0 1 3 9 3 2 4 0 1 3 9 3 I dP dt_ QTc QT 4 87 2 1 10 mg kg 1 10 mg kg
165. 26 p lt 0 001 a 95 0 LOCF 26 HbA1c FAS 26 26 Mean SD LS Mean SE LS Mean SE 0 8 18 081 8 27 0 10 ii 8 8 15 0 77 6 70 0 05 N 280 N 270 1 43 0 05 lt 0 001 NR 8 08 0 88 6 80 0 07 N 136 N 128 1 33 0 07 lt 0 001 N Mean SD LS Mean SE a b p MMRM 52 HbA1c 52 HbAlc
166. 3 HbAlc NGSP Visit 1 Visit 3 a ee os 7 0 10 0 7 0 10 0 4 20 6 5 9 0 7 0 10 0 5 BMI 18 5 kg mz 35 0 kg m 1 GLP 1 2 Visit 1 SU 3 TZD Visit 1 3 TZD 4 5 Visit 1 3 5 6 Visit 1 3
167. 83 1 54 65 TZD 77 3 51 66 62 0 44 71 HbAlc 6 5 SU 31 3 41 131 57 4 35 61 a GI 70 8 46 65 TZD 57 6 38 66 47 9 34 71 LOCF 41 14 52 LOCF p lt 0 001 t 52 LOCF SU 43 2 3 8 mg dL 36 0 4 2 mg dL o GI 47 0 4 7 mg dL TZD 39 6 5 0 mg dL 45 8 4 0 mg dL LOCF
168. 917 272 29 7 8 4 2 1 DPP 4 o
169. GBDY 65 65 a 0 75 mg 1 10 1 1 0 75 mg 71 21 1 0 75 mg 27
170. 1 10 7 3 2 1 0 1 5 mg 1 5 4 8 15 EE PE 4 BC Soreening day Day 30 to BL BL Baseline day Day 7 to 1 Aflrscreening StudY drug amp PK sampling PD sampling Glucese and Insulin PD sarmpling HhbA1c 1 20 gt 20 9
171. HbA1c 7 0 6 5 7 2 Homeostasis model assessment HOMA2 B gt 1 394 FAS SU 131 61 o GI 65 TZD 66 71 gt 52 SU 85 5 112 131 83 6 51 61 a GI 70 8 46 65 39 40 TZD 80 3 53 66 73 2 52 71 SU 44 3 58 131 23 0 14 61 w GI 32 3 21 65 TZD 25 8 17 66 36 6 26 71
172. 2 778 779 1998 HMN30395 36 53 7 505 508 2010 HMN19000 95 37 38 39 40 41 42 rasH2 2 96 XT 1 2 0 75 mg 1 2015 5 1 0 5 mL 0 75 mg 1
173. 26 0 48 0 17kg 0 94 0 17kg p lt 0 001 gt 26 75 1 136 181 61 7 111 180 p 0 007 29 8 54 181 2 2 4 180 p lt 0 001 5 8 3 15 181 7 7 14 181 6 6 12 181
174. b Visit 2 4 Visit 3 c Visit 2 2 d GLP 1 DPP 4 e Visit 3 7 Visit 4 Visit 8 f 8 gt 0 25 0 5 0 75 mg 1 12 12 HbA1c gt 1 145 FAS gt 12 HbA1c p lt 0 001 Cochran Armitage trend t
175. 0 90 0 74 2 00 0 83 0 98 0 65 0 85 0 00 2 00 0 99 0 87 0 30 0 90 1 09 0 79 0 97 0 00 2 00 1 01 0 89 0 50 0 86 1 17 0 73 1 08 0 00 1 02 0 93 0 77 0 50 0 79 1 09 0 63 0 94 0 00 1 00 1 2 48 t 1 1 N AUC AUC 2 AUC AUC C t 1 1 4 2 48 t 2 2
176. 11 2 2015 7 2 1 1 2 29 3 10 4 2
177. 27 23 4 5 32 8 8 32 6 7 32 5 7 32 5 5 Day 2 Day 5 40 20 18 2 3 0 mg 1 6 0 mg
178. LOCF 52 LOCF _HbAt1 c _HbAt1 c 6 5 6 5 1 5 0 52 9 4 68 1 68 48 68 36 68 3e 71 4 50 0 P 67 9 49 3 200 280 140 280 190 280 138 280 69 1 49 3 60 3 41 2 2 0 94 136 67 136 82 136 56 136 a b p lt 0 001 p GEE 26 52 26 39 18 1 60 mg dL 39 75 2 27 mg dL 1 03 3 30 mg dL
179. p lt 0 001 26 LOCF p lt 0 001 p 0 022 PR QTc QTcF 26 LOCF LOCF 2 1 6 280 1 5 2 137 1 4 1 70
180. 15 22 29 2 0 75 mg 1 GBDP gt 2 24 0 75 mg 1 1 5 1 5 t 48 5 t 4 5 108 5 AUC 5 1 1 45 2 0 75 mg 1 1 5 TT ngrhr mL a NN 2 L hr DL A mm a 8 21 22 45 87 94 67 71 3 145 22 24 ma M
181. HbAlc 1 44 0 05 0 90 0 05 HbA1c 0 54 95 0 67 0 41 95 0 4 70 mg dL 47 181 26 0 86 180 47 8 26 0 48 0 17 kg 0 94 0 17 kg 5 2 GBDY GBDQ 2 0 75 mg 1 52
182. s 5 4 4 3 96 3 2 2 1 0 Bo ee 0 mm 0 Go o S 2 26 OO OS WW 26 SW WAS SW ES W NV NV NV 7 7 7 3 9 8 7 7 6 6 5 gt 4 4 amp 4 9 3 3 2 2 y HHmmm 0 0 mm mm a RF EN NE 2 0 75 mg GBDP A RN 2 8 3 9
183. totot tit1 10W0W0W0 WmnmnmnmWWWWW 0 20 0 0 1 1 1657 6 3 5 2 3 58 2 2 0 1 1042 0 1 0 9O EE EC ER Eg EE EE 80 286 83 28 12 7 52 60 17 19 10 6 WWW 9 W WW 600 9 EE YW 3 0 2 1 0 0O WWW 0 1761 10 2 01 1042 1 0 0 0 0O OOOO 0 0 0 0 2693 3 7 8 8 30 0 0 1 2 621 3 2 0 1 20 2 0 0 0 34Q2 1 8 13 8 5 104 0 0 0 0 1 1657 6 5 5 0 0 9 1 0 20 0 102 0 207 1 0 1 0 1042 0 0 1 0O 1139 5 4
184. 6 gt 6 mg kg 20 20 mg kg 2 20 mg kg 20 mg kg NOAEL 16 29 mg kg gt 1 63 mg kg 0 1 63 4 89 16 29 0 1 63 4 89 16 29 NOAEL 16 29 mg kg gt 1 63 mg kg 0 NOAEL 10 mg kg 1 gt 1 mg kg 3 10 0 0 41 1 63 8 15 NOAEL 8 15 mg kg gt 0 41 mg kg gt 1 63 mg kg 8 15 mg kg 1 NOAEL 8 15 mg kg gt 0 41 mg kg 8 15 mg kg 1
185. d N 4 e N 5 f N 17 54 1000 0 3 mg n 8 1 0 mg n 8 3 0 mg n 8 gas a 6 0 mg n 8 3 7 100 4 yw be 8 o _ IN 1 0 Ma 0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 hr 2 0 3 1 0 3 0 6 0 mg 0 75 mg 1 I GBCL gt 2 14 1 0 1 5 mg 1 5 Day 1 8
186. t 10 mg 2 S R AUC _ R Ca S C 22 International normalized ratio INR NR INR tINR 6 S 4 R ty 6 INR AUC AUC 2 0 75 mg 1 61 62 5
187. 0 2 0 42 2 0 1 1 0O 6 4t 207 1 0 1 0O 186 9 3 3 3 429 3 0 0 0 1 0Q000 0 0 0 oO 725 5 0 2 0 EE NR EE WW EE EE N n MedDRA J Version 17 0 1 a 3 1 90 4 6 91 180 7 9 181 270 10 271 GBDP 2 0 9 9 8 8 1 7 7 6 6
188. 1 0 75 mg 149 2 84 1 2 0 49 1 63 4 89 mg kg 3 1 1 63 mg kg AUC 22 5 4 89 mg kg AUC 71 1 0 04 0 12 0 41 mg kg 3 1
189. 1500 mg e 100 150 mg 3 Visit 1 HbA1c 7 0 10 0 4 20 5 BMI 18 5 kg m 35 0 kg m 1 GLP 1 2 Visit 1 3 o GI TZD DPP 4 3 Visit 1 3 4 5 Visit 1 3 5 6 Visit 1 3 New York Heart Association IV 7 Visit 1
190. 2 Visit 1 3 SU TZD o GI Visit 1 8 a TZD or GI b SU 3 Visit 1 HbAlc NGSP 7 0 11 0 4 20 5 BMI 18 5 kg m 35 0 kg m 1 Visit 1 3 GLP 1 2 Visit 1 3 3
191. 26 26 gt 26 HbA1c HbAlc 52 HbAlc 7 0 6 5 C 7 2 Homeostasis Model Assessment 2 HOMA2 B gt gt 1 487 FAS 280 137 70 gt 26 HbA1c 26 HbAlc
192. 6 AUC 24 7 60 7 264 NOAEL mg kg 1 63 1 63 0 0 49 1 63 4 89 gt 0 49 mg kg 6 9 12 15 gt 1 63 mg kg AUC 7 15 4 89 mg kg 22 5 71 1 NOAEL mg kg 0 49 0 49 0 0 04 0 12 0 41 gt 0 12 mg kg 7 10 13 16 19 0 41 mg kg 13 2 AUC 1 92 7 22 21 2 NOAEL mg kg 0 04 0 12 SD39 25 0 0 2 0 49 1 63 6 9 12 15 18 gt 0 49 mg kg
193. Day 3 Day 10 2 2 AUC 2 4 2 Day 17 24 31 ts Day 10 88 87 84 0 75 mg 1 GBCH 30 1 0 mg 22 3 0 mg 8 1 4 Day 1 8 15 22 1000 mg Day 1 Day 3 24 tg Day 36 2
194. been established No data are available 99 X https ds pharmajp http kanja ds pharmajp products www iilyanswersjp Q amp A 100 541 0045 2 6 8 gt 651 0086 7 1 5 TEL 0120 034 389 9 00 18 30 https ds Dharma jp lt gt TEL 0120 360 605 8 45 17 30
195. www lillyanswers jp TLC FO01 R3 2015 9
196. 1 5 mg ME ngrhr mL ng hr mL ng mL hr hr L hr L 26 24 29 24 02 72 02 88 6 116 24 27 0 0 0 go ea 69 27 26 30 47 95 72 02 86 2 116 26 27 HB 19 14 28 47 10 95 97 75 1 104 14 20 13 5 18 71 90 71 98 76 4 121 5 24 CL F V F a b c N 5 1L 100 EE c 60 38 4 8 an n 4 dE 144 1 BB 35 1 5mg 0 75 mg 1 59 Intrinsic Factor PK Ratio and 90 C1 Recommendation PH ears UC No dose adjustment C
197. 2 2 DPP 4 3 8 12 SU oc GI 8 TZD 12 4 HbA1c Visit 1 Visit 1 Visit 3 bt 7 0 9 5 7 0 9 5 7 0 9 5 5 Visit 1 20 75 6 Visit 1 BMI 18 5 kg m 40 0 kg mz 7 Visit 1 12 1
198. 5 mg 1 12 0 5 mg 1 3 0 75 mg 2 2 70 mg dL 0 5 0 75 mg 0 75 mg HbA1c SU c GI ov TZD 0 75 mg 1
199. 66 3 4 5 6 16 1 5 mg 0 1 mg 2 AUC _ AUC 90 0 443 0 395 0 497 AUC _ AUC 90 0 371 0 335 0 410 0 75 1 5 mg 0 647 0 470 8 0 75 mg 2 AUC _ 90
200. 7 94 47 96 9 187 18 13 ee aol ean 23 12 26 47 88 97 02 83 3 168 12 36 a a OG _ 19 15 20 47 60 97 47 88 8 121 15 22 10400 18300 84 6 60 68 123 0 0819 14 6 ESRD 8 0 G9 G qeO29 Goro 0 CL F V F a b c N 15 d N 7 i Bild Imipairmernt oerate mipairment Sewere Impaimnent ESRD i gg Dulaglutide plas ma Doncentration ng mL 4B 144 192 34 BE 5 Time pcostdoses hi 1 5mg 0 75 mg 1 4 GBDO 11 Child Pugh A 6
201. 87 7 1 2 0 05 gt J S ei pa N Mean SD LS Mean SE HbA1c Dula 0 75 _ Glargins 179 179 178 178 176 179 Dula075 178 178 175 173 173 178 26 LOCF HbAlc PPS MMRM FAS LOCF ANCOVA LOOCF HbA1c 7 0 6 5 26 LOCF HbA1c 7 0 6 5 p lt 0 001 LOCF
202. 9 pmol h L 0 75 mg 1 4 GBDM 2 Day 1 Day 8 15 22 29 1 5 mg 15 10 Day 3 t Day 10 17 24 31 4 Day 3 AUC t t t 10 50 90 ps lt 0 001 t
203. Bi 21 24 22 67 96 48 71 7 167 21 35 11 CL F V F R a b c N 23 56 100 1 N 24 5 N 24 ep CO ng mL IO IN OO 72 96 120 144 168 hr 2 0 75 mg 1 1 5 2 65 2 GBCT 2 29 65 lt 76 0 5 0 75 1 5 mg 1 6 Day 1 8 15 22 29 36 1 Day 1 6 Day 36 t 48 72 t 117 131 Day 36
204. Day 1 7 100 mg 1 1 Day 5 5 1 5 mg AUC 19 C 32 p lt 0 016 69 t 0 75 mg 1 4 GBCS 28 1 10 mg 1 Day 1 1 5 mg Day 3
205. Insulin ResPOnSE Insulin ResPse Insulim Response Insulim Rss To a 19D m I BO rl EO 3 F 400 F 400 OD LL i Lt 3 5D 1 150 1 nl 3H ED Pd 150 1 Time after Glucnse Bolus Mimutes Time after Glucose Bolus Minutes ulaglutids 1 5 mm TAD I Elucose y urrm Piacsthin TD bolus nlus Day 1 1 5 mg Day 3 6 30 1 2 50 0 3 g kg 2 min 2 0 75 mg 1 GBCT 2 19 0 75 mg 11 8
206. est 12 HbA1c p lt 0 001 t 12 HbA1c FAS 12 p LS Mean MeantSD LS Mean SE 95 CI 96 0 0 18 0 025 mg gos oee 090 Oo9 i lt 0 001 n 36 CAA lt 0 001 J 0 5 mg 0 97 7 98 0 1 15 0 0 0 001 n 37 Pb 5 099 1920 073 0 75 mg 1 17 U oi U n 34 7 98 0 61 1 35 0 09 141 093 0 001 Mean SD LS Mean SE CI a 95 p MMRM b p MMRM nn mk ei a 1 0 2 0L5 4 0 5 0 6 LT rm LT m LT 7 rm FIcEhn HbA1c LY V
207. isit 5 Visit 6 Visit 7 Visit HbAlc FAS PPS MMRM FAS LOCF ANCOVA 12 9 00 4 75 mg dL 0 25 mg 29 21 4 67 mg dL 0 5 mg 28 55 4 62 mg dL 0 75 mg 37 48 4 81 mg dL p lt 0 001 12 p lt 0 05 LOOF 21 12
208. m T wmar5s ol UC No dose adjustment ma Renal Impairment mild U No dose adjustment Cm FCHErtE UC No dose adjustment Cm sewefe LC No dose adjustment Cm ESRD ALUC No dose adjustment Cm Hepatic Impairment mild UC hin dose adjustment ma a rmoderate LG No dose adjustment ma EE LC No dose adjustment Cm 0 0 0 5 1 0 1 5 2 0 Ratio Relative to Reference 65 65 4 5 1 GBCH
209. mg kg 10 20 25 mg kg 30 40 1 28 C 28 4 p lt 0 0001 C p lt 0 0008 28 53 ng mL 1 4 1500 30000 E _ 5000 Day 28 4 days post 4th dose HE 1000 K 500 HE 20 10 0 10 20 30 40 p 0 0001 Student t
210. on like peptide 1 at positions 1 31 and modified Fc domain of human IgG4 at positions 48 275 and whose amino acid residues at positions 2 16 30 57 63 and 64 are substituted by Gly Glu Gly Pro Ala and Ala respectively Dulaglutide is produced in Chinese hamster ovary cells Dulaglutide is a glycoprotein molecular weight ca 63 000 composed of 2 subunits consisting of 275 amino acid residues each 6 LY 2189265 7 CAS 923950 08 7 1 1 lt 2 3 5 6 7 pH 6 0 7 0 2 1 _ PETG PETG 20 C 120 khr
211. rndin 4 3 15 8 mh glucose 0 uh exendin 4 9 3 ma 15 8 mh glucose 1 uh exendin 4 9 3 td Insulin Concentration ng mml mean SEM Insulin Concentratinn nl rmean SEM mm C05 i GluUcose 3 nM 3 mm 3 EE mg Giucose_ nly LT 189 6 LTE1HB8B GLP 1 Foreknlin LY2189265 nM _1 10 30 100 300 Forskolin p 0 05 p lt 0 001 Dunnett 0 5 16 8 mM LY2189265 SGi yo Sprague Dawley 36 SGI 1 0 0 3 1 3 30 nmol kg 16 2 24 20
212. ttps ds pharmajp Lilly Answers TEL 0120 360 605 www jillyanswersjp IF 2015 7 http www pmda gojjp safety info services drugs 0001 html IF 1
213. y 7 p 0 0001 Dunnett SGI vivo 6 SGI ra 1 PBS 3 10 17 24 4 0 1 mg kg 28 10 mg kg 20 25 mg kg 20 40 10 0 10
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