Efficacy : Long Term(52week) - PDF 무료 다운로드

New DPP-IV inhibitor, Gemigliptin 세계를향한발돋움 Eun-Jung Rhee Department of Endocrinology Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine 1

당뇨병은얼마나많은가? 전세계인의문제 우리나라 20년 2011년전세계에 3억6천만명의당뇨병환자 ; 2006 년에 2 억 3 천만명 3 억 5 천만명 인도와아시아에서폭증할것이다 2010 년 350 만명 2030 년에는 5 억 5 천 2 백만명의당뇨병환자 2030 년 545 만명추정 자료출처 : EGDM IDF Diabetes Atlas, http://www.diabetesatlas.org/map

현재보이는당뇨병환자및당뇨병고위험군 진단되지않은당뇨병환자, 앞으로당뇨병이될위험군, 당뇨병으로인한합병증의부담

β-cell Status Metabolic Status Vascular Status Future therapies will be directed not only to achievement of euglycemia, but also changing the course of the disease by reversing the processes of ß cell failure. Modified from Hsueh, Am J Cardiol 92:(Supp 1) 10, 2003 and Prentki M, J Clin Invest. 2006 Jul;116(7):1802-12

제 2 형당뇨병은진행하는질병이다 : UKPDS 6 년연구 HbA 1c (Median %) 9 췌장에서의인슐린분비능의 손상이 8 가장문제가된다 7 6 6.2% HbA 1c upper limit of normal Conventional Chlorpropamide Glibenclamide Insulin Metformin 0 0 1 2 3 4 5 6 Time from Randomisation (years) UKPDS. Lancet. 1998;352:854-865. Reprinted from Lancet, 352, UKPDS, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), 854-865. Copyright 1998, with permission from Elsevier.

NGT IFG Diabetes &/or IGT Insulin sensitivity (A) and ß-cell function (B) from an OGTT in first-degree relatives of 4 different ethnic groups. ß-cell function is a major, early determinant of dysglycemia in all ethnic group especially in Asian-American. African-American Asian-American Caucasian Hispanic-American Jensen CC, Diabetes 2002 Jul;51(7):2170-8.

The change of Beta cell and Alpha cell mass ( I ) Islets stained with double immunohistochemical staining (A) Normal control (B) Diabetes Double immunohistochemical staining. Figure A shows normal pancreatic islets. Most of cells in the islet consist of beta cells (red) and the remnants cosisting of alpha cells (blue) are positioned at the periphery of the islets. Figure B shows diabetic islets. In contrast to figure A, this shows that alpha cell mass commands overwhelming majority in the islet.

Beta-cell loss in T2DM Scattered 1.0 β cell fraction in islet 0.64 (0.64~1.0) (0.0 ~ 0.64) 0 Control 1 : r = 0.64 DM : r = 0.55 Small & healthy Small & β-cell depleted Islet size (μ m2 ) 6415 6415 ~ (6415 ~ 75,000) Large & healthy Large & β-cell depleted 75,000 BMI and β-cell mass were linearly correlated both in control group and DM group. Yoon KH et al: J Clin Endocrinol & Metab 2003 May;88(5):2300-8

The two authors share a near identical BMI, but as DEXA shows the right author has substantially more body fat than the left author. The image is a useful reminder of the limitations of BMI as a measure of adiposity across populations. Lancet 2004; 363: 163

혈당조절에따른심혈관질환예방관련연구들 90 + BARI-2D N=2257 A1C=7.7% 심혈관질환이있는환자의비율 (%) 60 50 40 30 20 UKPDS (N=5102) RECORD (N=4447) A1C=8.0% PROactive (N=5238) A1C=7.9% ADVANCE (N=11,140) A1C=7.5% VADT (N=1791) A1C=9.4% ACCORD (N=10,251) A1C=8.3% 2 3 4 5 6 7 8 당뇨병유병기간 ( 년 ) 9 10 UKPDS Group. Lancet 1998;352:837-53; Home P et al. N Engl J Med 2007;357:28-8; Nissen SE, Wolski K. N Engl J Med 2007;356:2457-71; ACCORD study group. N Engl J Med 2008;358:2545-59; ADVANCE study group. N Engl J Med. 2008;358:2560-72; Duckworth W et al. N Engl J Med 2009;360:129-39.

Basic Characteristics of Main Trials ADVANCE ACCORD VADT UKPDS Number 11,140 10,251 1,791 3,869 Age (yrs) 66 62 60 53 Gender (% M/F) 58/42 62/38 97/3 61/39 DM Duration (yrs) 8 10 11.5 0 HbA1c(%) 7.5 8.1 9.4 7.1 CV Events(%) ~32 ~35 ~40 ~2 Insulin Use(%) ~1.5 ~35 ~50 0 Follow-Up(yrs) 5 3.5 5.6 ~10

ACCORD 연구에서의교훈 총 10000 명의당뇨병환자 3.5 년간추적관찰 열심히치료군, 대강치료군으로나누어관찰 조기종료 열심히치료군에서사망률의증가가관찰됨 혈당조절을열심히하는것이사망률을증가?

UKPDS (10-year follow-up) : Legacy Effect of Insulin/Sulfonylurea Therapy After median 8.8 years post-trial follow-up Aggregate Endpoint (Relative Risk Reduction) 1997 2007 Any diabetes related endpoint 12% (p=0.029) 9% (p=0.040) Microvascular disease 25% (p=0.009) 24% (p=0.001) Myocardial infarction 16% (p=0.052) 15% (p=0.014) All-cause mortality 6% (p=0.44) 13% (p=0.007) Holman RR et l. New England Journal of Medicine 2008; 359:1577-1589

Legacy ( 유산 ) 효과? UKPDS 연구 대사기억 (Metabolic memory) 발병초기의손상이세포내미토콘드리아에기억되어혈당조절이나중에잘되어도원래의손상정도는지속된다는이론 초기치료가중요하다!!! 초기의엄격한치료만이당뇨병합병증을예방할수있다.

미국, 유럽, 아시아의당뇨병의대부분이 혈당조절목표에도달하지못하고있다 100 80 미국 100 80 유럽 꿈의스코어? 69% 100 80 아시아 79% Subjects (%) 60 36% 64% Subjects (%) 20 31% Subjects (%) 20 21% 0 < 7% 7% HbA 1c (%) 0 6.5% > 6.5% HbA 1c (%) 0 < 7% 7% HbA 1c (%) 1 Koro CE, et al. Diabetes Care 2004; 27:17 20. 2 Liebl A. Diabetologia 2002; 45:S23 S28. Diabcare-Asia 1998 Study Group. Diabetic Medicine 2002; 19: 978 85.

당뇨병치료의현주소우리는어디에있는가..? 동물인슐린? 흡입형인슐린인슐린유도체장펩타이드 글루리신아스파트글라진글리나이드글리타존리스프로메트폴민인간인슐린설포닐유레아 1922 1950s 1982-85 1995 1996 2001 2003 Non-physiologic replacement of insulin Physiologic replacement of insulin + insulin sensitizer + beta-cell preservation?

제 2 형당뇨병의치료약제 약물종류작용부위부작용 설폰요소계 메글리티나이드계 췌장베타세포 저혈당 체중증가 비구아나이드 간 근육 소화기계이상 락토스산혈증 알파 - 글루코시데이즈억제제소장복부팽만, 가스 치아졸리딘디온계 인슐린 간근육지방 체중증가부종빈혈심혈관계위험성증가? 골다공증 저혈당, 체중증가 Moller DE. Nature. 2001;414:821-827.; Pickup JC, Williams G, eds. Textbook of Diabetes 2. Malden, MA: Blackwell;2003:45.5.

현재당뇨병약제의임상적문제점과미래의이상적인당뇨병약제 식후혈당조절의부족 체중증가 저혈당위험 특정군에서의적용불가 점진적인췌장베타세포의손상현재약제들의문제점 미래의이상적인당뇨병약제 감소시킬것 대혈관합병증위험 미세혈관합병증위험 증가시킬것 인슐린분비능과저항성개선능 안전성 낮은저혈당위험 체중증가의부재 다른임상적문제점의부재 혈당강하효과 공복 & 식후혈당강하효과 지속적인혈당강하효과의유지

대강치료군 엄격치료군 당화혈색소의증가는결국같지만, 어떤과정으로그당화혈색소에도달했는가가중요하다 당화혈색소의질 혈당의증감의폭이클경우, 혈관에대한스트레스는더크다.. Hirsch, Am J Med 118:S1 21, 2005

DECODE 연구공복고혈당과식후고혈당이심혈관질환에미치는영향 2.50 2.00 1.50 1.00 0.50 0.00 <6.1 6.1 6.9 7.0 7.7 7.8 공복혈당 (mmol/l) <7.8 11.1 7.8 11.0 DECODE Study Group. Lancet 354:617-21, 1999

혈당의변동폭과혈관탄력도와의관계 혈당의변동폭 혈관탄력도 혈당이증가함에따라서혈관탄력도가급속히줄어든다

식후고혈당의혈관에대한영향 염증반응 고혈당폭풍 산화스트레스 심혈관질환발생 아침식사점심식사저녁식사

Complications and Effects of Severe Hypoglycemia Plasma glucose level 110 6 100 5 90 4 3 2 80 70 60 50 40 30 Increased Risk of Cardiac Arrhythmia 1 Progressive Neuroglycopenia 2 Abnormal prolonged cardiac repolarization: QTc and QTd Sudden death Cognitive impairment Unusual behavior Seizure Coma Brain death 1 20 mmol/l 10 mg/dl 1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299 307. 2. Cryer PE. J Clin Invest. 2007;117(4):868 870.

Adverse events & Clinical measures of ACCORD ACCORD Study Group. NEJM.2008;358:2545-59

췌장의인슐린분비능을유지시킬수있는새로운당뇨병약제의필요성 심혈관위험도의감소 식후고혈당의효율적치료 체중증가식후, 고혈당의저혈당등의효율적인부작용의조절최소화

Typical pathophysiological features of hyperglycemic in type 2 diabetes Tahrani AA et al. Lancet 378:182-197, 2011

The Incretin Effect: Greater Insulin Response After Oral vs IV Glucose in Healthy Individuals Plasma glucose concentration, mg/dl 200 150 100 50 0 Glucose -30 0 30 60 90 120 150 180 210 Minutes Oral IV Plasma insulin concentration, pmol/l 400 300 Insulin n = 6 n = 6 200 100 0-30 0 30 60 90 120 150 180 Minutes 210 Nauck MA et al. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986. The Endocrine Society.

GLP-1 and GIP Are the Two Major Incretins GLP-1 Secreted by L-cells in the distal gut (ileum and colon) Stimulates glucose-dependent insulin release Inhibition of gastric emptying Reduction of food intake and body weight Suppresses hepatic glucose output by inhibiting glucagon secretion in a glucose-dependent manner Enhances beta-cell proliferation and survival in animal models and isolated human islets GIP Secreted by K-cells in the proximal gut (duodenum) Stimulates glucose-dependent insulin release Minimal effects on gastric emptying No significant effects on satiety or body weight Enhances beta-cell proliferation and survival in islet cell lines GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide Adapted from Drucker DJ Diabetes Care 2003;26:2929 2940; Ahrén B Curr Diab Rep 2003;3:365 372; Drucker DJ Gastroenterology 2002;122: 531 544; Farilla L et al Endocrinology 2003;144:5149 5158; Trümper A et al Mol Endocrinol 2001;15:1559 1570; Trümper A et al J Endocrinol 2002;174:233 246.

Continuously Infused GLP-1 Improves th e Defects of T2D T2D Defects 1,3 Continuously Infused GLP-1 1,2 Insulin production First-phase insulin response Glucagon; glucose output Gastric emptying Food intake 1. Aronoff SL, et al. Diabetes Spectrum. 2004;17:183-190; 2. Nielsen LL, et al. Regul Pept. 2004;117:77-88; 3. Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705.

Glucose-Dependent Effect of GLP-1 Glucose (mmol/l) Insulin (pmol/l) Glucagon (pmol/l) 15.0 12.5 10.0 7.5 5.0 250 200 150 100 50 20 15 10 5 * * * * Glucose * * * Infusion Insulin * * * * * * * * Glucagon * * * * Placebo GLP-1 infusion When glucose levels approach normal insulin levels return to baseline ( ), and glucagon levels rebound ( ) Glucosedependent means: Insulin only when needed Less risk of: Hypoglycemia Weight gain 0 60 120 180 240 Time (min) N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule was allowed for one day between the experiments with GLP-1 and placebo. *p<0.05 GLP-1 vs. placebo Adapted from Nauck MA et al Diabetologia 1993;36:741 744.

DPP-4 Inhibition Increases Concentrations of Active Incretins 1 3 Release of active incretins by the intestine a GLP-1 GIP DPP-4 enzyme X Inactive GLP-1 and GIP Glucose-dependent Glucagon from alpha cells Hepatic glucose production Glucose-dependent Insulin from beta cells Peripheral glucose uptake Blood glucose in fasting and postprandial states DPP-4 inhibitor By increasing and prolonging active incretin levels, DPP-4 inhibitors increase insulin release and decrease glucagon levels in the circulation in a glucosedependent manner. DPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. a Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. 1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876 913. 2. Drucker DJ. Diabetes Care. 2003;26(10):2929 2940. 33 3. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430 441.

Chemistry Gemigliptin 1- [2- amino- 4- (2, 4-bis-trifluoromethyl- 5, 8- dihydro- 6Hpyrido [3, 4-d] pyrimidin-7-yl)-4-oxo-butyl]-5, 5-difluoropiperidin-2-one tartrate sesquihydrate Compound Chemistry Binding Kinetics Gemigliptin (LG) Sitagliptiin (Merck) Vildagliptin (Novartis) Saxagliptin (BMS) Linagliptin (Boehringer Ingelheim) Pyrimidinopiperidine based, Substrate like Triazolopiperazine based, Substrate like Cyanopyrrolidine based, Substrate like Cyanopyrrolidine based, Substrate like Fused imidazole based, nonsubstrate-like Competitive, reversible inhibitor (Non-covalent interaction) Competitive, reversible inhibitor (Non-covalent interaction) Slow-tight binding inhibitor (Covalent interaction) Slow-tight binding inhibitor (Covalent interaction) Competitive, reversible inhibitor (Non-covalent interaction)

Potential Issue: Toxicities due to Non-Selective Inhibition: The DPP-4 Protease Family DPP9 Specificity Function unknown DPP-4 Gene Family DPP8 FAP DPP-4 DPP6 unknown NH 2 -Xaa-Pro~Yaa-- unknown GLP-1 / GIP cleavage catalytically inactive unknown PEP --Xaa-Pro~Yaa-- unknown Other Proline Specific Peptidases QPP/DPPII APP prolidase NH 2 -Xaa-Pro~Yaa-- NH 2 -Xaa~Pro-Yaa---- NH 2 -Xaa~Pro-COOH unknown unknown unknown

Enzyme Selectivity Gemigliptin is a selective DPP IV inhibitor Compound Fold Selectivity vs. DPP 8, 9 or FAP DPP 8 (fold) DPP 9 (fold) FAP (fold) Gemigliptin (LG) Sitagliptiin # (Merck) Vildagliptin # (Novartis) Saxagliptin # (BMS) Linagliptin # (Boehringer Ingelheim) High 9565 3412 22,458 High >2,600 >5,500 >5,500 Moderate 270 32 285 Moderate 390 77 >4,000 Moderate 40,000 >10,000 89 #Diabetes, Obesity and Metabolism 13: 7 18, 2011 Fold: vs. DPP IV activity

Enzyme Kinetics Gemigliptin is a potent and competitive DPP IV inhibitor 6 Lineweaver-Burk Plot 5 1/V 4 3 2 1 0.000 0.005 0.010 0.015 0.020 1/[S] 0nM 5 nm 10nM 20nM 40nM 80nM Ki of Gemigliptin: 9.04 ± 0.55 nm Lineweaver-Burk Plot of Recombinant Human DPP IV Activity Measured in the Presence of Varied Concentrations of Gemigliptin & Substrate (Gly-Pro-pNA)

Enzyme Kinetics Gemigliptin is a slowly reversible inhibitor Rapidly reversible Slowly reversible Dissociation of the Inhibitors-enzyme complex following dilution into substrate.

Efficacy in vivo DPP IV inhibition Higher DPP IV inhibition rate & longer duration of Gemigliptin 2006 ADA Poster No.502

Efficacy HbA1C Gemigliptin was superior to sitagliptin for reduction of HbA1c Animals male DIO C57BL/6 mice 28 weeks old N = 6 Diet 60 kcal% fat diet Dosing Oral gavage qd x 32 Compound 22 Hours after the 32 nd Dosing DPP IV Activity (%)* Vehicle Control 100.0 ± 8.7 Sitagliptin, 3 mg/kg 68.9 ± 4.2 Sitagliptin, 10 mg/kg 43.4 ± 7.6 Sitagliptin, 30 mg/kg 31.5 ± 8.5 Gemigliptin, 3 mg/kg 18.8 ± 1.9 Gemigliptin, 10 mg/kg 8.4 ± 0.3 Gemigliptin, 30 mg/kg 6.4 ± 0.5 Sitagliptin Gemigliptin DIO: diet induced obese mice Data are expressed as the mean ± SE * p<0.05, **p<0.01 vs Control (Dunnett's Test) 2006 ADA Poster No.502

Pharmacokinetics Half- life Gemigliptin exhibited linear pharmacokinetics properties Clinical Therapeutics, 2008; 30: 1817~1830 Gemigliptin Sitagliptin # Vildagliptin # Saxagliptin # Linagliptin # Half-life (hr) 17~21 8~14 2~3 2.5 (3.1) 120 #Drug, 2011;71(11):1441~1467

Study Design Ob je c tive Evaluate the efficacy & safety in T2DM. Patients Naïve (no anti- diabetes for 3 months prior to study), HbA 1c 7~ 11% No. = 180 (90/group, included 20% attrition) Dose Gemigliptin 50mg q.d. or placebo Treatment 24 weeks (extension to 52 weeks) Primary endpoint HbA 1c change from baseline Study sites 5 sites in Korea and 9 sites in India Run-in period Visit 2 Week-2 Visit 3 Week 0 Visit 4 Week 6 Visit 5 Week 12 Visit 6 Week 18 Visit 7 Week 24 Gemigliptin 50mg q.d. Placebo (Single Blinding) Placebo

Study End Points Efficacy [Primary endpoint] HbA 1c change from baseline (W24) [Secondary endpoint] HbA 1c responder rate (at Week 24: HbA 1c <7 %, <6.5 %) HbA 1c change from baseline (W18) Fasting plasma glucose (W18, W24) Fasting serum insulin (W24) Fasting serum proinsulin (W24) Fasting serum C-peptide (W24) HOMA-β (W24) HOMA-IR (W24) Safety [Tertiary endpoint] OGTT parameters : 2-h PPG, 2-h Insulin, 2-h C-peptide, 각 AUC 0-2h GLP-1 Insulinogenic index Proinsulin/Insulin ratio DPP IV activity Fasting lipid parameter : TC, LDL, HDL, Triglyceride Body weight Waist circumference Adverse events Vital signs Laboratory tests *W24 : Change from baseline at Week 24 *W18 : Change from baseline at Week 18

Subject Disposition Screened: 283 Not eligible: 91 Consent withdrawal :3 Visit 1 [Exercis / diet program: 198] Visit 2 [Placebo Run-in: 189] Not eligible: 4 Consent withdrawal :3 Randomization 182 Placebo (N=92) LC15-0444 50mg (N=90) (N=8) Withdrawn (N=84) Completed (N=83) Completed (N=7) Withdrawn Consent withdrawl (N=3) Violation of eligibility criteria (N=1) Other reasons (N=4) (N=82) (N=83) Consented to Extension study LC15-0444 50mg (N=165) Consent withdrawl (N=1) Violation of eligibility criteria (N=1) Other reasons (N=5)

Demographics 통계적으로유의한군간차이없음. Sex Safety Set Placebo (N=92) Ge mig lip tin 50mg (N=90) P- va lue Male (%) 48 (52.17 ) 58 (64.44 ) 0.0933 Female (%) 44 (47.83 ) 32 (35.56 ) Nationality Indian (%) 56 (60.87 ) 52 (57.78 ) 0.6712 Korean (%) 36 (39.13 ) 38 (42.22 ) Age (yrs) Mean (±SD) 52.21 ( 9.4 ) 52.49 ( 8.92 ) 0.5560 # Height (cm) Mean (±SD) 159.04 ( 9.48 ) 161.05 ( 8.6 ) 0.1188 # BMI (kg/m 2 ) Mean (±SD) 27.02 ( 3.72 ) 26.34 ( 4.25 ) 0.1105 # N=Number; SD=Standard Deviation # p-value obtained from Wilcoxon s rank test p-value obtained from Chi-square test

Efficacy HbA1C 제미글립틴 50mg 의임상적유효성이위약대비우월함을입증 Mean HbA 1c (%) Over Time (FAS) LS mean (95% CI) between group difference in HbA 1c : - 0.71 (- 1.041, - 0.368); p<0.0001

Efficacy Long Term (52week) 제미글립틴 50mg 의임상적유효성이 52 주투약시까지유지됨 - 0.87%* * p<0.0001 vs. baseline

Efficacy Response Rate 제미글립틴 50mg 은위약대비목표혈당도달율을유의하게증가시킴 HbA1c Response Rate at Week 24 (FAS)

Efficacy FPG 제미글립틴 50mg은기저치및위약대비 FPG를유의하게감소시킴 FPG(mg/dL) Over Time (FAS) LS mean between group difference in FPG : - 19.79mg/dL

Subgroup Country 제미글립틴 50mg은위약대비한국, 인도모두우월한효과를보임. Korea India HbA 1c (%) 9.0 8.5 8.0 7.5 Placebo (N=35) 8.35 + 0.17 7.86 8.03 7.96 Gemigliptin 50 mg (N=38) - 0.78 ** HbA 1c (%) 9.0 8.5 8.0 7.5 Placebo (N=52) Gemigliptin 50 mg (N=49) + 0.02 8.35 8.37 8.33-0.53 * 7.80 7.0 7.18 7.0 6.5 0 24 0 24 Study Weeks ** P<= 0.0001 vs. baseline LS mean (95% Cl) between group difference -0.935(-1.356, -0.515) 6.5 0 24 0 24 Study Weeks * p<= 0.0030 vs.baseline LS mean (95% Cl) between group difference -0.553(-1.064, -0.042)

Subgroup Baseline HbA1C 제미글립틴 50mg 은기저 HbA1C 가높은경우더우수한효과를보임. *P< 0.0001 vs. baseline LS mean (95% Cl) between group difference -0.595(-0.939, -0.252) ** P< 0.0008 vs. baseline LS mean (95% Cl) between group difference -0.994(-1.803, -0.185)

Subgroup Naïve, Non- naïve 제미글립틴 50mg 은당뇨약제경험군, 비경험군모두에서유의한혈당감소를보임 Naive Placebo (N=50) Gemigliptin 50 mg (N=48) Non-naive Placebo (N=37) Gemigliptin 50 mg (N=39) HbA 1c change from baseline at week 24 (%) 1.0 0.5 0.0-0.5-1.0-1.5 + 0.25-0.67 *P<=0.0004 vs. baseline LS mean (95% Cl) between group difference -0.862%(-1.351, -0.372) * - 0.15-0.60 ** ** P< 0.0001 vs. baseline LS mean (95% Cl) between group difference -0.493%(-0.933, -0.052)

Safety Summary of AEs 이상반응의발현율이위약과유사함. Adverse Events Summary Placebo Ge mig lip tin 50mg Number of patients 92 90 Number of patients experienced an AE 38 (41.30) 39 (43.33) Number of patients dropped out due toae 0 (0) 0 (0) Number of patients experienced a SAE 2 (2.17) 3 ( 3.33) Number of AEs 73 77 Number of SAEs 2 (2.74) 3 ( 3.90)

Safety Most Common AEs ( 2.5%) Preferred Term Placebo (N=92) Ge mig lip tin 50mg (N=90) Eosinophilia 3 ( 3.26) 2 ( 2.22) Pyrexia 5 ( 5.43) 1 ( 1.11) Nasopharyngitis 4 ( 4.35) 4 ( 4.44) Upper respiratory tract infection 3 ( 3.26) 1 ( 1.11) Alanine aminotransferase increased 3 ( 3.26) 0 ( 0.00) Blood creatine phosphokinase increased 5 ( 5.43) 2 ( 2.22) Hypercholesterolaemia 3 ( 3.26) 1 ( 1.11) Arthralgia 0 ( 0.00) 5 ( 5.56)

Safety ADRs System Organ Class/ Preferred Term Placebo (N=92) * Reported in Korean patients. All the other ADRs were experienced by Indian patients. Ge mig lip tin 50mg (N=90) Gastrointestinal disorders 3 ( 3.26) 1 ( 1.11) Constipation 0 ( 0.00) 1 ( 1.11)* Flatulence 1 ( 1.09) 0 ( 0.00) Gastritis 1 ( 1.09) 0 ( 0.00) Nausea 1 ( 1.09) 0 ( 0.00) Infections and infestations 0 ( 0.00) 2 ( 2.22) Nasopharyngitis 0 ( 0.00) 1 ( 1.11) Upper respiratory tract infection 0 ( 0.00) 1 ( 1.11) Investigations 0 ( 0.00) 1 ( 1.11) Blood creatine phosphokinase increased 0 ( 0.00) 1 ( 1.11) Metabolism and nutrition disorders 0 ( 0.00) 2 (2.22) Hypoglycaemia 0 ( 0.00) 2 ( 2.22) Skin and subcutaneous tissue disorders 0 ( 0.00) 1 ( 1.11) Rash 0 ( 0.00) 1 ( 1.11)

Safety Others No clinically meaningful abnormalities were found in the laboratory tests, urinalysis, ECG, or vital signs.

Conclusion 1. 제미글립틴 50mg은기저치및위약대비 HbA 1c & FPG를유의하게감소시킴. 2. 제미글립틴 50mg은위약대비목표혈당도달환자수를유의하게증가시킴. 제미글립틴 50mg 은우수한내약성을가지고, 위약과유사한이상반응발현율을보임.

Study Overview Ob je c tive Evaluate the efficacy and safety compared with Sitagliptin added to metformin therapy in T2DM. Patients Inadequate glycemic control while taking metformin monotherapy HbA 1c 7~ 11% No. = 426 (142/group, including 30% attrition) Dose Gemigliptin 50mg q.d., Gemigliptin 25mg b.i.d., or Sitagliptin 100mg q.d. Treatment 24 weeks (extension to 52 weeks) Primary endpoint HbA 1c change from baseline Study sites 28 sites in Korea and 10 sites in India Randomization Visit 3 Week 6 Visit 4 Week 12 Visit 5 Week 18 Visit 6 Week 24 Visit 1 Screening Visit 2 Week 0 Gemigliptin 50mg q.d. Gemigliptin 25mg b.i.d. Sitagliptin

Subject Disposition Screened: 604 Raadomized: 425 Not eligible: 63 Consent withdrawal :15 Other reason: 1 Sitagliptin 100mg qd (N=142) LC15-0444 25mg bid (N=141) LC15-0444 50mg qd (N=142) Early withdrawl = 22 Completed = 120 Safety set = 140 FAS = 133 PP = 92 Early withdrawl = 14 Completed = 127 Safety set = 141 FAS = 136 PP = 98 Early withdrawl = 18 Completed = 124 Safety set = 140 FAS = 135 PP = 105 N=107 N=117 N=111 Consented to Extension study LC15-0444 50mg qd (N=335)

Demographics 통계적으로유의한군간차이없음. Safety Set Ge mig lip tin 25mg bid (N=141) Ge mig lip tin 50mg qd (N=140) Sita g lip tin 100mg qd (N=140) P- va lue Sex Nationality Male (%) 70 (49.65) 83 (59.29) 74 (52.86) 0.2563 Female (%) 71 (50.35) 57 (40.71) 66 (47.14) Indian (%) 43 (30.50) 43 (30.71) 43 (30.71) 0.9990 Korean (%) 98 (69.50) 97 (69.29) 97 (69.29) Age (yrs) Mean (±SD) 51.96 ( 10.57 ) 53.68 ( 8.88 ) 53.01 ( 10.61 ) 0.3551 # Height (cm) Mean (±SD) 161.57 ( 8.85 ) 162.07 ( 8.42 ) 161.6 ( 9.93 ) 0.8497 ## BMI (kg/m 2 ) Mean (±SD) 26.04 ( 3.58 ) 25.6 ( 3.38 ) 26.32 ( 3.58 ) 0.1868 ## N=Number; SD=Standard Deviation # p-value obtained from Wilcoxon s rank test p-value obtained from Chi-square test

Efficacy HbA1C 제미글립틴의임상적유효성이시타글립틴대비비열등함을입증함. 24 주 Mean difference from s ita g lip tin : - 0.011% (- 0.181, 0.16) Mean difference from s ita g lip tin : 0.004% (- 0.15, 0.157) * P<0.0001 vs. baseline 제미글립틴군과시타글립틴군간의보정된평균의차이 : 50mg qd 군은 0.004% [90% CI -0.15 to 0.157] 25mg bid 군은 -0.011% [90% CI -0.181 to 0.16] 모든제미글립틴군에서양측 90% 신뢰구간의상한치가 0.4 보다작아 Sitagliptin 대비비열등성을성공적으로입증.

Efficacy Response Rate 제미글립틴 50mg qd 에서목표혈당도달률이우수함.

Efficacy FPG 세군모두기저치대비 FPG 를유의하게감소시킴. * P < 0.0001 vs. baseline

Efficacy HOMA- β 제미글립틴 50mg qd 에서 HOMA- β 증가율이우수함. * P < 0.0001 vs. baseline

Efficacy Postprandial Glucose, Insulin 제미글립틴은식후혈당의유의한감소를보임. *P < 0.05 vs. baseline ***p<0.0001 vs. baseline

Efficacy Active GLP- 1 제미글립틴 50mg qd 에서 ac tive GLP- 1 증가율이우수함. * P < 0.0001 vs. baseline

Efficacy DPP- IV Inhibition 제미글립틴은시타글립틴에비해유의하게높은 DPP IV 저해율을보임 Median(Q1,Q3) : (Q1,Q3) is interquartile range, Q1=first quartile, Q3=third quartile

Efficacy Lipid Profile 세군모두에서 Total cholestrol 의유의한감소를보임.

Subgroup Baseline HbA1C 세군모두에서기저 HbA1C 가높은경우더높은 HbA1C 강하효과를보임. Baseline HbA 1c < 8.5% Baseline HbA 1c 8.5% 8.5 Gemigliptin 25 mg bid + Metformin (N=97) Gemigliptin 50 mg qd + Metformin (N=97) 10.0 Gemigliptin 25 mg bid + Metformin (N=39) Gemigliptin 50 mg qd + Metformin (N=38) 8.0 Sitagliptin 100 mg qd + Metformin (N=93) 9.5 Sitagliptin 100 mg qd + Metformin (N=40) HbA 1c (%) 7.5 7.0 7.63 7.55 7.62 * * 6.99 6.90 * 7.00 HbA 1c (%) 9.0 8.5 8.0 9.16 8.91 9.04 * * * 6.5 7.5 7.92 7.85 7.83 6.0 0 24 7.0 0 24 Study Weeks Study Weeks * P < 0.0001 vs. baseline

Subgroup Country 세군모두에서한국과인도모두유의한효과를보임. Korean Indian Gemigliptin 25 mg bid + Metformin (N=97) Gemigliptin 25 mg bid + Metformin (N=39) 9.0 Gemigliptin 50 mg qd + Metformin (N=97) 9.0 Gemigliptin 50 mg qd + Metformin (N=38) HbA 1c (%) 8.5 8.0 7.5 7.0 7.94 7.85 Sitagliptin 100 mg qd + Metformin (N=95) 7.98 ** ** ** 7.11 7.05 7.03 HbA 1c (%) 8.5 8.0 7.5 7.0 8.39 8.16 Sitagliptin 100 mg qd + Metformin (N=38) 8.22 ** ** 7.63 7.47 * 7.80 6.5 6.5 6.0 0 24 Study Weeks 6.0 0 24 Study Weeks * p < 0.0043 vs. baseline ** p < 0.0001 vs. baseline

Safety Summary of AEs 세군에서이상반응의발현율이유사함. Adverse Events Summary Ge mig lip tin 25mg b id Ge mig lip tin 50mg qd Sita g lip tin 100mg qd Number of patients 141 (100) 140 (100) 140 (100) Number of patients experienced an AE 69 (48.94) 63 (45) 58 (41.43) Number of patients dropped out due toae 0 (0) 0 (0) 0 (0) Number of patients experienced a SAE 4 (2.84) 5 (3.57) 8 (5.71) Number of AEs 160 (100) 134 (100) 105 (100) Number of SAEs 4 (2.5) 5 (3.73) 9 (8.57)

Safety Most common AEs ( 2.5%) Preferred Term Ge mig lip tin 25mg bid (N=141) Ge mig lip tin 50mg qd (N=140) Sita g lip tin 100mg qd (N=140) No. of patients with AE 69 63 58 Total No. of AEs 160 (100) 134 (100) 105 (100) Constipation 3 (1.88) 1 (0.75) 3 (2.86) Dyspepsia 2 (1.25) 2 (1.49) 3 (2.86) Pyrexia 6 (3.75) 3 (2.24) 3 (2.86) Nasopharyngitis 13 (8.13) 9 (6.72) 4 (3.81) Upper respiratory tract infection 7 (4.38) 8 (5.97) 7 (6.67) ALT increased 4 (2.5) 0 (0.00) 0 (0.00) Lipase increased 7 (4.38) 6 (4.48) 4 (3.81) Arthralgia 2 (1.25) 2 (1.49) 4 (3.81) Back pain 4 (2.5) 3 (2.24) 0 (0.00) Urticaria 4 (2.5) 0 (0.00) 0 (0.00)

Safety ADRs 1/ 2 System Organ Cla s s Preferred Term Ge mig lip tin 25mg bid (N=141) Ge mig lip tin 50mg qd (N=140) Sita g lip tin 100mg qd (N=140) Investigations 5 (3.55) 6 (4.29) 1 (0.71) Investigations Alanine aminotransferase abnormal 0 (0.00) 1 (0.71) 0 (0.00) Investigations Alanine aminotransferase increased 1 (0.71) 0 (0.00) 0 (0.00) Investigations Blood amylase increased 0 (0.00) 2 (1.43) 1 (0.71) Investigations Blood creatine phosphokinase increased 0 (0.00) 1 (0.71) 0 (0.00) Investigations Hepatic enzyme increased 1 (0.71) 0 (0.00) 0 (0.00) Investigations Lipase increased 4 (2.84) 3 (2.14) 1 (0.71) Investigations Weight decreased 0 (0.00) 1 (0.71) 0 (0.00) Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders 1 (0.71) 0 (0.00) 0 (0.00) Epistaxis 1 (0.71) 0 (0.00) 0 (0.00) 2 (1.42) 0 (0.00) 1 (0.71) Alopecia 0 (0.00) 0 (0.00) 1 (0.71) Photosensitivity reaction 1 (0.71) 0 (0.00) 0 (0.00) Pruritus 1 (0.71) 0 (0.00) 0 (0.00) Pruritus generalised 1 (0.71) 0 (0.00) 0 (0.00) Urticaria 1 (0.71) 0 (0.00) 0 (0.00)

Safety ADRs 2/ 2 System Organ Cla s s Preferred Term Ge mig lip tin 25mg bid (N=141) Ge mig lip tin 50mg qd (N=140) Sita g lip tin 100mg qd (N=140) Gastrointestinal disorders 1 (0.71) 2 (1.43) 2 (1.43) Gastrointestinal disorders Abdominal pain 0 (0.00) 0 (0.00) 1 (0.71) Gastrointestinal disorders Constipation 0 (0.00) 0 (0.00) 1 (0.71) Gastrointestinal disorders Dyspepsia 0 (0.00) 1 (0.71) 1 (0.71) Gastrointestinal disorders Gastrointestinal disorder 1 (0.71) 0 (0.00) 0 (0.00) Gastrointestinal disorders Nausea 0 (0.00) 1 (0.71) 0 (0.00) General disorders and administration site 1 (0.71) 0 (0.00) 0 (0.00) conditions General disorders and administration site Swelling 1 (0.71) 0 (0.00) 0 (0.00) conditions Infections and infestations 2 (1.42) 2 (1.43) 2 (1.43) Infections and infestations Asymptomatic bacteriuria 2 (1.42) 1 (0.71) 2 (1.43) Infections and infestations Nasopharyngitis 0 (0.00) 1 (0.71) 0 (0.00) Metabolism and nutrition disorders 0 (0.00) 1 (0.71) 2 (1.43) Metabolism and nutrition disorders Hypoglycaemia 0 (0.00) 1 (0.71) 2 (1.43) Nervous system disorders 0 (0.00) 1 (0.71) 1 (0.71) Nervous system disorders Dizziness 0 (0.00) 1 (0.71) 0 (0.00) Nervous system disorders Headache 0 (0.00) 0 (0.00) 1 (0.71) Psychiatric disorders 0 (0.00) 1 (0.71) 0 (0.00) Psychiatric disorders Insomnia 0 (0.00) 1 (0.71) 0 (0.00)

Safety Others No clinically meaningful abnormalities were found in the laboratory tests, urinalysis, ECG, or vital signs.

Conclusion 1. 세군모두기저치대비 HbA1C & FPG 를유의하게감소시킴. 2. 제미글립틴 50mg 에서목표혈당도달률이가장우수함. 3. 제미글립틴 50mg 에서 HOMA- β & ac tive GLP- 1 증가율이가장우수함. 4. 제미글립틴은기저및시타글립틴대비 DPP IV 를유의하게저해함. 제미글립틴은우수한내약성을가지며, 시타글립틴과유사한이상반응발현율을보임.

Conclusion 1. Monotherapy, metformin 에 add 한연구에서혈당강하효과가우수함 2. 제미글립틴 50mg 에서목표혈당도달률이가장우수함. 3. 제미글립틴 50mg 에서 HOMA- β & ac tive GLP- 1 증가율이가장우수함. 4. 제미글립틴은기저및시타글립틴대비 DPP IV 를유의하게저해함. 제미글립틴은우수한내약성을가지며, 시타글립틴과유사한이상반응발현율을보임.

Plan 단일제허가 SU 병용임상진입 단일제출시 메트폴민복합제출시 인슐린병용임상진입 a-gi 병용임상 2012 이후 94

Thank you for your attention!!! 96