Lilly Diabetes: Pipeline Update

Transcription

1 Lilly Diabetes: Pipeline Update June 24, 2013

2 Safe Harbor Provision This presentation contains forward-looking statements that are based on management's current expectations, but actual results may differ materially due to various factors. The company's results may be affected by factors including, but not limited to, the risks and uncertainties in pharmaceutical research and development; competitive developments; regulatory actions; litigation and investigations; business development transactions; economic conditions; and changes in laws and regulations, including health care reform. For additional information about the factors that affect the company s business, please see the company s latest Forms 10-K and 10-Q filed with the Securities and Exchange Commission. The company undertakes no duty to update forward-looking statements. Lilly Diabetes 2

3 Lilly Diabetes: An Overview Enrique Conterno President, Lilly Diabetes

4 Lilly Diabetes Pipeline Empagliflozin* Empagliflozin* Tradjenta Tradjenta Tradjenta Empagliflozin* Tradjenta Dulaglutide* Bydureon** Bydureon** Tradjenta Dulaglutide* Novel Basal Insulin Analog* Orals GLP-1s Byetta** Byetta** Tradjenta Dulaglutide* New Insulin Glargine Product* New Insulin Glargine Product* Basal Insulins Humulin Humulin Humulin Humulin Humulin Humulin Marketed Insulins Humalog Humalog Humalog Humalog Humalog Humalog Delivery Devices Delivery Devices Delivery Devices Delivery Devices Delivery Devices Delivery Devices Delivery Devices The following assets are part of the Lilly-Boehringer Ingelheim collaboration: Tradjenta, Empagliflozin, New Insulin Glargine Product. *The safety and efficacy of the agents under investigation has not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated. **The exenatide transition from Lilly to BMS was completed on March 31 st 2013 Lilly Diabetes 4

5 Empagliflozin Thomas Seck, M.D. Associate Therapeutic Area Head, Medical Affairs, Boehringer Ingelheim *Empagliflozin came from Boehringer Ingelheim s research and is part of the Lilly-Boehringer Ingelheim Alliance. The safety and efficacy of empagliflozin has not been established. There is no guarantee that empagliflozin will receive regulatory approval and become commercially available for the uses being investigated.

6 Empagliflozin Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 6 6

7 Empagliflozin Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 7 7

8 Empagliflozin Mode of action of SGLT2 inhibitors: Urinary glucose excretion via SGLT2 inhibition 1 Schematic View of the Kidney Renal tubule GLUCOSE Blood stream GLUCOSE SGLT2 INHIBITION Urinary glucose excretion, removal of calories from the body 1. Gerich JE. Diabet Med. 2010;27:

9 Empagliflozin SGLT2 inhibition targets glucose directly, working independently of beta-cell function and insulin resistance Persistent hyperglycaemia High blood glucose levels over a long time 2. Impaired ß-cell function Reduced ability of the pancreas to produce insulin 3. Insulin resistance Cells require more insulin to absorb the same amount of glucose 1. DeFronzo RA. Diabetes. 2009;58: ; 2. Poitout V and Robertson RP. Endocrinology. 2002;143: ; 3. Robertson RP, et al. Diabetes. 2003;52: ; 4. DelFronzo RA. Diabetes Obesity Metab. 2012;14:

10 Empagliflozin Empagliflozin Overview 1-4 Empagliflozin is a potent (IC 50 = 3.1 nm) and selective (> 2500-fold over SGLT1) SGLT2 inhibitor Linear PK, rapidly absorbed Peak levels at 1.5 hours after dosing Half-life: hours Mean total radioactivity (human ADME study) recovered in urine and faeces was 54.4% and 41.2%, respectively, and approximately 28.6% of total radioactivity excreted in urine was unchanged No active metabolite 1. Clinicaltrials.gov 2. Aires I and Calado J. Curr Opin Investig Drugs. 2010;11: Grempler R, et al. ADA 2009; Poster no. 521 P 4. Rosenstock J, et al. ADA 2011; Poster no. 989 P Lilly Diabetes 10 10

11 Empagliflozin Empagliflozin Phase III Development Program 1 STUDY Number of patients Background Therapy Primary Efficacy Timepoint Comparator EMPA-REG BASAL 494 Basal Insulin 18 weeks Placebo EMPA-REG MONO 986 N/A 24 weeks Placebo EMPA-REG MET 706 Metformin 24 weeks Placebo EMPA-REG METSU 767 Metformin + SU 24 weeks Placebo EMPA-REG PIO 499 Pioglitazone (±metformin) 24 weeks Placebo EMPA-REG OUTCOME 7,000 Various N/A Placebo EMPA-REG H2H-SU 1,548 Metformin 104 weeks Glimepiride EMPA-REG RENAL 664 Various 24 weeks Placebo EMPA-REG BP 816 Various 12 weeks Placebo EMPA-REG COMBO JAPAN 1,082 Various 52 weeks Placebo 1. Clinicaltrials.gov = presented today 11

12 Empagliflozin Empagliflozin Phase III Development Program 1 STUDY Number of patients Background Therapy Primary Efficacy Timepoint Comparator EMPA-REG BASAL 494 Basal Insulin 18 weeks Placebo EMPA-REG MONO 986 N/A 24 weeks Placebo EMPA-REG MET 706 Metformin 24 weeks Placebo EMPA-REG METSU 767 Metformin + SU 24 weeks Placebo EMPA-REG PIO 499 Pioglitazone (±metformin) 24 weeks Placebo EMPA-REG OUTCOME 7,000 Various N/A Placebo EMPA-REG H2H-SU 1,548 Metformin 104 weeks Glimepiride EMPA-REG RENAL 664 Various 24 weeks Placebo EMPA-REG BP 816 Various 12 weeks Placebo EMPA-REG COMBO JAPAN 1,082 Various 52 weeks Placebo 1. Clinicaltrials.gov = included in pooled analyses presented today 12

13 Empagliflozin EMPA-REG MONO Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 13 13

14 Empagliflozin EMPA-REG MONO Study Design: Phase III Monotherapy, 24 Weeks Placebo (n = 228) Placebo run-in (2 weeks) Second assessment of eligibility Randomization (n = 899) 10 mg empagliflozin QD (n = 224) 25 mg empagliflozin QD (n = 224) Screening (n = 1,616) (first assessment of eligibility) If HbA 1c 7 to 10% If HbA 1c > 10% 100 mg sitagliptin QD (n = 223) Open-label (OL) 25 mg empagliflozin QD (n = 87) Poster 1085-P American Diabetes Association (ADA) 14

15 HbA1c - Change from Baseline at Week 24 Primary Efficacy Endpoint was Met Empagliflozin EMPA-REG MONO 0.2 Placebo (n = 228) 0.08 Empagliflozin 10 mg (n = 224) 25 mg (n = 224) Sitagliptin (n = 223) Comparison with placebo *Confirmatory tests; p< Change in HbA 1c (%) %* -0.85%* -0.73%* -1 Mean baseline: 7.91% 7.87% 7.86% 7.85% FAS (LOCF) adjusted mean (SE) change from baseline in HbA 1c (%). Poster 1085-P American Diabetes Association (ADA) 15

16 Empagliflozin EMPA-REG MONO Body Weight Change from Baseline at Week 24 Statistically Significant Reductions with Empagliflozin vs. Placebo Empagliflozin Comparison with placebo *Confirmatory tests; p< Placebo (n = 228) 10 mg (n = 224) 25 mg (n = 224) Sitagliptin (n = 223) # p=0.036 Change in Body Weight (kg) Mean baseline: 78.2 kg 78.4 kg 77.8 kg 79.3 kg kg* kg* 0.52 kg # FAS (LOCF) adjusted mean (SE) change from baseline in body weight (kg). Poster 1085-P American Diabetes Association (ADA) 16

17 Empagliflozin EMPA-REG MONO Systolic Blood Pressure Change from Baseline at Week 24 Statistically Significant Reductions with Empagliflozin vs. Placebo 2 1 Placebo (n = 228) Empagliflozin 10 mg (n = 224) 25 mg (n = 224) Sitagliptin (n = 223) 0.5 Comparison with placebo *Confirmatory tests; p<0.05 Change in SBP (mmhg) mmhg Mean baseline: mmhg mmhg mmhg -2.6 mmhg* 0.8 mmhg -3.4 mmhg* Placebo-corrected changes in diastolic blood pressure for empagliflozin 10 and 25 mg, -0.5 and -1.4* mmhg, respectively FAS (LOCF) adjusted mean (SE) change from baseline in SBP (mmhg). Poster 1085-P American Diabetes Association (ADA) 17

18 Empagliflozin EMPA-REG MONO Summary of Adverse Events (AEs) N (%) Placebo Empagliflozin 10 mg Empagliflozin 25 mg Sitagliptin OL Empagliflozin 25 mg Number of patients 229 (100.0) 224 (100.0) 223 (100.0) 223 (100.0) 87 (100.0) Patients with any AE 140 (61.1) 123 (54.9) 135 (60.5) 119 (53.4) 56 (64.4) Patients with investigatordefined, drug-related AEs* Patients with AEs leading to discontinuation of trial drug 17 (7.4) 27 (12.1) 39 (17.5) 19 (8.5) 11 (12.6) 8 (3.5) 2 (0.9) 4 (1.8) 5 (2.2) 3 (3.4) Patients with serious AEs 6 (2.6) 8 (3.6) 5 (2.2) 6 (2.7) 3 (3.4) *The 5 most common investigator-defined drug-related AEs were urinary tract infection, hyperglycemia, pollakiuria, pulyuria, and thirst Poster 1085-P American Diabetes Association (ADA) 18

19 Empagliflozin EMPA-REG MET Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 19 19

20 Empagliflozin EMPA-REG MET Study Design Phase III Add-on to Metformin with or without Sulfonylurea, 24 Weeks Placebo (n = 207) Metformin background Patients pre-treated with metformin or metformin + SU 2-week placebo run-in period Randomization (n = 637) 10 mg empagliflozin QD (n = 217) 25 mg empagliflozin QD (n = 213) Screening (n = 2287) (first assessment of eligibility) If HbA 1c 7 to 10% If HbA 1c > 10% Metformin background Open-label (OL) empagliflozin 25 mg QD (n = 69) Poster 1092-P American Diabetes Association (ADA) 20

21 HbA1c Change from Baseline at Week 24 Primary Efficacy Endpoint was Met Empagliflozin EMPA-REG MET Empagliflozin Comparison with placebo *Confirmatory tests; p< Placebo (n = 207) 10 mg (n = 217) 25 mg (n = 213) -0.1 Change in HbA 1c (%) % * -0.64% * Mean baseline: 7.90% 7.94% 7.86% FAS (LOCF) adjusted mean (SE) change from baseline in HbA1c (%). Poster 1092-P American Diabetes Association (ADA) 21

22 Empagliflozin EMPA-REG MET Body Weight Change from Baseline at Week 24 Statistically Significant Reductions with Empagliflozin vs. Placebo Empagliflozin Comparison with placebo Placebo (n = 207) 10 mg (n = 217) 25 mg (n = 213) *Confirmatory tests; p< Change in Body Weight (kg) Mean baseline: 79.7 kg 81.6 kg 82.2 kg kg * kg * FAS (LOCF) adjusted mean (SE) change from baseline in body weight (kg). Poster 1092-P American Diabetes Association (ADA) 22

23 Empagliflozin EMPA-REG MET Summary of Adverse Events (AEs) N (%) Placebo Empagliflozin 10 mg Empagliflozin 25 mg OL Empagliflozin 25 mg Treated patients 207 (100.0) 217 (100.0) 213 (100.0) 69 (100.0) Patients with any AE 121 (58.7) 124 (57.1) 106 (49.5) 38 (55.1) Patients with investigator-defined, drug-related AEs* 25 (12.1) 35 (16.1) 27 (12.6) 11 (15.9) Patients with AEs leading to discontinuation 7 (3.4) 2 (0.9) 5 (2.3) 1 (1.4) Patients with serious AEs 7 (3.4) 7 (3.2) 5 (2.3) 1 (1.4) * The 5 most common investigator-defined drug-related AEs were urinary tract infection, hyperglycemia, hypoglycemia, headache, and pollakiuria Poster 1092-P American Diabetes Association (ADA) 23

24 Empagliflozin EMPA-REG BASAL Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 24 24

25 Study Design EMPA-REG BASAL (Phase III, Add-on to basal insulin) Empagliflozin EMPA-REG BASAL Insulin stable Insulin titration Key eligibility: HbA 1c > 7% and 10.0% Placebo n = 170 Screening n = ~ 985 Placebo run-in period (2 weeks) Randomization Empagliflozin 10 mg n = 169 Post-treatment follow-up (4 weeks) Empagliflozin 25 mg n = weeks 60 weeks Poster 1102-P American Diabetes Association (ADA) 25

26 Empagliflozin EMPA-REG BASAL HbA1c Change from Baseline at Week 18 Primary Efficacy Endpoint was Met Empagliflozin Comparison with placebo 0.2 Placebo (N = 125) 10 mg (N =132) 25 mg (N = 117) *Confirmatory tests; p< Adjusted mean (SE) change from baseline in HbA1c (%) Mean baseline: 8.10% 8.26% 8.34% -0.56% * -0.70% * FAS 18-week completers (LOCF-18) Poster 1102-P American Diabetes Association (ADA) 26

27 Empagliflozin EMPA-REG BASAL Summary of Adverse Events (AEs) (78 Weeks) N (%) Placebo Empa 10 mg Empa 25 mg Number of patients Patients with any AE(s) 148 (87.1) 143 (84.6) 135 (87.1) Patients with investigator defined drug related AE(s)* Patients with AE(s) leading to discontinuation of trial drug 52 (30.6) 65 (38.5) 68 (43.9) 13 (7.6) 19 (11.2) 20 (12.9) Patients with serious AE(s) 28 (16.5) 28 (16.6) 28 (18.1) * The 5 most common investigator-defined drug-related AEs were urinary tract infection, hyperglycemia, hypoglycemia, dizziness, and polyuria Poster 1102-P American Diabetes Association (ADA) 27

28 AEs of Special Interest: Hypoglycemic Events Add-on to Basal Insulin (78 Weeks) Empagliflozin EMPA-REG BASAL N (%) Placebo Empagliflozin 10 mg Empagliflozin 25 mg Number of patients Patients with confirmed hypoglycemic AEs 60 (35.3) 61 (36.1) 56 (36.1) Events requiring assistance (1) Poster 1102-P American Diabetes Association (ADA) 28

29 Empagliflozin POOLED ANALYSIS Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 29 29

30 Pooled Efficacy Data from Four Pivotal Phase III Trials (EMPA-REG MONO, MET, MET + SU, PIO) Empagliflozin POOLED ANALYSIS Placebo (n=825) Empagliflozin 10 mg (n=831) Empagliflozin 25 mg (n=821) HbA 1c (%) Baseline (SE) 8.02 (0.03) 7.98 (0.03) 7.96 (0.03) Change from baseline at week 24 (SE) (0.03) (0.03) (0.03) Difference vs placebo (95% CI) (-0.69, -0.55)*** (-0.75, -0.61)*** FPG (mg/dl) Baseline (SE) (1.3) (1.2) (1.2) Change from baseline at week 24 (SE) 7.4 (1.0) (1.0) (1.0) Difference vs placebo (95% CI) (-30.7, -25.1)*** (-33.4, -27.8)*** Body weight (kg) Baseline (SE) (0.66) (0.65) (0.66) Change from baseline at week 24 (SE) (0.09) (0.09) (0.09) Difference vs placebo (95% CI) Full analysis set (all randomized and treated patients who had a baseline HbA 1c value). Inclusion criteria: HbA1c 7.0% to 10.0%. Treated set (all patients treated with at 1 dose of randomized study medication). *p<0.05 vs placebo; **p<0.01 vs placebo; ***p<0.001 vs placebo. Poster 69-LB American Diabetes Association (ADA) (-2.05, -1.57)*** (-2.25, -1.76)*** 30

31 Empagliflozin POOLED ANALYSIS Pooled Blood Pressure Data from Four Pivotal Phase III Trials (EMPA-REG MONO, MET, MET + SU, PIO) Changes in systolic blood pressure from baseline Overall population Changes in systolic blood pressure from baseline Population uncontrolled BP (SBP 130 mmhg or DBP 80 mmhg at baseline) Adjusted mean (SE) change from baseline in SBP (mmhg) Mean baseline * -6 * Placebo (n=825) Empagliflozin 10 mg (n=831) Empagliflozin 25 mg (n=821) *p<0.001 vs. placebo Adjusted mean (SE) change from baseline in SBP (mmhg) *p<0.001 vs. placebo -2.5 Mean baseline * Placebo (n=501) -7.7 * Empagliflozin 10 mg (n=517) Empagliflozin 25 mg (n=506) Poster 69-LB American Diabetes Association (ADA) 31

32 Empagliflozin POOLED ANALYSIS Pooled Blood Lipids Data from Four Pivotal Phase III Trials (EMPA-REG MONO, MET, MET + SU, PIO) Total cholesterol LDL-cholesterol HDL-cholesterol Triglycerides Adjusted mean (SE) change from baseline (mg/dl) * * * Placebo (N=816) Empagliflozin 10 mg (N=816) Empagliflozin 25 mg (N=818) *p<0.001 vs. placebo; p=0.008 vs. placebo; p=0.011 vs. placebo; p=0.052 vs. placebo; p=0.060 vs. placebo; p=0.321 vs. placebo # For LDL-cholesterol analyses, N=804 for placebo, N=793 for empagliflozin 10 mg and N=800 for empagliflozin 25 mg Poster 69-LB American Diabetes Association (ADA) 32

33 Empagliflozin POOLED ANALYSIS Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 33 33

34 Empagliflozin POOLED ANALYSIS Pooled data on Urinary Tract Infections (UTIs) and Genital Infections (GI) (EMPA-REG MONO, MET, MET + SU, PIO) Placebo (n=825) Events consistent with UTIs Empagliflozin 10 mg (n=830) Empagliflozin 25 mg (n=822) Patients with events consistent with UTI, n (%) 68 (8.2) 77 (9.3) 62 (7.5) Male, n/n (%) 16/424 (3.8) 9/463 (1.9) 5/464 (1.1) Female, n/n (%) 52/401 (13.0) 68/367 (18.5) 57/358 (15.9) Patients with events consistent with UTI leading to treatment discontinuation, n (%) 1 (0.1) 2 (0.2) 1 (0.1) Events consistent with GIs Patients with events consistent with genital infection, n (%) 6 (0.7) 35 (4.2) 30 (3.6) Male, n/n (%) 2/424 (0.5) 12/463 (2.6) 5/464 (1.1) Female, n/n (%) 4/401 (1.0) 23/367 (6.3) 25/358 (7.0) Patients with events leading to treatment discontinuation, n (%) 0 1 (0.1) 2 (0.2) Poster 74-LB American Diabetes Association (ADA) 34

35 Empagliflozin Empagliflozin Presentation Agenda Overview: SGLT2 inhibition and Empagliflozin Monotherapy Study (EMPA-REG MONO) Add-on to Metformin Study (EMPA-REG MET) Add-on to Basal Insulin Study (EMPA-REG BASAL) Pooled Analysis of Efficacy and Effects on Blood Pressure and Lipids Pooled Analysis of Genital Infections and Urinary Tract Infections Summary and Next Steps Lilly Diabetes 35 35

36 Empagliflozin Summary of Clinical Data Efficacy Reductions in HbA1c in patients with type 2 diabetes and various antihyperglycemic background therapies Decrease in body weight Reductions in systolic blood pressure, which were larger in patients who were not controlled for blood pressure at baseline Safety Increase in the incidence of genital infections in both genders Overall similar incidences of urinary tract infections with empagliflozin and placebo. However, in women higher incidences were observed compared to placebo Increases in LDL and HDL cholesterol Incidence of hypoglycemia similar to placebo, except when used in combination with sulphonylurea where an increased incidence compared to placebo was observed Lilly Diabetes 36 36

37 Empagliflozin Next Steps Submission of empagliflozin in the U.S. and EU occurred in the first quarter of this year Plan to submit in Japan later this year Cardiovascular Outcome Study (EMPA-REG OUTCOME) ongoing, expected to complete 2018 Fixed-dose combination (FDCs) with metformin and with linagliptin under development Lilly Diabetes 37 37

38 Dulaglutide Sherry Martin, M.D. Senior Medical Director, Lilly Diabetes *The safety and efficacy of dulaglutide has not been established. There is no guarantee that dulaglutide will receive regulatory approval and become commercially available for the uses being investigated.

39 Dulaglutide Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 39

40 Dulaglutide Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 40

41 Dulaglutide Dulaglutide A recombinant GLP-1 Fc fusion protein linking a human GLP-1 peptide analog and a variant of a human IgG4 Fc fragment 1,2 Extended plasma half-life (~5 days) Decreased renal clearance Low immunogenic potential Once-weekly dosing Solution injection: no reconstitution needed GLP-1 analog Linker Modified IgG4 Fc domain 1. Glaesner et al. Diabetes Metab Res Rev 2010;26(4): Data on file, Eli Lilly and Company and/or one of its subsidiaries. Lilly Diabetes 41

42 Dulaglutide Dulaglutide: Phase 3 Development Program 5 pivotal studies, AWARD 1 5 Long-term Phase 3 cardiovascular outcome study, REWIND, currently enrolling patients 3 ongoing Phase 3b studies: AWARD-6 (H2H Lira), AWARD-7 (CKD), AWARD-8 (Add-on SU) Study AWARD-1 Description Add-on to metformin + TZD, double blind vs. placebo, open label vs. exenatide Trial completion Q AWARD-2 Add-on to metformin + sulfonylurea, open label vs. glargine Q AWARD-3 Monotherapy, double blind vs. metformin Q AWARD-4 Combination with mealtime insulin (Humalog), open label vs. glargine Q AWARD-5 REWIND Adaptive / seamless Phase 2/3 trial, add-on to metformin, double blind vs. placebo, double blind vs. sitagliptin (dose-finding trial) Double-blind RCT to assess the CV effects of dulaglutide vs. placebo when added to existing antihyperglycemic regimen (N=~9600) Q Event-driven AWARD, Assessment of Weekly AdministRation of LY in Diabetes REWIND, Researching Cardiovascular Events with a Weekly INcretin in Diabetes = presented today Lilly Diabetes 42

43 Dulaglutide Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 43

44 Dulaglutide AWARD-5 An Adaptive, Double-blind Phase 3 Study Key Inclusion criteria: Diet or exercise, monotherapy (MET or OAM), or combination therapy (MET+1 OAM) A1C 7.0% and 9.5% Dose Finding Dulaglutide 0.25 mg 0.50 mg Decision Point c 52 week analysis 104 week analysis Metformin b 1.0 mg 2.0 mg 3.0 mg Placebo d Dulaglutide 0.75 mg once weekly Dulaglutide 1.5 mg once weekly Sitagliptin 100 mg once daily Sitagliptin 100 mg once daily Safety Follow-up Study Period Treatment Week Lead in -11 a 0 Poster 71-OR American Diabetes Association (ADA) Treatment Period Randomization e Primary Time Point Final Time Point a Lead-in period lasted from 2 weeks up to 11 weeks b Metformin concomitant therapy from lead-in period through treatment period c All patients on non-selected arms were discontinued d After 26 weeks, patients in the placebo arm transitioned to sitagliptin (100 mg/day) in a blinded fashion e Randomization, after dose selection, used a fixed allocation scheme (2:2:2:1 for dulaglutide 0.75 mg:dulaglutide 1.5 mg:sitagliptin:placebo/sitagliptin) Lilly Diabetes 44

45 Dulaglutide AWARD-5 A1C Change from Baseline Baseline A1C = 8.1% 0.2 Week 26 Week 52 A1C, Change from Baseline (%, LS Mean ± SE) , # -1.01, # * (-0.87, -0.55) DU 1.5 mg DU 0.75 mg SITA PL Poster 71-OR American Diabetes Association (ADA) *p< sitagliptin vs placebo # p<0.001 dulaglutide vs sitagliptin ITT, ANCOVA using LOCF analysis Multiplicity adjusted p-values a p<0.001, dulaglutide vs placebo p<0.001, dulaglutide vs sitagliptin a 1-sided p-value adjusted for multiplicity, based on tree gatekeeping strategy Lilly Diabetes 45

46 Dulaglutide AWARD-5 A1C Targets Achieved at 52 Weeks 70 Percent of Patients Achieving A1C Target, % # 58 # # 42 # DU 1.5 mg DU 0.75 mg SITA 10 0 <7.0% 6.5% # p<0.001 vs sitagliptin ITT, Logistic Regression using LOCF analysis Poster 71-OR American Diabetes Association (ADA) Lilly Diabetes 46

47 Dulaglutide AWARD-5 Fasting Plasma Glucose Change Over Time Baseline FPG = 175 mg/dl 10 FPG, Change from Baseline (mg/dl, LS Mean ± SE) * * #, * #, * * #, * * #, * # # DU 1.5 mg DU 0.75 mg SITA PL -50 #, * #, * #, * # #, * # *p<0.05 vs placebo # p<0.001 vs sitagliptin ITT, MMRM analysis, FPG (central laboratory) Weeks Poster 71-OR American Diabetes Association (ADA) Lilly Diabetes 47

48 Dulaglutide AWARD-5 Weight Change Over Time Baseline Weight = 86.4 kg Weight, Change from Baseline (kg, LS Mean ± SE) #, * #, * #, * #, * #, * #, * T T #, * # # DU 1.5 mg DU 0.75 mg SITA PL -4 *p<0.05 vs placebo # p<0.05 vs sitagliptin ITT, MMRM analysis #, * # Weeks # Poster 71-OR American Diabetes Association (ADA) Lilly Diabetes 48

49 Dulaglutide AWARD-5 Adverse Events/Hypoglycemia 52 Weeks DU 1.5 mg N = 304 DU 0.75 mg N = 302 SITA N = 315 Any AE, n (%) 233 (76.6) 231 (76.5) 219 (69.5) Gastrointestinal AE, n (%) Nausea 53 (17.4)* 42 (13.9)* 16 (5.1) Diarrhea 44 (14.5)* 30 (9.9)* 9 (2.9) Vomiting 39 (12.8)* 23 (7.6)* 7 (2.2) Injection site reaction, n (%) 3 (1.0) 3 (1.0) 3 (1.0) Hypoglycemia a ( 70 mg/dl) 104 Weeks Total (events/pt/year), mean (SD) 0.4 (1.6) 0.3 (2.6) 0.1 (1.1) Severe hypoglycemia, n (%) 0 (0.0) 0 (0.0) 0 (0.0) *p<0.001 for dulaglutide vs sitagliptin a Statistical significance was not assessed for hypoglycemia b All cases adjudicated as Acute DU 1.5 mg/du 0.75 mg N = 606 SITA N = 315 Pancreatitis, n (n/1000 pt yrs) 0 (0.0) 3 b (4.7) Pancreatic cancer, n 0 0 Poster 71-OR American Diabetes Association (ADA) Lilly Diabetes 49

50 Dulaglutide Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 50

51 Dulaglutide AWARD-1 Study Design Key inclusion criteria: Diagnosed T2DM A1C 7% BMI 23 and 45 kg/m 2 Stable body weight (±5%) for >3 months Key exclusion criteria: T1DM A1C 6.5% 1 week before randomization Signs, symptoms, and/or history of pancreatitis Elevated serum calcitonin ( 20 pcg/ml) Metformin & Pioglitazone a Placebo b Dulaglutide 1.5 mg Dulaglutide 0.75 mg *Exenatide BID (Open-label) Dulaglutide 1.5 mg Dulaglutide 0.75 mg Safety Follow-up Lead In Treatment Period Follow-up Week Randomization Primary Time Point Final Time Point Poster 66-OR American Diabetes Association (ADA) Rescue therapy initiated for prespecified thresholds for severe, persistent hyperglycemia a All patients start MET and pioglitazone during the lead-in period and continue for the duration of the trial b PL patients continued until Week 26; at that time, PL patients were randomized to DU 0.75 mg or 1.5 mg * First four weeks exenatide 5 µg BID; remaining study duration exenatide 10 µg BID Lilly Diabetes 51

52 Dulaglutide AWARD-1 A1C Change from Baseline Baseline A1C = 8.07% Week 26 A1C, Change from Baseline (%, LS Mean ± SE) , * DU 1.5 mg DU 0.75 mg EX BID PL Poster 66-OR American Diabetes Association (ADA) (-1.22, -0.88) * p<0.001, superiority vs EX BID 10 µg a ; *p<0.001, superiority vs PL a, p<0.001 vs PL a 1-sided p-value adjusted for multiplicity, based on a procedure to control Type 1 error ITT without post-rescue values, ANCOVA using LOCF analysis Lilly Diabetes 52

53 Dulaglutide AWARD-1 A1C Target Achieved at 26 Weeks 90 Percent of Patients Achieving A1C Target, % *, # 79 *, # *, # 64 *, # DU 1.5 mg DU 0.75 mg EX BID PL 10 0 <7.0% 6.5% * p<0.001 DU vs PL; # p DU vs EX; p<0.01 EX vs PL ITT without post-rescue values, Logistic Regression using LOCF analysis Poster 66-OR American Diabetes Association (ADA) Lilly Diabetes 53

54 Dulaglutide AWARD-1 Fasting Serum Glucose Change Over Time to 52 Weeks Baseline FSG = 162 mg/dl DU 1.5 mg 0 DU 0.75 mg FSG, Change from Baseline (mg/dl, LS Mean ± SE) * *, # *, # * *, # *, # * *, # *, # * *, # *, # * *, # *, # # # EX BID PL Weeks *p<0.001 vs PL; # p<0.001 vs EX BID; p<0.05 vs EX BID ITT without post-rescue values, MMRM analysis Poster 66-OR American Diabetes Association (ADA) Lilly Diabetes 54

55 Dulaglutide AWARD-1 Weight Change Over Time to 52 Weeks Baseline Weight = kg DU 1.5 mg DU 0.75 mg EX BID Weight, Change from Baseline (kg, LS Mean ± SE) * * *, # * *, # * * *, # *, # * * # # PL -2.0 *, # *, # * * Poster 66-OR American Diabetes Association (ADA) * p<0.05 vs PL; # p<0.05 vs EX BID ITT without post-rescue values, MMRM analysis Weeks Lilly Diabetes 55

56 Dulaglutide AWARD-1 Adverse Events/Hypoglycemia 26 Weeks DU 1.5 mg N = 279 DU 0.75 mg N = 280 EX BID N = 276 PL N = 141 Any AE, n (%) 215 (77.1) 199 (71.1) 198 (71.7) 104 (73.8) Gastrointestinal AE, n (%) Nausea 78 (28.0) * 45 (16.1) *,# 71 (25.7) * 8 (5.7) Vomiting 47 (16.8) *,# 17 (6.1) *,# 30 (10.9) * 2 (1.4) Diarrhea 31 (11.1) 22 (7.9) 16 (5.8) 8 (5.7) Injection site reaction, n (%) 8 (2.9) 10 (3.6) 13 (4.7) 2 (1.4) Hypoglycemia ( 70 mg/dl) Total (events/pt/year), mean (SD) 0.5 (2.3) 1.1 (5.9) 1.5 (5.7) 0.4 (2.6) Severe Hypoglycemia, n (%) Weeks DU 1.5 mg/du 0.75 mg N = 559 * p<0.05 vs PL; # p<0.05 vs EX BID a This case adjudicated as Chronic EX BID N = 276 PL N = 141 Pancreatitis, n (n/1000 pt yrs) 1 a (1.8) 0 (0.0) 0 (0.0) Pancreatic cancer, n Poster 66-OR American Diabetes Association (ADA) Lilly Diabetes 56

57 Dulaglutide Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 57

58 Dulaglutide AWARD-3 Study Design Key inclusion criteria: T2DM 3 months and 5 years A1C 6.5% and 9.5% Treatment naïve or on 1 OAM (except TZDs) low dose for 3 months BMI 23 and 45 kg/m 2 Stable body weight for 3 months Key exclusion criteria: T1DM Signs, symptoms, and/or history of pancreatitis Elevated serum calcitonin 20 pg/ml Diet and exercise Dulaglutide 0.75 mg + Oral placebo Dulaglutide 1.5 mg + Oral placebo Injectable placebo + Oral metformin* Safety Follow-up Lead in Treatment Period Follow-up Week Randomization Primary Time Point Final Time Point * Patients received 2000 mg/day or 1500 mg/day according to tolerability Rescue therapy initiated for prespecified thresholds for severe, persistent hyperglycemia Poster 69-OR American Diabetes Association (ADA) Lilly Diabetes 58

59 Dulaglutide AWARD-3 A1C Change from Baseline Baseline A1C = 7.6% -0.0 Week 26 Week 52 DU 1.5 mg DU 0.75 mg A1C, Change from Baseline (%, LS Mean ± SE) MET (-0.36, -0.08) Poster 69-OR American Diabetes Association (ADA) Adjusted p-values a p<0.025, noninferiority vs metformin; p<0.025, superiority vs metformin a 1-sided p-value adjusted for multiplicity, based on a procedure to control Type 1 error ITT without post-rescue values, ANCOVA using LOCF analysis Lilly Diabetes 59

60 Dulaglutide AWARD-3 A1C Targets Achieved at 26 Weeks # 62 # 63 DU 1.5 mg Percent of Patients Achieving A1C Target, % ## 46 # DU 0.75 mg MET 0 <7.0% 6.5% # p<0.05 vs. metformin; ## p<0.001 vs metformin ITT without post-rescue values, Logistic Regression using LOCF analysis Poster 69-OR American Diabetes Association (ADA) Lilly Diabetes 60

61 Dulaglutide AWARD-3 Weight Change Over Time Baseline Weight = kg 1 Weight, Change from Baseline (kg, LS Mean ± SE) ## ## # # p<0.05 vs metformin; ## p<0.001 vs metformin ITT without post-rescue values, MMRM analysis # Weeks Weeks ## ## DU 1.5 mg DU 0.75 mg MET Poster 69-OR American Diabetes Association (ADA) Lilly Diabetes 61

62 Dulaglutide AWARD-3 Adverse Events/Hypoglycemia at 52 Weeks DU 1.5 mg N = 269 DU 0.75 mg N = 270 MET N = 268 Any AE a, n (%) 179 (66.5) 177 (65.6) 170 (63.4) Gastrointestinal AE a, n (%) Nausea 53 (19.7) 31 (11.5) 43 (16.0) Diarrhea 30 (11.2) 21 (7.8) 37 (13.8) Vomiting 26 (9.7) 20 (7.4) 13 (4.9) Injection site reactions a, n (%) 10 (3.7) 6 (2.2) 4 (1.5) Hypoglycemia a ( 70 mg/dl) Total (events/pt/year), mean (SD) 0.89 (9.02) 0.47 (2.26) 0.29 (0.98) Severe hypoglycemia, n (%) 0 (0.0) 0 (0.0) 0 (0.0) DU 1.5 mg/du 0.75 mg N= 539 MET N = 268 Pancreatitis, n (n/1000 pt yrs) 0 (0.0) 0 (0.0) Pancreatic cancer, n 0 0 a No significant difference between DU and MET Poster 69-OR American Diabetes Association (ADA) Lilly Diabetes 62

63 Dulaglutide TOXICOLOGY Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 63

64 Dulaglutide TOXICOLOGY Evaluation of Serum Amylase and Lipase, and Expanded Pancreatic Histology in Monkeys Following 12 Month Administration of Dulaglutide Study Design Cynomolgus male monkeys (n=20 controls, n=19 treated); administration of twiceweekly dulaglutide doses at 500-fold the human exposure for 52 weeks Systematic micro-sections evaluated from head, body, and tail of pancreas (posteuthanasia) Examination of slides by board-certified veterinary pathologists and a human pancreatic pathologist Results No pancreatic inflammation or necrosis No pancreatic cancer or precursor changes (no ductal proliferation) Increase in goblet cells (mucin-producing) in 4/19 DU treated monkeys; not considered adverse to monkeys No increase in pancreatic enzymes, treated compared to controls Conclusion: Chronic dosing of dulaglutide in non-diabetic primates did not induce inflammatory or preneoplastic changes of the exocrine pancreas Lilly Diabetes 64

65 Dulaglutide Dulaglutide Presentation Agenda Overview: Dulaglutide s Clinical Development Program AWARD-5: Dulaglutide and Comparator Sitagliptin AWARD-1: Dulaglutide and Comparator Exenatide AWARD-3: Dulaglutide and Comparator Metformin Pre-clinical Toxicology Data: Primate Study Summary and Next Steps Lilly Diabetes 65

66 Dulaglutide Summary and Next Steps Efficacy Dulaglutide demonstrated significant, sustained glycemic lowering Superior to active comparators (sitagliptin, exenatide, and metformin) as measured by A1C reduction, in studies ranging from 52 weeks to 104 weeks Significantly more patients achieved A1C goals than active comparators Majority of significant improvement in fasting glucose demonstrated by first 2 weeks Dulaglutide demonstrated dose-dependent, sustained weight loss Safety Low rates of hypoglycemia (less than 2 events/patient/year for each trial and no severe hypoglycemia) Injection site reactions were infrequent (< 5%) The most common treatment emergent adverse events were gastrointestinal in nature, including nausea, diarrhea and vomiting Nausea was mostly mild to moderate, typically occurred in the first few weeks of therapy, and was transient Next Steps Submission planned to regulatory authorities in 2013 Lilly Diabetes 66

67 Questions and Answers