The Highlights of the AWARD Clinical Program FRANCESCO GIORGINO

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1 The Highlights of the AWARD Clinical Program FRANCESCO GIORGINO DEPARTMENT OF EMERGENCY AND ORGAN TRANSPLANTATION SECTION OF INTERNAL MEDICINE, ENDOCRINOLOGY, ANDROLOGY AND METABOLIC DISEASES

2 Disclaimer This material is only for use by participants during the DEF meeting in Gdynia on 2 3 June 2017 Any potential use of this material outside of this meeting must be approved in accordance with local legal and compliance requirements This presentation reflects the external speaker's point of view and not necessarily those of the meeting sponsor (Eli Lilly and Company) 2

3 Disclosures Advisory Boards: AstraZeneca/BMS; Eli Lilly; Roche Diagnostics; Takeda Consultant: AstraZeneca/BMS; Boehringer Ingelheim; Lifescan; Merck Sharp & Dohme; Novo Nordisk; Sanofi Research Support: AstraZeneca/BMS; Eli Lilly; Lifescan; Sanofi; Takeda 3

4 Antihyperglycaemic Therapy in Type 2 Diabetes: ADA General Recommendations ADA, American Diabetes Association, DPP-4-i, dipeptidyl peptidase-4 inhibitor; GLP-1-RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione Diabetes Care 2017

5 Dulaglutide Clinical Trial Programme: AWARD More than 5000 patients have been enrolled in phase 3 clinical trials 1 The AWARD programme is robust and spans the continuum of care Monotherapy 2-drug combinations 3-drug combinations More complex insulin strategies AWARD-3 2 vs metformin Drug-naïve or washout from 1 oral antidiabetic medication AWARD-5 3 vs sitagliptin Add-on to metformin AWARD-6 4 vs liraglutide Add-on to metformin AWARD-1 5 vs exenatide BID Add-on to metformin and TZD AWARD-2 6 vs glargine Add-on to metformin and SU AWARD-4 7 vs glargine Both with mealtime insulin lispro With or without metformin AWARD = Assessment of Weekly AdministRation of LY in Diabetes. 1. Trulicity (dulaglutide injection) [summary of product characteristics]. Houten, The Netherlands: Eli Lilly and Company; Umpierrez G, et al. Diabetes Care. 2014;37(8): Nauck M, et al. Diabetes Care. 2014;37(8): Dungan KM, et al. Lancet (9951): Wysham C, et al. Diabetes Care. 2014;37(8): Giorgino F, et al Dec;38(12): , Jendle J, et al. Poster presented at: American Diabetes Association s 74th Scientific Sessions; June San Francisco, CA, USA.

6 Dulaglutide: AWARD 1 6 Key Results Trial AWARD-1 (combination with met + pio) AWARD-2 (combination with met + SU) AWARD-3 (monotherapy) AWARD-4 (combination with Insulin lispro +/- met) AWARD-5 (combination with met) Patient Number Primary Endpoint Final Endpoint Active Comparator Change in HbA 1c at Primary Endpoint 0.75mg 1.5mg Exenatide BID Superior Superior Glargine Non-inferior Superior Metformin Superior Superior Glargine + lispro Superior Superior Sitagliptin Superior Superior AWARD-6 (combination with met) Liraglutide 1.8 mg n.a. Non-inferior Wysham C et al. Diabetes Care 2014;37: ; Giorgino F et al. Diabetes Care 2015 Dec;38(12):2241-9; Umpierrez G et al. Diabetes Care 2014;37(8): ; Blonde L, et al., Lancet. 2015; 385(9982): ; Nauck MA et al. Diabetes Care 2014;37: ; Dungan KM et al. Lancet 2014 July 11, doi: /s (14)

7 HbA1c, Change from Baseline (%, LS Mean) Dulaglutide 1.5 mg Demonstrated Significant HbA 1c Reduction vs Established Glucose-lowering Agents Baseline HbA1c (%) N= 0 AWARD-5 1 AWARD-1 2 AWARD-2 Add-on to metformin Add-on to metformin 3 Add-on to metformin and pioglitazone and SU % (-12.0) P< % (-4.3) vs sitagliptin (52 weeks) % (-16.5) P< % (-10.8) -0.46% (-5.0) *P<.001 P<.001 vs exenatide BID (26 weeks) % (-11.8) -0.63% (-6.9) P<.001 vs insulin glargine (52 weeks) HbA1c, Change from Baseline (mmol/mol, LS Mean) Dulaglutide 1.5 mg Comparator Placebo Data presented are mean values at primary time points. Values in parentheses are mmol/mol. P-values represent superiority. *P<.001 vs placebo. The recommended dose for Trulicity is 1.5 mg when prescribed as add-on therapy. For monotherapy or for potentially vulnerable populations such as patients 75 years of age or patients with severe heart failure, 0.75 mg once weekly can be considered as a starting dose. 1. Nauck M, et al. Diabetes Care. 2014;37(8): Wysham C, et al. Diabetes Care. 2014;37(8): Giorgino F, et al Dec;38(12):

Plasma Exenatide (pg/ml) Dulaglutide concentration (ng/ml) Pharmacokinetics of Exenatide BID/OW and Dulaglutide Pharmacokinetics of short (twice-daily, BID) or long (once-weekly, OW) acting exenatide

8 Plasma Exenatide (pg/ml) Dulaglutide concentration (ng/ml) Pharmacokinetics of Exenatide BID/OW and Dulaglutide Pharmacokinetics of short (twice-daily, BID) or long (once-weekly, OW) acting exenatide 1,2 Dulaglutide 1.5 mg once-weekly SC concentration time profile Exenatide BID Exenatide OW mg SC observed (mean, SE) Predicted (estimated mean plasma dulaglutide concentrations, 90% CI) Half-life ~ 5 days Peak plasma concentrations in 48 hours (range hours) Days Weeks Days BID, twice daily; CI, confidence interval; OW, once weekly; SC, subcutaneous; SE, standard error 1 Kim D, et al. Diabetes Care 2007;30: ; 2 Fineman M, et al. Clin Pharmacokinet 2011;50:65 74; 3 de la Peña A, et al. 50th EASD Annual Meeting, Vienna, Austria, September 2014 [PS 066 Novel therapies; P-857]

9 FSG change over time (mmol/l, LS Mean ±SE) Dulaglutide Works Quickly to Reduce FSG vs Exenatide BID (AWARD-1) * P<.001 vs exenatide BID P<.001 vs placebo Dulaglutide 1.5 mg N=279 Exenatide BID N= Placebo N= * * * * * Time (weeks) * Metformin + pioglitazone background Baseline FSG= mmol/l * The recommended dose for Trulicity is 1.5 mg when prescribed as add-on therapy. For monotherapy or for potentially vulnerable populations such as patients 75 years of age or patients with severe heart failure, 0.75 mg once weekly can be considered as a starting dose. FSG = fasting serum glucose. 1. Wysham C, et al. Diabetes Care. 2014;37(8):

10 Differentiation of GLP-1 RAs: Glycaemic Targets and Mechanisms of Action Compounds Parameters Short-acting (Prandial) GLP-1 receptor agonists Exenatide (twice daily) Lixisenatide (once daily) Long-acting GLP-1 receptor agonists Liraglutide (once daily) Albiglutide (once weekly) Dulaglutide (once weekly) Exenatide LAR (once weekly) Half-life 2 5 hours 12 hours several days Receptor activation Intermittent Continuous Effects Fasting glucose reduction Modest Strong Fasting insulin secretion No effect Stimulation Fasting glucagon secretion Mild reduction Strong reduction Postprandial glucose excursion Strong reduction Modest reduction Postprandial glucagon secretion Strong reduction Mild reduction (?) Postprandial insulin secretion Reduction Stimulation Gastric emptying Strong deceleration Mild deceleration HbA 1c reduction % % GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycated haemoglobin; LAR, long-acting release Meier JJ. Nat Rev Endocrinol 2012;8: ; Giorgino F, et al. Diabetes Metab Res Rev 2016;32:

11 HbA 1c, Change from Baseline (%, LS Mean) Average Reduction in Weight (kg, LS Mean ±SE) AWARD-1: Effects of Dulaglutide 1.5 mg and Exenatide BID on HbA 1c Reduction and Body Weight Baseline HbA 1c (%) N= % (-16.5) P< % (-10.8) *P<.001 P<.001 vs exenatide BID (26 weeks) AWARD-1 Add-on to metformin and pioglitazone (26 weeks) % (-5.0) -1.0 Dulaglutide 1.5 mg HbA 1c, Change from Baseline (mmol/mol, LS Mean) P< vs exenatide BID Dulaglutide 1.5 mg (n=279; baseline 96 kg) Exenatide BID (10 mcg BID) (n=276; baseline 97 kg) Comparator Placebo Data presented are mean values at primary time points. Values in parentheses are mmol/mol. P-values represent superiority. *P <.001 vs placebo. The recommended dose for dulaglutide is 1.5 mg when prescribed as add-on therapy BID, twice daily; HbA 1c, glycated haemoglobin; LS, least squares; SE, standard error Wysham C, et al. Diabetes Care. 2014;37(8):

12 AWARD-1: Effects of Dulaglutide vs. Exenatide BID on SMPG Data presented are least squares means ± standard error, mixed effect model repeat measurement. Solid lines are baseline; dashed lines are at 26 weeks BID, twice daily; DU, dulaglutide; EX, exenatide; PL, placebo; SMPG, self-monitored plasma glucose Wysham C, et al. Diabetes Care 2014;37(8):

13 HbA 1c Change from Baseline ±SE (%, LS Mean) AWARD-6: Dulaglutide 1.5 mg QW Vs. Liraglutide 1.8 mg QD Effects on HbA 1c Reduction HbA 1c Change from Baseline ±SE (%, LS Mean) Dulaglutide 1.5 mg (n=299; baseline HbA 1c : 8.1%) Liraglutide 1.8 mg (n=300; baseline HbA 1c : 8.1%) % (-16 mmol/mol) -1.36% (-15 mmol/mol) -16 P<.0001 Data presented are mean values at 26 weeks. The recommended dose for dulaglutide is 1.5 mg when prescribed as add-on therapy. For monotherapy or for potentially vulnerable populations such as patients 75 years of age or patients with severe heart failure, 0.75 mg once weekly can be considered as a starting dose. HbA 1c, glycated haemoglobin; LS, least squares; QD, once daily; QW, once weekly; SE, standard error Dungan KM, et al. Lancet 2014;384:

14 Average Reduction in Weight (kg, LS Mean ±SE) Most Dulaglutide 1.5 mg-treated Patients Experienced a Secondary Benefit of Weight Loss, Regardless of Concomitant Therapy AWARD-6 1 Add-on to metformin (26 weeks) P< AWARD-5 2 Add-on to metformin (52 weeks) P< AWARD-1 3 Add-on to metformin and pioglitazone (26 weeks) AWARD-2 4 Add-on to metformin and glimepiride (52 weeks) vs liraglutide vs sitagliptin vs exenatide BID vs insulin glargine Dulaglutide 1.5 mg (n=299; baseline 93.8 kg) Liraglutide 1.8 mg (n=300; baseline 94.4 kg) Dulaglutide 1.5 mg (n=304; baseline 87 kg) Sitagliptin (n=315; baseline 86 kg) Dulaglutide 1.5 mg (n=279; baseline 96 kg) Exenatide BID (10 mcg BID) (n=276; baseline 97 kg) Dulaglutide 1.5 mg (n=273) Insulin glargine (n=262; baseline weight across arms 86.3 kg) P<.474 P<.001 Trulicity is not indicated for weight loss; weight change was a secondary endpoint in clinical trials. The recommended dose for Trulicity is 1.5 mg when prescribed as add-on therapy. For monotherapy or for potentially vulnerable populations such as patients 75 years of age or patients with severe heart failure, 0.75 mg once weekly can be considered as a starting dose. 1. Dungan KM, et al. Lancet (9951): Nauck M, et al. Diabetes Care. 2014;37(8): Wysham C, et al. Diabetes Care. 2014;37(8): Giorgino F, et al. Diabetes Care Dec;38(12):

15 AWARD-2: Dulaglutide vs. Insulin Glargine in T2DM T2DM not optimally controlled on 1, 2 or 3 OAMs; HbA 1c 7.0% and 11% at screening; HbA 1c >6.5% at pre-randomisation visit Dulaglutide 1.5 mg Background Therapy a Dulaglutide 0.75 mg Insulin glargine titrated to target b Screening & Lead-in Treatment Period Safety Followup Followup Week Randomisation Primary Time Point Final Time Point a During the lead-in period, metformin ( 1,500 mg) and glimepiride ( 4 mg) were titrated up to maximum tolerated dose, then doses were stable for 6 8 weeks. OAMs continued for the duration of the trial. b Titrated to fasting plasma glucose target: <5.6 mmol/l according to Kennedy et al. 2006; GOAL HbA 1c Trial HbA 1c, glycated haemoglobin; OAM, oral anti-diabetes medication; T2DM, type 2 diabetes mellitus Giorgino F, et al. Diabetes Care 2015;38:

16 AWARD-2: Dulaglutide vs. Insulin Glargine in T2DM Baseline HbA 1c : 8.1% 8.2% Insulin Glargine QD Dulaglutide 0.75 mg OW Dulaglutide 1.5 mg OW Change in HbA 1c (%) Change in Body Weight (kg) Rates of Total Hypoglycaemia (event/patient/year) / ## 4.8 ## 23 # /18 # ## 5.2 # 29 # /39 ## Incidence of Diarrhoea/Nausea at 52 weeks (n) p <0.001 OW, superiority vs. glargine (1-sided, adjusted to control for type I error) p <0.001, noninferiority vs. glargine # p <0.05 vs. glargine ## p <0.001 vs. glargine HbA 1c, glycated haemoglobin; OW, once weekly; QD, once daily; T2DM, type 2 diabetes mellitus Giorgino F, et al. Diabetes Care 38:2241-9, 2015

17 Quality of Life in AWARD-2 Change from BL score, ITT, LOCF, LS mean (SE) DU 1.5 mg N= wks DU 0.75 mg N= wks Glargine N= wks EQ-5D VAS 3.17 (0.85)* 2.27 (0.85) # 1.06 (0.88) APPADL 0.9 (0.31)* # 0.4 (0.31) # -0.6 (0.32) IW-SP 0.5 (0.16)* 0.2 (0.16) 0.1 (0.16) LBSS, behaviour -2.1 (0.47)* # -2.1 (0.48)* # -0.8 (0.49) LBSS, worry -2.2 (0.50)* # -2.1 (0.50)* # -0.3 (0.52) *# 2-sided p<0.05 vs. BL and insulin glargine APPADL, Ability to Perform Physical Activities of Daily Living; BL, baseline; DU, dulaglutide; EQ-5D, EuroQoL-5 dimension; ITT, intention-to-treat population; IW-SP, Impact of Weight on Self-Perception; LBSS, low blood sugar survey; LOCF, last observation carried forward; LS, least squares; SE, standard error; VAS, visual analogue scale; wks, weeks Reaney M, et al. Patient-reported outcomes with once weekly dulaglutide 21 vs. insulin glargine (AWARD-2). ADA, 2014: abstract P-979

18 GLP-1 RA vs. Insulin: Change in HbA 1c Favours GLP-1 RA % Favours Insulin GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycated haemoglobin, OGLM, oral glucose lowering medication Abd El Aziz MS, et al. Diabetes Obes Metab 2017;19(2):

19 GLP-1 RA vs. Basal Insulin in T2DM: HbA 1c Reduction According to Baseline HbA 1c FPG, fasting plasma glucose; FSG, fasting serum glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycated haemoglobin OW, once weekly, T2DM, type 2 diabetes mellitus Buse JB, et al. Diabetes Obes Metab 2015;17:

20 DU, dulaglutide; HbA 1c, glycated haemoglobin Gallwitz B, et al. DOM 2017 Efficacy of Dulaglutide According to Gender, Duration of Diabetes, and Baseline HbA 1c (AWARD-1 to -6 and -8 clinical trials)

21 GLP-1 RA vs. Insulin: Change in Body Weight Favours GLP-1 RA kg Favours Insulin GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA 1c, glycated haemoglobin; OGLM, ordinal generalized linear model Abd El Aziz MS, et al. Diabetes Obes Metab 2017;19(2):

22 Insulin and GLP-1 RA in Type 2 diabetes Drug MoA/Effects Drug MoA/Effects Basal insulin Hepatic glucose production Reduction of FPG Body weight gain (+) Hypoglycaemia risk (+) GLP-1 RA long-acting Insulin secretion Glucagon secretion (fasting) Reduction of FPG > PPG Satiety and body weight loss Prandial insulin Skeletal muscle glucose disposal ( Hepatic glucose output) Reduction of PPG Body weight gain (++) Hypoglycaemia risk (++) GLP-1 RA short-acting then insulin secretion (postprandial) Glucagon secretion (post-prandial) Gastric emptying rates Reduction of PPG excursions Satiety and body weight loss Adapted from Inzucchi SE, et al. Diabetes Care 2012;35: ; Meier JJ. Nat Rev Endocrinol 2012;8:

23 AWARD-9: Study Design Key inclusion criteria Treatment with insulin glargine once daily (+/- metformin) for at least 3 months prior to study entry A1C 7.0% and 10.5% Required glargine dose increase at randomization per the treat-to-target algorithm Body mass index 45 kg/m 2 Key exclusion criteria Type 1 diabetes Treated with ANY other antihyperglycemia regimen egfr <30 ml/min/1.73 m 2 Dulaglutide 1.5 mg + Titrated Basal Insulin Glargine (+/- Metformin) Screening/ Lead-in a Placebo + Titrated Basal Insulin Glargine (+/- Metformin) Treatment Period Week Randomization 28 Primary/Final Time Point Stabilization Period Insulin Glargine Titration Period a Patients continued prestudy regimens; did not change antihyperglycemia medications used or their doses, except when allowed per protocol. Stabilization Period = Weeks 0 to 4 w/ restricted insulin dose adjustments. Glargine Titration Period = Weeks 4 to 28 w/ unrestricted insulin dose adjustments. Pozzilli P. et al., DOM 2017

24 AWARD-9: Change in A1C at 28 Weeks Data presented are LS mean ± SE *, # p<.001 vs baseline and placebo, respectively a Treatment difference (95% CI), ITT, MMRM analysis Pozzilli P. et al., DOM 2017

25 AWARD-9: Insulin Doses at 28 weeks Data presented are LS mean ± SE except baseline values are mean ± SE *, # p< vs baseline and placebo, respectively a Treatment difference (95% CI), ITT, MMRM analysis Pozzilli P. et al., DOM 2017

26 AWARD-9: Change in Body Weight at 28 Weeks Data presented are LS mean ± SE. *, # p<.001 vs baseline and placebo, respectively. a Treatment difference (95% CI), ITT, MMRM analysis Pozzilli P. et al., DOM 2017

27 AWARD-9: Overall Incidence and Rate of Hypoglycemia through 28 Weeks Variable Total Hypoglycemia Dulaglutide 1.5 mg N=150 Placebo N=150 Incidence, n (%) 82 (54.7) 76 (50.7) Mean (SD) Rate Adjusted for 1 Year 7.69 (15.15) 8.56 (16.13) Documented Symptomatic Hypoglycemia Incidence, n (%) 53 (35.3) 45 (30.0) Mean (SD) Rate Adjusted for 1 Year 3.38 (8.62) 4 38 (11.70) Nocturnal Hypoglycemia Incidence, n (%) 42 (28.0) 43 (28.7) Mean (SD) Rate Adjusted for 1 Year 2 76 (7.92) 3.03 (8.96) Severe Hypoglycemia Incidence, n (%) 1 (0.7) 0 (0.0) Mean (SD) Rate Adjusted for 1 Year 0.01 (0.15) 0 (0.0) ITT, Logistic regression using LOCF analysis, 70 mg/dl threshold Pozzilli P. et al., DOM 2017

28 Adverse Reactions Adverse Reaction Dulaglutide 1.5 mg Gastrointestinal (primary endpoint) a Nausea 7-28% Vomiting 3-17% Gastrointestinal events were mild or moderate, transient, and peaked during the first 2 weeks and rapidly declined over the next 4 weeks Hypoglycaemia, total Cardiovascular Systolic blood pressure Heart rate Atrioventricular block/ PR interval Injection-site reactions 1.9%* 1 event/patient/year (in trials without SU or insulin) Mean decrease 1-3 mmhg Mean increase 2-4 bpm Mean increase in PR interval 2-3 milliseconds 2.4% incidence of first-degree atrioventricular block a Gastrointestinal data from presentation 4, posters 919-P, 920-P, and 921-P, EASD, Barcelona, Spain, September 2013; Clinical Study Report, (GBDB_prd_SMTEAE11.RTF and GBDD_prd_SMTEAE14.RTF); and Integrated Safety Database * Pooled analysis across both doses.

29 Therapeutic Indications Trulicity is indicated in adults with type 2 diabetes mellitus to improve glycaemic control as: Add-on therapy In combination with other glucose-lowering medicinal products, including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. The recommended dose is 1.5 mg once weekly. For potentially vulnerable populations, such as patients 75 years, 0.75 mg once weekly can be considered as a starting dose. Monotherapy When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications. The recommended dose is 0.75 mg once weekly. Trulicity (dulaglutide injection) [draft summary of product characteristics]. Houten, The Netherlands: Eli Lilly and Company; 2014.

30 LEADER: Change in egfr during the Trial in Subgroups Stratified According to egfr at Baseline egfr >90 egfr egfr egfr <30 egfr, estimated GFR, ml/min/1.73m 2; Mann JFE, et al. N Engl J Med 2017;377:

31 AWARD-7: Study Design Screening a Dulaglutide 1.5 mg once weekly + prandial lispro Dulaglutide 0.75 mg once weekly + prandial lispro Insulin glargine + prandial lispro Safety Followup Lead In a Treatment Period Follow-up Visit: Group A 1 1A 2 3 b T 4 T 5 T 6 7 T 8 9 T T T T Group B 1 1A 2 Week: Group A b Group B -3 1A -1 Randomisation Primary Endpoint Final Endpoint AWARD-7 was a multicentre, parallel-arm, randomised, 52-week clinical trial that assessed the efficacy and safety of dulaglutide at two dose levels compared to insulin glargine in people with type 2 diabetes and moderate or severe chronic kidney disease Participants were randomised (1:1:1) to dulaglutide 1.5 mg (N=192) or dulaglutide 0.75 mg (N=190) or titrated insulin glargine (N=194) Key inclusion criteria: adults with T2D, egfr of <60 to 15 ml/min/1.73 m 2, BMI kg/m 2, HbA1c 7.5% and 10.5% for patients receiving insulin + OAM(s) and/or pramlintide or only insulin prior to screening a Group A: patients who were taking oral antihyperglycemic medication(s) ± pramlintide in addition to insulin at screening had a 13-week screening/lead-in period; Group B: patients who only take insulin at screening had a 3-week screening/lead-in period; b Once patients are randomised, there is no distinction between Groups A and B. Insulin glargine dose was adjusted to target fasting PG values between mg/dl ( mmol/l), and insulin lispro doses were adjusted to target pre-prandial PG values between mg/dl ( mmol/l). HbA1c, glycated haemoglobin; BMI, body mass index; egrf, estimated glomerular filtration rate; PG, plasma glucose; OAM, oral antidiabetic medication Tuttle KR, et al. Poster presented at the American Diabetes Association 77 th Scientific Sessions; San Diego, CA; June 9-13, 2017 [138-P]

32 Demographics AWARD-7: Baseline Characteristics DU 1.5 mg N=192 DU 0.75 mg N=190 Glargine N=194 Sex, women 88 (45.8) 86 (45.3) 101 (52.1) Age, years 64.7 ± ± ± 8.4 Duration of diabetes, years 17.6 ± ± ± 8.7 HbA1c, % 8.6 ± ± ± 1.0 FBG, mg/dl ± ± ± 72.2 Weight, kg 88.1 ± ± ± 18.5 BMI, kg/m ± ± ± 5.3 Daily total insulin dose, U 58.8 ± ± ± 34.2 egfr-epi-creatinine 1, ml/min/1.73m ± ± ± Baseline egfr <90 9 (4.7) 7 (3.7) 14 (7.2) 45 Baseline egfr <60 53 (27.6) 53 (27.9) 51 (26.3) 30 Baseline egfr <45 73 (38.0) 75 (39.5) 67 (34.5) 15 Baseline egfr <30 55 (28.6) 55 (28.9) 61 (31.4) Baseline egfr <15 2 (1.0) 0 (0.0) 1 (0.5) UACR, g/kg (mean [median]) (213.7) (233.6) (195.6) Microalbuminuria (30 UACR 300) 74 (38.5) 61 (32.3) 56 (28.9) Macroalbuminuria (UACR >300) 84 (43.8) 84 (44.4) 90 (46.4) Data presented as mean ± SD or n (%), unless otherwise noted, MMRM analysis. egfr was calculated based on the CKD-EPI equation 1. Abbreviations: A1c=glycated A1c; BMI=body mass index; DU=dulaglutide; FBG=fasting blood glucose.

33 HbA1c, Change from Baseline (%) AWARD-7: Key Results 0 26 Weeks 0-0,2-0,4-0,6-0,8-1 -1,2-1, ** ** ** (-0.26, 0.15),,a 0.02 (-0.18, 0.22),a HbA1c, Change from Baseline (mmol/mol) Dulaglutide 1.5 mg Dulaglutide 0.75 mg Insulin Glargine Data presented as LS mean (SE); mitt excluding post-rescue values and after study drug discontinuation, MMRM; **p<0.001 vs. BL,, p<0.001, non-inferiority vs. insulin glargine with a 0.4% margin or 0.3% margin; a Treatment difference [LSM difference (nominal 95% CI)]. BL, baseline; CI, confidence interval; LSM, least squares mean; mitt, modified intent-to-treat; MMRM, mixed-model repeated measures Tuttle KR, et al. Poster presented at the American Diabetes Association 77 th Scientific Sessions; San Diego, CA; June 9-13, 2017 [138-P]

34 AWARD-7: Key Results Tuttle KR, et al. Poster presented at the American Diabetes Association 77 th Scientific Sessions; San Diego, CA; June 9-13, 2017 [142-P]

AWARD-7: Change in UACR by Macroalbuminuria Data presented as LSM (95% CI); Safety population, MMRM analysis; *,**p<0.05 or p<0.001 vs. BL, # p<0.05 vs. insulin glargine.

35 AWARD-7: Change in UACR by Macroalbuminuria Data presented as LSM (95% CI); Safety population, MMRM analysis; *,**p<0.05 or p<0.001 vs. BL, # p<0.05 vs. insulin glargine. BL, baseline; CI, confidence interval; LSM, least squares mean; MMRM, mixed model repeated measures; UACR, urine albumin:creatinine ratio. Tuttle KR, et al. Poster presented at the American Diabetes Association 77 th Scientific Sessions; San Diego, CA; June 9-13, 2017 [142-P]

36 Evaluating Preferences for Profiles of GLP-1 Receptor Agonists among Injection-Naïve Type 2 Diabetes Patients in the UK Parameter Overall Part- Worth Utility Values 1 Relative Importance (%) 2 Dosing frequency Type of delivery system Frequency of nausea Weight change Blood sugar (HbA 1c ) change Rank Frequency of low blood sugar events (hypoglycaemia) When provided with a direct comparison, the vast majority of patients preferred the medication profile representing the characteristics of dulaglutide (83.1%) over the profile representing the characteristics of liraglutide (16.9%) 1 Overall utility values represent the range of utility values within each attribute 2 Relative importance for each attribute = overall utility value for each attribute/total utility value, where total utility value = sum of overall utility values across all attributes Gelhorn HL, et al. Patient Prefer Adherence 2015; 9:

Dulaglutide Pen Usability Outcomes In a usability study of injection-naïve patients, most patients were able to use the pen successfully and agreed or strongly agreed that dulaglutide

37 Dulaglutide Pen Usability Outcomes In a usability study of injection-naïve patients, most patients were able to use the pen successfully and agreed or strongly agreed that dulaglutide ready-to-use single-dose pen was overall easy to use. 99% 99% 97% Final injection success rate Rated easy to use Willing to continue use Matfin G, et al. J Diabetes Sci Technol 2015; 9:

38 Probability of Persistence Kaplan-Meyer Persistence Curves for Dulaglutide and Liraglutide CI, confidence interval; HR, hazard ratio Alatorre C, et al. Diabetes Obes Metab Epub 9 Feb doi: /dom.12902

39 Probability of Persistence Kaplan-Meyer Persistence Curves for Dulaglutide and Exenatide QW CI, confidence interval; HR, hazard ratio; QW, once weekly Alatorre C, et al. Diabetes Obes Metab Epub 9 Feb doi: /dom.12902

40 Long-Acting GLP-1 Receptor Agonists Characteristics of Dulagutide Robust efficacy on HbA1c lowering (e.g., vs basal insulin or short-acting GLP-1 RA) Rapidity of action Low hypoglycaemia risk Weight reduction Improved adherence (once-weekly dosing, ease of administration) Potential for CV protection Potential for renal protection

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Lilly Diabetes: Pipeline Update

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