A Randomized Study of Evolocumab in Patients with Type 2 Diabetes and Dyslipidemia on Background Statin: Primary Results of the BERSON Clinical Trial Alberto J

287 A Randomized Study of Evolocumab in Patients With Type 2 Diabetes and Dyslipidemia on Background Statin: Primary Results of the BERSON Clinical Trial Alberto J. Lorenzatti,1 Freddy G. Eliaschewitz,2 Yundai Chen,3 Juming Lu,4 Alexis Baass,5 Maria Laura Monsalvo,6 Nan Wang,6 Andrew W. Hamer,6 Junbo Ge7 TAP TO RETURN TO KIOSK MENU 1Department of Clinical Research and Cardiology, Instituto Medico DAMIC / Fundación Rusculleda, Córdoba, Argentina; 2Centro de Pesquisas Clínicas, Rua Goias, São Paulo, Brazil; 3Department of Cardiology, Chinese People Liberation Army General Hospital, Beijing, China; 4Department of Endocrinology, Chinese People Liberation Army General Hospital, Beijing, China; 5Department of Medicine, Royal Victoria Hospital, Montreal, Québec, Canada; 6Clinical Development, Amgen Inc., Thousand Oaks, California, USA; 7Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

Introduction • Diabetes mellitus is a major risk factor for Study Design (NCT02662569) myocardial infarction (MI), stroke, and other BERSON was a 12-week, randomized, double-blind, placebo-controlled phase 3 Methods cardiovascular (CV) disease1,2 study conducted in 10 countries and was designed to recruit one half of its Results 1 – China has the highest prevalence of diabetes of patients from China8 Results 2 all countries worldwide, with over 114 million estimated cases in 20172 Results 3 / • Evolocumab, a human monoclonal antibody to Evolocumab 140 mg SC Q2W + atorvastatin 20 mg PO QD Conclusions proprotein convertase subtilisin/kexin type 9 Screening, SC ~300 patients injection (PCSK9) significantly and consistently reduced low- tolerance, lipid density lipoprotein cholesterol (LDL-C) levels and stabilization Evolocumab 420 mg SC QM + atorvastatin 20 mg PO QD ~300 patients the risk of major CV events (MI, stroke, and SC injection of placebo coronary revascularization) on background statin Placebo SC QM + atorvastatin 20 mg PO QD therapy in patients with or without diabetes3-7 ~150 patients End of study Atorvastatin

• However, the efficacy and safety of evolocumab 20 mg QD Randomization 2:2:1:1 combined with background statin had not been ≥ 4 weeks Placebo SC Q2W + atorvastatin 20 mg PO QD ~150 patients assessed in a dedicated type 2 diabetes mellitus (T2DM) study

Max 8 weeks D1 W2 W4 W6 W8 W10 W12 W14 Study Objective Q2W SC IP EOS EOS QM Q2W • BERSON assessed the efficacy and safety of evolocumab QM SC IP combined with background atorvastatin in reducing LDL-C and Mandatory visit Administration at study site improving other lipid levels in a global population of patients with Other visit Administration in clinic or other setting T2DM and hyperlipidemia or mixed dyslipidemia D, day; EOS, end of study; IP, investigational product; PO, orally; Q2W, every 2 weeks; QD, daily; QM, monthly; SC, subcutaneous; W, week. © 2019 Amgen Inc. 287 A Randomized Study of Evolocumab in Patients With Type 2 Diabetes and Dyslipidemia on Background Statin: Primary Results of the BERSON Clinical Trial Alberto J. Lorenzatti,1 Freddy G. Eliaschewitz,2 Yundai Chen,3 Juming Lu,4 Alexis Baass,5 Maria Laura Monsalvo,6 Nan Wang,6 Andrew W. Hamer,6 Junbo Ge7 1Department of Clinical Research and Cardiology, Instituto Medico DAMIC / Fundación Rusculleda, Córdoba, Argentina; 2Centro de Pesquisas Clínicas, Rua Goias, São Paulo, Brazil; 3Department of Cardiology, Chinese People Liberation Army General Hospital, Beijing, China; 4Department of Endocrinology, Chinese People Liberation Army General Hospital, Beijing, China; 5Department of Medicine, Royal Victoria Hospital, Montreal, Québec, Canada; 6Clinical Development, Amgen Inc., Thousand Oaks, California, USA; 7Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

Introduction Key Eligibility Criteria Co-Primary Endpoints Methods • ≥ 18 to ≤ 80 years of age with T2DM • Percentage change from baseline in LDL-C at week 12 Results 1 • Receiving stable pharmacologic therapy for T2DM • Percentage change from baseline in LDL-C at the mean of weeks 10 and 12 Results 2 ≥ 6 months • Hemoglobin A (HbA ) ≤ 10% and fasting triglycerides Results 3 / 1c 1c ≤ 400 mg/dL (≤ 4.5 mmol/L) Key Secondary Efficacy and Safety Endpoints Conclusions • Patients on statin therapy at screening had an LDL-C of • Change from baseline to the mean of weeks 10 and 12 and to week ≥ 100 mg/dL (≥ 2.6 mmol/L); those not on statin therapy 12 in LDL-C were had an LDL-C of ≥130 mg/dL (≥ 3.4 mmol/L) • Percentage change from baseline to the mean of weeks 10 and 12 and to week 12 in non−HDL-C, ApoB100, triglycerides, HDL-C, and • Lipid-lowering therapy status unchanged for ≥ 4 weeks VLDL-C and achievement of target LDL-C < 70 mg/dL (1.8 mmol/L) before LDL-C screening • Patient incidence of treatment-emergent adverse events (AEs), • Key exclusion criteria included medical contraindications laboratory values, and anti-evolocumab binding and neutralizing to receiving 20 mg atorvastatin; NYHA III or IV heart antibodies failure; myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery Assessments bypass graft, or stroke within 6 months before randomization; eGFR <30 mL/min/1.73m2 at screening; • Lipid parameters were assessed by a central laboratory; results of and unwilling to discontinue lipid-lowering drugs or the lipid panel and lipoproteins were not reported to the investigator supplements between enrollment and end of study or sponsor study team post-screening and remained blinded until (except study-provided atorvastatin) unblinding of the clinical database • Efficacy and safety were assessed for all randomized patients who received ≥ 1 dose of study drug

Demographics and baseline characteristics Placebo Evolocumab Glucose metabolism and hemoglobin A Placebo Evolocumab Introduction (n=324) (n=657) 1c (n=324) (n=657) Methods Median age (range), years 62 (35−80) 62 (33−80) Median baseline glucose metabolism measures (Q1, Q3) Female, n (%) 195 (60.2) 367 (55.9) Results 1 Hemoglobin A1c, % 6.9 (6.2, 7.9) 7.1 (6.4, 8.2) Race, n (%) Fasting serum glucose, mg/dL 127.0 (107.0, 154.0)134.0 (110.0, 165.0) Results 2 Asian 160 (49.4) 330 (50.2) Hemoglobin A1c, n (%) Results 3 / White 139 (42.9) 278 (42.3) < 7% 176 (54.3) 275 (41.9) Black 13 (4.0) 29 (4.4) 7% to < 8% 72 (22.2) 187 (28.5) Conclusions Other 12 (3.4) 20 (3.0) 8% to < 9% 39 (12.0) 119 (18.1) Baseline clinical characteristics ≥ 9% 37 (11.4) 76 (11.6)

Mean systolic blood pressure (SD), mmHg 130.4 (13.9) 129.8 (13.6) Q1, Q3, interquartile range. Mean body mass index (SD), kg/m2 28.3 (5.6) 28.5 (5.3) Mean waist circumference (SD), cm 96.6 (13.3) 97.3 (12.2) Mean eGFR (SD), mL/min/1.73 m2 84.7 (20.6) 85.3 (21.4) Patients Statin therapy, n (%) 186 (57.4) 374 (56.9) Intensive statin use 14 (4.3) 36 (5.5) • 986 patients were randomized (453 at Chinese centers) Non-intensive statin use 172 (53.1) 338 (51.4) Hypertension, n (%) 239 (73.8) 478 (72.8) • 981 patients received evolocumab; 934 (94.7%) completed Cerebrovascular or peripheral arterial disease, n (%) 91 (28.1) 180 (27.4) Coronary artery disease, n (%) 97 (29.9) 191 (29.1) treatment Baseline diabetes-related medication use, n (%) 323 (99.7) 654 (99.5) • 984 patients received atorvastatin; 943 (95.6%) completed Mean baseline lipid values (SD) treatment LDL-C, mg/dL 91.6 (31.3) 93.0 (33.6) Non-HDL-C, mg/dL 119.3 (37.1) 121.3 (37.5) • Demographics and baseline characteristics were balanced ApoB100, mg/dL 82.7 (22.7) 84.6 (22.4) between treatment groups, except for median HbA , FSG, Triglycerides, mg/dL 143.9 (121.8) 142.8 (66.2) 1c HDL-C, mg/dL 48.6 (13.7) 47.1 (11.9) HbA1c ≥ 8%, and insulin use VLDL-C, mg/dL 27.8 (15.5) 28.2 (12.7) Lp(a), nmol/L 69.4 (93.6) 69.4 (94.3)

ApoB100, apolipoprotein B100; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); SD, standard deviation; VLDL-C, very low–density lipoprotein cholesterol.

© 2019 Amgen Inc. 287 A Randomized Study of Evolocumab in Patients With Type 2 Diabetes and Dyslipidemia on Background Statin: Primary Results of the BERSON Clinical Trial Alberto J. Lorenzatti,1 Freddy G. Eliaschewitz,2 Yundai Chen,3 Juming Lu,4 Alexis Baass,5 Maria Laura Monsalvo,6 Nan Wang,6 Andrew W. Hamer,6 Junbo Ge7 1Department of Clinical Research and Cardiology, Instituto Medico DAMIC / Fundación Rusculleda, Córdoba, Argentina; 2Centro de Pesquisas Clínicas, Rua Goias, São Paulo, Brazil; 3Department of Cardiology, Chinese People Liberation Army General Hospital, Beijing, China; 4Department of Endocrinology, Chinese People Liberation Army General Hospital, Beijing, China; 5Department of Medicine, Royal Victoria Hospital, Montreal, Québec, Canada; 6Clinical Development, Amgen Inc., Thousand Oaks, California, USA; 7Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China Mean Percentage Treatment Difference for Evolocumab Versus Introduction • Compared with placebo, evolocumab treatment administered every Q2W or QM significantly reduced LDL-C levels at week Placebo in Secondary Lipid Endpoints Methods 12 and at the mean of weeks 10 and 12, and allowed the vast Non–HDL-C Apolipoprotein B100 majority of patients to achieve LDL-C levels < 70 mg/dL 0 0 Results 1 –20 –20 (1.8 mmol/L) Results 2 –40 –40 • Treatment with evolocumab resulted in significant –60 –60 –49.4 –54.2 –59.4 –57.1 –56.9 –54.9 Results 3 / –80 –61.6 * –60.9 –80 * improvements in non-HDL-C, ApoB100, triglycerides, Lp(a), Difference,% * * * * * * –100 –100 Conclusions and HDL-C compared with placebo at week 12 and at the Week 12 Mean of Weeks Week 12 Mean of Weeks mean of weeks 10 and 12 Mean (±SE)Treatment 10 and 12 10 and 12 LDL-C Efficacy Results at Week 12 and at the Mean of Weeks 10 and 12 Triglycerides Lipoprotein (a) 0 0 Week 12 Mean of Weeks 10 and 12 –20 –12.3 –20 –16.4 –18.0 –15.6 EvoMab 140 EvoMab 420 EvoMab 140 EvoMab –40 * * –40 PBO Q2W mg Q2W PBO QM mg QM PBO Q2W mg Q2W PBO QM 420 mg QM **** * –60 –60 Parameter (n=324) (n=325) (n=160) (n=332) (n=164) (n=325) (n=160) (n=332) –45.3 –50.8 LDL-C –80 –80 * *

Difference,% –55.5 –62.5 n 148 288 150 295 157 312 155 320 –100 ** –100 *** Least squares Mean (±SE) Treatment Week 12 Mean of Weeks Week 12 Mean of Weeks mean change from 7.1 (3.7) −64.7 (3.2) 2.6 (3.4) −62.3 (3.0) 4.9 (3.5) −65.4 (3.1) 1.0 (3.3) −69.1 (3.0) 10 and 12 10 and 12 baseline (SE), % Mean treatment a − −71.8 (3.0) − −64.9 (2.6) − −70.3 (2.6) − −70.0 (2.4) HDL-C Evolocumab 140 mg Q2W Co-primary Endpoint Co-primary difference, (SE), % 95% CI − −77.6, −65.9 − −70.0, −59.9 − −75.4, −65.2 − −74.7, −63.4 15 Evolocumab 420 mg QM Adjusted P valueb − <0.0001 − <0.0001 − <0.0001 − <0.0001 * * 8.1* 7.9 Achievement of 70 10 ***** 31 (20.9) 254 (88.2) 32 (21.3) 266 (90.2) 34 (21.7) 281 (90.1) 30 (19.4) 292 (91.3) 5.9 6.3 mg/dL, n (%) HDL-C, high-density lipoprotein cholesterol; Q2W, every 2 weeks; QM, monthly. LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; SE, standard error. 5 Treatment difference is from the repeated measures linear effects model, which included treatment group, stratification factors, scheduled visit, and the Difference,% interaction of treatment with scheduled visit as covariates for all endpoints. The results of a pre-specified analysis of patients enrolled at Chinese centers in BERSON are 0 Error bars show standard error. HDL-C, high-density lipoprotein cholesterol.

presented in poster 294; Chen Y, et al. Diabetes Obes Metab. 2019;Epub ahead of print. Mean (±SE) Treatment Week 12 Mean of Weeks *P<0.0001 versus placebo; **P=0.004 versus placebo; ***P=0.0001 versus 10 and 12 placebo; ****P=0.0002 versus placebo; *****P=0.0003 versus placebo. © 2019 Amgen Inc. 287 A Randomized Study of Evolocumab in Patients With Type 2 Diabetes and Dyslipidemia on Background Statin: Primary Results of the BERSON Clinical Trial Alberto J. Lorenzatti,1 Freddy G. Eliaschewitz,2 Yundai Chen,3 Juming Lu,4 Alexis Baass,5 Maria Laura Monsalvo,6 Nan Wang,6 Andrew W. Hamer,6 Junbo Ge7 1Department of Clinical Research and Cardiology, Instituto Medico DAMIC / Fundación Rusculleda, Córdoba, Argentina; 2Centro de Pesquisas Clínicas, Rua Goias, São Paulo, Brazil; 3Department of Cardiology, Chinese People Liberation Army General Hospital, Beijing, China; 4Department of Endocrinology, Chinese People Liberation Army General Hospital, Beijing, China; 5Department of Medicine, Royal Victoria Hospital, Montreal, Québec, Canada; 6Clinical Development, Amgen Inc., Thousand Oaks, California, USA; 7Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

Placebo Evolocumab Treatment-Emergent AEs Median change from baseline in glycemic measures (Q1, Q3) Introduction (n=324) (n=657)

Methods Patients with AE, n (%) 138 (42.6) 288 (43.8) Hemoglobin A1c, % 0.1 (−0.2, 0.5) 0.1 (−0.3, 0.6) Fasting serum glucose, mg/dL 1.8 (−10.8, 16.2) 1.8 (−12.6, 21.6) Results 1 Patients with serious AE, n (%) 11 (3.4) 32 (4.9) Patients with AEs leading to treatment Abnormal laboratory tests, n (%) 7 (2.2) 10 (1.5) Results 2 discontinuation, n (%) Creatine kinase >5 x ULN 1 (0.3)a 1 (0.2)b Fatal AEs, n (%) 0 0 Alanine aminotransferase >3 x ULN 1 (0.3) 1 (0.2) Results 3 / Aspartate aminotransferase >3 x ULN 2 (0.6) 0 Common AEs,a n (%) aPatient was assigned to QM dosing, reported at week 8 visit, remained asymptomatic, and returned to baseline at week 12. Conclusions Diabetes mellitusb 8 (2.4) 38 (5.8) bPatient was assigned to QM dosing, reported at week 8 and 12 visits, remained asymptomatic. Upper respiratory tract infection 11 (3.4) 23 (3.5) • No meaningful changes from baseline to week 12 in glycemic parameters were observed in Nasopharyngitis 12 (3.7) 20 (3.0) either treatment group • No patients tested positive for binding or neutralizing ant-evolocumab antibodies Hypertension 10 (3.1) 13 (2.0) Dizziness 2 (0.6) 10 (1.5) Conclusions Urinary tract infection 5 (1.5) 9 (1.4) Back pain 4 (1.2) 8 (1.2) • In this global population of patients with T2DM and hyperlipidemia or mixed dyslipidemia, AE, adverse event; ULN, upper limit of treatment with evolocumab 140 mg Q2W and 420 mg QM, compared with placebo, with Headache 3 (0.9) 8 (1.2) normal. moderate intensity background atorvastatin aOccurring in at least 1% of patients in evolocumab treatment group. Blood uric acid increased 3 (0.9) 8 (1.2) – Led to significant reductions in LDL-C concentrations bIncludes preferred terms of diabetes mellitus (placebo, 1.9%; evolocumab, Cough 6 (1.9) 7 (1.1) 4.6%) and type 2 diabetes mellitus – Allowed the vast majority of patients to achieve LDL-C levels below 70 mg/dL (placebo, 0.6%; evolocumab, 1.2%). Toothache 3 (0.9) 7 (1.1) – Led to robust improvements in non−HDL-C and ApoB100 Peripheral edema 0 7 (1.1) – Was not associated with meaningful changes in HbA1c or FSG – Was safe and well tolerated • The overall patient incidence of AEs was similar between the evolocumab and placebo

groups; most were mild in severity (grades 1 or 2) Acknowledgments and Conflicts of Interest 1. Benjamin EJ, et al. Circulation. 2018;137:e67-e492. Disclosures • A.J.L. has served as an advisory board and steering 2. International Diabetes Federation. IDF Diabetes Atlas, 8th ed. 2017. 3. Blom DJ, et al. N Engl J Med. 2014;370:1809-1819. • This study was funded by Amgen Inc. committee member for and has received research grants and • The patient incidence of serious AEs was low, and the events were not treatment related 4. Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722. • Medical writing assistance in the speaker fees from Amgen Inc. F.G.E. has served as a speaker 5. Sabatine MS, et al. Lancet Diabetes Endocrinol. 2017;5:941-950. development of the poster was provided for and has received grants for research from Amgen Inc., except for gastric ulcer (n=1, evolocumab) and lacunar stroke (n=1, evolocumab) 6. Sattar N, et al. Lancet Diabetes Endocrinol. 2016;4:403-410. by Ben Scott (Scott Medical Sanofi, Boehringer, Eli Lilly, Novo Nordisk, and AstraZeneca. 7. Blom DJ, et al. Diabetes Obes Metab. 2017;19:98-107. Communications, LLC) and was funded M.L.M., N.W., and A.W.H. are employees of and own stock in 8. Lorenzatti AJ, et al. Clin Cardiol. 2018;41:1117-1122. • No patients tested positive for binding or neutralizing ant-evolocumab antibodies by Amgen Inc. Amgen Inc. Y.C., J.L., A.B., and J.G. have no conflicts of interest to disclose. 9. Chen Y, et al. Diabetes Obes Metab. 2019;Epub. © 2019 Amgen Inc.