Efficacy and Safety of Evolocumab (AMG 145) Monotherapy Compared With Ezetimibe and Placebo in Hypercholesterolemic Subjects: A Phase 3 Randomized Clinical Trial Michael J Koren, 1 Pernille Lundqvist, 2 Michael Bolognese, 3 Joel M Neutel, 4 Maria Laura Monsalvo, 5 Jingyuan Yang, 5 Jae B Kim, 5 Rob Scott, 5 Scott M Wasserman, 5 Harold Bays 6 for the MENDEL-2 Investigators 1 Jacksonville Center for Clinical Research, Jacksonville, FL, USA; 2 Center for Clinical and Basic Research, Ballerup, Denmark; 3 Bethesda Health Research Center, Bethesda, MD, USA; 4 Orange County Research Center, Tustin, CA, USA; 5 Amgen Inc., Thousand Oaks, CA, USA; 6 L-MARC Research Center, Louisville, KY, USA March 29, 2014, Featured Clinical Research Session 400 American College of Cardiology, Washington DC

Background  Evolocumab, a fully human monoclonal antibody against PCSK9, has emerged as a novel therapeutic option for lowering LDL-C in patients with hypercholesterolemia.  In Phase 2 studies, treatment with evolocumab was well tolerated and significantly reduced LDL-C in diverse groups of subjects, with LDL-C reductions maintained over 52 weeks. 1-5  Because statins up-regulate PCSK9 production, evaluation of evolocumab as monotherapy is required to fully understand its pharmacodynamics and safety profile in populations not confounded by statin use or a history of statin intolerance, particularly at doses anticipated for use in clinical practice. 2 1.Lancet. 2012;380: Lancet. 2012;380: JAMA. 2012;308: Circulation. 2012;126: Circulation. 2014;129:

The MENDEL-2 Study  Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy For Easing Lipid Levels-2 (NCT )  Design: A 12 week randomized, double-blind, placebo- and ezetimibe-controlled multicenter phase III study  Objective: To evaluate efficacy and safety of evolocumab in primary hypercholesterolemic patients not taking statins 3

MENDEL and MENDEL-2 Compared 4 Characteristics MENDELMENDEL-2 Phase23 N PopulationFramingham Risk < 10% Fasting LDL-C Range≥ 100 and < 190 mg/dL Background Lipid TherapyNone Evolocumab Dose 70, 105, or 140 mg biweekly 280, 350, or 420 mg monthly 140 mg biweekly 420 mg monthly Comparators Placebo biweekly or monthly Open ezetimibe 10 mg/day Placebo biweekly or monthly Blinded ezetimibe 10 mg/day Treatment Duration12 wks Evolocumab Delivery 70 mg/ml vial and syringe in clinics 140 mg/ml prefilled auto- injector in clinic and home

MENDEL-2: Study Design 5 *1 patient was randomized but not dosed. † Phone call for AEs, SAEs. AEs, adverse events. EOS, end of study; QD, daily; Q2W, biweekly; QM, monthly. 140 mg Evolocumab Q2W / Placebo PO QD N = 153 Placebo SC QM / Placebo PO QD N = 78* Placebo SC QM / 10 mg Ezetimibe PO QD N = 77 Placebo SC Q2W / 10 mg Ezetimibe PO QD N = 77 Placebo SC Q2W / Placebo PO QD N = mg Evolocumab QM / Placebo PO QD N = 153 Screening Period with Placebo Injection End of Study Randomization Day 1Week 2Week 4Week 6Week 8Week 10Week 12Week 14 † Q2W EOS QM EOS Biweekly SC administration: Monthly SC administration: 2:2:1:1:1:1

MENDEL-2: Primary Endpoints  Co-primary endpoints: Percent change from baseline in LDL-C at week 12 and mean of weeks 10 and 12  Secondary endpoints: At mean of weeks 10 and 12 and at week 12:  Percent change from baseline in ApoB, ApoA-I, lipoprotein(a), TG, and HDL-C  Percent of patients with LDL-C <70 mg/dL  Key safety endpoints:  Treatment-emergent and serious adverse events  Muscle and hepatic enzyme elevations  Anti-evolocumab antibodies 6

7 MENDEL-2: Baseline Demographics BiweeklyMonthly PBO Q2W + PBO QD (N = 76) PBO Q2W + EZE QD (N = 77) Evolocumab 140 mg Q2W + PBO QD (N = 153) PBO QM + PBO QD (N = 78) PBO QM + EZE QD (N = 77) Evolocumab 420 mg QM + PBO QD (N = 153) Age (years), mean (SD)54 (10)54 (11)53 (14)53 (11)53 (13)53 (12) Female, % Race, white, % NCEP risk categories*, % High Moderately high Moderate Low *Risk category definitions: high, diagnosed CHD or risk equivalent; moderately high, 2 or more risk factors and Framingham risk score 10%-20%; moderate, 2 or more risk factors and Framingham risk score <10%; lower, 0 or 1 risk factor. CV, cardiovascular; EZE, ezetimibe; PBO, placebo; Q2W, biweekly; QM, monthly; QD, daily.

8 MENDEL-2: Baseline Lipids BiweeklyMonthly PBO Q2W + PBO QD (N = 76) PBO Q2W + EZE QD (N = 77) Evolocumab 140 mg Q2W + PBO QD (N = 153) PBO QM + PBO QD (N = 78) PBO QM + EZE QD (N = 77) Evolocumab 420 mg QM + PBO QD (N = 153) LDL-C*, mg/dL, mean (SD) 140 (21)143 (24)142 (22)144 (24)144 (23) ApoB, md/dL, mean (SD) 104 (17)107 (20)105 (17)107 (20)106 (18)108 (18) Lp(a), nmol/L, median (Q1,Q3) 21 (9, 49) 28 (11, 120) 20 (7, 58) 22 (7, 62) 28 (12, 64) 28 (9, 104) TG, mg/dL, median (Q1,Q3) 114 (83, 178) 113 (84, 158) 112 (82, 148) 118 (86, 179) 117 (90, 159) 119 (83, 169) PCSK9, ng/mL, mean (SD) 281 (89)270 (94)272 (81)270 (82)265 (94)274 (84) *Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was 400 mg/dL (3.9 mmol/L). CV, cardiovascular; EZE, ezetimibe; PBO, placebo; Q2W, biweekly; QM, monthly; QD, daily.

MENDEL-2: Evolocumab Primary Endpoint Biweekly Dose 9 0 –30 –40 –50 –60 BLWeek 2Week 8 Study Week Week 10Week 12 –20 –10 10 Biweekly SC administration Day 1 Week 4 Week 6 Mean Percent Change in LDL-C from Baseline BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted. Placebo (N = 76)Ezetimibe (N = 77)Evolocumab biweekly (N = 153) 0.1% –18% –57% Treatment Difference vs Placebo Average at weeks 10 and 12-57% P<0.001 At week 12-57% Treatment Difference vs Ezetimibe Average at weeks 10 and 12-39% P<0.001 At week 12-39%

MENDEL-2: Evolocumab Primary Endpoint Monthly Dose 10 0 –30 –40 –50 –60 BLWeek 2Week 8 Study Week Week 10Week 12 –20 –10 10 Day 1 Week 4 Week 6 Mean Percent Change in LDL-C from Baseline BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted. Placebo (N = 78)Ezetimibe (N = 77)Evolocumab monthly (N = 153) –1% –19% –56% Treatment Difference vs Placebo Average at weeks 10 and 12-57% P<0.001 At week 12-55% Treatment Difference vs Ezetimibe Average at weeks 10 and 12-40% P<0.001 At week 12-38% Monthly SC administration

MENDEL-2: % Change in LDL-C from Baseline at Week 12 for Individual Patients 11  Subjects with early termination of subcutaneous or oral study drug No notable difference in results for average at weeks 10 and 12 Placebo (N = 78) –100 –80 –60 –40 – –100 –80 –60 –40 – Percent Change in LDL-C (mg/dL) Ezetimibe (N = 77)Evolocumab (N = 153) Placebo (N = 76)Ezetimibe (N = 77)Evolocumab (N = 153) Biweekly Monthly

MENDEL-2: Other Lipids at Week Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference. No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted. Treatment difference (biweekly and monthly) vs placebo P < vs ezetimibe P < Treatment difference (biweekly and monthly) vs placebo P < vs ezetimibe P < ApoB Lp(a) Biweekly Monthly Placebo Ezetimibe

Treatment difference (monthly) vs placebo P < (biweekly and monthly) vs ezetimibe P < 0.05 MENDEL-2: Other Lipids at Week 12 - II 13 Triglycerides Non-HDL-C Placebo Ezetimibe Treatment difference (biweekly and monthly) vs placebo P < vs ezetimibe P < Biweekly Monthly Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference. No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted.

MENDEL-2: Other Lipids at Week 12 - III 14 Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference. No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted. Treatment difference (biweekly and monthly) vs placebo P < 0.05 vs ezetimibe P < 0.05 HDL-C ApoA-I Placebo Ezetimibe Treatment difference (monthly only) vs placebo P < 0.01 vs ezetimibe P < 0.05 Biweekly Monthly

MENDEL-2: Treatment Difference According to Subgroups at Week Evolocumab Q2W vs Ezetimibe Percent Change from Baseline at Week 12 Overall <130mg/dL Sex Age Race History of Met Syn Screening LDL-C Triglycerides ≥130mg/dL <65 years ≥65 years Female Male White Black Other Yes No <200 mg/dL ≥200 mg/dL Evolocumab Q2W vs Placebo Evolocumab QM vs Ezetimibe Evolocumab QM Vs Placebo Met Syn: metabolic syndrome

MENDEL-2: Treatment Difference According to Subgroups at Week Overall Hypertension Smoker PCSK9 Region Baseline CHD risk factors Yes No Yes No <2 ≥2 North America Europe Other <baseline median (261.0 ng/mL) ≥baseline median (261.0 ng/mL) Evolocumab Q2W vs Ezetimibe Evolocumab Q2W vs Placebo Evolocumab QM vs Ezetimibe Evolocumab QM vs Placebo Percent Change from Baseline at Week

17 MENDEL-2: Safety and Tolerability Adverse Events (AEs), n (%) Placebo (N = 154) Ezetimibe (N = 154) Evolocumab (N = 306) Treatment-emergent AEs68 (44)70 (46)134 (44) Common treatment-emergent AEs* Headache Diarrhea Nausea Urinary Tract Infection Constipation Nasopharyngitis Upper Respiratory Infection 4 (3) 6 (4) 1 (1) 2 (1) 4 (3) 3 (2) 4 (3) 5 (3) 3 (2) 1 (1) 6 (4) 5 (3) 10 (3) 9 (3) 8 (3) 7 (2) 6 (2) 5 (2) Serious AEs1 (1) 4 (1) AEs leading to study drug discontinuation6 (4)5 (3)7 (2) Deaths0 (0) Potential injection site reactions † 8 (5)7 (5)16 (5) Muscle-related SMQ ‡ Myalgia Musculoskeletal pain 6 (4) 3 (2) 2 (1) 5 (3) 3 (2) 1 (1) 8 (3) 3 (1) 3 (1) Neurocognitive AEs0 (0) CK > 5 x ULN2 (1)0 (0)2 (1) ALT or AST > 5 x ULN2 (1)0 (0)1 (0.3) Anti-evolocumab antibodies § NA 0 *Reported in ≥3% of patients in one or more treatment arms. † Reported using high-level term grouping, which includes injection site (IS) rash, IS inflammation, IS pruritus, IS reaction, and IS urticaria. ‡ Standard MedDRA Queries. § Binding or neutralizing.

MENDEL-2: Conclusions  In the largest monotherapy trial with a PCSK9 inhibitor to date, evolocumab biweekly (140 mg) or monthly (420 mg) rapidly and markedly lowered LDL-C over 12 weeks compared with placebo or ezetimibe in patients with hypercholesterolemia not taking statins.  Evolocumab 140 mg biweekly and 420 mg monthly dosing regimens are clinically equivalent.  Evolocumab treatment resulted in favorable changes in other lipoproteins.  Evolocumab was well tolerated over the 12-week study  The overall incidence of treatment-emergent AEs, CK, and AST/ALT elevations was comparable across treatment groups. 18

MENDEL-2: Conclusions  Though we anticipate that evolocumab treatment will find use primarily as a treatment for high risk patients in conjunction with statins, MENDEL-2 demonstrated that evolocumab produces large LDL-C lowering effects as monotherapy.  These lipid effects occur consistently across several pre- specified sub-groups.  The MENDEL-2 findings support future investigation of evolocumab in higher-risk patient population who might benefit from anti-PCSK9 monotherapy. 19

Disclosures 20 This study was funded by Amgen Inc. MJ Koren: Employee of Jacksonville Center for Clinical Research, which has received research grants from Amgen Inc. and other PCSK9-related research funding from Regeneron, Sanofi, Roche, and Pfizer. P Lundqvist: None. MA Bolognese: Research grant from Amgen Inc. JM Neutel: None ML Monsalvo, J Yang, JB Kim, R Scott, SM Wasserman: Employees of Amgen Inc. and own Amgen stock/stock options. H Bays: Research grant and consultant/advisory board from Amgen Inc., and consultant/advisory board/speaker's bureau for many other pharmaceutical companies. Amgen Inc. provided editorial support for the development of this presentation.