Background

1. 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,1Pernille Lundqvist,2 Michael Bolognese,3Joel M Neutel,4 Maria Laura Monsalvo,5 Jingyuan Yang,5 Jae B Kim,5 Rob Scott,5 Scott M Wasserman,5 Harold Bays6for the MENDEL-2 Investigators 1Jacksonville Center for Clinical Research, Jacksonville, FL, USA; 2Center for Clinical and Basic Research, Ballerup, Denmark; 3Bethesda Health Research Center, Bethesda, MD, USA; 4Orange County Research Center, Tustin, CA, USA; 5Amgen Inc., Thousand Oaks, CA, USA; 6L-MARC Research Center, Louisville, KY, USA March 29, 2014, Featured Clinical Research Session 400 American College of Cardiology, Washington DC

2. 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. Lancet. 2012;380:1995-2006. Lancet. 2012;380:2007-2017. JAMA. 2012;308:2497-2506. Circulation. 2012;126:2408-2417. Circulation. 2014;129:234-243.

3. 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 (NCT01763827) • 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

4. MENDEL and MENDEL-2 Compared

5. MENDEL-2: Study Design 140 mg Evolocumab Q2W / Placebo PO QD N = 153 420 mg Evolocumab QM / Placebo PO QD N = 153 • Placebo SC Q2W / 10 mg Ezetimibe PO QD Screening Period with • Placebo • Injection N = 77 • 2:2:1:1:1:1 • Randomization End of Study • Placebo SC QM / 10 mg Ezetimibe PO QD N = 77 • Placebo SC Q2W / Placebo PO QD N = 77 • Placebo SC QM / Placebo PO QD N = 78* Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14† Q2W Biweekly SC administration: QM EOS Monthly SC administration: EOS *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.

6. 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

7. MENDEL-2: Baseline Demographics *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 *Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was <40 mg/dL (1.0 mmol/L) or triglyceride levels were >400 mg/dL (3.9 mmol/L). CV, cardiovascular; EZE, ezetimibe; PBO, placebo; Q2W, biweekly; QM, monthly; QD, daily.

9. MENDEL-2: EvolocumabPrimary Endpoint Biweekly Dose 10 0.1% 0 –10 –18% –20 • Mean Percent Change in LDL-C • from Baseline –30 –40 –50 –57% –60 Week 4 BL Day 1 Week 2 Week 6 Week 8 Week 10 Week 12 Biweekly SCadministration Study Week Placebo (N = 76) Ezetimibe (N = 77) Evolocumab biweekly (N = 153) 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.

10. MENDEL-2: EvolocumabPrimary Endpoint Monthly Dose 10 –1% 0 –10 –19% –20 • Mean Percent Change in LDL-C • from Baseline –30 –40 –50 –56% –60 Week 4 BL Day 1 Week 2 Week 6 Week 8 Week 10 Week 12 Monthly SCadministration Study Week Placebo (N = 78) Ezetimibe (N = 77) Evolocumab monthly (N = 153) 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.

11. MENDEL-2: % Change in LDL-C from Baseline at Week 12 for Individual Patients Placebo (N = 76) Ezetimibe (N = 77) Evolocumab (N = 153) 60 40 20 0 • Percent Change in LDL-C (mg/dL) Biweekly –20 –40 –60 –80 –100 Placebo (N = 78) Ezetimibe (N = 77) Evolocumab (N = 153) 60 40 20 0 Monthly • Percent Change in LDL-C (mg/dL) –20 –40 –60 –80 –100  Subjects with early termination of subcutaneous or oral study drug No notable difference in results for average at weeks 10 and 12

12. MENDEL-2: Other Lipids at Week 12 ApoB Biweekly Monthly Treatment difference (biweekly and monthly) vs placebo P < 0.001 vs ezetimibe P < 0.001 • Lp(a) Biweekly Monthly Treatment difference (biweekly and monthly) vs placebo P < 0.001 vs ezetimibe P < 0.001 Placebo Ezetimibe 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.

13. MENDEL-2: Other Lipids at Week 12 - II Triglycerides Biweekly Monthly Treatment difference (monthly) vs placebo P < 0.001 (biweekly and monthly) vs ezetimibe P < 0.05 • Non-HDL-C Biweekly Monthly Treatment difference (biweekly and monthly) vs placebo P < 0.001 vs ezetimibe P < 0.001 Placebo Ezetimibe 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.

14. MENDEL-2: Other Lipids at Week 12 - III HDL-C Biweekly Monthly Treatment difference (biweekly and monthly) vs placebo P < 0.05 vs ezetimibe P < 0.05 • ApoA-I Biweekly Monthly Treatment difference (monthly only) vs placebo P < 0.01 vs ezetimibe P < 0.05 Placebo Ezetimibe 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.

15. MENDEL-2: Treatment Difference According to Subgroups at Week 12 EvolocumabQ2W vs Placebo EvolocumabQ2W vs Ezetimibe EvolocumabQM Vs Placebo EvolocumabQM vs Ezetimibe Sex Female Male Age <65 years ≥65 years Race White Black Other History of Met Syn Yes No Screening LDL-C <130mg/dL ≥130mg/dL Triglycerides <200 mg/dL ≥200 mg/dL Overall -100 -80 -60 -40 -20 0 -100 -80 -60 -40 -20 0 -100 -80 -60 -40 -20 0 -100 -80 -60 -40 -20 0 Percent Change from Baseline at Week 12 Met Syn: metabolic syndrome

16. MENDEL-2: Treatment Difference According to Subgroups at Week 12 EvolocumabQ2W vs Placebo EvolocumabQ2W vs Ezetimibe EvolocumabQM vsPlacebo EvolocumabQM vs Ezetimibe Hypertension Yes No Smoker Yes No Baseline CHD risk factors <2 ≥2 Region North America Europe Other PCSK9 <baseline median (261.0 ng/mL) ≥baseline median (261.0 ng/mL) Overall -100 -80 -60 -40 -20 0 -100 -80 -60 -40 -20 0 -100 -80 -60 -40 -20 0 -100 -80 -60 -40 -20 0 Percent Change from Baseline at Week 12

17. MENDEL-2: Safety and Tolerability *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.

18. 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.

19. 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.

20. Disclosures 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.