Evolocumab HCP presentation.pptx

role PSCK9 ito decrase LDL

1. New Approaches in Dyslipidemia Management:How does Evolocumab change clinical practice in Dyslipidemia management?

2. Agenda Unmet medical need in Cardiovascular Disease PROFICIO Clinical Trials Program (Amgen Research program to evaluate efficacy & safety of Evolocumab ) Updated guidelines in Dyslipidemia Management Summary Discussion

3. Every hour 5 adults in Saudi Arabia die from Cardiovascular disease causes WHO. Noncommunicable diseases country profiles 2014. Available online at: http://www.who.int/nmh/publications/ncd-profiles-2014/en/

4. INTERHEART: Multiple Risk Factors All inhabited continents Yusuf S Lancet 2004;364:937-952

5. LDL is Strongly Associated with Coronary Heart Disease Kolodgie FD, et al. Heart 2004;90:1385-91. Grundy S, et al. Circulation. 2004;110:227-239. Cannon CP, et al. JACC 2006;48-438-445. Every 39 mg/ dL (1 mmol /L) decrease in LDL-C decreases relative risk for CHD by ~1-2% (20-25%) MRFIT ARIC PROCAM Cholesterol hypothesis originated with observations Cholesterol Clefts Clinical trials validate the hypothesis

6. PCSK9 Inhibition in clinical practice: Mechanisms of action and prescription of therapy

7. PCSK9 Inhibitors (PCSK9i) P roprotein C onvertase S ubtilisin/ K exin type 9 Fully humanized monoclonal antibody Subcutaneous injection New and unique opportunities for CVD risk reduction Additional LDL-C lowering when used in combination with statin + ezetimibe

8. Discovering the role of PCSK9 in LDL-C regulation and ASCVD risk 1 Cohen et al NEJM 2006;354:1264-1272 3 Benn et al JACC 2010;55:2833-2842 2 Cohen et al Nat Genet 2005;37:161-165 4 Zhao et al Jrnl of Hum Gen 2006;79:514-534 He LOF mutations found in 1-3% of population Associated w/ : lifelong modestly lower serum LDL-C Lower incidence of CHD due to prolonged LDL-C reduction

9. Duration of LDL-C Lowering : Genetics vs Statins Willer Nat Gen 2008; Linsel-Nitchke PlosOne 2008; Stender JACC 2014; Stitziel NEJM 2014 -100% -80% -60% -40% -20% 0% Reduction in CHD Reduction in LDL-C 0% -10% -20% -30% -40% Genetic Variants Lifelong Statin Trials 5 Years PCSK9 Y142X C679X PCSK9 R46L NPC1L1 LDLR ABCG8 APOB 4S WOSCOPS HPS CARE Lifelong reductions in PCSK9 reduce CHD CHD=Coronary Heart Death

10. LDL Receptor (LDL-R) Function and Life Cycle Receptor re-used ~200x Hepatocyte LDL Reduction

11. Role of PCSK9 in the Regulation of LDLR Expression X Hepatocyte LDLR destroyed Reduced LDLR density No LDL-C Reduction

12. Impact of PCSK9i on LDLR Expression PCSK9 antibody PCSK9 mAb-PCSK9 Complex Receptor recycled ~200x Increased LDLR density LDL-C Reduction

13. Evolocumab is a Fully Human Monoclonal Antibody Against PCSK9 and Inhibits PCSK9/LDL-R Interaction Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.

14. Evolocumab clinical benefits

15. HeFH , heterozygous hypercholesterolemia; HoFH , homozygous hypercholesterolemia. ClinicalTrials.gov. Accessed September 2015. Evolocumab: PROFICIO addresses key areas of unmet need in the management of dyslipidemia Combination therapy Statin intolerant Monotherapy HeFH Long-term safety and efficacy Open-label extension HoFH/ Severe FH Secondary Prevention Atherosclerosis Phase 2 (n=631) Phase 3 (n=1896) Phase 2 (n=411) Phase 3 (n=614) Phase 2 (n=160) Phase 3 (n=329) Phase 2 (n=168) Phase 2 (n=1324) Phase 3 (n=4428) Phase 3 (n=901) Phase 3 (n=27,564) Phase 3 (n=950) Phase 2/3 (n=300) Phase 2/3 (n=58) Neurocognition Phase 3 (n=1972) Phase 3 (n=307) Phase 3 (n=519) >35,000 patients

16. Evolocumab consistency in Reducing LDL-C among all patients (High Risk & FH Patients: Phase III LDL-C Lowering Summary 10 -10 -20 -30 -40 -50 -60 -60 -50 -40 -30 -20 -10 10 % Change from Baseline In Reflexive LDL-C MENDEL-2* (Monotherapy) QM Q2W QM Q2W –57% –56.9% –0.1% * Ezetimibe comparator Koren MJ, et al. J Am Coll Cardiol . 2014;63(23):2531-2540 (MENDEL-2); Stroes E, et al. JACC 2014:10.1016/j.jacc.2014.03.019 (GAUSS-2); Robinson JG, et al. JAMA. 2014;311(18):1870-1882. doi:10.1001/jama.2014.4030 (LAPLACE-2); Raal F, et al.  Lancet . 2014. Published Online October 2, 2014. http://dx.doi.org/10.1016/S0140-6736(14)61399-4.(RUTHERFORD-2) . 10 -10 -20 -30 -40 -50 -60 -60 -50 -40 -30 -20 -10 10 QM Q2W QM Q2W Placebo wk10&12 Placebo wk12 EvoMab wk10&12 EvoMab wk12 Ezetimibe wk10&12 Ezetimibe wk12 LAPLACE-2 ( Combo with Statin ) GAUSS-2* (Statin Intolerance) RUTHERFORD-2 (FH, Combo with Statin ) –17.5% –17.8% –0.4% –1.4% –1.3% –58.8% –56.1% –19.1% –18.6% –62% –63% –64% –58% +6.8% +8.1% +3.2% +4.6% –56.1% –56.1% –19.2% –18.1% –55.3% –52.6% –16.6% –15.1% –61% –61% –64% –56% –1% +2% –1% +5%

17. Repatha provided a -32% reduction in LDL-C compared to placebo Repatha may provide a viable alternative for patients in whom LDL apheresis is the only suitable treatment option In patients with HoFH, Repatha is the only PCSK9 inhibitor approved for the treatment of HoFH and reduces LDL-C by up to 32% compared with other LLTs Sources: (TESLA study) Raal et al, 2014; Repatha EPAR, Last Updated Oct 2016 Wang et al., 2016. MEAN LDL-C % CHANGE FROM BASELINE FOR HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HoFH) SUBJECTS -23% LS Mean LDL-C % Change From Baseline Between Week 12 +9% *High- to moderate-intensity statin therapy. Placebo + Background Statin* Repatha 420mg QM + Background Statin*

18. Marc S. Sabatine, MD, MPH, a Robert P. Giugliano, MD, a Anthony C. Keech , MD, b Narimon Honarpour, MD, PhD, c Stephen D. Wiviott , MD, a Sabina A. Murphy, MPH, a Julia F. Kuder , MA, a Huei Wang, PhD, c Thomas Liu, PhD, c Scott M. Wasserman, MD, c Peter S. Sever, PhD, FRCP, d and Terje R. Pedersen, MD e for the FOURIER Steering Committee and Investigators From the a TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, b Sydney Medical School, NHMRC Clinical Trials Centre, University of Sydney, Sydney, c Amgen, Thousand Oaks, CA, d International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, and e Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo. Repatha Outcomes Trial: Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664 SC-MEA-AMG145-00114 Apr 17

19. Evolocumab Outcomes Trial: Study Design Overview Screening Age 40–85 years MI, stroke, or PAD Additional risk factors (one major or two minor) Optimal background lipid therapy (including effective dose of statin ± ezetimibe) LDL-C ≥ 70 mg/dL or non–HDL-C ≥ 100 mg/dL Evolocumab SC 140 mg Q2W or 420 mg QM (per subject preference) n ~ 13,750 Placebo SC Q2W or QM (per subject preference) n ~ 13,750 Randomization 1:1 End of Study (EOS) Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of key 2 endpoints achieved D = day; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; PAD = peripheral artery disease; Q2W = every 2 weeks; Q24W = every 24 weeks; QM = every month; SC = subcutaneous; W = week. Sabatine MS, et al. Am Heart J . 2016;173:94-101.

20. Evolocumab Outcomes Trial: Study Endpoints Endpoint Description Primary* Composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization Key secondary † Composite of CV death, MI, or stroke Other Secondary All-cause death; CV death; MI; stroke; coronary revascularization; CV death or hospitalization for heart failure; ischemic stroke or transient ischemic attack * Time to CV death, MI, stroke, hospitalization for UA, or coronary revascularization, whichever occurs first † Time to CV death, MI, or stroke, whichever occurs first CV = cardiovascular; MI = myocardial infarction Sabatine MS, et al. Am Heart J . 2016;173:94-101. Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664 Sample size based on key secondary endpoint and powered to detect a 15% risk reduction at 90% power Assuming 2% per year event rate in placebo arm, 27,500 patients followed up for a median of ~43 months should have provided 1,630 key secondary endpoints Efficacy analysis was hierarchical: If primary endpoint was significantly reduced, then key secondary endpoint was to be tested, followed in order by CV death, all-cause mortality, then additional secondary endpoints

21. Baseline Characteristics

22. Baseline CV Risk Factors *Patients could have more than one type of atherosclerosis. CV = cardiovascular; MI = myocardial infarction. Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664 Characteristics Evolocumab (N = 13,784) Placebo (N = 13,780) Type of atherosclerosis* – n (%) Myocardial infarction 11,145 (80.9) 11,206 (81.3) Time from most recent prior MI – yr (IQR) 3.4 (1.0-7.4) 3.3 (0.9-7.7) Non-hemorrhagic stroke 2,686 (19.5) 2,651 (19.2) Time from most recent prior stroke – yr (IQR) 3.2 (1.1-7.1) 3.3 (1.1-7.3) Peripheral artery disease – n (%) 1,858 (13.5) 1,784 (12.9) Cardiovascular risk factors     Hypertension – n/total n (%) 11,045/13,784 (80.1) 11,039/ 13,779 (80.1) Diabetes mellitus – n (%) 5,054 (36.7) 5,027 (36.5) Current cigarette use – n/total n (%) 3,854/13,783 (28.0) 3,923/13,779 (28.5)

23. Baseline Lipid-Lowering Therapies and Lipid Parameters * Statin intensity was categorized per the ACC/AHA Guidelines. Note, that in some countries where FOURIER was conducted, higher statin doses are not approved. HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp (a) = Lipoprotein(a); IQR = Inter-quartile range Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664 Malinowski HJ, et all. J Clin Pharmacol . 2008;48:900-908 Characteristics Evolocumab (N = 13,784) Placebo (N = 13,780) Statin use* – n (%)     High intensity 9,585 (69.5) 9,518 (69.1) Moderate intensity 4,161 (30.2) 4,231 (30.7) Low intensity, unknown intensity, or no data 38 (0.3) 31 (0.2) Ezetimibe – n (%) 726 (5.3) 714 (5.2) Other cardiovascular medications – n/total n (%)     Aspirin and/or P2Y 12 inhibitor 12,766 / 13,772 (92.7) 12,666/ 13,767 (92.0) Beta-blocker 10,441 / 13,772 (75.8) 10,374/ 13,767 (75.4) ACE inhibitor or ARB and/or aldosterone antagonist 10,803/ 13,772 (78.4) 10,730/ 13,767 (77.9) Lipid measures - Median (IQR) – mg/ dL LDL cholesterol – mg/ dL 92 (80, 109) 92 (80, 109) Total cholesterol – mg/ dL 168 (151, 188) 168 (151, 189) HDL cholesterol – mg/ dL 44 (37, 53) 44 (37, 53) Triglycerides – mg/ dL 134 (101, 183) 133 (99, 181) Lp (a) - nmol /L 37 (13, 166) 37 (13, 164)

24. Median LDL-C Levels Over Time: All Patients LDL-C was significantly reduced in the evolocumab group (median: 30 mg/ dL ) including 42% who achieved levels ≤ 25 mg/ dL vs < 0.1% in the placebo group Placebo Median 92 mg/ dL Evolocumab Median 30 mg/ dL 13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 790 13,779 Placebo 13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 768 13,784 Evolocumab No. at risk 4 10 20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks 59% mean reduction (95%CI 58-60), P < 0.001 Absolute reduction: 56 mg/ dL (95% CI 55-57) LDL Cholesterol (mg/ dL ) Data shown are median values with 95% confidence intervals in the two arms; ITT. Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664

25. Primary & Key Secondary Endpoints Evolocumab Placebo Months after Randomization Primary Endpoint: CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 6 12 18 24 30 36 Hazard ratio 0.85 (95% CI, 0.79-0.92) P<0.0001 6 12 18 24 30 36 Key Secondary Endpoint: CV Death, MI, or Stroke Hazard ratio 0.80 (95% CI, 0.73-0.88) P<0.00001 Evolocumab Placebo Sabatine MS et al. NEJM 2017;376:1713-1722

26. Primary, Key Secondary, and Other Endpoints Outcome Evolocumab (n = 13,784) n (%) Placebo (n = 13,780) n (%) HR (95% CI) P-value ‡ Primary endpoint* 1,344 (9.8) 1,563 (11.3) 0.85 (0.79-0.92) <0.001 Key secondary endpoint † 816 (5.9) 1,013 (7.4) 0.80 (0.73-0.88) <0.001 Other endpoints         CV death 251 (1.8) 240 (1.7) 1.05 (0.88-1.25) 0.62 Death from any cause 444 (3.2) 426 (3.1) 1.04 (0.91-1.19) 0.54 MI 468 (3.4) 639 (4.6) 0.73 (0.65-0.82) <0.001 Hospitalization for UA 236 (1.7) 239 (1.7) 0.99 (0.82-1.18) 0.89 Stroke 207 (1.5) 262 (1.9) 0.79 (0.66-0.95) 0.01 Coronary revascularization 759 (5.5) 965 (7.0) 0.78 (0.71-0.86) <0.001 CV Death or Hospitalization for Worsening Heart Failure 402 (2.9) 408 (3.0) 0.98 (0.86-1.13) 0.82 Ischemic stroke or TIA 229 (1.7) 295 (2.1) 0.77 (0.65-0.92) 0.003 CTTC composite endpoint ** 1,271 (9.2) 1,512 (11.0) 0.83 (0.77-0.90) <0.001 *Time to CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first † CV death, myocardial infarction, or stroke, whichever occurs first ‡ Given the hierarchical nature of the statistical testing, the P values for the primary and key secondary endpoint should be considered statistically significant, whereas all other P values should be considered nominal. ** CTTC stands for Cholesterol Treatment Trialists Collaboration and the composite endpoint consists of coronary heart death, nonfatal MI, stroke, or coronary revascularization MI = Myocardial infarction; UA = Unstable angina; TIA = Transient ischemic attack Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664 The primary endpoint was driven by reductions in MI, stroke, and coronary revascularization

27. Safety

28. Adverse Events in the Safety Population* Adverse Events, n (%) Evolocumab (N = 13,769) Placebo (N = 13,756) Any 10,664 (77.4) 10,644 (77.4) Serious 3,410 (24.8) 3,404 (24.7) Thought to be related to the study agent and leading to discontinuation of study regimen 226 (1.6) 201 (1.5) No notable differences in the rate of AEs, SAEs, or AEs leading to discontinuation *Safety evaluations included all randomized patients who received at least one dose of study treatment and for whom post-dose data are available. Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664

29. Adverse Events of Interest and Laboratory Measures in the Safety Population* Adverse Events, n (%) Evolocumab (N = 13,769) Placebo (N = 13,756) Injection-site reaction** 296 (2.1) 219 (1.6) Allergic reactions 420 (3.1) 393 (2.9) Muscle-related event 682 (5.0) 656 (4.8) Rhabdomyolysis 8 (0.1) 11 (0.1) Cataract 228 (1.7) 242 (1.8) Adjudicated case of new-onset diabetes † 677 (8.1) 644 (7.7) Neurocognitive event 217 (1.6) 202 (1.5) Laboratory results - n/total n (%)     Aminotransferase >3x ULN 240/13,543 (1.8) 242/13,523 (1.8) Creatinine kinase >5x ULN 95/13,543 (0.7) 99/13,523 (0.7) ULN = Upper Limit of Normal Sabatine MS, et al. NEJM . [published online ahead of print March 17, 2017]. doi : 10.1056/NEJMoa1615664 Incidence of neurocognitive events, cataracts, and new-onset diabetes were similar between the two arms Post-baseline anti- evolocumab antibodies were detected in 0.3%, with no neutralizing antibodies detected *Safety evaluations included all randomized patients who received at least one dose of study treatment and for whom post-dose data are available. **The between-group difference was nominally significant (P<0.001). † HR 1.05 (95% CI 0.94-1.17); denominators of 8337 ( evolocumab ) and 8339 (placebo) because patients with prevalent diabetes at the start of the trial were excluded.

30. Clinical Benefit of Evolocumab in Patients with a History of MI: An Analysis from FOURIER Marc S. Sabatine, Gaetano M. De Ferrari, Robert P. Giugliano, Kurt Huber, Basil S. Lewis, Jorge Ferreira, Julia F. Kuder, Sabina A. Murphy, Stephen D. Wiviott, Christopher Kurtz, Narimon Honarpour, Anthony C. Keech, Peter S. Sever, and Terje R. Pedersen, for the FOURIER Steering Committee & Investigators American Heart Association – Annual Scientific Session Late-Breaking Science in Prevention November 13, 2017 SC-MEA-AMG145-00190 Nov17

31. High-Risk Features and Other Baseline Characteristics Characteristic <2 y ago N=8402 (38%) ≥2 y ago N=13,918 (62%) ≥2 N=5285 (24%) 1 N=17,047 (76%) MVD N=5618 (25%) No MVD N=16,715 (75%) Age , mean (SD) 60 (9 ) 63 (9) 62 (9 ) 62 (9) 62 (9 ) 62 (9) Male sex (%) 77 79 82 77 81 78 Hypertension (%) 75 81 81 78 82 78 Diabetes mellitus (%) 31 38 36 35 35 35 Current smoker (%) 28 28 26 28 26 28 High-intensity statin (%) 76 69 75 70 74 70 LDL-C , mg/ dL ( IQR) 90 (79-106) 93 (80-110) 92 (81-109) 92 (80-108) 93 (81-110) 92 (80-108) LDL-C w/ EvoMab at 48 wk , mg/ dL ( IQR) 29 (19-45) 30 (18-46) 30 (19-46) 29 (19-46) 30 (19-46) 29 (18-46) Time from Qualifying MI Residual Multivessel CAD # Prior MIs

32. Risk of CV Death, MI or Stroke with Each Risk Factor HR 1.19 (1.04-1.37) P=0.01 HR 2.04 (1.78-2.35) P<0.001 HR 1.47 (1.27-1.70) P<0.001 Analyses in placebo arm

33. Benefit of EvoMab Based on Time from Qualifying MI Qualifying MI <2 yrs ago Months after Randomization CV Death, MI, or Stroke 6 12 18 24 30 36 24% RRR HR 0.76 (95% CI 0.64-0.89) P<0.001 7.9% 10.8% P interaction =0.18 D 2.9% NNT 35 Evolocumab Placebo 8.3% 9.3% D 1.0% NNT 101 Qualifying MI ≥2 yrs ago 13% RRR HR 0.87 (95% CI 0.76-0.99) P=0.04 6 12 18 24 30 36

34. Benefit of EvoMab Based on # of Prior MIs ≥2 Prior MIs Months after Randomization CV Death, MI, or Stroke 6 12 18 24 30 36 21% RRR HR 0.79 (95% CI 0.67-0.94) P=0.006 12.4% 15.0% P interaction =0.57 D 2.6% NNT 38 Evolocumab Placebo 6.6% 8.2% D 1.7% NNT 60 1 Prior MI 16% RRR HR 0.84 (95% CI 0.74-0.96) P=0.008 6 12 18 24 30 36

35. Benefit of EvoMab Based on Multivessel Disease Multivessel Disease Months after Randomization CV Death, MI, or Stroke 6 12 18 24 30 36 30% RRR HR 0.70 (95% CI 0.58-0.84) P<0.001 9.2% 12.6% P interaction =0.03 D 3.4% NNT 29 Evolocumab Placebo 7.6% 8.9% D 1.3% NNT 78 No Multivessel Disease 11% RRR HR 0.89 (95% CI 0.79-1.00) P=0.055 6 12 18 24 30 36

36. Landmark Analyses in Pts w/ a High-Risk MI Feature Evolocumab Placebo Months from Randomization CV Death, MI, Stroke 3 9 12 24 30 36 6 12 18 19% RRR HR 0.81 (95%CI 0.68-0.95) P=0.01 27% RRR HR 0.73 (95%CI 0.62-0.86) P<0.001 High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or multivessel disease

37. Clinical Efficacy and Safety of Achieving Very Low LDL-C Levels With the PCSK9 Inhibitor Evolocumab in the FOURIER Outcomes Trial RP Giugliano, TR Pedersen, AC Keech, PS Sever, JG Park, and MS Sabatine, for the FOURIER Steering Committee & Investigators European Society of Cardiology 2017 Clinical Trial Update I August 28, 2017 SC-MEA-AMG145-00165 Sep 17

38. Aims To explore the clinical efficacy and safety associated with progressively lower achieved LDL-C levels Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

39. Methods - 1 LDL-C assessed at 4 wks (ultracentrifugation if <1 mM) Analyzed 5 groups by achieved LDL-C at 4 weeks <0.5mM (20 mg/dL) 0.5-1.3 mM (20- 49 mg/dL) 3) 1.3-1.8 mM (50-69 mg/dL) 4) 1.8-2.6mM (70-99 mg/dL) 5) > 2.6 mM ( > 100 mg/dL) was the referent group Pooled results across 2 Rx groups ( evo , placebo) Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 1582 pts with events in first 4 wks or no LDL-C at week 4 were excluded

40. Methods - 2 Prespecified 1° and 2° efficacy composite endpoints 10 safety adverse events evaluated: Serious AE - AE->drug discon - AST/ALT>3x Cancer - cataracts AEs - CK > 5x ULN Hem stroke - Neurocognitive - Non-CV death New onset diabetes (adjudicated by CEC) Cognition 1 assessed using CANTAB tool and pt survey of everyday cognition (ECog) 1. Giugliano RP et al. N Engl J Med 2017377:633-43 Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

41. LDL ( mM ) %Evo 99.6% 96.5% 41% 10% 9.6% %Placebo 0.4% 3.5% 59% 90% 90.4% Median [IQR] LDL-C at 4 Weeks Evo 0.8 mM [0.5-1.2] Pbo 2.2 mM [1.9-2.7] 32 mg/dL [21-45] 87 mg/dL [74-104] Achieved LDL-C at 4 Weeks Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 <0.5 0.5-1.3 1.3-1.8 1.8-2.6 > 2.6

42. Baseline Characteristics Achieved LDL-C in mM at 4 Weeks <0.5 (N=2669) 0.5-1.3 (N=8003) 1.3-1.8 (N=3444) 1.8-2.6 (N=7471) > 2.6 (N=4395) Age (median), yrs* 64 63 62 63 61 Female s* 16 23 27 24 28 Caucasian race* 80 86 84 85 88 Current smoker* 26 27 29 28 32 Prior MI 81 81 80 82 81 Prior stroke 20 19 19 19 20 Prior PAD 12 14 14 12 14 Hypertension 78 80 82 80 81 TIMI Risk Score 2° Prevention* 3.2 3.3 3.4 3.3 3.4 Data shown are % patients unless otherwise specified *P trend < 0.0001 Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

43. Lipids and Lipid Rx at Randomization Achieved LDL-C in mM at 4 Weeks At Randomization <0.5 (N=2669) 0.5-1.3 (N=8003) 1.3-1.8 (N=3444) 1.8-2.6 (N=7471) > 2.6 (N=4395) Median Lipid values LDL-C , mM 2.1 2.4 2.2 2.3 3.0 Total cholesterol , mM 4.0 4.3 4.2 4.2 5.0 Triglycerides , mM 1.5 1.5 1.6 1.4 1.6 HDL-C, mM 1.1 1.1 1.1 1.1 1.2 Lipoprotein (a) , nM 22 43 32 37 48 High potency statin, % ( > Atorvastatin 40 mg/d) 63 69 70 70 72 Ezetimibe, % 4.1 5.0 5.4 4.6 7.4 P trend < 0.0001 for each Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

44. LDL-C Over Time Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

45. CV Death, MI, Stroke, UA, or Coronary Revasc Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 LDL-C (mM) Adj HR (95% CI) <0.5 0.76 (0.64-0.90) 0.5-1.3 0.85 (0.76-0.96) 1.3-1.8 0.94 (0.82-1.09) 1.8-2.6 0.97 (0.86-1.09) > 2.6 referent P = 0.0012 LDL-C ( mM ) at 4 weeks

46. CV Death, MI, or Stroke Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 LDL-C (mM) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent P = 0.0001 LDL-C ( mM ) at 4 weeks

47. Safety Events - 1 % Patients (n/N) Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 Adj P-values for trend >0.10 for each comparison % pts

48. Safety Events - 2 % Patients (n/N) Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 Adj P-values for trend >0.10 for each comparison % pts

49. Exploratory Analysis Pts with LDL-C <0.26 mM (<10 mg/dL) at 4 wks Cardiovascular Efficacy Adj HR 0.69 (0.49-0.97) P=0.03 Adj HR 0.59 (0.37-0.92) P=0.02 N=504: Median [IQR] LDL-C 0.18 [0.13-0.23] mM = 7 [5-9] mg/dL Adj HR 0.94 (0.74-1.20) P=0.61 Adj HR 1.08 (0.63-1.85) P=0.78 Safety Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

50. Conclusions LDL-C can now be reduced to unprecedented low levels with statin + PCSK9i (<< 1 mM ) A strong progressive relationship of achieved LDL-C and CV events seen, down to LDL <0.26 mM (<10 mg/ dL ) No excess in safety events with very low achieved LDL-C <0.5 mM (<20 mg/ dL ) at 2.2 years Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017 These data suggest that we should target considerably lower LDL-C than is currently recommended for our patients with atherosclerotic CV disease

51. Guidelines updates after PCSK9 inhibitors after the release of outcome data

52. Secondary Prevention

53. Table 4. Very High-Risk* of Future ASCVD Events Major ASCVD Events Recent ACS (within the past 12 mo) History of MI (other than recent ACS event listed above) History of ischemic stroke Symptomatic peripheral arterial disease (history of claudication with ABI <0.85, or previous revascularization or amputation)

54. Table 4 continued High-Risk Conditions Age ≥65 y Heterozygous familial hypercholesterolemia History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD event(s) Diabetes mellitus Hypertension CKD (eGFR 15-59 mL/min/1.73 m 2 ) Current smoking Persistently elevated LDL-C (LDL-C ≥100 mg/dL [ ≥2.6 mmol/L]) despite maximally tolerated statin therapy and ezetimibe History of congestive HF

55. AHA/ACC 2018 Recommendations in FH patients Recommendations for Primary Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L]) COR LOE Recommendations IIb B-R In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL (≥2.6 mmol/L) or higher while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. IIb C-LD In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL ( ≥ 5.7 mmol/L) or higher and who achieve an on-treatment LDL-C level of 130 mg/dL (≥ 3.4 mmol/L) or higher while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. CITATION: J Am Coll Cardiol . Nov 2018; DOI: 10.1016/j.jacc.2018.11.003

56. New CAD risk Categories

57. AACE: CAD Risk Categories and LDL-C Treatment Goals Treatment goals Risk category Risk factors a /10-year risk b LDL-C (mg/ dL ) Non-HDL-C (mg/ dL ) Apo B (mg/ dL ) Extreme risk Progressive ASCVD including unstable angina in patients after achieving an LDL-C < 70 mg/ dL Established clinical cardiovascular disease in patients with DM, CKD 3/4, or HeFH History of premature ASCVD (< 55 male, < 65 female) < 55 < 80 < 70 Very high risk Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease Diabetes or CKD 3/4 with 1 or more risk factors(s) Heterozygous familial hypercholesterolemia < 70 < 100 < 80 High risk ≥ 2 risk factors and 10-year risk > 10% or CHD risk equivalent c , including diabetes or CKD 3, 4 with no other risk factors < 100 < 130 < 90 Moderate risk ≥ 2 risk factors and 10-year risk < 10% < 130 < 160 NR Low risk ≤ 1 risk factor < 160 <190 NR a Major independent risk factors are high low-density lipoprotein cholesterol, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure ≥ 140/90 mm Hg or on hypertensive medication), low high-density lipoprotein cholesterol (< 40 mg/dL), family history of coronary artery disease (in male, first-degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD) stage 3, 4, evidence of coronary artery calcification and age (men ≥ 45; women ≥ 55 years). Subtract 1 risk factor if the person has high high-density lipoprotein cholesterol . b Framingham risk scoring is applied to determine 10-year risk. c Coronary artery disease risk equivalents include diabetes and clinical manifestations of noncoronary forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease). AACE = American Association of Clinical Endocrinologists; Apo B = Apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CHD = coronary heart disease; CKD = chronic kidney disease; DM = diabetes mellitus; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; NR = not recommended. Jellinger PS, et al. Endocr Pract . 2017;23:1-87.

58. Which patients deserve Evolocumab?

59. How to Use? Method of administration Subcutaneous use Repatha is for subcutaneous injection into the abdomen, thigh or upper arm region. Injection sites should be rotated and injections should not be given into areas where the skin is tender, bruised, red, or hard. Repatha must not be administered intravenously or intramuscularly Repatha is intended for patient self-administration after proper training. Administration of Repatha can also be performed by an individual who has been trained to administer the product Each pre-filled pen is for single use only Upper arm Belly Thigh

60. Summary Back to Contents

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