Prevention 2014: PCSK9 Inhibitors

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Matthew T. Roe, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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  • PurposeTo review findings of 2 population studies on the beneficial effects of loss-of-function proproteinconvertasesubtilisin/kexin Type 9 (PCSK9) mutations on low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular outcomes.Take-AwaySubjects with loss-of-function mutations in PCSK9 or total lack of PCSK9 have naturally low levels of LDL-C and reduced risk of coronary heart disease (CHD). These patients are also generally healthy with no other apparent metabolic abnormalities.
  • PurposeTo review the dynamic relationship between alirocumab concentration and free proprotein convertase subtilisin/kexin Type 9 (PCSK9) and low-density lipoprotein cholesterol (LDL-C) levels.Take-AwayThe blue curve shows the close relationship between suppression of free PCSK9 and LDL-C reductions following a single subcutaneous (SC) infusion alirocumab150 mg.
  • PurposeTo review the design of the phase 2 study investigating the safety and efficacy of alirocumab in patients with primary hypercholesterolemia on stable atorvastatin therapy.Take-AwayPatients were randomized into 1 of 6 treatment groups: placebo every other week (Q2W); alirocumab 50, 10, or 150 mg every other week; or alirocumab 200 or 300 mg every 4 weeks (Q4W) alternating with placebo Q4W.Patients were treated for 12 weeks and were followed up for 8 weeks after that. The primary endpoint was percent change in low-density lipoprotein cholesterol (LDL-C) levels from baseline at Week 12.Dose ranging study
  • PurposeTo review the evolution of the main measure over 12 weeks in the phase 2 study investigating the safety and efficacy of alirocumab in patients with primary hypercholesterolemia on stable atorvastatin therapy.Take-AwayThe percent decrease in low-density lipoprotein cholesterol (LDL-C) levels from baseline to Week 12 was lowest in the placebo group and highest in the biweekly alirocumab groups receiving the 100-mg and 150-mg doses.LDL-C reduction in the placebo group reached a maximum at Week 6, after which LDL-C rose again up to Week 12. In the bi-weekly alirocumab groups, LDL-C decreased significantly from baseline at 2 weeks with further reductions reaching at week 12.
  • PurposeTo summarize the findings of the phase 2 study investigating the safety and efficacy of alirocumab in patients with primary hypercholesterolemia on stable atorvastatin therapy.Take-AwayAlirocumab produced significant, dose-dependent, low-density lipoprotein cholesterol (LDL-C) reductions in patients with primary hypercholesterolemia on stable atorvastatin therapy. Bi-weekly regimens showed more sustained efficacy compared with every-4-week regimens.Alirocumab also had robust beneficial effects for all other apolipoprotein (Apo)-based lipoproteins. The effect on triglycerides was minimal, and trends towards increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 were observed compared with placebo.Overall, alirocumab was well tolerated over 20 weeks of follow-up.
  • PurposeTo present a summary of the ODYSSEY phase 3 clinical trial program.Take-Away14 global phase 3 trials that include more than 23,500 patients across more than 2000 study centers comprise the ODYSSEY Phase 3 clinical trial program.
  • PurposeTo present a summary of the ODYSSEY OUTCOMES study design.Take-AwayODYSSEY OUTCOMES is a double-blind, placebo-controlled, 64-week study.Treatment groups include alirocumab versus placebo post acute coronary syndrome.The primary endpoint is a composite of CHD death, non-fatal MI, ischemic stroke, and high-risk UA requiring hospitalization.
  • Prevention 2014: PCSK9 Inhibitors

    1. 1. PCSK9 Inhibitors Matthew T. Roe, MD, MHS
    2. 2. LARGE SCALE Amgen is preparing three sites, including a 75-acre plant in Rhode Island, to make a cholesterol drug if production is approved. Her cholesterol was astoundingly low. Her low- density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard- of in healthy adults, whose normal level is over 100. The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation. The discovery of the mutation and of the two women with their dazzlingly low LDL levels has set off one of the greatest medical chases ever. It is a fevered race among three pharmaceutical companies, Amgen, Pfizer and Sanofi. By GINA KOLATA Published: July 9, 2013 She was a 32-year-old aerobics instructor from a Dallas suburb — healthy, college educated, with two young children. Nothing out of the ordinary, except one thing.
    3. 3. Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK9) • PCSK9 plays pivotal role in LDL cholesterol (LDL-C) metabolism − Serine protease expressed by liver and intestine − Promotes intracellular degradation of LDL receptor (LDLR) − Prevents LDLR recycling to the cell surface − Reduces LDLR population on cell surface − Reduces clearance of LDL from circulation Lambert et al Atherosclerosis 2009;203:1–7 Lambert et al J Lipid Res 2012;53:2515-24
    4. 4. LDL Receptor Function and Life Cycle 1 2 3 4 5 1. Serum levels of LDL-C are controlled by hepatic LDL receptors (LDLR) 2. LDLR mediates uptake of LDL by binding to its surface apolipoprotein B-100 moiety • receptor also recognizes apolipoprotein E found in chylomicron and VLDL remnants 3. LDLR are present in pits on the cell surface. When LDL is bound, the pits pinch off to form vesicles inside the cell (endocytosis) • Endocytosis allows LDL particles to be internalized rather than diffusing into cell membrane 4. Internalized vesicle fuses with an acidic endosome  conformational change releases the LDL particle 5. LDLR is recycled back to the cell surface where the neutral pH causes it to revert to its native conformation, ready to receive another LDL particle
    5. 5. Role of PCSK9 in regulation of LDL receptor 1 2 3 4 1. In the hepatocyte, PCSK9 undergoes obligatory autocatalytic cleavage in the endoplasmic reticulum and is secreted into the bloodstream 2. Secreted PCSK9 binds to the LDL receptor (LDLR) on the cell surface 3. When an LDL particle binds to the LDLR in the presence of PCSK9, the entire endosomal content, including the LDLR, undergoes lysosomal degradation 4. Recycling of the LDLR to the cell surface is prevented Cell surface population of LDLR is diminished LDL clearance from the circulation is reduced
    6. 6. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. Population Studies PCSK9 Loss-of-Function Mutations 6 ARIC=Atherosclerosis Risk in the Community; CCHS=Copenhagen City Heart Study; CGPS=Copenhagen General Population Study; CIHDS=Copenhagen Ischemic Heart Disease Study; LDL-C=low-density lipoprotein cholesterol. Cohen JC et al. N Engl J Med. 2006;354:1264-1272; Benn M et al. J Am Coll Cardiol. 2010; 55:2833-2842; Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18-28. PCSK9 Mutation LDL-C Reduction CHD Reduction Population Benn et al. JACC. 2010 R46L 13% 30% CCHS N=10,032 CGPS N=26,013 CIHDS N=9654 (Denmark) Cohen et al. NEJM. 2006 R46L Y142X Or C679X 15% 28% 47% 88% ARIC Study (US) (Black patients N=3363; White patients N=9524)  Subjects with loss-of- function mutations in PCSK9 or total lack of PCSK9 – Have naturally low levels of LDL-C and reduced Coronary Heart Disease ( efficacy) – Are generally healthy with no other apparent metabolic abnormalities ( safety)
    7. 7. Effects of statins and other lipid-modifying therapies on PCSK9 • Statins increase LDLR expression and density on cell surface • PCSK9 levels increase as a feedback response to statin treatment, rising by 10%-50% • Fenofibrate and ezetimibe may also significantly increase PCSK9 levels Konrad et al Lipids Health Dis 2011;10:38
    8. 8. • Upregulation of PCSK9 in response to statin therapy may attenuate the LDL-C reduction produced by statins • PCSK9 inhibition with an anti-PCSK9 monoclonal antibody could potentially modify this barrier which limits efficacy of statins and other lipid-modifying therapies Effects of statins on PCSK9
    9. 9. Impact of PCSK9 monoclonal antibody on LDL receptor Alirocumab Evolocumab Bococizumab *1 1. Monoclonal antibody neutralizes the secreted PCSK9 molecule, rendering it unable to bind to the LDL-receptor (LDLR) 2 2. LDL particle binds to the LDLR in the absence of PCSK93. LDL/LDLR complex undergoes endocytosis 3 4 4. Under acidic conditions of the endosome, the LDL/LDLR complex dissociates. LDL undergoes lysosomal degradation, LDLR is released 5. Thus, PCSK9 antibody acts to increase LDLR density on the surface of hepatocytes, and thereby decrease levels of LDL-C in the circulation 5
    10. 10. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. Alirocumab: Dynamic Relationship Between mAb Levels, PCSK9, and LDL-C -70 -60 -50 -40 -30 -20 -10 0 0 20 40 60 80 100 120 140 160 180 200 0 500 1000 1500 2000 2500 LDL-Cmean%change Free/TotalPCSK9Conc.(ng/mL) TotalAlirocumab(ng/mL)X0.01 Time (hours) Free PCSK9, Total Alirocumab Concentration and Mean % Change LDL-C vs Time free PCSK9 LDL-cTotal Alirocumab 10 4LDL=low-density lipoprotein cholesterol; mAb=monoclonal antibody; PCSK9=proprotein convertase subtilisin/kinexin type 9. 4Regeneron Data on File.
    11. 11. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. Study Study Population Design Treatment Period Number of patients Primary Endpoint DFI115651 (NCT-01288443) HC patients on atorvastatin 10, 20, or 40 mg/day R, DB, PC, PG 12 weeks N=183 % change LDL-C at 12 weeks R727-CL-10032 (NCT-01266876) HeFH patients R, DB, PC 12 weeks N=77 % change LDL-C at 12 weeks DFI115663 (NCT-01288469) HC patients on atorvastatin 10 mg/day R, DB, PC, PG 8 weeks N=92 % change LDL-C at 8 weeks Overview of Alirocumab Phase 2 Studies HC=hypercholesterolemic; R=randomized; DB=double-blind; PC=placebo-controlled; PG=parallel-group 1. McKenney JM et al. J Am Coll Cardiol. 2012;59:2344-2353. 2. Stein EA et al. Lancet. 2012;380:29-36. 3. Roth EM et al. N Engl J Med. 2012;367:1891-1900. 11
    12. 12. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. Study Design LDL-C ≥100 mg/dL at Week 1 while taking atorva 10, 20, or 40 mg for ≥6 weeks Placebo Q2W W-7 V1a Alirocumab 50 mg Q2W Alirocumab 100 mg Q2W Alirocumab 150 mg Q2W Alirocumab 200 mg Q4W w/alt placebo Alirocumab 300 mg Q4W w/alt placebo N=31 N=30 N=31 N=31 N=30 N=30 Diet* *NCEP ATPIII TLC or equivalent diet Treatment Period (12 weeks) Follow-up Period (8 weeks) W-1 V1 W0 V2 W2 V3 W4 V4 W6 V5 W8 V6 W10 V7 W12 V8 W16 V9 W20 V10 Screening Period (7 weeks) Primary Endpoint % change in LDL-C from baseline to week 12 Secondary Endpoints % change in other lipoproteins and apolipoproteins and % patients reaching pre-specified LDL-C levels 12 Q2W=every other week; Q4W=every 4 weeks. McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353.
    13. 13. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. PCSK9-041812000 Alirocumab 150 mg Q2WAlirocumab 50 mg Q2W Alirocumab 100 mg Q2W 13 McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353.
    14. 14. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc.  Alirocumab produced significant, dose-dependent LDL-C reductions – Up to 72% LDL-C reduction with 150 mg Q2W – LDL-C reductions were generally unaffected by baseline atorvastatin dose  More sustained efficacy with Q2W versus Q4W regimen  Consistent and robust reductions for all other Apo B-containing lipoproteins – Important reduction in Lp(a), consistent with prior studies  Minimal effect on TG, and trend towards increased HDL-C and Apo A1 versus placebo  Alirocumab was well tolerated during this short study – No signals for persistent or prevalent clinical or laboratory adverse events including hepatic and muscle assessments – One patient experienced an occurrence of leukocytoclastic vasculitis; no similar reactions reported in prior studies  These results support further evaluation of alirocumab in larger, more diverse patient populations with different background therapies to fully assess its efficacy and safety Summary and Conclusions 14 Apo=apolipoprotein; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; Lp=lipoprotein; Q2W=every other week; Q4W=every 4 weeks. McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353.
    15. 15. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. Overview of ODYSSEY Phase 3 Clinical Trial Program 4ODYSSEY FH II (NCT01709500; CL1112) 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=250; 18 months 14 global phase 3 trials including >23,500 patients across >2,000 study centers 4HeFH population 4HC in high CV risk population 4Additional populations 4ODYSSEY HIGH FH (NCT01617655; EFC12732) 4LDL-C ≥160 mg/dL 4N=105; 18 months 4ODYSSEY ALTERNATIVE (NCT01709513; CL1119) 4Patients with defined statin intolerance 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=250; 6 months 4ODYSSEY OPTIONS II (NCT01730053; CL1118) 4Patients not at goal on moderate dose rosuvastatin 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=300; 6 months 4ODYSSEY MONO (NCT01644474; EFC11716) 4Patients on no background LMTs 4LDL-C ≥100 mg/dL 4N=100; 6 months 4ODYSSEY OPTIONS I (NCT01730040; CL1110) 4Patients not at goal on moderate dose atorvastatin 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=350; 6 months 4ODYSSEY COMBO I (NCT01644175; EFC11568) 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=306; 12 months 4ODYSSEY FH I (NCT01623115; EFC12492) 4LDL-C ≥ 70 mg/dL OR LDL-C ≥100 mg/dL 4N=471; 18 months 4ODYSSEY LONG TERM (NCT01507831; LTS11717) 4LDL-C ≥70 mg/dL 4N=2,100; 18 months 4ODYSSEY OUTCOMES (NCT01663402; EFC11570) 4LDL-C ≥70 mg/dL 4N=18,000; 64 months 4Add-on to max-tolerated statin 4(± other LMT) 4Add-on to max-tolerated statin 4(± other LMT) 4*ODYSSEY COMBO II (NCT01644188; EFC11569) 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=660; 24 months 4FH=familial hypercholesterolemia; HC=hypercholesterolemia; LMT=lipid-modifying therapy; OLE=open-label extension. 4*For the ODYSSEY COMBO II other LMT not allowed at entry. 4ClinicalTrials.gov. ODYSSEY Phase 3 Trials. http://clinicaltrials.gov. Accessed February 12, 2014. 15 4ODYSSEY CHOICE I (NCT01926782; CL1308) 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL N=700; 12 months 4ODYSSEY CHOICE II (NCT02023879; EFC13786) 4Patients not treated with a statin 4LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL 4N=200; 6 months 4ODYSSEY OLE (NCT01954394; LTS 13463) 4Open-label study for FH from EFC 12492, CL 1112, EFC 12732 or LTS 11717 4N≥1000; 30 months
    16. 16. CONFIDENTIAL – NOT FOR PROMOTIONAL USE – DO NOT COPY OR DISTRIBUTE ©2014, Regeneron Pharmaceuticals, Inc. ODYSSEY OUTCOMES – Study Design 4Population • Patients 4–52 weeks post- ACS 4LDL-C at Entry • ≥70 mg/dL (1.81 mmol/L) 4Primary Endpoint • Composite of – CHD death – Non-fatal MI – Ischemic stroke – High-risk UA requiring hospitalization 4ACS=acute coronary syndrome; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; MI=myocardial infarction; Q2W=every other week; SC=subcutaneous; TLC=therapeutic lifestyle changes; UA=unstable angina. 4*75 mg SC Q2W with titration (as necessary) to 150 mg SC Q2W, if LDL-C ≥50 mg/dL (1.29 mmol/L). 4ClinicalTrials.gov. ODYSSEY OUTCOMES Study. http://clinicaltrials.gov/ct2/show/NCT01663402. Accessed February 12, 2014. 4Double-Blind Treatment Period (64 Weeks) 4n=9000 4n=9000 4R 4Placebo SC 4Run-in 4Screening visit 4Injection training visit 4NCEP-ATPIII TLC diet or equivalent 4Alirocumab SC* 4Patients on maximum tolerated potent statins 4atorvastatin 40–80 mg or rosuvastatin 20–40 mg 16
    17. 17. Confidential and proprietary – Do not distribute – For internal discussion only 0 20 40 60 80 100 120 140 160 0 4 8 12 16 20 24 LSmean(SE)LDL-C,mg/dL mITT Alirocumab 75/150 mg Q2W mITT Ezetimibe 10 mg QD ODYSSEY MONO: Change in LDL-C levels ITT and mITT population Week 14 patients in the alirocumab group were automatically up-titrated in a blinded manner at Week 12 from 75 mg to 150 mg Q2W. However, a threshold for up- titration of 70 mg/dL instead of 100 mg/dL was programmed incorrectly. Among the 14 patients who have been up-titrated, only 1 patient was eligible for up- titration as per protocol. Sensitivity analyses were performed mITT population analysis, all LDL-C values obtained on-treatment. Values above Week 12 and Week 24 data points indicate LS mean (SE) % change from baseline mITT: –20.4 (2.0) % mITT: –17.2 (2.0) % mITT: –53.2 (2.0) % mITT: –54.1 (2.0) % ITT: –15.6 (3.1) %ITT: –19.2 (2.6) % ITT: –47.2 (3.0) %ITT: –48.1 (2.6) % Difference vs ezetimibe ITT: –31.6 (4.32) % mITT: -36.9 (2.89)% P<0.0001 ITT Alirocumab 75/150 mg Q2W ITT Ezetimibe 10 mg QD
    18. 18. Confidential and proprietary – Do not distribute – For internal discussion only ●Baseline characteristics and lipid parameters were similar across treatment groups –Higher BMI observed in the alirocumab group as compared to the eze group –Mean (SD) baseline LDL-C was 139.7(25.8) mg/dL ● Efficacy results (ITT and sensitivity analysis): –At W12, prior to alirocumab up-titration, statistical significance already reached •LS mean values of -48.1% and -19.6%, for alirocumab and eze respectively, LS mean difference of -28.5%; p <0.0001 –Apo B, non-HDL-C and Total-C % change from baseline at W24 and W12 also showed significant reduction but not Lp(a), HDL, nor TG ●Alirocumab was well tolerated during the 24-week treatment period –Number of patients reporting at least one TEAE was comparable in both groups. –No particular signal was detected for TEAEs related to allergic events LS mean % change in LDL-C from baseline to Week 24 Ezetimibe Alirocumab ITT population –15.6 (3.1) –47.2 (3.0) LS mean difference of -31.6%; p < 0.0001 ITT population excluding 13 of 14 patients up-titrated -15.61 (3.19) -44.31 (3.38) mITT population -17.17 (2.04) -54.10 (2.04) Summary for ODYSSEY MONO
    19. 19. Confidential and proprietary – Do not distribute – For internal discussion only
    20. 20. Confidential and proprietary – Do not distribute – For internal discussion only
    21. 21. Confidential and proprietary – Do not distribute – For internal discussion only
    22. 22. Confidential and proprietary – Do not distribute – For internal discussion only
    23. 23. Confidential and proprietary – Do not distribute – For internal discussion only
    24. 24. Confidential and proprietary – Do not distribute – For internal discussion only
    25. 25. Confidential and proprietary – Do not distribute – For internal discussion only
    26. 26. Confidential and proprietary – Do not distribute – For internal discussion only
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    28. 28. Confidential and proprietary – Do not distribute – For internal discussion only
    29. 29. Confidential and proprietary – Do not distribute – For internal discussion only CV Outcomes Trials for PCSK9 inhibitors FOURIER - Evolocumab - AMGEN SPIRE I / II - Bococizumab PFIZER ODYSSEY OUTCOMES-Alirocumab SANOFI/REGENERON Timelines • Start: Jan 2013 • End: Feb 2018 • Start: October 2013 • End: August 2017 • Start: October 2012 • End: March 2018 Patients type included History of clinically evident cardiovascular disease (MI, stroke, symptomatic PAD) at high risk for a recurrent event High risk subjects of a CV event receiving background lipid lowering therapy ACS within the last 4 to 52 weeks Lipid parameters at entry (mg/dL) LDL-C ≥70 or non-HDL ≥100 SPIRE I: LDL-C ≥ 70 and <100 or non-HDL-C > 100 and < 130 SPIRE II: LDL-C ≥ 100 mg/dL or non-HDL-C ≥ 130 mg/dL LDL-C ≥ 70 or non-HDL ≥100 or ApoB ≥80 Statin/ LMT dose regimen atorva 20 to 80 mg (or an equivalent statin) Not specified atorva 40-80 mg or rosuva 20-40 mg Total number of patients 22,500 (including 9000 ≥ 65 y) SPIRE I: 12,000 SPIRE 2: 6,300 18,000 Primary Endpoint • CV death, MI, hospitalization for unstable angina, stroke, or coronary revascularization • CV death, non fatal MI, non fatal stroke, or hospitalization for unstable angina needing urgent revascularization • CHD death, MI, stroke or unstable angina Dosing regimen or doses 140 Q2W (1 ml pen) or 420 QM (3 x 1ml pen or 3.5ml via personal injector (9’ injection time) 150 mg Q2W 75mg or 150mg Q2W 4| 29
    30. 30. 4All Rights Reserved, Duke Medicine 2007 PCSK9 Inhibitors • PCSK9 inhibitors hold great promise for lipid treatment in the near future • Dramatic lowering of LDL levels – with or without statins • Cardiovascular outcomes trials ongoing for the combination of PCSK9 inhibitors + statins • Impact of much lower LDL targets to be determined • Treatment paradigm of long-term use of injectable monoclonal antibodies for lipid lowering represents a significant shift in secondary prevention for CV disease • Cost, compliance, tolerance, and safety

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