New Strategies for Lowering LDL - Are They Really Worth It?

New Strategies for Lowering LDL - Are They Really Worth It? Gregg C. Fonarow, MD, FACC, FAHA, FHFSA Eliot Corday Professor of CV Medicine and Science Director, Ahmanson-UCLA Cardiomyopathy Center Co-Director, UCLA Preventative Cardiology Program Co-Chief, UCLA Division of Cardiology Los Angeles, California

Disclosures Consultant: Amgen, Novartis

Burden of Atherosclerotic Cardiovascular Disease: CAD, CVD, PVD With the Current Approach to Prevention and Treatment. Annual rates Myocardial infarction 1.2 million Strokes-715,000 CVD Mortality 1,344,185 (every 30 seconds a death) Cardiac catheterization 1.0 million Percutaneous revascularization 492,000 Surgical revascularization 291,000 Annual cost >$315 billion American Heart Association. 2016 Heart and Stroke Statistical Update. At: http://www.americanheart.org.

Why LDL-C Lowering is Paramount Courtesy of Alan Fogelman

LDL Level and Risk of Acute Coronary Events Relative Risk for CHD, Log Scale Log-Linear Relationship Between LDL-C Levels and Relative Risk for CHD 3.7 2.9 2.2 1.7 1.3 92% of patients with ACS have LDL < 160 mg/dl 77% of patients with ACS have LDL < 130 mg/dl 49% of patients with ACS have LDL < 100 mg/dl 1.0 40 70 100 130 160 190 LDL-C, mg/dl Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227 23 136,905 patients hospitalized with ACS Fonarow GC et al. Am Heart J 2009;157:111-7.e2

Statin Endpoint Clinical Trials: Reduction in Major Coronary Events Primary High Risk Secondary Trial N LDL 0 AF/TexCAPS 6605-27% WOS 6595-26% ASCOT 10305-26% HPS 20,536-29% 4S 4444-36% LIPID 9014-25% CARE 4159-28% Reduction (%) -20-40 -38* -31* -36-27 -38* -25* -25 *P<0.001; P=0.0005; P<0.0001; P=0.002. HPS Collaborative Group. Lancet. 2002;360:7-22; LaRosa et al. JAMA. 1999;282:2340-2346; Sever et al. Lancet. 2003;361:1149-1158.

Statin Effects on Major Vascular Events Endpoint Events (%) Treatment Control Rate Ratio (CI) Non-fatal MI 2001 (4 4) 2769 (6 2) 0 74 (0 70 0 79) CHD death 1548 (3 4) 1960 (4 4) 0 81 (0 75 0 87) Any major coronary event 3337 (7 4) 4420 (9 8) 0 77 (0 74 0 80) CABG 713 (3 3) 1006 (4 7) 0 75 (0 69 0 82) PTCA 510 (2 4) 658 (3 1) 0 79 (0 69 0 90) Unspecified 1397 (3 1) 1770 (3 9) 0 76 (0 69 0 84) Any coronary revascularisation 2620 (5 8) 3434 (7 6) 0 76 (0 73 0 80) Haemorrhagic stroke 105 (0 2) 99 (0 2) 1 05 (0 78 1 41) Presumed ischaemic stroke 1235 (2 8) 1518 (3 4) 0 81 (0 74 0 89) Any stroke 1340 (3 0) 1617 (3 7) 0 83 (0 78 0 88) Any major vascular event 6354 (14 1) 7994 (17 8) 0 79 (0 77 0 81) 0 5 1 0 1 5 Favors statin CTT. Lancet 2008 371: 117-125

Meta-Analysis of CV Outcomes Trials Comparing High vs Moderate Intensive Statin Therapy Reduction in Risk of Coronary Death or MI Odds Ratio (95% CI) Odds Reduction High Dose Event Rates No./Total (%) Std Dose PROVE IT- TIMI 22 A-to-Z -17% -15% 147/2099 (7.0) 205/2265 (9.1) 172/2063 (8.3) 235/2232 (10.5) TNT -21% 334/4995 (6.7) 418/5006 (8.3) IDEAL Total OR, 0.84 95% CI, 0.77-0.91 P=0.00003-12% -16% 411/4439 (9.3) 1097/13798 (8.0) 463/4449 (10.4) 1288/13750 (9.4).66 1 1.5 High-dose better High-dose worse Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:438-445.

Efficacy & Safety of Achieving LDL <50 mg/dl with Rosuvastatin in JUPITER Enrolled apparently healthy men (age 50 and above) and women (age 60 and above) with LDL <130 mg/dl without atherosclerosis or diabetes About half of JUPITER participants attained on-treatment LDL-C <50 mg/dl with rosuvastatin 20 mg (n=4154) In the group attaining LDL-C <50 mg/dl, rosuvastatin was associated with lower CV events and death when compared with placebo Major CV events 65% 0.35 (0.25-0.49) P<0.0001 MI/stroke/CV death 74% 0.26 (0.16-0.43) P<0.0001 All-cause mortality 46% 0.54 (0.37-0.78) P=0.004 Major CV events/vte/death 59% 0.41 (0.32-0.53) P<0.0001 Rates of adverse events and cancers were similar among rosuvastatin-treated subjects with and without LDL-C <50 mg/dl with those on placebo. New onset diabetes risk slightly higher. J Am Coll Cardiol 2011;57:1666-75

ACC/AHA Statin Benefit Groups Secondary Prevention Clinical ASCVD Age < 75: High-intensity statin Age > 75: Moderate-intensity statin Primary Prevention LDL-C > 190 mg/dl Diabetes Mellitus Age 40 75 with diabetes and LDL 70 189 mg/dl, Primary Prevention Age 40 75, > 7.5% 10-yr ASCVD risk High-intensity statin Low risk (10-yr risk < 7.5%): Moderateintensity statin High risk (10-yr risk > 7.5%): Highintensity statin Moderate or high intensity statin Stone NJ et al. Circulation. 2014;129:S1-45. Stone NJ et al. Circulation. 2014;129:S1-45.

We Haven t Yet Seen the Floor of LDL-C Lowering Benefits J Am Coll Cardiol 2014;64:485 94

IMPROVE IT Primary Endpoint Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR 0.936 CI (0.887, 0.988) p=0.016 Simva 34.7% 2742 events NNT= 50 EZ/Simva 32.7% 2572 events 7-year event rates

Safety of Achieving Ultra-Low LDL Among the 15,281 patients followed for 6 years of median f/u in IMPROVE-IT JAMA Cardiol. doi:10.1001/jamacardio.2017.0083

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) A secreted protein which targets the LDL receptor for degradation Gain of function mutations cause high LDL-C Loss of function mutations cause low LDL-C Inhibition lowers LDL-C levels Up-regulated by statin therapy

PCSK9 as a Target LDL Particle Apo B: acts as ligand binding LDL particle to receptor Liver cell X PCSK9: enzyme that targets the LDL receptor for degradation Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009.; Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795 1803. http://www.dls.ym.edu.tw/ol_biology2/ultranet/endocytosis.html.

PCSK9 Inhibitors Molecule Description Clinical Stage Alirocumab Fully human IgG1 mab 3* Evolocumab Fully human IgG1 mab 3* Bococizumab Humanized IgG1 mab 3 * FDA approved

Alirocumab: ODYSSEY LONGTERM Study Design Double-blind treatment (18 months) Patients with HeFH or high CV risk -on maximally tolerated statin -LDL-C > 70 mg/dl R Alirocumab 150 mg SC Q2W Placebo SC Q2W Robinson JG, et al. NEJM. March 15, 2015. doi:10.1056/nejmoa1501031.

Alirocumab (ODYSSEY LONGTERM) LDL-Cholesterol Levels Over Time (ITT) 140 Least-Squares Mean Calculated LDL-C Level (mg/dl) 120 100 80 60 40 20 0 0-61.0%* Placebo + statin therapy at maximum tolerated dose +/- LLT Alirocumab + statin therapy at maximum tolerated dose +/- LLT 4 8 12 16 24 36 52 64 78 Week -52.4%* Robinson JG, et al. NEJM. March 15, 2015

Alirocumab (ODYSSEY LONGTERM) Safety Analysis Summary of Adverse Events Alirocumab (n = 1,550) Placebo (n = 788) P Value Serious adverse event 290 (18.7%) 154 (19.5%) 0.66 Adverse event leading to discontinuation 111 (7.2%) 46 (5.8%) 0.26 Adverse event leading to death 8 (0.5%) 10 (1.3%) 0.08 General allergic reaction events 156 (0.1%) 75 (9.5%) 0.71 Treatment-related local injection site reactions 91 (5.9%) 33 (4.2%) 0.10 Neurologic events 65 (4.2%) 35 (4.4%) 0.83 Neurocognitive events 18 (1.2%) 4 (0.5%) 0.17 Robinson JG, et al. NEJM. March 15, 2015. doi:10.1056/nejmoa1501031.

Post Hoc Analysis of a Subgroup of Major Adverse Cardiovascular Events 1.0 0.8 0.06 Cumulative probability of event 0.6 0.4 0. 2 0.04 0.02 0.00 Cox model analysis HR = 0.52 (95% CI 0.31 to 0.90) Nominal P-value = <0.01 0 12 24 36 52 64 78 86 No. at Risk 0.0 0 12 24 36 52 64 78 86 Time (weeks) Placebo 788 776 731 700 670 653 644 597 Alirocumab 1550 1533 1445 1392 1342 1306 1266 1170 Placebo + statin therapy at maximum tolerated dose +/- LLT Alirocumab + statin therapy at maximum tolerated dose +/- LLT Robinson JG, et al. NEJM. March 15, 2015.

Evolocumab: OSLER LONGTERM Study Design Patients with HeFH, hyperlipidemia, statin intolerance or high CV risk on standard care -LDL-C > 75 mg/dl R N=1553 N=788 NO blinding; median follow up 11.1 months Evolocumab 140 mg SC Q2W or 420 mg SC Q 4W Standard care. (NO Placebo) Robinson JG, et al. NEJM. March 15, 2015. doi:10.1056/nejmoa1501031.

Evolocumab (OSLER-1 and OSLER-2): LDL Cholesterol Levels Over Time 140 LDL-Cholesterol (mg/dl) 120 100 80 60 40 20 Standard Therapy Evolocumab 0 Baseline 4 12 24 36 48 Weeks Sabatine MS, et al. NEJM March 15, 2015.

Evolocumab (OSLER-1 and OSLER-2) Incidence of Cardiovascular Events Sabatine MS, et al. NEJM March 15, 2015.

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: GLAGOV JAMA. doi:10.1001/jama.2016.16951

PCSK9 Outcome Studies ODYSSEY OUTCOMES Alirocumab Start October 2012 - Anticipated end early 2018 N= 18,000 FOURIER Evolocumab Start January 2013 Reported at ACC 2017 N= 22,500 SPIRE Bococizumab Start October 2013 Stopped early, Reported ACC 2017 N= 12,000

FOURIER Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks Sabatine MS et al. Am Heart J 2016;173:94-101

Efficacy Endpoints Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc Key secondary: CV death, MI or stroke Safety AEs/SAEs Events of interest incl. muscle-related, new-onset diabetes, neurocognitive Development of anti-evolocumab Ab (binding and neutralizing) TIMI Clinical Events Committee (CEC) Adjudicated all efficacy endpoints & new-onset diabetes Members unaware of treatment assignment & lipid levels Sabatine MS et al. Am Heart J 2016;173:94-101

Follow-up Randomized 27,564 patients Evolocumab (N=13,784) Placebo (N=13,780) Follow-up median 26 months (IQR 22-30) 2907 patients experienced primary endpoint 1829 experienced key secondary endpoint Premature perm. drug discontinuation 5.6%/yr 5.8%/yr Withdrew consent 0.29%/yr 0.35%/yr Lost to follow-up 5 patients 13 patients Ascertainment for primary endpoint was complete for 99.5% of potential patient-years of follow up NEJM 2017 DOI: 10.1056/NEJMoa1615664

Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs NEJM 2017 DOI: 10.1056/NEJMoa1615664 Pooled data; no differences between treatment arms

Lipid Lowering Therapy & Lipid Levels at Baseline Characteristic Statin use (%)* Value High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 (151-189) HDL-C 44 (37-53) Triglycerides 133 (100-182) *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. NEJM 2017 DOI: 10.1056/NEJMoa1615664 Pooled data; no differences between treatment arms

LDL Cholesterol 100 90 Placebo LDL Cholesterol (mg/dl) 80 70 60 50 40 30 20 10 59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% Hazard ratio 0.85 14.6% (95% CI, 0.79-0.92) P<0.0001 Placebo 12.6% Evolocumab 0% 0 6 12 18 24 30 36 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization NEJM 2017 DOI: 10.1056/NEJMoa1615664

Key Secondary Endpoint CV Death, MI, or Stroke 10% 9% 8% 7% 6% 5% 4% 3% Hazard ratio 0.80 (95% CI, 0.73-0.88) P<0.00001 Placebo Evolocumab 9.9% 7.9% 2% 1% 0% 0 6 12 18 24 30 36 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization

Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CVD, MI, stroke, UA, or revasc 12.6 14.6 0.85 (0.79-0.92) CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88) Cardiovascular death 2.5 2.4 1.05 (0.88-1.25) MI 4.4 6.3 0.73 (0.65-0.82) Stroke 2.2 2.6 0.79 (0.66-0.95) Hosp for unstable angina 2.2 2.3 0.99 (0.82-1.18) Coronary revasc 7.0 9.2 0.78 (0.71-0.86) Urgent 3.7 5.4 0.73 (0.64-0.83) Elective 3.9 4.6 0.83 (0.73-0.95) Death from any cause 4.8 4.3 1.04 (0.91-1.19) NEJM 2017 DOI: 10.1056/NEJMoa1615664

Key Subgroups Subgroup Patients Overall 27564 Type of disease MI alone 19113 Stroke alone 3366 PAD alone 1505 Polyvascular disease 3563 Baseline LDL-C Q1 (<80 mg/dl) 6961 Q2 (80-<92 mg/dl) 6886 Q3 (92-109 mg/dl) 6887 Q4 (>109 mg/dl) 6829 Baseline statin intensity High 19103 Not high 8461 Ezetimibe Yes 1440 No 26124 Initial Dosing Regimen Every 2 weeks 24774 Monthly 2790 PEP HR (95% CI) Key SEP HR (95% CI) All P interactions NS An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School 0.4 1.0 2.5 0.4 1.0 2.5 EvoMab better Pbo better EvoMab better Pbo better

Subgroups

Comparison to Cholesterol Treatment Trialists Collaboration Hazard Ratio (95% CI) per 1 mmol/l reduction in LDL-C Major Coronary Events 0.78 (0.70-0.86) 0.80 (0.71-0.90) Stroke Coronary revascularization Urgent Elective 0.77 (0.66-0.91) 0.77 (0.63-0.94) 0.75 (0.67-0.84) 0.73 (0.62-0.86) 0.84 (0.73-0.98) CTTC Meta-analysis Year 2 FOURIER Year 2 Major Vascular Events 0.77 (0.73-0.82) 0.83 (0.76-0.90) 0.5 Lipid-lowering therapy better 1.0 Lipid-lowering therapy worse 2.0 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School CTTC data from Lancet 2010;376:1670-81

Lower LDL-C Is Better Patients divided by quartile of baseline LDL-C and by treatment arm P<0.0001 Q4 Q3 Q3 Q4 Q1 Q2 Q1 Q2 Placebo Evolocumab

Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any 77.4 77.4 Serious 24.8 24.7 Allergic reaction 3.1 2.9 Injection-site reaction 2.1 1.6 Treatment-related and led to d/c of study drug 1.6 1.5 Muscle-related 5.0 4.8 Cataract 1.7 1.8 Diabetes (new-onset) 8.1 7.7 Neurocognitive 1.6 1.5 Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC NEJM 2017 DOI: 10.1056/NEJMoa1615664

Summary for Evolocumab LDL-C by 59% Consistent throughout duration of trial Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl) CV outcomes in patients already on statin therapy 15% broad primary endpoint; 20% CV death, MI, or stroke Consistent benefit, incl. in those on high-intensity statin, low LDL-C 25% reduction in CV death, MI, or stroke after 1 st year Long-term benefits consistent w/ statins per mmol/l LDL-C Safe and well-tolerated Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo Rates of EvoMab discontinuation low and no greater than pbo No neutralizing antibodies developed NEJM 2017 DOI: 10.1056/NEJMoa1615664

At its current list price of $14 523, the addition of evolocumab to standard background therapy in patients with atherosclerotic cardiovascular disease exceeds generally accepted costeffectiveness thresholds. To achieve an ICER of $150 000 per QALY, the annual net price would need to be substantially lower ($9669 for US clinical practice and $6780 for trial participants), or a higher-risk population would need to be treated.

Potential Population Benefits with Optimal Implementation Adding a PCSK9 inhibitor to maximally tolerated statin therapy in patients with established ASCVD is estimated to be able to result in 316,300 fewer major adverse cardiovascular events over the next 5 years. Substantial population health improvements and further progress toward reduction in noncommunicable diseases could result. However, costs is a major concern. Targeting a subset of patients with ASCVD who are at particularly high risk for events based on clinical factors, formal risk scores, or use of a higher LDL cholesterol treatment initiation threshold for the addition of PCSK9 inhibitor therapy would be approaches to improve value and limit expenditures.

Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol: ORION-1 Inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, administered SQ every 3 or 6 months N Engl J Med 2017; 376:1430-1440

Conclusions All patients with or at risk for cardiovascular disease should receive statin therapy, unless contraindicated LDL-C reduction is the primary goal of lipid therapy LDL-C levels can now be safely and effectively driven to historic lows with PCSK9 inhibitors Risk based treatment algorithms have a role but LDL-C targets and % LDL reduction should also return (LDL-C < 40 mg/dl is a reasonable secondary prevention goal) HDL-C raising is NOT a goal. Improving implementation and adherence to therapy is key to improving outcomes