Novel Therapeutic Strategies in Lipid Management: Lowering LDL C to Improve Patient Outcomes

Novel Therapeutic Strategies in Lipid Management: Lowering LDL C to Improve Patient Outcomes Rajat Deo, MD, MTR Assistant Professor of Medicine Division of Cardiology University of Pennsylvania April 25, 2014 Disclosures None 1

Objectives The new cholesterol guidelines Unmet needs for CV risk reduction in setting of optimal statin based management Current challenges and limitations to treatment strategies for reaching recommended LDL C goals Efficacy and safety data for novel therapeutic agents targeting LDL C reduction (including PCSK9 inhibitors) The Role of Lipoproteins in Atherogenesis HDL High plasma LDL Endothelial injury LDL + VLDL Liver Cholesterol excreted LCAT APO-A1 APO-A1=Apolipoprotein A1, HDL=High density lipoprotein, LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein, PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein LDL infiltration into intima Oxidative modification of LDL + Macrophages Foam cells Fatty streak Other growth factors Adherence of platelets Release of PDGF Advanced fibrocalcific lesion 2

CHD Risk According to LDL-C Level 3.7 Relative Risk for Coronary Heart Disease (Log Scale) 2.9 2.2 1.7 1.3 1.0 40 70 100 130 160 190 LDL-Cholesterol (mg/dl) CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol Grundy S et al. Circulation 2004;110:227-39 Therapies to Lower LDL-C Class 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins] Bile acid sequestrants Cholesterol absorption inhibitor Nicotinic acid Dietary Adjuncts Drug(s) Atorvastatin (Lipitor) Fluvastatin (Lescol XL) Lovastatin (generic and Mevacor) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Cholestyramine (generic and Questran) Colesevelam (Welchol) Colestipol (Colestid) Ezetimibe (Zetia) Niacin Soluble fiber Soy protein Stanol esters 3

HMG-CoA Reductase Inhibitor: Mechanism of Action Inhibition of the Cholesterol Biosynthetic Pathway HMG-CoA Reductase Squalene synthase Dolichol Acetyl CoA HMG- CoA Mevalonate Farnesyl pyrophosphate Squalene Cholesterol Farnesylated proteins Farnesyltransferase E,E,E- Geranylgeranyl pyrophosphate Geranylgeranylated proteins Ubiquinones HMG-CoA Reductase Inhibitor: Mechanism of Action Cholesterol synthesis LDL receptor (B E receptor) synthesis Apo B VLDL R Apo E VLDL LDL-R mediated hepatic uptake of LDL and VLDL remnants Intracellular Cholesterol LDL Apo B Serum LDL-C Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-hdl particles from the systemic circulation 4

HMG-CoA Reductase Inhibitor: Dose-Dependent Effect The Rule of 6 s Lovastatin 20/80 28 12 Pravastatin 20/40 27 6 Simvastatin 20/80 35 12 Fluvastatin 20/80 19 12 Atorvastatin 10/80 37 18 0 10 20 30 40 50 60 Reduction of LDL Cholesterol (%) - Recommended starting dose: 19-37% LDL reduction - Doubling of dose produces an additional 6% reduction - Titration to max dose resuts in mean reduction 31 51% Illingworth DR. Med Clin North Am 2000;84:23-42 The New Cholesterol Guidelines 5

Expert Panel 5-year collaborative effort between a diverse set of expert reviewers Reviewers assessed evidence from randomized controlled trials (RCTs), as well as meta-analyses and systematic reviews of RCTs Highlights of 2013 Guidelines New Pooled Cohort Equations for atherosclerotic cardiovascular disease (ASCVD) risk assessment Stroke now included in ASCVD risk assessment, in addition to myocardial infarction (MI) Separate equations for nonwhite populations Statin therapy recommended in 4 groups: 1. Adults with clinical ASCVD 2. Adults with LDL-C 190 mg/dl 3. Adults 40 to 75 years of age with diabetes 4. Adults 7.5% estimated 10-year risk of ASCVD No LDL-C or non-hdl-c treatment targets 6

Pooled Cohort Equations for Risk Assessment Equations predict 10-year risk of stroke & myocardial infarction Former guidelines focused only on heart attacks Highlights the large burden of disability from nonfatal events Separate equations for nonwhite populations Importance of race/ethnicity in risk of ASCVD Primary Prevention: Central Role of Statin Therapy Statin therapy recommended for primary prevention of ASCVD Based on RCTs, statins reduce morbidity and mortality associated with ASCVD Cost-effective: many statins are now generic Lifestyle modification also critical to primary prevention efforts DASH-like diet: high in fruits, vegetables, fish, and low in sweets, red meat, and sodium Regular moderate to vigorous physical activity 7

Statin Therapy Recommended in Four Groups 1. Individuals with known ASCVD, without Class II-IV heart failure or receiving hemodialysis 2. Individuals with LDL-C 190 mg/dl 3. Individuals 40 to 75 years of age with diabetes and LDL-C 70-189 mg/dl 4. Individuals 40 to 75 years of age with estimated 10-year ASCVD risk 7.5% and LDL-C 70-189 mg/dl Treatment Threshold: 7.5% Lowered from former threshold of 20% risk of MI over 10 years or > 10% with multiple risk factors Based on NHANES data: Men 50% of all African-American men and 30% white men in 50 s Almost all men in 70 s Women 70% African-American women and 60% white women in 60 s 8

What about individuals of intermediate risk (<7.5% ASCVD risk)? Optional additional risk measurement tools to refine predicted risk Family history of premature ASCVD? High-sensitivity CRP Coronary artery calcium Ankle brachial Indices (ABI) No Cholesterol Treatment Target Goals Appropriate intensity of statin therapy is recommended to reduce the risk of ASCVD by lowering LDL-C and non- HDL-C Treat to target and lower is best strategies are no longer advocated More clinical trials needed 9

Algorithm for Risk Assessment: Evaluation of ASCVD Risk Medical history, family history Symptoms of CVD Physical examination, including blood pressure, body mass index (BMI), waist circumference Laboratory tests, including cholesterol and glucose measurements 2013 Pooled Cohort Equation risk score Is the Patient at High Risk of ASCVD? High-risk defined as 1 of the following: Clinically established coronary heart disease Cerebrovascular disease Peripheral arterial disease Abdominal aortic aneurysm Diabetes mellitus Chronic kidney disease 10-year predicted ASCVD risk 7.5% by Pooled Cohort Equation 10

Yes: Patient is at High-Risk of ASCVD Implement treatment recommendations: A Aspirin / Antiplatelet therapy B Blood pressure control C Cholesterol control /Cigarette smoking cessation D Diet and weight management / Diabetes and blood sugar control E Exercise No: Patient is NOT at High- Risk Is the patient at intermediate risk of ASCVD? Intermediate-risk defined as 5% to 7.5% 10-year ASCVD risk by Pooled Cohort Equation 11

Yes: Patient is at Intermediate Risk of ASCVD Consider additional testing to further assess risk: CT scan for coronary artery calcium (CAC) score Measure high-sensitivity C-reactive protein (hscrp) Do additional tests indicate that patient may benefit from treatment because they are really at higher risk? Yes: Intermediate-Risk Patient May Benefit from Treatment Implement treatment recommendations: A Aspirin / Antiplatelet therapy B Blood pressure control C Cholesterol control / Cigarette smoking cessation D Diet and weight management / Diabetes and blood sugar control E Exercise 12

No: Patient NOT at Intermediate Risk of ASCVD or No: Additional Tests Do NOT Indicate Intermediate-Risk Patient May Benefit from Treatment Does the patient have a family history of premature heart disease? Premature heart disease defined as a firstdegree relative <55 years for men and <65 years for women Yes: Patient Has a Family History of Premature Heart Disease Implement treatment recommendations: A Aspirin / Antiplatelet therapy B Blood pressure control C Cholesterol control / Cigarette smoking cessation D Diet and weight management / Diabetes and blood sugar control E exercise 13

No: Patient Does NOT Have Family History of Premature Heart Disease Reassess the patient every five years or sooner if he/she has a change in risk factors. For ALL Patients Regardless of Risk Factors Implement lifestyle recommendations: DASH-like diet Physical activity Weight management Complete smoking cessation 14

3 Genes Affecting LDL Clearance Can Cause FH 1000+ Mutations Identified to Date LDL particle APOB (6 mutations identified) Codes for production of ligand protein, ApoB, which connects LDL particle to receptor Circulation Liver cell LDLR (>1000 mutations) codes for LDL receptor which binds to ApoB on LDL particle inducing endocytosis of LDL PCSK9 (8 GOF mutations identified to date) codes for PCSK9 enzyme, which degrades the LDL receptor 29 Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. Normally, LDL Receptors on hepatocytes help to clear LDL Particles from plasma LDL particle Circulation Liver cell 30 Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. 15

LDL Receptor (LDLR) Mutations Alter LDL Receptors, Preventing Attachment to Particle LDL particle ApoB LDL receptor LDL receptor binding site impaired function prevents binding to LDL particle Normal FH: LDLR- 31 Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. PCSK9 Mutations Increase Degradation of LDL Receptors, Limiting Binding and Endocytosis LDL particle ApoB LDL receptor PCSK9 Normal LDL receptors degraded at a faster rate by increased PCSK9 activity FH: PCSK9+ 32 Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. 16

PCSK9 Inhibitors Traditional statin based therapies still has a less than desired benefit in optimizing CV risk reduction Monoclonal antibodies to PCSK9 great interest Completion of Phase 2 studies Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized, Placebo-controlled Study Presented at the American College of Cardiology March 29, 2014 Washington DC Published March 29, 2014 in NEJM 17

Background: PCSK9 Inhibition PCSK9 is a well validated therapeutic target based on gain and loss of function human genetic abnormalities, Mendelian randomization studies, and its recently elucidated role in LDL receptor function and regulation of LDL cholesterol. Evolocumab (AMG 145), a fully human monoclonal antibody against PCSK9, reduced LDL-C by up to 65% and was well tolerated in 4 randomized, placebo-controlled, phase 2 clinical trials of 12 weeks duration in over 1300 hypercholesterolemic patients. 1-4 An open label extension study of patients from phase 2 trials with evolocumab (OSLER) recently reported 1 year safety and efficacy data. 5 1. Lancet. 2012;380:1995-2006 2. Circulation. 2012;126:2408-2417 3. JAMA. 2012;308:2497-2506 4. Lancet. 2012;380:2007-2017 5. Circulation 2014;129:234-243 35 The DESCARTES Study Durable Effect of PCSK9 antibody CompARed with placebo Study (NCT01516879) A 52 week global, randomized, double-blind, placebocontrolled multicenter study to provide longer term data on the efficacy and safety of evolocumab Included patients with a wide range of cardiovascular risk Lipid-lowering therapy, ranging from diet alone to atorvastatin 80 mg plus ezetimibe, was optimized to reach NCEP ATP III LDL-C treatment goals 36 18

DESCARTES: Endpoints Primary: % change from baseline in LDL-C measured by ultracentrifugation (UC) at week 52 Secondary % change from baseline in UC LDL-C at week 12 Change from baseline in UC LDL-C at week 52 % of patients with UC LDL-C < 70 mg/dl at week 52 % changes from baseline for TC, HDL-C, ApoB, VLDL-C, triglycerides, and Lp(a) at week 52 % changes in total cholesterol/hdl cholesterol ratio and apolipoprotein B/apolipoprotein A1 ratio at week 52 37 DESCARTES: Patients Adults aged 18 to 75 years Screening LDL-C 75 mg/dl and TG 400 mg/dl Exclusion: LDL-C 99 mg/dl with CHD or risk equivalent and not receiving a statin Following lipid stabilization period At NCEP ATP III target or receiving maximal therapy (atorvastatin 80 mg plus ezetimibe 10 mg) LDL-C 75 mg/dl 38 19

DESCARTES: Screening and Lipid Stabilization Screening LDL-C 75 mg/dl Initial LDL-C < 75 mg/dl = Screen Fail Screening Period 4 Weeks to 16 Weeks Background Therapy Assigned Based on CV Risk, LDL-C, and Current Therapy: 1) Diet alone 2) Diet and atorvastatin 10 mg 3) Diet and atorvastatin 80 mg 4) Diet, atorvastatin 80 mg, and ezetimibe 10 mg 4 Week Dietary Run-in and Lipid Stabilization Up-titrate Background Therapy CHD/risk equivalent: LDL < 100 mg/dl OR No CHD/risk equivalent: LDL < 130 mg/dl OR On Maximal background therapy Yes Randomization 2:1 (~900 Subjects) Evolocumab 420 mg SC QM Placebo SC QM No LDL < 75 mg/dl = Screen Fail (except on maximal background therapy allowed one downtitration 39 DESCARTES: Study Overview Screening - Assign background Rx based on CV risk, LDL, and +/- prior statin: 1. No drug 2. Low dose: 10 mg atorvastatin 3. High dose: 80 mg atorvastatin 4. Maximal: 80 mg atorvastatin + 10 mg ezetimibe Subcutaneous injection of 6 ml Placebo Lipid Stabilization Period Fasting LDL-C 5 10 days before randomization Randomization 2:1 Placebo SC QM n = 303 Evolocumab 420 mg SC QM n = 602 End of Study Period = Max. 16 weeks / Min: 4 weeks Study Drug (Evolocumab or Placebo) QM: * Last dose administered at week 48 Visits: Day 1 Week 4 Week 8 Week 52* 40 20

DESCARTES: Patient Disposition Screened: 2120 635 screen failures 1485 entered lipid stabilization period 905 randomized to evolocumab or placebo 580 lipid stabilization period failures 41 DESCARTES: Patient Disposition II 905 Randomized 2:1 allocation to evolocumab or placebo 112 Diet alone (38 P: 74 Evo) 385 Atorvastatin 10 (129 P: 256 Evo) 219 Atorvastatin 80 (73 P: 146 Evo) 189 Atorvastatin 80 + Ezetimibe 10 (63 P: 126 Evo) 4 never received SD* 73 discontinued evolocumab 28 discontinued placebo 800 completed 52 weeks of Study Drug E = Ezetimibe, Evo = Evolocumab, P = Placebo * Study Drug 42 21

DESCARTES: Baseline Characteristics Characteristic Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d +E10 mg/d All n 111 383 218 189 901 Age, y, mean (SD) 51.7 (12.1) 57.1 (10.4) 58.0 (9.2) 54.8 (10.7) 56.2 (10.6) Male, % 45.0 43.9 50.0 54.5 47.7 BMI, kg/m 2, mean (SD) 30.5 (7.6) 29.8 (6.2) 30.8 (5.7) 29.8 (4.8) 30.1 (6.0) Race/White, % 67.6 85.9 86.2 69.8 80.4 A = Atorvastatin E = Ezetimibe Full Analysis Set (FAS) data presented: Patients who received at least one dose of study drug 43 DESCARTES: Baseline Patient Characteristics II Characteristic Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d +E10 mg/d Coronary artery disease,% 1.8 2.6 15.6 47.6 15.1 Type 2 diabetes,% 2.7 7.0 15.1 21.7 11.5 Current smoker, % 17.1 11.7 14.2 21.2 15.0 Hypertension, % 42.3 41.8 57.3 56.1 48.6 Family history of premature CAD, % 13.5 14.6 22.0 47.1 23.1 2 or more CV risk factors, % 29.7 26.6 46.3 61.4 39.1 All A = Atorvastatin E = Ezetimibe 44 22

DESCARTES: Baseline Lipids Placebo Evolocumab n 302 599 *UC LDL-C, mg/dl, mean (SD) 104 (22) 104 (22) ApoB, mg/dl, mean (SD) 88 (16) 87 (16) Lipoprotein(a), nmol/l, median (Q1, Q3) 40 (12,145) 38 (14,137) HDL-C mg/dl mean, (SD) 54 (16) 53 (16) ApoA1, mg/dl mean, (SD) 155 (28) 152 (27) Triglycerides, mg/dl, median, 110 105 (Q1, Q3) *UC = ultracentrifugation (85,155) (80,140) 45 DESCARTES: Baseline LDL-C on Background Therapy Prior to First Dose of Study Drug Treatment Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d + E 10 mg/d All Group P EVO P EVO P EVO P EVO P EVO n 37 74 129 254 73 145 63 126 302 599 UC LDL-C Baseline mg/dl mean (SD) 112 (16) 112 (15) 98 (15) 101 (15) 96 (13) 95 (13) 120 (32) 117 (35) 104 (22) 104 (22) A = Atorvastatin E = Ezetimibe EVO = Evolocumab P = Placebo 46 23

DESCARTES: % Change in UC LDL-C From Baseline - FAS UC LDL-C Percent Change from Baseline, Mean (± SE) 20 10 0-10 -20-30 -40-50 -60-70 -80 Number of patients: Treatment difference 57% 6.0% -51.5% 302 294 264 599 582 542 Baseline Week 12 Week 52 Study Week Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599) FAS = Full analysis set, UC = ultracentrifugation 47 DESCARTES: % Change in UC LDL-C from Baseline at Week 52 Mean Percent Change in UC LDL-C 20 10 0-10 -20-30 -40-50 -60-70 Overall Placebo Diet Alone Atorvastatin 10 mg Evolocumab Error bars represent standard error for treatment difference Treatment difference are least squares mean derived from a repeated measures model Atorvastatin 80 mg Treatment Difference Atorvastatin 80 mg + Ezetimibe 10 mg 48 24

DESCARTES: UC LDL-C Goal Achievement LDL-C < 70 mg/dl at Week 52 Diet Alone Diet + Atorvastatin 10 mg Diet + Diet + Atorvastatin Atorvastatin 80 mg 80 mg + Ezetimibe 10 mg Total 49 Changes in Mean Levels of Unbound PCSK9 Mean ± SE PCSK9 Level, ng/ml 700 600 500 400 300 200 100 Placebo Diet Only Atorvastatin 10 mg Evolocumab Atorvastatin 80 mg Atorvastatin 80 mg + Ezetimibe 10 mg 0 Baseline Week 12 Week 13 Week 52 4 weeks post-dose 1 week post-dose 4 weeks post dose 50 25

DESCARTES: Other Lipids at Week 52 ApoB Percent Change from Baseline, Mean (%) 10 0-10 -20-30 -40-50 2% -42% HDL-C Percent Change from Baseline, Mean (%) 6 4 2 0-2 0 6% Lp(a) Triglycerides Percent Change from Baseline, Median (%) Percent Change from Baseline, Median (%) 0-5 -10-15 -20-25 -30 6 4 2 0-2 -4-6 -8-10 -6% (-21 to 1) 3% (-17 to 25) -28% (-49 to -6) -9% (-26 to 13) ApoA1 Percent Change from Baseline, Mean (%) 3 2 1 0-1 -2 Placebo QM -1% Evolocumab 420 mg QM 2% Error bars represent standard error Data in parentheses represent Q1 to Q3 51 DESCARTES: Safety and Tolerability 26

DESCARTES: Treatment Emergent Adverse Events n (%) Placebo N=302 Evolocumab N=599 Any Treatment Emergent Adverse Event 224 (74.2) 448 (74.8) Serious 13 (4.3) 33 (5.5) Death 0 (0.0) 2 (0.3) Adjudicated events 2 (0.7) 6 (1.0) Leading to discontinuation of study drug 3 (1.0) 13 (2.2) Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study 53 DESCARTES: Treatment Emergent Adverse Events II n (%) Placebo N=302 Evolocumab N=599 Most Common Treatment Emergent AEs Nasopharyngitis 29 (9.6) 63 (10.5) Upper respiratory tract infection 19 (6.3) 56 (9.3) Influenza 19 (6.3) 45 (7.5) Back pain 17 (5.6) 37 (6.2) Neurocognitive AEs 2 (0.7) 1 (0.2) Amnesia - Short-term memory loss 0 (0.0) 1 (0.2) Dementia With Lewy Bodies 1 (0.3) 0 (0.0) Encephalopathy 1 (0.3) 0 (0.0) Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study 54 27

DESCARTES: Hepatic and Muscle Safety n (%) Liver function tests Placebo N=302 Evolocumab N=599 ALT or AST > 3 ULN* 3 (1.0) 5 (0.8) ALT or AST > 5 ULN* 1 (0.3) 3 (0.5) Muscle TEAEs and Laboratory Results Myalgia 9 (3.0) 24 (4.0) CK > 5 ULN* 1 (0.3) 7 (1.2) CK > 10 ULN* 1 (0.3) 3 (0.5) * At any visit post baseline, TEAE = treatment emergent adverse event 55 Conclusions New Guidelines have resulted in a larger patient population Statin therapy alone has been successful but still undertreating DESCARTES largest and longest RCT of a monoclonal antibody to PCSK9 Evolocumab 420 mg QM reduced placebo adjusted UC LDL-C 57% from baseline in patients receiving background lipid lowering therapies. Durable effect with consistent LDL-C reductions at weeks 12 and 52 Similar AE profile in placebo and active treatment groups Cardiovascular outcome trial is ongoing 56 28