New Horizons in Dyslipidemia Management in Primary Care

Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

Presenter Disclosure Presenter Peter Lin, MD Optimal control of dyslipidemia in Relationships with commercial interests: patients with CVD Grants/Research Support: N/A Speakers Bureau/Honoraria: AstraZeneca, BMS, Takeda, Purdue, Boehringer Ingelheim, Bayer, Lilly, Amgen, Janssen, Forest Laboratories, J&J, Merck, Novartis, Pfizer, Servier, Sanofi, Abbott, Mylan Consulting Fees: AstraZeneca, Boerhinger Ingelheim, Bayer, Lilly, Merck, Sanofi, Amgen Other: N/A

Learning Objectives Upon completion of this activity, participants will be able to: Discuss the role of LDL-C lowering in cardiovascular risk reduction with emphasis on the results of recently completed clinical trials Evaluate recommendations for lipid lowering agents beyond or in addition to statin therapy for patients with atherosclerotic cardiovascular disease Explain the mechanism of action of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and apply the latest clinical data to patient management strategies Apply best guideline practice recommendations into routine clinical practice based on specific patient characteristics

Blood Pressure Clot Cholesterol

History of Statin Development 70 s Dr. Akira Endo - Sankyo 70 s drug companies focus on antibiotics 1971 Funghi research project started ML 236 B potent inhibitor of HMG Co A reductase

Searching for more patients to protect with Statins HeFH MI Stroke PAD

Percent with CHD event Where did we get our LDL-C Targets? 4S-Pl 25 Rx - Drug group Pl - Placebo group 20 15 10 HPS-Rx CARE-Rx 4S-Rx Lipid-Pl CARE-Pl HPS-Pl LIPID-Rx 5 Target LDL-C 2.5 (100 mg/dl) 0 End of study LDL-C 1.3 1.8 2.3 2.84 3.36 3.87 4.39 4.91 5.43 mmol/l (50) (70) (90) (110)(130)(150)(170)(190)(210) (mg/dl) 2.5 (100) Adapted from Kastelein JJ. Atherosclerosis 1999;143(Suppl 1):S17 S21 Heart Protection Study Collaborative Group. Lancet 2002;360:7 22

Percent with CHD event Where did we get our LDL-C Targets? 4S-Pl 25 A 10mg Rx - Drug group Pl - Placebo group 20 15 10 A 80mg HPS-Rx CARE-Rx 4S-Rx Lipid-Pl CARE-Pl HPS-Pl LIPID-Rx 5 Target LDL-C 1.8 (70 mg/dl) 0 End of study LDL-C 1.3 1.8 2.3 2.84 3.36 3.87 4.39 4.91 5.43 mmol/l (50) (70) (90) (110)(130)(150)(170)(190)(210) (mg/dl) 1.8 (70) Adapted from Kastelein JJ. Atherosclerosis 1999;143(Suppl 1):S17 S21 Heart Protection Study Collaborative Group. Lancet 2002;360:7 22

Proportion of patients experiencing major CV event Residual Risk 0.14 0.12 0.10 0.08 0.06 0.04 0.02 HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 atorvastatin 10 mg atorvastatin 80 mg Residual Risk 0 0 1 2 3 4 5 6 Time (years) *CHD death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke LaRosa JC, et al. N Engl J Med. 2005;352:1425 35

Residual Risk

In Serum the Presence LDL-Cholesterol of PCSK9, Binds the to LDL-Receptors. Is Degraded Following and Does Not Cycle Internalization, Back to Cell LDL Surface is Degraded and the Receptor Recycled LDL Plasma PCSK9 LDL LDL-R LDL-R Endocytosis Hepatocyte Endocytosis Endosome PCSK9 Self-procession LDL-R Recycling Endosome LDL Degradation LDL, LDL-R and PCSK9 Degradation Nucleus Golgi Apparatus Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved. Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

Distribution of Plasma LDL Cholesterol Levels (Panel A) and Incidence of Coronary Heart Disease (Panel B) among Black Subjects, According to the Presence or Absence of a PCSK9 142X or PCSK9 679X Allele Cohen, J. et al. N Engl J Med 2006;354:1264-1272

PCSK9 Inhibitors: Targeted Therapy Blocking Monoclonal PCSK9 Antibody Activity binds Inhibits to PCSK9 and inhibits Binding to the Intracellular LDL-Receptor Degradation of LDL-R PCSK9 mab Plasma LDL LDL-R Recycling LDL-R Endocytosis Hepatocyte Endosome PCSK9 Self-procession Lysosome LDL Degradation Nucleus Golgi Apparatus Endoplasmic Reticulum (ER) 2013 Amgen Canada Inc. All rights reserved. Qian YW, et al. J Lipid Res. 2007;48:1488-1498; Horton JD, et al. J Lipid Res. 2009;50(suppl):S172-S177.

Even Maximal Statin Therapy May Not Be Sufficient In Achieving LDL-C Target 0% 10% 20% 30% 40% 50% 60% Rosuvastatin 10 5 mg 20 mg 10 mg 20 mg 40 mg Atorvastatin 10 mg 20 mg 40 mg 80 mg Simvastatin 10 mg 20 mg 40 mg Pravastatin 10 mg 20 mg 40 mg Doubling the statin dose results in only 6% LDL-C reduction Lovastatin 20 mg 40 mg 80 mg Fluvastatin 20 mg 40 mg *As per Canadian Product Monographs 1. Crestor (rosuvastatin) Product Monograph. AstraZeneca. April 21, 2015. 2. Lipitor (atorvastatin) Product Monograph. Pfizer. Feb 18, 2016. 3. Pravachol (pravastatin) Product Monograph Bristol-Myers Squibb Canada. Nov 30, 2015. 4. Mevacor (lovastatin) Product Monograph. Merck. Jul. 24, 2012. 5. Zocor (simvastatin) Product Monograph. Merck. Dec 10, 2014. 6. Lescol (fluvastatin) Product Monograph. Novartis. Aug. 26, 2016. 7. Adapted from CURVES Investigators. Am J Cardiol. 1998;81:582-587.

Statin Influence on LDL-C Metabolism plus LDL-R and PCSK9 Acetyl-CoA + acetoacetyl-coa HMG-CoA reductase STATIN PCSK9 Secretion Plasma HMG-CoA LDL Intracellular Cholesterol Biosynthesis LDL-R LDL Protein at Cell Surface PCSK9 Protein Hepatocyte Cholesterol Content Hepatocyte LDL-R Expression PCSK9 Expression SREBP Activation Nucleus Endoplasmic Reticulum (ER)

PCSK9 (mg/ml) PCSK9 and Statin Therapy 75 * 50 25 Baseline Placebo Endpoint Baseline Endpoint Atorvastatin 40 mg * P < 0.05 versus baseline and placebo baseline and endpoint 1. Amgen, data on file. 2. Careskey HE, Davis RA, et al. J Lipid Res. 2008;49:394 398. This mechanism may explain the limitation in LDL lowering by statins and why doubling the dose, only results in 6% further LDL reduction

Change in LDL-C from baseline (%) LDL-C Efficacy Across the Dose Range The STELLAR Study 0 Dose, mg (log scale) 10 20 40 80 10 20 X Rosuvastatin Atorvastatin Simvastatin Pravastatin 30 X n=485 X 40 X 50 60 * n=473 X n=648 n=634 *p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg Adapted from Jones P et al. Am J Cardiol 2003; 92: 152 160

Change in LDL-C from baseline (%) LDL-C Efficacy Across the Dose Range The STELLAR Study 0 Dose, mg (log scale) 10 20 40 80 10 20 X Rosuvastatin Atorvastatin Simvastatin Pravastatin 30 8 X 40 50 60 * n=473 n=634 *p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg Adapted from Jones P et al. Am J Cardiol 2003; 92: 152 160

PROFICIO (Latin): To advance ;To make progress Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations

Evolocumab Clinical Program: PROFICIO Reduce LDL-C (FH, ASCVD, Intolerant) Atherosclerosis CV Events

PROFICIO Addresses Key Scientific Questions for Evolocumab Question Description Study What is the safety/efficacy of evolocumab alone? What is the safety/efficacy with statins? Does AMG 145 work in patients with LDLR mutations? Does AMG 145 work in patients with mutations in both LDLR alleles? What is the safety/efficacy in statinintolerant patients? What is the long-term safety/efficacy? Does LDL-C reduction via evolocumab slow or reverse atherosclerosis? Does LDL-C reduction via evolocumab impact CV outcomes? Combination therapy HoFH/ severe FH Long-term effect CV outcomes LAPLACE-1/-2 TESLA/ TAUSSIG DESCARTES, OSLER-1/-2 FOURIER

PROFICIO Addresses Key Scientific Questions for Evolocumab Question Description Study What is the safety/efficacy of evolocumab alone? What is the safety/efficacy with statins? Does AMG 145 work in patients with LDLR mutations? Does AMG 145 work in patients with mutations in both LDLR alleles? What is the safety/efficacy in statinintolerant patients? What is the long-term safety/efficacy? Does LDL-C reduction via evolocumab slow or reverse atherosclerosis? Does LDL-C reduction via evolocumab impact CV outcomes? Monotherapy Combination therapy HeFH HoFH/ severe FH Statinintolerant Long-term effect IVUS CV outcomes

PROFICIO Addresses Key Scientific Questions for Evolocumab Question Description Study What is the safety/efficacy of evolocumab alone? What is the safety/efficacy with statins? Does AMG 145 work in patients with LDLR mutations? Does AMG 145 work in patients with mutations in both LDLR alleles? What is the safety/efficacy in statinintolerant patients? What is the long-term safety/efficacy? Does LDL-C reduction via evolocumab slow or reverse atherosclerosis? Does LDL-C reduction via evolocumab impact CV outcomes? Monotherapy Combination therapy HeFH HoFH/ severe FH Statinintolerant Long-term effect IVUS CV outcomes MENDEL-1/-2 LAPLACE-1/-2 RUTHERFORD-1/-2 TESLA/ TAUSSIG GAUSS-1/-2/-3 DESCARTES, OSLER-1/-2 GLAGOV FOURIER

Evolocumab Clinical Program: PROFICIO Reduce LDL-C (FH, ASCVD, Intolerant) Atherosclerosis CV Events Fourier Trial

An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School 2.37 mmol/l

LDL Cholesterol (mmol/l) FOURIER: Median LDL-C Levels Over Time: All Patients No. at risk Placebo Evolocumab 13,779 13,784 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 59% mean reduction (95% CI 58-60), P < 0.001 Absolute reduction: 1.45 mmol/l (95% CI 1.43-1.47) Placebo Median 2.38 mmol/l Evolocumab Median 0.78 mmol/l 0 4 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks 13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 790 13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 768 LDL-C was significantly reduced in the evolocumab group (median: 0.78 mmol/l) including 42% who achieved levels 0.65 mmol/l vs < 0.1% in the placebo group 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

Proportion of patients experiencing major cardiovascular event Primary Efficacy Outcome Measure: Major Cardiovascular Events* 0.15 HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 10.9 % 0.10 Atorvastatin 10 mg Atorvastatin 80 mg 8.7 % 0.05 0 RRR 22% ARR 2.2% NNT 6 45 Screening 0 1 2 3 4 5 6 Time (years) *CHD death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke LaRosa JC, et al. N Eng J Med. 2005;352 29

Cumulative Incidence (%) FOURIER: Composite of CV Death, MI, or Stroke No. at Risk Placebo Evolocumab 11 10 9 8 7 6 5 4 3 2 1 Key Secondary Endpoint 3.7 3.1 Placebo + SOC 6.8 9.9 Evolocumab + SOC 0 0 6 12 18 24 30 36 Months 13,780 13,449 13,142 12,288 7,944 3,893 731 13,784 13,501 13,241 12,456 8,094 3,935 724 5.5 RRR 22% ARR 2.2% NNT 6 45 7.9 RRR 20 % ARR 2.0 % NNT 3 50 HR 0.80 (95% CI 0.73 to 0.88); P < 0.001 CV = Cardiovascular; MI = Myocardial infarction; HR = Hazard ratio Sabatine MS, et al. NEJM. [published online ahead of print March 17, 2017]. doi: 10.1056/NEJMoa1615664

FOURIER RRR 20% ARR 2% NNT 3 50 3 YEARS TNT 6 YEARS RRR 22% ARR 2.2% NNT 6 45

Primary Endpoint ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke Simva 34.7% 2742 events EZ/Simva 32.7% 2572 events 6.4% RRR 2% ARR NNT 7 50 7-year event rates

Proportion alive Total Mortality: 4S 1.00 simvastatin 0.95 0.90 placebo 0.85 0.80 Log rank p=0.0003 0.00 0.0 1 2 3 4 5 Years since randomisation 6 4S Group. Lancet 1994;344:1383 1389.

Mortality No. of patients (%) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) All-cause mortality 282 (5.6) 284 (5.7) Cardiovascular CHD death Stroke death Hemorrhagic stroke death Noncardiovascular Cancer Trauma Other 155 (3.1) 127 (2.5) 8 (0.2) 2 (0) 127 (2.5) 75 (1.5) 9 (0.2) 43 (0.9) 126 (2.5) 101 (2.0) 7 (0.1) 3 (0.1) 158 (3.2) 85 (1.7) 15 (0.3) 58 (1.2) No single Screening cause of death (by body system, or pathological process) and no single cancer type drove the non-significant difference in all-cause mortality between groups No statistically significant differences were observed between treatment groups for any cause of death LaRosa JC, et al. N Eng J Med. 2005;352 35

Mortality (%) Mortality in Statin Secondary Prevention Trials 36 10 9 8 7 non-cv CV 6 5 4 3 2 1 0 4S S20 4S PL CARE P40 CARE PL LIPID P40 LIPID PL HPS S40 HPS PL TNT A80 TNT A10 IDEAL A80 IDEAL S20 Against placebo Statin vs Statin

Individual Cardiovascular Endpoints and CVD/MI/Stroke HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003 0.6 1.0 1.4 Ezetimibe/Simva Better Simva Better *7-year event rates (%)

Fourier Trial

An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

Are they all the sme?

PCSK9 Inhibitors PCSK9 inhibitors (PCSK9i) Evolocumab Alirocumab Bococizumab PCSK9 = Proprotein Convertase Subtilisin Kexin Type 9

Terminology of Monoclonal Antibodies Source (% human protein) Mouse (0% human) Chimeric (65% human) Humanized (> 90% human) Human (100% human) Generic suffix: High -omab -ximab Potential for immunogenicity -zumab -umab Low 1. Weiner LM. J Immunother. 2006;29:1-9; 2. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23; 3. Lonberg N. Nat Biotechnol. 2005;23:1117-1125; 4. Gerber DE. Am Fam Physician. 2008;77:311-319.

PCSK9 Inhibitors PCSK9 inhibitors (PCSK9i) Evolocumab Alirocumab Bococizumab* * Investigational product, not approved by Health Canada PCSK9 = Proprotein Convertase Subtilisin Kexin Type 9

Anti-PCSK9 Antibodies The detection of anti-drug binding antibody formation is highly dependent on the sensitivity and specificity of the assay. Comparison of the incidence of antibodies to evolocumab with incidence of antibodies to other products may be misleading. FAQ Evolocumab Overall incidence of antievolocumab binding antibodies after at least one dose of evolocumab was 0.3% (13 of 4915) Responses were of low-titer, most were transient No neutralizing antibodies have been detected No impact of binding antibodies on safety, pharmacokinetics, or pharmacodynamics Alirocumab Observed in 4.8% of patients following alirocumab treatment vs. 0.6% of patients in control group Most responses were of low-titer, non-neutralizing, and/or transient higher incidence of local injection site reactions (10.2% vs 5.9% if no antibodies) Neutralizing antibodies were reported in 1.2% of patients treated with alirocumab FDA Briefing Document Praluent (alirocumab) injection June 9, 2015; FDA Briefing Document Evolocumab June 10, 2015.

PCSK9 Inhibitor Ongoing OUTCOME Studies Evolocumab FOURIER Outcome Study (5 yrs), N=27 500 Inclusion criteria: High-risk 2º prevention population with LDL-C 1.8 mmol/l or non-hdl 2.6 mmol/l Evolocumab 140mg Q2W or 420mg QM + optimal LLT 1º endpoint: Time to CV death, MI, hospitalization for unstable angina, stroke, or coronary revascularization Alirocumab ODYSSEY Outcomes Outcome Study (64 months), N=18 000 Inclusion criteria: Hospitalized for ACS within past 1-12 months LDL 1.8mmol/L Alirocumab 75mg Q2W, up-titrate to 150mg Q2W as needed 1º endpoint: Time to CHD death, any non-fatal MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization ACS: acute coronary syndrome; CHD: coronary heart disease; CV: cardiovascular; LLT: lipid lowering therapy; MI: myocardial infarction clinicaltrials.gov accessed August 31, 2015; Swartz GG, et al. Am Heart J. 2014;168(5):682-9.

Meta-analyses suggest earlier, prolonged exposure to lower LDL-C is associated with greater reduction in the risk of CHD Lower LDL-C Meta-Analysis Sample Size (N) OR (95% CI) p (difference) 1.0 mmol/l Genetic Studies 312,321 0.46 (0.41-0.51) 8.4x10-19 (38.7 mg/dl) Statin Trials 169,138 0.76 (0.74-0.78) 0.5 mmol/l Genetic Studies 312,321 0.67 (0.64-0.72) 8.4x10-19 (19.3 mg/dl) Statin Trials 169,138 0.87 (0.86-0.88) 0.25 mmol/l Genetic Studies 312,321 0.82 (0.80-0.85) 8.4x10-19 (9.7 mg/dl) Statin Trials 169,138 0.93 (0.93-0.94) 0.125 mmol/l Genetic Studies 312,321 0.91 (0.89-0.92) 8.4x10-19 (4.8 mg/dl) Statin Trials 169,138 0.96 (0.96-0.97) 0.40 0.50 0.60 0.70 0.80 0.90 1.0 CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol Ference BA, et al. J Am Coll Cardiol. 2012;60:2631-9.

3.1 1.2

53% RRR 1.2% ARR NNT 1 83

PCSK9 Inhibitors and Their Current Indications Alirocumab 1 o Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with HeFH Clinical ASCVD Evolocumab 2 o Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with HeFH Clinical ASCVD o Adjunct to diet and other LDL-C lowering therapies in persons 12 years with HoFH who require additional LDL-C lowering ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin type 9. 1. Praluent Canadian Product Monograph, April 11, 2016; 2. IRepatha Canadian Product Monograph, June 29 2016;

PCSK9 Inhibitors and Their Indications Alirocumab 1 Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with HeFH Clinical ASCVD Evolocumab 2 Adjunct to diet and maximally tolerated statin therapy where additional LDL-C lowering is needed in adults with HeFH Clinical ASCVD Adjunct to diet and other LDL-C lowering therapies in persons 12 years with HoFH who require additional LDL-C lowering ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin type 9. 1. Praluent Canadian Product Monograph, April 11, 2016; 2. IRepatha Canadian Product Monograph, June 29 2016;

Recommendations for PCSK9i in FH and ASCVD We suggest the use of PCSK9 inhibitors (evolocumab, alirocumab) to lower LDL-C for patients with heterozygous familial hypercholesterolemia whose LDL-C remains above target despite maximally tolerated statin therapy (Conditional recommendation, moderate quality evidence) We suggest that PCSK9 inhibitors be considered to lower LDL-C for patients with atherosclerotic cardiovascular disease in those not at LDL-C goal despite maximally tolerated statin +/- ezetimibe therapy (Conditional recommendation, moderate quality evidence) We suggest that evolocumab be added to background therapy in patients with homozygous familial hypercholesterolemia and continued if LDL-C lowering is documented (Conditional recommendation, moderate quality evidence) Anderson et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult Canadian Journal of Cardiology 2016;32:1263-1282

Then PCSK9 Inhibitors Maximize Statin First