Elevated LDL-C Cardiovascular Pathobiology MEDX Dallas/Fort Worth - - PDF document

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCI AL PROBLEM OF ASCVD Can New Therapeutic Options Resolve I t?

Jam es A. Underberg, MD, MS, FACPM, FACP, FNYAM, FASPC, FNLA Lipidology and Cardiovascular Disease Prevention Clinical Assistant Professor of Medicine NYU Medical School and NYU Center for CV Prevention Director, Bellevue Hospital Lipid Clinic Past President, National Lipid Association New York, NY Twitter: @LipidDoc

Jointly provided by and This activity is supported by educational funding provided by Amgen.

Elevated LDL-C

Cardiovascular Pathobiology

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Support for LDL-C Causality in ASCVD

• Four compelling lines of evidence

– Experimental models – Observational human data – Genetic studies – Interventional human trials

ASCVD = atherosclerotic cardiovascular disease

Substantial CVD Risk Remains after ACS

43,810 Patients with ACS in GRACE Registry: 6-month Death Rate

Substantial CVD Risk Remains after ACS

43,810 Patients with ACS in GRACE Registry: 6-month Death Rate

GRACE = global registry of acute coronary events STEMI: ST-segment elevation MI NSTEMI: nonST-segment elevation MI UA: unstable angina

Fox KAA et al. BMJ. 2006;333:1091.

16 12 8 4 0 0 30 60 90 120 150 180 STEMI UA NSTEMI Death (%) Days

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Disease Trajectories and CVD Risk Reduction Disease Trajectories and CVD Risk Reduction

Packard CJ et al. Vasc Pharmacol. 2015;71:37-39.

LDL-C Reduction

Cardiovascular Benefits

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Table 6. Risk-Enhancing Factors for Clinician– Patient Risk Discussion

Risk‐Enhancing Factors  Family history of premature ASCVD (males, age <55 y; females, age <65 y)  Primary hypercholesterolemia (LDL‐C, 160–189 mg/dL [4.1–4.8 mmol/L); non– HDL‐C 190–219 mg/dL [4.9–5.6 mmol/L])*  Metabolic syndrome (increased waist circumference, elevated triglycerides [>175 mg/dL], elevated blood pressure, elevated glucose, and low HDL‐C [<40 mg/dL in men; <50 in women mg/dL] are factors; tally of 3 makes the diagnosis)  Chronic kidney disease (eGFR 15–59 mL/min/1.73 m2 with or without albuminuria; not treated with dialysis or kidney transplantation)  Chronic inflammatory conditions such as psoriasis, RA, or HIV/AIDS  History of premature menopause (before age 40 y) and history of pregnancy‐ associated conditions that increase later ASCVD risk such as preeclampsia  High‐risk race/ethnicities (e.g., South Asian ancestry)

Table 6 (continued)

Risk‐Enhancing Factors  Lipid/biomarkers: Associated with increased ASCVD risk

• Persistently* elevated, primary hypertriglyceridemia (≥175 mg/dL);
• If measured:
• Elevated high‐sensitivity C‐reactive protein (≥2.0 mg/L)
• Elevated Lp(a): A relative indication for its measurement is family

history of premature ASCVD. An Lp(a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk‐enhancing factor especially at higher levels of Lp(a).

• Elevated apoB ≥130 mg/dL: A relative indication for its

measurement would be triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL‐C >160 mg/dL and constitutes a risk‐ enhancing factor

• ABI <0.9

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Treatments for Hypercholesterolemia

Lifestyle Change

• Physical activity
• Medical nutrition therapy
• Smoking cessation

Jellinger P et al. Endocr Practice. 2017;23:479-497.

Pharmacologic Therapy

• Statins
• Cholesterol absorption inhibitors
• Bile acid sequestrants
• Fibrates
• Omega-3 fish oil
• PCSK9 inhibitors
• MTP inhibitors
• Antisense apo B oligonucleotide
• Combination therapies

Statins

The Gold Standard for LDL-C Reduction and ASCVD Prevention

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Statins Protect against Recurrence in ASCVD Patients

Secondary Prevention Statin Trials: CHD Event Rates

O’Keefe JH et al. J Am Coll Cardiol. 2004;43:2142-2146.

• P=placebo; -AT=atorvastatin; -PR=pravastatin

Lower On-treatment LDL-C with Statins Predicts Lower ASCVD Risk Lower On-treatment LDL-C with Statins Predicts Lower ASCVD Risk

Boekholdt SM et al. J Am Coll Cardiol. 2014;64:485-494.

≥ 175 150−<175 125−<150 100−<125 75−<100 50−<75 <50 0.25 0.5 0.75 1 Adjusted Hazard Ratio 95% Cl LDL-C (mg/dL)

LDL-C Levels and Risk of CV Events

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Elevated LDL Causes ASCVD

LDL-C lowering Reduces ASCVD

• Cumulative LDL burden → atheroprogression
• ↓ On-treatment LDL-C → ↓ ASCVD

– Best evidence is for ↑ LDL receptors – But likely not exclusive to this mechanism

• Early treatment to ↓ LDL-C is better than late treatment
• Lowest LDL-C is best

Ference BA et al. Eur Heart J. 2017;38:2459-2472.

Primary Prevention: Assess ASCVD Risk in Each Age Group Emphasize Adherence to Healthy Lifestyle

LDL-C ≥190 mg/dL (24.9 mmol/L) No risk assessment; High-Intensity statin (Class I) Diabetes mellitus and age 40-75 y Risk assessment to consider high-intensity statin (Class IIa) Age >75 y Clinical assessment, Risk reduction Age 0-19 y

Lifestyle to prevent or reduce ASCVD risk Diagnosis of Familial Hypercholesterolemia statin

Age 20-39 y

Estimate lifetime risk to encourage lifestyle to reduce ASCVD risk Consider statin is family history premature ASCVD and LDL-C >160 mg/dL (>4.1 mmol/L0

Age 40-75 y and LDL-C ≥70-<190 mg/dL (≥1.8-<4.9 mmol/L)

without diabetes mellitus 10 year ASCVD risk percent begins risk discussion

Diabetes mellitus and age 40-75 y Moderate-Intensity statin (Class I)

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

<5% “Low Risk” 5% - <7.5% “Borderline Risk” ≥ 7.5% - <20% “Intermediate Risk” ≥ 20% “High Risk” Risk discussion: Emphasize lifestyle to reduce risk factors (Class I) Risk discussion: If risk enhancers present then risk discussion regarding moderate- intensity statin therapy (Class IIb) Risk discussion: If risk estimate + risk enhancers favor statin, initiate moderate-intensity statin to reduce LDL- C by 30% - 49% (Class I) Risk discussion: Initiate statin to reduce LDL-C ≥50% (Class I) If risk decision is uncertain: Consider measuring CAC in selected adults: CAC = zero (lowers risk; consider no statin, unless diabetes, family history of premature CHD, or cigarette smoking are present) CAC = 1.99 favors statin (especially after age 55) CAC = 100+ and/or ≥75th percentile, initiate statin therapy

Secondary Prevention

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

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)

Table 4 (continued)

High-Risk Conditions Age ≥65 y Heterozygous familial hypercholesterolemia History of prior coronary artery bypass surgery or percutaneous coronary intervention

• utside of the major ASCVD event(s)

Diabetes mellitus Hypertension CKD (eGFR 15-59 mL/min/1.73 m2) 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

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018 4,162 patients with an Acute Coronary Syndrome <10 days

ASA + Standard Medical Therapy “Standard Statin Therapy” Pravastatin 40 mg “Intensive StatinTherapy” Atorvastatin 80 mg Duration: Mean 2 year follow-up (>925 events)

Primary Endpoint: Death, MI, documented UA requiring hospitalization, revascularization (>30 days after randomization), or stroke

Intensive Statin Therapy Reduces MACE

PROVE IT - TIMI 22: Study Design

Intensive Statin Therapy Reduces MACE

PROVE IT - TIMI 22: Study Design

2x2 Factorial: Gatifloxacin vs placebo

Double-blind

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

Intensive Statin Therapy: PROVE IT-TIMI 22

All-Cause Death or Major CV Events

3 18 21 24 27 30 6 9 12 15

% of Patients with MACE Months of Follow-up

Intensive Statin Therapy Pravastatin 40mg (26.3%) Standard Statin Therapy Atorvastatin 80mg (22.4%)

16% RR (P=0.005)

30 25 20 15 10 5

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

High-intensity Statin Therapy Moderate-intensity Statin Therapy Low-intensity Statin Therapy Daily dose lowers LDL-C, on average, by approximately ≥50% Daily dose lowers LDL-C, on average, by approximately 30% to <50% Daily dose lowers LDL-C, on average, by approximately <30% Atorvastatin 40*-80* mg Rosuvastatin 20*-40** mg Atorvastatin 10* (20**) mg Rosuvastatin (5**) 10* mg Simvastatin 20*-40* mg Pravastatin 40* (80**) mg Lovastatin 40* mg Fluvastatin XL 80** mg Fluvastatin 40 mg BID* Pitavastatin 2-4** mg Simvastatin 10** mg Pravastatin 10*-20* mg Lovastatin 20* mg Fluvastatin 20**-40** mg Pitavastatin 1** mg

Intensity of Statin Therapies, Based on Clinical Trials

High, Moderate, and Low-intensity

Intensity of Statin Therapies, Based on Clinical Trials

High, Moderate, and Low-intensity

Stone NJ et al. Circulation. 2014;129(25 Suppl 2):S1-45. Goff DC et al. Circulation. 2014;129(25 Suppl 2):S49-73.

*Statins demonstrated reduction in major CVD events **FDA-approved doses not tested in clinical trials

Add-on Therapies to Statins

To Enhance LDL-C Reduction and Lower CVD Risk

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Efficacy of Statin Treatment to Lower LDL-C

Only about 1/3 of High-risk Patients Achieve LDL-C Goal

Efficacy of Statin Treatment to Lower LDL-C

Only about 1/3 of High-risk Patients Achieve LDL-C Goal

Jones PH et al. J Am Heart Assoc. 2012;1:e001800.

Electronic Medical Records (2003-2010)

80 Patients Achieving LDL-C Goal (%)

60 70

40

20

All Patients

10 50 30

High-Risk 1o Prevention Secondary Prevention

High-Risk Patients

51

CHD Patients

22

At High-Risk 1o Prev Goal (<100 mg/dL)

30

At High-Risk LDL-C Goal (<70 mg/dL)

13

CHD Patients at LDL-C Goal (<100 mg/dL)

71 31

At 2o Prev Goal (<70 mg/dL)

Residual CHD Risk Despite Statin Monotherapy

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

• 10
• 20
• 30
• 40
• 50
• 60
• 70
• 80
• 90
• 100

4S CARE WOSCOPS LIPID AFCAPS HPS CARDS ASCOT

Relative Risk Reduction (%) –34% –24% –29% –24% –37% –24% –37% –36% –44%

JUPITER

R E S I D U A L R I S K

Considerable ASCVD Risk Remains Despite Even Intensive Statin Monotherapy

• 1. Adapted from Rader DJ et al. http://www.medscape.org/viewarticle/569095.
• 2. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
• 3. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
• 4. Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.
• 5. Sacks FM et al. N Engl J Med. 1996;335:1001-1009.
• 6. Downs JR et al. JAMA. 1998;279:1615-1622.
• 7. LIPID Study Group. N Engl J Med. 1998;339:1349-1357.
• 8. Brown BG. Eur Heart J Suppl. 2005;7:F34-F40.
• 9. Grundy SM et al. Circulation. 2004;110:227-239.
• 10. Ridker PM et al. N Engl J Med. 2008;359:2195-2207.

Statin-based LDL-C lowering to reduce CAD risk2-10 Statins reduce CAD/CVD risk by ~24%-44% but 56% to 76% residual risk remains1-10

Non-statin Add-on LDL-lowering Therapies

Ezetimibe

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Ezetimibe: IMPROVE IT Trial Design Ezetimibe: IMPROVE IT Trial Design

Cannon CP et al. Am Heart J. 2008;156:826-832. Study drug is administered once daily in the evening.

Patients stabilized post-ACS ≤10 days LDL-C ≤125 mg/dL (or ≤100 mg/dL if prior statin)

Double-blind n ~ 18,000 ASA + Standard Medical Therapy Simvastatin 40 mg* Ezetimibe / Simvastatin 10/40 mg* Follow-up visit day 30, every 4 months Duration: Minimum 2.5 year follow-up (5250 events) Primary Endpoint: CV death, MI, Hospitalization for UA, Revascularization (>30 days after randomization), or Stroke

*up-titrated to 80 mg if LDL-C >79 mg/dL

IMPROVE-IT Trial

LDL-C and Other Lipid Effects with Ezetimibe

IMPROVE-IT Trial

LDL-C and Other Lipid Effects with Ezetimibe

1 Yr Mean LDL-C TC TG HDL hsCRP Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dL

• 16.7
• 19.3
• 16.7

+0.6

• 0.5

Median Time avg 69.5 vs. 53.7 mg/dL

Cannon CP et al. Am Heart J. 2008;156:826-832.

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

IMPROVE IT Trial: Ezetimibe + Simvastatin

Lowers ASCVD More than Simvastatin Alone

IMPROVE IT Trial: Ezetimibe + Simvastatin

Lowers ASCVD More than Simvastatin Alone

Cannon CP et al. N Engl J Med. 2015;372:2387-2397. Primary endpoint: cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization

~10% ↓relative risk after 1st year

Non-statin Add-on LDL-lowering Therapies

PCSK9 Inhibitors

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Rationale Behind PSCK9 as a Therapeutic Target

Rationale Behind PSCK9 as a Therapeutic Target

PCSK9 # of LDL Receptors LDL-C PCSK9 # of LDL Receptors LDL-C

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Sever P, Mackay J. Br J Cardiol. 2014;21:91-93. Giugliano RP et al. Lancet. 2012;380:2007-2017. Sabatine MS et al. N Engl J Med. 2015;372:1500-1509.

PCSK9 retains LDL-R in endosome  LDL-R destruction   LDL removal   plasma LDL-C

Physiology of PCSK9

Proprotein Convertase Subtilisin/Kexin Type 9

Physiology of PCSK9

Proprotein Convertase Subtilisin/Kexin Type 9

PCSK9 Mutations and Effect on LDL Metabolism

↓LDL-R levels ↓LDL clearance

↑LDL

High risk for ASCHD)

↓LDL

Protection from atherosclerosis and CHD

↑LDL-R levels ↑LDL clearance Gain of Function Loss of Function

LDL = low-density lipoprotein Adapted from Catapano AL, Papadopoulos N. Atherosclerosis. 2013;228:18-28. Soufi M et al. Gene. 2013;521:200-203.

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

PCSK9 Loss-of-Function Mutations

Resulted in Lower LDL-C Levels and Reduced CHD Rates

• Wild-type PCSK9 degrades LDL

receptors1,2

• 1%-3% of population have a loss-of-

function (LOF) mutation

• LOF mutations increase hepatic LDL

receptor expression, reducing LDL-C levels by 15%-40%2,3

• CHD incidence was reduced 47%-

88% in PCSK9 loss-of-function mutation carriers compared with normal individuals3

• 1. Peterson AS et al. J Lipid Res. 2008;49:1595-1599.
• 2. Cohen J et al. Nature Genetics. 2005;37:161-165.
• 3. Cohen JC et al. N Engl J Med. 2006;354:1264-1272.

n=301 n=9,223

11.8 6.3

Black Subjects

12

CHD (%)

2 8 10 6

White Subjects

Normal Subject Mutation Carrier

n=85 n=3,278

9.7 1.2 4

P=0.008 P=0.008

PCSK9 Inhibition

Enhanced LDL-C Reduction and Reduced CVD Risk

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

LDL-C Lowering Efficacy Dose-Response of Alirocumab and Evolocumab* LDL-C Lowering Efficacy Dose-Response of Alirocumab and Evolocumab*

ALIROCUMAB

mAb added to stable atorva dose of 10-40 mg QD with LDL-C ≥100 mg/dL n=183, Duration = 12 wks

% Change LDL-C EVOLOCUMAB

mAb added to stable statin and LDL-C > ~85 mg/dL n=631, Duration = 12 wks

% Change LDL-C 50 mg Q2W

• 35%

70 mg Q2W

• 42%

100 mg Q2W

• 59%

105 mg Q2W

• 60%

150 mg Q2W

• 67%

140 mg Q2W

• 66%

300 mg Q4W

• 43%

280 mg Q4W

• 42%

350 mg Q4W

• 50%

420 mg Q4W

• 50%

*Added to Stable Statin Therapy - Week 12

Giugliano et al. Lancet. 2012;380:2007-2017. McKenney et al. J Am Coll Cardiol. 2012;59:2344-2353.

Clinical Outcomes of PCSK9 Inhibitors

Meta-Analysis of 35 Randomized Clinical Trials

Clinical Outcomes of PCSK9 Inhibitors

Meta-Analysis of 35 Randomized Clinical Trials

End Point Fixed-effects Odds Ratio (95% CI) P Myocardial Infarction 0.72 (0.64-0.81) <0.001 Stroke 0.8l (0.68-0.97) 0.02 Coronary Revascularization 0.79 (0.72-0.86) <0.001 All Cause Mortality* 1.00 (0.88-1.14) 0.999 Cardiovascular Mortality 1.01 (0.85-1.19) 0.936 Neurocognitive Adverse Events 1.12 (0.94-1.33) 0.218

*: A significant association was shown between LDL-C and benefit in all-cause mortality

Karatasakis A et al. J Am Heart Assoc. 2017;6:e006910.

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Clinical Data on Alirocumab

Schwartz GG. Am Heart J. 2014;168:682-689.

Alirocumab: ODYSSEY Outcomes

Evaluation of Alirocumab After ACS

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018 Undesirably high baseline range 50 70 LDL-C (mg/dL) 15 25

Schwartz GG et al. Am Heart J. 2014;168:682-689.e1.

ODYSSEY Outcomes Design: Alirocumab Dose Adjustments to Stay within LDL-C Target Range

Undesirably high baseline range Target range Alirocumab Below target 50 70 LDL-C (mg/dL) 15 25 Acceptable range

Schwartz GG et al. Am Heart J. 2014;168:682-689.e1. Steg G. Presented at: American College of Cardiology; March 2018.

We attempted to maximize the number of patients in the target range and minimize the number below target by blindly titrating alirocumab (75 or 150 mg SC Q2W) or blindly switching to placebo.

Approximately 75% of months of active treatment were at the 75 mg dose

ODYSSEY Outcomes Design: Alirocumab Dose Adjustments to Stay within LDL-C Target Range

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

96.4 37.6 42.3 53.3 105 90 75 60 45 30 15 0 0 4 Mean LDL-C (mg/dL) 8 12 16 20 24 28 32 36 40 44 48 Months Since Randomization 93.3

 55.7 mg/dL –62.7% 54.1 mg/dL –61.0%

101.4

48.1 mg/dL –54.7%

ODYSSEY Outcomes: Alirocumab Lowers LDL-C

Placebo Alirocumab

Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo Approximately 75% of months of active treatment were at the 75 mg dose Steg G. Presented at: American College of Cardiology; March 2018.

ARR* 1.6%

Steg G. Presented at: American College of Cardiology; March 2018.

4-Point MACE =

• CHD death,
• Non-fatal MI,
• Ischemic stroke
• Unstable angina

requiring hospitalization 4-Point MACE =

• CHD death,
• Non-fatal MI,
• Ischemic stroke
• Unstable angina

requiring hospitalization

Alirocumab: ODYSSEY Outcomes

Alirocumab ↓MACE by 15%

*Based on cumulative incidence.

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

4-Point MACE =

• CHD death,
• non-fatal MI,
• ischemic stroke
• unstable angina

requiring hospitalization

Steg G. Presented at: American College of Cardiology; March 2018.

4-Point MACE =

• CHD death,
• Non-fatal MI,
• Ischemic stroke
• Unstable angina

requiring hospitalization 4-Point MACE =

• CHD death,
• Non-fatal MI,
• Ischemic stroke
• Unstable angina

requiring hospitalization

*Based on cumulative incidence.

ARR* 1.6%

Alirocumab: ODYSSEY Outcomes

Alirocumab ↓MACE by 15%, same as Evolocumab

Steg G. Presented at: American College of Cardiology; March 2018. Late-Breaker Presentation.

Alirocumab: ODYSSEY Outcomes

Alirocumab Reduces MACE

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

*Nominal P-value Steg G. Presented at: American College of Cardiology; March 2018. Late-Breaker Presentation.

Alirocumab Effects on Main Secondary Efficacy Endpoints: Hierarchical Testing in ODYSSEY Outcomes

Steg G. Presented at: American College of Cardiology; March 2018. Late-Breaker Presentation.

Alirocumab: ODYSSEY Outcomes

Alirocumab May Reduce Total Mortality*

ARR† 0.6%

*Nominal P-value †Based on cumulative incidence

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Steg G. Presented at: American College of Cardiology; March 2018. Late-Breaker Presentation.

Alirocumab: ODYSSEY Outcomes

Post Hoc Analysis: All-cause Death by Pre-specified Baseline LDL-C Subgroups

Clinical Data on Evolocumab

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Evolocumab: FOURIER

LDL Cholesterol

Evolocumab: FOURIER

LDL Cholesterol

Sabatine MS et al. Am Heart J. 2016;173:94-101.

Evolocumab: FOURIER

Primary Efficacy Endpoint

Evolocumab: FOURIER

Primary Efficacy Endpoint

Sabatine MS et al. Am Heart J. 2016;173:94-101.

ARR 2.0%

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Evolocumab: FOURIER

Key Secondary Endpoint

Evolocumab: FOURIER

Key Secondary Endpoint

Sabatine MS et al. Am Heart J. 2016;173:94-101.

Evolocumab: FOURIER

Landmark Analysis

Evolocumab: FOURIER

Landmark Analysis

Sabatine MS et al. Am Heart J. 2016;173:94-101.

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

20 40 60 80 100 120 140 160 180

LDL-C (mg/dL) at 4 weeks

20 40 60 80 100 120 140 160 180

Lowest LDL-C is Best for ASCVD Prevention

Evolocumab (FOURIER) Key 2o Endpoint (CV Death, MI, or Stroke)

P = 0.0001

LDL-C (mg/dL) Adj HR (95% CI) <20 0.69 (0.56-0.85) 20-50 0.75 (0.64-0.86) 50-70 0.87 (0.73-1.04) 70-100 0.90 (0.78-1.04) > 100 referent

Giugliano RP et al. Lancet. 2017;390:1962-1971.

Evolocumab Appears Effective (CVD) and Safe (SAE, D/C) to LDL-C <10 mg/dL*

7.3 4.4 5 10 15 CVD, MI, Stroke, UA, Cor Revasc CVD, MI, Stroke

CARDIOVASCULAR EFFICACY

HR 0.69 (0.49-0.97) P=0.03

11.9

HR 0.59 (0.37-0.92) P=0.02

7.8 5 10 15 20 25 30 Serious adverse event AE -> drug discontinued ≥100 mg/dL <10 mg/dL

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

Giugliano RP. Presented at:ESC Congress 2017, Barcelona; 8/28/2017.

HR 1.08 (0.63-1.85) P=0.78

3.4 3.4

HR 0.94(0.74-1.20) P=0.61

23.3 22.8

SAFETY

≥100 mg/dL <10 mg/dL

n = 504: Median [IQR] LDL-C: 7 [5-9] mg/dL

Percent Percent

*Exploratory Analysis of FOURIER

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Ebbinghaus: Evolocumab

Evaluation of Cognition with Aggressive LDL-C Lowering

Giugliano RP et al. N Engl J Med. 2017;377:633-643.

Even slightly better scores at lower achieved LDL-C CANTAB Tests Adj Ptrend Executive function 0.11 Working memory 0.61 Episodic memory 0.61 Reaction Time 0.47 Global Score 0.30 Everyday Cognition Self Survey Adj Ptrend Memory 0.11 Executive function 0.12 Planning 0.27 Organization 0.98 Divided attention 0.038 Total Score 0.017

New Guidance for PCSK9 Inhibitors and Ezetimibe

In Light of Cardiovascular Outcomes Data

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Recommendations for Primary Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L]) COR LOE Recommendations I B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL (≥4.9 mmol/L) or higher, maximally tolerated statin therapy is recommended. IIa B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL (≥4.9 mmol/L) or higher who achieve less than a 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/or have an LDL-C level of 100 mg/dL (≥2.6 mmol/L)

• r higher, ezetimibe therapy is reasonable.

Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L])

Recommendations for Primary Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L]) COR LOE Recommendations IIb B-R In patients 20 to 75 years of age with a baseline LDL-C level ≥190 mg/dL (≥4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides ≤300 mg/dL (≤3.4 mmol/L). while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid sequestrant may be considered. 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.

Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L])

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Recommendations for Primary Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L]) COR LOE Recommendations 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. Value Statement: Uncertain Value (B-NR) Among patients with FH without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at 2018 U.S. list prices.

Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L])

Cohen JD et al. J Clin Lipidol. 2017;11:891-900.

64% of respondents with ASCVD patients and 57% of respondents with FH patients were unable to get 3 out of every 4 PCSK9 inhibitor prescriptions approved, despite multiple appeals

None 1-25% 26-50% 51-75% More Than 75% Successful approvals, % ASCVD (n=298) FH (n=284) 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% Responses, %

Approval/Reimbursement Barriers Faced by Patients

% of Attempts to Get a PCSK9 Inhibitor Prescription that are Successful

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

Defining a “Reimbursement Roadmap”

To Address Cumbersome Approval/Reimbursement Process

• More consistent criteria by payers and checklists, algorithms,

apps, sharing of best practices which:

– Improve patient selection – Help to assure that required documentation is submitted – Reduce wasted time – Avoid frustration by healthcare providers and patients in the approval/denial process

Visit the resource table in the foyer to pick up a copy of the NLA’s Recom m endations for Patient-Centered Managem ent of Dyslipidem ia, part I and part II, Pocket Guides. W ant m ore? Visit Lipid.org to gain access to free online activities, educational flyers for your office, and more.

Educational Resources from the National Lipid Association

THE CRUCIAL PROBLEM OF ASCVD Can New Therapeutic Options Resolve It? MEDX Dallas/Fort Worth – November 17, 2018

THE CRUCI AL PROBLEM OF ASCVD Can New Therapeutic Options Resolve I t?

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