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Extending the Evidence: What did the FOURIER trial teach us on managing high risk patients? PCSK9i, Changing Practice in Cardiology: The Emerging Story ESC Satellite Symposium August 31, 2019 Marc S. Sabatine, MD, MPH Chairman, TIMI Study

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Extending the Evidence: What did the FOURIER trial teach us on managing high risk patients?

Marc S. Sabatine, MD, MPH

Chairman, TIMI Study Group Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine, BWH Professor of Medicine, HMS

PCSK9i, Changing Practice in Cardiology: The Emerging Story ESC Satellite Symposium – August 31, 2019

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

Trial Design

Evolocumab SC

140 mg Q2W or 420 mg QM

Placebo SC

Q2W or QM LDL-C ≥70 mg/dL (1.8 mmol/L) or non-HDL-C ≥100 mg/dL (2.6 mmol/L)

Follow-up Q 12 weeks Median f/up 2.2 yrs

Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED DOUBLE BLIND

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

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

Summary of Effects of PCSK9i Evolocumab

 LDL-C by 59% down to a median of 30 mg/dl
 CV outcomes in patients on statin
Safe and well-tolerated

Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) Placebo 59% reduction P<0.00001 Absolute  56 mg/dl 14,6 9,9 12,6 7,9

5 10 15 KM Rate (%) at 3 Years

HR 0.85 (0.79-0.92) P<0.0001 HR 0.80 (0.73-0.88) P<0.0001

CVD death, MI, stroke, UA, cor revasc CVD death, MI, stroke

Sabatine MS et al. NEJM 2017;376:1713-22

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

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 1° Endpoint HR (95% CI) Key 2° Endpoint HR (95% CI)

1.0

EvoMab better Pbo better

0.4 2.5 1.0

EvoMab better Pbo better

0.4 2.5

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

10 20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120 132 144 LDL Cholesterol (mg/dl) Weeks

LDL Cholesterol

2034 patients w/ baseline LDL-C<70 mg/dL

Evolocumab (median 21 mg/dl, IQR 11.5-37 mg/dl) Placebo (median 66 mg/dl, IQR 56-78 mg/dl) 66% mean reduction (95%CI 62-69), P<0.00001

Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91

(median 0.5 mmol/L, IQR 0.3-1.0 mmol/L) (median 1.7 mmol/L, IQR 1.4-2.0 mmol/L)

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

CVD, MI, stroke, UA, or cor revasc HR (95% CI) Pinteraction All Patients 0.85 (0.79-0.92) Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07) Baseline LDL-C ≥70 mg/dL 0.86 (0.79-0.92)

Clinical Outcomes

by Baseline LDL-C

0.65

1.0

EvoMab better Pbo better

0.4 2.5

CVD, MI, or stroke All Patients 0.80 (0.73-0.88) Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01) Baseline LDL-C ≥70 mg/dL 0.81 (0.73-0.89)

1.0 0.4 2.5

0.44

Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91

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

Efficacy of LDL-C Lowering Even When LDL-C ≤70 mg/dL (1.8 mM)

Sabatine MS et al. JAMA Cardiol 2018;3:823-8

Trial LDL-C (mg/dl) Expt Arm Ctrl Arm RR (95% CI) per 1 mM  in LDL-C Statins CTTC <2 mmol/L subgp 66 910 1012 0.78 (0.65-0.94) Non-statin LDL-C Lowering IMPROVE-IT 70 2455 2649 0.79 (0.67-0.93) FOURIER <1.8 mmol/L subgp 66 81 103 0.80 (0.61-1.04) REVEAL 63 2068 2214 0.77 (0.63-0.96) Summary 4604 4966 0.79 (0.70-0.88) OVERALL SUMMARY 5514 5978 0.79 (0.71-0.87) P=0.00005 P=0.000001

0.2 0.5 1 2 5 LDL-C Lowering Better LDL-C Lowering Worse

Events Starting Major Vascular Events

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

Efficacy by Diabetes Status

13,0 17,1 11,4 14,4

5 10 15 20

No Diabetes Diabetes

CV Death, MI or Stroke, UA or Cor Revasc (KM Rate at 3 yrs)

Sabatine MS et al. Lancet Diab Endocrin 2017;5:941-50

RRR 13% 17% ARR 1.6% 2.7%

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

Efficacy by Baseline CKD Stage

7,1 7,7 12,8 5,4 6,2 10,3

5 10 15

≥90 60 to <90 <60

CV Death, MI or Stroke KM Rate (%) at 30 Months

eGFR (ml/min/1.73 m2)

Charytan et al. JACC 2019;73:2961-70

RRR 25% 18% 21% ARR 1.7% 1.5% 2.5%

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

Benefit of EvoMab Based on Time from Qualifying MI

Qualifying MI <2 yrs ago

Months after Randomization

CV Death, MI, or Stroke

6 12 18 24 30 36

24% RRR HR 0.76 (95% CI 0.64-0.89) P<0.001 7.9% 10.8%

Pinteraction=0.18

D 2.9% NNT 35 Evolocumab Placebo 8.3% 9.3% D 1.0% NNT 101 Qualifying MI ≥2 yrs ago 13% RRR HR 0.87 (95% CI 0.76-0.99) P=0.04

6 12 18 24 30 36

Sabatine et al. Circ 2018;138:756-66

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

Benefit of EvoMab Based on # of Prior MIs

≥2 Prior MIs

Months after Randomization

CV Death, MI, or Stroke

6 12 18 24 30 36

21% RRR HR 0.79 (95% CI 0.67-0.94) P=0.006 12.4% 15.0%

Pinteraction=0.57

D 2.6% NNT 38 Evolocumab Placebo 6.6% 8.2% D 1.7% NNT 60 1 Prior MI 16% RRR HR 0.84 (95% CI 0.74-0.96) P=0.008

6 12 18 24 30 36

Sabatine et al. Circ 2018;138:756-66

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

Benefit of EvoMab Based on Multivessel Disease

Multivessel Disease

Months after Randomization

CV Death, MI, or Stroke

6 12 18 24 30 36

30% RRR HR 0.70 (95% CI 0.58-0.84) P<0.001 9.2% 12.6%

Pinteraction=0.03

D 3.4% NNT 29 Evolocumab Placebo 7.6% 8.9% D 1.3% NNT 78 No Multivessel Disease 11% RRR HR 0.89 (95% CI 0.79-1.00) P=0.055

6 12 18 24 30 36

Sabatine et al. Circ 2018;138:756-66

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

Overlap Between Factors

22,351 patients w/ prior MI 8402 Pts <2 y from MI 5618 Pts w/ MVD 5285 Pts ≥2 MIs

63% of the population w/ at least 1 risk factor 37% of the population

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

0% 2% 4% 6% 8% 10% 12%

Benefit of EvoMab Based on # of High-Risk MI Features

Months after Randomization

CV Death, MI, or Stroke

6 12 18 24 30 36

Pinteraction=0.11

Evolocumab Placebo ≥1 Feature 22% RRR 2.5% ARR

High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or residual multivessel disease

Sabatine et al. Circulation 2018;138:756-66 0 Features 6% RRR 0.5% ARR

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

0% 2% 4% 6% 8% 0% 2% 4% 6% 8%

Landmark Analyses in Pts w/ a High-Risk MI Feature

Evolocumab Placebo

Months from Randomization

CV Death, MI, Stroke

3 9 12 24 30 36 6 12 18

19% RRR

HR 0.81 (95%CI 0.68-0.95) P=0.01

27% RRR

HR 0.73 (95%CI 0.62-0.86) P<0.001

High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or multivessel disease

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

Landmark Analyses in Pts w/ a High-Risk MI Feature

Months from Randomization

CV Death, MI, Stroke

3 9 12 6

19% RRR

HR 0.81 (95%CI 0.68-0.95) P=0.01

24 30 36 12 18

27% RRR

HR 0.73 (95%CI 0.62-0.86) P<0.001 Evolocumab Placebo 2% absolute risk reduction

ver 2 years

If same pattern continues, would extrapolate to 5% ARR

ver 5 years

NNT5y of ~20

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

CV Death, MI or Stroke in Patients w/ & w/o Peripheral Artery Disease

Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50

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

Major Adverse Limb Events

Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50

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

Conclusions

1. Evolocumab reliably reduces LDL-C by ~60% 2. Reduces risk of major vascular events in Pts w/ ASCVD already on statin

Confirms benefit from lowering LDL-C to <1 mM
Benefit grows over time

3. Largest absolute risk reductions in Pts w/ highest baseline risk & largest amount of athero

Diabetes, CKD
Closer to MI, multiple prior MIs, multivessel CAD
PAD