The Use of Monoclonal Antibodies in Primary and Secondary

Prevention

Michael D. Shapiro Associate Professor of Medicine and Radiology

Center for Preventive Cardiology Knight Cardiovascular Institute

Oregon Health & Science University

Disclosures

Research funding NIH K12 HD043488 Knight Cardiovascular Institute FH Foundation

Contracted Research Akcea, Amarin

Advisory Boards Esperion, Regeneron, Novartis

Questions

• Why do we need additional preventive therapies?

• How do PCSK9 inhibitors work and in whom should they be used?

• What are the clinical data for the safety and efficacy of PCSK9 inhibitors?

Case

62 yo male presents to clinic after recent ACS

Prior history of CAD DES to mid-LAD 2013 NSTEMI with DES to mid-RCA 3-months ago

Feels well, active; no angina

BP 128/74 P 62 BMI 27 kg/m2

Otherwise unremarkable

Medications

Atorvastatin 80 mg daily Ezetimibe 10 mg daily ASA 81 mg daily Clopidogrel 75 mg daily Metoprolol succinate 100 mg daily Lisinopril 20 mg po qd

Case

K 3.9 mEq/L

Cre 1.0 mg/dL

AST 27 U/L

ALT 20 U/L

TSH normal

hs-CRP 2.6 mg/L

Glucose 92 mg/dL

HgbA1c 5.6%

Labs (on LLT)

Total Chol 176 mg/dl LDL-C 110 mg/dL Triglycerides 140 mg/dL HDL-C 38 mg/dL

Case

1) Does this patient require additional treatment?

2) If so, what?

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

0

20

40

60

80

100

120

140

160

180

200

LDL-

C (m

g/dL

) TAKE HOME MESSAGE:

After a Quarter of a Century of Treating LDL-C

1994 1996-2002 2004-2005 2015 2017

TNT

Residual Risk Despite Statins

Lancet. 2005;366:1267-1278

Is Even Lower LDL-C Better?

IMPROVE-IT: Primary Results

*Primary end point (cardiovascular death, MI, unstable angina, coronary revascularization, or stroke). Cannon CP, et al. N Engl J Med. 2015;372(25):2387-97.

18,144 ACS patients randomized to simvastatin alone or ezetimibe (EZ)/simvastatin, Mean Follow-up 5.68 Years

100

40 8

50

90

60

80

70

72

Mea

n LD

L-C

(mg/

dL)

Time since Randomization (months) 1 48 R 36 QE 24 4 60 16 96 12 84

Median Time avg 69.5 vs 53.7 mg/dL

Simvastatin EZ/Simvastatin

Even

t Rat

e (%

)*

40

0

5

35

10

25

15

Time since Randomization (years) 4 3 0 2 5 1 7 6

30

20

Simvastatin – 34.7% (2742 Events)

EZ/Simvastatin – 32.7% (2572 Events)

NNT = 50 HR 0.936 CI (0.887, 0.988), P = 0.016

• Any patient with hypercholesterolemia not achieving LDL-C goal1,2

• Patients who are intolerant or have a inadequate response to statin therapy3,4

• Difficult to treat patients5,6

– Familial hypercholesterolemia

– Diabetes

Who may need additional therapies beyond statins to control LDL-C?

1. Ballantyne CM, et al. Am Heart J. 2005;149:464-73. 2. Karalis DG, et al. Cholesterol. 2012;2012:861924. 3. Sullivan D, et al. JAMA. 2012;308(23):2497-2506. 4. Kataoka Y, et al. Arterioscler Thromb Vasc Biol. 2015; 35(4):990-5. 5. Stein EA, et al. Am J Cardiol. 2003;92(11):1287-93. 6. Stark Casgrande S, et al. Diabetes Care. 2013;36(8):2271-9.

LDLR Function and Life Cycle

Role of PCSK9 in the Regulation of LDLR Expression

Impact of PCSK9i on LDLR Expression

Efficacy and Safety of PCSK9 Inhibitors

Mean percentage change in calculated LDL-C from baseline in the modified intent-to-treat (mITT) population by treatment group. McKenney JM, et al. J Am Coll Cardiol. 2012;59:2344-2353.

LDL-C Dose Response to Alirocumab Every 2 Weeks

-80

0

-60

-20

-40

-10

-70

LDL-

C M

ean

(±SE

E)

% C

hang

e fr

om B

asel

ine

Randomized, double-blind trial of 183 pts with LDL-C ≥100 mg/dL on a stable dose of atorvastatin 10, 20, or 40 mg for 6 weeks

Week 6 Week 10 Week 12 Week 8 Baseline Week 2 Week 4

-30

-50

∆ -5.1%

∆ -39.6%

∆ -64.2%

∆ -72.4%

Alirocumab 50 mg Q2W Alirocumab 100 mg Q2W Placebo

Alirocumab 150 mg Q2W

∆ -8.5%

∆ -30.5%

∆ -53.6%

∆ -62.9%

ODYSSEY LONG TERM: LDL-C Goal Attainment

Robinson JG, et al. N Engl J Med. 2015;372:1489-99.

Alirocumab 150 mg Q2W Placebo

Proportion of Patients Reaching LDL-C Goal at Week 24

90

Patie

nts

(%)

10

50

0 Very High-Risk:

LDL-C <1.8 mmol/L (70 mg/dL) High-Risk:

<2.6 mmol/L (100 mg/dL)

20

80

<1.8 mmol/L (70 mg/dL) Regardless of Risk

30

70

8 9

79 81

60

40

P < 0.0001 P < 0.0001

LAPLACE-TIMI 57: Dose Response to Evolocumab Every 2 Weeks

Giugliano RP, et al. Lancet. 2012:380:2007-17.

Randomized, double-blind trial of 631 pts with LDL-C ≥ 85 mg/dL on a stable dose of statin with or without ezetimibe for ≥ 4 weeks

Baseline -100

10

-70

-30

Week 4 Week 12

-50

-10

-90

Mea

n %

Cha

nge

from

Bas

elin

e in

Cal

cula

ted

LDL-

C

Week 2 Week 6 Week 8 Week 10

0

-80

-40

-60

-20

AMG145 70 mg Q2W (n=79) AMG145 105 mg Q2W (n=79) Placebo Q2W (n=78)

AMG145 140 mg Q2W (n=78)

Study Drug Administration

p < 0.0001 for weeks 2-12 for each dose vs placebo

Number of

Patients 79 79 78 78

78 76 77 74

77 76 76 77

75 77 77 78

76 73 75 76

76 77 76 77

76 74 73 74

DESCARTES: LDL-C Goal Attainment

Blom DJ, et al. NEJM. 2014:370:1809-19.

Evolocumab Placebo

Proportion of Patients Reaching LDL-C Goal at Week 52

90

Patie

nts

(%)

10

50

0 LDL-C <1.8 mmol/L (70 mg/dL)

20

80

30

70

6

82

60

40

P < 0.0001

Cardiovascular Outcomes Trials FOURIER vs. ODYSSEY

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

New-Onset Diabetes

4.0%

7.3%

11.6%

3.8%

7.0%

10.9%

0%

4%

8%

12%

16%

20%

End of Year 1 End of Year 2 End of Year 3

Kapl

an-M

eier

Rat

e in

Pa

tient

s w/o

Dia

bete

s at B

asel

ine

EvolocumabPlacebo

P=0.43

P=0.64

P=0.32

In all patients w/o diabetes at baseline (1294 incident cases in 16,510 patients): HR 1.05 (0.94-1.17)

In patients w/ prediabetes at baseline (1163 incident cases in 10,338 patients): HR 1.00 (0.89-1.13)

Sabatine MS et all, Lancet Diabetes Endocrinol 2017; 5(12):941-50

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

Safety Events by Achieved LDL-C

0

5

10

15

20

25% Patients (n/N)

Adj P-values for trend >0.10 for each comparison

% pts

0

5

10

<20

20-49

50-69

70-99

≥100

LDL-C (mg/dL)

% pts

Giugliano RP et al, Lancet 2017;309:1962–71

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

0%

3%

6%

9%

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31

KM

Eve

nt R

ate

of C

VD

, MI,

Stro

ke

Months after Randomization

≥100 <10

LDL-C (mg/dL) at 4 wks

504 Pts, LDL <10 mg/dl at 4 wks (Median LDL 7 mg/dL [IQR 5-9]

Adj RRR

41%

NZ White Rabbit

Havel RJ, Arteriosclerosis 1982: 2:467-74

LDL-C (mg/dL) Males: 11.5 + 3.3 Females: 11.3 + 1.3

Giugliano RP et al, Lancet 2017;309:1962–71

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

Exploratory Analysis Pts with Single Digit LDL-C at 4 wks

11.9

7.8 7.3

4.4

0

5

10

15

CVD, MI, Stroke,UA, Cor Revasc

CVD, MI, Stroke

≥100 mg/dL <10 mg/dL

Cardiovascular Efficacy Adj HR 0.69 (0.49-0.97)

P=0.03 Adj HR 0.59 (0.37-0.92)

P=0.02

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

23.3

3.4

22.8

3.4

0

5

10

15

20

25

30

Serious adverseevent

AE -> drugdiscontinued

≥100 mg/dL <10 mg/dL

Adj HR 0.94 (0.74-1.20)

P=0.61

Adj HR 1.08 (0.63-1.85)

P=0.78

Safety

Giugliano RP et al, Lancet 2017;309:1962–71

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

0%

2%

4%

6%

8%

10%

12%

14%

0%

2%

4%

6%

8%

10%

12%

14%

Effect of Evolocumab on Key 2° EP Stratified by DM

Patients w/o Diabetes at Baseline Patients w/ Diabetes at Baseline

Months after Randomization

CV

Dea

th, M

I, St

roke

0 6 12 18 24 30 36

Hazard Ratio 0.82 (95% CI 0.72-0.93)

P=0.0021 10.2%

12.2%

0 6 12 18 24 30 36

Hazard Ratio 0.78 (95% CI 0.69-0.89)

P=0.0002

6.4%

8.4%

Pinteraction=0.65

∆ 2.0% NNT 50

∆ 2.0% NNT 50

Evolocumab

Placebo

Sabatine MS et all, Lancet Diabetes Endocrinol 2017; 5(12):941-50

ODYSSEY Outcomes Trial

Presented at ACC.18

Main Inclusion Criteria

• Age ≥40 years • Recent ACS

– 1 to 12 months prior to randomization – High-intensity (or maximally tolerated) statin therapy

• Atorvastatin 40 to 80 mg daily or • Rosuvastatin 20 to 40 mg daily or

• Maximum tolerated dose of one of these agents for ≥2 weeks • Inadequate control of lipids

– LDL-C ≥70 mg/dL or – Non-HDL-C ≥100 mg/dL or – Apolipoprotein B ≥80 mg/dL

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

Patient Disposition

LBCT ACC.18

Primary Efficacy Outcome

Time of first occurrence of: • Coronary heart disease (CHD) death, or • Non-fatal MI, or • Fatal or non-fatal ischemic stroke, or • Unstable angina requiring hospitalization

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

Treat to Target

LBCT ACC.18

Treat to Target

LBCT ACC.18

Treat to Target

LBCT ACC.18

Baseline Lipids

LBCT ACC.18

Baseline Lipid Lowering Therapy

LBCT ACC.18

LDL-C: ITT and On-Treatment Analyses

LBCT ACC.18

Primary Endpoint: MACE

LBCT ACC.18

All-Cause Death

LBCT ACC.18

Subgroup with baseline LDL-C >100

p-value for interaction of treatment-benefit with starting LDL-C = 0.12

No formal evidence that RRR varies by starting LDL-C

LBCT ACC.18

PCSK9 inhibition improves CV Outcomes

Case

62 yo male presents to clinic after recent ACS

Prior history of CAD DES to mid-LAD 2013 NSTEMI with DES to mid-RCA 3-months ago

Feels well, active; no angina

BP 128/74 P 62 BMI 27 kg/m2 Otherwise unremarkable

Medications and Labs

Atorvastatin 80 mg daily Ezetimibe 10 mg daily

Total Chol 176 mg/dl LDL-C 110 mg/dL Triglycerides 140 mg/dL HDL-C 38 mg/dL

Case

1) Does this patient require additional treatment?

2) If so, what?

Summary

Discovery of PCSK9 15 years ago has ushered in an exciting era of LDL-C lowering

Now have data from 2 large CVOTs that demonstrate improvement in CV outcomes

Ongoing research is needed to understand optimal candidates for therapy

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

0

20

40

60

80

100

120

140

160

180

200

LDL-

C (m

g/dL

) TAKE HOME MESSAGE:

After a Quarter of a Century of Treating LDL-C

1994 1996-2002 2004-2005 2015 2017

TNT

Thank you

shapirmi@ohsu.edu