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