Evolocumab HCP presentation.pptx

New Approaches in Dyslipidemia
Management:How does Evolocumab
change clinical practice in Dyslipidemia
management?

Agenda
• Unmet medical need in Cardiovascular Disease
• PROFICIO Clinical Trials Program (Amgen Research
program to evaluate efficacy & safety of Evolocumab)
• Updated guidelines in Dyslipidemia Management
• Summary
• Discussion

3
EVERY HOUR 5 ADULTS IN SAUDI ARABIA DIE FROM
CARDIOVASCULAR DISEASE CAUSES
WHO. Noncommunicable diseases country profiles 2014. Available online at: http://www.who.int/nmh/publications/ncd-profiles-2014/en/
Cardiovascular Disease
46%
Cancers
10%
Chronic respiratory diseases
3%
Diabetes
5%
Other Non-Communicable
Diseases
14%
Communicable, maternal, perinatal,
and nutritional conditions
13%
Injuries
9%
PERCENTAGE OF TOTAL ANNUAL KSA DEATHS
(n=90,000)

4
INTERHEART: MULTIPLE RISK FACTORS
ALL INHABITED CONTINENTS
36
14 12
7
18
10
20
33
50
90
Smoking Fruit/Veg Exercise Alcohol Hypertension Diabetes Abd Obesity Psychosocial Lipids All 9 Risk
Acute Myocardial Infarction : >90% of
attributable burden is from
9 modifiable risk factors
Yusuf S Lancet 2004;364:937-952

LDL is Strongly Associated with Coronary Heart Disease
Kolodgie FD, et al. Heart 2004;90:1385-91.
Grundy S, et al. Circulation. 2004;110:227-239.
Cannon CP, et al. JACC 2006;48-438-445.
Every 39 mg/dL (1 mmol/L) decrease in LDL-C
decreases relative risk for CHD by ~1-2% (20-25%)
MRFIT
ARIC
PROCAM
Cholesterol hypothesis
originated with observations
Cholesterol Clefts
Clinical trials validate
the hypothesis

PCSK9 Inhibition in clinical practice:
Mechanisms of action and prescription
of therapy

PCSK9 Inhibitors (PCSK9i)
• Proprotein Convertase Subtilisin/Kexin type 9
–Fully humanized monoclonal antibody
–Subcutaneous injection
• New and unique opportunities for CVD risk reduction
–Additional LDL-C lowering when used in combination with
statin + ezetimibe

Discovering the role of PCSK9 in LDL-C
regulation and ASCVD risk
1 Cohen et al NEJM 2006;354:1264-1272 3 Benn et al JACC 2010;55:2833-2842
2 Cohen et al Nat Genet 2005;37:161-165 4 Zhao et al Jrnl of Hum Gen 2006;79:514-534
• He LOF mutations found in
1-3% of population
• Associated w/ : lifelong
modestly lower serum
LDL-C
• Lower incidence of CHD
due to prolonged LDL-C
reduction

Duration of LDL-C Lowering : Genetics vs Statins
Willer Nat Gen 2008; Linsel-Nitchke PlosOne 2008; Stender JACC 2014; Stitziel NEJM 2014
-100%
-80%
-60%
-40%
-20%
0%
Reduction
in
CHD
Reduction in LDL-C
0% -10% -20% -30% -40%
Genetic Variants
Lifelong
Statin Trials
5 Years
PCSK9
Y142X
C679X
PCSK9
R46L
NPC1L1
LDLR
ABCG8
APOB
4S
WOSCOPS
HPS
CARE
Lifelong reductions in
PCSK9 reduce CHD
CHD=Coronary Heart Death

LDL Receptor (LDL-R) Function and Life Cycle
Receptor
re-used
~200x
Hepatocyte
LDL
Reduction

Role of PCSK9 in the Regulation of LDLR
Expression
X
Hepatocyte
LDLR
destroyed
Reduced
LDLR density
No LDL-C
Reduction

Impact of PCSK9i on LDLR Expression
PCSK9
antibody
PCSK9 mAb-PCSK9 Complex
Receptor
recycled
~200x
Increased
LDLR density
LDL-C
Reduction

Evolocumab is a Fully Human Monoclonal Antibody
Against PCSK9 and Inhibits PCSK9/LDL-R Interaction
Chan JC, Piper DE, Cao Q, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.

HeFH, heterozygous hypercholesterolemia; HoFH, homozygous hypercholesterolemia. ClinicalTrials.gov. Accessed September 2015.
Evolocumab: PROFICIO addresses key areas of
unmet need in the management of dyslipidemia
Combination
therapy
Statin intolerant
Monotherapy
HeFH
Long-term
safety and efficacy
Open-label
extension
HoFH/ Severe
FH
Secondary
Prevention
Atherosclerosis
Phase 2
(n=631)
Phase 3
(n=1896)
Phase 2
(n=411)
Phase 3
(n=614)
Phase 2
(n=160)
Phase 3
(n=329)
Phase 2
(n=168)
Phase 2
(n=1324)
Phase 3
(n=4428)
Phase 3
(n=901)
Phase 3
(n=27,564)
Phase 3
(n=950)
Phase 2/3
(n=300)
Phase 2/3
(n=58)
Neurocognition
Phase 3
(n=1972)
Phase 3
(n=307)
Phase 3
(n=519)
>35,000 patients

Evolocumab consistency in Reducing LDL-C among all patients
(High Risk & FH Patients: Phase III LDL-C Lowering Summary
10
0
-10
-20
-30
-40
-50
-60
-60
-50
-40
-30
-20
-10
0
10
%
Change
from
Baseline
In
Reflexive
LDL-C
MENDEL-2*
(Monotherapy)
QM
Q2W
QM
Q2W
–57%
–56.9%
–0.1%
*Ezetimibe comparator
Koren MJ, et al. J Am Coll Cardiol. 2014;63(23):2531-2540 (MENDEL-2); Stroes E, et al. JACC 2014:10.1016/j.jacc.2014.03.019 (GAUSS-2); Robinson JG, et al. JAMA. 2014;311(18):1870-
1882. doi:10.1001/jama.2014.4030 (LAPLACE-2); Raal F, et al. Lancet. 2014. Published Online October 2, 2014. http://dx.doi.org/10.1016/S0140-6736(14)61399-4.(RUTHERFORD-2).
10
0
-10
-20
-30
-40
-50
-60
-60
-50
-40
-30
-20
-10
0
10
QM
Q2W
QM
Q2W
Placebo wk10&12
Placebo wk12
EvoMab wk10&12
EvoMab wk12
Ezetimibe wk10&12
Ezetimibe wk12
LAPLACE-2
(Combo with Statin)
GAUSS-2*
(Statin Intolerance)
RUTHERFORD-2
(FH, Combo with Statin)
–17.5%
–17.8%
–0.4% –1.4% –1.3%
–58.8% –56.1%
–19.1%
–18.6%
–62% –63% –64% –58%
+6.8%
+8.1%
+3.2%+4.6%
–56.1% –56.1%
–19.2%
–18.1%
–55.3% –52.6%
–16.6%
–15.1%
–61% –61%
–64%
–56%
–1%
+2%
–1%
+5%

17
Repatha provided a -32%
reduction in LDL-C compared to
placebo
Repatha may provide a viable
alternative for patients in whom
LDL apheresis is the only
suitable treatment option
IN PATIENTS WITH HOFH,
REPATHA IS THE ONLY PCSK9 INHIBITOR APPROVED FOR THE TREATMENT OF
HOFH AND REDUCES LDL-C BY UP TO 32% COMPARED WITH OTHER LLTS
-30%
-20%
-10%
0%
10%
Sources: (TESLA study) Raal et al, 2014; Repatha EPAR, Last Updated Oct 2016 Wang et al., 2016.
MEAN LDL-C % CHANGE FROM BASELINE
FOR HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HoFH) SUBJECTS
-23%
LS
Mean
LDL-C
%
Change
From
Baseline
Between
Week
12
+9%
*High- to moderate-intensity statin therapy.
Placebo +
Background Statin*
Repatha 420mg QM + Background
Statin*

Marc S. Sabatine, MD, MPH,a Robert P. Giugliano, MD,a Anthony C. Keech, MD,b
Narimon Honarpour, MD, PhD,c Stephen D. Wiviott, MD,a Sabina A. Murphy, MPH,a
Julia F. Kuder, MA,a Huei Wang, PhD,c Thomas Liu, PhD,c Scott M. Wasserman, MD,c
Peter S. Sever, PhD, FRCP,d and Terje R. Pedersen, MDe for the FOURIER Steering
Committee and Investigators
From the aTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, bSydney Medical School, NHMRC
Clinical Trials Centre, University of Sydney, Sydney, cAmgen, Thousand Oaks, CA, dInternational Centre for Circulatory Health, National Heart and Lung Institute, Imperial
College London, London, and eOslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo.
Repatha Outcomes Trial:
Evolocumab and Clinical Outcomes
in Patients with Cardiovascular
Disease
Sabatine MS, et al. NEJM. [published online ahead of print March 17, 2017]. doi: 10.1056/NEJMoa1615664
SC-MEA-AMG145-00114 Apr 17

Evolocumab Outcomes Trial:
Study Design Overview
Screening
• Age 40–85 years
• MI, stroke, or PAD
• Additional risk factors (one
major or two minor)
• Optimal background lipid
therapy (including effective dose
of statin ± ezetimibe)
• LDL-C ≥ 70 mg/dL or
non–HDL-C ≥ 100 mg/dL
Evolocumab SC
140 mg Q2W or 420 mg QM
(per subject preference)
n ~ 13,750
Placebo SC
Q2W or QM
(per subject preference)
n ~ 13,750
Randomization
1:1
End
of
Study
(EOS)
Maximum approximately 15 weeks D1 W4 W12 W24 Q24W Number of
key 20
endpoints
achieved
D = day; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol;
MI = myocardial infarction; PAD = peripheral artery disease; Q2W = every 2 weeks; Q24W = every 24 weeks; QM = every
month; SC = subcutaneous; W = week.
Sabatine MS, et al. Am Heart J. 2016;173:94-101.

Evolocumab Outcomes Trial:
Study Endpoints
Endpoint Description
Primary*
• Composite of CV death, MI, stroke, hospitalization for unstable
angina, or coronary revascularization
Key secondary† • Composite of CV death, MI, or stroke
Other
Secondary
• All-cause death; CV death; MI; stroke; coronary
revascularization; CV death or hospitalization for heart failure;
ischemic stroke or transient ischemic attack
*Time to CV death, MI, stroke, hospitalization for UA, or coronary revascularization, whichever occurs first
†Time to CV death, MI, or stroke, whichever occurs first
CV = cardiovascular; MI = myocardial infarction
Sabatine MS, et al. Am Heart J. 2016;173:94-101.
• Sample size based on key secondary endpoint and powered to detect a
15% risk reduction at 90% power
– Assuming 2% per year event rate in placebo arm, 27,500 patients followed up
for a median of ~43 months should have provided 1,630 key secondary
endpoints
• Efficacy analysis was hierarchical:
– If primary endpoint was significantly reduced, then key secondary endpoint was
to be tested, followed in order by CV death, all-cause mortality, then additional
secondary endpoints

Baseline CV Risk Factors
*Patients could have more than one type of atherosclerosis.
CV = cardiovascular; MI = myocardial infarction.
Characteristics
Evolocumab
(N = 13,784)
Placebo
(N = 13,780)
Type of atherosclerosis* – n (%)
Myocardial infarction 11,145 (80.9) 11,206 (81.3)
Time from most recent prior MI – yr (IQR) 3.4 (1.0-7.4) 3.3 (0.9-7.7)
Non-hemorrhagic stroke 2,686 (19.5) 2,651 (19.2)
Time from most recent prior stroke – yr (IQR) 3.2 (1.1-7.1) 3.3 (1.1-7.3)
Peripheral artery disease – n (%) 1,858 (13.5) 1,784 (12.9)
Cardiovascular risk factors
Hypertension – n/total n (%) 11,045/13,784 (80.1) 11,039/13,779 (80.1)
Diabetes mellitus – n (%) 5,054 (36.7) 5,027 (36.5)
Current cigarette use – n/total n (%) 3,854/13,783 (28.0) 3,923/13,779 (28.5)

Baseline Lipid-Lowering Therapies
and Lipid Parameters
*Statin intensity was categorized per the ACC/AHA Guidelines. Note, that in some countries where FOURIER was conducted, higher statin doses
are not approved. HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a) = Lipoprotein(a); IQR = Inter-quartile range
Malinowski HJ, et all. J Clin Pharmacol. 2008;48:900-908
Characteristics
Evolocumab
(N = 13,784)
Placebo
(N = 13,780)
Statin use* – n (%)
High intensity 9,585 (69.5) 9,518 (69.1)
Moderate intensity 4,161 (30.2) 4,231 (30.7)
Low intensity, unknown intensity, or no data 38 (0.3) 31 (0.2)
Ezetimibe – n (%) 726 (5.3) 714 (5.2)
Other cardiovascular medications – n/total n (%)
Aspirin and/or P2Y12 inhibitor 12,766/13,772 (92.7) 12,666/13,767 (92.0)
Beta-blocker 10,441/13,772 (75.8) 10,374/13,767 (75.4)
ACE inhibitor or ARB and/or aldosterone
antagonist 10,803/13,772 (78.4) 10,730/13,767 (77.9)
Lipid measures - Median (IQR) – mg/dL
LDL cholesterol – mg/dL 92 (80, 109) 92 (80, 109)
Total cholesterol – mg/dL 168 (151, 188) 168 (151, 189)
HDL cholesterol – mg/dL 44 (37, 53) 44 (37, 53)
Triglycerides – mg/dL 134 (101, 183) 133 (99, 181)
Lp(a) - nmol/L 37 (13, 166) 37 (13, 164)

Median LDL-C Levels Over Time:
All Patients
LDL-C was significantly reduced in the evolocumab group (median: 30 mg/dL)
including 42% who achieved levels ≤ 25 mg/dL vs < 0.1% in the placebo group
Placebo
Median 92 mg/dL
Evolocumab
Median 30 mg/dL
13,251 13,151 12,954 12,596 12,311 10,812 6,926 3,352 790
13,779
Placebo
13,288 13,144 12,964 12,645 12,359 10,902 6,958 3,323 768
13,784
Evolocumab
No. at risk
4
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Weeks
59% mean reduction (95%CI 58-60), P < 0.001
Absolute reduction: 56 mg/dL (95% CI 55-57)
LDL
Cholesterol
(mg/dL)
Data shown are median values with 95% confidence intervals in the two arms; ITT.

Primary & Key Secondary Endpoints
0%
2%
4%
6%
8%
10%
12%
14%
16%
Evolocumab
Placebo
Months after Randomization
Primary
Endpoint:
CV
Death,
MI,
Stroke,
Hosp
for
UA,
or
Cor
Revasc
0 6 12 18 24 30 36
Hazard ratio 0.85
(95% CI, 0.79-0.92)
P<0.0001
0%
2%
4%
6%
8%
10%
12%
14%
16%
0 6 12 18 24 30 36
Key
Secondary
Endpoint:
CV
Death,
MI,
or
Stroke
Hazard ratio 0.80
(95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo
Sabatine MS et al. NEJM 2017;376:1713-1722

Primary, Key Secondary, and Other Endpoints
Outcome
Evolocumab
(n = 13,784)
n (%)
Placebo
(n = 13,780)
n (%)
HR
(95% CI)
P-
value‡
Primary endpoint* 1,344 (9.8) 1,563 (11.3) 0.85 (0.79-0.92) <0.001
Key secondary endpoint† 816 (5.9) 1,013 (7.4) 0.80 (0.73-0.88) <0.001
Other endpoints
CV death 251 (1.8) 240 (1.7) 1.05 (0.88-1.25) 0.62
Death from any cause 444 (3.2) 426 (3.1) 1.04 (0.91-1.19) 0.54
MI 468 (3.4) 639 (4.6) 0.73 (0.65-0.82) <0.001
Hospitalization for UA 236 (1.7) 239 (1.7) 0.99 (0.82-1.18) 0.89
Stroke 207 (1.5) 262 (1.9) 0.79 (0.66-0.95) 0.01
Coronary revascularization 759 (5.5) 965 (7.0) 0.78 (0.71-0.86) <0.001
CV Death or Hospitalization for
Worsening Heart Failure
402 (2.9) 408 (3.0) 0.98 (0.86-1.13) 0.82
Ischemic stroke or TIA 229 (1.7) 295 (2.1) 0.77 (0.65-0.92) 0.003
CTTC composite endpoint** 1,271 (9.2) 1,512 (11.0) 0.83 (0.77-0.90) <0.001
*Time to CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs first †CV death,
myocardial infarction, or stroke, whichever occurs first ‡Given the hierarchical nature of the statistical testing, the P values for the primary and key secondary
endpoint should be considered statistically significant, whereas all other P values should be considered nominal.
**CTTC stands for Cholesterol Treatment Trialists Collaboration and the composite endpoint consists of coronary heart death, nonfatal MI, stroke, or coronary
revascularization
MI = Myocardial infarction; UA = Unstable angina; TIA = Transient ischemic attack
The primary endpoint was driven by reductions in MI,
stroke, and coronary revascularization

Adverse Events in the Safety Population*
Adverse Events, n (%)
Evolocumab
(N = 13,769)
Placebo
(N = 13,756)
Any 10,664 (77.4) 10,644 (77.4)
Serious 3,410 (24.8) 3,404 (24.7)
Thought to be related to the study agent and
leading to discontinuation of study regimen 226 (1.6) 201 (1.5)
No notable differences in the rate of AEs, SAEs, or AEs leading to discontinuation
*Safety evaluations included all randomized patients who received at least one dose of study
treatment and for whom post-dose data are available.

Adverse Events of Interest and Laboratory Measures in the
Safety Population*
Adverse Events, n (%)
Evolocumab
(N = 13,769)
Placebo
(N = 13,756)
Injection-site reaction** 296 (2.1) 219 (1.6)
Allergic reactions 420 (3.1) 393 (2.9)
Muscle-related event 682 (5.0) 656 (4.8)
Rhabdomyolysis 8 (0.1) 11 (0.1)
Cataract 228 (1.7) 242 (1.8)
Adjudicated case of new-onset diabetes†
677 (8.1) 644 (7.7)
Neurocognitive event 217 (1.6) 202 (1.5)
Laboratory results - n/total n (%)
Aminotransferase >3x ULN 240/13,543 (1.8) 242/13,523 (1.8)
Creatinine kinase >5x ULN 95/13,543 (0.7) 99/13,523 (0.7)
ULN = Upper Limit of Normal
• Incidence of neurocognitive events, cataracts, and new-onset diabetes were
similar between the two arms
• Post-baseline anti-evolocumab antibodies were detected in 0.3%, with no
neutralizing antibodies detected
*Safety evaluations included all randomized patients who received at least one dose of study treatment and for whom post-dose data are available. **The between-
group difference was nominally significant (P<0.001). †HR 1.05 (95% CI 0.94-1.17); denominators of 8337 (evolocumab) and 8339 (placebo) because patients with prevalent
diabetes at the start of the trial were excluded.

An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Clinical Benefit of Evolocumab
in Patients with a History of MI:
An Analysis from FOURIER
Marc S. Sabatine, Gaetano M. De Ferrari, Robert P. Giugliano,
Kurt Huber, Basil S. Lewis, Jorge Ferreira, Julia F. Kuder,
Sabina A. Murphy, Stephen D. Wiviott, Christopher Kurtz,
Narimon Honarpour, Anthony C. Keech,
Peter S. Sever, and Terje R. Pedersen,
for the FOURIER Steering Committee & Investigators
American Heart Association – Annual Scientific Session
Late-Breaking Science in Prevention
November 13, 2017
SC-MEA-AMG145-00190 Nov17

High-Risk Features and Other
Baseline Characteristics
Characteristic <2 y ago
N=8402
(38%)
≥2 y ago
N=13,918
(62%)
≥2
N=5285
(24%)
1
N=17,047
(76%)
MVD
N=5618
(25%)
No MVD
N=16,715
(75%)
Age, mean (SD) 60 (9) 63 (9) 62 (9) 62 (9) 62 (9) 62 (9)
Male sex (%) 77 79 82 77 81 78
Hypertension (%) 75 81 81 78 82 78
Diabetes mellitus (%) 31 38 36 35 35 35
Current smoker (%) 28 28 26 28 26 28
High-intensity statin (%) 76 69 75 70 74 70
LDL-C, mg/dL (IQR) 90
(79-106)
93
(80-110)
92
(81-109)
92
(80-108)
93
(81-110)
92
(80-108)
LDL-C w/ EvoMab at 48
wk, mg/dL (IQR)
29
(19-45)
30
(18-46)
30
(19-46)
29
(19-46)
30
(19-46)
29
(18-46)
Time from
Qualifying MI
Residual
Multivessel CAD
# Prior MIs

Risk of CV Death, MI or Stroke
with Each Risk Factor
10.8%
9.3%
0%
2%
4%
6%
8%
10%
12%
14%
16%
<2 yrs ≥2 yrs
CVD,
MI
or
Stroke
(3-yr
KM)
in
Pbo
Years from Qualifying MI
HR 1.19
(1.04-1.37)
P=0.01 15.0%
8.2%
0%
2%
4%
6%
8%
10%
12%
14%
16%
≥2 1
# of Prior MIs
HR 2.04
(1.78-2.35)
P<0.001
12.6%
8.9%
0%
2%
4%
6%
8%
10%
12%
14%
16%
Yes No
Multivessel Disease
HR 1.47
(1.27-1.70)
P<0.001
Analyses in placebo arm

Benefit of EvoMab Based on
Time from Qualifying MI
Qualifying MI <2 yrs ago
CV
Death,
MI,
or
Stroke
0 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
0 6 12 18 24 30 36

# of Prior MIs
≥2 Prior MIs
CV
Death,
MI,
or
Stroke
0 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
0 6 12 18 24 30 36

Multivessel Disease
Multivessel Disease
CV
Death,
MI,
or
Stroke
0 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
0 6 12 18 24 30 36

Landmark Analyses in Pts
w/ a High-Risk MI Feature
Evolocumab
Placebo
Months from Randomization
CV
Death,
MI,
Stroke
0 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

Clinical Efficacy and Safety of
Achieving Very Low LDL-C Levels With
the PCSK9 Inhibitor Evolocumab in the
FOURIER Outcomes Trial
RP Giugliano, TR Pedersen, AC Keech, PS Sever, JG
Park, and MS Sabatine, for the FOURIER Steering
Committee & Investigators
European Society of Cardiology 2017
Clinical Trial Update I
August 28, 2017
SC-MEA-AMG145-00165 Sep 17

Aims
To explore the clinical efficacy and
safety associated with progressively
lower achieved LDL-C levels
Giugliano RP, ESC Congress 2017, Barcelona 8/28/2017

Methods - 1
– LDL-C assessed at 4 wks (ultracentrifugation if <1 mM)
– Analyzed 5 groups by achieved LDL-C at 4 weeks
1) <0.5mM (20 mg/dL)
2) 0.5-1.3 mM (20- 49 mg/dL)
3) 1.3-1.8 mM (50-69 mg/dL)
4) 1.8-2.6mM (70-99 mg/dL)
5) >2.6 mM (>100 mg/dL) was the referent group
– Pooled results across 2 Rx groups (evo, placebo)
1582 pts with events in first 4 wks or no LDL-C at week 4 were excluded

Methods - 2
– Prespecified 1° and 2° efficacy composite endpoints
– 10 safety adverse events evaluated:
– Serious AE - AE->drug discon - AST/ALT>3x
– Cancer - cataracts AEs - CK > 5x ULN
– Hem stroke - Neurocognitive - Non-CV death
– New onset diabetes (adjudicated by CEC)
– Cognition1 assessed using CANTAB tool and pt survey
of everyday cognition (ECog)
1. Giugliano RP et al. N Engl J Med 2017377:633-43

0
1
2
3
4
5
6
0 1 2 3 4 5 6
Percent
of
Patients
LDL-C at Week 4 (mM)
LDL (mM)
%Evo 99.6% 96.5% 41% 10% 9.6%
%Placebo 0.4% 3.5% 59% 90% 90.4%
Median [IQR] LDL-C at 4 Weeks
Evo 0.8 mM [0.5-1.2] Pbo 2.2 mM [1.9-2.7]
32 mg/dL [21-45] 87 mg/dL [74-104]
Achieved LDL-C at 4 Weeks
<0.5 0.5-1.3 1.3-1.8 1.8-2.6 > 2.6

Baseline Characteristics
Achieved LDL-C in mM at 4 Weeks
<0.5
(N=2669)
0.5-1.3
(N=8003)
1.3-1.8
(N=3444)
1.8-2.6
(N=7471)
>2.6
(N=4395)
Age (median), yrs* 64 63 62 63 61
Females* 16 23 27 24 28
Caucasian race* 80 86 84 85 88
Current smoker* 26 27 29 28 32
Prior MI 81 81 80 82 81
Prior stroke 20 19 19 19 20
Prior PAD 12 14 14 12 14
Hypertension 78 80 82 80 81
TIMI Risk Score 2° Prevention* 3.2 3.3 3.4 3.3 3.4
Data shown are % patients unless otherwise specified *Ptrend <0.0001

Lipids and Lipid Rx at Randomization
Achieved LDL-C in mM at 4 Weeks
At Randomization
<0.5
(N=2669)
0.5-1.3
(N=8003)
1.3-1.8
(N=3444)
1.8-2.6
(N=7471)
>2.6
(N=4395)
Median Lipid values
LDL-C, mM 2.1 2.4 2.2 2.3 3.0
Total cholesterol, mM 4.0 4.3 4.2 4.2 5.0
Triglycerides, mM 1.5 1.5 1.6 1.4 1.6
HDL-C, mM 1.1 1.1 1.1 1.1 1.2
Lipoprotein (a), nM 22 43 32 37 48
High potency statin, %
(> Atorvastatin 40 mg/d)
63 69 70 70 72
Ezetimibe, % 4.1 5.0 5.4 4.6 7.4
Ptrend <0.0001 for each

0
1
2
3
4
0 24 48 72 96 120 144 168
Mean
LDL-C
(mM)
Weeks After Randomization
<0.5 0.5-1.3 1.3-1.8 1.8-2.6 ≥ 2.6
LDL-cholesterol at 4 weeks in mM
4 12
LDL-C Over Time

CV Death, MI, Stroke, UA,
or Coronary Revasc
LDL-C (mM) Adj HR (95% CI)
<0.5 0.76 (0.64-0.90)
0.5-1.3 0.85 (0.76-0.96)
1.3-1.8 0.94 (0.82-1.09)
1.8-2.6 0.97 (0.86-1.09)
> 2.6 referent P = 0.0012
LDL-C (mM) at 4 weeks

CV Death, MI, or Stroke
LDL-C (mM) Adj HR (95% CI)
<0.5 0.69 (0.56-0.85)
0.5-1.3 0.75 (0.64-0.86)
1.3-1.8 0.87 (0.73-1.04)
1.8-2.6 0.90 (0.78-1.04)
> 2.6 referent P = 0.0001
LDL-C (mM) at 4 weeks

Safety Events - 1
0
5
10
15
20
25
SAE AE->Discon New DM Cancer Cataract
<0.5
0.5-1.3
1.3-1.8
1.8-2.6
≥2.6
LDL-C (mM) at 4 wks
% Patients (n/N)
Adj P-values for trend >0.10
for each comparison
% pts

Safety Events - 2
0
5
10
Neurocog AST/ALT↑ CK↑ Non-CV death Hem stroke
<0.5
0.5-1.3
1.3-1.8
1.8-2.6
≥2.6
LDL-C (mM) at 4wks
% Patients (n/N)
Adj P-values for trend >0.10
for each comparison
% pts

Exploratory Analysis Pts with LDL-C
<0.26 mM (<10 mg/dL) at 4 wks
11.9
7.8
7.3
4.4
0
5
10
15
CVD, MI, Stroke, UA,
Cor Revasc
CVD, MI, Stroke
≥2.6 mM
<0.26 mM
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 [IQR] LDL-C 0.18 [0.13-0.23] mM = 7 [5-9] mg/dL
23.3
3.4
22.8
3.4
0
5
10
15
20
25
30
Serious adverse event AE -> drug
discontinued
≥2.6 mM
<0.26 mM
Adj HR 0.94
(0.74-1.20)
P=0.61
Adj HR 1.08
(0.63-1.85)
P=0.78
Safety

Conclusions
 LDL-C can now be reduced to unprecedented low
levels with statin + PCSK9i (<< 1 mM)
A strong progressive relationship of achieved LDL-C
and CV events seen, down to LDL <0.26 mM (<10 mg/dL)
No excess in safety events with very low achieved
LDL-C <0.5 mM (<20 mg/dL) at 2.2 years
These data suggest that we should target
considerably lower LDL-C than is currently
recommended for our patients with
atherosclerotic CV disease

Guidelines updates after PCSK9 inhibitors
after the release of outcome data

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 outside 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

AHA/ACC 2018 Recommendations in FH patients
Recommendations for Primary Severe Hypercholesterolemia (LDL-C ≥190 mg/dL
[≥4.9 mmol/L])
COR LOE Recommendations
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.
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.
CITATION: J Am Coll Cardiol. Nov 2018; DOI: 10.1016/j.jacc.2018.11.003

57
AACE: CAD Risk Categories and LDL-C Treatment Goals
Treatment goals
Risk category Risk factorsa/10-year riskb
LDL-C
(mg/dL)
Non-HDL-C
(mg/dL)
Apo B
(mg/dL)
Extreme risk
• Progressive ASCVD including unstable angina in patients
after achieving an LDL-C < 70 mg/dL
• Established clinical cardiovascular disease in patients with
DM, CKD 3/4, or HeFH
• History of premature ASCVD (< 55 male, < 65 female)
< 55 < 80 < 70
Very high risk
• Established or recent hospitalization for ACS, coronary,
carotid or peripheral vascular disease
• Diabetes or CKD 3/4 with 1 or more risk factors(s)
• Heterozygous familial hypercholesterolemia
< 70 < 100 < 80
High risk
• ≥ 2 risk factors and 10-year risk > 10% or CHD risk
equivalentc, including diabetes or CKD 3, 4 with no other
risk factors
< 100 < 130 < 90
Moderate risk • ≥ 2 risk factors and 10-year risk < 10% < 130 < 160 NR
Low risk • ≤ 1 risk factor < 160 <190 NR
aMajor independent risk factors are high low-density lipoprotein cholesterol, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure
≥ 140/90 mm Hg or on hypertensive medication), low high-density lipoprotein cholesterol (< 40 mg/dL), family history of coronary artery disease (in male, first-
degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD) stage 3, 4, evidence of coronary
artery calcification and age (men ≥ 45; women ≥ 55 years). Subtract 1 risk factor if the person has high high-density lipoprotein cholesterol. bFramingham risk
scoring is applied to determine 10-year risk. cCoronary artery disease risk equivalents include diabetes and clinical manifestations of noncoronary forms of
atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease).
AACE = American Association of Clinical Endocrinologists; Apo B = Apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease;
CAD = coronary artery disease; CHD = coronary heart disease; CKD = chronic kidney disease; DM = diabetes mellitus; HDL-C = high-density
lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol;
NR = not recommended.
Jellinger PS, et al. Endocr Pract. 2017;23:1-87.

Which patients deserve Evolocumab?

How to Use?
Method of administration
• Subcutaneous use
• Repatha is for subcutaneous injection into the
abdomen, thigh or upper arm region. Injection
sites should be rotated and injections should
not be given into areas where the skin is
tender, bruised, red, or hard. Repatha must not
be administered intravenously or
intramuscularly
• Repatha is intended for patient self-
administration after proper training.
Administration of Repatha can also be
performed by an individual who has been
trained to administer the product
• Each pre-filled pen is for single use only
Upper arm
Belly
Thigh

Evolocumab HCP presentation.pptx

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