Efficacy and Safety of Evolocumab
(AMG 145) Monotherapy Compared
With Ezetimibe and Placebo in
Hypercholesterolemic Subjects:
A Phase 3 Randomized Clinical Trial
Michael J Koren,1 Pernille Lundqvist,2 Michael Bolognese,3
Joel M Neutel,4 Maria Laura Monsalvo,5 Jingyuan Yang,5 Jae B Kim,5
Rob Scott,5 Scott M Wasserman,5 Harold Bays6
for the MENDEL-2 Investigators
1Jacksonville
Center for Clinical Research, Jacksonville, FL, USA; 2Center for Clinical and Basic
Research, Ballerup, Denmark; 3Bethesda Health Research Center, Bethesda, MD, USA;
4Orange County Research Center, Tustin, CA, USA; 5Amgen Inc., Thousand Oaks, CA, USA;
6L-MARC Research Center, Louisville, KY, USA
March 29, 2014, Featured Clinical Research Session 400
American College of Cardiology, Washington DC
Background
 Evolocumab, a fully human monoclonal antibody against
PCSK9, has emerged as a novel therapeutic option for
lowering LDL-C in patients with hypercholesterolemia.
 In Phase 2 studies, treatment with evolocumab was well
tolerated and significantly reduced LDL-C in diverse groups of
subjects, with LDL-C reductions maintained over 52 weeks.1-5
 Because statins up-regulate PCSK9 production, evaluation of
evolocumab as monotherapy is required to fully understand its
pharmacodynamics and safety profile in populations not
confounded by statin use or a history of statin intolerance,
particularly at doses anticipated for use in clinical practice.
1.Lancet. 2012;380:1995-2006.
2.Lancet. 2012;380:2007-2017.
3.JAMA. 2012;308:2497-2506.
4.Circulation. 2012;126:2408-2417.
5.Circulation. 2014;129:234-243.
2
The MENDEL-2 Study
 Monoclonal Antibody Against PCSK9 to Reduce Elevated
LDL-C in Patients Currently Not Receiving Drug Therapy
For Easing Lipid Levels-2 (NCT01763827)
 Design:
A 12 week randomized, double-blind, placebo- and
ezetimibe-controlled multicenter phase III study
 Objective:
To evaluate efficacy and safety of evolocumab
in primary hypercholesterolemic patients not taking statins
3
MENDEL and MENDEL-2 Compared
Characteristics
Phase
N
Population
Fasting LDL-C Range
Background Lipid Therapy
MENDEL
MENDEL-2
2
3
406
614
Framingham Risk < 10%
Framingham Risk < 10%
≥ 100 and < 190 mg/dL
≥ 100 and < 190 mg/dL
None
None
Evolocumab Dose
• 70, 105, or 140 mg biweekly
• 280, 350, or 420 mg monthly
• 140 mg biweekly
• 420 mg monthly
Comparators
• Placebo biweekly or monthly
• Open ezetimibe 10 mg/day
• Placebo biweekly or monthly
• Blinded ezetimibe 10 mg/day
Treatment Duration
Evolocumab Delivery
12 wks
12 wks
70 mg/ml vial and syringe in
clinics
140 mg/ml prefilled autoinjector in clinic and home
4
MENDEL-2: Study Design
140 mg Evolocumab Q2W / Placebo PO QD
N = 153
End of Study
Screening
Period
with
Placebo
Injection
Randomization
420 mg Evolocumab QM / Placebo PO QD
N = 153
Placebo SC Q2W / 10 mg Ezetimibe PO QD
N = 77
2:2:1:1:1:1
Placebo SC QM / 10 mg Ezetimibe PO QD
N = 77
Placebo SC Q2W / Placebo PO QD
N = 77
Placebo SC QM / Placebo PO QD
N = 78*
Day 1
Week 2
Week 4
Week 6
Week 8 Week 10 Week 12 Week 14†
Biweekly SC administration:
Monthly SC administration:
*1 patient was randomized but not dosed. †Phone call for AEs, SAEs. AEs, adverse events.
EOS, end of study; QD, daily; Q2W, biweekly; QM, monthly.
QM
EOS
Q2W
EOS
5
MENDEL-2: Primary Endpoints
 Co-primary endpoints:
Percent change from baseline in LDL-C at week 12 and mean of
weeks 10 and 12
 Secondary endpoints:
At mean of weeks 10 and 12 and at week 12:
 Percent change from baseline in ApoB, ApoA-I,
lipoprotein(a), TG, and HDL-C
 Percent of patients with LDL-C <70 mg/dL
 Key safety endpoints:
 Treatment-emergent and serious adverse events
 Muscle and hepatic enzyme elevations
 Anti-evolocumab antibodies
6
MENDEL-2: Baseline Demographics
Biweekly
Monthly
PBO Q2W
+ PBO QD
(N = 76)
PBO Q2W
+ EZE QD
(N = 77)
Evolocumab
140 mg Q2W
+ PBO QD
(N = 153)
54 (10)
54 (11)
53 (14)
53 (11)
53 (13)
53 (12)
Female, %
63
69
68
60
68
66
Race, white, %
83
82
86
81
78
84
NCEP risk categories*, %
High
Moderately high
Moderate
Low
0
8
33
59
0
4
47
49
1
3
41
55
3
5
26
67
1
5
40
53
1
5
34
60
Age (years), mean (SD)
PBO QM
+ PBO QD
(N = 78)
PBO QM
+ EZE QD
(N = 77)
Evolocumab
420 mg QM
+ PBO QD
(N = 153)
*Risk category definitions: high, diagnosed CHD or risk equivalent; moderately high, 2 or more risk factors and
Framingham risk score 10%-20%; moderate, 2 or more risk factors and Framingham risk score <10%; lower, 0 or 1 risk factor.
CV, cardiovascular; EZE, ezetimibe; PBO, placebo; Q2W, biweekly; QM, monthly; QD, daily.
7
MENDEL-2: Baseline Lipids
Biweekly
Monthly
PBO Q2W
+ PBO QD
(N = 76)
PBO Q2W
+ EZE QD
(N = 77)
Evolocumab
140 mg Q2W
+ PBO QD
(N = 153)
LDL-C*, mg/dL, mean
(SD)
140 (21)
143 (24)
142 (22)
144 (24)
144 (23)
144 (23)
ApoB, md/dL, mean
(SD)
104 (17)
107 (20)
105 (17)
107 (20)
106 (18)
108 (18)
21
(9, 49)
28
(11, 120)
20
(7, 58)
22
(7, 62)
28
(12, 64)
28
(9, 104)
TG, mg/dL, median
(Q1,Q3)
114
(83, 178)
113
(84, 158)
112
(82, 148)
118
(86, 179)
117
(90, 159)
119
(83, 169)
PCSK9, ng/mL, mean
(SD)
281 (89)
270 (94)
272 (81)
270 (82)
265 (94)
274 (84)
Lp(a), nmol/L, median
(Q1,Q3)
PBO QM
+ PBO QD
(N = 78)
PBO QM
+ EZE QD
(N = 77)
Evolocumab
420 mg QM
+ PBO QD
(N = 153)
*Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C
was <40 mg/dL (1.0 mmol/L) or triglyceride levels were >400 mg/dL (3.9 mmol/L). CV, cardiovascular; EZE, ezetimibe;
PBO, placebo; Q2W, biweekly; QM, monthly; QD, daily.
8
MENDEL-2: Evolocumab
Primary Endpoint Biweekly Dose
Treatment Difference vs Placebo
Mean Percent Change in LDL-C
from Baseline
Treatment Difference vs Ezetimibe
Average at weeks 10 and 12
At week 12
Average at weeks 10 and 12
At week 12
-57%
-57%
-39%
-39%
P<0.001
P<0.001
10
0
0.1%
–10
–18%
–20
–30
–40
–50
–57%
–60
BL Day 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Biweekly SC
administration
Study Week
Placebo (N = 76)
Ezetimibe (N = 77)
Evolocumab biweekly (N = 153)
BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for
missing values. P values are multiplicity adjusted.
9
MENDEL-2: Evolocumab
Primary Endpoint Monthly Dose
Treatment Difference vs Placebo
Mean Percent Change in LDL-C
from Baseline
Treatment Difference vs Ezetimibe
Average at weeks 10 and 12
At week 12
Average at weeks 10 and 12
At week 12
-57%
-55%
-40%
-38%
P<0.001
P<0.001
10
–1%
0
–10
–19%
–20
–30
–40
–50
–56%
–60
BL Day 1
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Monthly SC
administration
Study Week
Placebo (N = 78)
Ezetimibe (N = 77)
Evolocumab monthly (N = 153)
BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for
missing values. P values are multiplicity adjusted.
10
Percent Change in LDL-C (mg/dL)
Percent Change in LDL-C (mg/dL)
Monthly
Biweekly
MENDEL-2: % Change in LDL-C from
Baseline at Week 12 for Individual Patients
Placebo (N = 76)
Ezetimibe (N = 77)
Evolocumab (N = 153)
Placebo (N = 78)
Ezetimibe (N = 77)
Evolocumab (N = 153)
60
40
20
0
–20
–40
–60
–80
–100
60
40
20
0
–20
–40
–60
–80
–100
 Subjects with early termination of subcutaneous or oral study drug
No notable difference in results for average at weeks 10 and 12
11
MENDEL-2: Other Lipids at Week 12
ApoB
Biweekly
Monthly
Treatment Difference,
Mean (%)
0
Treatment difference
(biweekly and monthly)
vs placebo P < 0.001
vs ezetimibe P < 0.001
-10
-20
-30
-50
–48%
–48%
-60
Treatment Difference,
Median (%)
Lp(a)
–33%
–34%
-40
Biweekly
Monthly
Treatment difference
(biweekly and monthly)
vs placebo P < 0.001
vs ezetimibe P < 0.001
0
-5
-10
-15
Placebo
Ezetimibe
-20
-25
-30
–20%
–20%
–18%
–16%
Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference.
No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted.
12
MENDEL-2: Other Lipids at Week 12 - II
Treatment Difference,
Median (%)
Triglycerides 10
Biweekly
Treatment difference
(monthly)
vs placebo P < 0.001
(biweekly and monthly)
vs ezetimibe P < 0.05
0
-10
-20
–6%
–8%
–13%
–18%
-30
Non-HDL-C
Treatment Difference,
Mean (%)
Monthly
Biweekly
Monthly
0
-10
Treatment difference
(biweekly and monthly)
vs placebo P < 0.001
vs ezetimibe P < 0.001
-20
-30
-40
–33%
–35%
Placebo
Ezetimibe
-50
-60
–50%
–51%
Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference.
No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted.
13
MENDEL-2: Other Lipids at Week 12 - III
HDL-C
Biweekly
Treatment Difference,
Median (%)
15
9%
Monthly
8%
10
6%
6%
5
Treatment difference
(biweekly and monthly)
vs placebo P < 0.05
vs ezetimibe P < 0.05
0
-5
-10
ApoA-I
Biweekly
Treatmemt Difference,
Mean (%)
8
6
Treatment difference
(monthly only)
vs placebo P < 0.01
vs ezetimibe P < 0.05
Monthly
5%
3%
3%
3%
4
2
Placebo
Ezetimibe
0
Error bars represent standard error for mean treatment difference and 95% CI for median treatment difference.
No notable difference in results for average at weeks 10 and 12. P values are multiplicity adjusted.
14
MENDEL-2: Treatment Difference
According to Subgroups at Week 12
Evolocumab Q2W Evolocumab Q2W
vs Placebo
vs Ezetimibe
Evolocumab QM
Vs Placebo
Evolocumab QM
vs Ezetimibe
Sex
Female
Male
Age
<65 years
≥65 years
Race
White
Black
Other
History of Met Syn
Yes
No
Screening LDL-C
<130mg/dL
≥130mg/dL
Triglycerides
<200 mg/dL
≥200 mg/dL
Overall
-100 -80 -60 -40 -20 0
Met Syn: metabolic syndrome
-100 -80 -60 -40 -20 0
-100 -80 -60 -40 -20
0
Percent Change from Baseline at Week 12
-100 -80 -60 -40 -20 0
15
MENDEL-2: Treatment Difference
According to Subgroups at Week 12
Evolocumab Q2W Evolocumab Q2W
vs Placebo
vs Ezetimibe
Evolocumab QM
vs Placebo
Evolocumab QM
vs Ezetimibe
Hypertension
Yes
No
Smoker
Yes
No
Baseline CHD
risk factors
<2
≥2
Region
North America
Europe
Other
PCSK9
<baseline median
(261.0 ng/mL)
≥baseline median
(261.0 ng/mL)
Overall
-100 -80 -60 -40 -20 0
-100 -80 -60 -40 -20 0
-100 -80 -60 -40 -20
0
Percent Change from Baseline at Week 12
-100 -80 -60 -40 -20 0
16
MENDEL-2: Safety and Tolerability
Placebo
(N = 154)
Ezetimibe
(N = 154)
Evolocumab
(N = 306)
68 (44)
70 (46)
134 (44)
Common treatment-emergent AEs*
Headache
Diarrhea
Nausea
Urinary Tract Infection
Constipation
Nasopharyngitis
Upper Respiratory Infection
4 (3)
6 (4)
1 (1)
2 (1)
4 (3)
3 (2)
4 (3)
5 (3)
3 (2)
3 (2)
3 (2)
1 (1)
6 (4)
5 (3)
10 (3)
9 (3)
8 (3)
7 (2)
6 (2)
6 (2)
5 (2)
Serious AEs
1 (1)
1 (1)
4 (1)
AEs leading to study drug discontinuation
6 (4)
5 (3)
7 (2)
Deaths
0 (0)
0 (0)
0 (0)
Potential injection site reactions†
8 (5)
7 (5)
16 (5)
Muscle-related SMQ‡
Myalgia
Musculoskeletal pain
6 (4)
3 (2)
2 (1)
5 (3)
3 (2)
1 (1)
8 (3)
3 (1)
3 (1)
Neurocognitive AEs
0 (0)
0 (0)
0 (0)
CK > 5 x ULN
2 (1)
0 (0)
2 (1)
ALT or AST > 5 x ULN
2 (1)
0 (0)
1 (0.3)
NA
NA
0
Adverse Events (AEs), n (%)
Treatment-emergent AEs
Anti-evolocumab antibodies§
*Reported in ≥3% of patients in one or more treatment arms. †Reported using high-level term grouping, which includes injection site (IS) 17
rash, IS inflammation, IS pruritus, IS reaction, and IS urticaria. ‡Standard MedDRA Queries. §Binding or neutralizing.
MENDEL-2: Conclusions
 In the largest monotherapy trial with a PCSK9 inhibitor to
date, evolocumab biweekly (140 mg) or monthly (420 mg)
rapidly and markedly lowered LDL-C over 12 weeks
compared with placebo or ezetimibe in patients with
hypercholesterolemia not taking statins.
 Evolocumab 140 mg biweekly and 420 mg monthly dosing
regimens are clinically equivalent.
 Evolocumab treatment resulted in favorable changes in other
lipoproteins.
 Evolocumab was well tolerated over the 12-week study
 The overall incidence of treatment-emergent AEs, CK, and
AST/ALT elevations was comparable across treatment
groups.
18
MENDEL-2: Conclusions
 Though we anticipate that evolocumab treatment will find use
primarily as a treatment for high risk patients in conjunction
with statins, MENDEL-2 demonstrated that evolocumab
produces large LDL-C lowering effects as monotherapy.
 These lipid effects occur consistently across several prespecified sub-groups.
 The MENDEL-2 findings support future investigation of
evolocumab in higher-risk patient population who might
benefit from anti-PCSK9 monotherapy.
19
Disclosures
This study was funded by Amgen Inc.
MJ Koren: Employee of Jacksonville Center for Clinical Research, which has received
research grants from Amgen Inc. and other PCSK9-related research funding from
Regeneron, Sanofi, Roche, and Pfizer.
P Lundqvist: None.
MA Bolognese: Research grant from Amgen Inc.
JM Neutel: None
ML Monsalvo, J Yang, JB Kim, R Scott, SM Wasserman: Employees of Amgen Inc.
and own Amgen stock/stock options.
H Bays: Research grant and consultant/advisory board from Amgen Inc., and
consultant/advisory board/speaker's bureau for many other pharmaceutical companies.
Amgen Inc. provided editorial support for the development of this presentation.
20