Long-term Tolerability and Efficacy
of Evolocumab (AMG 145) in
Hyperlipidemic Subjects: A 52 Week
Phase 3 Double-blind, Randomized,
Placebo-controlled Study
Dirk Blom, Tomas Hala, Michael Bolognese, Michael J Lillestol,
Phillip D Toth, Lesley Burgess, Richard Ceska, Eli Roth,
Michael J Koren, Maria Laura Monsalvo, Kate Tsirtsonis,
Jae B Kim, Scott M Wasserman, Rob Scott,
Christie M Ballantyne, Evan A Stein, for the DESCARTES
Investigators
March 29, 2014, Featured Clinical Research Session 400
American College of Cardiology, Washington DC
Background: PCSK9 Inhibition
 PCSK9 is a well validated therapeutic target based on gain
and loss of function human genetic abnormalities, Mendelian
randomization studies, and its recently elucidated role in LDL
receptor function and regulation of LDL cholesterol.
 Evolocumab (AMG 145), a fully human monoclonal antibody
against PCSK9, reduced LDL-C by up to 65% and was well
tolerated in 4 randomized, placebo-controlled, phase 2 clinical
trials of 12 weeks duration in over 1300 hypercholesterolemic
patients.1-4
 An open label extension study of patients from phase 2 trials
with evolocumab (OSLER) recently reported 1 year safety and
efficacy data.5
1. Lancet. 2012;380:1995-2006
2. Circulation. 2012;126:2408-2417
3. JAMA. 2012;308:2497-2506
4. Lancet. 2012;380:2007-2017
5. Circulation 2014;129:234-243
2
The DESCARTES Study
 Durable Effect of PCSK9 antibody CompARed wiTh
placEbo Study (NCT01516879)
 A 52 week global, randomized, double-blind, placebocontrolled multicenter study to provide longer term data on
the efficacy and safety of evolocumab
 Included patients with a wide range of cardiovascular risk
 Lipid-lowering therapy, ranging from diet alone to
atorvastatin 80 mg plus ezetimibe, was optimized to reach
NCEP ATP III LDL-C treatment goals
3
DESCARTES: Endpoints
 Primary: % change from baseline in LDL-C measured
by ultracentrifugation (UC) at week 52
 Secondary
 % change from baseline in UC LDL-C at week 12
 Change from baseline in UC LDL-C at week 52
 % of patients with UC LDL-C < 70 mg/dL at week
52
 % changes from baseline for TC, HDL-C, ApoB,
VLDL-C, triglycerides, and Lp(a) at week 52
 % changes in total cholesterol/HDL cholesterol
ratio and apolipoprotein B/apolipoprotein A1 ratio at
week 52
4
DESCARTES: Patients
 Adults aged 18 to 75 years
 Screening
 LDL-C ≥ 75 mg/dL and TG ≤ 400 mg/dL
 Exclusion: LDL-C ≤ 99 mg/dL with CHD or risk
equivalent and not receiving a statin
 Following lipid stabilization period
 At NCEP ATP III target or receiving maximal therapy
(atorvastatin 80 mg plus ezetimibe 10 mg)
 LDL-C ≥ 75 mg/dL
5
DESCARTES: Screening and Lipid
Stabilization
Screening Period
4 Weeks to 16 Weeks
Screening
LDL-C ≥ 75 mg/dL
Initial LDL-C < 75 mg/dL
= Screen Fail
Background Therapy Assigned Based on
CV Risk, LDL-C, and Current Therapy:
1)
2)
3)
4)
Diet alone
Diet and atorvastatin 10 mg
Diet and atorvastatin 80 mg
Diet, atorvastatin 80 mg, and ezetimibe 10 mg
4 Week Dietary Run-in and
Lipid Stabilization
 CHD/risk equivalent: LDL < 100 mg/dL OR
 No CHD/risk equivalent: LDL < 130 mg/dL OR
 On Maximal background therapy
Yes
Randomization 2:1 (~900 Subjects)
 Evolocumab 420 mg SC QM
 Placebo SC QM
Up-titrate Background
Therapy
No
LDL < 75 mg/dL
= Screen Fail (except on
maximal background
therapy – allowed one
downtitration
6
1. No drug
2. Low dose: 10 mg
atorvastatin
3. High dose: 80 mg
atorvastatin
4. Maximal: 80 mg
atorvastatin +
10 mg ezetimibe
Lipid
Stabilization
Period
Fasting LDL-C
5–10 days
before
randomization
Placebo SC QM
n = 303
End of Study
Screening Assign
background Rx
based on
CV risk, LDL,
and
+/- prior statin:
Randomization
2:1
DESCARTES: Study Overview
Evolocumab 420 mg SC QM
n = 602
Subcutaneous
injection of
6 mL Placebo
Period = Max. 16 weeks /
Min: 4 weeks
Visits: Day 1
Week 4
Week 8
Week 52*
Study Drug (Evolocumab or Placebo)
QM:
* Last dose administered at week 48
7
DESCARTES: Patient Disposition
Screened: 2120
635 screen failures
1485 entered lipid stabilization period
580 lipid
stabilization
period failures
905 randomized to evolocumab or placebo
8
DESCARTES: Patient Disposition II
905 Randomized
2:1 allocation to evolocumab or placebo
112
Diet alone
(38 P: 74 Evo)
385
Atorvastatin 10
(129 P: 256 Evo)
219
Atorvastatin 80
(73 P: 146 Evo)
189
Atorvastatin 80 +
Ezetimibe 10
(63 P: 126 Evo)
73 discontinued
evolocumab
4 never received
SD*
28 discontinued placebo
800 completed 52 weeks of Study Drug
E = Ezetimibe, Evo = Evolocumab, P = Placebo
* Study Drug
9
DESCARTES: Baseline Characteristics
Characteristic
n
Diet
A 10 mg/d
Alone
A 80 mg/d
A 80 mg/d
+E10 mg/d
All
111
383
218
189
901
51.7
(12.1)
57.1
(10.4)
58.0
(9.2)
54.8
(10.7)
56.2
(10.6)
Male, %
45.0
43.9
50.0
54.5
47.7
BMI, kg/m2, mean
(SD)
30.5
(7.6)
29.8
(6.2)
30.8
(5.7)
29.8
(4.8)
30.1
(6.0)
Race/White, %
67.6
85.9
86.2
69.8
80.4
Age, y, mean
(SD)
A = Atorvastatin
E = Ezetimibe
Full Analysis Set (FAS) data presented: Patients who received at least one dose of study drug
10
DESCARTES: Baseline Patient
Characteristics II
Characteristic
Diet
A 10 mg/d
Alone
A 80 mg/d
A 80 mg/d
+E10 mg/d
All
Coronary artery
disease,%
1.8
2.6
15.6
47.6
15.1
Type 2 diabetes,%
2.7
7.0
15.1
21.7
11.5
Current smoker, %
17.1
11.7
14.2
21.2
15.0
Hypertension, %
42.3
41.8
57.3
56.1
48.6
13.5
14.6
22.0
47.1
23.1
29.7
26.6
46.3
61.4
39.1
Family history of
premature CAD, %
2 or more CV risk
factors, %
A = Atorvastatin
E = Ezetimibe
11
DESCARTES: Baseline Lipids
Placebo
Evolocumab
302
599
*UC LDL-C, mg/dL, mean (SD)
104 (22)
104 (22)
ApoB, mg/dL, mean (SD)
88 (16)
87 (16)
40 (12,145)
38 (14,137)
HDL-C mg/dL mean, (SD)
54 (16)
53 (16)
ApoA1, mg/dL mean, (SD)
155 (28)
152 (27)
110
105
(85,155)
(80,140)
n
Lipoprotein(a), nmol/L, median (Q1,
Q3)
Triglycerides, mg/dL, median,
(Q1, Q3)
*UC = ultracentrifugation
12
DESCARTES: Baseline LDL-C on Background
Therapy Prior to First Dose of Study Drug
Diet
Alone
Treatment
A 10 mg/d
A 80 mg/d
A 80 mg/d
+ E 10
mg/d
All
Group
P
EVO
P
EVO
P
EVO
P
EVO
P
EVO
n
37
74
129
254
73
145
63
126
302
599
98
(15)
101
(15)
96
(13)
95
(13)
120
(32)
117
(35)
104
(22)
104
(22)
UC LDL-C
Baseline 112 112
mg/dL
(16) (15)
mean (SD)
A = Atorvastatin
E = Ezetimibe
EVO = Evolocumab
P = Placebo
13
UC LDL-C Percent Change
from Baseline, Mean (± SE)
DESCARTES: % Change in UC LDL-C
From Baseline - FAS
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
6.0%
Treatment difference
57%
-51.5%
Number of patients:
302
599
294
582
Baseline
Week 12
264
542
Week 52
Study Week
Placebo QM (N = 302)
FAS = Full analysis set, UC = ultracentrifugation
Evolocumab 420 mg QM (N = 599)
14
DESCARTES: % Change in UC LDL-C from
Baseline at Week 52
Mean Percent Change in UC LDL-C
20
Overall
Diet
Alone
Atorvastatin
10 mg
Atorvastatin
80 mg +
Atorvastatin
Ezetimibe 10 mg
80 mg
10
0
-10
-20
-30
-40
-50
-60
-70
Placebo
Evolocumab
Treatment Difference
Error bars represent standard error for treatment difference
Treatment difference are least squares mean derived from a repeated measures model
15
DESCARTES: UC LDL-C Goal Achievement
Proportion of Patients, %
LDL-C < 70 mg/dL at Week 52
100
90
80
70
60
50
40
30
20
10
0
90%
84%
82%
81%
67%
3%
Diet Alone
6%
5%
11%
Diet +
Diet +
Atorvastatin Atorvastatin
80 mg +
80 mg
Ezetimibe 10 mg
Placebo
Evolocumab
Diet +
Atorvastatin
10 mg
6%
Total
16
Changes in Mean Levels of Unbound
PCSK9
Placebo
Mean ± SE PCSK9 Level, ng/mL
700
Evolocumab
Diet Only
Atorvastatin 10 mg
600
Atorvastatin 80 mg
Atorvastatin 80 mg +
Ezetimibe 10 mg
500
400
300
200
100
0
Baseline
Week 12
Week 13
Week 52
4 weeks
post-dose
1 week
post-dose
4 weeks
post dose
17
2%
HDL-C
0
-10
-20
-30
-40
-42%
-50
0
ApoA1
-5
-10
-6%
-15
(-21 to 1)
-20
-25
-30
-28%
Triglycerides
Percent Change from
Baseline, Median (%)
(-49 to -6)
6
4
2
0
-2
-4
-6
-8
-10
3%
Percent Change from
Baseline, Mean (%)
10
Percent Change from
Baseline, Mean (%)
Lp(a)
Percent Change from
Baseline, Median (%)
ApoB
Percent Change from
Baseline, Mean (%)
DESCARTES: Other Lipids at Week 52
6%
6
4
0
2
0
-2
2%
3
2
1
0
-1
-2
-1%
(-17 to 25)
Placebo QM
Evolocumab 420 mg QM
-9%
(-26 to 13)
Error bars represent standard error
Data in parentheses represent Q1 to Q3
18
DESCARTES: Safety and
Tolerability
DESCARTES: Treatment Emergent
Adverse Events
Placebo
N=302
Evolocumab
N=599
224 (74.2)
448 (74.8)
Serious
13 (4.3)
33 (5.5)
Death
0 (0.0)
2 (0.3)
Adjudicated events
2 (0.7)
6 (1.0)
Leading to discontinuation of study drug
3 (1.0)
13 (2.2)
n (%)
Any Treatment Emergent Adverse Event
Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study
20
DESCARTES: Treatment Emergent
Adverse Events II
Placebo
N=302
Evolocumab
N=599
Nasopharyngitis
29 (9.6)
63 (10.5)
Upper respiratory tract infection
19 (6.3)
56 (9.3)
Influenza
19 (6.3)
45 (7.5)
Back pain
17 (5.6)
37 (6.2)
2 (0.7)
1 (0.2)
Amnesia - Short-term memory loss
0 (0.0)
1 (0.2)
Dementia With Lewy Bodies
1 (0.3)
0 (0.0)
Encephalopathy
1 (0.3)
0 (0.0)
n (%)
Most Common Treatment Emergent AEs
Neurocognitive AEs
Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study
21
DESCARTES: Hepatic and Muscle Safety
Placebo
N=302
Evolocumab
N=599
ALT or AST > 3 × ULN*
3 (1.0)
5 (0.8)
ALT or AST > 5 × ULN*
1 (0.3)
3 (0.5)
Myalgia
9 (3.0)
24 (4.0)
CK > 5 × ULN*
1 (0.3)
7 (1.2)
CK > 10 × ULN*
1 (0.3)
3 (0.5)
n (%)
Liver function tests
Muscle TEAEs and Laboratory Results
* At any visit post baseline, TEAE = treatment emergent adverse event
22
DESCARTES: Glycemic Parameters
Changes from baseline at week 52
Placebo
n
273
Glucose, (mg/dL);
mean (SE)
n
HbA1C, (%); mean
(SE)
A = Atorvastatin
E = Ezetimibe
0.4 (0.9)
Evolocumab
Diet
alone
A 10
mg/d
A 80
mg/d
A 80
mg/d +
E10 mg/d
63
225
131
114
-0.5 (1.5) 1.7 (1.2) 0.3 (1.0) 2.6 (1.9)
273
64
227
129
115
0.00
(0.03)
-0.09
(0.04)
0.04
(0.02)
-0.02
(0.03)
0.09
(0.04)
23
DESCARTES: Injection Sites and
Antibodies
 Potential injection site reactions
 Evolocumab 34 (5.7%)
 Placebo 15 (5.0%)
 Antibodies to evolocumab
 2 patients (allocated to evolocumab) had binding
antibodies prior to evolocumab exposure
 One patient on evolocumab developed transient
binding antibodies during therapy
 No neutralizing antibodies detected throughout study
24
DESCARTES: Conclusions
 Largest and longest double-blind, randomized placebo
controlled trial reported to date, of a monoclonal antibody
to PCSK9
 Evolocumab 420 mg QM reduced placebo adjusted UC
LDL-C 57% from baseline in patients with a wide range
of cardiovascular risk receiving background lipid lowering
therapies ranging from diet alone to the combination of
atorvastatin 80 mg/d and ezetimibe 10 mg/d
 Durable effect with consistent LDL-C reductions at
weeks 12 and 52
 Similar AE profile in placebo and active treatment groups
 No adverse laboratory signals observed
 Cardiovascular outcome trial is ongoing
25