dirk blom, tomas hala, michael bolognese, michael j lillestol, phillip d toth, lesley burgess,...
DESCRIPTION
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, - PowerPoint PPT PresentationTRANSCRIPT
Long-term Tolerability and Efficacy of Evolocumab (AMG 145) in
Hyperlipidemic Subjects: A 52 Week Phase 3 Double-blind, Randomized,
Placebo-controlled StudyDirk 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 400American College of Cardiology, Washington DC
2
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;380:1995-20062. Circulation. 2012;126:2408-2417
3. JAMA. 2012;308:2497-2506
4. Lancet. 2012;380:2007-20175. Circulation 2014;129:234-243
3
The DESCARTES Study
Durable Effect of PCSK9 antibody CompARed wiTh placEbo Study (NCT01516879)
A 52 week global, randomized, double-blind, placebo-controlled 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
4
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
5
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
6
DESCARTES: Screening and Lipid Stabilization
Screening LDL-C ≥ 75 mg/dL
Background Therapy Assigned Based on CV Risk, LDL-C, and Current Therapy:
1) Diet alone2) Diet and atorvastatin 10 mg3) Diet and atorvastatin 80 mg4) Diet, atorvastatin 80 mg, and ezetimibe 10 mg
4 Week Dietary Run-in andLipid StabilizationSc
reen
ing
Perio
d 4
Wee
ks t
o 16
Wee
ks
Yes
No
Initial LDL-C < 75 mg/dL= Screen Fail
LDL < 75 mg/dL= Screen Fail (except on
maximal background therapy – allowed one
downtitration
CHD/risk equivalent: LDL < 100 mg/dL OR No CHD/risk equivalent: LDL < 130 mg/dL OR
On Maximal background therapy
Up-titrate Background Therapy
Randomization 2:1 (~900 Subjects) Evolocumab 420 mg SC QM Placebo SC QM
7
DESCARTES: Study Overview
Day 1 Week 8
End
of S
tudy
Week 52*Week 4Visits:
Placebo SC QM n = 303
Evolocumab 420 mg SC QM n = 602
Ran
dom
izat
ion
2:1
QM:Study Drug (Evolocumab or Placebo)
Screening - Assign
background Rx based on
CV risk, LDL, and
+/- prior statin:
1. No drug2. Low dose: 10 mg
atorvastatin 3. High dose: 80 mg
atorvastatin 4. Maximal: 80 mg
atorvastatin + 10 mg ezetimibe
Subcutaneous injection of 6 mL Placebo
Period = Max. 16 weeks / Min: 4 weeks
Lipid Stabilization
Period
Fasting LDL-C 5–10 days
before randomization
* Last dose administered at week 48
8
DESCARTES: Patient Disposition
Screened: 2120
1485 entered lipid stabilization period
905 randomized to evolocumab or placebo
635 screen failures
580 lipid stabilization
period failures
9
DESCARTES: Patient Disposition II
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)
905 Randomized2:1 allocation to evolocumab or placebo
800 completed 52 weeks of Study Drug
E = Ezetimibe, Evo = Evolocumab, P = Placebo* Study Drug
4 never received SD*73 discontinued evolocumab28 discontinued placebo
10
DESCARTES: Baseline Characteristics
Characteristic Diet Alone A 10 mg/d A 80 mg/d A 80 mg/d
+E10 mg/d All
n 111 383 218 189 901
Age, y, mean (SD)
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
A = AtorvastatinE = Ezetimibe
Full Analysis Set (FAS) data presented: Patients who received at least one dose of study drug
11
DESCARTES: Baseline Patient Characteristics II
Characteristic Diet Alone A 10 mg/d 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
Family history of premature CAD, % 13.5 14.6 22.0 47.1 23.1
2 or more CV risk factors, % 29.7 26.6 46.3 61.4 39.1
A = AtorvastatinE = Ezetimibe
12
DESCARTES: Baseline Lipids
Placebo Evolocumab
n 302 599
*UC LDL-C, mg/dL, mean (SD) 104 (22) 104 (22)
ApoB, mg/dL, mean (SD) 88 (16) 87 (16)
Lipoprotein(a), nmol/L, median (Q1, Q3)
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)
Triglycerides, mg/dL, median, (Q1, Q3)
110 (85,155)
105 (80,140)
*UC = ultracentrifugation
13
DESCARTES: Baseline LDL-C on Background Therapy Prior to First Dose of Study Drug
Treatment Diet Alone 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
UC LDL-C Baseline mg/dL
mean (SD)
112 (16)
112 (15)
98 (15)
101 (15)
96 (13)
95 (13)
120 (32)
117 (35)
104 (22)
104 (22)
A = AtorvastatinE = EzetimibeEVO = EvolocumabP = Placebo
14
DESCARTES: % Change in UC LDL-C From Baseline - FAS
UC
LD
L-C
Per
cent
Cha
nge
from
Bas
elin
e, M
ean
(± S
E)
Baseline Week 12 Week 52
-80-70-60-50-40-30-20-10
01020
Number of patients:
Study Week
599 582 542302 294 264
Placebo QM (N = 302) Evolocumab 420 mg QM (N = 599)
FAS = Full analysis set, UC = ultracentrifugation
-51.5%
6.0%
Treatment difference57%
15
-70
-60
-50
-40
-30
-20
-10
0
10
20
Mea
n Pe
rcen
t Cha
nge
in U
C LD
L-C
DESCARTES: % Change in UC LDL-C from Baseline at Week 52
Error bars represent standard error for treatment difference Treatment difference are least squares mean derived from a repeated measures model
EvolocumabPlacebo Treatment Difference
OverallDiet
AloneAtorvastatin
10 mgAtorvastatin
80 mg
Atorvastatin80 mg +
Ezetimibe 10 mg
16
0102030405060708090
100
3% 5% 6%11% 6%
84%90%
81%
67%
82%
Placebo Evolocumab
Prop
ortio
n of
Pat
ient
s, %
Diet Alone Diet + Atorvastatin
10 mg
Diet + Atorvastatin
80 mg
Diet + Atorvastatin
80 mg +Ezetimibe 10 mg
DESCARTES: UC LDL-C Goal Achievement
LDL-C < 70 mg/dL at Week 52
Total
17
Changes in Mean Levels of Unbound PCSK9
0
100
200
300
400
500
600
700
Baseline Week 12 Week 13 Week 52
Mea
n ±
SE P
CSK
9 Le
vel,
ng/m
L
PlaceboDiet OnlyAtorvastatin 10 mg
Atorvastatin 80 mgAtorvastatin 80 mg +Ezetimibe 10 mg
4 weekspost-dose
1 weekpost-dose
4 weekspost dose
Evolocumab
18
DESCARTES: Other Lipids at Week 52
0
6%
-2
0
2
4
6
3%(-17 to 25)
-9%(-26 to 13)
2%ApoB
Lp(a)
HDL-C
ApoA1
Triglycerides
-42%-50
-40
-30
-20
-10
0
10
-1%
2%
-2
-1
0
1
2
3-6%
(-21 to 1)
-28%(-49 to -6)
-30-25-20-15-10
-50
Placebo QM
Evolocumab 420 mg QM
Perc
ent C
hang
e fr
omB
asel
ine,
Mea
n (%
)Pe
rcen
t Cha
nge
from
Bas
elin
e, M
edia
n (%
)Pe
rcen
t Cha
nge
from
Bas
elin
e, M
edia
n (%
)
Perc
ent C
hang
e fr
omB
asel
ine,
Mea
n (%
)Pe
rcen
t Cha
nge
from
Bas
elin
e, M
ean
(%)
-6-4-20246
-10-8 Error bars represent standard error
Data in parentheses represent Q1 to Q3
DESCARTES: Safety and Tolerability
20
DESCARTES: Treatment Emergent Adverse Events
n (%) PlaceboN=302
EvolocumabN=599
Any Treatment Emergent Adverse Event 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)
Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study
21
DESCARTES: Treatment Emergent Adverse Events II
n (%) PlaceboN=302
EvolocumabN=599
Most Common Treatment Emergent AEs
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)
Neurocognitive AEs 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)
Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study
22
DESCARTES: Hepatic and Muscle Safety
n (%) PlaceboN=302
EvolocumabN=599
Liver function tests
ALT or AST > 3 × ULN* 3 (1.0) 5 (0.8)
ALT or AST > 5 × ULN* 1 (0.3) 3 (0.5)
Muscle TEAEs and Laboratory Results
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)
* At any visit post baseline, TEAE = treatment emergent adverse event
23
DESCARTES: Glycemic Parameters
Changes from baseline at week 52
Placebo Evolocumab
Diet alone
A 10 mg/d
A 80 mg/d
A 80 mg/d +
E10 mg/d
n 273 63 225 131 114
Glucose, (mg/dL); mean (SE) 0.4 (0.9) -0.5 (1.5) 1.7 (1.2) 0.3 (1.0) 2.6 (1.9)
n 273 64 227 129 115
HbA1C, (%); mean (SE)
0.00(0.03)
-0.09 (0.04)
0.04 (0.02)
-0.02 (0.03)
0.09 (0.04)
A = AtorvastatinE = Ezetimibe
24
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
25
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