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Randomized Comparison of the Safety,
Tolerability, and Efficacy of Long-term
Administration of AMG 145: 52-Week
Results From the OSLER Study
Michael J Koren1, Robert P Giugliano2, Frederick Raal3, David Sullivan4,
Michael Bolognese5, Gisle Langslet6, Fernando Civeira7, Ransi
Somaratne8, Patric Nelson8, Thomas Liu8, Rob Scott8, Scott M
Wasserman8, Marc S Sabatine2 for the OSLER Investigators
1Jacksonville
Center for Clinical Research, Jacksonville, FL; 2TIMI Study Group/
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA; 3Carbohydrate & Lipid
Metabolism Research Unit, Division of Endocrinology & Metabolism, Department of Medicine,
University of the Witwatersrand, Johannesburg, South Africa; 4Department of Clinical
Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia; 5Bethesda Health
Research Center, Bethesda, MD; 6Lipid Clinic, Oslo University Hospital, Oslo, Norway;
7Hospital Universitario Miguel Servet, Zaragoza, Spain; 8Amgen, Thousand Oaks, CA
November 19, 2013, Session CS.03
American Heart Association Scientific Sessions, Dallas, TX
Background: PCSK9 Inhibition For LDL-C Reduction
PCSK9 inhibition has emerged as a new approach for
treating hypercholesterolemia.
AMG 145 (Evolocumab), a fully human monoclonal
antibody against PCSK9, reduced LDL-C by up to 65%
and was well tolerated in 4 randomized, placebocontrolled, phase 2 clinical trials of 12 weeks duration in
over 1300 hypercholesterolemic patients. 1-4
Longer-term efficacy and safety of PCSK9 inhibition have
not been reported to date.
1. Koren MJ, et al. Lancet. 2012;380:1995-2006
2. Raal FJ, et al. Circulation. 2012;126:2408-2417
3. Sullivan D, et al. JAMA. 2012;308:2497-2506
4. Giugliano RP, et al. Lancet. 2012;380:2007-2017
PCSK9, Proprotein convertase subtilisin/kexin type 9
2
The OSLER Trial
To provide longer-term data, patients completing any of
the 4 phase 2 trials could participate in the Open-label
Study of Long-tERm Evaluation Against LDL-C (OSLER)
trial of evolocumab 420 mg Q4W + SOC or SOC alone.
OSLER is a global, multicenter, randomized, controlled,
open-label extension trial.
We report the efficacy and safety results for 1104
hypercholesterolemic patients treated in OSLER for 1
year.
Q4W, every 4 weeks; SOC, standard of care
3
OSLER Study Design
Standard of Care
N = 368
Evolocumab +
Standard of Care
Evolocumab +
Standard of Care
N = 736
Blinded
Stabilization
Period
Visits*
End of parent 4
study / Day 1
Primary
Objectives:
Years 2–5
8
End of Study
12-week studies:
MENDEL
(monotherapy)
LAPLACE-TIMI 57
(patients on statins)
GAUSS
(statin intolerance)
RUTHERFORD
(Familial hypercholesterolemia)
Randomization 2:1
Year 1
Unblinded
Lipid
Treatment
12
Q4W
52
Q4W
OSLER Week
• Effects on LDL-C over 1 year
• Safety and Tolerability
Q4W, every 4 weeks. * Patients in the evolocumab + SOC group had in-person visits every 4 weeks. Patients in the
SOC group had in-person visits at week 4, then every 3 months, with telephone visits every 4 weeks.
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OSLER: Baseline Patient Characteristics
SOC
N = 368
Evolocumab
+ SOC
N = 736
56
55
56.7 (12)
56.1 (12)
Race, white, %
88
88
Established CAD*, %
16
21
Type 2 diabetes, %
10
10
Metabolic syndrome†, %
36
40
On statins at baseline, %
58
65
Characteristic
Female, %
Age, years, mean (SD)
* Based
on presence of angina, myocardial infarction, coronary artery bypass graft, or percutaneous coronary
intervention, †Metabolic syndrome defined as 3 or more risk factors including elevated waist circumference, triglycerides
≥ 150 mg/dL, low HDL-C (< 40 mg/dL in men and < 50 mg/dL in women), hypertension, diabetes or fasting glucose
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≥110 mg/dL. CAD, coronary artery disease; SD, standard deviation
OSLER: Baseline Lipid Characteristics
Characteristic
SOC
N = 368
Evolocumab
+ SOC
N = 736
LDL-C, UC, mg/dL, mean (SD)
144 (40)
140 (39)
Apolipoprotein B, mg/dL, mean (SD)
113 (27)
110 (25)
Lipoprotein (a), nmol/L, median (IQR)
36 (11–115)
40 (12–151)
Triglycerides, mg/dL, median (IQR)
121 (89-169)
124 (93-170)
HDL-C, mg/dL, mean (SD)
54 (17)
53 (17)
Apolipoprotein A1, mg/dL, mean (SD)
154 (29)
154 (29)
Total cholesterol, mg/dL, mean (SD)
224 (45)
218 (45)
IQR, interquartile range; SD, standard deviation; UC, ultracentrifugation
6
UC LDL-C Percentage Change from
Baseline to Week 52, Mean (SE)
OSLER: Percentage Change in LDL-C, by
UC, From Baseline to 1 Year
-2%
10
0
-10
-20
-30
-40
-50
-60
-3%
-52%
-52%
Baseline
Parent Study
Week 12
12
24
36
OSLER Study Week
48
52
Not Evolocumab / SOC Only (n = 96)
Not Evolocumab / Evolocumab + SOC (n = 192)
Evolocumab / Evolocumab + SOC (n = 544)
Evolocumab / SOC Only (n = 272)
SE, standard error; SOC, standard of care; UC, ultracentrifugation
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< 100 mg/dL
Proportion of Patients, %
< 70 mg/dL
Proportion of Patients, %
OSLER: LDL-C Goal Achievement
SOC
Evolocumab + SOC
LDL-C values by ultracentrifugation. SOC, standard of care
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OSLER: Effect of Evolocumab on Other
Lipid Parameters at 1 Year
Error bars represent standard error.
Data in parentheses represent interquartile ranges.
Week 52 vs baseline:
* P < 0.0001; † P < 0.001; § P < 0.01; ‡ P < 0.05
Evolocumab vs placebo:
§ P< 0.0001; ¶ P< 0.001
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OSLER: Safety and Tolerability
Adverse events, %
Any adverse event
Serious
Possibly treatment-related (none serious)
Leading to discontinuation of evolocumab
Deaths
Most common adverse events
Nasopharyngitis
Upper respiratory tract infection
Arthralgia
Back pain
Muscle-related
Injection-site reactions
73.1
6.3
NA
NA
0.5
Evolocumab
+ SOC
N = 736
81.4
7.1
5.6*
3.7
0.1
9.8
7.6
4.3
5.4
9.8
NA†
12.2
7.7
6.9
6.5
9.2
5.2
SOC
N = 368
NA, not applicable; SOC, standard of care. *Percentage of adverse events. †Patients in the SOC group did not
receive injections.
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OSLER: Key Laboratory Results
SOC
N = 368
Evolocumab
+ SOC
N = 736
ALT or AST > 3 × ULN at any
post-baseline visit
6 (1.6)
13 (1.8)
Creatine kinase > 5 × ULN at any
post-baseline visit
7 (1.9)
7 (1.0)
Laboratory Results, n (%)
SOC, standard of care. ALT, alanine aminotransferase; AST, aspartate aminotransferase;
ULN, upper limit of normal
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OSLER: Adverse Events by
Lowest Post-Baseline LDL-C Value
LDL-C
< 25 mg/dL*
LDL-C
< 50 mg/dL*
Evolocumab
+ SOC
N = 98
81.6
Evolocumab +
SOC
N = 409
82.2
N = 359
74.7
Evolocumab
+ SOC
N = 323
81.1
Serious AEs
5.1
6.6
6.1
7.7
Hepatobiliary AE
1.0
0.7
0.8
0.3
Renal and Urinary AE
1.0
2.2
3.1
2.5
Adverse events, %
Any AE
LDL-C ≥ 50 mg/dL
SOC
AE, adverse event; SOC, standard of care.
*In the SOC group, no patients had LDL-C <25 mg/dL, and 2 patients had LDL-C <50 mg/dL.
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OSLER: Nervous System/Psychiatric AEs
By Lowest Post-Baseline LDL-C Value
LDL-C < 25
mg/dL*
LDL-C < 50
mg/dL*
LDL-C ≥ 50 mg/dL
Evolocumab +
SOC
N = 98
19 (19.4)
Evolocumab +
SOC
N = 409
64 (15.6)
Evolocumab +
SOC
SOC
N = 359
N = 323
37 (10.3)
44 (13.6)
Headache
9 (9.2)
25 (6.1)
10 (2.8)
21 (6.5)
Dizziness
4 (4.1)
11 (2.7)
11 (3.1)
5 (1.5)
Migraine
1 (1.0)
4 (1.0)
1 (0.3)
7 (2.2)
Amnesia
1 (1.0)
1 (0.2)
0 (0.0)
1 (0.3)
Memory impairment†
0 (0.0)
4 (1.0)
0 (0.0)
1 (0.3)
Psychiatric AEs
5 (5.1)
20 (4.9)
12 (3.3)
15 (4.6)
Insomnia
4 (4.1)
9 (2.2)
4 (1.1)
4 (1.2)
Depression
1 (1.0)
6 (1.5)
5 (1.4)
5 (1.5)
Anxiety
0 (0.0)
4 (1.0)
2 (0.6)
5 (1.5)
Adverse events, n (%)
Nervous System AEs
* In the SOC group, no patients had LDL-C <25 mg/dL, and 2 patients had LDL-C <50 mg/dL.
† Includes “memory impairment” and “mental impairment” terms.
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OSLER: Musculoskeletal AEs
LDL-C < 25
mg/dL*
Adverse events,
n (%)
Musculoskeletal and
Connective Tissue
Disorders
LDL-C < 50
mg/dL*
Evolocumab + Evolocumab +
SOC
SOC
N = 98
N = 409
LDL-C ≥ 50 mg/dL
N = 359
Evolocumab +
SOC
N = 323
SOC
34 (34.7)
135 (33.0)
89 (24.8)
84 (26.0)
Back pain
12 (12.2)
31 (7.6)
20 (5.6)
17 (5.3)
Arthralgia
7 (7.1)
34 (8.3)
16 (4.5)
17 (5.3)
Pain in extremity
7 (7.1)
21 (5.1)
10 (2.8)
15 (4.6)
AE, adverse event; SOC, standard of care.
* In the SOC group, no patients had LDL-C <25 mg/dL, and 2 patients had LDL-C <50 mg/dL.
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OSLER: Laboratory Results by
Lowest Post-Baseline LDL-C Value
LDL-C
< 25 mg/dL*
Adverse events,
%
Evolocumab +
SOC
N = 98
LDL-C
< 50 mg/dL*
LDL-C ≥ 50 mg/dL
Evolocumab +
Evolocumab +
SOC
SOC
SOC
N = 409
N = 323
N = 359
CK > 5 × ULN
2.0
0.5
1.9
1.5
CK > 10 × ULN
0.0
0.0
0.6
0.6
ALT or AST
> 3 × ULN
1.0
0.7
1.7
3.1
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; SOC,
standard of care; ULN, upper limit of normal.
* In the SOC group, no patients had LDL-C <25 mg/dL, and 2 patients had LDL-C <50 mg/dL.
15
OSLER: Adjudicated Cardiovascular
Clinical Events
Event, Patient Incidence, n (%)
Any positively adjudicated cardiovascular
clinical event
Death
Myocardial infarction (fatal and non-fatal)
Hospitalization for unstable angina
Revascularization
Cerebrovascular event
Transient ischemic attack
Ischemic stroke
Hemorrhagic stroke
Hospitalization for heart failure
SOC, standard of care
SOC
N = 368
Evolocumab
+ SOC
N = 736
8 (2.2)
9 (1.2)
2 (0.5)
3 (0.8)
2 (0.5)
4 (1.1)
1 (0.3)
1 (0.3)
0 (0.0)
0 (0.0)
1 (0.3)
1 (0.1)
0 (0.0)
2 (0.3)
6 (0.8)
3 (0.4)
2 (0.3)
1 (0.1)
0 (0.0)
0 (0.0)
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OSLER: Conclusions
The 1 year OSLER analysis evaluated evolocumab in a
diverse patient population in the largest and longest
study of an anti-PCSK9 antibody reported to date.
Findings over > 1000 patient-years suggest a highly
effective, consistent, and well tolerated therapy.
Evolocumab reduced LDL-C by an average of 50%
beyond that achieved with optimal SOC in various
hypercholesterolemic patient populations.
AE profile was generally balanced.
No adverse laboratory signals were observed.
No major increase in AEs was observed in patients
who reached low or very low LDL-C levels.
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OSLER Study
Thanks for your attention!
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Presenter Disclosure Information
Financial Disclosures:
Amgen Inc. funded this study.
M J Koren: employee of Jacksonville Center for Clinical Research, which has received research grants for PCSK9
studies from Amgen, Pfizer, Regeneron, Roche and Sanofi.
R P Giugliano: member of the TIMI Study Group, which received research grant support from Amgen for the conduct of
the LAPLACE-TIMI 57 trial; honoraria for lectures and consultation from Amgen, Merck, Regeneron, and Sanofi-Aventis;
research-grant support from Merck for work related to lipid-lowering therapies.
F. Raal: consulting fees from Amgen and Sanofi re: PCSK9 inhibitors; his institution, research funding re: PCSK9 inhibitor
clinical trials from Amgen and Sanofi.
D Sullivan: research funding from Amgen, Abbott Products, AstraZeneca, Merck, Sharp and Dohme, and Sanofi Aventis;
funding for educational programs from Abbott Products, AstraZeneca, Merck, Sharp, and Dohme, Pfizer Australia, and
Roche; travel support from Merck, Sharp, and Dohme; advisory boards for Abbott Products, Merck, Sharp, and Dohme,
and Pfizer Australia.
M Bolognese: research grants from Amgen, Unigene Laboratories Inc., Eli Lilly and Company, and Radius Health, Inc;
speakers’ bureaus for Amgen, Eli Lilly and Company, and Genentech.
G Langslet: consultant/advisory board for Janssen Pharmaceuticals.
F Civeira: consulting/advisory fees from Amgen Inc.
M S Sabatine: member of the TIMI Study Group, which received research grant support from Amgen for the conduct of
the LAPLACE-TIMI 57 trial; has received research-grant support through Brigham and Women’s Hospital from
AstraZeneca/Bristol-Myers Squibb Alliance, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Daiichi-Sanyo, Eisai,
Genzyme, GlaxoSmithKline, Merck, Sanofi-Aventis, Takeda, Abbott Laboratories, Accumetrics, Critical Diagnostics,
Nanosphere, and Roche Diagnostics; and has consulted for Aegerion, Amgen, Bristol-Myers Squibb, GlaxoSmithKline,
Intarcia, Merck, Pfizer, Sanofi-Aventis, AstraZeneca, and Vertex.
R Somaratne, P Nelson, T Liu, R Scott, and SM Wasserman: employees of Amgen who have received Amgen
stock/stock options.
Unlabeled/unapproved uses disclosure: Evolocumab in patients with hyperlipidemia is investigational.
The authors acknowledge the editorial support of Meera Kodukulla, PhD, Amgen Inc., and Sue
Hudson, BA, on behalf of Amgen Inc.
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