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.
4
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
5
≥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
7
< 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
8
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
9
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.
10
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
11
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.
12
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.
13
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.
14
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)
16
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.
17
OSLER Study
Thanks for your attention!
18
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.
19