1. 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

2. 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, placebo- controlled, 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.
Koren MJ, et al. Lancet. 2012;380:
Sullivan D, et al. JAMA. 2012;308:
Raal FJ, et al. Circulation. 2012;126:
Giugliano RP, et al. Lancet. 2012;380:
PCSK9, Proprotein convertase subtilisin/kexin type 9

3. 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 hypercholesterolemic patients treated in OSLER for 1 year.
Q4W, every 4 weeks; SOC, standard of care

4. OSLER Study Design Effects on LDL-C over 1 year
Years 2–5
12-week studies:
MENDEL (monotherapy)
LAPLACE-TIMI 57 (patients on statins)
GAUSS
(statin intolerance)
RUTHERFORD (Familial hyper- cholesterolemia)
Standard of Care
N = 368
Evolocumab + Standard of Care
Randomization 2:1
End of Study
Evolocumab + Standard of Care
N = 736
Blinded Stabilization Period
Unblinded
Lipid Treatment
Visits*
End of parent study / Day 1 4 8 12
Q4W 52
Q4W
OSLER Week
Effects on LDL-C over 1 year
Safety and Tolerability
Primary Objectives:
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.

5. OSLER: Baseline Patient Characteristics
SOC
N = 368
Evolocumab + SOC
N = 736
Female, % 56 55
Age, years, mean (SD)
56.7 (12)
56.1 (12)
Race, white, % 88
Established CAD*, % 16 21
Type 2 diabetes, % 10
Metabolic syndrome†, % 36 40
On statins at baseline, % 58 65
* 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 ≥110 mg/dL. CAD, coronary artery disease; SD, standard deviation

6. OSLER: Baseline Lipid Characteristics
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)
Total cholesterol, mg/dL, mean (SD)
224 (45)
218 (45)
IQR, interquartile range; SD, standard deviation; UC, ultracentrifugation

7. OSLER: Percentage Change in LDL-C, by UC, From Baseline to 1 Year
-2% 10
-10
-3%
-20
UC LDL-C Percentage Change from
Baseline to Week 52, Mean (SE)
-30
-52%
-40
-50
-60
-52%
Baseline
Parent Study 12 24 36 48 52
Week 12
OSLER Study Week
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

8. OSLER: LDL-C Goal Achievement
< 100 mg/dL
Proportion of Patients, %
< 70 mg/dL
Proportion of Patients, %
SOC
Evolocumab + SOC
LDL-C values by ultracentrifugation. SOC, standard of care

9. 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 < ; † P < 0.001; § P < 0.01; ‡ P < 0.05
Evolocumab vs placebo:
§ P< ; ¶ P< 0.001

10. OSLER: Safety and Tolerability
Adverse events, %
SOC
N = 368
Evolocumab
+ SOC
N = 736
Any adverse event
73.1
81.4
Serious
6.3
7.1
Possibly treatment-related (none serious) NA
5.6*
Leading to discontinuation of evolocumab
3.7
Deaths
0.5
0.1
Most common adverse events
Nasopharyngitis
9.8
12.2
Upper respiratory tract infection
7.6
7.7
Arthralgia
4.3
6.9
Back pain
5.4
6.5
Muscle-related
9.2
Injection-site reactions
NA†
5.2
NA, not applicable; SOC, standard of care. *Percentage of adverse events. †Patients in the SOC group did not receive injections.

11. OSLER: Key Laboratory Results
Laboratory Results, n (%)
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)
SOC, standard of care. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal

12. OSLER: Adverse Events by Lowest Post-Baseline LDL-C Value
< 25 mg/dL*
LDL-C < 50 mg/dL*
LDL-C ≥ 50 mg/dL
Adverse events, %
Evolocumab + SOC N = 98
Evolocumab + SOC N = 409
SOC
N = 359
Evolocumab + SOC N = 323
Any AE
81.6
82.2
74.7
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
2.2
3.1
2.5
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.

13. 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
Adverse events, n (%)
Evolocumab + SOC N = 98
Evolocumab + SOC N = 409
SOC
N = 359
Evolocumab + SOC N = 323
Nervous System AEs
19 (19.4)
64 (15.6)
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 (0.2)
0 (0.0)
Memory impairment†
Psychiatric AEs
5 (5.1)
20 (4.9)
12 (3.3)
15 (4.6)
Insomnia
9 (2.2)
4 (1.1)
4 (1.2)
Depression
6 (1.5)
5 (1.4)
Anxiety
2 (0.6)
* 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.

14. OSLER: Musculoskeletal AEs
LDL-C < 25 mg/dL*
LDL-C < 50 mg/dL*
LDL-C ≥ 50 mg/dL
Adverse events, n (%)
Evolocumab + SOC N = 98
Evolocumab + SOC N = 409
SOC
N = 359
Evolocumab + SOC N = 323
Musculoskeletal and Connective Tissue Disorders
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)
Pain in extremity
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.

15. OSLER: Laboratory Results by Lowest Post-Baseline LDL-C Value
< 25 mg/dL*
LDL-C < 50 mg/dL*
LDL-C ≥ 50 mg/dL
Adverse events, %
Evolocumab + SOC N = 98
Evolocumab + SOC N = 409
SOC
N = 359
Evolocumab + SOC N = 323
CK > 5 × ULN
2.0
0.5
1.9
1.5
CK > 10 × ULN
0.0
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.

16. OSLER: Adjudicated Cardiovascular Clinical Events
Event, Patient Incidence, n (%)
SOC
N = 368
Evolocumab
+ SOC
N = 736
Any positively adjudicated cardiovascular clinical event
8 (2.2)
9 (1.2)
Death
2 (0.5)
1 (0.1)
Myocardial infarction (fatal and non-fatal)
3 (0.8)
0 (0.0)
Hospitalization for unstable angina
2 (0.3)
Revascularization
4 (1.1)
6 (0.8)
Cerebrovascular event
1 (0.3)
3 (0.4)
Transient ischemic attack
Ischemic stroke
Hemorrhagic stroke
Hospitalization for heart failure
SOC, standard of care

17. 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.

18. Thanks for your attention!
OSLER Study
Thanks for your attention!

19. 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.