November 19, 2013, Session CS.03 American Heart Association Scientific Sessions, Dallas, TX

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.03American 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, 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.

2PCSK9, Proprotein convertase subtilisin/kexin type 9

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.

3Q4W, every 4 weeks; SOC, standard of care

OSLER Study Design

4

12-week studies:

MENDEL (monotherapy)

LAPLACE-TIMI 57 (patients on statins)

GAUSS

(statin intolerance)

RUTHERFORD (Familial hyper-cholesterolemia)

Ran

do

miz

atio

n 2

:1Evolocumab +

Standard of CareN = 736

Standard of CareN = 368

Evolocumab + Standard of Care

En

d o

f S

tud

y

End of parent study / Day 1 OSLER Week

4 8 12 Q4W 52

Blinded Stabilization

Period

UnblindedLipid

Treatment

Q4W

• Effects on LDL-C over 1 year • Safety and Tolerability

Primary Objectives:

Visits*

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.

OSLER: Baseline Patient Characteristics

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CharacteristicSOC

N = 368

Evolocumab + SOCN = 736

Female, % 56 55

Age, years, mean (SD) 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

* 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

OSLER: Baseline Lipid Characteristics

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CharacteristicSOC

N = 368

Evolocumab+ SOCN = 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

OSLER: Percentage Change in LDL-C, by UC, From Baseline to 1 Year

7

Baseline Parent StudyWeek 12

12 24 36 48 52OSLER Study Week

-60-50-40-30-20-10

10

UC

LD

L-C

Per

cen

tag

e C

han

ge

fro

mB

asel

ine

to W

eek

52,

Mea

n (

SE

)

SE, standard error; SOC, standard of care; UC, ultracentrifugation

Not Evolocumab / Evolocumab + SOC (n = 192)Not Evolocumab / SOC Only (n = 96)

Evolocumab / SOC Only (n = 272)Evolocumab / Evolocumab + SOC (n = 544)

-52%

-52%

-2%

-3%

0

OSLER: LDL-C Goal Achievement

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< 100 mg/dL

Evolocumab + SOC

SOC

LDL-C values by ultracentrifugation. SOC, standard of care

< 70 mg/dL

Pro

port

ion

of P

atie

nts,

%P

ropo

rtio

n of

Pat

ient

s, %

OSLER: Effect of Evolocumab on Other Lipid Parameters at 1 Year

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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

OSLER: Safety and Tolerability

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Adverse events, %SOC

N = 368

Evolocumab+ SOCN = 736

Any adverse event 73.1 81.4Serious 6.3 7.1Possibly treatment-related (none serious) NA 5.6*Leading to discontinuation of evolocumab NA 3.7Deaths 0.5 0.1Most common adverse events    

Nasopharyngitis 9.8 12.2Upper respiratory tract infection 7.6 7.7Arthralgia 4.3 6.9Back pain 5.4 6.5

Muscle-related 9.8 9.2Injection-site reactions NA† 5.2NA, not applicable; SOC, standard of care. *Percentage of adverse events. †Patients in the SOC group did not receive injections.

OSLER: Key Laboratory Results

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Laboratory Results, n (%)SOC

N = 368

Evolocumab + SOCN = 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

OSLER: Adverse Events by Lowest Post-Baseline LDL-C Value

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LDL-C < 25 mg/dL*

LDL-C < 50 mg/dL*

LDL-C ≥ 50 mg/dL

Adverse events, %

Evolocumab + SOCN = 98

Evolocumab + SOC

N = 409

SOC

N = 359

Evolocumab + SOCN = 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 1.0 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.

OSLER: Nervous System/Psychiatric AEs By Lowest Post-Baseline LDL-C Value

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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 (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)

* 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.

OSLER: Musculoskeletal AEs

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LDL-C < 25 mg/dL*

LDL-C < 50 mg/dL*

LDL-C ≥ 50 mg/dL

Adverse events,n (%)

Evolocumab +

SOCN = 98

Evolocumab + SOC

N = 409

SOC

N = 359

Evolocumab + SOC

N = 323Musculoskeletal 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) 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.

OSLER: Laboratory Results by Lowest Post-Baseline LDL-C Value

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LDL-C < 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 0.0 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.

OSLER: Adjudicated Cardiovascular Clinical Events

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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 (0.5) 2 (0.3)Revascularization 4 (1.1) 6 (0.8)Cerebrovascular event 1 (0.3) 3 (0.4)

Transient ischemic attack 1 (0.3) 2 (0.3)Ischemic stroke 0 (0.0) 1 (0.1)Hemorrhagic stroke 0 (0.0) 0 (0.0)

Hospitalization for heart failure 1 (0.3) 0 (0.0)

SOC, standard of care

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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