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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.

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

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  1. Randomized Comparison of the Safety, Tolerability, and Efficacy of Long-term Administration of AMG 145: 52-Week Results From the OSLER Study Michael JKoren1, 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

  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;380:1995-2006 • Raal FJ, et al. Circulation. 2012;126:2408-2417 • Sullivan D, et al. JAMA. 2012;308:2497-2506 • Giugliano RP, et al. Lancet. 2012;380:2007-2017 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 1104 hypercholesterolemic patients treated in OSLER for 1 year. Q4W, every 4 weeks; SOC, standard of care

  4. OSLER Study Design Year 1 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* 4 8 12 Q4W 52 Q4W End of parent study / Day 1 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 * 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 IQR, interquartile range; SD, standard deviation; UC, ultracentrifugation

  7. OSLER: Percentage Change in LDL-C, by UC, From Baseline to 1 Year -2% 10 0 -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 / Evolocumab + SOC (n = 192) Not Evolocumab / SOC Only (n = 96) 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, % Evolocumab + SOC < 70 mg/dL SOC Proportion of Patients, % 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 < 0.0001; † P < 0.001; § P < 0.01; ‡ P < 0.05 Evolocumab vs placebo: § P< 0.0001; ¶ P< 0.001

  10. OSLER: Safety and Tolerability 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 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 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 * 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 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 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 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. 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.

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