Randomized Comparison of the Safety, Tolerability, and Efficacy of Long-term Administration of AMG 145: 52-Week Results From the OSLER Study Michael J Koren 1, Robert P Giugliano 2, Frederick Raal 3, David Sullivan 4, Michael Bolognese 5, Gisle Langslet 6, Fernando Civeira 7, Ransi Somaratne 8, Patric Nelson 8, Thomas Liu 8, Rob Scott 8, Scott M Wasserman 8, Marc S Sabatine 2 for the OSLER Investigators 1 Jacksonville Center for Clinical Research, Jacksonville, FL; 2 TIMI Study Group/ Cardiovascular Division, Brigham and Women s Hospital, Boston, MA; 3 Carbohydrate & Lipid Metabolism Research Unit, Division of Endocrinology & Metabolism, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa; 4 Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia; 5 Bethesda Health Research Center, Bethesda, MD; 6 Lipid Clinic, Oslo University Hospital, Oslo, Norway; 7 Hospital Universitario Miguel Servet, Zaragoza, Spain; 8 Amgen, 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 + or 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;, standard of care 3
Randomization 2:1 End of Study OSLER Study Design 12-week studies: MENDEL (monotherapy) LAPLACE-TIMI 57 (patients on statins) GAUSS (statin intolerance) RUTHERFORD (Familial hypercholesterolemia) Blinded Stabilization Period Year 1 Years 2 5 Standard of Care N = 368 Standard of Care N = 736 Unblinded Lipid Treatment Standard of Care Visits* End of parent study / Day 1 Primary Objectives: 4 8 12 Q4W 52 OSLER Week Effects on LDL-C over 1 year Safety and Tolerability Q4W Q4W, every 4 weeks. * Patients in the evolocumab + group had in-person visits every 4 weeks. Patients in the group had in-person visits at week 4, then every 3 months, with telephone visits every 4 weeks. 4
OSLER: Baseline Patient Characteristics Characteristic N = 368 Evolocumab + N = 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 5
OSLER: Baseline Lipid Characteristics Characteristic N = 368 Evolocumab + 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 10 0-10 -20-30 -40-50 -60-2% -3% -52% -52% Baseline Parent Study Week 12 12 24 36 48 52 OSLER Study Week Not Evolocumab / Only (n = 96) Evolocumab / (n = 544) Not Evolocumab / (n = 192) Evolocumab / Only (n = 272) SE, standard error;, standard of care; UC, ultracentrifugation 7
OSLER: LDL-C Goal Achievement < 100 mg/dl Proportion of Patients, % Proportion of Patients, % < 70 mg/dl LDL-C values by ultracentrifugation., 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, % N = 368 Evolocumab + 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 NA 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 9.8 9.2 Injection-site reactions NA 5.2 NA, not applicable;, standard of care. *Percentage of adverse events. Patients in the group did not receive injections. 10
OSLER: Key Laboratory Results Laboratory Results, n (%) N = 368 Evolocumab + 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), 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 Adverse events, % LDL-C < 25 mg/dl* Evolocumab + N = 98 LDL-C < 50 mg/dl* N = 409 LDL-C 50 mg/dl N = 359 Evolocumab + 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 1.0 2.2 3.1 2.5 AE, adverse event;, standard of care. *In the 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 Adverse events, n (%) LDL-C < 25 mg/dl* N = 98 LDL-C < 50 mg/dl* N = 409 LDL-C 50 mg/dl N = 359 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 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 Adverse events, n (%) Musculoskeletal and Connective Tissue Disorders LDL-C < 25 mg/dl* N = 98 LDL-C < 50 mg/dl* N = 409 LDL-C 50 mg/dl N = 359 N = 323 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;, standard of care. * In the 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* LDL-C < 50 mg/dl* LDL-C 50 mg/dl Adverse events, % N = 98 N = 409 N = 359 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;, standard of care; ULN, upper limit of normal. * In the 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 N = 368 Evolocumab + N = 736 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), standard of care 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 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
CIRCULATION Circulation 2013;128(21): epub ahead of print Nov. 19, 2013 Available at http://circ.ahajournals.org 18
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. 20