Efficacy and Safety of Evolocumab (AMG 145), a Fully Human Monoclonal Antibody to PCSK9, in Hyperlipidemic Patients on Various Background Lipid Therapies: Pooled Analysis of 1359 Patients in Four Phase 2 Trials

Study Questions:

What is the effect of a monoclonal antibody to proprotein convertase subtilizin/kexin type 9 (PCSK9 inhibitor) on low-density lipoprotein cholesterol (LDL-C) and other lipoproteins including lipoprotein (a) [Lp(a)], triglycerides, high-density lipoprotein cholesterol (HDL-C), and apolipoproteins (apo B and apo A-1), and adverse events (AEs)?


A pooled analysis was conducted from four phase 2 studies of evolocumab (AMG 145), a monoclonal antibody to PCSK9. The trials randomized 1,359 patients to various doses of subcutaneous evolocumab every 2 weeks (Q2W) or 4 weeks (Q4W), placebo, or ezetimibe for 12 weeks; 1,252 patients contributed to efficacy and 1,314 contributed to safety analyses.


The mean (standard deviation) age was 56 (11.7) years, 56% were women, and 86% were white. At baseline, a total of 60% were taking a statin and 11.8% ezetamibe. The baseline mean LDL-C was 141 (39) mg/dl. Mean percentage (95% confidence interval) reductions in LDL-C versus placebo ranged from 40.2% (44.6%, 35.8%) to 59.3% (63.7%, 54.8%) among the evolocumab groups (all p < 0.001). Statistically significant reductions in apo B, apo B/apo A-1, non-HDL-C, triglycerides, and Lp(a), and increases in HDL-C were also observed. AEs and serious AEs with evolocumab were reported in 56.8% and 2.0% of patients, compared with 49.2% and 1.2% with placebo. Adjudicated cardiac and cerebrovascular events were reported in 0.3% and 0% in the placebo and 0.9% and 0.3% in the evolocumab arms, respectively.


In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W, demonstrated significant and favorable changes in other atherogenic and anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment period.


The PCSK9 inhibitors are very potent lipid and apolipoprotein modifiers. Outcome trials are ongoing and should provide evidence as to whether lower is better and whether very low levels of LDL-C are safe. The Food and Drug Administration recently wisely requested that the studies of alirocumab, a second monoclonal antibody to PCSK9, obtain regular assessment of mental status. It is not clear whether a similar request will be made for evolocumab.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Advanced Lipid Testing, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: Proprotein Convertases, Lipoprotein(a), Cholesterol, LDL, Cholesterol, HDL, Triglycerides

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