Evolocumab (Repatha®): A Comprehensive Monograph on a PCSK9 Inhibitor for Cardiovascular Risk Reduction

Executive Summary

Evolocumab represents a significant advancement in lipid-lowering therapy, embodying the successful translation of genetic discovery into a targeted biologic agent for cardiovascular risk reduction. As a fully human immunoglobulin G2 (IgG2) monoclonal antibody, evolocumab functions by selectively inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein receptor (LDLR) metabolism. By preventing PCSK9-mediated degradation of LDLRs, evolocumab enhances the liver's capacity to clear low-density lipoprotein cholesterol (LDL-C) from circulation, resulting in profound and sustained reductions in plasma LDL-C levels.

The clinical development of evolocumab, under the comprehensive PROFICIO program, has furnished a robust body of evidence supporting its efficacy and safety across a wide spectrum of patient populations. The landmark cardiovascular outcomes trial, FOURIER, demonstrated that the addition of evolocumab to statin therapy in patients with established atherosclerotic cardiovascular disease (ASCVD) significantly reduces the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and coronary revascularization. This benefit was shown to accrue over time, a finding reinforced by long-term open-label extension studies. Furthermore, pivotal trials have established its efficacy in patients with heterozygous and homozygous familial hypercholesterolemia (HeFH and HoFH), including pediatric populations, as well as in patients with statin intolerance.