Evinacumab (Evkeeza®): A Comprehensive Monograph on the First-in-Class ANGPTL3 Inhibitor for Homozygous Familial Hypercholesterolemia

1.0 Executive Summary

Evinacumab, marketed under the brand name Evkeeza®, is a first-in-class, fully human recombinant IgG4 monoclonal antibody that represents a significant advancement in the management of lipid disorders.[1] It is specifically designed to inhibit angiopoietin-like protein 3 (ANGPTL3), a key regulator of lipoprotein metabolism.[1] The primary therapeutic indication for evinacumab is as an adjunct to other lipid-lowering therapies for the treatment of homozygous familial hypercholesterolemia (HoFH), a rare and severe genetic disorder characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) from birth.[1]

The novelty of evinacumab lies in its mechanism of action, which is independent of the low-density lipoprotein receptor (LDLR) pathway.[4] By inhibiting ANGPTL3, evinacumab restores the activity of lipoprotein lipase (LPL) and endothelial lipase (EL), thereby enhancing the clearance of VLDL remnants and reducing the production of LDL-C.[4] This unique mechanism addresses a critical unmet medical need for patients with HoFH, particularly those with null/null LDLR mutations who are refractory to conventional LDLR-dependent therapies such as statins and PCSK9 inhibitors.[9]

Clinical development has been anchored by the pivotal Phase 3 ELIPSE HoFH trial, which demonstrated that evinacumab, administered at a dose of 15 mg/kg intravenously every four weeks, achieved a profound reduction in LDL-C levels. When added to maximally tolerated background therapies, evinacumab lowered LDL-C by approximately 49% compared to placebo at 24 weeks.[2] This robust efficacy has been consistently observed across adult, adolescent, and pediatric populations as young as one year old.[15]