Evinacumab, an ANGPTL3 Inhibitor, in the Treatment of Dyslipidemia

Abstract

Familial hypercholesterolemia (FH) is an inherited disorder. The level of low-density lipoprotein cholesterol (LDL-C) in patients with homozygous FH can be twice as high as that in patients with heterozygous FH. The inhibition of ANGPTL3 shows an important therapeutic approach in reducing LDL-C and triglycerides (TG) levels and, thus, is a potentially effective strategy in the treatment of FH. Evinacumab is a monoclonal antibody inhibiting circulating ANGPTL3, available under the trade name Evkeeza® for the treatment of homozygous FH. It was reported that evinacumab is effective and safe in patients with homozygous and heterozygous FH, as well as resistant hypercholesterolemia and hypertriglyceridemia. This paper summarizes existing knowledge on the role of ANGPTL3, 4, and 8 proteins in lipoprotein metabolism, the findings from clinical trials with evinacumab, a fully human ANGPTL3 mAb, and the place for this new agent in lipid-lowering therapy.

Hypercholesterolemia: a literature review on management using tafolecimab: a novel member of PCSK9 monoclonal antibodies

“…However, their effectiveness in homozygous FH (HoFH) patients depends on residual LDLR activity 99 . ANGPTL3 inhibitors, such as evolocumab, have shown promise in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, owing to their LDLR-independent mechanism of action, present a potential alternative for patients who do not respond to PCSK9 inhibitors due to null mutations in LDLR 100 . Furthermore, novel lipid-lowering agents, including inclisiran, a small interfering RNA targeting PCSK9, have shown comparable effects to PCSK9 monoclonal antibodies 101 .…”

Drug development advances in human genetics‐based targets

“…One ANGPTL3 inhibitor is currently approved for marketing, the human monoclonal antibody evinacumab developed by Regeneron. 141,164 Currently, evinacumab is used primarily in patients with HoFH (both children and adults over the age of 5 years), 165 and several studies have validated the long-term safety and efficacy of evinacumab. 141 Second, there are several ANGPTL3 inhibitors in the development stages (Table 2), among which the more hotly researched ones are ASO and siRNA drugs targeting ANGPTL3 mRNA, such as ARO-ANG3 and Vupanorsen.…”

“…One ANGPTL3 inhibitor is currently approved for marketing, the human monoclonal antibody evinacumab developed by Regeneron 141,164 . Currently, evinacumab is used primarily in patients with HoFH (both children and adults over the age of 5 years), 165 and several studies have validated the long‐term safety and efficacy of evinacumab 141 .…”

A Look to the Past - What Has Had the Biggest Impact on Lipids in the Last Four Decades? A Personal Perspective

“…So far, there have been no effective pharmacological methods to lower the concentration of triglycerides (with significant cardiovascular benefits) and Lp(a). Recently, the armamentarium of triglyceride-lowering treatment has been supplemented with volanesorsen (a European Medicines Agency-approved therapeutic antisense oligonucleotide (ASO) that targets the messenger RNA for apolipoprotein C-III (apo-CIII)), olezarsen (a currently investigated hepatocyte-targeted modified ASO that reduces apo-CIII plasma levels), and possibly evinacumab (an ANGPTL3 inhibitor, which was approved by the US Food and Drug Administration and EMA in the therapy of homozygous familial hypercholesterolemia) [ 18 , 19 ]. It also needs to be emphasized that triglycerides and triglyceride-rich lipoproteins can still be effectively reduced with fenofibrate, which, beside its benefits in the reduction of micro- and macrovascular complications, was confirmed to have long-term cardiovascular efficacy in the ACCORDION study [ 19 , 20 ].…”

“…It seems, however, that study was too short, taking into account the previous experience from trials with fibrates, and, what is even more important, pemafibrate was also the first fibrate that increased the LDL-C by 12%, which definitely affected the primary endpoint result [ 21 ]. It is also worth emphasizing that soon we should have very effective drugs to reduce Lp(a) levels by as much as 70–95% (olpasiran, SLN360, LY3819469 and pelacarsen, which are currently undergoing clinical trials) [ 13 , 18 , 19 , 22 ]. These therapies might finally help to resolve the problem of lipid-related residual CVD risk.…”