Evinacumab: a new option in the treatment of homozygous familial hypercholesterolemia

ABSTRACT

Introduction

Familial hypercholesterolemia is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) since birth and an exceedingly high risk of premature cardiovascular disease, especially in the homozygous form (HoFH). Despite the availability of effective cholesterol-lowering drugs, substantial LDL-C and cardiovascular risk reductions in these patients are still problematic, especially in those carrying mutations in the low-density lipoprotein receptor (LDLR) gene.

Areas covered

Loss-of-function mutations in angiopoietin-like 3 (ANGPTL3) encoding gene are associated with lower levels of LDL-C and reduced cardiovascular risk; the pharmacological inhibition of ANGPTL3 reduces LDL-C levels independently of LDLR. This approach can thus improve the treatment of HoFH using a monoclonal antibody targeting ANGPTL3 (evinacumab).

Expert opinion

Most lipid-lowering agents available so far are insufficient to achieve an appropriate response in HoFH patients. The inhibition of ANGPTL3 with evinacumab halves LDL-C levels in HoFH patients by an LDLR-independent mechanism. The results obtained so far have clearly indicated a promising improvement in the management of these patients. As the reduction of CV risk is proportional to the absolute reduction in LDL-C levels, we can expect that treatment with evinacumab, added to the maximally tolerated lipid-lowering therapy, will turn into a significant clinical benefit.

KEYWORDS:

• Angiopoietin like-3
• cardiovascular disease
• evinacumab
• low-density lipoprotein cholesterol
• homozygous familial hypercholesterolemia
• monoclonal antibody

Article highlights

• HoFH is a genetic disorder characterized by elevated LDL-C levels since birth and a high risk of premature cardiovascular events

• HoFH patients have a limited, non-adequate response to currently available lipid-lowering therapies, and require specific drugs or procedures

• ANGPTL3 inhibits the activity of lipoprotein lipase and endothelial lipase, resulting in increased levels of triglycerides and HDL-C

• ANGPTL3 deficiency is associated with lower LDL-C and reduced risk of cardiovascular events

• Evinacumab is a monoclonal antibody targeting ANGPTL3 that reduces LDL-C levels independently of LDLR

• In HoFH patients, evinacumab, added to the maximally tolerated lipid-lowering therapy, halves LDL-C levels

• This effect is of particular interest for HoFH patients who do not respond to therapies with statins or PCSK9 inhibitors

• The treatment with evinacumab reduces the need for lipoprotein apheresis

Declaration of interest

AL Catapano receives research grants/support from Akcea, Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi/Regeneron and acts as a consultant for Akcea, Amarin, Amgen, Daiichi Sankyo, Eli Lilly, Esperion, Kowa, Ionis Pharmaceuticals, Menarini, Merck Sharp & Dohme, Mylan, Novartis, Recordati, Regeneron, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Additional information

Funding

This paper is not funded.