Evinacumab for treatment of familial hypercholesterolemia

ABSTRACT

Introduction: Familial hypercholesterolemia (FH) is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), early onset coronary atherosclerosis, and premature death. FH is underdiagnosed and undertreated, but requires aggressive LDL-C-lowering to prevent complications. Current treatment strategies such as lifestyle modification and numerous LDL-C-lowering medications are often insufficient to achieve lipid goals in FH.

Areas covered: Angiopoietin-like 3 protein (ANGPTL3) is intricately involved in lipid metabolism. Loss-of-function mutations in ANGPTL3 are associated with panhypolipidemia and reduced coronary atherosclerosis. Evinacumab, a fully human monoclonal antibody, inhibits ANGPTL3 and reduces multiple lipoprotein fractions ~50%, including LDL-C. The use of evinacumab within the FH population is described as well as its regulatory journey to an approved therapeutic.

Expert opinion: Evinacumab, with its capacity to lower multiple lipoprotein fractions, particularly LDL-C, independently of LDLR function has potential to revolutionize treatment for FH patients. Current FDA-approval is only for homozygous FH (HoFH), arguably the most impactful indication, but use in other lipid disorders is under investigation. The short-term tolerability of evinacumab is very good, with infrequent, mild, and transient adverse events; however, long-term safety data are needed. The high cost and requirement for intravenous administration may limit adoption of evinacumab, but dramatic LDL-C-lowering and need for new therapeutic options for HoFH will drive interest.

KEYWORDS:

• Monoclonal antibody
• lipid-lowering therapy
• familial hypercholesterolemia
• FH
• homozygous FH
• evinacumab
• ANGPTL3

Article highlights

• Familial hypercholesterolemia is an underdiagnosed and undertreated condition that is associated with lifelong elevations of LDL-C, early onset coronary atherosclerosis and premature death.

• Evinacumab, a fully human monoclonal antibody against ANGPTL3, is a novel treatment approach for reducing Apo-B-containing lipoproteins, particularly LDL-C, in patients with familial hypercholesterolemia.

• Evinacumab was FDA-approved in February 2021 for use in HoFH and will likely be used as add-on therapy after high-intensity statin, ezetimibe, and PCSK9 inhibitor.

• Evinacumab is administered intravenously at dose of 15 mg/kg over a 60 minute infusion every 4 weeks.

• Evinacumab has the potential to lower LDL-C by 49% in both HoFH and HeFH patients with effects seen as soon as 2 weeks from initial infusion and independent of the LDL receptor function.

• Adverse effects are infrequent, mild, and transient, consisting primarily of injection site reactions, flu/cold-like symptoms, pain, and fatigue. However, long-term safety is currently unknown.

• Potential barriers to care include the high cost, intravenous administration, and requirement for use in a health-care setting or home infusion

Declaration of interest

B Warden received an institutional grant from Akcea. PB Duell serves as a consultant for Akcea, Amryt, Esperion, Kaneka, Regeneron, and Regenxbio, and has received institutional research grants from Regeneron, Regenxbio, and Retrophin. 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 disclosure

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

Additional information

Funding

This paper was not funded.