Current and emerging monoclonal antibodies for treating familial hypercholesterolemia in children

ABSTRACT

Introduction

Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder caused by pathogenic variants in the LDL-C metabolism. Lifelong exposure to elevated LDL-C levels leads to a high risk of premature cardiovascular disease. To reduce that risk, children with HeFH should be identified and treated with lipid-lowering therapy. The cornerstone consists of statins and ezetimibe, but not in all patients this lowers the LDL-C levels to treatment targets. For these patients, more intensive lipid-lowering therapy is needed.

Areas covered

In this review, we provide an overview of the monoclonal antibodies which are currently available or being tested for treating HeFH in childhood.

Expert opinion

Monoclonal antibodies that inhibit PCSK9 are first in line lipid-lowering treatment options if oral statin and ezetimibe therapy are insufficient, due to intolerance or very high baseline LDL-C levels. Both evolocumab and alirocumab have been shown to be safe and effective in children with HeFH. For children, evolocumab has been registered from the age of 10 years old and alirocumab from the age of 8 years old. The costs of these new agents are much higher than oral therapy, which makes it important to only use them in a selected patient population.

KEYWORDS:

• Children
• familial hypercholesterolemia
• LDL-C
• monoclonal antibodies
• PCSK9

Article highlights

• Children with heterozygous familial hypercholesterolemia have a high risk of premature cardiovascular disease

• To reduce cardiovascular risk, statin treatment should be initiated in childhood to lower LDL-C levels to the treatment target (<3.5 mmol/L), but not all children are able to achieve this target

• If treatment with statin and ezetimibe is insufficient, monoclonal antibodies inhibiting PCSK9 are first in line lipid-lowering treatment options

• Specifically children with the highest baseline LDL-C and children with statin-intolerance are more likely to need PCSK9 inhibition

• Currently, evolocumab and alirocumab are registered monoclonal antibodies for treating children with heterozygous familial hypercholesterolemia

• Due to cost considerations, monoclonal antibodies should be reserved for patients not reaching LDL-C treatment targets despite optimal statin and ezetimibe treatment

Declarations of interest

A Wiegman has received research grants from Amgen, Sanofi, Regeneron, Novartis, Silence Therapeutics, Esperion, and Ultragenyx, is a member of the safety board for Lomitapid in children (Amryt) and is chair of steering committee for Inclisiran in adolescents (Novartis). 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 received an honorarium from Expert Opinion on Biological Therapy for their review work. The reviewers have no other relevant financial relationships to disclose.

Additional information

Funding

This paper was not funded.