Homozygous familial hypercholesterolemia and its treatment by inclisiran

ABSTRACT

Introduction

Homozygous familial hypercholesterolemia (hoFH), a genetic disorder characterized by markedly impaired hepatic clearance of LDL and LDL cholesterol concentration exceeding 12 mmol/L, causes coronary artery and aortic valve disease before adulthood. The hoFH phenotype is mostly due to bi-allelic mutations in the LDL receptor gene.

Areas covered

HoFH as a clinical phenotype has distinct genetic causes which may affect response to treatment. The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism and other physiologic processes including inflammation and sepsis. Strategies that may lower plasma PCSK9 activity so that uptake of plasma LDL into the liver is improved. Inclisiran, a synthetic oligonucleotide, specifically targets the liver to limit production of PCSK9. Adverse effects due to oligonucleotides in general and specific to low PCSK9 concentration are considered.

Expert opinion

HoFH requires expert diagnostic work-up for best management and prediction of response to treatment, including inclisiran. Though most hoFH patients will not reach the ideal LDL cholesterol concentration target by adding agents that lower PCSK9 activity to treatment with statins and ezetimibe, additional benefit is expected. Some patients may not respond. The safety to date appears good but patients with hoFH require treatment from childhood and long-term safety remains to be established.

KEYWORDS:

• Homozygous familial hypercholesterolemia
• inclisiran
• PCSK9
• phytosterolemia
• autosomal recessive hypercholesterolemia

Article highlights

• The importance of differentiating the different causes of the clinical entity of homozygous familial hypercholesterolemia is described as this affects the expected response to treatment.

• The powerful lowering of LDL concentration in other disorders is contrasted with the efficacy in homozygous familial hypercholesterolemia.

• Several approaches to manipulate PCSK9 concentration are summarised.

• The safety of inclisiran is encouraging but some possible longterm or unexpected safety concerns are explored.

Declaration of interest

D Marais has a research grant for FH investigation from Sanofi-Regeneron 2018, collaboration; a past Medical Research Council of South Africa Research grant; was a participant in multinational trials for Aegerion, Bayer, Bristol Myers Squibb, Merck Sharp Dohme, Parke Davis, Pfizer, Takeda. D Blom receives honoraria from Aegerion, Amgen, AstraZeneca, and Sanofi, and consultancy/advisory board fees from Akcea, Amgen, Gemphire, and Sanofi. F Raal has Research grants, honoraria, or consulting fees for professional input and/or delivered lectures from Sanofi, Regeneron, Amgen and The Medicines Company. 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.

Additional information

Funding

This paper was not funded.