An evaluation of alirocumab for the treatment of hypercholesterolemia

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipoprotein metabolism, mainly by modulating LDL receptor activity. Alirocumab is a fully human IgG1 monoclonal antibody that binds PCSK9, increases the number of LDL receptors and decreases the levels of LDL cholesterol. The efficacy of alirocumab has been evaluated in more than 6000 subjects with primary hypercholesterolemia; in Phase III trials, alirocumab consistently reduced LDL-cholesterol up to 62% with every 2 weeks dosing compared with placebo and up to 36% compared with ezetimibe. Two doses, 75 and 150 mg, have been developed to propose a tailored approach in the treatment of hypercholesterolemic patients not controlled by maximally tolerated lipid-lowering therapy. Alirocumab was generally well-tolerated, with an acceptable safety profile. The ongoing ODYSSEY OUTCOMES trial will provide definitive evidence on the effect of alirocumab on cardiovascular morbidity and mortality and complementary data on the long-term safety and tolerability. Moreover, a cost–effectiveness analysis would be useful to determine the appropriate price of alirocumab.

Keywords:

• alirocumab
• hypercholesterolemia
• LDL-cholesterol
• PCSK9
• cardiovascular disease

Key issues

• PCSK9 – a circulating protein secreted by the liver – is a key regulator of LDL receptor activity.

• Alirocumab is a fully human IgG1 monoclonal antibody binding with a high affinity to free PCSK9.

• Inactivating PCSK9 increases the number of functional LDL receptors, resulting in decreased circulating LDL particles and significant reduction in LDL-cholesterol (LDL-C).

• Alirocumab is given as a 1 ml subcutaneous injection, with 2 doses: 75 and 150 mg. The Phase III program has been conducted mainly with an every 2 weeks treatment strategy.

• In Phase III, alirocumab reduced LDL-C up to 62% with every 2 weeks dosing, compared with placebo, and up to 36%, compared with ezetimibe.

• Alirocumab also decreased other atherogenic lipid parameters: non-HDL cholesterol, apolipoprotein B and lipoprotein (a).

• The safety and tolerability profile of alirocumab appears comparable to placebo, with the exception of mild injection-site reactions and flu-like symptoms.

• The effect on cardiovascular morbidity and mortality is being evaluated in the ongoing ODYSSEY OUTCOMES trial.

Financial & competing interests disclosure

The author has received grant/research support and speaker’s honoraria from and served as a consultant and advisor for Abbott, Amgen, AstraZeneca, Eli Lilly, Kowa, Merck and Co, Pfizer, Roche, Sanofi-Regeneron and Servier. The author has 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. No writing assistance was utilized in the production of this manuscript.