Alirocumab: PCSK9 inhibitor for LDL cholesterol reduction

Abstract

The proof of concept that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition affects cholesterol levels was first established after the demonstration that PCSK9 loss-of-function mutations result in a significant drop in circulating LDL cholesterol levels. Subsequent studies revealed that PCSK9 binds the epidermal growth factor precursor homology domain-A on the surface LDL Receptor (LDLR) and directs LDLR and PCSK9 for lysosomal degradation. Alirocumab (also known as SAR236553/REGN727) is a monoclonal antibody that binds circulating PCSK9 and blocks its interactions with surface LDLR. Alirocumab clinical trials with different doses on different administration schedules were shown to significantly reduce LDL cholesterol both as a mono-therapy and in combination with statins or ezetimibe. Although there is great potential for anti-PCSK9 therapies in the management of cholesterol metabolism, there is no clear evidence yet that blocking PCSK9 reduces cardiovascular disease outcome. This is being investigated in ongoing Phase III clinical trials with alirocumab.

Keywords::

• familial hypercholesterolemia
• low-density lipoprotein
• low-density lipoprotein receptor
• monoclonal antibodies
• PCSK9

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Erratum

Financial & competing interests disclosure

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Current lipid-lowering therapy leaves many patients outside LDL-cholesterol (LDL-c) goal due to the severity of their hypercholesterolemia or intolerance to lipid-lowering medications.

• PCSK9 is a protein that degrades the LDL receptor; gain-of-function mutations in the PCSK9 gene also cause familial hypercholesterolemia, making inhibition of PCSK9 a novel target for LDL-lowering drug development.

• Monoclonal antibody to PCSK9 reduced circulating LDL-c by >50% as early as 2 weeks after the first injection in a Phase II trial for heterozygous familial hypercholesterolemia.

• Injection of 150 mg every 2 weeks was the most efficient treatment in keeping low stable LDL-c levels, with no serious adverse events.

• The therapy will likely be FDA approved in 2016, onging Phase III trail should provide important insights into CAD outcome and long-term safety.

Notes