Experimental Monoclonal Antibody-Based Drug Lowers LDL-cholesterol Levels

An experimental cholesterol-lowering drug was found to augment the action of statins to further lower LDL-cholesterol (low-density lipoprotein – cholesterol) levels in patients with elevated cholesterol due to the hereditary condition heterozygous familial hypercholesterolemia.

The drug REGN727 was the result of collaboration between the American biopharmaceutical company Regeneron (Tarrytown, NY, USA) and the French healthcare giant Sanofi (Paris, France). REGN727 is a monoclonal antibody specific for the enzyme proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9).

PCSK9 belongs to the proteinase K subfamily of the secretory subtilase family. The protein is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. This protein plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the low-density lipoprotein receptor (LDLR), inducing LDLR degradation. Reduced LDLR levels result in decreased metabolism of low-density lipoproteins, which could lead to hypercholesterolemia.

A paper describing a clinical trial in which 77 patients with heterozygous familial hypercholesterolemia were treated with REGN727 plus high-dose statins, with or without ezetimibe or with only the statins (with or without ezetimibe) was published in the May 26, 2012, online edition of the journal the Lancet.

Results of the study revealed that after 12 weeks, patients taking REGN727 saw their cholesterol levels reduced by between 28.9% and 67.9% depending on their dosing regimen, compared with 10.7% among those taking a dummy treatment.

The investigators concluded, “REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe.”

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