Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol
What is the effect of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition on levels of low-density lipoprotein (LDL) cholesterol?
In healthy volunteers, two randomized studies of an antibody to PCSK9 (REGN727) given intravenously (40 subjects) or subcutaneously (32 subjects) was compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and in nonfamilial hypercholesterolemia subjects who were on atorvastatin (30 subjects) (baseline LDL >100 mg/dl) or a modified diet alone (10 subjects) (baseline LDL >130 mg/dl). The primary outcome for all studies was safety, whereas the secondary outcome was the lipid profile.
Among subjects receiving REGN727, there were no discontinuations because of adverse events, and REGN727 lowered LDL in all the studies. In a multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced LDL levels in the combined atorvastatin-treated populations to 77.5, 61.3, and 53.8 mg/dl, for a difference in the change from baseline of −39.2, −53.7, and −61.0%, respectively, as compared with placebo (p < 0.001 for all comparisons).
In three phase 1 trials, REGN727 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia.
PCSK9 is a serine protease that targets LDL receptors for destruction leading to reduced LDL clearance capacity and elevated LDL levels. A gain of function PCSK9 mutation was originally described in a familial form of autosomal dominant hypercholesterolemia that was also associated with increased coronary artery disease risk. Loss of function mutations have been described, leading to low levels of LDL and reduced coronary artery disease risk. Thus, this protease is a promising therapeutic target that when blocked, should lead to reduced LDL and reduced coronary artery disease risk. This study demonstrates that a monoclonal antibody to PCSK9 leads to dose-dependent, prolonged reductions in LDL, and this effect is additive to statins in a diverse hyperlipidemic population. This therapy may be useful in statin-intolerant patients and in combination with statins in high-risk populations to achieve extreme lowering of LDL. The effects of REGN727 on vascular events and the long-term safety profile will require further study.
Keywords: Healthy Volunteers, Coronary Artery Disease, Cholesterol, LDL, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Saccharomyces cerevisiae Proteins, Receptors, LDL, Heptanoic Acids, Serine Proteases, Subtilisin, Mutation, Proprotein Convertases, Pyrroles, Lipoproteins, LDL, Biological Markers
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