Proprotein convertase subtilisin kexin type 9 (PCSK9) is a circulating protein that binds to Low Density Lipoprotein LDL Receptors (LDLR), leading to their accelerated degradation, impairing LDL clearance and increasing LDL cholesterol levels.
PCSK9 is mainly of hepatic origin, but is also highly expressed in the intestine and kidneys. There is an inverse relationship between PCSK9 expression and LDLR levels. The proof of concept of PCSK9 inhibition in humans is validated by the phenotype of patients carrying PCSK9 loss of function (LOF mutations), who exhibit reduced LDL-C levels and cardiovascular (CV) events.
The demonstration that PCSK9 mutations are related to either hypo- or hypercholesterolemic phenotypes and atherosclerosis have raised clinical interest in this protein and its impact in CV risk. PCSK9 has emerged as a new pharmacological target for hypercholesterolemia, and different “PCSK9 inhibitors” are now under evaluation in clinical trials.
Although there is a potential role of circulating PCSK9 as a new biomarker of lipid metabolism, there is no clear evidence at this point to suggest that PCSK9 dosage can improve patient management in a clinical setting.
Aim of the study
The present study investigated the safety and secondary efficacy of REGN727, an investigational fully human monoclonal antibody that is highly specific for human PCSK9 and blocks its interaction with the LDL receptor. The authors reported the results from the three initial studies of REGN727.
Two randomized, single ascending-dose studies of REGN727 were administered intravenously (40 subjects) or subcutaneously (32 subjects) in healthy volunteers and compared with placebo. All subjects were men and women between the ages of 18 and 65 yearswith a body weight from 50 to 95 kg and a BMI ranging from 18 to 30.
All subjects had a serum LDL cholesterol level of >100 mg/dL (2.59 mmol/L). The use of non-study agents to alter lipid levels was prohibited.
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 others with non-familial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg/dL [2.6 mmol/L]) or a modified diet alone (10 subjects) but with baseline LDL cholesterol >130 mg/dL [3.4 mmol/L].
All subjects in the multiple-dose study were between the ages of 18 and 65 years, had a BMI of 18 to 35, and did not have diabetes or a known atherosclerotic vascular disease.
REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43.
The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile.
Among subjects receiving REGN727, there were no discontinuations because of adverseevents.
In all three studies REGN727 significantly reduced LDL cholesterol levels compared with placebo. This effect was significant both in healthy volunteers and in subjects with familial or non-familial forms of hypercholesterolemia. The effect was also significant in subjects who were concomitantly taking atorvastatin. The effects of REGN727 and atorvastatin in lowering LDL cholesterol appeared to be additive, not synergistic, since the mean percentage reductions were similar when REGN727 was administered alone or in subjects already receiving atorvastatin.
In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced the measured LDL cholesterol levels in the combined atorvastatin treated populations to 77.5 mg/dL (2.00 mmol/L), 61.3 mg/dL (1.59 mmol/L), and 53.8 mg/dL (1.39 mmol/L), resulting in a change from the baseline of −39.2, −53.7, and −61.0 percentage points, respectively, compared with placebo (P<0.001 for all comparisons).
A reduction in lipoprotein(a) was also seen, although this effect was not significant at all doses and the possible effect on lipoprotein(a) is still uncertain. Therefore, additional studies are required to investigate and explain this observation.
The authors concluded that in three phase I trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or non-familial hypercholesterolemia
These results of this study confirm a role for PCSK9 in the regulation of LDL cholesterol levels. Furthermore, the demonstration of a good correlation between a reduction in free PCSK9 levels and a reduction in LDL cholesterol levels after the administration of REGN727 in humans supports results from previous studies involving rodents and nonhuman primates, suggesting that PCSK9 in the circulation rather than intracellular PCSK9 is primarily responsible for regulating hepatic LDL receptors.
However there is no clear evidence at the present time that plasma PCSK9 “dosage” can improve the clinical management of hyperlipidemic patients.
PCSK9 has recently emerged as a target of extreme importance for hypercholesterolemia treatment. The physiological role of PCSK9 as an LDLR pathway inhibitor has been extensively studied, and despite the fact that PCSK9 probably diminishes the hypolipidemic efficacy of statins we foresee a promissory horizon in the severe hypercholesterolemic patient approach.
Corresponding author for the original paper: Stein E, Metabolic and Atherosclerosis Research Center, 4685 Forest Ave., Cincinnati, OH 45212, USA. firstname.lastname@example.org
Citation: N Engl J Med 2012; 366:1108-18