Novel Monoclonal Antibody to PCSK9

Studies of animal models have found that proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, has a role in the post-translational regulation of LDL-receptor activity. PCSK9, which is synthesized primarily in the liver, enters the circulation, where it binds to hepatic LDL receptors and targets them for degradation. This process reduces the capacity of the liver to bind and remove LDL cholesterol and results in increased LDL cholesterol levels. Subsequent studies revealed that some patients with low levels of LDL cholesterol had PCSK9 loss-of-function mutations and showed that these patients had a reduced incidence of coronary heart disease. These studies raised the possibility that pharmacologic inhibition of PCSK9 might lower LDL cholesterol levels in patients with hypercholesterolemia.

REGN727/SAR236553 (REGN727) is an investigational, fully human monoclonal antibody that is highly specific for human PCSK9 and blocks its interaction with the LDL receptor. In this article [N Engl J Med. 2012;366(12):1108-1118], the investigators wished to report the results of the initial studies of REGN727 in humans.

The investigators performed 3 separate clinical studies of REGN727. Two were randomized, single ascending-dose studies of REGN727, administered either intravenously or subcutaneously, in healthy volunteers. The third study was a randomized, placebo-controlled, multiple-dose study of subcutaneously administered REGN727 in subjects with either familial or nonfamilial hypercholesterolemia.

For the single-dose studies, 40 subjects were enrolled in the group receiving intravenous REGN727 and 32 were enrolled in the group receiving subcutaneous REGN727. All subjects were healthy men and women between 18 and 65 years of age with a body weight ranging from 50 to 95 kg and a body mass index (BMI) ranging from 18 to 30. All subjects had a serum LDL cholesterol level of >100 mg per deciliter (2.59 mmol/L).

The multiple-dose study included 3 separate cohorts of subjects. The first cohort consisted of 21 subjects with heterozygous familial hypercholesterolemia, and the second cohort consisted of 30 subjects with nonfamilial hypercholesterolemia. All subjects in these 2 cohorts were receiving atorvastatin therapy and had an LDL cholesterol level of >100 mg per deciliter (2.59 mmol/L). The third cohort consisted of 10 subjects with nonfamilial hypercholesterolemia who had an LDL cholesterol level of >130 mg per deciliter (3.36 mmol/L) and were only being treated with a modified diet.

All subjects in the multiple-dose study were between 18 and 65 years of age, had a BMI ranging from 18 to 35, and did not have diabetes or a known atherosclerotic vascular disease. Subjects in the multiple-dose study were randomly assigned to receive subcutaneous REGN727 (50, 100, or 150 mg) or placebo administered on days 1, 29, and 43.

The primary outcome measure for all studies was the occurrence of adverse events. The principal secondary outcome measure was the effect of REGN727 on the lipid profile. There were no discontinuations because of adverse events among subjects receiving REGN727.

In the multiple-dose study, 50-, 100-, and 150-mg doses of REGN727 reduced measured LDL cholesterol in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol/L), 61.3 mg per deciliter (1.59 mmol/L), and 53.8 mg per deciliter (1.39 mmol/L), for a difference in the change from baseline of −39.2, −53.7, and −61.0 percentage points, respectively, as compared with placebo (P<.001 for all comparisons).

The degree and duration of LDL cholesterol reduction in the different dose groups corresponded to the reduction of free PCSK9 in plasma. The mean difference in the change from baseline in LDL cholesterol, as compared with placebo, exceeded −46 percentage points 2 weeks after the first administration of 150 mg in all 3 cohorts studied. The LDL cholesterol response was similar in all subjects, regardless of whether they had familial or nonfamilial hypercholesterolemia or were treated with atorvastatin or with a modified diet alone.