Gain-of-function mutations in a serine protease, proprotein convertase subtilisin/kexin 9 (PCSK9), have been associated with high plasma levels of low-density lipoprotein (LDL) cholesterol and an increased incidence of coronary heart disease. Previous studies showed that PCSK9 loss-of-function mutations in patients were associated with low levels of LDL cholesterol and a reduced incidence of coronary heart disease. This suggested that pharmacologic inhibition of PCSK9 could lower LDL cholesterol levels in patients with hypercholesterolemia. REGN727/SAR236553 (REGN727) is an investigational, fully human monoclonal antibody highly specific for human PCSK9. This antibody blocks the interaction of PCSK9 with LDL receptors.This report presents the results of 3 phase 1 studies of REGN727 in humans. The participants were healthy volunteers and patients with familial or nonfamilial hypercholesterolemia. Three separate clinical studies of REGN727 were conducted. The first two compared the effect of single doses of REGN727, administered either intravenously (n = 40) or subcutaneously (n = 32), in healthy volunteers and a placebo. After these 2 single-dose studies, a randomized, placebocontrolled multiple-dose trial that investigated the effect of REGN727in 3 separate cohorts with hypercholesterolemia was conducted. The first cohort was composed of 21 subjects with heterozygous familial hypercholesterolemia and the second cohort consisted of 30 subjects with nonfamilial hypercholesterolemia. All patients in these 2 cohorts were receiving atorvastatin therapy and had a baseline LDL cholesterol level greater than 100 mg/dL (2.6 mM). The third cohort was composed of 10 subjects with nonfamilial hypercholesterolemia who had a baseline LDL cholesterol level greater than 130 mg/dL (3.4 mM); these patients were treated only with a modified diet.Patients 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 study outcome was the incidence of adverse events. The major secondary end point evaluated was the effect of REGN727 on the lipid profile.None of the subjects receiving REGN727 withdrew from the study early because of an adverse event. There was a significant reduction in levels of LDL cholesterol among patients receiving REGN727 in all studies. Levels of LDL in the multiple-dose study were as follows: REGN727 doses of 50, 100, and 150 mg reduced LDL levels in the combined atorvastatin-treated populations to 77.5 mg/dL (2.00 mL), 61.3 mg/dL (1.59 mL), and 53.8 mg/dL (1.39 mL), respectively; differences in the change from baseline with the 50-, 100-, and 150-mg doses were j39.2, j53.7, and j61.0 percentage points compared with placebo (P G 0.001 for all 3 comparisons).These phase 1 trials suggest a role for PCSK9 in the regulation of LDL cholesterol in humans.