BACKGROUND: Despite statin treatment, many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol (LDL-C) targets. AMG 145, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease, demonstrated significant reductions in LDL-C in phase 1 studies. This phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients. METHODS AND RESULTS: Patients with heterozygous familial hypercholesterolemia diagnosed by Simon Broome criteria with LDL-C ≥2.6 mmol/L (100 mg/dL) despite statin therapy with or without ezetimibe were randomized 1:1:1 to AMG 145 350 mg, AMG 145 420 mg, or placebo-administered subcutaneously every 4 weeks. The primary end point was percentage change from baseline in LDL-C at week 12. Of 168 patients randomized, 167 received investigational product and were included in the full analysis set (mean [SD] age, 50 [13] years; 47% female; 89% white; mean [SD] baseline LDL-C, 4.0 [1.1] mmol/L (156 [42] mg/dL)). At week 12, LDL-C reduction measured by preparative ultracentrifugation (least squares mean [standard error (SE)]) was 43 (3)% and 55 (3)% with AMG 145 350 mg and 420 mg, respectively, compared with 1 (3)% increase with placebo (P<0.001 for both dose groups). Serious adverse events (not considered treatment-related) occurred in 2 patients on AMG 145. CONCLUSIONS: AMG 145 administered every 4 weeks yielded rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients despite intensive statin use, with or without ezetimibe, with minimal adverse events and good tolerability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01375751.