Effect of the PCSK9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia

Study Questions:

Human monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK-9) reduce low-density lipoprotein cholesterol (LDL-C) in heterozygous familial hypercholesterolemia. What is the efficacy and safety of AMG 145, a PCSK-9 inhibitor, in patients with homozygous hypercholesterolemia (HoFH)?


This was an open-label, single-arm, multicenter, dose-scheduling pilot study in patients with HoFH. Eight patients with LDL receptor-negative or -defective HoFH on stable drug therapy were treated with subcutaneous AMG 145 420 mg every 4 weeks for ≥12 weeks, followed by AMG 145 420 mg every 2 weeks for an additional 12 weeks.


Mean (range) change from baseline in LDL-C at week 12 was –16.5% (+5.2% to –43.6%; p = 0.0781) and –13.9% (+39 .9 to –43.3%; p = 0.1484) with 4- and 2-week dosing, respectively. No reduction was seen in the two receptor-negative patients. Over the treatment periods, mean (standard deviation) reduction in LDL-C in the six LDL receptor-defective patients were 19.3% (16)% and 26.3% (20)% with 4- and 2-week dosing, respectively (p = 0.0313 for both), ranging from 4% to 48% with 2-week dosing. No serious side effects were reported.


This study demonstrates significant and dose-related LDL-C lowering with a PCSK-9 monoclonal antibody in HoFH patients with defective LDL receptor activity, but no reduction in those who were receptor negative.


PCSK-9 is an enzyme that enhances the degradation of hepatic LDL-receptors (LDL-R). Two other novel agents are available for treating HoFH. When used in combination with available treatments, lomitapide (Juxtapid™, Aegerion Pharm.), an oral microsomal triglyceride transfer protein inhibitor, lowers LDL-C by about 50%, and mipomersen (Kynamro, ISIS Pharm.), an apo B anti-sense given subcutaneously weekly, reduces the LDL-C by an average of 25%, but with a response varying from 0 to >50%. That the LDL-R activity in HoFH can vary between 2-25% of normal explains why the effect of AMG 145 and mipomersen, whose effect is dependent on up-regulating LDL-R activity, is so variable. This is not the case for lomitapide, which reduces very LDL (VLDL) particle formation and thus LDL particle number directly.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Oligonucleotides, Hyperlipoproteinemia Type II, Saccharomyces cerevisiae Proteins, Receptors, LDL, Heptanoic Acids, Hypercholesterolemia, Subtilisin, Up-Regulation, Endocytosis, Proprotein Convertases, Cholesterol, Dyslipidemias, Benzimidazoles, Carrier Proteins

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