AMG 145 Monoclonal Antibody Significantly Reduces Low-Density Lipoprotein

Results from two randomized Phase1 clinical trials show that treatment with the investigational monoclonal antibody drug AMG 145 significantly reduces low-density lipoprotein cholesterol levels by up to 64 percent in healthy individuals and up to 81 percent in statin-treated hypercholesterolemic individuals, according to a study published on Oct. 17 in the Journal of the American College of Cardiology.

The study, "Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels," reports that in a Phase1a trial, 56 healthy individuals were randomized to receive AMG 145, a fully human immunoglobulin G2 monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), or placebo. Single doses of intravenous or subcutaneous AMG 145 ranging from 21 to 420 mg reduced mean low-density cholesterol levels in a dose-dependent fashion by as much as 64 percent compared to placebo (p < 0.0001).

In a Phase1b study, 57 statin-treated patients with hypercholesterolemia, including six with heterozygous familial hypercholesterolemia and 11 receiving high-dose statins, were randomized to receive subcutaneous doses of AMG 145 ranging from 14 to 420 mg or placebo. Their low-density cholesterol levels were reduced by as much as 81 percent versus placebo (p < 0.001).

AMG 145 therapy also significantly reduced apolipoprotein B levels in both studies — by up to 55 percent in the Phase1a study (p < 0.0001) and up to 59 percent in the Phase1b study (p < 0.001). In addition, in the Phase1b trial, treatment with AMG 145 reduced mean serum levels of lipoprotein(a) by up to 50 percent (p < 0.001). 

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There were also significant dose-related reductions in total cholesterol levels by up to 52 percent in both studies. However, AMG 145 treatment had no effect on high-density lipoprotein cholesterol or triglyceride levels. The incidence of adverse events was similar in the treated groups and the placebo groups, and no clinically serious adverse events occurred in either group.

Previous studies have indicated that statins increase serum levels of PCSK9, which in turn increase plasma low-density cholesterol levels. In both studies, AMG 145 significantly reduced free PCSK9 levels, and the magnitude and duration of reductions in PCSK9 influenced the extent and duration of the low-density cholesterol reductions found in the studies.

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