Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels: Results From 2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1 Studies in Healthy Volunteers and Hypercholesterolemic Subjects on Statins

Study Questions:

What are the safety, tolerability, and effects of AMG 145 (a proprotein convertase subtilisin/kexin type 9 [PCSK-9] enzyme inhibitor) on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy?

Methods:

Healthy adults (phase 1a) were randomized to one dose of AMG 145: ranging from 7 to 420 mg subcutaneously (SC); 21 or 420 mg intravenously (IV); or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) × 6, 140 or 280 mg every 2 weeks (Q2W) × 3, 420 mg every 4 weeks × 2, or matching placebo. Eleven subjects receiving high-dose statins and six subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W × 3.

Results:

In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). Treatment with AMG 145 in phase 1b reduced mean serum levels of lipoprotein a [Lp(a)] by 27-50% compared to placebo. The reduction in LDL-C was comparable in those on high, intermediate, and lower dose statins.

Conclusions:

In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.

Perspective:

AMG-145 is a fully human monoclonal antibody to PCSK-9, the natural inhibitor of the LDL receptor. The drug lowers LDL-C and maximizes the potential benefit of statins. Clinical trials are ongoing with at least two PCSK-9 inhibitors, including one that is a clinical outcome study. While requiring an injection biweekly or monthly, the absence of side effects and adverse events in the early studies makes this a very attractive lipid-lowering drug for resistant hypercholesterolemia, and has the potential to reduce the ‘residual risk’ in coronary heart disease patients on maximal doses of statins.

Clinical Topics: Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Fluorobenzenes, Outcome Assessment (Health Care), Coronary Artery Disease, Lipoprotein(a), Hyperlipoproteinemia Type II, Lipoproteins, Organization and Administration, Hypercholesterolemia, Proprotein Convertases, Pyrroles, Cholesterol, Incidence, Biological Markers, Sulfonamides


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