Abstract 17630: Reduction in Lipoprotein (a) with the PCSK9 Inhibitor AMG145 in Hypercholesterolemic Patients on Background Statin: Results from the LAPLACE-TIMI 57 Trial

Abstract

Background: Epidemiological and Mendelian randomization studies suggest that lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. Currently, there are limited treatment options to lower Lp(a). AMG 145 is a fully human monoclonal antibody that binds proprotein subtilisin kexin 9 (PCSK9) and was shown to significantly lower LDL cholesterol (LDL-C) and Lp(a) in Phase 1 studies. We examined its effect on circulating levels of Lp(a) in LAPLACE-TIMI 57, a Phase 2, double-blind, dose-ranging, randomized, placebo-controlled trial of AMG145 in patients with hypercholesterolemia on background statin therapy.

Methods: Lp(a) was measured (Polymedco immunoturbidometric assay, Cortlandt Manor, New York) at baseline and at week 12 (2 or 4 weeks after last dose of study drug) in 612 patients who were randomized and received drug. The percent change in Lp(a) between these two timepoints was calculated in each treatment arm and the medians of this value were compared with placebo using the Wilcoxon Rank Sum test. Spearman correlation coefficients were calculated for the correlation of Lp(a) and change in LDL-C.

Results: At baseline, the median Lp(a) concentration was 43 nmol/L (IQR 13-160 nmol/L). Baseline Lp(a) and LDL-C levels were not correlated (P=0.87). After 12 weeks of treatment, all doses of AMG 145 significantly reduced circulating Lp(a) levels compared with placebo (P < 0.001), with 23-30% reductions seen with the higher AMG 145 dose regimens (Figure). Reduction in Lp(a) was not strongly correlated with reduction in LDL-C (ρ=0.27, P<0.001).

Conclusion: PCSK9 inhibition with AMG145 lowers Lp(a) by up to 30% at 12 weeks. This observation adds to the favorable effect PCSK9 inhibition has on the lipid profile and thus further supports the rationale for evaluating the effects of AMG145 on clinical cardiovascular outcomes.