Abstract 12009: Effect of RG7652, a mAb Against PCSK9, on Apolipoprotein B, Oxidized LDL, Lipoprotein(a) and Lipoprotein-Associated Phospholipase A2 in Healthy Individuals With Elevated LDL-c
Background: RG7652 (MPSK3169A) is a fully human IgG1 monoclonal antibody (mAb) directed against proprotein convertase subtilisin/kexin type 9 (PCSK9). In a randomized, double-blind, placebo-controlled Phase I study, RG7652, as monotherapy and in combination with atorvastatin, produced significant and sustained reductions in LDL-c levels in subjects with elevated LDL-c (130-220 mg/dL). The effect of RG7652 on lipid and inflammatory biomarkers in the study are reported here.
Methods: RG7652 and placebo were given subcutaneously to 80 healthy subjects with elevated LDL-c, either as single doses (10-800 mg) or as multiple weekly doses (40 or 150 mg) with or without background atorvastatin. Total PCSK9 (bound and unbound), apolipoprotein B (ApoB), oxidized LDL (OxLDL), lipoprotein(a) [Lp(a)] and lipoprotein-associated phospholipase A2 (Lp-PLA2) mass levels were determined using qualified immunoassays.
Results: RG7652 produced dose-related increases in plasma PCSK9 levels suggesting slower clearance of PCSK9-RG7652 complexes compared with unbound PCSK9. Pre-dose total PCSK9 levels were slightly higher in statin-treated vs statin-naïve subjects, but there was no marked difference in total PCSK9 levels between these groups following RG7652. RG7652 treatment resulted in a dose-related reduction in serum ApoB and OxLDL by up to 50% from baseline. In the 800 mg single-dose cohort, mean levels of both ApoB and OxLDL remained suppressed by 45% 2 months after RG7652 administration. A single dose of RG7652 reduced serum Lp(a) levels in a dose-related manner with a mean 45% reduction following a 800 mg dose. The magnitude of reductions in Lp(a) correlated with RG7652-related changes in ApoB and LDL-c. Treatment with RG7652 also resulted in a decrease in serum Lp-PLA2 levels by up to 30%; again, in the single 800 mg dose cohort, levels remained decreased for 2 months. There were no significant changes in apolipoprotein A-I or C-reactive proteinlevels following treatment with RG7652.
Conclusions: In addition to lowering LDL-c, inhibition of PCSK9 with RG7652 produces favorable changes in ApoB, OxLDL, Lp(a) and Lp-PLA2 levels. To our knowledge, this is the first report showing the potential for PCSK9 inhibition to reduce Lp[[Unable to Display Character: ‐]]PLA2 and OxLDL.
- © 2013 by American Heart Association, Inc.