Abstract 11174: Effect of APOCIII-L Rx on Lipoprotein Size and Particle Numbers Measured by NMR in Patients with Hypertriglyceridemia: Results of the AKCEA-APOCIII-L Rx Trial

Abstract

Background: APOCIII-L Rx is a hepatocyte-targeted, GalNAc-modified antisense oligonucleotide that decreases plasma levels of apoC-III and triglyceride-rich lipoproteins (TRLs). We examined the effect of APOCIII-L Rx on a variety of lipoprotein fractions measured by nuclear magnetic resonance (NMR) spectroscopy. Methods: The AKCEA-APOCIII-L Rx trial was a dose-ranging study in 114 patients with, or at risk for, ASCVD and fasting serum triglycerides 200-500 mg/dL. Patients (n=114) received AKCEA-APOCIII-L Rx (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. Comprehensive NMR LipoProfile ® analysis was performed by LipoScience/LabCorp in frozen EDTA plasma samples collected at baseline and at the primary analysis timepoint (PAT) at 6 months. Results: Results are reported as change from baseline to PAT for the 50 mg every 4 weeks dose versus placebo. APOCIII-L Rx resulted in a significant reduction in total TRL particle (TRLP) concentration by 51% (P<0.0001) with largest reductions in large-size (by 68%, P<0.0001) and medium-size (by 63%, P<0.0001) TRLPs. Total LDL particle (LDLP) concentration was not changed, small LDLP numerically decreased by 39% (P= 0.0713) while medium LDLP increased by 187% (P=0.0119), accompanied by an increase in average LDL size by xx 2% (p=0.0039xx). Total HDL particle (HDLP) concentration increased by 15% (P=0.0006), represented primarily by an increase in small HDL subspecies (particle diameters <8.3 mm) of 32% (P=0.0008). Lower cumulative doses of APOCIII-L Rx generally reflected a dose-dependent relationship in the above parameters. Conclusion: APOCIII-L Rx results in favorable changes in lipoprotein concentration and particle size, primarily manifested by reduction in TRLs, remodeling to larger LDL particles, and increase in small HDLP. These findings suggest an improvement in overall atherogenic risk profile.