Abstract 11482: The PCSK9-Targeted Antisense Oligonucleotide AZD8233 Reduces LDL-C, ApoB, and Lp(a) in Patients With Dyslipidemia on Statin Treatment - Data From the Phase 2b ETESIAN Study

Abstract

Introduction: Elevated blood levels of lipoprotein(a) [Lp(a)] are an independent causal risk factor for atherosclerotic cardiovascular disease. Lp(a) particles are formed by a lipid domain and an apolipoprotein B (apoB) protein that is bound to apolipoprotein(a). Standard low-density lipoprotein cholesterol (LDL-C) and ApoB lowering treatments have minimal Lp(a)-lowering efficacy. We have previously shown that AZD8233 inhibits hepatic PCSK9 synthesis and causes substantial reductions in LDL-C. Here we report the significant effects of AZD8233 on Lp(a) and ApoB. Methods: ETESIAN was a multicenter phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study (NCT04641299). Eligible participants were 18-75 years old, on statin therapy, with LDL-C of ≥ 70 to < 190 mg/dL, and with fasting triglycerides of < 400 mg/dL. Participants were randomized 1:1:1:1 to subcutaneous injections (days 1, 8, 29, and 57) of either 15, 50, or 90 mg AZD8233, or placebo. The primary objective was to evaluate the effect of AZD8233 versus placebo on LDL-C at week 12. Secondary objectives were to assess Lp(a) levels and other lipid parameters. Results: A total of 119 patients were enrolled in ETESIAN. AZD8233 was well tolerated and demonstrated dose-dependent and clinically meaningful reductions in LDL-C, Lp(a), and ApoB ( Table ). The relative distribution of these effects across participant subgroups and the interaction of effects on Lp(a), ApoB, and LDL-C will be presented. Conclusion: In patients with dyslipidemia on statins, AZD8233 caused substantial reductions in LDL-C and Lp(a), two independent risk factors for major adverse cardiovascular events. The broad lipid-modifying effect of AZD8233 may, hence, provide an opportunity to reduce cardiovascular risk in patients with ASCVD beyond currently available medications.