Abstract 17091: ARO-APOC3, an Investigational RNAi Therapeutic, Silences APOC3 and Reduces Atherosclerosis-Associated Lipoproteins in Patients With Mixed Dyslipidemia: MUIR Study Results

Abstract

Background: Despite the availability of potent LDL-C-lowering therapies, patients with mixed dyslipidemia (MD) remain at high risk of cardiovascular (CV) disease due to residual risk from triglyceride (TG)-rich atherogenic lipoproteins (TRLs), ie, remnant cholesterol and/or VLDL-C. Inhibition of APOC3 has emerged as a promising therapeutic strategy for reducing this residual CV risk. Aim: We report interim results through Week 24 from MUIR, an ongoing, randomized, placebo-controlled, Phase 2b study (NCT04998201) evaluating the effects of ARO-APOC3 in patients with MD (fasting TGs 150 to 499 mg/dL and either LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL). Methods: Eligible subjects (n=353) were randomized 3:1 to receive either subcutaneous injections of 10, 25, or 50 mg ARO-APOC3 or matched placebo on Day 1 and at Week 12 or 50 mg ARO-APOC3 on Day 1 and Week 24. Subjects were on a stable diet and optimal lipid-lowering therapies. The primary endpoint was the percent change from baseline in fasting TGs at Week 24. Statistically significant differences were determined using mixed model repeat measures analysis. Results: At Week 24, when dosed on Day 1 and Week 12, ARO-APOC3 significantly decreased APOC3 in a dose-dependent manner up to 80% (p<0.0001). Least squares (LS) mean TGs were significantly reduced by 52 to 64% (p<0.0001). Least squares (LS) mean atherogenic lipoproteins were reduced by up to 27% for non-HDL-C, 19% for apolipoprotein B, and 55% for remnant cholesterol. LS mean HDL-C was increased by up to 51%. The most frequent adverse events were COVID-19 infection, worsening of glycemic control, and upper respiratory infection. Conclusions: By silencing APOC3 expression, ARO-APOC3 significantly reduced circulating TGs and atherogenic TRLs in patients with MD. The effect of ARO-APOC3 on CV relative risk reduction will be evaluated in an upcoming outcomes trial.