Zodasiran silences hepatic ANGPTL3 leading to deep and durable reductions in atherogenic lipids and lipoproteins in mixed dyslipidemia patients: final results from ARCHES-2, double-blind period.

Abstract

Background and Aims: Despite potent LDL-C lowering treatments, patients with mixed dyslipidemia remain at high ASCVD residual risk attributed to remnant cholesterol (RC) carried in triglyceride (TG)-rich lipoproteins (TRLs-RC). Angiopoietin-like protein 3 (ANGPTL3) regulates lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases and hepatic lipoprotein uptake. ANGPTL3 loss-of-function carriers have lower levels of TG and LDL-C and lower risk of ASCVD. Zodasiran (ARO-ANG3) is an investigational RNAi therapeutic that inhibits hepatic ANGPTL3 expression. To report the efficacy and safety of a 36-week, phase 2b, double-blind, placebo-controlled study of zodasiran in adults with mixed dyslipidemia (fasting TG 2-5.64-mmol/L [150-499mg/dL] and LDL-C >=1.8-mmol/L [>=70mg/dL] or non-HDL-C >=2.59-mmol/L [>=100mg/dL ](ARCHES-2:NCT04832971). Method(s): 204 patients randomized 3:1 received 50/100/200mg zodasiran or placebo subcutaneously on Day1 and Week12. Primary endpoint was percent change in TG at Week24 (trough for quarterly dosing). Hepatic fat change was assessed by MRI-PDFF in a steatotic subgroup. Result(s): Zodasiran reduced ANGPTL3, TG, and RC from baseline in a dose-dependent manner compared with placebo. At Week24, the between-group least-squares mean difference vs placebo was -54%/-70%/-74% for ANGPTL3, -51%/-57%/-63% for TG, and -73%/-76%/-82% for RC. (p<0.0001 for all) with significant reductions (p<0.05) in non-HDL-C (up to -36%), LDL-C (up to -20%), and ApoB (up to -22%). Reductions in ANGPTL3, TG and other atherogenic lipoprotein parameters remained durable and significant to Week36 (24weeks after last dose). Mean liver-fat reductions of -27% reached significance with 200mg zodasiran vs placebo at 24-weeks (p<0.05). 88% of patients receiving 200mg of zodasiran had normalization of TG, below the clinical target (<2mmol/L [<150 mg/dL]). TEAEs were balanced between zodasiran and placebo with favorable safety across all doses. Conclusion(s): Zodasiran demonstrated significant and durable reductions in ANGPTL3, TG, atherogenic lipids and lipoproteins with a reassuring safety profile. These results support evaluating zodasiran's potential use in subjects with residual ASCVD risk attributable to elevated TRLs-RC.Copyright © 2024