Please use this identifier to cite or link to this item: https://repository.monashhealth.org/monashhealthjspui/handle/1/52331
Conference/Presentation Title: 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.
Authors: Rosenson R.;Gaudet D.;Hegele R.;Ballantyne C.;Nicholls S. ;Lucas K.;Hellawell J.;Chang T.;Fu R.;Muhsin M.A.;Leeper N.;Watts G.
Monash Health Department(s): Cardiology (MonashHeart)
Institution: (Rosenson) Mount Sinai Icahn School of Medicine, New York, United States
(Gaudet) ECOGENE-21 and Universite de Montreal, Chicoutimi, Canada
(Hegele) Robarts Research Institute, London, ON, Canada
(Ballantyne) Baylor College of Medicine, Houston, United States
(Nicholls) Monash University, Victorian Heart Institute, Melbourne, Australia
(Lucas) Lucas Research, Morehead City, United States
(Hellawell, Chang, Fu, Muhsin) Arrowhead Pharmaceuticals, Pasadena, United States
(Leeper) Stanford University School of Medicine, Palo Alto, United States
(Watts) Cardiometabolic Services, School of Medicine, University of Western Australia, Perth, Australia
Presentation/Conference Date: 21-Aug-2024
Copyright year: 2024
Publisher: Elsevier Ireland Ltd
Publication information: Atherosclerosis. Conference: EAS 2024. Padova Italy. 395(Supplement 1) (no pagination), 2024. Article Number: 118515. Date of Publication: August 2024.
Journal: Atherosclerosis
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
Conference Name: EAS 2024
Conference Start Date: 2024-07-01
Conference End Date: 2024-07-05
Conference Location: Padova, Italy
DOI: http://monash.idm.oclc.org/login?url=https://dx.doi.org/10.1016/j.atherosclerosis.2024.118515
URI: https://repository.monashhealth.org/monashhealthjspui/handle/1/52331
Type: Conference Abstract
Subjects: coronary atherosclerosis
lipoprotein metabolism
MRI scanner
nuclear magnetic resonance imaging
high density lipoprotein cholesterol
lipoprotein
Type of Clinical Study or Trial: Clinical trial
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