Abstract Body (Do not enter title and authors here): Hypothesis and Purpose: Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism primarily by inhibiting lipoprotein lipase and endothelial lipase. ANGPTL3 loss-of-function genetic variants are associated with reduced low-density lipoprotein cholesterol (LDL-C), lower serum triglycerides (TG), and decreased risk of atherosclerotic cardiovascular disease (ASCVD) without known adverse health effects.
CTX310^TM is an investigational lipid nanoparticle (LNP) therapy targeting the liver, delivering mRNA encoding a Cas9 nuclease and a guide RNA designed to induce a loss-of-function mutation in the ANGPTL3 gene in hepatocytes. CTX310 is being developed as a potential one-course treatment for elevated LDL-C and/or TG. This first-in-human Phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and lipid-lowering effects of CTX310.
Study Design and Methods: This is a Phase 1 single ascending dose clinical trial that studied doses from 0.1mg/kg to 0.8 mg/kg of estimated lean body weight administered intravenously. Patients were enrolled between June 2024 and August 2025 at 6 sites in Australia and New Zealand.
Sample Size: Fifteen patients were treated with CTX310.
Population Studied: Patients 18-75 years of age with or without clinical ASCVD, and with medically refractory homozygous familial hypercholesterolemia (FH), severe hypertriglyceridemia, heterozygous FH, or mixed dyslipidemia were eligible for this study. Patients were required to have serum triglyceride levels of > 150 mg/dL and/or serum LDL-C levels of >100 mg/dL (or >70 mg/dL for patients with ASCVD), and/or ApoB > 100 mg/dL and/or non-HDL-C > 160 mg/dL at the time of enrollment.
Intervention(s): Each enrolled patient received a single intravenous infusion of CTX310 at one of five dose levels in an ascending dose study.
Primary Endpoints: Comprehensive safety data will be presented for all patients. At the time of the data cutoff, all patients will have completed a minimum of 30 days of safety follow-up.
Secondary Endpoints: Secondary endpoints include CTX310 pharmacokinetics, pharmacodynamics, and efficacy data. Efficacy data will be assessed by changes in lipid biomarkers, including LDL-C, serum triglycerides, non-HDL-C, and apolipoprotein B.
Outcome(s): To be presented at conference.