Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial

Mixed dyslipidaemia, characterised by elevated concentrations of circulating triglycerides and LDL cholesterol (LDL-C), is associated with an increased risk of atherosclerotic cardiovascular disease. Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), reduced triglycerides and LDL-C concentrations in a phase 1 study. This study aimed to assess the durability and efficacy of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidaemia. This double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial enrolled adults (aged ≥18 years) with mixed dyslipidaemia at 41 clinical research units across seven countries. Patients receiving moderate-intensity or high-intensity statins, and with concentrations of fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L were included. Using an interactive web-response system, patients were randomly assigned (1:2:2:2) to receive either solbinsiran 100 mg, solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on days 0 and 90. Patients were followed up for at least 270 days. The primary outcome was percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand (in patients who received at least one dose of the study drug). This trial is completed and registered with ClinicalTrials.gov, NCT05256654. Of 585 patients screened, 205 patients were enrolled in the study between July 20, 2022, and March 4, 2024. Patients (111 [54%] female and 94 [46%] male; median age 57 years [IQR 49-65]) were randomly assigned to receive solbinsiran 100 mg (n=30), solbinsiran 400 mg (n=58), solbinsiran 800 mg (n=59), or placebo (n=58). At baseline, median concentrations were 111 mg/dL (IQR 96-130) for apoB, 2·64 mmol/L (2·06-3·29) for triglycerides, and 3·16 mmol/L (2·57-3·82) for LDL-C. The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg. Solbinsiran administration was well tolerated, with a low incidence of adverse events. The number of patients with treatment-emergent adverse events was 18 [60%] of 30 patients in the solbinsiran 100 mg group, 30 [52%] of 58 patients in the solbinsiran 400 mg group, 26 [44%] of 59 patients in the solbinsiran 800 mg group, and 37 [65%] of 57 patients in the placebo group. Solbinsiran 400 mg reduced apoB in patients with mixed dyslipidaemia and was generally well tolerated. The impact of solbinsiran on cardiovascular outcomes remains to be investigated. Eli Lilly and Company.