Robert S. Rosenson, MD is a professor of cardiology at the Icahn School of Medicine at Mount Sinai.

Robert S. Rosenson, MD

Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), at a dose of 400 mg, achieved sustained reductions in apolipoprotein B concentration among patients with 

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, results from the Phase 2 PROLONG-ANG3 study showed solbinsiran was well tolerated, with a low incidence of adverse events, but its impact on cardiovascular outcomes has yet to be determined.

“These data related to the efficacy and the safety of the medication set the foundation for a phase three cardiovascular outcome trial,” trial investigator Robert S. Rosenson, MD, a professor of cardiology at the Icahn School of Medicine at Mount Sinai, told 

. “I'm quite excited about ANGPTL3 inhibitors as adjunctive therapy to what we have available today

Mixed dyslipidemia is characterized by raised levels of circulating triglycerides and low-density lipoprotein cholesterol (LDL) linked to an elevated likelihood of atherosclerotic cardiovascular disease (ASCVD). Solbinsiran achieved targeted reductions in both levels of triglycerides and LDL-C in a Phase 1 trial.

Investigators sought to further evaluate the therapy, specifically its durability and efficacy, in reducing concentrations of atherogenic lipoprotein in adults with mixed dyslipidemia. A double-blind, parallel-arm, randomized, placebo-controlled trial, the team enrolled adults with mixed dyslipidemia at 41 clinical units across 7 countries.

Enrollment criteria included patients receiving moderate-intensity or high-intensity statins, with concentrations of fasting triglycerides between 1.69 mmol/L and 5.64 mmol/L, LDL-C of >1.81 mmol/L, and non-HDL-cholesterol of ≥3.36 mmol/L.

Patients were randomly assigned 1:2:2:2 to either solbinsiran 100 mg or solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on Days 0 and 90. Follow-up occurred for at least 270 days in all patients. The primary outcome was the percent change in apoB concentration from baseline to Day 180 with solbinsiran, compared with placebo, as analyzed by an efficacy estimand: patients who received ≥1 dose of solbinsiran.

Among 585 screened patients, 205 were enrolled between July 2022 and March 2024. The population was more than half (54%) female, and the median age was 57 years. Randomization assigned patients to solbinsiran 100 mg (n = 30), solbinsiran 400 mg (n = 58), solbinsiran 800 mg (n = 59), or placebo (n = 58).

Baseline mean concentrations were 111 mg/dL for apoB, 2.64 mmol/L for triglycerides, and 3.16 mmol/L for LDL-C. Upon analysis, the placebo-adjusted percent change in apoB concentration at Day 180 was –2.8% (95% CI, –15.5 to 11.9; 

 =.69) for solbinsiran 100 mg, –14.3% (95% CI, –23.6 to –3.9; 

 =.0085) for solbinsiran 400 mg, and –8.3% (95% CI, –18.3 to 2.9; 

Safety analysis revealed treatment-emergent adverse events in 18 (60%) of 30 patients in the solbinsiran 100 mg cohort, 30 (52%) of 58 patients in the solbinsiran 400 mg cohort, 26 (44%) of 59 patients in the solbinsiran 800 mg cohort, and 37 (65%) of 57 patients in the placebo cohort. Notably, the 400 mg dose was associated with reductions in hepatic fat fraction of 27.6%.

“By these therapies, often we're thinking about adverse changes in the liver with statins, fibrates, and other agents. These data contrast and actually show improvement in the hepatic fat fraction,” Rosenson told 

. “I'm quite encouraged about the opportunities for some of our very difficult to treat patients.”

Learn more about the trial in an interview with Rosenson at ACC.25.

Solbinsiran Significantly Reduces apoB in Mixed Dyslipidemia in Phase 2 Trial

Ray, Kausik K et al. 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. The Lancet, Volume 0, Issue 0. March 31, 2025. Accessed March 31, 2025.

Ray KK, Linnebjerg H, Michael LF, et al. Effect of ANGPTL3 inhibition with solbinsiran in preclinical and early human studies. JACC (in press) 10.1016/j.jacc.2025.03.005

Videos

At ACC.25, Robert S. Rosenson, MD, discusses the efficacy and safety of solbinsiran, an ANGPTL3 inhibitor, in a population with mixed dyslipidemia.

Robert S. Rosenson, MD

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