Key Points:
- Many patients with ASCVD are on LDL-lowering therapy, but many patients with elevated TGs remain at elevated risk
- Solbinsiran, a novel siRNA therapy, may lower cholesterol by targeting hepatic ANGPTL3 and thereby increasing hepatic clearance of triglyceride lipoprotein components
- This trial demonstrated solbinsiran 400mg had significant reduction in apoB, ANGPTL3, hepatic fat, and other cholesterol markers
- Given a favorable safety profile, though limitations are noted, the trial suggests investigation of targeting hepatic ANGPTL3 reduction in mixed hyperlipidemia patients at high ASCVD risk
Many patients with cardiovascular disease are on medicine targeting LDL reduction. However, there’s an unmet need of patients with elevated triglycerides (TGs) who are at higher risk of atherosclerotic cardiovascular disease (ASCVD), despite adherence to LDL-lowering therapy. TG-rich lipoproteins (TRLs) contain cholesterol esters and are known to be twice as atherogenic as LDL particles. A novel therapy, solbinsiran, targets hepatic ANGPTL3, which inhibits lipoprotein lipase, thereby inhibiting lipolysis and clearance of TRL remnants. Solbinsiran is a siRNA therapy that has shown success in pre-clinical trials, reducing hepatic ANGPTL3 mRNA in mice, reduces ANGPTL3 and TGs in humans, and is under investigation to treat many hyperlipidemias. The main results of the trial were presented at ACC 2025 with simultaneous publication in Lancet.
This trial evaluated if solbinsiran was superior to placebo for the treatment of mixed dyslipidemia, as measured by placebo-corrected percent change in apoB from baseline at day 180 (ClinicalTrials.gov, NCT05256654.). The trial enrolled 205 adults with mixed dyslipidemia randomized 1:2:2:2 to solbinsiran 100mg, 400mg, 800mg, or placebo, with 189 adults completing treatment. Participants were 54% female with a median age of 57 years (IQR 49, 65), median BMI 30 (IQR 26.9, 33.9), with 58% on moderate-intensity and 38% on high-intensity statin therapy.
Ultimately, solbinsiran 400mg demonstrated significant reductions in ApoB at day 180 (p=0.0085) and day 270 (p=0.033) with similar reductions in ANGPTL3 at 400mg (p<0.0001) and 800mg (p<0.0001). In addition, solbinsiran led to significant reductions in TG and VLDL-C, and solbinsiran 400mg and 800mg led to significant reductions in LDL-C, non-HDL-C, and HDL-C. Solbinsiran was also well tolerated with minimal adverse effects or discontinuations.
The study notes some important limitations. The si-RNA based therapies have a long duration of action, so long-term safety of repeat dosing and effect durability is unknown. In addition, more diverse populations are needed: only one Black patient was enrolled; however, about 2/3rds of patients were Hispanic or Latino. In the placebo group, ApoB, hepatic fat, and hsCRP were all significantly lower at 180 days than baseline, which was not seen in the placebo arm of other trials.
Even so, this trial demonstrated that solbinsiran 400mg had durable reudctions in serum ANGPTL3 over 270 days with significant reductions in apoB, TG, VLDL-C, and non-HDL-C over time. As such, this suggests a role for evaluation of ANGPTL3 inhibition in mixed dyslipidemia patients at high risk of ASCVD.