Solbinsiran at the 400 mg dose reduced apolipoprotein B (apoB) concentration in patients with mixed dyslipidemia, according to research presented during a Featured Clinical Research session at ACC.25 in Chicago and simultaneously published in The Lancet. The novel treatment is a GalNAc-conjugated small interfering RNA targeting hepatic ANGPTL3 protein expression.

In the double-blind, parallel-arm phase 2 PROLONG-ANG3 trial, conducted between July 2022 and March 2024 across 41 centers in seven countries, 205 patients (median age 57 years, 54% women) were randomized to 1:2:2:2 to either subcutaneous doses of solbinsiran at 100 mg (n=30), 400 mg (n=58), 800 mg (n=59) or placebo (n=58) on days 0 and 90. Patients were eligible if they had statin-treated mixed dyslipidemia. The median apoB concentrations at baseline were 111 mg/dL.

Results showed that the primary endpoint, placebo-adjusted percent change in apoB concentration from baseline to day 180 was –3% for solbinsiran at 100 mg, –14% for solbinsiran at 400 mg, and –8% at 800 mg.

Secondary endpoints revealed significant reductions in concentrations of triglycerides, non–HDL-C and LDL-C with different doses of solbinsiran as well. The 400 mg dose was associated with a reduction in concentration of non-HDL-C by 25.5%, LDL-C by 16.8%, triglycerides by 50.3%, very-low-density-lipoprotein cholesterol by 50.1%, high-density-lipoprotein cholesterol by 16.4% and hepatic fat fraction by 27.6%.

Hepatic MRI assessment conducted before randomization and at day 180 revealed reductions in hepatic fat in all four arms, but there was no evidence of dose-dependent effects.

Overall, solbinsiran was well-tolerated. there were treatment-emergent adverse events in 60% of patients in the 100 mg arm, 52% in the 400 mg arm and 44% in the 800 mg arm compared to 65% in the placebo group. The most common adverse event was COVID-19. Treatment-emergent adverse events related to study treatment were seen in 7% of patients in the 100 mg, 12% in the 400 mg arm and 8% in the 800 mg arm compared to 9% of patients taking placebo.

Investigators note that the follow-up period of 160 days was too short to completely evaluate safety – especially considering the long duration of action of siRNA-based therapies. Although the study took place across North America, South America, Europe and Asia, investigators also noted that there was a lack of diversity in the patient population, and the population was predominantly Hispanic. The authors write that the data support further evaluation of the drug in this population.