Solbinsiran (LY3561774), a GalNAc conjugated, small interfering RNA oligonucleotide designed to reduce ANGPTL3 protein expression, has significantly reduced human ANGPTL3 mRNA expression in hepatocytes and serum ANGPTL3 protein expression.
Solbinsiran efficacy was measured by RT-qPCR of liver from CD-1 female mice overexpressing human ANGPTL3, and the degree and durability of ANGPTL3 mRNA knockdown and circulating protein level reduction were evaluated in cynomolgus monkeys administered single dose solbinsiran 3 mg/kg or phosphate buffered saline (PBS).
A single dose of solbinsiran 1 mg/kg s.c. reduced human ANGPTL3 mRNA by 65% in hepatocytes compared to vehicle-treated mice. A single dose of solbinsiran reduced liver ANGPTL3 mRNA expression by up to 72.9% (p<0.0001) and serum ANGPTL3 protein expression by 68.6% (p<0.001). Solbinsiran showed a long duration of activity, with >50% mRNA knockdown remaining 12 weeks after a single dose.
A Phase 1 ascending and repeat dose study of solbinsiran in patients with dyslipidaemia (fasting TG ≥150 mg/dL and <500 mg/dL, as well as LDL-C ≥70 mg/dL) has been completed (NCT04644809).
Reference
Dudek H, Abrams M, Saxena U et al. Identification and Characterization of Solbinsiran, a GalNAc Conjugated siRNA Targeting Angiopoietin-Like 3. Presented at American Heart Association Scientific Sessions 2023 (11-13 November, Philadelphia, USA); CA.AOS.514 – Spotlight on Cardiovascular Gene Therapy, 86.
