Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia.

Apolipoprotein C-III (APOC3) plays a crucial role in triglyceride metabolism, and its high expression leads to hypertriglyceridemia, which can contribute to an increased risk of cardiovascular disease and, when severely increased, can lead to acute pancreatitis. Loss-of-function variants in APOC3 are linked to lower triglyceride levels and reduced incidence of coronary artery disease. APOC3 mRNA, primarily synthesized by hepatocytes, is an ideal target for GalNAc-conjugated RNA-targeted therapies such as the antisense oligonucleotide (ASO) oleszarsen and small-interference RNA (siRNA) plozasiran. Herein, we systematically evaluate siRNA chemical modifications or multiple siRNAs to identify a long-acting APOC3 siRNA with a minimal number of 2'-F nucleotides. Using a series of structure-activity relationship (SAR) studies, we explored the effects of various oligonucleotide chemical modification scaffolds on siRNA potency, efficacy, and durability. These efforts led to the identification of an APOC3 targeting siRNA containing a novel chemical scaffold with robust activity and an extended duration of action in preclinical models. Additionally, selectivity and tolerability assessments in human cells, rodents, and nonhuman primates showed excellent safety and tolerability. A comparative analysis of the lead APOC3 siRNA with a surrogate of a clinical-stage APOC3 siRNA drug suggests the potential for similar or better potency and efficacy combined with less frequent dosing, potentially reducing the treatment burden on patients with hypertriglyceridemia.