Apolipoprotein and inflammatory biomarker changes following marked triglyceride reduction with the GalNAc-conjugated APOC3 siRNA RBD5044

Introduction RBD5044, a GalNAc-conjugated small interfering RNA (siRNA) targeting APOC3, demonstrated robust lipid-lowering efficacy in a Phase I clinical trial. It achieved a 70% reduction in plasma triglyceride (TG) levels, with over 50% reduction maintained at six months. Elevated apoC-III concentrations have previously been associated with dysregulated lipid metabolism and pro-inflammatory states. Purpose This biomarker substudy aimed to characterize changes in circulating apolipoproteins and systemic inflammatory biomarkers following the administration of a single dose of RBD5044 in healthy participants. Methods In the single-ascending-dose phase of the randomised, double-blind, placebo-controlled Phase I trial, six cohorts received subcutaneous RBD5044 in doses ranging from 5 to 150 mg. Biomarker analyses were performed at baseline and on day 31 post dosing, the established timepoint for maximum pharmacodynamic effect. Serum apolipoproteins were quantified using a proteomic platform based on mass spectrometry (ApoEdge™, ProteomEdge), and inflammatory biomarkers were evaluated using the Olink Target 96 Inflammation panel. The analysis focused on participants achieving >50% TG reduction post-treatment. Multivariate modelling (OPLS-DA) was applied to identify biomarker signatures associated with treatment response. Results RBD5044 induced dose-dependent decrease in apoC-I, apoC-II, apoC-III and apoC-IV. OPLS-DA revealed a distinct biomarker profile among subjects with pronounced TG lowering. Notably, broad downregulation of systemic inflammatory mediators, including cytokines and chemokines, was observed, together with upregulation of apoptosis-related proteins involved in resolving inflammation. Conclusions Profound TG reduction achieved by APOC3 siRNA therapy is associated with an apolipoprotein pattern resembling APOC3 heterozygous deficiency, as well as a coordinated anti-inflammatory response. These findings suggest that deep APOC3 silencing remodels lipoprotein composition and may contribute to inflammation resolution by modulating apoptosis-related pathways.