A complement C5-targeted GalNAc-conjugated siRNA with sustained efficacy in a non-human primate model of IgA nephropathy.

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is pathologically characterized by excessive complement activation. While multiple therapeutic approaches have been explored for IgAN, efficacious complement-targeted therapies for clinical use are still scarce. In the present work, we describe the preclinical profile of a GalNAc-conjugated small interfering RNA (GalNAc-siRNA) targeting complement component 5 (C5) for the treatment of IgAN. This C5-siRNA exhibited picomolar inhibitory activity in vitro, with an IC50 value of 0.013 nM. In cynomolgus non-human primates, a single subcutaneous injection yielded sustained C5 suppression of over 80% for two months and more than 50% for up to four months, a duration significantly longer than existing complement inhibitors. Furthermore, we conducted a head-to-head efficacy comparison with Nefecon, an approved therapeutic agent for IgAN, in a cynomolgus monkey IgAN model. While both treatments showed comparable improvements in key renal function parameters, the C5-siRNA achieved superior pathological remission and near-complete blockade of glomerular C5 deposition and membrane attack complex (MAC) formation. Collectively, this study provides a strong rationale for the clinical development of C5-siRNA as an excellent therapy for IgAN, either as a standalone monotherapy or in combination with agents targeting upstream pathogenic pathways.