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

Immunoglobulin A 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 N-acetylgalactosamine-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 2 months and more than 50% for up to 4 months, a duration significantly longer than is possible with 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 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.