Silencing hepatic complement factor B inhibits alternative pathway activation and attenuates arthritis in CAIA model

The complement system comprises tightly regulated enzymatic cascades that are essential for innate immune defense and tissue homeostasis. Although protective under physiological conditions, complement dysregulation can drive inflammation and tissue injury and contributes to the pathogenesis of autoimmune and inflammatory diseases, prompting the development of complement-targeted therapies. Here, we describe the development and nonclinical evaluation of AZD6912, a GalNAc-conjugated small interfering RNA (siRNA) designed to silence hepatic complement factor B (CFB) as a potential treatment for rheumatoid arthritis. AZD6912 produced potent on-target knockdown of CFB in a hepatocyte cell line and a primary human hepatocyte spheroid model, with no evidence of off-target effects. In mice, a surrogate siRNA targeting hepatic Cfb achieved >90% reduction in liver Cfb mRNA and >95% reduction in circulating CFB protein. This target-specific silencing reduced local complement production, attenuated joint inflammation, and provided therapeutic benefit in the collagen antibody-induced arthritis (CAIA) model. In non-human primates, AZD6912 showed high hepatic exposure, >80% suppression of hepatic CFB mRNA, sustained reductions in serum CFB, and >95% inhibition of complement activity. Safety assessments were unremarkable. Collectively, these findings demonstrate durable siRNA-mediated silencing of CFB with downstream pharmacologic and therapeutic effects, support the clinical development of AZD6912, and highlight the potential of GalNAc-siRNA therapeutics in immune-mediated diseases.