Potent and Sustained Lowering of Serum Uric Acid by <scp>YJH</scp> ‐012‐D, a <scp>G</scp> al <scp>NA</scp> c‐Conjugated si <scp>RNA</scp> Targeting Xanthine Dehydrogenase

Hyperuricemia (HUA) is primarily driven by hepatic overproduction of urate, mediated by xanthine dehydrogenase (XDH). This preclinical study evaluates YJH-012-D, a N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting hepatic XDH. Functional assays demonstrated that YJH-012-D potently suppressed both XDH mRNA and protein expression in primary hepatocytes. In mice, a single subcutaneous dose of 8 mg/kg significantly reduced serum uric acid levels and suppressed hepatic XDH expression for more than 42 days. In cynomolgus monkeys, administration of YJH-012-D at 10 mg/kg lowered serum uric acid for up to 180 days, with sustained XDH inhibition observed for 120 days. Pharmacokinetic analysis revealed a high liver-to-plasma area under the curve (AUC) ratio (2000-6100) and a hepatic half-life exceeding 10 days, consistent with prolonged pharmacological activity. Comprehensive toxicity assessments-including clinical biochemistry, histopathology, and RNA sequencing (RNA-seq)-based off-target profiling-identified no significant adverse effects. Collectively, YJH-012-D exhibits potent, durable urate-lowering efficacy and a favorable safety profile, underscoring its potential as a novel therapeutic candidate for HUA.