Potent and Sustained Lowering of Serum Uric Acid by YJH ‐012‐D, a G al NA c‐Conjugated si

ABSTRACT

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.